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We identified no evidence on CV outcomes among e-cigarette users using HC . Limited data reporting mostly acute outcomes suggested that CV events are rare among e-cigarette users in the general population and that e-cigarettes may affect heart rate and blood pressure less than conventional cigarettes .

BACKGROUND Women who use combined hormonal contraceptives and cigarettes have an increased risk for cardiovascular ( CV ) events . We review ed the literature to determine whether women who use hormonal contraceptives ( HC ) and electronic cigarettes ( e-cigarettes ) also have an increased risk .

The purpose of this study was to compare circadian blood pressure and heart rate patterns and other cardiovascular effects of nicotine delivered rapidly ( via nasal spray , NNS ) , slowly ( transdermal nicotine , TDN ) , by cigarette smoking ( rapid delivery of nicotine plus other smoke toxins ) , and placebo NNS . Twelve healthy cigarette smokers were studied on a research ward when they smoked cigarettes ( 16 per day ) or used TDN ( 15 mg/16 h ) , NNS ( 24 1-mg doses per day ) , or placebo NNS , each for 5 days . There were no significant differences in systolic blood pressure , but diastolic blood pressure was slightly increased during cigarette smoking . Plasma epinephrine , & bgr;-thromboglobulin , and fibrinogen levels were higher during cigarette smoking than with TDN . For most measurements , NNS values were intermediate between and not significantly different from those of cigarette smoking and TDN . We conclude that , at recommended doses , TDN and NNS have fewer effects on biomarkers of cardiovascular risk than does cigarette smoking INTRODUCTION Tobacco smoking leads to changes in hemodynamic parameters such as heart rate and systolic or diastolic blood pressure . It has a direct influence on the elasticity of blood vessels and increases arterial stiffness , which can result in development of atherosclerosis . Data show that the nicotine in tobacco smoke probably is responsible for these changes . Electronic cigarettes ( e-cigarettes ) were supposedly a healthier alternative to combustible cigarettes because they imitate a process of cigarettes smoking but generate nicotine aerosol without the toxic substances from tobacco combustion . However , the use of e-cigarettes is still controversial because their toxicity , safety and long term use health impact have not been sufficiently studied . AIM The aim of this study was to evaluate changes in arterial stiffness parameters after smoking a cigarette or e-cigarette use . METHODS Fifteen healthy women , aged 19 - 25 years old , smoking ≥5 cigarettes per day for at least two years participated in the study . A non-invasive measurement of arterial stiffness parameters - Stiffness Index ( SI ) and Reflection Index ( RI ) - was conducted and systolic and diastolic blood pressure and heart rate were measured before and after smoking a conventional cigarette as well as use of an e-cigarette . RESULTS Statistically significant changes in the SI and RI were observed before and after smoking of a conventional cigarette [ SI : 6.75 m/s ( 6.66 - 6.85 , 95 % CI ) vs 6.56 m/s ( 6.46 - 6.65 . 95 % CI ) , p=0.0056 ; RI : 54.0 % ( 51.5 - 56.7 , 95 % CI ) vs 49.6 % ( 47.5 - 51.8 , 95 % CI ) , p=0.010 ] . The use of e-cigarettes result ed in no statistically significant changes in the SI and RI . After both product use systolic and diastolic blood pressure and heart rate increased but the changes were not statistically significant . CONCLUSIONS In contrast to conventional cigarette use , the use of electronic cigarettes causes no changes in arterial stiffness . This may indicate lower bioavailability of nicotine from the e-cigarette or an additional effect of other substances present in cigarette smoke but absent in an e-cigarette aerosol Background Electronic cigarettes ( e-cigarettes ) are becoming increasingly popular with smokers worldwide . Users report buying them to help quit smoking , to reduce cigarette consumption , to relieve tobacco withdrawal symptoms , and to continue having a ‘ smoking ’ experience , but with reduced health risks . Research on e-cigarettes is urgently needed in order to ensure that the decisions of regulators , healthcare providers and consumers are based on science . Methods ECLAT is a prospect i ve 12-month r and omized , controlled trial that evaluates smoking reduction/abstinence in 300 smokers not intending to quit experimenting two different nicotine strengths of a popular e-cigarette model ( ‘ Categoria ’ ; Arbi Group Srl , Italy ) compared to its non-nicotine choice . GroupA ( n = 100 ) received 7.2 mg nicotine cartridges for 12 weeks ; GroupB ( n = 100 ) , a 6-week 7.2 mg nicotine cartridges followed by a further 6-week 5.4 mg nicotine cartridges ; GroupC ( n = 100 ) received no-nicotine cartridges for 12 weeks . The study consisted of nine visits during which cig/day use and exhaled carbon monoxide ( eCO ) levels were measured . Smoking reduction and abstinence rates were calculated . Adverse events and product preferences were also review ed . Results Declines in cig/day use and eCO levels were observed at each study visits in all three study groups ( p<0.001 vs baseline ) , with no consistent differences among study groups . Smoking reduction was documented in 22.3 % and 10.3 % at week-12 and week-52 respectively . Complete abstinence from tobacco smoking was documented in 10.7 % and 8.7 % at week-12 and week-52 respectively . A substantial decrease in adverse events from baseline was observed and withdrawal symptoms were infrequently reported during the study . Participants ’ perception and acceptance of the product under investigation was satisfactory . Conclusion In smokers not intending to quit , the use of e-cigarettes , with or without nicotine , decreased cigarette consumption and elicited enduring tobacco abstinence without causing significant side effects . Trial Registration Clinical Trials.gov NCT01164072 Objective . To examine the effects of maternal prenatal smokeless tobacco use on infant birth size . Design . A retrospective medical record review of 502 r and omly selected deliveries . Population and Setting . Singleton deliveries to Alaska Native women residing in a defined geographical region in western Alaska , 1997–2005 . Methods . A regional medical center 's electronic records were used to identify singleton deliveries . Data on maternal tobacco exposure and pregnancy outcomes were abstract ed from medical records . Logistic models were used to estimate adjusted mean birthweight , length and head circumference for deliveries to women who used no tobacco ( n=121 ) , used smokeless tobacco ( n=237 ) or smoked cigarettes ( n=59 ) . Differences in mean birthweight , length and head circumference , 95 % confidence intervals and p‐values were calculated using non‐users as the reference group . Main Outcome Measures . Infant birthweight , crown – heel length and head circumference . Results . After adjustment for gestational age and other potential confounders , the mean birthweight of infants of smokeless tobacco users was reduced by 78 g compared with that of infants of non‐users ( p=0.18 ) and by 331 g in infants of smokers ( p<0.01 ) . No association was found between maternal smokeless tobacco use and infant length or infant head circumference . Conclusions . We found a modest but non‐significant reduction in the birthweight of infants of smokeless tobacco users compared with infants of tobacco non‐users . Because smokeless tobacco contains many toxic compounds that could affect other pregnancy outcomes , results of this study should not be construed to mean that smokeless tobacco use is safe during pregnancy Objective To evaluate the safety and efficacy as a tool of smoking cessation of electronic cigarettes ( e-cigarettes ) , directly comparing users of e-cigarettes only , smokers of tobacco cigarettes only , and smokers of both . Design Prospect i ve cohort study . Final results are expected in 2019 , but given the urgency of data to support policies on electronic smoking , we report the results of the 12-month follow-up . Data Sources Direct contact and structured question naires by phone or via internet . Methods Adults ( 30–75 years ) were included if they were smokers of ≥1 tobacco cigarette/day ( tobacco smokers ) , users of any type of e-cigarettes , inhaling ≥50 puffs weekly ( e-smokers ) , or smokers of both tobacco and e-cigarettes ( dual smokers ) . Carbon monoxide levels were tested in a sample of those declaring tobacco smoking abstinence . Main Outcome Measures Sustained smoking abstinence from tobacco smoking at 12 months , reduction in the number of tobacco cigarettes smoked daily . Data Synthesis We used linear and logistic regression , with region as cluster unit . Results Follow-up data were available for 236 e-smokers , 491 tobacco smokers , and 232 dual smokers ( overall response rate 70.8 % ) . All e-smokers were tobacco ex-smokers . At 12 months , 61.9 % of the e-smokers were still abstinent from tobacco smoking ; 20.6 % of the tobacco smokers and 22.0 % of the dual smokers achieved tobacco abstinence . Adjusting for potential confounders , tobacco smoking abstinence or cessation remained significantly more likely among e-smokers ( adjusted OR 5.19 ; 95 % CI : 3.35–8.02 ) , whereas adding e-cigarettes to tobacco smoking did not enhance the likelihood of quitting tobacco and did not reduce tobacco cigarette consumption . E-smokers showed a minimal but significantly higher increase in self-rated health than other smokers . Non significant differences were found in self-reported serious adverse events ( eleven overall ) . Conclusions Adding e-cigarettes to tobacco smoking did not facilitate smoking cessation or reduction . If e-cigarette safety will be confirmed , however , the use of e-cigarettes alone may facilitate quitters remaining so . Registration Number NCT01785537 We conducted a case-control study to test the hypothesis that women smokers who use oral contraceptives have an increased risk of developing venous thrombosis . Patients and controls were drawn from two sets of hospital patients already included in the Boston Collaborative Drug Surveillance Programme . Sixty patients with uncomplicated thromboembolism were matched with 180 controls with other diagnoses ; all were premenopausal women taking oral contraceptives . Patients with conditions that might predispose to thromboembolism or be related to smoking were excluded . We found no association between smoking habits and thromboembolism . Similarly , we found no association between thromboembolism , smoking , and duration of oral contraceptive use . Thus we conclude that differences in fibrinolytic activity between smokers and non-smokers are not major factors in the aetiology of uncomplicated thromboembolism in women using oral contraceptives Background Electronic cigarettes have been developed and marketed in recent years as smoking substitutes . However , no studies have evaluated their effects on the cardiovascular system . The purpose of this study was to examine the immediate effects of electronic cigarette use on left ventricular ( LV ) function , compared to the well-documented acute adverse effects of smoking . Methods Echocardiographic examinations were performed in 36 healthy heavy smokers ( SM , age 36 ± 5 years ) before and after smoking 1 cigarette and in 40 electronic cigarette users ( ECIG , age 35 ± 5 years ) before and after using the device with “ medium-strength ” nicotine concentration ( 11 mg/ml ) for 7 minutes . Mitral flow diastolic velocities ( E , A ) , their ratio ( E/A ) , deceleration time ( DT ) , isovolumetric relaxation time ( IVRT ) and corrected-to-heart rate IVRT ( IVRTc ) were measured . Mitral annulus systolic ( Sm ) , and diastolic ( Em , Am ) velocities were estimated . Myocardial performance index was calculated from Doppler flow ( MPI ) and tissue Doppler ( MPIt ) . Longitudinal deformation measurements of global strain ( GS ) , systolic ( SRs ) and diastolic ( SRe , SRa ) strain rate were also performed . Results Baseline measurements were similar in both groups . In SM , IVRT and IVRTc were prolonged , Em and SRe were decreased , and both MPI and MPIt were elevated after smoking . In ECIG , no differences were observed after device use . Comparing after-use measurements , ECIG had higher Em ( P = 0.032 ) and SRe ( P = 0.022 ) , and lower IVRTc ( P = 0.011 ) , MPI ( P = 0.001 ) and MPIt ( P = 0.019 ) . The observed differences were significant even after adjusting for changes in heart rate and blood pressure . Conclusions Although acute smoking causes a delay in myocardial relaxation , electronic cigarette use has no immediate effects . Electronic cigarettes ’ role in tobacco harm reduction should be studied intensively in order to determine whether switching to electronic cigarette use may have long-term beneficial effects on smokers ’ health . Trial registration Current Controlled Trials IS RCT OBJECTIVE We examined screening practice s and attitudes of obstetricians-gynecologists toward the use of noncombustible tobacco products ( chewing tobacco , snuff/snus , electronic cigarettes , and dissolvables ) during pregnancy . STUDY DESIGN The authors mailed a survey in 2012 to 1024 members of the American College of Obstetricians and Gynecologists , including Collaborative Ambulatory Research Network ( CARN ) and non-CARN members . Stratified r and om selection was used to generate CARN and non-CARN sample s. RESULTS Response rates were 52 % and 31 % for CARN and non-CARN members , respectively . Of 252 total eligible respondents ( those currently providing obstetrics care ) 53 % reported screening pregnant women at intake for noncombustible tobacco product use all or some of the time , and 40 % reported none of the time . Respondents who reported that noncombustible products have adverse health effects during pregnancy , but are safer than cigarettes , ranged from 20.2 % ( dissolvables ) to 29 % ( electronic cigarettes ) and that the health effects are the same as those of cigarettes from 13.5 % ( electronic cigarettes ) to 53.6 % ( chewing tobacco ) . Approximately 14 % reported that electronic cigarettes have no adverse health effects ; < 1 % reported no health effects for the remaining products . Two-thirds of the respondents wanted to know more about the potential health effects of noncombustible tobacco products ; only 5 % believed themselves to be fully informed . CONCLUSION A large proportion of obstetrician-gynecologists reported never or inconsistently screening their pregnant patients for the use of noncombustible tobacco products . Responses regarding the harms of these products relative to cigarettes were mixed and most respondents wanted more information . Development and dissemination of guidance for providers is needed to improve decision-making regarding noncombustible tobacco products Objectives To investigate the impact of cigarette smoking and oral contraceptive ( OC ) use on hemodynamic stress responses of women . Also , to examine gender differences in stress reactivity as a function of smoking status and acute nicotine administration . Methods : Thirty men and 46 women , differing in smoking status and OC use , were tested for cardiovascular stress responses to a variety of behavioral and physical stressors . Each was tested twice , once under a transdermal nicotine patch condition and once under a placebo patch condition . Impedance cardiography was used to estimate hemodynamic reactivity noninvasively . Results : In response to behavioral stressors , women smokers , irrespective of OC use or nicotine vs placebo , demonstrated significantly blunted cardiac output and heart rate reactivity to stressors , and showed significantly greater estimated total peripheral resistance ( TPR ) under stress relative to women nonsmokers . There were no differences in hemodynamic stress reactivity between men smokers and nonsmokers . The only significant effect involving nicotine administration on stress reactivity was seen in men where , regardless of smoking status , nicotine increased heart rate reactivity to all stressors relative to placebo responses . Conclusions : Results suggest that cigarette smoking may act differently in men and women to increase risk for cardiovascular disease ( CVD ) . For men , nicotine may exert pathogenic influences via increasing the magnitude of heart rate reactivity to stressors . For women , however , smoking seems to have deleterious effects on hemodynamic stress reactivity patterns , reducing myocardial but increasing TPR contributions to blood pressure responses AIMS To provide an initial abuse liability assessment of an electronic cigarette ( EC ) in current tobacco cigarette smokers . DESIGN The first of four within-subject sessions was an EC sampling session that involved six , 10-puff bouts ( 30 seconds inter-puff interval ) , each bout separated by 30 minutes . In the remaining three sessions participants made choices between 10 EC puffs and varying amounts of money , 10 EC puffs and a varying number of own br and cigarette ( OB ) puffs , or 10 OB puffs and varying amounts of money using the multiple-choice procedure ( MCP ) . The MCP was completed six times at 30-minute intervals , and one choice was reinforced r and omly at each trial . SETTING Clinical laboratory . PARTICIPANTS Twenty current tobacco cigarette smokers . MEASUREMENTS Sampling session outcome measures included plasma nicotine , cardiovascular response and subjective effects . Choice session outcome was the cross-over value on the MCP . FINDINGS EC use result ed in significant nicotine delivery , tobacco abstinence symptom suppression and increased product acceptability ratings . On the MCP , participants chose to receive 10 EC puffs over an average of $ 1.06 or three OB puffs and chose 10 OB puffs over an average of $ 1.50 ( P < 0.003 ) . CONCLUSIONS Electronic cigarettes can deliver clinical ly significant amounts of nicotine and reduce cigarette abstinence symptoms and appear to have lower potential for abuse relative to traditional tobacco cigarettes , at least under certain laboratory conditions OBJECTIVE The purpose of the study was to evaluate the effects of smokeless tobacco use during pregnancy . STUDY DESIGN We examined birth weight , preterm delivery , and preeclampsia in women who were delivered of singleton , live-born infants in Sweden from 1999 through 2000 . For each snuff user , 10 cigarette smokers and 10 tobacco nonusers were selected r and omly . RESULTS After exclusions , 789 snuff users , 11,240 smokers , and 11,495 nonusers remained . Compared with nonusers , adjusted mean birth weight was reduced in snuff users by 39 g ( 95 % CI , 6 - 72 g ) and in smokers by 190 g ( 95 % CI , 178 - 202 g ) . Preterm delivery was increased in snuff users and smokers ( adjusted odds ratios , 1.98 [ 95 % CI , 1.46 - 2.68 ] and 1.57 [ 95 % CI , 1.38 - 1.80 ] , respectively ) . Preeclampsia was reduced in smokers ( adjusted odds ratio , 0.63 ; 95 % CI , 0.53 - 0.75 ) but increased in snuff users ( adjusted odds ratio , 1.58 ; 95 % CI , 1.09 - 2.27 ) . CONCLUSION Snuff use was associated with increased risk of preterm delivery and preeclampsia . Snuff does not appear to be a safe alternative to cigarettes during pregnancy With regard to oral contraceptives , much research has concentrated on venous thrombosis and on the coronary and cerebral forms of atherosclerotic disease , while peripheral arterial disease ( PAD ) has received little attention . In this case-control study , we assessed oral contraceptive use and the risk of PAD in young women using a population -based case-control study . The women were 18 - 49 years of age , and had been admitted to a collaborating hospital between January 1990 and October 1995 , and had a diagnosis of PAD . Participants were patients with PAD ( n = 152 ) , and control women ( n = 925 ) , identified by r and om digit dialing . The diagnosis of PAD was based almost exclusively on intra-arterial angiography . Patients and control subjects filled out the same structured question naire , which included questions on medical history , cardiovascular risk factors , and contraceptive use . The adjusted odds ratio for PAD in women using any type of oral contraceptives vs. no use , was 3.8 ( 95 % CI 2.4 - 5.8 ) . When first generation oral contraceptive use was compared with no use , the odds ratio was 8.7 ( 95 % CI 3.6 - 21.3 ) . For second and third generation oral contraceptives , the adjusted odds ratios ( compared with non-users ) were 2.6 ( 95 % CI 1.4 - 4.9 ) and 3.0 ( 95 % CI 1.4 - 6.6 ) , respectively . This is the first study on oral contraceptive use and PAD in humans . All types of oral contraceptives were associated with an increased risk of PAD INTRODUCTION Electronic cigarettes ( ECs ) are marketed as nicotine delivery devices . Two studies with EC-naïve participants suggest that ECs deliver little or no nicotine . In those studies , st and ard-sized ECs were used , though experienced EC users often use larger devices that house higher voltage and /or longer lasting batteries . Whether user experience and device characteristics influence EC nicotine delivery is uncertain . The purpose of the present study was to examine the effects of ECs in experienced users who were using their preferred devices . METHODS Eight EC users ( 3 women ) who had been using ECs for at least 3 months , completed one 5-hr session using devices they provided and the flavor/strength nicotine cartridges they selected . Sessions consisted of 4 phases : baseline , 10 puffs ( 30-s interpuff interval ) from the device , 1-hr ad lib puffing period , and a 2-hr rest period ( no puffing ) . Outcome measures in each phase included plasma nicotine concentration , heart rate , and subjective ratings of nicotine/product effects and abstinence symptoms . RESULTS Relative to baseline , plasma nicotine and heart rate increased significantly within 5 min of the first puff and remained elevated throughout the ad lib puffing period . Increases in ratings of direct effects of nicotine and product were observed as well as decreases in abstinence symptoms . CONCLUSIONS User experience and /or device characteristics likely influence EC nicotine delivery and other effects . Systematic manipulation of these and other variables could eluci date conditions that produce intended effects INTRODUCTION This study examined overall changes in nicotine concentrations when using a popular e-cigarette and 18 mg/mL nicotine e-Juice , and it further explored effects of sex and flavorings on these concentrations . METHODS We recruited nontreatment-seeking smokers who were willing to try e-cigarettes for 2 weeks and abstain from cigarette smoking . Subjects were r and omized to either menthol tobacco or non-menthol tobacco-flavored e-cigarette use for 7 - 10 days , and the next week they were crossed over to the other condition . On the last day of e-cigarette use of each flavor , subjects completed a laboratory session in which they used the e-cigarette for 5 min ad libitum . Nicotine concentrations were obtained 5 min before and 5 , 10 , 15 , 20 , and 30 min after the onset of e-cigarette use . RESULTS Twenty subjects completed at least 1 monitoring session . Nicotine concentrations significantly increased from baseline to 5 min by 4 ng/mL at the first laboratory session ( p < .01 ) and by 5.1 ng/mL at the second laboratory session ( p < .01 ) . Combining sessions , there were no main effects of sex or preferred flavor ( based on smoking history ) on changes in nicotine concentrations . After adding preferred flavor , sex , and visit order to the model , there was a significant preferred flavor by sex interaction ( p < .01 ) , such that women who received nonpreferred flavors had lower nicotine concentrations and rated their e-cigarette as less likeable ( p < .01 ) . CONCLUSION We found nicotine concentrations significantly increase after e-cigarette use for 5 min , and flavor may impact nicotine concentrations with e-cigarette use in women The development of electronic cigarettes ( e-cigs ) has the potential to offer a less harmful alternative for tobacco users . This clinical study was design ed to characterize e-cig users ' exposure to nicotine , and to investigate the acute effects of e-cigs on the hemodynamic measurements ( blood pressure and heart rate ) in comparison with the effects of regular smoking . Five e-cigs and one Marlboro ® cigarette were r and omized for twenty-three participants under two exposure scenarios from Day 1 to Day 11 : half-hour controlled administration and one hour ad lib use . The nicotine plasma concentrations after 1.5h of product use ( C90 ) were significantly lower in the users of e-cigs than of Marlboro ® cigarettes . The combination of glycerin and propylene glycol as the vehicle facilitated delivery of more nicotine than glycerin alone . The heart rate , systolic and diastolic blood pressure were significantly elevated after use of Marlboro ® cigarettes , but the elevation was less after use of most of the e-cigs . Use of e-cigs had no impact on the exhaled CO levels , whereas the Marlboro ® cigarette significantly increased the exhaled CO more than 8 times above the baseline . In conclusion , e-cigs could be a less harmful alternative for tobacco users

The study confirmed that non-pharmacological smoking cessation methods available in Pol and , i.e. the physician 's advice and individual and group counseling , increase the probability of smoking abstinence , and determined the 12-month effects of these interventions

OBJECTIVES The present paper discusses available data concerning the efficacy of non-pharmacological methods used in smoking cessation and describes the results of newly performed meta-analyses testing the 12-month efficacy of these methods . This study is part of a more comprehensive program analyzing the efficacy and cost-effectiveness of different methods used in smoking cessation .

Objective - To compare the effectiveness of two different stop smoking interventions . Design - A r and omised , controlled trial . Results based on intention to treat . Setting - Three towns in the south-eastern part of Norway . Interventions - Visits to GP for " practice as usual " ( GP group ) or participation in the behavioural programme SmokEnders ( SE group ) with follow-up 2 weeks , 2 months and 1 year after an agreed stopping date . Subjects - 139 smokers recruited through open invitation . Main outcome measure - Self-reported smoking stop rate 2 weeks , 2 months and 1 year after an agreed stopping date , completed with biochemical indicators by the 1-year registration . Results ? Two weeks after the agreed cessation date , 10/70 ( 14 % ) of the GP group and 46/69 ( 67 % ) of the SE group had stopped smoking . After 2 months , 9/70 ( 13 % ) in the GP group and 37/69 ( 54 % ) in the SE group were non-smokers . One year after cessation 5/70 ( 7 % ) in the GP group and 21/69 ( 30 % ) in the SE group were non-smokers . Conclusions ? Both interventions were effective as measured by the smoking cessation rate . However , the intervention in the SE group was considerably more effective than in the GP group , which suffered from a sizeable number of drop-outs OBJECTIVES To compare the effects of a worksite intervention by the occupational physician offering simple advice of smoking cessation with a more active strategy of advice including a “ quit date ” and extra support . POPULATION Employees of an electrical and gas company seen at the annual visit by their occupational physicians . CRITERIA END POINTS Smoking point prevalence defined as the percentage of smokers who were non-smokers at one year . Secondary criteria were the percentage of smokers who stopped smoking for more than six months and the difference in prevalence of smoking in both groups . METHODS R and omised controlled trial . The unit of r and omisation was the work site physician and a r and om sample of the employees of whom he or she was in charge . The length of the follow up was one year . Each of 30 work site physicians included in the study 100 to 150 employees . RESULTS Among 504 subjects classified as smokers at baseline receiving simple advice ( group A ) and 591 the more active programme ( group B ) , 68 ( 13.5 % ) in group A and 109 ( 18.4 % ) were non-smokers one year later ( p=0.03 ; p=0.01 taking the occupational physician as the statistical unit and using a non-parametric test ) . Twenty three subjects ( 4.6 % ) in group A and 36 ( 6.1 % ) in group B ( p=0.26 ) declared abstinence of six months or more . Among non-smokers at baseline , 3.4 % in both groups were smokers after one year follow up . The prevalence of smokers did not differ significantly at baseline ( 32.9 % and 32.4 % , p=0.75 ) . After the intervention the prevalence of smoking was 30.8 % in group A and 28.7 % in group B ( p=0.19 ) . An increase of the mean symptoms score for depression in those who quit was observed during this period . CONCLUSIONS A simple cessation intervention strategy during a m and atory annual examination , targeting a population of smokers independently of their motivation to stop smoking or their health status , showed a 36 % relative increase of the proportion of smokers who quit smoking as compared with what can be achieved through simple advice The purpose of this study was to examine the effectiveness of different practice -based approaches to assist patients of primary care physicians to quit smoking and sustain cessation . Forty-four nonsmoking general practitioners volunteered for the study . After a period of training , they r and omized 923 smoking clients , unselected for motivation toward quitting , to four different intervention groups : ( i ) minimal intervention , consisting of one single counselling session and a brief h and out on quitting techniques ; ( ii ) repeated counselling including reinforcing sessions at Months 1 , 3 , 6 , and 9 ; ( iii ) repeated counselling and use of nicotine gum ; and ( iv ) repeated counselling and spirometry . Biochemically vali date d smoking status was assessed at six and 12 months after recruitment . The proportion of verified quitters at 12 months was 4.8 percent among subjects r and omized to the minimal intervention group , compared to 5.5 percent , 7.5 percent , and 6.5 percent among those r and omized to the three repeated-counselling groups . In no treatment group was the outcome significantly different from that for one-time counselling at the ( P<0.05 ) level . Lack of power , contamination , and low attendance at reinforcing sessions should be taken into account in interpreting the results This study was design ed to see whether the offer and prescription of nicotine chewing gum would enhance the efficacy of general practitioners ' advice to stop smoking . A sample of 1938 cigarette smokers who attended the surgeries of 34 general practitioners in six group practice s were assigned by week of attendance ( in a balanced design ) to one of three groups : ( a ) non-intervention controls , ( b ) advice plus booklet , and ( c ) advice plus booklet plus the offer of nicotine gum . Follow up was done after four months and one year . The results show a clear advantage for those offered the nicotine gum ( p less than 0.001 ) . After correction for those who refused or failed chemical validation and those who switched from cigarettes to a pipe or cigars , the proportions who were abstinent at four months and still abstinent at one year were 3.9 % , 4.1 % , and 8.8 % in the three groups , respectively . These percentages are based on all cigarette smokers who attended the surgeries including those who did not wish to stop and those in the gum group who did not try the gum ( 47 % ) . The effect of the offer and prescription of gum was to motivate more smokers to try to stop , to increase the success rate among those who tried , and to reduce the relapse rate of those who stopped . The self selected subgroup of 8 % who used more than one box of 105 pieces of gum achieved a success rate of 24 % . It would be feasible and effective for general practitioners to include the offer of nicotine gum and brief instructions on its use as part of a minimal intervention routine with all cigarette smokers . A general practitioner who adopts such a routine with similar success could expect to achieve about 35 - 40 long term ex-smokers a year and so save the lives of about 10 of them . If replicated by all general practitioners throughout the country the yield of ex-smokers would be about one million a year The effect of different follow-up programs reinforced or not reinforced with the nicotine chewing gum Nicorette was tested by 13 physicians working in the open health care system . A total of 151 patients were advised to stop smoking , and were asked to participate in the program if judged sufficiently motivated by the physicians . After inclusion they were r and omized into short or long follow-up , and nicotine gum vs no gum . The physicians conducted the follow-up therapy in their own personal way . Short follow-up was comprised of one appointment 14 days after cessation , while long follow-up consisted of a telephone call ( 1 week ) , an appointment ( 2 weeks ) , a second appointment ( 1 month ) , and a letter ( 3 months ) . The results at 12 months were that long follow-up showed a trend ( P less than 0.12 toward being better than short follow-up , while nicotine gum was significantly better than no gum ( P less than 0.05 ) in maintaining abstinence . The group with the best outcome was the one receiving long follow-up and nicotine gum , which yielded an expired air carbon monoxide-controlled , 12-month abstinence rate of 27 % . The abstinence outcomes at 12 months for the other groups were short follow-up and nicotine gum , 22 % ; long follow-up and no gum , 15 % ; and short follow-up and no gum , 3 % . The physicians ' reactions to the smoking cessation treatment were largely positive . The nicotine gum seems to be a relatively simple , cost-effective , and practical tool for physicians to enhance and reinforce their antismoking advice . With a longer active follow-up period than was used here ( 1 month ) , even better results may be possible A 2 × 2 r and omized , factorial pretest/posttest group design was used to evaluate the effectiveness of self-help smoking cessation methods at the worksite . The study investigated the effect of a multicomponent health education and skill intervention versus the effect of a monetary incentive to the employee for quitting . All employees received , in addition , a st and ardized self-help smoking cessation manual and maintenance manual . Following agreement to participate and a baseline smoking history , all participants were followed for 6 weeks , 6 months , and 12 months . Saliva was obtained for thiocyanate ( SCN ) analysis of smoking status . Of the estimated 2000 smokers at the site , 387 smokers were recruited . Employees were r and omly assigned to one of four groups . Results of this r and om trial indicate that those employees receiving a multicomponent program were most successful in quitting and remaining abstinent . The monetary incentive appears to have no effect on quit rate Physician-delivered , stop-smoking interventions significantly improve quit rates among smoking patients [ 1 - 6 ] . Unfortunately , only about one half of physicians in non research setting s consistently counsel smokers [ 7 - 11 ] , and fewer than one half of all smokers report that a physician has ever advised them to quit [ 12 - 14 ] . Given the pressures of routine medical practice , it is not surprising that physicians do not take 3 to 5 minutes to counsel every smoking patient they see . Tobacco counseling competes with other pressing clinical tasks ; physicians are often too busy to routinely and repeatedly counsel all patients who smoke [ 11 , 15 - 17 ] . Physicians will deliver a cessation protocol as part of a study [ 5 , 6 , 18 ] , but barriers such as a lack of time , training , and confidence make counseling in non research setting s less likely [ 1 , 4 , 19 , 20 ] . New approaches [ 21 - 23 ] , such as involving other office staff in counseling [ 17 , 24 , 25 ] , are needed if tobacco counseling is to become a consistent and sustainable part of medical care delivery [ 26 ] . Because physicians see roughly 70 % , or 38 million , of the 53 million smokers in the United States each year [ 15 ] , even a modestly effective physician-driven intervention would have considerable impact on the nation 's health . This study tested the feasibility and effectiveness of a team counseling approach design ed to minimize the burden on physicians by using non-physician clinic staff to provide the more time-consuming parts of cessation counseling . Key features of the team approach were a brief ( 30-second ) physician-delivered cessation message , referral to an on-site nurse or other staff for additional cessation support , and the use of videos to deliver much of the intervention in an efficient and st and ardized manner . A previous report of process and short-term outcome measures showed that this organized team approach proved practical and sustainable [ 27 ] . The participating physicians and other providers delivered brief advice to 86 % of identified smokers during the 1-year intake period , and most patients ( 87 % ) saw the counselor for material s and additional counseling . Nurse-Assisted counseling led to significantly improved quit rates at 3 months compared with brief physician advice alone . We present the effects of the intervention on long-term abstinence at 1 year . Methods Setting We conducted our study in two large primary care facilities of Kaiser Permanente Northwest Region , a group- practice health maintenance organization ( HMO ) in Portl and , Oregon . Receptionists asked patients between 18 and 70 years of age to complete a health habit survey while waiting for their visit . The patients were seeing 1 of 60 primary care physicians ( n = 42 ) , physician assistants ( n = 7 ) , or nurse practitioners ( n = 11 ) in outpatient internal medicine and family practice offices . Intervention Regular clinic nurses and clinical assistants collected the surveys as patients were taken to examination rooms and attached a notice to the medical charts of smokers ( n = 3161 ) to alert providers to deliver a brief stop-smoking advice message . Providers were oriented to their role in a 1-hour training session . They were encouraged to use their own words but to not go beyond the following basic 30-second message : The best thing you can do for your health is to stop smoking and I want to advise you to stop as soon as possible . I know it can be hard and many try several times before they finally make it . You may or may not want to stop now , but I want you to talk briefly with our health counselor , who has some tips to make stopping easier when you decide the time is right . The 2707 ( 86 % ) smokers who received the provider advice message were considered participants in the study , regardless of whether they were willing to see the counselor or had any interest in quitting smoking . By the end of follow-up , 16 patients died , leaving a total sample of 2691 . At the conclusion of the physician consultation , patients were seen by an on-site project nurse or health counselor who described what would be offered and obtained verbal consent to proceed . Patients who would not see the health counselor were mailed material s appropriate to their treatment assignment . Two r and om digits contained in the patient 's health record number were used to assign patients to one of the following four interventions : advice , self-quit , group-referral , or combination treatment . Physicians remained blind to treatment assignment . Advice participants received the 30-second provider advice message and a brief pamphlet , Why Do You Smoke ? , from the health counselor . This clear and systematic advice would probably be more effective than no treatment or usual care , which were not included for logistic and ethical reasons . The self-quit condition included cessation advice , a carbon monoxide assessment , and a 10-minute How to Quit Smoking video design ed specifically for this population . The video focused on the need to make a personal decision to quit , the steps to successful quitting , the frequent need for repeated efforts , and the importance of setting a specific quit date and using substitutes to smoking . The counselor provided a stop-smoking kit including smoking substitutes such as gum , toothpicks , and cinnamon sticks . A choice of one of three stop-smoking manuals was offered . Most participants chose the National Cancer Institute 's manual , Quit for Good ( 54 % ) , although others chose Calling it Quits ( 17 % ) or a two-part workbook produced by the American Lung Association titled , Freedom from Smoking in 20 Days and A Lifetime of Freedom from Cigarettes , respectively ( 29 % ) . Patients were encouraged to set a specific quit date or some other specific plan of action and the counselor arranged to call the patient , usually within 2 to 4 weeks , to check on progress toward cessation . Patients were also mailed a set of stop-smoking tip sheets and a series of six professionally design ed bimonthly newsletters devoted to smoking cessation . Group-referral participants also received advice , the carbon monoxide assessment , and a video . In this case , however , the video encouraged patients to join the HMO 's intensive stop-smoking group program known as Freedom from Cigarettes . This program entails nine group meetings over 2 months . In a recent study , this program achieved roughly a 35 % biochemically verified 1-year quit rate [ 28 ] . Patients were provided a brochure , a schedule of group sessions , and a time-limited coupon to waive the program fee . Efforts were made to schedule the patient for an upcoming group . Reminder postcards were sent 1 week before the scheduled meeting , and patients were called several days after the meeting to check on progress and , if necessary , to reschedule . Combination participants also received advice , the carbon monoxide assessment , and a third video , which described both the self-directed and the professionally led group approaches to smoking cessation . Self-directed cessation techniques , as well as the pros and cons of joining a professionally run program , were presented . Participants were asked to choose an approach that made sense for them . The self-help manual , stop-smoking kit , group material s , and fee-waiver coupon were all provided . Participants were encouraged to either set a quit date or sign up for a specific group session , and a telephone call was arranged to check on progress . Tip sheets and the bimonthly newsletters were mailed to all combination participants . Follow-up and Analyses Participants were surveyed by mail 3 and 12 months after their initial visits . Nonresponders were interviewed by telephone by an assessor who was blind to treatment assignment . Participants reporting abstinence from tobacco for at least 7 days before the 12-month assessment were asked to schedule appointments at a convenient clinic location or at their homes to provide saliva sample s for biochemical confirmation . The primary end point was a two-point prevalence measure , which was defined as consecutive abstinence at both the 3- and 12-month assessment s. Nonrespondents and those lost to follow-up were considered to be smokers . Results As shown in Table 1 , participants in the four treatment groups were similar in terms of baseline age , sex , race , education , occupation , cigarettes smoked per day , stage of change , confidence in ability to quit , perceived degree of overweight , and subjective health status [ 27 ] . Table 1 . Baseline Characteristics by Treatment Group * Self-reported smoking status was obtained on a high percentage of participants at both the 3-month ( 88 % ) and 12-month ( 86 % ) follow-up assessment s. Response rates did not differ significantly across treatment groups . The proportion of participants who reported one or more serious attempts to quit in the year following their clinic visit was significantly higher ( P < 0.004 ) among self-quit participants ( 53 % ) relative to advice participants ( 46 % ) . Group-referral ( 48 % ) and combination participants ( 50 % ) did not differ from advice participants in terms of quit attempts . All three nurse-assisted interventions self-quit , group referral , and combination result ed in higher 3-month point prevalence quit rates than did the advice treatment ( Table 2 ) . At the 12-month follow-up , a larger percentage of participants reported abstinence , although differences between treatment arms were reduced . The 12-month point prevalence definition of abstinence , however , includes both long-term ex-smokers and those who quit as little as 1 week before the 1-year follow-up . With the more conservative primary end point , consecutive abstinence at both the 3-month and 12-month assessment s , the three nurse-assisted interventions were superior to the advice intervention . Because quit rates for the three nurse-assisted interventions were similar for all analyses ( P > 0.2 ) , they were collapsed and compared to the advice intervention . Quit rates in the nurse-assisted groups were significantly higher than advice for the 3-month ( 6 Two hundred smokers who were judged by their general practitioner to be motivated to stop smoking were allocated to one of two groups . All were offered an initial appointment at which they were advised to stop smoking and offered nicotine gum . One group then received no further appointments . The other was offered four further appointments over three months . Both groups were followed up at six and 12 months . At one year follow up 15.5 % overall had stopped smoking , 14 % in the low and 17 % in the high contact group . This is better than most results so far reported for nicotine chewing gum in general practice , suggesting that general practitioners can use it to good effect . We compare this result with others achieved in general practice Smokers registering for a televised cessation program who also expressed interest in joining a support group and who had a nonsmoking buddy were r and omly assigned to 3 conditions : no-contact control , discussion , and social support . All Ss received a self-help manual and were encouraged to watch the daily TV program . Ss in the discussion and social support conditions were scheduled to attend 3 group meetings ( one with a buddy ) . Social support Ss and buddies received training in support and relapse prevention . A 4th analysis group was composed of Ss who failed to attend any of the scheduled meetings ( no shows ) . There were strong group effects at the end of treatment . Abstinence rates were highest in the social support group , followed , in order , by the discussion group , no shows , and no-contact controls . The social support group improved outcome by increasing both the level of support and program material use ( reading the manual and watching TV ) The effects of various smoking cessation strategies were studied in two multicentre trials with new patients attending hospital or a chest clinic because of a smoking related disease . In the first trial ( study A , 1462 patients ) the effect of the physician 's usual advice to stop smoking was compared with the effect of the same advice reinforced by a signed agreement to stop smoking by a target date within the next week , two visits by a health visitor in the first six weeks , and a series of letters of encouragement from the physician . The second trial ( study B , 1392 patients ) compared ( 1 ) advice only , ( 2 ) advice supplemented by a signed agreement , ( 3 ) advice supplemented by a series of letters of encouragement , and ( 4 ) advice supplemented by a signed agreement and a series of letters of encouragement . Patients were review ed at six months and those cl aim ing to have stopped smoking were seen again at 12 months . Cl aims of abstinence were checked by carboxyhaemoglobin measurement . In study A 9 % of the intervention group had succeeded in stopping smoking at six months compared with 7 % of the " advice only " patients ( p = 0.17 ) . In study B success rates were 5.2 % , 4.9 % , 8.5 % , and 8.8 % respectively . The signed agreement did not influence outcome , whereas postal encouragement increased the effect of the physician 's advice . In both studies patients review ed clinical ly between the initial and the six month visit were more likely to stop smoking than those not review ed . Success rates increased with age and men tended to do better than women . The studies suggest that physician 's advice alone will persuade 5 % of out patients with a smoking related disease to stop smoking . Subsequent postal encouragement will increase the cessation rate by more than half as much again . Such small improvements in success rates are worth while , especially if they can be achieved cheaply and on a wide scale OBJECTIVE To study the efficacy of two types of intervention to stop tobacco dependency . DESIGN R and omised clinical trial . SETTING Primary care centre . PATIENTS AND OTHER PARTICIPANTS Smokers recruited from among the health centre users through the preventive activities and health promotion programme . INTERVENTIONS INDEPENDENT VARIABLE type of intervention . General variables : age , sex , marital status , educational level , work situation , cohabitation with children , smokers at home , number of years smoking , type of tobacco . There were two types of intervention : a ) Minimal Intervention ( MI ) . b ) Advanced Intervention ( AI ) . 54 patients were included , with 6 losses . 21 were assigned at r and om to the MI group and 27 to the AI group . Progress was measured at 15 days , 1 month , 3 months , 6 months and a year . RESULTS In the MI , 23.8 % were abstinent at 15 days ; the same percentage at one month and 3 months ; 19 % at 6 months ; and 14.3 % remained abstinent after a year . In the AI , 51.9 % were abstinent at 15 days ; 48.1 % at both one and 3 months ; 25.9 % at 6 months ; and 22.2 % were still not smoking after a year . No significant differences between the two interventions were found in any of the observations . CONCLUSIONS These data do not show that one intervention is better than the other . With the passage of time the effect of the intervention decreased in both groups BACKGROUND Smoking cessation after myocardial infa rct ion ( MI ) has been associated with a 50 % reduction in mortality but in-hospital smoking cessation interventions are rarely part of routine clinical practice . METHODS One hundred cigarette smokers consecutively admitted during 1996 with MI were assigned to minimal care or to a hospital-based smoking cessation program . Intervention consisted of bedside cessation counseling followed by seven telephone calls over the 6 months following discharge . Primary outcomes were abstinence rates measured at 6 months and 1 year post-discharge . RESULTS At follow-up , 43 and 34 % of participants in minimal care and 67 and 55 % of participants in intervention were abstinent at 6 and 12 months . respectively ( P<0.05 ) . Abstinence rates were calculated assuming that participants lost to attrition were smokers at follow-up . Intervention and self-efficacy were independent predictors of smoking status at follow-up . Low self-efficacy combined with no intervention result ed in a 93 % relapse rate by 1 year ( P<0.01 ) . CONCLUSIONS A hospital-based smoking cessation program consisting of inpatient counseling and telephone follow-up substantially increases smoking abstinence 1 year after discharge in patients post-MI . Patients with low self-efficacy are almost certain to relapse without intervention . Such smoking cessation programs should be part of the management of patients with MI OBJECTIVE --To evaluate a structured , behavioural change , smoking cessation intervention design ed for use within general practice . DESIGN --R and omised controlled clinical trial . SETTING --General practice s in Newcastle , Australia . PATIENTS --311 Patients identified as smokers by a screening question were enrolled in the study . Of these , 101 were assigned to a structured behavioural change programme , 104 to a simple advice programme adapted from previous research , and 106 to a control group . No significant differences were found between groups for demographic and smoking related variables before the study . INTERVENTIONS -- Patients in the simple advice group received a brief statement of advice from the general practitioner as well as three pamphlets ; those in the structured intervention group were given strategies which included attitude and behavioural change programmes as well as techniques to aid compliance . The amount of smoking in all groups was assessed by self reports with validation by measurement of salivary cotinine concentrations . MAIN OUTCOME MEASURE -- Significant increase in cessation rates . CONCLUSIONS --Significant differences between controls and the structured behavioural change group were found at the one month follow up , but only for self reported abstinence . The simple advice programme did not produce any significant differences over the control group . General practitioner evaluation of the structured programme highlighted difficulties in relation to the duration of the intervention . Overall the structured programme in its present form did not appear to be an effective programme for use within general practice BACKGROUND Brief advice to stop smoking from general practitioners ( GPs ) has been repeatedly shown to increase smoking cessation by a small , but measurable amount . Some studies have suggested that adding more intensive interventions to brief advice may increase its effectiveness , but it is unclear whether this is true in general practice . AIMS To determine whether brief advice from a doctor together with counselling and follow-up from a trained practice nurse is more effective than brief advice alone in helping people to stop smoking . METHODS The design was a r and omized controlled trial . Four hundred and ninety-seven general practice patients aged older than 18 years and smoking at least one cigarette per day in six general practice s in Oxfordshire , Berkshire , and Buckinghamshire were r and omized to one of two interventions : brief verbal or written advice from a GP plus extended counselling and follow-up from a trained practice nurse ; brief advice from a GP alone . The primary outcome was sustained abstinence from smoking at three and 12 months . A secondary outcome was forward movement in the stages of change cycle . RESULTS The proportion showing sustained abstinence was 3.6 % in the extended counselling group , and 4.4 % in the brief advice group ( difference = -0.8 % ; 95 % confidence interval = -4.3 % to 2.6 % ) . Seventy-four ( 30 % ) of those r and omized to extended counselling actually took up this offer . No significant progression in stages of change was detected between the two groups . CONCLUSIONS In unselected general practice patients who smoke , brief advice from a GP combined with intensive intervention and follow-up by a practice nurse is no more effective than brief advice alone The results of a physician-based intervention on smoking done by general practitioners in Barcelona ( Spain ) are described one month and one year after its inception . Among the 208 smokers in the intervention group there were more attempts to quit , and they were more successful than in the 216 smokers in the control group . The proportions of quitters after a year was 5.3 % and 2.3 % in each group ( p less than 0.05 ) . Among the variables related to success in quitting are self-reliance , the willingness to reduce or quit smoking , the intensity of the habit and the family environment BACKGROUND Cigarette smoking is the greatest cause of preventable mortality in the United States . Because most smokers would like to quit and most hospitals are smoke free , surgical admissions represent a window of opportunity for tobacco cessation interventions . METHODS A total of 324 patients ( 98 % men ) , aged 25 to 82 years , who were current smokers and who underwent noncardiac surgery were enrolled in a r and omized controlled trial at the Veterans Affairs Medical Center , San Francisco , Calif. One hundred sixty-eight participants ( 52 % ) received a multicomponent intervention design ed to increase self-efficacy and coping skills that included face-to-face in-hospital counseling , viewing a smoking cessation videotape , self-help literature , nicotine replacement therapy , and 3 months of telephone follow-up . One hundred fifty-six participants ( 48 % ) received self-help literature and brief counseling lasting 10 minutes . Serum or saliva cotinine levels were measured to confirm self-reported smoking cessation . RESULTS At 12 months of follow-up , the self-reported quit rate was 27 % among the intervention group and 13 % among the comparison group ( relative risk , 2.1 ; 95 % confidence interval , 1.2 - 3.5 ; P < .01 ) . Based on biochemical confirmation , 15 % of the intervention group , compared with 8 % of the comparison group , quit smoking at 12 months ( relative risk , 2.0 ; 95 % confidence interval , 1.0 - 3.9 ; P = .04 ) . CONCLUSIONS A smoking cessation intervention targeted at smokers hospitalized for noncardiac surgery can increase long-term quit rates . Surgical hospitalizations provide an opportunity to reach smokers who want to quit smoking

Thus , the body of evidence suggests that preparedness theory does not explain the origin of specific phobias

& NA ; Preparedness theory is one of the most influential ideas in explaining the origin of specific phobias . The theory proposes that fear conditioning is selective to animals that have posed a threat to survival throughout human evolution , and that acquired fear memories to such threats are resistant to extinction . We review ed fear conditioning studies testing whether autonomic responses conditioned to pictures of snakes and spiders show greater resistance to extinction than neutral cues .

Objective To examine the prevalence rate , impairment , comorbidity , course of illness and determinants of eight specific phobia variants : animals ( animal subtype ) ; heights , water , storms ( natural environment subtype ) ; flying , enclosed spaces , being alone ( situational subtype ) ; and blood/injury ( blood/injury subtype ) . Method Data were obtained from the Netherl and s Mental Health Survey and Incidence Study , a prospect i ve study in the Dutch general population aged 18–65 ( N = 7,076 ) . Results The most prevalent condition was specific phobia with a fear of heights ( 4.9 % ) . On all parameters except duration , specific phobia with a fear of being alone emerged as the most severe condition . Phobias with fear of enclosed spaces and phobias with fear of blood showed a slightly greater likelihood of impairment , comorbidity and personality problems than phobias with fear of animals , heights , water or storms . Conclusion The situational and blood/injury phobia subtypes appear to be a more significant index for impairments and for comorbid psychiatric disorders than the animal and natural environment phobia subtypes Experimental tests of the preparedness theory of phobias have found that skin conductance responses ( SCRs ) conditioned to fear-relevant stimuli ( e.g. pictures of snakes and spiders ) exhibit more resistance to extinction than those conditioned to fear-irrelevant stimuli ( e.g. pictures of flowers and geometric figures ) . However , there are no published replications of this phenomenon outside the laboratories of Ohman and his associates . The experiment reported here failed to replicate previous findings insofar as SCRs established to fear-relevant stimuli were no more resistant to extinction than those established to fear-irrelevant stimuli . Indeed , ‘ preparedness ’ effects were absent even in Ss who reported prior fear of snakes and spiders . Correlational analyses indicated that the strength of conditioning was the only predictor of resistance to extinction to fear-relevant stimuli — a finding consistent with general process-learning theories The effects of conditioned stimulus ( CS ) pre-exposure and fear- relevance of the CS on human Pavlovian electrodermal conditioning were investigated . A differential delayed conditioning paradigm was used with a CS-unconditioned stimulus ( US ; shock ) interval of 8 s. In Experiment 1 , 64 subjects were r and omized into four groups , two of which received fear-relevant stimuli and the other two fear-irrelevant stimuli . Half of the subjects were pre-exposed to the to-be-CSs and the other half to two not-to-be-CSs , with 15 exposure of each stimulus . During acquisition , subjects received 8 reinforced and 8 nonreinforced CS+ and CS- trials , and during the extinction phase 15 nonreinforced trials of each CS . Pre-exposure to the to-be-CSs retarded conditioning for the first and second interval anticipatory responses ( FIRs and SIRs ) ; that is , a latent inhibition effect was demonstrated , although the results for the FIR were inconclusive . The expected effects of fear- relevance were not revealed . Experiment 2 addressed the question whether the long pre-exposure period interfered with the frequently observed " preparedness effect " of higher resistance to extinction to fear-relevant stimuli . The design was similar to that of Experiment 1 , but for half of the subjects the acquisition phase was initiated immediately after a short rest period , and for the other half acquisition started after an extended rest period , equal to the duration of the pre-exposure phase in Experiment 1 . Twenty extinction trials of each CS were presented . A reliable difference in arousal in terms of spontaneous fluctuations was produced by the rest periods , but although differential conditioning was observed , no effect of fear- relevance was seen during extinction

However , these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction . There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity . Recorded consumption of AS-AQ was low in the locations and times Pfmdr1 data were collected . SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ , by 7 - 10 years after AL introduction .

Artemether-lumefantrine ( AL ) and artesunate-amodiaquine ( AS-AQ ) are the most commonly used artemisinin-based combination therapies ( ACT ) for treatment of Plasmodium falciparum in Africa . Both treatments remain efficacious , but single nucleotide polymorphisms ( SNPs ) in the Plasmodium falciparum multidrug resistance 1 ( Pfmdr1 ) gene may compromise sensitivity . AL and AS-AQ exert opposing selective pressures : parasites with genotype 86Y , Y184 and 1246Y are partially resistant to AS-AQ treatment , while N86 , 184 F and D1246 are favoured by AL treatment .

Background The emergence of resistance against artemisinin combination treatment is a major concern for malaria control . ACTs are recommended as the rescue treatment , however , there is limited evidence as to whether treatment and re-treatment with ACTs select for drug-resistant P. falciparum parasites . Thus , the purpose of the present study is to investigate the impact of (re-)treatment using artesunate-amodiaquine ( ASAQ ) and artemether-lumefantrine ( AL ) on the selection of P. falciparum multidrug resistance-1 ( Pfmdr1 ) alleles in clinical setting s. Methods P. falciparum positive sample s were collected from children aged 12–59 months in a clinical trial in DR Congo and Ug and a. Pfmdr1 single nucleotide polymorphisms ( SNPs ) analysis at codons N86Y , Y184F , and D1246Y were performed at baseline and post-treatment with either AL or ASAQ as a rescue treatment using nested PCR followed by restriction fragment length polymorphism ( RFLP ) assays . Results The pre-treatment prevalence of Pfmdr1 N86 and D1246Y varied significantly between the sites , ( p>0.001 ) and ( p = 0.013 ) , respectively . There was borderline significant directional selection for Pfmdr1 184F in recurrent malaria infections after treatment with AL in Ug and a site ( p = 0.05 ) . Pfmdr1 NFD haplotype did not significantly change in post-treatment infections after re-treatment with either AL or ASAQ . Comparison between pre-treatment and post-treatment recurrences did not indicate directional selection of Pfmdr1 N86 , D1246 alleles in the pre- RCT , RCT and post- RCT phases in both AL and ASAQ treatment arms . Pfmdr1 86Y was significantly associated with reduced risk of AL treatment failure ( RR = 0.34 , 95 % CI:0.11–1.05 , p = 0.04 ) while no evidence for D1246 allele ( RR = 1.02 ; 95 % CI : 0.42–2.47 , p = 1.0 ) . Survival estimates showed that the Pfmdr1 alleles had comparable mean-time to PCR-corrected recrudescence and new infections in both AL and ASAQ treatment arms . Conclusion We found limited impact of (re-)treatment with AL or ASAQ on selection for Pfmdr1 variants and haplotypes associated with resistance to partner drugs . These findings further supplement the evidence use of same or alternative ACTs as a rescue therapy for recurrent P.falciparum infections . Continued monitoring of genetic signatures of resistance is warranted to timely inform malaria (re-)treatment policies and guidelines Background The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies . Methods On the Kenyan coast we studied the treatment responses in 474 children 6–59 months old with uncomplicated P. falciparum malaria in a r and omized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008 . ( IS RCT N88705995 ) Results The proportion of patients with residual parasitemia on day 1 rose from 55 % in 2005–2006 to 87 % in 2007–2008 ( odds ratio , 5.4 , 95%CI , 2.7–11.1 ; P<0.001 ) and from 81 % to 95 % ( OR , 4.1 , 95%CI , 1.7–9.9 ; P = 0.002 ) in the DHA-PPQ and AM-LM groups , respectively . In parallel , Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7 % to 14 % ( P = 0.1 ) and from 6 % to 15 % ( P = 0.05 ) with DHA-PPQ and AM-LM , respectively . Coinciding with decreasing transmission in the study area , clinical tolerance to parasitemia ( defined as absence of fever ) declined between 2005–2006 and 2007–2008 ( OR body temperature > 37.5 ° C , 2.8 , 1.9–4.1 ; P<0.001 ) . Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof . Conclusions The significant , albeit small , decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity , to the coincident reduction in population -level clinical immunity , or both . Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better underst and ing of the mechanisms underlying reduced parasite clearance rates . Trial Registration Controlled-Trials.com IS RCT Summary Background Artemisinin-based combination therapies ( ACTs ) are the most effective treatment for uncomplicated Plasmodium falciparum malaria infection . A commonly used indicator for monitoring and assessing progress in coverage of malaria treatment is the proportion of children younger than 5 years with reported fever in the previous 14 days who have received an ACT . We propose an improved indicator that incorporates parasite infection status ( as assessed by a rapid diagnostic test [ RDT ] ) , which is available in recent household surveys . In this study we estimated the annual proportion of children younger than 5 years with fever and a positive RDT in Africa who received an ACT in 2003–15 . Methods Our modelling study used cross-sectional data on treatment for fever and RDT status for children younger than 5 years compiled from all nationally available representative household surveys ( the Malaria Indicator Surveys , Demographic and Health Surveys , and Multiple Indicator Cluster Surveys ) across sub-Saharan Africa between 2003 and 2015 . Estimates for the proportion of children younger than 5 years with a fever within the previous 14 days and P falciparum infection assessed by RDT who received an ACT were incorporated in a generalised additive mixed model , including data on ACT distributions , to estimate coverage across all countries and time periods . We did r and om effects meta-analyses to examine individual , household , and community effects associated with ACT coverage . Findings We obtained data on 201 704 children younger than 5 years from 103 surveys ( 22 MIS , 61 DHS , and 20 MICS ) across 33 countries . RDT results were available for 40 of these surveys including 40 261 ( 20 % ) children , and we predicted RDT status for the remaining 161 443 ( 80 % ) children . Our results showed that ACT coverage in children younger than 5 years with a fever and P falciparum infection increased across sub-Saharan Africa in 2003–15 , but even in 2015 , only 19.7 % ( 95 % CI 15.6–24.8 ) of children younger than 5 years with a fever and P falciparum infection received an ACT . In meta-analyses , children younger than 5 years were more likely to receive an ACT for fever and P falciparum infection if they lived in an urban area ( vs rural area ; odds ratio [ OR ] 1.18 , 95 % CI 1.06–1.31 ) , had household wealth above the national median ( vs wealth below the median ; OR 1.26 , 1.16–1.39 ) , had a caregiver with any education ( vs no education ; OR 1.31 , 1.22–1.41 ) , had a household insecticide-treated net ( ITN ; vs no ITN ; OR 1.21 , 1.13–1.29 ) , were older than 2 years ( vs ≤2 years ; OR 1.09 , 1.01–1.17 ) , or lived in an area with a higher mean P falciparum prevalence in children aged 2–10 years ( OR 1.12 , 1.02–1.23 ) . In the subgroup of children for whom treatment was sought , those who sought treatment in the public sector were more likely to receive an ACT ( vs the private sector ; OR 3.18 , 2.67–3.78 ) . Interpretation Despite progress during the 2003–15 malaria programme , ACT treatment for children with malaria remains unacceptably low . More work is needed at the country level to underst and how health-care access , service delivery , and ACT supply might be improved to ensure appropriate treatment for all children with malaria . Funding US President 's Malaria Initiative and Medicines for Malaria Venture Background Molecular tools for detection of low-density asymptomatic Plasmodium infections are needed in malaria elimination efforts . This study reports results from the hitherto largest implementation of loop-mediated isothermal amplification ( LAMP ) for central ized mass screening of asymptomatic malaria in Zanzibar . Methods Healthy individuals present and willing to participate in r and omly selected households in 60 villages throughout Zanzibar were screened for malaria by rapid diagnostic tests ( RDT ) . In 50 % of the study households , participants were asked to provide 60 μL of finger-prick blood for additional LAMP screening . LAMP was conducted in two central ized laboratories in Zanzibar , by trained technicians with limited or no previous experience of molecular methods . The LAMP assay was performed with LoopampTM MALARIA Pan/Pf Detection Kit ( Eiken Chemical Company , Japan ) . Sample s positive for Plasmodium genus (Pan)-LAMP were re-tested using Plasmodium falciparum-specific LAMP kits . Results Paired RDT and LAMP sample s were available from 3983 individuals . The prevalence of asymptomatic malaria was 0.5 % ( CI 95 % 0.1 - 0.8 ) and 1.6 % ( CI 95 % 1.1 - 2.2 ) by RDT and Pan-LAMP , respectively . LAMP detected 3.4 ( CI 95 % 2.2 - 5.2 ) times more Plasmodium positive sample s than RDT . DNA contamination was experienced , but solved by repetitive decontamination of all equipment and reagents . Conclusions LAMP is a simple and sensitive molecular tool , and has potential in active surveillance and mass-screening programmes for detection of low-density asymptomatic malaria in pre-elimination setting s. However , in order to deploy LAMP more effectively in field setting s , protocol s may need to be adapted for processing larger numbers of sample s. A higher throughput , affordable closed system would be ideal to avoid contamination Background Plasmodium falciparum uncomplicated malaria can successfully be treated with an artemisinin-based combination therapy ( ACT ) . However resistance is spreading to the different ACT compounds ; the artemisinin derivative and the partner drug . Studies of P. falciparum polymorphisms associated with drug resistance can provide a useful tool to track resistance and guide treatment policy as well as an in-depth underst and ing of the development and spread of resistance . Methods The role of P. falciparum molecular markers in selection of reinfections was assessed in an efficacy trial comparing artesunate – amodiaquine fixed-dose combination with artemether – lumefantrine to treat malaria in Nimba County , Liberia 2008–2009 . P. falciparum polymorphisms in pfcrt 76 , pfmdr1 86 , 184 and 1246 , and pfmrp1 876 and 1466 were analysed by PCR-RFLP and pyrosequencing . Results High baseline prevalence of pfmdr1 1246Y was found in Nimba county ( 38 % ) . Pfmdr1 1246Y and pfmdr1 86 + 184 + 1246 haplotypes NYY and YYY were selected in reinfections in the artesunate – amodiaquine arm and pfcrt K76 , pfmdr1 N86 and pfmdr1 haplotype NFD were selected in artemether – lumefantrine reinfections . Parasites harbouring pfmdr1 1246Y could reinfect earlier after treatment with artesunate – amodiaquine and parasites carrying pfmdr1 N86 could reinfect at higher lumefantrine concentrations in patients treated with artemether – lumefantrine . Conclusions Although treatment is highly efficacious , selection of molecular markers in reinfections could indicate a decreased sensitivity or tolerance of parasites to the current treatments and the baseline prevalence of molecular markers should be closely monitored . Since individual drug levels and the day of reinfection were demonstrated to be key determinants for selection of reinfections , this data needs to be collected and taken into account for accurate evaluation of molecular markers for anti-malarial treatments . The protocol s for the clinical trial was registered with Current Controlled Trials , under the Identifier Number IS RCT N51688713 on 9 October Artemisinin derivative-based combination therapy is expected to suppress the development of Plasmodium falciparum drug resistance in Africa . We have performed an artemether-lumefantrine ( Coartem ; Novartis ) follow-up clinical trial in Zanzibar , in which pfcrt K76 T and pfmdr1 N86Y frequencies were determined before drug administration and in all recurrent parasites during a follow-up period of 42 days . A significant increase in pfmdr1 86N was observed after exposure to the drug . This points to 86N as a potential marker of lumefantrine resistance in vivo , while suggesting that Coartem is not robust enough to avoid selection of resistance-associated mutations in some malarial setting ABSTRACT In 2008 , artemether-lumefantrine was introduced in Guinea-Bissau , West Africa , but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria . An efficacious high-dose chloroquine treatment regimen was used previously . Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine , lumefantrine , and quinine have been described . P. falciparum chloroquine resistance transporter ( pfcrt ) K76 T , pfmdr1 gene copy numbers , pfmdr1 polymorphisms N86Y and Y184F , and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods . Blood sample s came from virtually all ( n = 1,806 ) children < 15 years of age who had uncomplicated P. falciparum monoinfection and presented at a health center in suburban Bissau ( from 2003 to 2012 ) . The pfcrt K76 T and pfmdr1 N86Y frequencies were stable , and seasonal changes were not seen from 2003 to 2007 . Since 2007 , the mean annual frequencies increased ( P < 0.001 ) for pfcrt 76 T ( 24 % to 57 % ) , pfmdr1 N86 ( 72 % to 83 % ) , and pfcrt 76 + pfmdr1 86 TN ( 10 % to 27 % ) , and pfcrt 76 T accumulated during the high transmission season ( P = 0.001 ) . The pfmdr1 86 + 184 NF frequency increased from 39 % to 66 % ( from 2003 to 2011 ; P = 0.004 ) . One sample had two pfmdr1 gene copies . pfcrt 76 T was associated with a lower parasite density ( P < 0.001 ) . Following the discontinuation of an effective chloroquine regimen , probably highly artemether-lumefantrine-susceptible P. falciparum ( with pfcrt 76 T ) accumulated , possibly due to suboptimal use of quinine and despite a fitness cost linked to pfcrt 76 T . ( The studies reported here were registered at Clinical Trials.gov under registration no. NCT00137514 [ PSB-2001-chl-amo ] , NCT00137566 [ PSB-2004-paracetamol ] , NCT00426439 [ PSB-2006-coartem ] , NCT01157689 [ AL-eff 2010 ] , and NCT01704508 [ Eurartesim 2012 ] . BACKGROUND In treating malaria in Ug and a , artemether-lumefantrine ( AL ) has been associated with a lower risk of recurrent parasitemia , compared with artesunate-amodiaquine ( AS/AQ ) , but changing treatment practice s may have altered parasite susceptibility . METHODS We enrolled 602 children aged 6 - 59 months with uncomplicated falciparum malaria from 3 health centers in 2013 - 2014 and r and omly assigned them to receive treatment with AS/AQ or AL . Primary outcomes were risks of recurrent parasitemia within 28 days , with or without adjustment to distinguish recrudescence from new infection . Drug safety and tolerability and Plasmodium falciparum resistance-mediating polymorphisms were assessed . RESULTS Of enrolled patients , 594 ( 98.7 % ) completed the 28-day study . Risks of recurrent parasitemia were lower with AS/AQ at all 3 sites ( overall , 28.6 % vs 44.6 % ; P < .001 ) . Recrudescences were uncommon , and all occurred after AL treatment ( 0 % vs 2.5 % ; P = .006 ) . Recovery of the hemoglobin level was greater with AS/AQ ( 1.73 vs 1.39 g/dL ; P = .04 ) . Both regimens were well tolerated ; serious adverse events were uncommon ( 1.7 % in the AS/AQ group and 1.0 % in the AL group ) . AS/AQ selected for mutant pfcrt/pfmdr1 polymorphisms and AL for wild-type pfcrt/pfmdr1 polymorphisms associated with altered drug susceptibility . CONCLUSIONS AS/AQ treatment was followed by fewer recurrences than AL treatment , contrasting with older data . Each regimen selected for polymorphisms associated with decreased treatment response . Research should consider multiple or rotating regimens to maintain treatment efficacies Background Management of uncomplicated Plasmodium falciparum malaria relies on artemisinin-based combination therapies ( ACTs ) . These highly effective regimens have contributed to reductions in malaria morbidity and mortality . However , artemisinin resistance in Asia and changing parasite susceptibility to ACT in Africa have now been well documented . Strategies that retain current ACT as efficacious treatments are urgently needed . Methods We present an open-label , r and omised three-arm clinical trial protocol in three African setting s representative of varying malaria epidemiology to investigate whether prolonged ACT-based regimens using currently available formulations can eliminate potentially resistant parasites . The protocol investigates whether a sequential course of two licensed ACT in 1080 children aged 6–120 months exhibits superior efficacy against acute P. falciparum malaria and non-inferior safety compared with st and ard single-course ACT given to 540 children . The primary endpoint is PCR-corrected clinical and parasitological response at day 42 or day 63 of follow-up . Persistence of PCR-detectable parasitaemia at day 3 is analysed as a key covariate . Secondary endpoints include gametocytaemia , occurrence of treatment-related adverse events in the double-ACT versus single-ACT arms , carriage of molecular markers of drug resistance , drug kinetics and patient adherence to treatment . Discussion This protocol addresses efficacy and safety of sequential ACT regimens in P. falciparum malaria in Africa . The approach is design ed to extend the useful life of this class of antimalarials with maximal impact and minimal delay , by deploying licensed medicines that could be swiftly implemented as sequential double ACT by National Malaria Control Programmes , before emerging drug resistance in Africa becomes a major threat to public health BACKGROUND The borders of Thail and harbour the world 's most multidrug resistant Plasmodium falciparum parasites . In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria , but substantial resistance developed within 6 years . A combination of artesunate with mefloquine now cures more than 95 % of acute infections . For both treatment regimens , the underlying mechanisms of resistance are not known . METHODS The relation between polymorphisms in the P falciparum multidrug resistant gene 1 ( pfmdr1 ) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 sample s from patients with falciparum malaria studied prospect ively over 12 years . pfmdr1 copy number was assessed by a robust real-time PCR assay . Single nucleotide polymorphisms of pfmdr1 , P falciparum chloroquine resistance transporter gene ( pfcrt ) and P falciparum Ca2 + ATPase gene ( pfATP6 ) were assessed by PCR-restriction fragment length polymorphism . FINDINGS Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine , and also to reduced artesunate sensitivity in vitro . In a Cox regression model with control for known confounders , increased pfmdr1 copy number was associated with an attributable hazard ratio ( AHR ) for treatment failure of 6.3 ( 95 % CI 2.9 - 13.8 , p<0.001 ) after mefloquine monotherapy and 5.4 ( 2.0 - 14.6 , p=0.001 ) after artesunate-mefloquine therapy . Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro , but not in vivo . INTERPRETATION Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria . RELEVANCE TO PRACTICE Multidrug resistant P falciparum malaria is common in southeast Asia , but difficult to identify and treat . Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance . In this study we show that increase in copy number of pfmdr1 , a gene encoding a parasite transport protein , is the best overall predictor of treatment failure with mefloquine . Increase in pfmdr1 copy number predicts failure even after chemotherapy with the highly effective combination of mefloquine and 3 days ' artesunate . Monitoring of pfmdr1 copy number will be useful in epidemiological surveys of drug resistance in P falciparum , and potentially for predicting treatment failure in individual patients

This is consistent with contact studies in Africa , which show that children 10–14 years have the highest frequency of contacts . Targeting older children in Africa for conjugate vaccination may be effective in reducing meningococcal transmission

Meningococcal carriage dynamics drive patterns of invasive disease . The distribution of carriage by age has been well described in Europe , but not in the African meningitis belt , a region characterised by frequent epidemics of meningitis . We aim ed to estimate the age-specific prevalence of meningococcal carriage by season in the African meningitis belt .

Overdispersion is a common feature of models of biological data , but research ers often fail to model the excess variation driving the overdispersion , result ing in biased parameter estimates and st and ard errors . Quantifying and modeling overdispersion when it is present is therefore critical for robust biological inference . One means to account for overdispersion is to add an observation-level r and om effect ( OLRE ) to a model , where each data point receives a unique level of a r and om effect that can absorb the extra-parametric variation in the data . Although some studies have investigated the utility of OLRE to model overdispersion in Poisson count data , studies doing so for Binomial proportion data are scarce . Here I use a simulation approach to investigate the ability of both OLRE models and Beta-Binomial models to recover unbiased parameter estimates in mixed effects models of Binomial data under various degrees of overdispersion . In addition , as ecologists often fit r and om intercept terms to models when the r and om effect sample size is low ( < 5 levels ) , I investigate the performance of both model types under a range of r and om effect sample sizes when overdispersion is present . Simulation results revealed that the efficacy of OLRE depends on the process that generated the overdispersion ; OLRE failed to cope with overdispersion generated from a Beta-Binomial mixture model , leading to biased slope and intercept estimates , but performed well for overdispersion generated by adding r and om noise to the linear predictor . Comparison of parameter estimates from an OLRE model with those from its corresponding Beta-Binomial model readily identified when OLRE were performing poorly due to disagreement between effect sizes , and this strategy should be employed whenever OLRE are used for Binomial data to assess their reliability . Beta-Binomial models performed well across all context s , but showed a tendency to underestimate effect sizes when modelling non-Beta-Binomial data . Finally , both OLRE and Beta-Binomial models performed poorly when models contained < 5 levels of the r and om intercept term , especially for estimating variance components , and this effect appeared independent of total sample size . These results suggest that OLRE are a useful tool for modelling overdispersion in Binomial data , but that they do not perform well in all circumstances and research ers should take care to verify the robustness of parameter estimates of OLRE models ABSTRACT The serogroup A meningococcal conjugate vaccine MenAfriVac has the potential to confer herd immunity by reducing carriage prevalence of epidemic strains . To better underst and this phenomenon , we initiated a meningococcal carriage study to determine the baseline carriage rate and serogroup distribution before vaccine introduction in the 1- to 29-year old population in Burkina Faso , the group chosen for the first introduction of the vaccine . A multiple cross-sectional carriage study was conducted in one urban and two rural districts in Burkina Faso in 2009 . Every 3 months , oropharyngeal sample s were collected from > 5,000 r and omly selected individuals within a 4-week period . Isolation and identification of the meningococci from 20,326 sample s were performed by national laboratories in Burkina Faso . Confirmation and further strain characterization , including genogrouping , multilocus sequence typing , and porA-fetA sequencing , were performed in Norway . The overall carriage prevalence for meningococci was 3.98 % ; the highest prevalence was among the 15- to 19-year-olds for males and among the 10- to 14-year-olds for females . Serogroup Y dominated ( 2.28 % ) , followed by serogroups X ( 0.44 % ) , A ( 0.39 % ) , and W135 ( 0.34 % ) . Carriage prevalence was the highest in the rural districts and in the dry season , but serogroup distribution also varied by district . A total of 29 sequence types ( STs ) and 51 porA-fetA combinations were identified . The dominant clone was serogroup Y , ST-4375 , P1.5 - 1,2 - 2/F5 - 8 , belonging to the ST-23 complex ( 47 % ) . All serogroup A isolates were ST-2859 of the ST-5 complex with P1.20,9/F3 - 1 . This study forms a solid basis for evaluating the impact of MenAfriVac introduction on serogroup A carriage A prospect i ve carriage and serological study was conducted in Burkina Faso during the 2003 meningitis season , which was characterized by hyperendemic Neisseria meningitidis serogroup W135 ( NmW135 ) and serogroup A ( NmA ) disease . Participants were evaluated five times at monthly intervals . In the presence of moderate NmW135 carriage , we found a low prevalence of putatively protective levels of specific immunoglobulin G ( IgG ) and serum bactericidal antibody ( SBA ) against NmW135 . Specific IgG concentrations and SBA titers against NmA were relatively high in this recently vaccinated population , while no NmA carriage was detected . NmW135 carriage infrequently induced protective immunity against reference or homologous strains , while natural immunity against NmW135 was frequently lost . A vaccine that is effective against W135 will be beneficial for sub-Saharan Africa Summary In a study of carriage of Neisseria meningitidis in family contacts of patients with group A meningococcal meningitis in the African meningitis belt an overall carrier rate of 17 per cent was observed . The rate was higher in the younger age groups ( 5–19 years ) . No overall sex difference was observed . The carrier rate was significantly higher in the contacts who had been sleeping in the same room as the patient . Rifampicin reduced the carrier rate from 20 per cent to five per cent within two weeks of treatment and a further drop of 2·5 per cent was observed four weeks later . The corresponding results for sulphadimidine were 14 , 14 and 10 per cent . More than 90 per cent of the strains isolated were resistant to 50 μg/ml of sulphadiazine in vitro . All of the strains initially isolated were sensitive to rifampicin , but of the 11 strains isolated after treatment with this drug four were partially resistant A combined group A and group C meningococcal polysaccharide vaccine was given to 438 Nigerian schoolboys shortly before an outbreak of group A meningococcal disease occurred in their school . Four months after vaccination the carriage rate of group A meningococci among vaccinated subjects ( 11 % ) was no different from that found among the controls ( 12 % ) , although a good antibody response to both components of the vaccine was observed . One case of group A meningococcal disease was recorded amongst 438 vaccinated subjects while five cases occurred among 874 controls

Antithrombin , evaluated in one study involving paediatric patients , had no significant effect on VTE or on major bleeding when compared with no antithrombin . AUTHORS ' CONCLUSIONS In this second up date , we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy . In addition , the uLMWH semuloparin , which is not commercially available , significantly reduced the incidence of symptomatic VTE .

BACKGROUND Venous thromboembolism ( VTE ) often complicates the clinical course of cancer . The risk is further increased by chemotherapy , but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain . This is the second up date of a review first published in February 2012 . OBJECTIVES To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis .

Background Cancer patients receiving chemotherapy are at increased risk of thrombosis . Nadroparin has been demonstrated to reduce the incidence of venous and arterial thrombotic events ( TEs ) by about 50 % in cancer out patients receiving chemotherapy . The aims of this retrospective analysis were to evaluate the thromboembolic risk and the benefit of thromboprophylaxis according to type of chemotherapy . Methods Cancer out patients were r and omly assigned to receive subcutaneous injections of nadroparin or placebo . The incidence of symptomatic TEs was assessed according to the type of chemotherapy . Results were reported as risk ratios with associated 95 % CI and two-tailed probability values . Results 769 and 381 patients have been evaluated in the nadroparin and placebo group , respectively . In the absence of thromboprophylaxis , the highest rate of TEs was found in patients receiving gemcitabine- ( 8.1 % ) or cisplatin-based chemotherapy ( 7.0 % ) . The combination of gemcitabine and cisplatin or carboplatin increased the risk to 10.2 % . Thromboprophylaxis reduced TE risk by 68 % in patients receiving gemcitabine ; with a further decrease to 78 % in those receiving a combination of gemcitabine and platinum . Conclusions This retrospective analysis confirms that patients undergoing chemotherapy including gemcitabine , platinum analogues or their combination are at higher risk of TEs . Our results also suggest that out patients receiving chemotherapy regimens including these agents might achieve an increased benefit from thromboprophylaxis with nadroparin . Clinical Trial registration number : NCT Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma ( MM ) but is associated with an increased risk of venous thromboembolism ( VTE ) . This prospect i ve , open-label , r and omized sub study of a phase 3 trial compared the efficacy and safety of thromboprophylaxis with low-dose aspirin ( ASA ) or low-molecular-weight heparin ( LMWH ) in patients with newly diagnosed MM , treated with lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation . Overall , 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant therapy were r and omly assigned to receive ASA 100 mg/d ( n = 176 ) or LMWH enoxaparin 40 mg/d ( n = 166 ) . The incidence of VTE was 2.27 % in the ASA group and 1.20 % in the LMWH group . Compared with LMWH , the absolute difference in the proportion of VTE was 1.07 % ( 95 % confidence interval , -1.69 - 3.83 ; P = .452 ) in the ASA group . Pulmonary embolism was observed in 1.70 % of patients in the ASA group and none in the LMWH group . No arterial thrombosis , acute cardiovascular events , or sudden deaths were reported . No major hemorrhagic complications were reported . In previously untreated patients with MM receiving lenalidomide with a low thromboembolic risk , ASA could be an effective and less-expensive alternative to LMWH thromboprophylaxis PURPOSE Studies by the Veterans Administration Cooperative Studies Program and Cancer and Leukemia Group B ( CALGB ) suggested that the addition of warfarin to chemotherapy might enhance response and /or survival in small-cell lung cancer ( SCLC ) . This r and omized study evaluated the effect of warfarin with chemotherapy and radiation therapy in limited-stage SCLC . PATIENTS AND METHODS Patients were r and omized to receive warfarin or no warfarin . All patients received three cycles of doxorubicin , cyclophosphamide , and etoposide ( ACE ) . Cycles 4 and 5 ( cisplatin , cyclophosphamide , and etoposide [ PCE ] ) were given concurrently with radiation therapy . Three cycles of ACE were given after chemoradiation therapy , but were discontinued due to a high rate of pulmonary toxicity . RESULTS There were no significant differences in response rates , survival , failure-free survival , disease-free survival , or patterns of relapse between the warfarin-treated and control groups . In patients treated according to the initial design , an increase in failure-free survival seen with warfarin treatment approached significance ( P = .07 ) . Preamendment results , while not significant , did not have superimposable treatment survival curves . A l and mark analysis at 8 months showed a median survival time after the l and mark for complete responders of 33 months with warfarin treatment compared with < or = 13.75 months for complete or partial responders not treated with warfarin ( P = .05 ) . Differences between the complete responders in this preamendment population were not significant ( P = .103 ) . CONCLUSION Warfarin does not appear to improve outcome significantly in limited-stage SCLC . However , the differences in some variables between population s before the protocol amendment correspond to the favorable effects of anticoagulants observed in previous studies PURPOSE Initial heparinization followed by vitamin K antagonists is the treatment of choice for patients with venous thromboembolism . There is controversy whether known malignancy is a risk factor for recurrences and bleeding complications during this treatment . Furthermore , the incidence of such events in these patients is dependent on the achieved International Normalized Ratio ( INR ) . The aim of this study was to assess the incidence of venous thromboembolic recurrence and major bleeding among patients with venous thromboembolism in relation to both malignancy and the achieved INR . PATIENTS AND METHODS In a retrospective analysis , the INR-specific incidence of venous thromboembolic and major bleeding events during oral anticoagulant therapy was calculated separately for patients with and without malignancy . Eligible patients participated in two multicenter , r and omized clinical trials on the initial treatment of venous thromboembolism . Patients were initially treated with heparin ( st and ard or low-molecular weight ) . Treatment with vitamin K antagonists was started within 1 day and continued for 3 months , with a target INR of 2.0 to 3.0 . RESULTS In 1,303 eligible patients ( 264 with malignancy ) , 35 recurrences and 12 bleeds occurred . Patients with malignancy , compared with nonmalignant patients , had a clinical ly and statistically significantly increased overall incidence of recurrence ( 27.1 v 9.0 , respectively , per 100 patient-years ) as well as bleeding ( 13.3 v 2.1 , respectively , per 100 patient-years ) . In both groups of patients , the incidence of recurrence was lower when the INR was above 2.0 compared with below 2.0 . CONCLUSION Although adequately dosed vitamin K antagonists are effective in patients with malignant disease , the incidence of thrombotic and bleeding complications remains higher than in patients without malignancy Background Advanced pancreatic cancer , in addition to its high mortality , is characterized by one of the highest rates of venous thromboembolic events ( VTE ) as compared to other types of cancer . Enoxaparin , a low molecular weight heparin ( LMWH ) , has proven to be effective for the prevention and treatment of VTE in surgical and general medical patients . Results of some small studies suggest that this benefit might extend to patients with cancer , however , enoxaparin is not currently indicated for this use . This phase IIb study was design ed to analyze the efficacy of enoxaparin in patients with locally advanced or metastatic pancreatic cancer undergoing systemic chemotherapy . Methods The aim of this prospect i ve multicenter trial is to compare concomitant treatment with enoxaparin to no anticoagulation in 540 patients . Primary endpoint is the incidence of clinical ly relevant VTE ( symptomatic deep venous thrombosis ( DVT ) of the leg and /or pelvic and /or pulmonary embolism ( PE ) ) within the first 3 months . Secondary endpoints include the incidence of symptomatic and asymptomatic VTE after 6 , 9 and 12 months as well as remission at 3 , 6 , 9 and 12 months , overall survival and bleeding . Trial registration : is rct n.org identifier CCT-NAPN-16752 , controlled-trials.com identifier : IS RCT N02140505 . Results An interim analysis for safety performed after inclusion of 152 patients revealed no increased risk of bleeding ( 5 pts vs. 6 pts , Chi2 : 0.763 ) . Conclusion PROSPECT is a pivotal study in elucidating the role of low molecular weight heparins in advanced pancreatic cancer . Its results will lead to a new underst and ing of the role of heparins in the prevention of venous thromboembolism and of their effect on survival , remission rates and toxicity of chemotherapeutic regimens Background The heterogeneity statistic I2 , interpreted as the percentage of variability due to heterogeneity between studies rather than sampling error , depends on precision , that is , the size of the studies included . Methods Based on a real meta- analysis , we simulate artificially ' inflating ' the sample size under the r and om effects model . For a given inflation factor M = 1 , 2 , 3 , ... and for each trial i , we create a M-inflated trial by drawing a treatment effect estimate from the r and om effects model , using si2MathType@MTEF@5@5@+=feaagaart1ev2aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacPC6xNi = xH8viVGI8Gi = hEeeu0xXdbba9frFj0xb9qqpG0dXdb9aspeI8k8fiI+fsY = rqGqVepae9pg0db9vqaiVgFr0xfr = xfr = xc9adbaqaaeGaciGaaiaabeqaaeqabiWaaaGcbaGaem4Cam3aa0baaSqaaiabdMgaPbqaaiabikdaYaaaaaa@2FBE@/M as within-trial sampling variance . Results As precision increases , while estimates of the heterogeneity variance τ2 remain unchanged on average , estimates of I2 increase rapidly to nearly 100 % . A similar phenomenon is apparent in a sample of 157 meta-analyses . Conclusion When deciding whether or not to pool treatment estimates in a meta- analysis , the yard-stick should be the clinical relevance of any heterogeneity present . τ2 , rather than I2 , is the appropriate measure for this purpose OBJECTIVE To study the efficacy of daily low-dose aspirin ( 81 mg orally ) in decreasing the incidence of venous thromboembolic events ( VTEs ) in patients with multiple myeloma receiving pegylated doxorubicin , vincristine , and decreased-frequency dexamethasone , plus thalidomide ( DVd-T ) . PATIENTS AND METHODS In this phase 2 clinical trial of DVd-T , conducted by the Clevel and Clinic Foundation from August 2001 to October 2003 , 105 patients were enrolled . The first 35 patients experienced increased numbers of VTEs . von Willebr and levels and platelet aggregation to ristocetin before and after treatment with DVd-T increased significantly , suggesting a pathophysiology involving platelet-endothelial interaction . Aspirin was added to the regimen , thus generating 3 patient groups : group 1 received aspirin from the start of DVd-T treatment before the study began ( 58 patients ) , group 2 received aspirin after the start of DVd-T treatment and after the study began ( 26 patients ) , and group 3 did not receive daily low-dose aspirin during the study ( 19 patients ) . Two patients being treated with warfarin for other indications were excluded from the study . The primary end point for this study was the incidence of VTE in the form of either deep venous thrombosis or pulmonary embolism . Secondary end points were the time to the first VTE , time to the composite end point of death or first VTE , and incidence of bleeding complications . RESULTS After a median follow-up of 24 months , on an intent-to-treat basis , 26 posttreatment VTEs occurred after a median of 90 days , with 19 % occurring in group 1 , 15 % in group 2 , and 58 % in group 3 . Following multivariate time-to-event analysis , aspirin use continued to be associated with lower relative risk of VTE ( hazard ratio , 0.22 ; confidence interval , 0.10 - 0.47 ; P<.001 ) and of the composite end point ( hazard ratio , 0.28 ; confidence interval , 0.15 - 0.51 ; P<.001 ) . CONCLUSION Daily low-dose aspirin ( 81 mg orally ) given to patients with newly diagnosed and relapsed/refractory multiple myeloma who were receiving DVd-T reduced the incidence of VTEs without an increase in bleeding complications BACKGROUND Children with acute lymphoblastic leukemia ( ALL ) have a substantial risk for thromboembolism ( TE ) that is related to L-asparaginase-induced antithrombin ( AT ) deficiency and placement of central venous lines . Recent in vitro studies showed that the anticoagulant effects of low-molecular-weight heparin were profoundly affected by endogenous AT levels in children undergoing ALL therapy . METHODS A total of 112 consecutively recruited children with newly diagnosed ALL treated according to BFM 95/2000 protocol s were enrolled in this trial . This prospect i ve cohort study was carried out to determine the influence of combined low molecular weight heparin-prophylaxis ( enoxaparin 1 mg/kg/ per day ) and AT supplementation versus AT alone ( noncontemporaneous control group ) on the incidence of symptomatic TE during a follow-up of 240 days . RESULTS To maintain AT plasma levels above 50 % , nearly 60 % of all children needed at least one , most children two or three AT supplementations during induction therapy . 12.7 % of the children that did receive only AT-prophylaxis ( n = 71 ) ( 95 % CI = 6.0 - 22.7 ) developed objective ly confirmed symptomatic TE , as compared with no TE in children after combined prophylaxis ( n = 41 ) ( 95 % CI = 0.0 - 8.6 , P < 0.05 ) . Thromboses were located in the sinovenous system in the brain ( n = 3 ) , the lower deep veins ( n = 3 ) , the upper deep veins ( n = 2 ) and in an upper deep vein combined with pulmonary embolism ( n = 1 ) . CONCLUSION Prophylaxis with enoxaparin was safe and effective in preventing TE . Although our data are encouraging , the in vivo efficacy of combined enoxaparin and AT prophylaxis to prevent symptomatic venous TE in children with ALL should be evaluated in a prospect i ve r and omized clinical trial A consecutive , r and omly allocated , controlled clinical trial of the prophylactic effect of intermittent pneumatic compression of the calf on the incidence of postoperative deep vein thrombosis showed that in patients without malignant disease there was a highly significant reduction in the incidence of thrombosis . In patients with malignant disease the incidence of thrombosis was higher than in those without , and there was no reduction in incidence by the application of intermittent compression . In the absence of malignant disease , severity of operation and the age of the patient were the most significant aetiological factors . We found no relation between the incidence of deep venous thrombosis and obesity , length of preoperative stay , location of hospital , or duration of anaesthesia . We suggest that intermittent pneumatic compression as used in this trial is a safe , effective , and extremely practical method of preventing postoperative deep vein thrombosis in patients not suffering from malignant disease PURPOSE Venous thromboembolism ( VTE ) is common in cancer patients . Evidence has suggested that low molecular weight heparin ( LMWH ) might improve survival in patients with cancer by preventing both VTE and the progression of metastases . No trial in a single cancer type has been powered to demonstrate a clinical ly significant survival difference . The aim of this trial was to investigate this question in patients with lung cancer . PATIENTS AND METHODS We conducted a multicenter , open-label , r and omized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to st and ard treatment in patients with newly diagnosed lung cancer of any stage and histology . The primary outcome was 1-year survival . Secondary outcomes included metastasis-free survival , VTE-free survival , toxicity , and quality of life . RESULTS For this trial , 2,202 patients were r and omly assigned to the two treatment arms over 4 years . The trial did not reach its intended number of events for the primary analysis ( 2,047 deaths ) , and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee . There was no evidence of a difference in overall or metastasis-free survival between the two arms ( hazard ratio [ HR ] , 1.01 ; 95 % CI , 0.93 to 1.10 ; P = .814 ; and HR , 0.99 ; 95 % CI , 0.91 to 1.08 ; P = .864 , respectively ) . There was a reduction in the risk of VTE from 9.7 % to 5.5 % ( HR , 0.57 ; 95 % CI , 0.42 to 0.79 ; P = .001 ) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinical ly relevant nonmajor bleeding in the LMWH arm . CONCLUSION LMWH did not improve overall survival in the patients with lung cancer in this trial . A significant reduction in VTE is associated with an increase in clinical ly relevant nonmajor bleeding . Strategies to target those at greatest risk of VTE are warranted Background Venous thromboembolism ( VTE ) occurs when blood clots in the leg , pelvic or other deep vein ( deep vein thrombosis ) with or without transport of the thrombus into the pulmonary arterial circulation ( pulmonary embolus ) . VTE is common in patients with cancer and is increased by surgery , chemotherapy , radiotherapy and disease progression . Low molecular weight heparin ( LMWH ) is routinely used to treat VTE and some evidence suggests that LMWH may also have an anticancer effect , by reduction in the incidence of metastases . The FRAGMATIC trial will assess the effect of adding dalteparin ( FRAGMIN ) , a type of LMWH , to st and ard treatment for patients with lung cancer . Methods / Design The study design is a r and omised multicentre phase III trial comparing st and ard treatment and st and ard treatment plus daily LMWH for 24 weeks in patients with lung cancer . Patients eligible for this study must have histopathological or cytological diagnosis of primary bronchial carcinoma ( small cell or non-small cell ) within 6 weeks of r and omisation , be 18 or older , and must be willing and able to self-administer 5000 IU dalteparin by daily subcutaneous injection or have it administered to themselves or by a carer for 24 weeks . A total of 2200 patients will be recruited from all over the UK over a 3 year period and followed up for a minimum of 1 year after r and omisation . Patients will be r and omised to one of the two treatment groups in a 1:1 ratio , st and ard treatment or st and ard treatment plus dalteparin . The primary outcome measure of the trial is overall survival . The secondary outcome measures include venous thrombotic event ( VTE ) free survival , serious adverse events ( SAEs ) , metastasis-free survival , toxicity , quality of life ( QoL ) , levels of breathlessness , anxiety and depression , cost effectiveness and cost utility . Trial registration Current Controlled Trials IS RCT Elevated levels of circulating tissue factor‐bearing microparticles ( TFMP ) have been associated with an increased risk of developing venous thromboembolism ( VTE ) in cancer patients . We performed a r and omized phase II study to evaluate the cumulative incidence of VTE in advanced cancer patients with lower levels of TFMP not receiving thromboprophylaxis and those with higher levels of circulating TFMP r and omized to enoxaparin or observation . The cumulative incidence of VTE at 2 months in the higher TFMP group r and omized to enoxaparin ( N = 23 ) was 5·6 % while the higher TFMP group observation arm ( N = 11 ) was 27·3 % ( Gray test P = 0·06 ) . The cumulative incidence of VTE in the low TFMP was 7·2 % ( N = 32 ) . No major haemorrhages were observed in the enoxaparin arm . The median survival for patients with higher levels of TFMP followed by observation was 11·8 months compared with 17·8 months on enoxaparin ( P = 0·58 ) . In a prospect i ve r and omized trial , increased numbers of circulating TFMP detected by impedance flow cytometry identified cancer patients with a high incidence of VTE . Enoxaparin demonstrated a clear trend towards reducing the rate of VTE in patients with elevated levels of TFMP , with an overall rate of VTE similar in magnitude to the lower TFMP group A small proportion of patients with deep vein thrombosis develop recurrent venous thromboembolic complications or bleeding during anticoagulant treatment . These complications may occur more frequently if these patients have concomitant cancer . This prospect i ve follow-up study sought to determine whether in thrombosis patients those with cancer have a higher risk for recurrent venous thromboembolism or bleeding during anticoagulant treatment than those without cancer . Of the 842 included patients , 181 had known cancer at entry . The 12-month cumulative incidence of recurrent thromboembolism in cancer patients was 20.7 % ( 95 % CI , 15.6%-25.8 % ) versus 6.8 % ( 95 % CI , 3.9%- 9.7 % ) in patients without cancer , for a hazard ratio of 3.2 ( 95 % CI , 1.9 - 5.4 ) The 12-month cumulative incidence of major bleeding was 12.4 % ( 95 % CI , 6.5%-18.2 % ) in patients with cancer and 4.9 % ( 95 % CI , 2.5%-7.4 % ) in patients without cancer , for a hazard ratio of 2.2 ( 95 % CI , 1.2 - 4.1 ) . Recurrence and bleeding were both related to cancer severity and occurred predominantly during the first month of anticoagulant therapy but could not be explained by sub- or overanticoagulation . Cancer patients with venous thrombosis are more likely to develop recurrent thromboembolic complications and major bleeding during anticoagulant treatment than those without malignancy . These risks correlate with the extent of cancer . Possibilities for improvement using the current paradigms of anticoagulation seem limited and new treatment strategies should be developed Risk of venous thromboembolism ( VTE ) is elevated in cancer , but individual risk factors can not identify a sufficiently high-risk group of out patients for thromboprophylaxis . We developed a simple model for predicting chemotherapy-associated VTE using baseline clinical and laboratory variables . The association of VTE with multiple variables was characterized in a derivation cohort of 2701 cancer out patients from a prospect i ve observational study . A risk model was derived and vali date d in an independent cohort of 1365 patients from the same study . Five predictive variables were identified in a multivariate model : site of cancer ( 2 points for very high-risk site , 1 point for high-risk site ) , platelet count of 350 x 10(9)/L or more , hemoglobin less than 100 g/L ( 10 g/dL ) and /or use of erythropoiesis-stimulating agents , leukocyte count more than 11 x 10(9)/L , and body mass index of 35 kg/m(2 ) or more ( 1 point each ) . Rates of VTE in the derivation and validation cohorts , respectively , were 0.8 % and 0.3 % in low-risk ( score = 0 ) , 1.8 % and 2 % in intermediate-risk ( score = 1 - 2 ) , and 7.1 % and 6.7 % in high-risk ( score > /= 3 ) category over a median of 2.5 months ( C-statistic = 0.7 for both cohorts ) . This model can identify patients with a nearly 7 % short-term risk of symptomatic VTE and may be used to select cancer out patients for studies of thromboprophylaxis INTRODUCTION The haemostatic system plays an important role in the process of cancer development and spread . Anticoagulants , mainly low molecular weight heparins , could prolong survival in cancer patients , particularly in patients with lung cancer , beyond prevention of thromboembolic events . METHODS In a multicenter , investigator-initiated , open-label , r and omized , sequential study , 38 patients with newly-diagnosed , limited-stage small-cell lung cancer were r and omized to receive st and ard chemoradiotherapy or the same therapy plus 3,500 IU daily of bemiparin for a maximum of 26 weeks . The primary outcome was progression-free survival . RESULTS The study was terminated early due to slow recruitment . Median progression-free survival was 272 days with chemoradiotherapy alone and 410 days in the bemiparin group ; hazard ratio , 2.58 ( 95 % confidence interval [ CI ] , 1.15 - 5.80 ) ; p=0.022 . Median overall survival was 345 days with chemoradiotherapy alone and 1133 days in the bemiparin group ; hazard ratio , 2.96 ( 95 % CI , 1.22 - 7.21 ) ; p=0.017 . The rate of tumor response was similar in both study arms . There was no significant between-group difference in the rates of major bleeding . Toxicity related with the experimental treatment was minimal . CONCLUSION The addition of bemiparin to first line therapy with chemoradiotherapy significantly increases survival in patients with newly-diagnosed , limited-stage small-cell lung cancer . ( Funded by the Instituto Científico y Tecnológico , University of Navarra . Clinical Trials.gov identifier : NCT00324558 ) PURPOSE In patients with myeloma , thalidomide significantly improves outcomes but increases the risk of thromboembolic events . In this r and omized , open-label , multicenter trial , we compared aspirin ( ASA ) or fixed low-dose warfarin ( WAR ) versus low molecular weight heparin ( LMWH ) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens . PATIENTS AND METHODS A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were r and omly assigned to receive ASA ( 100 mg/d ) , WAR ( 1.25 mg/d ) , or LMWH ( enoxaparin 40 mg/d ) . A composite primary end point included serious thromboembolic events , acute cardiovascular events , or sudden deaths during the first 6 months of treatment . RESULTS Of 659 analyzed patients , 43 ( 6.5 % ) had serious thromboembolic events , acute cardiovascular events , or sudden death during the first 6 months ( 6.4 % in the ASA group , 8.2 % in the WAR group , and 5.0 % in the LMWH group ) . Compared with LMWH , the absolute differences were + 1.3 % ( 95 % CI , -3.0 % to 5.7 % ; P = .544 ) in the ASA group and + 3.2 % ( 95 % CI , -1.5 % to 7.8 % ; P = .183 ) in the WAR group . The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib . Three major ( 0.5 % ) and 10 minor ( 1.5 % ) bleeding episodes were recorded . CONCLUSION In patients with myeloma treated with thalidomide-based regimens , ASA and WAR showed similar efficacy in reducing serious thromboembolic events , acute cardiovascular events , and sudden deaths compared with LMWH , except in elderly patients where WAR showed less efficacy than LMWH In a controlled , r and omized study , survival of patients with small cell carcinoma of the lung ( SCCL ) was prolonged on addition of warfarin sodium to combination chemotherapy plus radiation therapy . Median survival for 25 control patients was 24 weeks and for 25 warfarin-treated patients was 50 weeks . This difference could not be accounted for by differences between groups in performance status , extent of disease , age , or sex . The survival advantage associated with warfarin administration was observed both for patients with extensive disease and for those who failed to achieve complete or partial remission . The warfarin-treated group also demonstrated a significantly increased time to first evidence of disease progression . These results suggest that warfarin may be useful in the treatment of SCCL and also support the hypothesis that the blood coagulation mechanism may be involved in the growth and spread of cancer in man Goals The objective of this study was to determine utility of prophylactic anti-coagulation in cancer patients hospitalised for palliative care in a specialised centre . Material s and methods Prospect i ve 1:1 open r and omised study was design ed . Twenty patients aged 55 to 88 years with advanced cancer and an estimated life expectancy of less than 6 months were assigned to either receive treatment with 2,850/3,800 U ( < 70/>70 kg ) of daily subcutaneous nadroparin or no treatment . Suspicion of venous thrombo-embolism ( deep vein thrombosis and pulmonary embolism ) was confirmed by echo-Doppler examination of the lower limbs and /or by spiral computed tomography scan of the lungs . Bleeding episodes were recorded . Platelet count was measured on days 7 and 14 . Survival time from study entry was determined . Main results One venous thrombo-embolism and one major bleeding occurred in the group receiving nadroparin , whereas two minor bleedings occurred in the control group . At 3 months , nine of ten participants had died in the control group vs five of ten in the group receiving nadroparin ( P = 0.141 ) . Five participants could be discharged home ( P = 0.141 ) . Conclusions Decision to administer prophylactic nadroparin in hospitalised cancer patients under palliative care remains a challenge . Better mobility score at admission and the likelihood to be discharged home may be useful for practical purpose s. The observation of a potential influence of prophylactic nadroparin on survival deserves further studies BACKGROUND Annualised figures show an up to 7-fold higher incidence of vascular thromboembolism ( VTE ) in patients with advanced pancreatic cancer ( APC ) compared to other common malignancies . Concurrent VTE has been shown to confer a worse overall prognosis in APC . METHODS One hundred and twenty three APC patients were r and omised to receive either gemcitabine 1000 mg/m(2 ) or the same with weight-adjusted dalteparin ( WAD ) for 12 weeks . Primary end-point was the reduction of all-type VTE during the study period . NCT00462852 , IS RCT N : 76464767 . FINDINGS The incidence of all-type VTE during the WAD treatment period ( < 100 days from r and omisation ) was reduced from 23 % to 3.4 % ( p = 0.002 ) , with a risk ratio (RR)of 0.145 , 95 % confidence interval ( CI ) ( 0.035 - 0.612 ) and an 85 % risk reduction . All-type VTE throughout the whole follow-up period was reduced from 28 % to 12 % ( p = 0.039 ) , RR = 0.419 , 95 % CI ( 0.187 - 0.935 ) and a 58 % risk reduction . Lethal VTE < 100 days was seen only in the control arm , 8.3 % compared to 0 % ( p = 0.057 ) , RR = 0.092 , 95 % CI ( 0.005 - 1.635 ) . INTERPRETATION Weight adjusted dalteparin used as primary prophylaxis for 12 weeks is safe and produces a highly significant reduction of all-type VTE during the prophylaxis period . The benefit is maintained after dalteparin withdrawal although decreases with time OBJECTIVE To prospect ively assess whether low-molecular-weight heparin ( LMWH ) provides a survival benefit in patients with advanced cancer . PATIENTS AND METHODS Between December 1998 and June 2001 , we performed a r and omized controlled study of patients with advanced cancer . Initially , the study was double blinded and placebo controlled , with the patients receiving daily injections of 5000 U of LMWH or saline . However , because of low accrual midway through the study , the placebo injection arm was eliminated , and the study became open labeled , with patients receiving either LMWH injections plus st and ard clinical care or st and ard clinical care alone . The primary study end point was overall survival . RESULTS Of 141 patients r and omized to this clinical trial , 3 dropped out , leaving 138 patients . The median survival time was 10.5 months ( 95 % confidence interval , 7.6 - 12.2 months ) for the combined st and ard care and placebo groups . The median survival time for the combined LMWH arms was 7.3 months ( 95 % confidence interval , 4.8 - 12.2 months ) . These median survival times were not significantly different ( log-rank P = .46 ) . The median survival times for the blinded and unblinded LMWH groups were 6.2 months and 9.0 months , respectively . The median survival times were 10.3 months for the blinded placebo arm and 10.5 months for the st and ard care arm . The rate of severe or life-threatening venous thromboembolism was 6 % in the LMWH arms and 7 % in the control arms . The rate of severe or life-threatening bleeding was 3 % in the LMWH arms and 7 % in the control arms Background . A positive influence of anticoagulant treatment in small cell lung cancer ( SCLC ) has been sug gested by experimental and clinical data BACKGROUND AND OBJECTIVES Venous thromboembolism ( VTE ) occurs in 20 - 30 % of patients with malignant glioma per year of survival . We tested the efficacy of long-term dalteparin low-molecular-weight heparin ( LMWH ) for prevention of VTE in these patients . PATIENTS / METHODS Adults with newly diagnosed malignant glioma were r and omized to receive dalteparin 5000 anti-Xa units or placebo , both subcutaneously once daily for 6 months starting within 4 weeks of surgery . Treatment continued for up to 12 months . The primary outcome was the cumulative risk of VTE over 6 months . The target sample size was 512 patients . Events were adjudicated by a committee unaware of treatment . RESULTS The trial began in 2002 and closed in May 2006 because of expiration of study medication . Ninety-nine patients were r and omized to LMWH and 87 to placebo . Twenty-two patients developed VTE in the first 6 months : nine in the LMWH group and 13 in the placebo group [ hazard ratio ( HR ) = 0.51 , 95 % confidence interval ( CI ) : 0.19 - 1.4 , P = 0.29 ] . At 6 months , there were three major bleeds on LMWH and none on placebo ; at 12 months , 5 ( 5.1 % ) major bleeds on LMWH and 1 ( 1.2 % ) on placebo occurred ( HR = 4.2 , 95 % CI : 0.48 - 36 , P = 0.22 ) . All major bleeds were intracranial and occurred while on study medication . The 12-month mortality rates were 47.8 % for LMWH and 45.4 % for placebo ( HR = 1.2 , 95 % CI : 0.73 - 2.0 , P = 0.48 ) . CONCLUSIONS Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group . The role of long-term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain The aim of the present study was to assess the role of tissue factor and serum-induced cell invasion in patients with advanced pancreatic cancer ( APC ) . A cohort of 39 patients with APC , without thrombosis , receiving chemotherapy , were entered in a r and omized controlled trial ( IS RCT N = 76464767 ) of thromboprevention with weight-adjusted dalteparin ( WAD ) . A total of 19 patients received WAD , the remaining 20 acting as a control group . Serum from baseline and week 8 was analysed for circulating-tissue factor antigen using ELISA . Circulating-tissue factor antigen rose from 324 pg/ml , [ interquartile range ( IQR ) 282–347 pg/ml ] to 356 pg/ml , ( IQR 319–431 pg/ml ) in controls ( C ) , and decreased in the dalteparin-treated group ( D ) from 336 pg/ml ( IQR 281–346 pg/ml ) to 303 pg/ml ( IQR 274–339 pg/ml ) . The difference in median percentage change between D and C was statistically significant [ −4.0 ( D ) vs. 4.7 ( C ) ; P = 0.005 , n = 39 ] . Serum-induced cellular invasion of MIA-Paca-2 cells in response to patient serum was studied using a Boyden chamber assay in 30 patients ( 14 WAD and 16 C ) . The median percentage change between C and D was significant [ + 54.9 ( C ) vs. −21.9 ( D ) P = 0.025 , n = 30 ] . There was a weak correlation between BB-tissue factor reduction and cellular invasion reduction ( Spearman ) [ 0.384 ( P = 0.037 , n = 30 ) ] . APC patients treated with WAD have lower tissue factor antigen levels and attenuated induction of cellular invasion in their blood . These assays may provide useful markers to guide appropriate dalteparin ( and other low-molecular weight heparin ) dosing schedules to optimize anticancer effects of dalteparin in APC The Cancer and Leukemia Group B ( CALGB ) conducted a prospect i ve r and omized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer ( SCCL ) . After stratification for sex and performance status , patients were r and omly assigned to receive chemotherapy with methotrexate , doxorubicin ( Adriamycin ; Adria Laboratories , Columbus , OH ) , cyclophosphamide , and lomustine ( CCNU ) ( MACC ) , or MACC plus warfarin ( MACC + W ) , or mitomycin , etoposide , cisplatin , and hexamethylmelamine alternating with MACC ( MEPH/MACC ) . Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values . A total of 328 patients were enrolled , and 294 were evaluable . There was a statistically significant advantage in objective response rates ( complete [ CR ] and partial responses [ PR ] , respectively ) for MACC + W ( 17 % and 50 % ) as compared with MACC alone ( 8 % and 43 % ) or MEPH/MACC ( 10 % and 38 % ) ( P = .012 ) . Both failure-free survival ( P = .054 Wilcoxon test ) and overall survival ( P = .098 Wilcoxon test ) were higher on MACC + W ( median , 6.6 months and 9.3 months , respectively ) , as compared with MACC ( 5.0 months and 7.9 months ) and MEPH/MACC ( 5.0 months and 7.9 months ) . Toxicity was comparable among the three arms , except for increased hemorrhagic events on MACC + W , which were life-threatening in four patients ( 4 % ) , and lethal in two others ( 2 % ) . These data support the role of warfarin in the treatment of SCCL , but do not establish its mechanism of action . Warfarin deserves further studies in SCCL , particularly in patients with limited disease VA Cooperative Study # 75 was established to test in a controlled , r and omized trial the hypothesis that warfarin anticoagulation would favorably affect the course of certain types of malignancy . No differences in survival were observed between warfarin‐treated and control groups for advanced non‐small cell lung , colorectal , head and neck and prostate cancers . However , warfarin therapy was associated with a significant prolongation in the time to first evidence of disease progression ( P = 0.016 ) and a significant improvement in survival ( P = 0.018 ) for patients with small cell carcinoma of the lung , including the subgroup of patients with disseminated disease at the time of r and omization ( P = 0.013 ) . A trend toward improved survival with warfarin treatment was observed for the few patients admitted to this study with non‐small cell lung cancer who had minimal disease at r and omization . These results suggest that warfarin , as a single anticoagulant agent , may favorably modify the course of some , but not all , types of human malignancy , among which is small cell carcinoma of the lung . Further trials of warfarin may be indicated in patients with limited disease who have cell types that failed to respond when advanced disease was present BACKGROUND Small cell lung cancer ( SCLC ) is a chemotherapy-responsive tumor type but most patients ultimately experience disease progression . SCLC is associated with alterations in the coagulation system . The present r and omized clinical trial ( RCT ) was design ed to determine whether addition of low-molecular-weight heparin ( LMWH ) to combination chemotherapy ( CT ) would improve SCLC outcome compared with CT alone . METHODS Combination CT consisted of cyclophosphamide , epirubicine and vincristine ( CEV ) given at 3-weekly intervals for six cycles . Eighty-four patients were r and omized to receive either CT alone ( n = 42 ) or CT plus LMWH ( n = 42 ) . LMWH consisted of dalteparin given at a dose of 5000 U once daily during the 18 weeks of CT . Results Overall tumor response rates were 42.5 % with CT alone and 69.2 % with CT plus LMWH ( P = 0.07 ) . Median progression-free survival was 6.0 months with CT alone and 10.0 months with CT plus LMWH ( P = 0.01 ) . Median overall survival was 8.0 months with CT alone and 13.0 months with CT plus LMWH ( P = 0.01 ) . Similar improvement in survival with LMWH treatment occurred in patients with both limited and extensive disease stages . The risk of death in the CT + LMWH group relative to that in the CT group was 0.56 ( 95 % confidence interval 0.30 , 0.86 ) ( P = 0.012 by log rank test ) . Toxicity from the experimental treatment was minimal and there were no treatment-related deaths . CONCLUSIONS These results support the concept that anticoagulants , and particularly LMWH , may improve clinical outcomes in SCLC . Further clinical trials of this relatively non-toxic treatment approach are indicated PURPOSE Studies in cancer patients with venous thromboembolism suggested that low molecular weight heparin may prolong survival . In a double-blind study , we evaluated the effect of low molecular weight heparin on survival in patients with advanced malignancy without venous thromboembolism . METHODS Patients with metastasized or locally advanced solid tumors were r and omly assigned to receive a 6-week course of subcutaneous nadroparin or placebo . The primary efficacy analysis was based on time from r and om assignment to death . The primary safety outcome was major bleeding . RESULTS In total , 148 patients were allocated to nadroparin and 154 patients were allocated to placebo . Mean follow-up was 1 year . In the intention-to-treat analysis the overall hazard ratio of mortality was 0.75 ( 95 % CI , 0.59 to 0.96 ) with a median survival of 8.0 months in the nadroparin recipients versus 6.6 months in the placebo group . After adjustment for potential confounders , the treatment effect remained statistically significant . Major bleeding occurred in five ( 3 % ) of nadroparin-treated patients and in one ( 1 % ) of the placebo recipients ( P = .12 ) . In the a priori specified subgroup of patients with a life expectancy of 6 months or more at enrollment , the hazard ratio was 0.64 ( 95 % CI , 0.45 to 0.90 ) with a median survival of 15.4 and 9.4 months , respectively . For patients with a shorter life expectancy , the hazard ratio was 0.88 ( 95 % CI , 0.62 to 1.25 ) . CONCLUSION A brief course of subcutaneous low molecular weight heparin favorably influences the survival in patients with advanced malignancy and deserves additional clinical evaluation PURPOSE In experimental systems , interference with coagulation can affect tumor biology . Furthermore , it has been suggested that low molecular weight heparin therapy may prolong survival in patients with cancer . The primary aim of this study was to assess survival at 1 year of patients with advanced cancer . PATIENTS AND METHODS Patients with advanced malignancy ( N = 385 ) were r and omly assigned to receive either a once-daily subcutaneous injection of dalteparin ( 5,000 IU ) , a low molecular weight heparin , or placebo for 1 year . RESULTS The Kaplan-Meier survival estimates at 1 , 2 , and 3 years after r and omization for patients receiving dalteparin were 46 % , 27 % , and 21 % , respectively , compared with 41 % , 18 % , and 12 % , respectively , for patients receiving placebo ( P = .19 ) . In an analysis not specified a priori , survival was examined in a subgroup of patients ( dalteparin , n = 55 ; and placebo , n = 47 ) who had a better prognosis and who were alive 17 months after r and omization . In these patients , Kaplan-Meier survival estimates at 2 and 3 years from r and omization were significantly improved for patients receiving dalteparin versus placebo ( 78 % v 55 % and 60 % v 36 % , respectively , P = .03 ) . The rates of symptomatic venous thromboembolism were 2.4 % and 3.3 % for dalteparin and placebo , respectively , with bleeding rates of 4.7 % and 2.7 % , respectively . CONCLUSION Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy . However , the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease . Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications . We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis . Women receiving chemotherapy for metastatic breast cancer were r and omly assigned either very-low-dose warfarin ( 152 patients ) or placebo ( 159 ) . The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio ( INR ) of 1.3 to 1.9 . Study treatment continued until 1 week after the end of chemotherapy . The average daily dose from initiation of titration was 2.6 ( SD 1.2 ) mg for the warfarin group and the mean INR was 1.52 . The mean time at risk of thrombosis was 199 ( 126 ) days for warfarin-treated patients and 188 ( 137 ) days for placebo recipients ( p = 0.45 ) . There were 7 thromboembolic events ( 6 deep-vein thrombosis , 1 pulmonary embolism ) in the placebo group and 1 ( pulmonary embolism ) in the warfarin group , a relative risk reduction of about 85 % ( p = 0.031 ) . Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient . There was no detectable difference in survival between the treatment groups . Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy PURPOSE Advanced pancreatic cancer ( APC ) , in addition to its high mortality , accounts for the highest rates of venous thromboembolic events ( VTEs ) . Enoxaparin , a low-molecular weight heparin , is effective in prevention and treatment of VTEs . Some small studies have indicated that this benefit might extend to patients with cancer . PATIENTS AND METHODS Patients with histologically proven APC were r and omly assigned to ambulant first-line chemotherapy and prophylactic use of enoxaparin or chemotherapy alone to investigate the probable reduction in symptomatic VTEs and the impact on survival . RESULTS A total of 312 patients were recruited as one of the protocol end points was reached . Within the first 3 months , the numbers of symptomatic VTEs were as follows : 15 of 152 patients in the observation group and two of 160 patients in the enoxaparin group ( hazard ratio [ HR ] , 0.12 ; 95 % CI , 0.03 to 0.52 ; χ(2 ) P = .001 ) . The numbers of major bleeding events were as follows : five of 152 patients in the observation arm and seven of 160 patients in the enoxaparin arm ( HR , 1.4 ; 95 % CI , 0.35 to 3.72 ; χ(2 ) P = 1.0 ) . Overall cumulative incidence rates of symptomatic VTEs were 15.1 % ( observation ) and 6.4 % ( enoxaparin ; HR , 0.40 ; 95 % CI , 0.19 to 0.83 ; P = .01 ) . Progression-free ( HR , 1.06 ; 95 % CI , 0.84 to 1.32 ; P = .64 ) and overall survival ( HR , 1.01 ; 95 % CI , 0.87 to 1.38 ; P = .44 ) did not differ between groups . CONCLUSION This study demonstrates the high efficacy and feasibility of primary pharmacologic prevention of symptomatic VTEs in out patients with APC . Treatment efficacy was not affected by simultaneous treatment with enoxaparin in this trial setting PURPOSE Earlier studies showed that low molecular weight heparin significantly prolongs the survival of a wide variety of patients with cancer without venous thromboembolism . This study was design ed to confirm these findings in a more homogeneous group of patients with cancer . PATIENTS AND METHODS In this multicenter , r and omized , open-label study , patients with non-small-cell lung cancer ( stage IIIB ) , hormone-refractory prostate cancer , or locally advanced pancreatic cancer were r and omly assigned to nadroparin or to no nadroparin in addition to their st and ard anticancer treatment . In the nadroparin arm , subcutaneous nadroparin was administered for 6 weeks ( 2 weeks at therapeutic dose , and 4 weeks at half therapeutic dose ) . The patients were eligible to receive additional cycles of nadroparin ( 2 weeks at therapeutic dose , and 4 weeks of washout period ) . Outcomes were overall survival , time to progression , and major bleeding . All study outcomes were adjudicated by an independent , blinded committee . RESULTS A total of 244 patients were allocated to nadroparin , and 259 were allocated to the control group . A median survival of 13.1 months was observed in the nadroparin recipients compared with 11.9 months in the no-treatment arm ( hazard ratio , 0.94 ; 95 % CI , 0.75 to 1.18 , adjusted for cancer type ) . No difference in time to progression was observed . The number of major bleedings was comparable at 4.1 % in the nadroparin set and 3.5 % in the control set . CONCLUSION This study did not show a survival benefit of nadroparin in patients with advanced prostate , lung , or pancreatic cancer . Given the ongoing studies in this area and the previous data , the role of low molecular weight heparins in cancer survival remains undefined An association has been reported between thrombotic events and the use of L-asparaginase ( ASP ) in children with acute lymphoblastic leukaemia ( ALL ) . The mechanism for thrombosis is likely related to an acquired antithrombin deficiency . Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis , the PARKAA ( Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase ) study was performed . The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1 ) incidence of thrombosis 2 ) incidence of bleeding and 3 ) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis . The study was not powered to answer the question of efficacy and safety , but rather to detect a trend . PARKAA was an open , r and omised , controlled study in children with ALL being treated with ASP . Children were r and omised to receive antithrombin infusions or no antithrombin treatment . All thrombotic events were confirmed using bilateral venography , ultrasound , echocardiography and MRI . The incidence of thrombosis in patients treated with antithrombin was 28 % ( 95 % CI 10 - 46 % ) , compared to 37 % ( 95 % CI 24 - 49 % ) in the non treated arm . Two minor bleeds occurred in patients in the treated arm , but were not considered to be related to antithrombin . No significant differences were seen in plasma markers by the treatment group . In conclusion , treatment with antithrombin concentrate shows a trend to efficacy and safety . In contrast , there was no difference in surrogate markers for thrombosis . Carefully design ed clinical trials are needed to test the efficacy and safety of antithrombin in this population BACKGROUND Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism . Limited data support the clinical benefit of antithrombotic prophylaxis . METHODS In this double-blind , multicenter trial , we evaluated the efficacy and safety of the ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer . Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were r and omly assigned to receive subcutaneous semuloparin , 20 mg once daily , or placebo until there was a change of chemotherapy regimen . The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis , any nonfatal pulmonary embolism , and death related to venous thromboembolism . Clinical ly relevant bleeding ( major and nonmajor ) was the main safety outcome . RESULTS The median treatment duration was 3.5 months . Venous thromboembolism occurred in 20 of 1608 patients ( 1.2 % ) receiving semuloparin , as compared with 55 of 1604 ( 3.4 % ) receiving placebo ( hazard ratio , 0.36 ; 95 % confidence interval [ CI ] , 0.21 to 0.60 ; P<0.001 ) , with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism . The incidence of clinical ly relevant bleeding was 2.8 % and 2.0 % in the semuloparin and placebo groups , respectively ( hazard ratio , 1.40 ; 95 % CI , 0.89 to 2.21 ) . Major bleeding occurred in 19 of 1589 patients ( 1.2 % ) receiving semuloparin and 18 of 1583 ( 1.1 % ) receiving placebo ( hazard ratio , 1.05 ; 95 % CI , 0.55 to 1.99 ) . Incidences of all other adverse events were similar in the two study groups . CONCLUSIONS Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer , with no apparent increase in major bleeding . ( Funded by Sanofi ; Clinical Trials.gov number , NCT00694382 . ) OBJECTIVE Low molecular weight heparin reduces the risk of venous thromboembolism ( VTE ) and may have antineoplastic effects by interfering with angiogenesis and with tumor growth and metastasis . A multicentre phase II r and omized trial was done to evaluate the antineoplastic potential of dalteparin in ovarian cancer ( OC ) . MATERIAL S AND METHODS Women with newly-diagnosed epithelial OC were r and omized to receive st and ard chemotherapy ( CT ) and one of 3 doses of dalteparin ( 50 IU/kg , 100 IU/kg , or 150 IU/kg ) subcutaneously once daily during the first 3 of 6 cycles of 3-weekly CT . Blood was drawn on day 1 of each cycle for CA125 and , in a sub study of r and omized patients , for markers of coagulation activation and angiogenesis . The primary outcome was tumor response defined by ≥ 50 % reduction in serum CA125 from baseline sustained for at least 28 days . Patients were followed until the end of CT . RESULTS The study was terminated early due to poor recruitment . Seventy-seven women were evaluable for the primary outcome . A 50 % drop in CA125 at the end of cycle 3 was seen in 85 % of the 50 IU/kg group , 92 % of the 100 IU/kg group , and 85 % of the 150 IU/kg group . There were no symptomatic VTE or major bleeding events while on dalteparin . Two patients experienced VTE several days after discontinuing study drug . Women on dalteparin had lower levels of D-dimer and thrombin-antithrombin , and higher levels of tissue factor pathway inhibitor , relative to baseline . CONCLUSION Dalteparin is safe and well tolerated in women receiving CT for newly-diagnosed epithelial OC . A dose-response effect was not identified . The lack of control group precluded any inference on the antineoplastic effect of dalteparin The risk of venous thromboembolism ( VTE ) is increased in cancer patients . To improve prediction of VTE in cancer patients , we performed a prospect i ve and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission . A previously developed risk scoring model for prediction of VTE that included clinical ( tumor entity and body mass index ) and laboratory ( hemoglobin level and thrombocyte and leukocyte count ) parameters was exp and ed by incorporating 2 biomarkers , soluble P-selectin , and D-Dimer . Of 819 patients 61 ( 7.4 % ) experienced VTE during a median follow-up of 656 days . The cumulative VTE probability in the original risk model after 6 months was 17.7 % in patients with the highest risk score ( ≥ 3 , n = 93 ) , 9.6 % in those with score 2 ( n = 221 ) , 3.8 % in those with score 1 ( n = 229 ) , and 1.5 % in those with score 0 ( n = 276 ) . In the exp and ed risk model , the cumulative VTE probability after 6 months in patients with the highest score ( ≥ 5 , n = 30 ) was 35.0 % and 10.3 % in those with an intermediate score ( score 3 , n = 130 ) as opposed to only 1.0 % in patients with score 0 ( n = 200 ) ; the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 ( 8.0 - 84.6 ) . Clinical and st and ard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE

Conclusion : The overall validity of clinical diagnosis of PD is not satisfying . The accuracy did not significantly improve in the last 25 years , particularly in the early stages of disease , where response to dopaminergic treatment is less defined and hallmarks of alternative diagnoses such as atypical parkinsonism may not have emerged .

Objective : To evaluate the diagnostic accuracy of clinical diagnosis of Parkinson disease ( PD ) reported in the last 25 years by a systematic review and meta- analysis .

Dementia with Lewy Bodies ( DLB ) was initially identified and confirmed primarily by pathology , but is soon to be incorporated into the Diagnostic and Statistical Manual criteria as a clinical disease entity . Despite these advances over more than 20 years , current data suggest that the sensitivity of accurate clinical diagnosis of DLB is still very low , although there is mounting evidence that supportive features may increase diagnostic accuracy . Although DLB remains easy to identify pathologically with different cellular pathologies differentiating it from other dementia syndromes , pathological identification using only Lewy body pathology has been shown to be inaccurate due to overlap with patients without dementia symptoms . A number of studies now suggest that a combination of cellular pathologies , which include α-synuclein and β-amyloid deposition as well as dopamine denervation , assist with differentiating this dementia syndrome from others . The clinical and pathological overlap with the tauopathy of Alzheimer ’s disease still remains to be clarified . To determine more robust and independent clinicopathological correlates from Alzheimer ’s disease , longitudinal prospect i ve studies , using specific clinical batteries on dementia patients reaching the proposed criteria for DLB , with post-mortem assessment of the multiple pathologies associated with dementia , are required . Identifying genetic causes for DLB is another approach to investigate the pathogenesis of DLB . However this approach has been hindered to date by difficulties with identifying DLB clinical ly . The use of novel techniques is likely to advance knowledge on the pathogenesis of DLB and assist with redefining clinical and pathologic diagnostic criteria . To achieve the goal of more accurate clinical diagnosis of DLB , breakthroughs are necessary on the pathogenesis of DLB We have review ed the clinical and pathological diagnoses of 143 cases of parkinsonism seen by neurologists associated with the movement disorders service at The National Hospital for Neurology and Neurosurgery in London who came to neuropathological examination at the United Kingdom Parkinson 's Disease Society Brain Research Centre , over a 10-year period between 1990 and the end of 1999 . Seventy-three ( 47 male , 26 female ) cases were diagnosed as having idiopathic Parkinson 's disease ( IPD ) and 70 ( 42 male , 28 female ) as having another parkinsonian syndrome . The positive predictive value of the clinical diagnosis for the whole group was 85.3 % , with 122 cases correctly clinical ly diagnosed . The positive predictive value of the clinical diagnosis of IPD was extremely high , at 98.6 % ( 72 out of 73 ) , while for the other parkinsonian syndromes it was 71.4 % ( 50 out of 70 ) . The positive predictive values of a clinical diagnosis of multiple system atrophy ( MSA ) and progressive supranuclear palsy ( PSP ) were 85.7 ( 30 out of 35 ) and 80 % ( 16 out of 20 ) , respectively . The sensitivity for IPD was 91.1 % , due to seven false-negative cases , with 72 of the 79 pathologically established cases being diagnosed in life . For MSA , the sensitivity was 88.2 % ( 30 out of 34 ) , and for PSP it was 84.2 % ( 16 out of 19 ) . The diagnostic accuracy for IPD , MSA and PSP was higher than most previous prospect i ve clinicopathological series and studies using the retrospective application of clinical diagnostic criteria . The seven false-negative cases of IPD suggest a broader clinical picture of disease than previously thought acceptable . This study implies that neurologists with particular expertise in the field of movement disorders may be using a method of pattern recognition for diagnosis which goes beyond that inherent in any formal set of diagnostic criteria Background : The long-term effectiveness of three different initial drug regimes in patients with early , mild PD was evaluated by the PD Research Group of the United Kingdom ( PDRGUK ) . In 1995 , the selegiline arm of the trial was terminated following an interim analysis . Method : This was an open , r and omized trial . Between 1985 and 1990 , 782 patients with de-novo PD were recruited and r and omized to one of three treatment arms : levodopa plus dopa decarboxylase inhibitor ; levodopa plus decarboxylase inhibitor and selegiline ; or bromocriptine . The main endpoints were mortality , disability , and adverse events . Intention-to-treat analysis was used . Results : There was no significant difference in mortality between the bromocriptine and the levodopa arms ( hazard ratio 1.15 [ 95 % CI 0.90 , 1.47 ] ) . Patients initially r and omized to bromocriptine had slightly worse disability scores throughout follow-up . This difference was significant during the first years . Patients in the bromocriptine arm returned to pretreatment disability levels one year earlier than those in the levodopa arm . Patients r and omized to bromocriptine had a significantly lower incidence of dyskinesias than those r and omized to levodopa ( rate ratio 0.73 [ 95 % CI 0.57 , 0.93 ] ) . However , this difference was not significant when only moderate to severe dyskinesias were considered . Patients in the bromocriptine arm had slightly lower rates of dystonias and on-off fluctuations , but moderate and severe forms were equally frequent in both arms . Conclusion : Starting treatment with the dopamine agonist bromocriptine does not reduce mortality in PD . A slightly lower incidence of motor complications is achieved at the expense of significantly worse disability scores throughout the first years of therapy Few detailed clinico-pathological correlations of Parkinson 's disease have been published . The pathological findings in 100 patients diagnosed prospect ively by a group of consultant neurologists as having idiopathic Parkinson 's disease are reported . Seventy six had nigral Lewy bodies , and in all of these Lewy bodies were also found in the cerebral cortex . In 24 cases without Lewy bodies , diagnoses included progressive supranuclear palsy , multiple system atrophy , Alzheimer 's disease , Alzheimer-type pathology , and basal ganglia vascular disease . The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82 % . These observations call into question current concepts of Parkinson 's disease as a single distinct morbid entity Overdiagnosis of Parkinson 's disease ( PD ) is suggested by specialist review of community diagnosis , and in postmortem studies . In specialist centers 4 to 15 % of patients entered into clinical trials as early PD do not have functional imaging support for a PD diagnosis . In a European multicenter , prospect i ve , longitudinal study , we compared clinical diagnosis with functional SPECT imaging using [123I]FP-CIT ( DaTSCAN , GE Healthcare ) . Repeat observations were performed over 3 years in patients with tremor and /or parkinsonism in whom there was initial diagnostic uncertainty between degenerative parkinsonism and nondegenerative tremor disorders . Video-recording of clinical features was scored independently of functional imaging results by two blinded clinicians at 36 months (= gold st and ard clinical diagnosis ) . Three readers , unaware of the clinical diagnosis , classified the images as normal or abnormal by visual inspection . The main endpoint was the sensitivity and specificity of SPECT imaging at baseline compared with the gold st and ard . In 99 patients completing the three serial assessment s , on-site clinical diagnosis overdiagnosed degenerative parkinsonism at baseline in diagnostically uncertain cases compared with the gold st and ard clinical diagnosis ( at 36 months ) , the latter giving a sensitivity of 93 % and specificity of 46 % . The corresponding baseline [123I]FP-CIT SPECT results showed a mean sensitivity of 78 % and a specificity of 97 % . Inter-reader agreement for rating scans as normal or abnormal was high ( Cohen 's kappa = 0.94 - 0.97 ) Background This study examines the clinical accuracy of movement disorder specialists in distinguishing tremor dominant Parkinson 's disease ( TDPD ) from other tremulous movement disorders by the use of st and ardised patient videos . Patients and methods Two movement disorder specialists were asked to distinguish TDPD from patients with atypical tremor and dystonic tremor , who had no evidence of presynaptic dopaminergic deficit ( subjects without evidence of dopaminergic deficit ( SWEDDs ) ) according to 123I-N-ω-fluoro-propyl- 2β-carbomethoxy-3β-(4-iodophenyl ) nortropane ( [ 123I ] FP-CIT ) single photon emission computed tomography ( SPECT ) , by ‘ blinded ’ video analysis in 38 patients . A diagnosis of parkinsonism was made if the step 1 criteria of the Queen Square Brain Bank criteria for Parkinson 's disease were fulfilled . The review er diagnosis was compared with the working clinical diagnosis drawn from the medical history , SPECT scan result , long term follow-up and in some cases the known response to dopaminergic medications . This comparison allowed a calculation for false positive and false negative rate of diagnosis of PD . Results High false positive ( 17.4 - 26.1 % ) and negative ( 6.7 - 20 % ) rates were found for the diagnosis of PD . The diagnostic distinction of TDPD from dystonic tremor was reduced by the presence of dystonic features in treated and untreated PD patients . Conclusion Clinical distinction of TDPD from atypical tremor , monosymptomatic rest tremor and dystonic tremor can be difficult due to the presence of parkinsonian features in tremulous SWEDD patients . The diagnosis of bradykinesia was particularly challenging . This study highlights the difficulty of differentiation of some cases of SWEDD from PD BACKGROUND Parkinson 's disease is a common disorder among older people . Accurate epidemiological information is essential to identify possible aetiological factors , plan health services and set priorities for medical research . OBJECTIVE to determine the incidence of idiopathic Parkinson 's disease in a defined geographical area in the North-East of Engl and . METHODS using a prospect i ve , longitudinal design , we sought to identify every new case of Parkinson 's disease arising in the Newcastle and Gateshead area in the North-East of Engl and . The base population comprised 488 576 individuals and multiple sources of case ascertainment were employed . All the patients with newly diagnosed idiopathic Parkinson 's disease or parkinsonism between 1 June 2009 and 31 May 2011 were invited to participate . Patients were examined by a specialist and followed longitudinally to permit diagnostic review . RESULTS we identified 257 potential cases , of whom 181 had suspected idiopathic Parkinson 's disease . After a follow-up period of 18 months , 155 patients retained a clinical diagnosis of probable Parkinson 's disease . The mean age at diagnosis was 72.4 ± 10 years . The crude incidence of PD in Newcastle and Gateshead was 15.9 per 100 000 persons per year ( 95 % CI : 13.4 - 18.4 ) . Age-st and ardised to the European population the incidence of Parkinson 's disease was 12.0 per 100 000 ( 95 % CI : 10.1 - 14.0 ) . We found a higher crude incidence among men 17.7 per 100 000 ( 95 % CI : 14.0 - 21.4 ) than women 14.0 per 100 000 ( 95 % CI : 10.7 - 17.4 ) . CONCLUSION in this prospect i ve longitudinal study , the incidence rate of Parkinson 's disease in North-East Engl and is similar to that of other modern European and American studies CONTEXT Since there is no diagnostic biological marker for Parkinson disease ( PD ) , the diagnosis is based on the results of clinical assessment . The accuracy of diagnosis improves with time and repeated assessment s. Studies that require only inclusion of early cases of PD present a diagnostic challenge . Previous studies concluded that initial diagnoses of PD made by general neurologists were incorrect in 24 % to 35 % of the cases when patients were examined at autopsy . Experts in movement disorders are expected to have greater accuracy of initial diagnosis of PD . OBJECTIVE To determine the evolution of clinical diagnosis in patients with early PD made initially by experts in PD . DESIGN Eight hundred patients with mild parkinsonian symptoms ( Hoehn and Yahr stage 1 or 2 ) who received a diagnosis of PD less than 5 years before the beginning of the study were included in the original Deprenyl and Tocopherol Antioxidative Therapy for Parkinson 's Disease study . These patients were followed up prospect ively with repeated clinical assessment s. The following clinical criteria were used to reassess the initial diagnosis : investigator 's confidence in the diagnosis of PD , presence of atypical clinical features , findings of imaging studies , response to levodopa , and results of autopsy examinations . RESULTS The mean + /- SD duration of illness in the 800 cases at enrollment was 2.2+/-1.3 years , and the mean + /- SD Hoehn and Yahr stage was 1.6+/-0.5 . The mean + /- SD follow-up was 6.0+/-1.4 years ( range , 0.2 - 7.6 years ) . In 5 cases , PD was not confirmed at autopsy , and in 15 patients , the results of imaging studies indicated the presence of other pathological conditions . Of the 550 cases treated with levodopa , 49 ( 8.9 % ) had little or no improvement ; 6 of these cases overlap with either autopsy or imaging study exclusion criteria . Two other cases had at least 4 of the 6 atypical clinical features arguing against the diagnosis of PD . Thus , of the 800 patients , 65 ( 8.1 % ) did not have PD according to the study criteria . Compared with those patients with the final diagnosis of PD , in the diagnoses of 60 patients without autopsy , the duration of symptoms ( mean + /- SD , 7.2+/-2.0 years vs. 8.3+/-1.9 years ; P<.001 ) and the duration of follow-up ( 5.3+/-1.6 years vs. 6.1+/-1.3 years ; P<.001 ) were shorter . CONCLUSIONS We found that 65 ( 8.1 % ) of patients initially diagnosed as having PD were later found to have an alternate diagnosis based on multifactorial clinical diagnostic criteria . This alternate diagnosis indicated that experts in PD changed their diagnoses infrequently during the 7.6-year follow-up The differential diagnosis of parkinsonian disorders is difficult , especially early in the course of the diseases . The clinical subtypes of Parkinson 's disease ( PD ) have not so far been described in newly diagnosed patients . We present a prospect i ve incidence cohort study of patients with idiopathic parkinsonian syndromes in the Umeå region in northern Sweden identified over a 4-year period . The clinical diagnoses were re-evaluated at follow-up visits at 12 months . We found 138 patients with parkinsonism : 112 PD , 12 multiple system atrophy with predominant parkinsonism ( MSA-P ) , six progressive supranuclear palsy ( PSP ) and eight unclassifiable patients . The crude incidences for all age ranges per 100,000 were : PD 19.7 ( 95 % confidence interval 16.1 - 23.3 ) ; MSA-P 2.1 ( 1.1 - 3.7 ) ; PSP 1.1 ( 0.4 - 2.4 ) ; idiopathic parkinsonism 24.3 ( 20.2 - 28.4 ) . Age-st and ardized to the average Swedish population 2004 - 2007 : PD 22.5 ( 18.3 - 26.7 ) ; MSA-P 2.4 ( 1.2 - 4.2 ) ; PSP 1.2 ( 0.4 - 2.6 ) ; idiopathic parkinsonism 27.5 ( 22.9 - 32.1 ) . The crude annual incidence rate for PD , with exclusion of patients with normal dopamine receptor uptake ( FP-CIT-SPECT ) , was 18.8 per 100,000 ( 95 % confidence interval 15.2 - 22.4 ) , age-adjusted to the average Swedish population 2004 to 2007 : 21.5 ( 17.4 - 25.6 ) . The incidence rates did not differ significantly between men and women . The cumulative incidence of PD up to 89 years of age was for men 3.4 % , for women 2.6 % , and for both sexes combined 2.9 % . The annual incidence rates found for PD , idiopathic parkinsonism , MSA-P and PSP are among the highest reported A retrospective study of a 50-year autopsy series of 900 patients with the clinical diagnosis of parkinsonism ( 31.2 % with dementia ) revealed pure Lewy body disease ( LBD ) in 84.9 % , but only 44.7 % with idiopathic Parkinson disease ( PD ) ; 16 % were associated with cerebrovascular lesions , 14.8 % with Alzheimer pathology ; 8.9 % were classified dementia with Lewy bodies ( DLB ) , 9.4 % showed other degenerative disorders , and 5.6 % other/ secondary parkinsonian syndromes . The frequency of LBD during different periods was fairly stable , with increase of DLB and PD plus Alzheimer changes , but decrease of associated cerebrovascular lesions during the last decades . Using variable clinical diagnostic criteria not only by specified neurologists , the misdiagnosis rate ranged from 11.5 to 23 % and was similar to that in most previous clinico-pathological studies . The majority of cases with false clinical diagnosis of PD had a final pathological diagnosis of DLB with or without Alzheimer lesions . A postmortem series of 330 elderly patients clinical ly diagnosed as parkinsonism with ( 37.6 % ) and without dementia showed that IPD , Braak stages 3 - 5 were rarely associated with cognitive impairment , which was frequently seen in IPD with associated Alzheimer pathology ( 35.5 % ) , DLB ( 33.9 % ) , and in Alzheimer disease ( AD ) or mixed dementia ( 17 % ) , whereas it almost never was associated with minor cerebrovascular lesions . Clinico-pathological studies in DBL , demented and nondemented PD , and AD cases showed a negative relation between cognitive impairment and Alzheimer changes , suggesting that these either alone or in combination with cortical Lewy body pathologies are major causes of cognitive dysfunction . Further prospect i ve clinico-pathological studies are needed to vali date the currently used clinical criteria for PD , to increase the diagnostic accuracy until effective biomarkers are available , and to clarify the impact of structural and functional changes on cognitive function in parkinsonism as an ultimate goal of early disease detection and effective treatment BACKGROUND Patients with idiopathic rapid-eye-movement sleep behaviour disorder ( IRBD ) may develop neurodegenerative conditions associated with substantia nigra dysfunction such as Parkinson 's disease . In patients with Parkinson 's disease , ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane ( ¹²³I-FP-CIT ) SPECT detects striatal dopamine dysfunction result ing from nigral pathology whereas transcranial sonography ( TCS ) shows increased substantia nigra echogenic size , even before parkinsonism is clinical ly evident . We postulated that these neuroimaging changes could occur in a proportion of IRBD individuals who might then be at increased risk for development of a neurodegenerative disorder associated with substantia nigra dysfunction . METHODS In our prospect i ve study , we identified patients with IRBD from individuals referred to our sleep disorders centre in Barcelona , Spain . At baseline , we assessed dopamine transporter [ corrected ] uptake by use of ¹²³I-FP-CIT SPECT , and estimated echogenicity of the substantia nigra by use of TCS . After a follow-up of 2·5 years , participants were clinical ly assessed to establish whether they had developed neurodegenerative syndromes . Data were compared with those of matched healthy controls . FINDINGS 43 individuals with IRBD agreed to participate in the study . We found reduced ¹²³I-FP-CIT binding in the striatum ( p=0·045 ) in 17 ( 40 % ) of 43 participants compared with 18 controls , and substantia nigra hyperechogenicity in 14 ( 36 % ) of 39 participants with IRBD , compared with 16 ( 11 % ) of 149 controls ( p=0·0002 ) . Tracer uptake reduction was more pronounced in the putamen than it was in the cau date nucleus . 27 ( 63 % ) participants had reduced ¹²³I-FP-CIT binding or substantia nigra hyperechogenicity at baseline . Eight ( 30 % ) of these participants developed a neurodegenerative disorder ( five Parkinson 's disease , two dementia with Lewy bodies , and one multiple system atrophy ) . Individuals with normal neuroimaging results remained disease-free . Sensitivity of combined ¹²³I-FP-CIT SPECT and TCS to predict conversion to synucleinopathy after 2·5 years was 100 % and specificity was 55 % . INTERPRETATION In patients with IRBD , ¹²³I-FP-CIT SPECT and TCS can detect sub clinical changes much the same as those typically seen in patients with early Parkinson 's disease . Decreased striatal ¹²³I-FP-CIT binding and substantia nigra hyperechogenicity might be useful markers to identify individuals at increased risk for development of synucleinopathies . FUNDING None BACKGROUND SN hyperechogenicity ( SN+ ) , determined by transcranial sonography , has been proposed as a risk factor for Parkinson 's disease ( PD ) . Recently , we reported a 17.4-fold increased risk for PD in individuals with SN+ older than 50 years within 3 years . METHODS This is the second follow-up of a prospect i ve , longitudinal , three-center observational study after 5 years . Of the initial 1,847 at baseline PD-free participants 50 years or older , 1,271 underwent the 5-year re assessment . RESULTS Within 5 years , 21 individuals developed incident PD . Participants with SN+ at baseline had a more than 20.6 times increased risk to develop PD in this time span than those without this echo feature . CONCLUSION We thus confirm our finding of the 3-year follow-up examination in a longer observation time and higher number of individuals with incident PD and suggest SN+ as an important risk marker for PD BACKGROUND Increased echogenicity of the substantia nigra ( SN ) , as determined by transcranial sonography ( TCS ) , is characteristic of idiopathic Parkinson 's disease ( iPD ) . The results of initial retrospective studies indicate that this ultrasound sign is specific for iPD and can help to differentiate it from atypical parkinsonian syndromes ( aPS ) ; however , these early studies were done in patients with later disease stages and known clinical diagnosis . We aim ed to determine the diagnostic value of TCS in the early stages of parkinsonian syndromes , when the clinical symptoms often do not enable a definite diagnosis to be made . METHODS 60 patients who presented with the first , but still unclear , clinical symptoms of parkinsonism had TCS in this prospect i ve blinded study . Investigators were blinded to the results of the clinical investigations , the ultrasound findings , and the diagnosis at time of investigation . The patients were followed-up every 3 months for 1 year to assess and re-evaluate the clinical symptoms . The patients in whom a clinical diagnosis could not be made with certainty were investigated with raclopride PET or dopamine transporter single-photon emission computed tomography ( SPECT ) , or both . FINDINGS A clinical diagnosis of parkinsonism could not be established at baseline in 38 patients . At 12 months , 39 patients were clinical ly categorised as having iPD . Compared with endpoint diagnosis , the sensitivity of TCS at baseline was 90%7 % and the specificity was 82.4 % ; the positive predictive value of TCS for iPD was 92.9 % and the classification accuracy was 88.3 % . INTERPRETATION TCS is an easy to implement , non-invasive , and inexpensive technique that could help in the early differential diagnosis of parkinsonian syndromes . The routine use of TCS in the clinic could enable disease-specific therapy to be started earlier . FUNDING Michael J Fox Foundation for Parkinson 's Research BACKGROUND Whether Parkinson disease ( PD ) and dementia with Lewy bodies ( DLB ) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate . OBJECTIVES To determine the accuracy of the diagnoses of Lewy body disease , PD , and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses . METHODS Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease ( post hoc analysis of 15 patients with PD and 14 with DLB ) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings . MAIN OUTCOME MEASURES Sensitivity and positive predictive value ( PPV ) were chosen as validity measures and the K statistic as a reliability measure . RESULTS Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last , whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last . Median sensitivity for diagnosis of Lewy body disease was 56.9 % for the first visit and 67.2 % for the last ; median PPV was 60.0 % and 77.4 % , respectively . Median sensitivity for the diagnosis of PD was 73.3 % for the first visit and 80.0 % for the last ; median PPV was 45.9 % and 64.1 % , respectively . Median sensitivity for the diagnosis of DLB was 17.8 % for the first visit and 28.6 % for the last ; median PPV was 75.0 % for the first visit and 55.8 % for the last . The raters ' results were similar to those of the primary neurologists . Several features differentiated PD from DLB , predicted each disorder , and could be used as clinical pointers . CONCLUSIONS The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis . Conversely , the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis . Although the case mix included in the study may not reflect the frequency of these disorders in practice , limiting the clinical applicability of the validity measures , the raters ' results were similar to those of the primary neurologists who were not exposed to such limitations . Overall , our study confirms features suggested to predict these disorders , except for the early presence of postural imbalance , which is not indicative of either disorder Objective : The aim of the present study was to determine the predictive value of olfactory dysfunction for the early development of a synuclein-mediated neurodegenerative disease in subjects with idiopathic REM sleep behavior disorder ( iRBD ) over an observational period of 5 years . Methods : Thirty-four patients with polysomnography-confirmed iRBD underwent olfactory testing using the entire Sniffin ' Sticks test assessing odor identification , odor discrimination , and olfactory threshold . Patients with iRBD were prospect ively followed up over a period of 4.9 ± 0.3 years ( mean ± SD ) . The diagnosis of neurodegenerative diseases was based on current clinical diagnostic criteria . Results : After 2.4 ± 1.7 years ( mean ± SD ) , 9 patients ( 26.5 % ) with iRBD developed a Lewy body disease ( 6 Parkinson disease and 3 dementia with Lewy bodies ) . The entire Sniffin ' Sticks test and the identification subtest had the same overall diagnostic accuracy of 82.4 % ( 95 % confidence interval : 66.1%–92.0 % ) in predicting conversion . The relative risk for a Lewy body disease in the lowest tertile of olfactory function was 7.3 ( 95 % confidence interval : 1.8–29.6 ) compared with the top 2 tertiles . Conclusions : Assessment of olfactory function , particularly odor identification , may help to predict the development of a Lewy body disease in patients with iRBD over a relatively short time period and thus to identify patients suitable for future disease modification trials Many authorities have drawn attention to the difficulties in clinical ly distinguishing Parkinson 's disease ( PD ) from other parkinsonian syndromes . We assessed the clinical features of 100 patients diagnosed prospect ively by a group of consultant neurologists as having idiopathic PD according to their pathologic findings . Seventy-six percent of these cases were confirmed to have PD . By using selected criteria ( asymmetrical onset , no atypical features , and no possible etiology for another parkinsonian syndrome ) the proportion of true PD cases identified was increased to 93 % , but 32 % of pathologically confirmed cases were rejected on this basis . These observations suggest that studies based on consultant diagnosis of PD , using st and ard diagnostic criteria , will include cases other than PD , thus distorting results from clinical trials and epidemiologic studies . The strict use of additional criteria can reduce misdiagnosis but at the cost of excluding genuine PD cases Data on the incidence of Parkinson 's disease ( PD ) and atypical parkinsonian syndromes ( APS ) in East European countries and Asia are limited . The objective of this prospect i ve population -based study was to determine the incidence of PD and APS in the Russian population . The study area was a large district of Moscow with a population of 1,237,900 inhabitants . Multiple sources of case ascertainment were used to identify incident cases of PD and APS between July 2006 and December 2008 . All incident cases were examined by a specialist and followed up prospect ively to confirm the diagnosis . The age-st and ardized incidence rates per 100,000/year were 9.03 [ 95 % confidence interval ( CI ) 8.01 - 10.15 ] for PD , 0.11 ( 95 % CI 0.03 - 0.23 ) for multiple system atrophy , 0.14 ( 95 % CI 0.08 - 0.21 ) for progressive supranuclear palsy , and 0.02 ( 95 % CI 0.01 - 0.12 ) for corticobasal degeneration . The age-st and ardized male-to-female ratio of PD was 0.87 for all ages and 1.46 for those aged 60 and older . A high proportion of new cases with PD ( 34 % ) and APS ( 50 % ) had comorbid depressive symptoms . Given the rapid growth of the elderly population in Eastern Europe and Asia , the epidemiology of PD and APS in these regions should be investigated in greater depth . The incidence of PD in our study was slightly lower than in studies of Western population s and the male-to-female ratio was closer to those reported in studies from Asia . The clinical implication of our study is that it highlights the need for better diagnosis and treatment of depression in early stages of PD

The rhEPO treatment has beneficial effect on the neurodevelopment outcomes without severe adverse side effect in preterm infants

The purpose of this study is to assess the efficacy and safety of recombinant human erythropoietin ( rhEPO ) for improving neurodevelopment outcomes in preterm infants .

OBJECTIVE : To compare the neurodevelopmental outcome of premature infants treated with recombinant human erythropoietin with that of control infants . STUDY DESIGN : A total of 20 treated infants and 20 control infants who had completed r and omized , double-blind , placebo-controlled studies of recombinant human erythropoietin as treatment for anemia of prematurity were followed for growth and developmental outcome in an intensive care nursery follow-up program . Infants were assessed by st and ard developmental tests . RESULTS : No differences were found between groups for neurologic outcome , cognitive outcome , or growth patterns . All infants treated with recombinant human erythropoietin were neurologically normal . The rate of cognitive deficits was similar in the two groups . CONCLUSION : In this small sample we did not see differences in neurodevelopmental outcome between infants treated with recombinant human erythropoietin and control infants OBJECTIVE . Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants . Recent animal studies using erythropoietin doses to achieve serum concentrations > 1000 mU/mL report neuroprotective effects . We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants . METHODS . Preterm infants who weighed ≤1000 g at birth were r and omly assigned to erythropoietin ( 400 U/kg 3 times per week ) or placebo/control . Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week . All infants received supplemental parenteral and enteral iron . Peak serum erythropoietin concentrations were obtained every 2 weeks . Follow-up evaluation included anthropometric measurements , Bayley scales of mental and psychomotor development , neurologic examination , and determination of overall neurodevelopmental impairment . Data were collected at 18 to 22 months ' corrected age by certified examiners who were masked to the treatment group . Analyses were performed to identify correlations between erythropoietin concentrations and outcomes . RESULTS . Sixteen extremely low birth weight infants were enrolled ; 1 infant died at 2 weeks ( placebo/control ) , and 15 had erythropoietin concentrations measured ( 7 erythropoietin , 8 placebo/control ) . Peak erythropoietin concentrations were significantly different between groups during the study ( erythropoietin : 2027 ± 1464 mU/mL ; placebo/control : 26 ± 11 mU/mL ) . Before follow-up , 3 infants died ( 1 erythropoietin , 2 placebo/control ) , and 12 were available for follow-up ( 6 erythropoietin , 6 placebo/control ) . At 18 to 22 months ' follow-up , none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores < 70 . Erythropoietin recipients had Mental Development Index scores of 96 ± 11 , and placebo/control infants had Mental Development Index scores of 78 ± 7 . Psychomotor Development Index scores were similar between groups ( 87 ± 13 vs 80 ± 7 ) . There were no differences between groups with respect to anthropometric measurements . Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment . Posthoc analysis showed that infants with erythropoietin concentrations ≥500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations < 500 mU/mL. CONCLUSIONS . Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment ; however , infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations . Close follow-up of infants who are enrolled in large , multicenter , high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome Erythropoietin has been reported to possess neuroprotective properties in animal studies . No previous studies have investigated the neurodevelopmental outcome of extremely low birth weight ( ELBW ) infants treated with recombinant human erythropoietin ( rEpo ) and evaluated it at school age Background . Clinical trials evaluating the use of erythropoietin ( Epo ) have demonstrated a limited reduction in transfusions ; however , long-term developmental follow-up data are scarce . Objective . We compared anthropometric measurements , postdischarge events , need for transfusions , and developmental outcomes at 18 to 22 months ' corrected age in extremely low birth weight ( ELBW ) infants treated with early Epo and supplemental iron therapy with that of placebo/control infants treated with supplemental iron alone . Methods . The National Institute of Child Health and Human Development Neonatal Research Network completed a r and omized , controlled trial of early Epo and iron therapy in preterm infants ≤1250 g. A total of 172 ELBW ( ≤1000-g birth weight ) infants were enrolled ( 87 Epo and 85 placebo/control ) . Of the 72 Epo-treated and 70 placebo/control ELBW infants surviving to discharge , follow-up data ( growth , development , rehospitalization , transfusions ) at 18 to 22 months ' corrected age were collected on 51 of 72 Epo-treated infants ( 71 % ) and 51 of 70 placebo/controls ( 73 % ) by certified examiners masked to the treatment group . Statistical significance was determined using χ2 analysis . Results . There were no significant differences between treatment groups in weight or length or in the percentage of infants weighing < 10th percentile either at the time of discharge or at follow-up , and no difference was found in the mean head circumference between groups . A similar percentage of infants in each group was rehospitalized ( 38 % Epo and 35 % placebo/control ) for similar reasons . There were no differences between groups with respect to the percentage of infants with Bayley-II Mental Developmental Index < 70 ( 34 % Epo and 36 % placebo/control ) , blindness ( 0 % Epo and 2 % placebo/control ) , deafness or hearing loss requiring amplification ( 2 % Epo and 2 % placebo/control ) , moderate to severe cerebral palsy ( 16 % Epo and 18 % placebo/control ) or the percentage of infants with any of the above-described neurodevelopmental impairments ( 42 % Epo and 44 % placebo/control ) . Conclusions . Treatment of ELBW infants with early Epo and iron does not significantly influence anthropometric measurements , need for rehospitalization , transfusions after discharge , or developmental outcome at 18 to 22 months ' corrected age OBJECTIVE To evaluate the effect of the early use of recombinant human erythropoietin ( rhu-EPO ) on neurobehavioral development in preterm infants . METHODS Forty-four preterm infants ( 30 males and 14 females ) were r and omly divided into two groups : Rhu-EPO treatment and untreated control ( n=22 each ) . From postnatal day 7 , the Rhu-EPO treatment group received intravenous rhu-EPO ( 250 IU/kg3 times weekly ) for 4 weeks . A Neonatal Behavioral Neurological Assessment ( NBNA ) was performed at 40 weeks of corrected gestational age . A Gesell Development Schedule was used to evaluate neurological development 6 and 12 months after birth . RESULTS The NBNA score in the rhu-EPO treatment group ( 36.20+/-0.75 ) was significantly higher than that in the control group ( 34.40+/-1.05 ) at 40 weeks of corrected gestational age ( P<0.05 ) . The developmental quotient of fine motor in the rhu-EPO treatment group was significantly higher than that in the control group 6 months after birth ( P<0.05 ) . By 12 months after birth , the developmental quotient of gross motor , fine motor and language in the rhu-EPO treatment group was significantly higher than that in the control group ( P<0.05 ) . CONCLUSIONS Early use of Rhu-EPO can promote neurobehavioral development in preterm infants OBJECTIVE . Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture , animal models of brain injury , and clinical trials of adult humans . The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury ( intraventricular hemorrhage and periventricular leukomalacia ) in very preterm infants and improve neurodevelopmental outcome . We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome . METHODS . This was a r and omized , double-masked , single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin . Preterm infants ( gestational age : 24 to 31 weeks ) were given recombinant human erythropoietin or NaCl 0.9 % intravenously 3 , 12 to 18 , and 36 to 42 hours after birth . RESULTS . The percentage of infants who survived without brain injury or retinopathy was 53 % in the recombinant human erythropoietin group and 60 % in the placebo group . There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage , retinopathy , sepsis , necrotizing enterocolitis , and bronchopulmonary dysplasia . For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of < 26 weeks , withdrawal of intensive care was decided ( 3 of 5 with severe bilateral intraventricular hemorrhage , 2 of 5 with pulmonary insufficiency ) ; no infant of the control group died . Recombinant human erythropoietin treatment did not result in significant differences in blood pressure , cerebral oxygenation , hemoglobin , leukocyte , and platelet count . CONCLUSIONS . No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified . These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months ' and 5 years ' corrected age OBJECTIVES . High-dose recombinant erythropoietin is neuroprotective in animal models of neonatal brain injury . Extremely low birth weight infants are at high risk for brain injury and neurodevelopmental problems and might benefit from recombinant erythropoietin . We design ed a phase I/II trial to test the safety and determine the pharmacokinetics of high-dose recombinant erythropoietin in extremely low birth weight infants . METHODS . In a prospect i ve , dose-escalation , open-label trial , we compared 30 infants who were treated with high-dose recombinant erythropoietin with 30 concurrent control subjects . Eligible infants were < 24 hours old , ≤1000 g birth weight , and ≤28 weeks of gestation and had an umbilical artery catheter in place . Each infant received 3 intravenous doses of 500 , 1000 , or 2500 U/kg at 24-hour intervals beginning on day 1 of age . Blood sample s were collected at scheduled intervals to determine recombinant erythropoietin pharmacokinetics . Safety parameters were also evaluated . In the concurrent control group , only clinical data were collected . RESULTS . Mean erythropoietin concentrations 30 minutes after recombinant erythropoietin infusion were 5973 ± 266 , 12291 ± 403 , and 34197 ± 1641 mU/mL after 500 , 1000 , or 2500 U/kg , respectively . High-dose recombinant erythropoietin followed nonlinear pharmacokinetics as a result of decreasing clearance from the lowest dosage ( 17.3 mL/hour per kg for 500 U/kg ) to the highest dosage ( 8.2 mL/hour per kg for 2500 U/kg ) . Steady state was achieved within 24 to 48 hours . Both 1000 and 2500 U/kg recombinant erythropoietin produced peak serum erythropoietin concentrations that were comparable to neuroprotective concentrations that previously were seen in experimental animals . No excess adverse events occurred in the recombinant erythropoietin – treated infants compared with control infants . CONCLUSIONS . Early high-dose recombinant erythropoietin is well tolerated by extremely low birth weight infants , causing no excess morbidity or mortality . Recombinant erythropoietin dosages of 1000 and 2500 U/kg achieved neuroprotective serum levels

Some evidence shows that fiber may be more effective than placebo in improving both the frequency and consistency of stools and in reducing abdominal pain . Compared with normal fluid intake , we found no evidence that water intake increases or that hyperosmolar fluid treatment is more effective in increasing stool frequency or decreasing difficulty in passing stools . We found no evidence to recommend the use of prebiotics or probiotics . Behavioral therapy with laxatives is not more effective than laxatives alone . : There is some evidence that fiber supplements are more effective than placebo . No evidence for any effect was found for fluid supplements , prebiotics , probiotics , or behavioral intervention .

OBJECTIVE : To summarize the evidence and assess the reported quality of studies concerning nonpharmacologic treatments for childhood constipation , including fiber , fluid , physical movement , prebiotics , probiotics , behavioral therapy , multidisciplinary treatment , and forms of alternative medicine .

OBJECTIVE Constipation and encopresis are common problems in children . Still today , the role of fiber in the treatment of chronic constipation in childhood is controversial . The aim of our study was to evaluate whether fiber supplementation is beneficial in the treatment of children with functional constipation with or without encopresis . We used glucomannan as the fiber supplement . METHODS We evaluated the effect of fiber ( glucomannan , a fiber gel polysaccharide from the tubers of the Japanese Konjac plant ) and placebo in children with chronic functional constipation with and without encopresis in a double-blind , r and omized , crossover study . After the initial evaluation , the patients were disimpacted with 1 or 2 phosphate enemas if a rectal impaction was felt during rectal examination . Patients continued with their preevaluation laxative . No enemas were given during each treatment period . Fiber and placebo were given as 100 mg/kg body weight daily ( maximal 5 g/day ) with 50 mL fluid/500 mg for 4 weeks each . Parents were asked to have children sit on the toilet 4 times daily after meals and to keep a stool diary . Age , frequency of bowel movements into the toilet and into the undergarment , presence of abdominal pain , dietary fiber intake , medications , and the presence of an abdominal and /or a rectal fecal mass were recorded on a structured form at the time of recruitment and 4 weeks and 8 weeks later . Children were rated by the physician as successfully treated when they had > or =3 bowel movements/wk and < or = 1 soiling/3 weeks with no abdominal pain in the last 3 weeks of each 4-week treatment period . Parents made a global assessment s to whether they believed that the child was better during the first or second treatment period . RESULTS Forty-six chronically constipated children were recruited into the study , but only 31 children completed the study . These 31 children ( 16 boys and 15 girls ) were 4.5 to 11.7 years of age ( mean : 7 + /- 2 years ) . All children had functional constipation ; in addition , 18 had encopresis when recruited for the study . No significant side effects were reported during each 4-week treatment period . Significantly fewer children complained of abdominal pain and more children were successfully treated while on fiber ( 45 % ) as compared with placebo treatment ( 13 % ) . Parents rated significantly more children ( 68 % ) as being better on fiber versus 13 % as being better on placebo . The initial fiber intake was low in 22 ( 71 % ) children . There was no difference in the percentage of children with low fiber intake living in the United States ( 70 % ) and Italy ( 71 % ) . Successful treatment ( physician rating ) and improvement ( parent rating ) were independent of low or acceptable initial fiber intake . The duration of chronic constipation ranged from 0.6 to 10 years ( mean : 4.0 + /- 2.5 years ) . Duration of constipation did not predict response to fiber treatment . Children with constipation only were significantly more likely to be treated successfully with fiber ( 69 % ) than those with constipation and encopresis ( 28 % ) . CONCLUSION We found glucomannan to be beneficial in the treatment of constipation with and without encopresis in children . Symptomatic children who were already on laxatives still benefited from the addition of fiber . Therefore , we suggest that we continue with the recommendation to increase the fiber in the diet of constipated children with and without encopresis OBJECTIVE To determine if Lactobacillus GG ( LGG ) is an effective adjunct to lactulose for treating constipation in children . STUDY DESIGN Eighty-four children ( 2 - 16 years of age ) with constipation ( <3 spontaneous bowel movements [ BMs ] per week for at least 12 weeks ) were enrolled in a double-blind , r and omized placebo-controlled trial in which they received 1 mL/kg/day of 70 % lactulose plus 10 9 colony-forming units ( CFU ) of LGG ( experimental group , n = 43 ) or a placebo ( control group , n = 41 ) orally twice daily for 12 weeks . The primary outcome measure was treatment success , and analyses were performed on an intention-to-treat basis . RESULTS Treatment success , defined as > or=3 spontaneous BMs per week with no fecal soiling , was similar in the control and experimental groups at 12 weeks ( 28/41 [ 68 % ] vs 31/43 [ 72 % ] , respectively ; P = .7 ) and at 24 weeks ( 27/41 [ 65 % ] vs 27/42 [ 64 % ] , respectively ; P = 1.0 ] . Groups also did not differ in their mean number of spontaneous BMs per week or episodes of fecal soiling per week at 4 , 8 , and 12 weeks . Adverse events and overall tolerance did not differ between groups . CONCLUSION LGG , as dosed in this study , was not an effective adjunct to lactulose in treating constipation in children OBJECTIVE To develop an evidence -based guideline for the primary pediatric care of children ( birth to 18 years old ) with idiopathic constipation and soiling . DATA SOURCES References were identified through a MEDLINE search from January 1975 through January 1998 to address 3 focus questions : ( 1 ) the best path to early , accurate diagnosis ; ( 2 ) best methods for adequate clean-out ; and ( 3 ) best approaches to promote patient and family compliance with management . DATA SELECTION Twenty-five references were identified . DATA EXTRACTION References were review ed by a multidisciplinary team and grade d according to the following criteria : r and omized controlled trial ; controlled trial , no r and omization ; observational study ; and expert opinion . Evidence tables were developed for each focus question . DATA SYNTHESIS An algorithm and clinical care guideline were developed by consultation and consensus among team members . Emphasis was placed on methods to promote early identification of pediatric idiopathic constipation and soiling , to recognize points of referral , and to increase patient and family compliance with treatment through use of education , developmentally based interventions , and variables for tracking success of management . CONCLUSION An algorithm and guideline for pediatric idiopathic constipation and soiling are presented for use by primary care physicians Simple , incentive based behaviour modification , with or without a modest programme of psychotherapy involving outpatient visits every four to six weeks , seems to be associated with a useful cure rate in children with lower bowel function disorders . Appreciable social disadvantage seems to be the most important factor mitigating against a successful outcome , associated with non-compliance with treatment . Failure to respond to treatment was associated with important psychological problems . These were more common in the socially disadvantaged groups . Children from satisfactory social background s who have lower bowl disturbances can be effectively treated by fairly simple programmes . More elaborate and expensive strategies should be reserved for those whose psychosocial circumstances make it possible to predict a less satisfactory outcome Background Nutrilon Omneo ( new formula ; NF ) contains high concentration of sn-2 palmitic acid , a mixture of prebiotic oligosaccharides and partially hydrolyzed whey protein . It is hypothesized that NF positively affects stool characteristics in constipated infants . Methods Thirty-eight constipated infants , aged 3–20 weeks , were included and r and omized to NF ( n = 20 ) or a st and ard formula ( SF ; n = 18 ) in period 1 and crossed-over after 3 weeks to treatment period 2 . Constipation was defined by at least one of the following symptoms : 1 ) defecation frequency < 3/week ; 2 ) painful defecation ; 3 ) abdominal or rectal palpable mass . Results Period 1 was completed by 35 infants . A significant increase in defecation frequency ( NF : 3.5 pre versus 5.6/week post treatment ; SF 3.6 pre versus 4.9/week post treatment ) was found in both groups , but was not significantly different between the two formulas ( p = 0.36 ) . Improvement of hard stool consistency to soft stool consistency was found more often with NF than SF , but did not reach statistical significance ( 90 % versus 50 % ; RR , 1.8 ; 95 % CI , 0.9–3.5 ; p = 0.14 ) . No difference was found in painful defecation or the presence of an abdominal or rectal mass between the two groups . Twenty-four infants completed period 2 . Only stool consistency was significantly different between the two formulas ( 17 % had soft stools on NF and hard stools on SF ; no infants had soft stools on SF and hard stools on NF , McNemar test p = 0.046 ) . Conclusion The addition of a high concentration sn-2 palmitic acid , prebiotic oligosaccharides and partially hydrolyzed whey protein result ed in a strong tendency of softer stools in constipated infants , but not in a difference in defecation frequency . Formula transition to NF may be considered as treatment in constipated infants with hard stools BACKGROUND The purpose of the present paper was to evaluate the efficacy of probiotics ( Lactobacillus casei rhamnosus , Lcr35 ) for treating children with chronic constipation and to compare its effect with magnesium oxide ( MgO ) and placebo . METHODS This double-blind placebo-controlled , r and omized study enrolled 45 children under 10 years old with chronic constipation . They were r and omly assigned to receive Lcr35 ( 8 x 10(8 ) c.f.u./day ; n = 18 ) , MgO ( 50 mg/kg/day ; n = 18 ) , or placebo ( n = 9 ) orally twice daily for 4 weeks . Lactulose use ( 1 mL/kg per day ) was allowed when no stool passage for 3 days was noted . Glycerin enema was used only when no defecation was noted for > 5 days or abdominal pain was suffered due to stool impaction . Bacterial cultures of stool were performed before and after treatment to evaluate the change of intestinal flora . Comparisons of the frequency of defecation , consistency of stool and the use of lactulose or enema during the period of treatment were made among the three groups . RESULTS The patients who received MgO or probiotics had a higher defecation frequency ( P = 0.03 ) , higher percentage of treatment success ( P = 0.01 ) , less use of glycerin enema ( P = 0.04 ) and less hard stool ( P = 0.01 ) than the placebo group . There was no significant difference between MgO and probiotic groups in the aforementioned comparisons . The first effect of MgO ( second week ) on constipation was slightly earlier than that of probiotic ( second to third week ) . Abdominal pain occurred less frequently in the probiotic group than in both the MgO and the placebo groups ( P = 0.03 ) . There was no statistically significant difference among the three groups in the use of lactulose , episodes of fecal soiling , and change of appetite . No adverse effect was noted in probiotic and placebo groups . Only one patient in the MgO group suffered from mild diarrhea . CONCLUSION Lcr35 was effective in treating children with chronic constipation . There is no statistically significant difference in efficacy between MgO and Lcr35 , but less abdominal pain occurred when using Lcr35 . Study with larger case number and longer follow up is needed in the future OBJECTIVES : This study examines long-term prognoses for children with constipation in adulthood and identifies prognostic factors associated with clinical outcomes . METHODS : In a Dutch tertiary hospital , children ( 5–18 years of age ) who were diagnosed as having functional constipation were eligible for inclusion . After a 6-week treatment protocol , prospect i ve follow-up evaluations were conducted at 6 and 12 months and annually thereafter . Good clinical outcomes were defined as ≥3 bowel movements per week for ≥4 weeks , with ≤2 fecal incontinence episodes per month , irrespective of laxative use . RESULTS : A total of 401 children ( 260 boys ; median age : 8 years [ interquartile range : 6–9 years ] ) were included , with a median follow-up period of 11 years ( interquartile range : 9–13 years ) . The dropout rate during follow-up was 15 % . Good clinical outcomes were achieved by 80 % of patients at 16 years of age . Thereafter , this proportion remained constant at 75 % . Poor clinical outcomes at adult age were associated with : older age at onset ( odds ratio [ OR ] : 1.15 [ 95 % confidence interval [ CI ] : 1.02–1.30 ] ; P = .04 ) , longer delay between onset and first visit to our outpatient clinic ( OR : 1.24 [ 95 % CI : 1.10–1.40 ] ; P = .001 ) , and lower defecation frequency at study entry ( OR : 0.92 [ 95 % CI : 0.84–1.00 ] ; P = .03 ) . CONCLUSIONS : One-fourth of children with functional constipation continued to experience symptoms at adult age . Certain risk factors for poor clinical outcomes in adulthood were identified . Referral to a specialized clinic should be considered at an early stage for children who are unresponsive to first-line treatment Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists Increasing the amount and type of fluid intake in children with simple constipation remains a common intervention recommended by both the medical profession and lay consumers . Efforts to increase overall water intake and /or high osmolarity liquid intake have no research or physiological basis that would result in softer and /or more frequent stools . The purpose of this project was to identify whether an effect on stooling characteristics would be noted with a concerted effort to increase liquid intake OBJECTIVE . Although a diet that is rich in fiber is widely recommended for preventing and treating constipation , the efficacy of fiber supplements have not been tested sufficiently in children . Our aim with this pilot study was to evaluate if fiber supplementation is beneficial for the treatment of children with idiopathic chronic constipation . METHODS . Using a parallel , r and omized , double-blind , controlled trial , we conducted an interventional study to evaluate the efficacy of a supplement of cocoa husk rich in dietary fiber on intestinal transit time and other indices of constipation in children with constipation . After screening , the patients were r and omly allocated to receive , for a period of 4 weeks , either a cocoa husk supplement or placebo plus st and ardized toilet training procedures . Before and after 4 weeks of treatment , we ( 1 ) performed anthropometry , a physical examination , and routine laboratory measurements , ( 2 ) determined total and segmental colonic transit time , ( 3 ) evaluated bowel movement habits and stool consistency using a diary , and ( 4 ) received a subjective evaluation from the parents regarding the efficacy of the treatment . The main variable for verifying the efficacy of the treatment was the total colonic transit time . RESULTS . Fifty-six chronically constipated children were r and omly assigned into the study , but only 48 children completed it . These children , who were aged between 3 and 10 years , had a diagnosis of chronic idiopathic constipation . With respect to total , partial colon , and rectum transit time , there seemed to be a trend , although statistically nonsignificant , toward faster transit times in the cocoa husk group than in the placebo group . When we analyzed the evolution of the intestinal transit time throughout the study of children whose total basal intestinal transit time was > 50th percentile , significant differences were observed between the groups . The total transit time decreased by 45.4 ± 38.4 hours in the cocoa husk group and by 8.7 ± 28.9 hours in the placebo group ( −38.1 hours ) . In the case of the right colon , changes in transit time also were significant between groups . Mean changes tended toward faster transit times in the left colon and the rectum , although the differences were not statistically significant . The children who received cocoa husk supplements tended to increase the number of bowel movements by more than that of the children of the placebo group . We also observed a reduction in the percentage of patients who reported hard stools ( hard scybalous or pebble-like stools ) , although this reduction was significantly greater in the cocoa husk group . At the end of the intervention , 41.7 % and 75.0 % of the patients who received cocoa husk supplementation or placebo , respectively , reported having hard stools . Moreover , a significantly higher number of children ( or their parents ) reported a subjective improvement in stool consistency . No significant adverse effects were reported during the study . CONCLUSIONS . This study confirms the beneficial effect of a supplement of cocoa husk that is rich in dietary fiber on chronic idiopathic constipation in children . These benefits seem to be more evident in pediatric constipated patients with slow colonic transit time Background : Constipation is a common problem in children . As first-line treatment , increased dietary fiber is often advocated . To our knowledge , however , no large studies evaluating the effect of dietary fibers in childhood constipation have been published . Patients and Methods : A r and omized , double-blind , prospect i ve controlled study was performed . Patients received either a fiber mixture or lactulose in a yogurt drink . After a baseline period of 1 week , patients were treated for 8 weeks followed by 4 weeks of weaning . Polyethylene glycol 3350 was added if no clinical improvement was observed after 3 weeks . Using a st and ardized bowel diary , parents recorded defecation frequency during the treatment period . In addition , incontinence frequency , stool consistency , presence of abdominal pain and flatulence , necessity for step-up medication , and dry weight of feces were recorded , as were adverse effects . Results : A total of 147 children were eligible ; 12 children wished not to participate . Of the remaining children , 65 were r and omized to treatment with fiber mixture and 70 to treatment with lactulose . In all , 97 children completed the study . No difference was found between the groups after the treatment period concerning defecation frequency ( P = 0.481 ) and fecal incontinence frequency ( P = 0.084 ) . However , consistency of stools was softer in the lactulose group ( P = 0.01 ) . Abdominal pain and flatulence scores were comparable ( P = 0.395 and P = 0.739 , respectively ) . The necessity of step-up medication during the treatment period was comparable ( P = 0.996 ) , as were taste scores ( P = 0.657 ) . No serious adverse effects were registered . Conclusions : A fluid fiber mixture and lactulose give comparable results in the treatment of childhood constipation

Results The general verdict from the check list type evaluations in nine relevant systematic review s was that Burke et al. ( 1991 ) is a good quality trial . All relevant meta-analyses extensively used its data to formulate therapeutic evidence . My comprehensive evaluation , on the other h and , brought to the surface a series of serious problems in the design , conduct , analysis and report of this trial that were missed by the earlier evaluations . Conclusion A check-list or instrument based approach , if used as a short-cut , may at times rate deeply flawed trials as good quality trials .

Background Assessing the quality of included trials is a central part of a systematic review . Many check-list type of instruments for doing this exist . Using a trial of antibiotic treatment for acute otitis media , Burke et al. , BMJ , 1991 , as the case study , this paper illustrates some limitations of the check-list approach to trial quality assessment .

Although r and omised trials are important for evidence -based medicine , little is known about their overall characteristics . We assessed the epidemiology and reporting of method ological details for all 519 PubMed -indexed r and omised trials published in December , 2000 ( 383 [ 74 % ] parallel-group , 116 [ 22 % ] crossover ) . 482 ( 93 % ) were published in specialty journals . A median of 80 participants ( 10th-90th percentile 25 - 369 ) were recruited for parallel-group trials . 309 ( 60 % ) were blinded . Power calculation , primary outcomes , r and om sequence generation , allocation concealment , and h and ling of attrition were each adequately described in less than half of publications . The small sample sizes are worrying , and poor reporting of method ological characteristics will prevent reliable quality assessment of many published trials Abstract Objective : To determine the effect of antibiotic treatment for acute otitis media in children between 6 months and 2 years of age . Design : Practice based , double blind , r and omised , placebo controlled trial . Setting : 53 general practice s in the Netherl and s. Subjects : 240 children aged 6 months to 2 years with the diagnosis of acute otitis media . Intervention : Amoxicillin 40 mg/kg/day in three doses . Main outcome measures : Persistent symptoms at day four and duration of fever and pain or crying , or both . Otoscopy at days four and 11 , tympanometry at six weeks , and use of analgesic . Results : Persistent symptoms at day four were less common in the amoxicillin group ( risk difference 13 % ; 95 % confidence interval 1 % to 25 % ) . The median duration of fever was two days in the amoxicillin group versus three in the placebo group ( P=0.004 ) . No significant difference was observed in duration of pain or crying , but analgesic consumption was higher in the placebo group during the first 10 days ( 4.1 v 2.3 doses , P=0.004 ) . In addition , no otoscopic differences were observed at days four and 11 , and tympanometric findings at six weeks were similar in both groups . Conclusions : Seven to eight children aged 6 to 24 months with acute otitis media needed to be treated with antibiotics to improve symptomatic outcome at day four in one child . This modest effect does not justify prescription of antibiotics at the first visit , provided close surveillance can be guaranteed BACKGROUND Traditional and largely qualitative review s of evidence are now giving way to much more structured systematic overviews that use a quantitative method to calculate the overall effect of treatment . The latter approach is dependent on the quality of primary studies , which may introduce bias if they are of poor method ologic quality . OBJECTIVE To test the hypothesis that the inclusion of poor- quality trials in meta-analyses would bias the conclusions and produce incorrect estimates of treatment effect . METHODS An overview of r and omized trials of antiestrogen therapy in subfertile men with oligospermia was performed to test the hypothesis . Data sources included online search ing of MEDLINE and Science Citation Index data bases between 1966 and 1994 , scanning the bibliography of known primary studies and review articles , and contacting experts in the field . After independent , blind assessment , nine of 149 originally identified studies met the inclusion criteria and were selected . We assessed study quality independently . Outcome data from each study were pooled and statistically summarized . RESULTS There was a marginal improvement in pregnancy rate with antiestrogen treatment ( odds ratio , 1.6 ; 95 % confidence interval , 0.9 to 2.6 ) . Sensitivity analyses on the basis of method ologic quality demonstrated that poor- quality studies produced a positive effect with treatment , whereas no benefit was observed with high- quality studies . CONCLUSION The results of a meta- analysis are influenced by the quality of the primary studies included . Method ologically , poor studies tend to exaggerate the overall estimate of treatment effect and may lead to incorrect inferences CONTEXT Selective reporting of outcomes within published studies based on the nature or direction of their results has been widely suspected , but direct evidence of such bias is currently limited to case reports . OBJECTIVE To study empirically the extent and nature of outcome reporting bias in a cohort of r and omized trials . DESIGN Cohort study using protocol s and published reports of r and omized trials approved by the Scientific-Ethical Committees for Copenhagen and Frederiksberg , Denmark , in 1994 - 1995 . The number and characteristics of reported and unreported trial outcomes were recorded from protocol s , journal articles , and a survey of trialists . An outcome was considered incompletely reported if insufficient data were presented in the published articles for meta- analysis . Odds ratios relating the completeness of outcome reporting to statistical significance were calculated for each trial and then pooled to provide an overall estimate of bias . Protocol s and published articles were also compared to identify discrepancies in primary outcomes . MAIN OUTCOME MEASURES Completeness of reporting of efficacy and harm outcomes and of statistically significant vs nonsignificant outcomes ; consistency between primary outcomes defined in the most recent protocol s and those defined in published articles . RESULTS One hundred two trials with 122 published journal articles and 3736 outcomes were identified . Overall , 50 % of efficacy and 65 % of harm outcomes per trial were incompletely reported . Statistically significant outcomes had a higher odds of being fully reported compared with nonsignificant outcomes for both efficacy ( pooled odds ratio , 2.4 ; 95 % confidence interval [ CI ] , 1.4 - 4.0 ) and harm ( pooled odds ratio , 4.7 ; 95 % CI , 1.8 - 12.0 ) data . In comparing published articles with protocol s , 62 % of trials had at least 1 primary outcome that was changed , introduced , or omitted . Eighty-six percent of survey responders ( 42/49 ) denied the existence of unreported outcomes despite clear evidence to the contrary . CONCLUSIONS The reporting of trial outcomes is not only frequently incomplete but also biased and inconsistent with protocol s. Published articles , as well as review s that incorporate them , may therefore be unreliable and overestimate the benefits of an intervention . To ensure transparency , planned trials should be registered and protocol s should be made publicly available prior to trial completion OBJECTIVE --To examine the efficacy and safety of conservative management of mild otitis media ( " the acute red ear " ) in children . DESIGN --Double blind placebo controlled trial . SETTING --17 group general practice s ( 48 general practitioners ) in Southampton , Bristol , and Portsmouth . PATIENTS --232 children aged 3 - 10 years with acute earache and at least one abnormal eardrum ( 114 allocated to receive antibiotic , 118 placebo ) . INTERVENTIONS --Amoxycillin 125 mg three times a day for seven days or matching placebo ; 100 ml paracetamol 120 mg/5 ml . MAIN OUTCOME MEASURES --Diary records of pain and crying , use of analgesic , eardrum signs , failure of treatment , tympanometry at one and three months , recurrence rate , and ear , nose , and throat referral rate over one year . RESULTS --Treatment failure was eight times more likely in the placebo than the antibiotic group ( 14.4 % v 1.7 % , odds ratio 8.21 , 95 % confidence interval 1.94 to 34.7 ) . Children in the placebo group showed a significantly higher incidence of fever on the day after entry ( 20 % v 8 % , p less than 0.05 ) , mean analgesic consumption ( 0.36 ml/h v 0.21 ml/h , difference 0.14 , 95 % confidence interval 0.07 to 0.23 ; p = 0.0022 ) , mean duration of crying ( 1.44 days v 0.50 days , 0.94 ; 0.50 to 1.38 ; p less than 0.001 ) , and mean absence from school ( 1.96 days v 0.52 days , 1.45 ; 0.46 to 2.42 ; p = 0.0132 ) . Differences in recorded pain were not significant . The prevalence of middle ear effusion at one or three months , as defined by tympanometry , was not significantly different , nor was there any difference in recurrence rate or in ear , nose , and throat referral rate in the follow up year . No characteristics could be identified which predicted an adverse outcome . CONCLUSIONS --Use of antibiotic improves short term outcome substantially and therefore continues to be an appropriate management policy R and omised controlled trials ( RCTs ) must be internally valid ( i.e. , design and conduct must eliminate the possibility of bias ) , but to be clinical ly useful , the result must also be relevant to a definable group of patients in a particular clinical setting ( i.e. , they must be externally valid ) . Lack of external validity is the most frequent criticism by clinicians of RCTs , systematic review s , and guidelines , and is one explanation for the widespread underuse in routine practice of many treatments that have been shown to be beneficial in trials and are recommended in guidelines [ 1 ] . Yet medical journals , funding agencies , ethics committees , the pharmaceutical industry , and governmental regulators seem to give external validity a low priority . Admittedly , whereas the determinants of internal validity are intuitive and can generally be worked out from first principles , underst and ing of the determinants of the external validity of an RCT requires clinical rather than statistical expertise , and often depends on a detailed underst and ing of the particular clinical condition under study and its management in routine clinical practice . However , reliable judgments about the external validity of RCTs are essential if treatments are to be used correctly in as many patients as possible in routine clinical practice . The results of RCTs or systematic review s will never be relevant to all patients and all setting s , but they should be design ed and reported in a way that allows clinicians to judge to whom the results can reasonably be applied . Table 1 lists some of the important potential determinants of external validity , each of which is review ed briefly below . Many of the considerations will only be relevant in certain types of trials , for certain interventions , or in certain clinical setting s , but they can each sometimes undermine external validity . Moreover , the list is not exhaustive and requires more detailed annotation and explanation than is possible in this short review . Table 1 Main Issues That Can Affect External Validity and Should Be Addressed in Reports of the Results of R and omised Controlled Trials or Systematic Review s and Considered by Clinicians Some of the issues that determine external validity are relevant to the distinction between pragmatic trials and explanatory trials [ 2 ] , but it would be wrong to assume that pragmatic trials necessarily have greater external validity than explanatory trials . For example , broad eligibility criteria , limited collection of baseline data , and inclusion of centres with a range of expertise and differing patient population s have many advantages , but they can also make it very difficult to generalise the overall average effect of treatment to a particular clinical setting The results of a r and omized clinical trial can be reported using relative and /or absolute estimators of treatment effect . These various measures convey different information , and the choice can influence the physician 's appreciation of the size of treatment effect and , subsequently , treatment decisions . We compare the estimators with respect to the clinical ly relevant information conveyed to physicians , and identify which clinical questions can and can not be answered directly by each . We also identify opportunities for misinterpretation when one estimator is substituted for another , or when an estimator is mislabeled . Clinical ly important questions are addressed most directly by reporting both relative and absolute effects using relative risk and its complement , relative risk reduction , and risk difference and its reciprocal , number needed to treat . This is true of estimates of treatment effect derived from a single trial and also from meta- analysis of a group of trials . Because the control group 's risk affects the numerical value of the odds ratio , the odds ratio can not substitute for the risk ratio in conveying clinical ly important information to physicians . This is especially important when large treatment effects are shown in trials carried out in population s at high baseline risk Controlled clinical trials of the treatment of acute myocardial infa rct ion offer a unique opportunity for the study of the potential influence on outcome of bias in treatment assignment . A group of 145 papers was divided into those in which the r and omization process was blinded ( 57 papers ) , those in which it may have been unblinded ( 45 papers ) , and those in which the controls were selected by a nonr and om process ( 43 papers ) . At least one prognostic variable was maldistributed ( P less than 0.05 ) in 14.0 per cent of the blinded-r and omization studies , in 26.7 per cent of the unblinded-r and omization studies , and in 58.1 per cent of the nonr and omized studies . Differences in case-fatality rates between treatment and control groups ( P less than 0.05 ) were found in 8.8 per cent of the blinded-r and omization studies , 24.4 per cent of the unblinded-r and omization studies , and 58.1 per cent of the nonr and omized studies . These data emphasize the importance of keeping those who recruit patients for clinical trials from suspecting which treatment will be assigned to the patient under consideration BACKGROUND Conflicting reports exist in the medical literature regarding the association between industry funding and published research findings . In this study , we examine the association between industry funding and the statistical significance of results in recently published medical and surgical trials . METHODS We examined a consecutive series of 332 r and omized trials published between January 1999 and June 2001 in 8 leading surgical journals and 5 medical journals . Each eligible study was independently review ed for method ological quality using a 21-point index with 5 domains : r and omization , outcomes , eligibility criteria , interventions and statistical issues . Our primary analysis included studies that explicitly identified the primary outcome and reported it as statistically significant . For studies that did not explicitly identify a primary outcome , we defined a " positive " study as one with at least 1 statistically significant outcome measure . We used multivariable regression analysis to determine whether there was an association between reported industry funding and trial results , while controlling for study quality and sample size . RESULTS Among the 332 r and omized trials , there were 158 drug trials , 87 surgical trials and 87 trials of other therapies . In 122 ( 37 % ) of the trials , authors declared industry funding . An unadjusted analysis of this sample of trials revealed that industry funding was associated with a statistically significant result in favour of the new industry product ( odds ratio [ OR ] 1.9 , 95 % confidence interval [ CI ] 1.3 - 3.5 ) . The association remained significant after adjustment for study quality and sample size ( adjusted OR 1.8 , 95 % CI 1.1 - 3.0 ) . There was a nonsignificant difference between surgical trials ( OR 8.0 , 95 % CI 1.1 - 53.2 ) and drug trials ( OR 1.6 , 95 % CI 1.1 - 2.8 ) , both of which were likely to have a pro-industry result ( relative OR 5.0 , 95 % CI 0.7 - 37.5 , p = 0.14 ) . INTERPRETATION Industry-funded trials are more likely to be associated with statistically significant pro-industry findings , both in medical trials and surgical interventions Evidence that is both accurate ( internally valid ) and relevant ( externally valid ) is needed to decide which treatment is best for a particular patient . Evidence rankings facilitate the marshalling of evidence on clinical decisions in the common context of an overwhelming number of studies , some with conflicting results . Evidence from r and omized control trials is typically ranked above evidence from non-experimental studies since rankings are based primarily , if not exclusively , on considerations of internal validity . We propose that evidence rankings should consider equally both internal and external validity . External validity includes how closely the study population , the institution types in the study , the types of physicians in the study , the role of clinician decision-making ( e.g. dose adjustment ) in the study , and the role of patient preferences in the study resemble those in actual practice . The example of spironolactone use in heart failure illustrates the danger in using evidence that is internally but not externally valid . Ideally , a treatment should only be used when both internally and externally valid evidence indicates that it will be useful for the particular patient Abstract Objective To determine whether poor reporting of methods in r and omised controlled trials reflects on poor methods . Design Observational study . Setting Reports of r and omised controlled trials conducted by the Radiation Therapy Oncology Group since its establishment in 1968 . Participants The Radiation Therapy Oncology Group . Outcome measures Content of reports compared with the design features described in the protocol s for all r and omised controlled trials . Results The method ological quality of 56 r and omised controlled trials was better than reported . Adequate allocation concealment was achieved in all trials but reported in only 42 % of papers . An intention to treat analysis was done in 83 % of trials but reported in only 69 % of papers . The sample size calculation was performed in 76 % of the studies , but reported in only 16 % of papers . End points were clearly defined and α and βerrors were prespecified in 76 % and 74 % of the trials , respectively , but only reported in 10 % of the papers . The one exception was the description of drop outs , where the frequency of reporting was similar to that contained in the original statistical files of the Radiation Therapy Oncology Group . Conclusions The reporting of method ological aspects of r and omised controlled trials does not necessarily reflect the conduct of the trial . Review ing research protocol s and contacting trialists for more information may improve quality assessment BACKGROUND The quality of clinical trials has received increasing attention with the growth of evidence -based medicine and systematic review s. We aim ed to identify whether errors and omissions commonly encountered when undertaking Cochrane review s in this field are still passing peer review . METHODS We undertook a review of trials published in 2001 by two major journals . We selected from Medline only trials in which authors compared pregnancy rates under two interventions by allocating women to different groups . RESULTS We identified 39 trials meeting our criteria . Six trials were fatally flawed by design , either by inappropriate use of a cross-over design or by systematic allocation described by the authors as ' r and om ' . Only six reports cl aim ed to apply the intention-to-treat principle , and the principle was misunderstood by four of these . Only five trials reported live birth rates sufficiently to allow valid meta- analysis . Most trials ( 82 % ) included at least one ' unit of analysis ' error . CONCLUSIONS We selected simple trials from respected journals , assuming that our sample would represent trials of highest method ological quality in the field . Nevertheless , the st and ards of design , analysis and reporting of many subfertility trials are not sufficient to allow reliable interpretation of results , or inclusion in meta-analyses In a double-blind study 171 children with acute otitis media ( 239 affected ears ) were treated by four different methods : neither antibiotics nor myringotomy ; myringotomy only ; antibiotics only ; or both antibiotics and myringotomy . All received symptomatic treatment . There were no significant differences in clinical course ( pain , temperature , duration of discharge , otoscopic appearances , audiography , recurrence rate ) between the four groups . In the groups treated without antibiotics , the ears discharge for slightly longer and the eardrums took a little longer to heal ; these differences were not significant . No complications were seen . Symptomatic therapy with nosedrops and analgesics seems a reasonable initial approach to acute otitis media in children . Myringotomy and antibiotics can be reserved for cases in which the course of otitis is irregular , there are complications such as mastoiditis , or ear discharge continues beyond 14 days EVIDENCE THAT routine antimicrobial treatment improves the course and outcomes after acute otitis media is weak . Given the lack of evidence for benefit and the potential for adverse effects , including altering normal respiratory flora and development of resistant organisms , routine treatment using 10 days of antimicrobials for all cases of acute otitis media is not warranted . See also p 1640 . There have been 7 r and omized , blinded , placebo-controlled trials of acute otitis media over the past 30 years . Neither short- nor long-term differences were demonstrated in 3,1 - 3 and minor differences noted in the other 4 studies were limited to short-term benefits of antimicrobials.4 - 7In a study by Howie and Ploussard,4all case patients receiving placebo were asymptomatic at early follow-up ( 2 to 7 days ) but had more positive tympanocentesis cultures than those receiving antimicrobials . Mygind et al5found decreased pain in the penicillin group compared with

It is important to emphasize that the decision to exclude overweight and obese children from the determination of reference points has led to BP cutoffs that were lower than those in the tables we had been using so far .

DOI : 10.25060/residpediatr-2018.v8n1 - 12 In September 2017 , the Subcommittee on Screening and Management of High Blood Pressure in Children of the American Academy of Pediatrics published an up date to their well-known 2004 document in the journal Pediatrics . Their original Fourth Report on the Diagnosis , Evaluation , and Treatment of High Blood Pressure in Children and Adolescents has been adopted in Brazil to diagnose , evaluate , and treat children and adolescents with high blood pressure .

A r and omized crossover trial on the effect of salt restriction on blood pressure was carried out involving 124 adolescents ( mean age 16 years ) . Dietary sodium was reduced from approximately 110 to 45 mEq/24 h for a period of 24 days . Blood pressure was non-significantly lower at the end of the experimental diet for all participants . A slight ( 0.7 kg ) , yet statistically significant fall in weight was observed ( P less than 0.05 ) . Subgroup analysis demonstrated that participants whose body mass index was below the median had a statistically significant fall in systolic blood pressure ( P less than 0.05 ) ; fall in weight and increase in heart rate were also more pronounced in the less obese individuals . It would appear that moderate sodium reduction does not have an overall short-term effect on blood pressure in normotensive adolescents . However , body size as reflected in body mass index may influence blood pressure response to sodium reduction The aim of this study was to assess the relation between blood pressure ( BP ) and arterial compliance in a healthy sample of young adults . School children ( aged 10 to 14 years at entry ) were surveyed in 1977 to 1978 , and 1,207 were followed once to twice yearly until age 23 years . Arterial compliance was measured in 179 adults at the last follow-up visit . The sample included individuals in the upper tertile of systolic BP during the last three follow-up visits and race- and sex-matched individuals in the lower two tertiles . We obtained radial artery waveforms using a calibrated tonometer device and characterized waveform morphology to determine large artery ( C1 ) and oscillatory ( C2 ) compliance . Blood pressure was measured using r and om zero sphygmomanometers . The mean and st and ard deviation of C1 was 2.13 + /- 0.59 mL/mm Hg and of C2 was 0.083 + /- 0.02 mL/mm Hg . Systolic BP was inversely related to C1 ( P < .001 ) and C2 ( P < .01 ) after adjustment for gender , height , weight , insulin , and HDL and LDL cholesterol . After adjustment , a 1 SD change in systolic BP was associated with a -0.30 mL/mm Hg change in C1 and a -.008 mL/mm Hg change in C2 . Data from the Minnesota Children 's Blood Pressure Study indicate that systolic BP is inversely related to arterial compliance , particularly C1 ( the large artery , or capacitive compliance ) To examine the long-term effects of weight loss and dietary sodium reduction on the incidence of hypertension , we studied 181 men and women who participated in the Trials of Hypertension Prevention , phase 1 , in Baltimore , Md. At baseline ( 1987 to 1988 ) , subjects were 30 to 54 years old and had a diastolic blood pressure ( BP ) of 80 to 89 mm Hg and systolic BP < 160 mm Hg . They were r and omly assigned to one of two 18-month lifestyle modification interventions aim ed at either weight loss or dietary sodium reduction or to a usual care control group . At the posttrial follow-up ( 1994 to 1995 ) , BP was measured by blinded observers who used a r and om-zero sphygmomanometer . Incident hypertension was defined as systolic BP > or = 160 mm Hg and /or diastolic BP > or = 90 mm Hg and /or treatment with antihypertensive medication during follow-up . Body weight and urinary sodium were not significantly different among the groups at the posttrial follow-up . After 7 years of follow-up , the incidence of hypertension was 18.9 % in the weight loss group and 40.5 % in its control group and 22.4 % in the sodium reduction group and 32.9 % in its control group . In logistic regression analysis adjusted for baseline age , gender , race , physical activity , alcohol consumption , education , body weight , systolic BP , and urinary sodium excretion , the odds of hypertension was reduced by 77 % ( odds ratio 0.23 ; 95 % confidence interval 0.07 to 0.76 ; P=0.02 ) in the weight loss group and by 35 % ( odds ratio 0.65 ; 95 % confidence interval 0.25 to 1.69 ; P=0.37 ) in the sodium reduction group compared with their control groups . These results indicate that lifestyle modification such as weight loss may be effective in long-term primary prevention of hypertension The roots of essential hypertension extend back into the first two decades of life , suggesting that effective intervention during those years may lead to a reduction in the incidence of adult hypertension . Decreasing the dietary sodium/potassium ratio offers a potentially effective approach to blood pressure reduction . This study tested the feasibility of 3-year sodium reduction or potassium supplementation in adolescents and the effect of these interventions on the rate of rise of blood pressure during adolescence . After 19,452 5th to 8th grade students were screened , 210 from the upper 15 percentiles of blood pressure distribution ( 105 boys , 105 girls ) were r and omly assigned to one of three groups : low sodium diet ( 70 mmol sodium intake per day ) , potassium chloride supplementation ( normal diet plus 1 mmol/kg potassium chloride per day ) , or placebo ( normal diet plus placebo capsule ) . Capsules for the potassium chloride and placebo groups were administered in a double blind protocol . Blood pressure was measured every 3 months for 3 years . The effect of the intervention was determined by comparing the rate of rise ( slope ) of blood pressure among the groups using a r and om-coefficient growth curve model . The boys groups and the girls placebo group had similar positive blood pressure slopes that were significantly different from zero . The girls low sodium group had a slightly negative slope ( significantly lower than the slope of the girls placebo group ) , and the girls potassium group had a slightly positive slope . Both of these slopes were not significantly different from zero and were significantly lower than the slopes of the respective boys groups . ( ABSTRACT TRUNCATED AT 250 WORDS In 1980 , a r and omized trial was conducted among 476 Dutch newborn infants to study the effect of a low or normal sodium diet on blood pressure during the first 6 months of life . At the end of the trial , systolic blood pressure in the low sodium group ( n = 231 ) was 2.1 mm Hg lower than in the control group ( n = 245 ) . To investigate whether contrasting levels of sodium intake in infancy are associated with blood pressure differences in adolescence , we measured blood pressure in 167 children from the original cohort ( 35 % ) after 15 years of follow-up . We assessed the differences in systolic and diastolic blood pressure levels between the diet groups using a multivariate regression model with adjustment for potential confounders . The adjusted systolic blood pressure at follow-up was 3.6 mm Hg lower ( 95 % confidence interval , -6.6 to -0.5 ) and the diastolic pressure was 2.2 mm Hg lower ( 95 % confidence interval , -4.5 to 0.2 ) in children who had been assigned to the low sodium group ( n = 71 ) compared with the control group ( n = 96 ) . These findings suggest that sodium intake in infancy may be important in relation to blood pressure later in life The position of both the body and the arm during indirect blood pressure ( BP ) measurement is often neglected . The aim of the present study was to test the influence of the position of the patient on BP readings : ( 1 ) sitting with the arms supported precisely at the right atrium level and ( 2 ) supine : ( a ) with the arms precisely at the right atrium level and ( b ) with the arms on the examination bed . In a first group of 57 hypertensive patients , two sessions of BP and heart rate ( HR ) measurements were performed in two positions : sitting and supine with the arms supported precisely at right atrium level in both positions . BP was measured simultaneously at both arms , with a Hawksley R and om Zero sphygmomanometer at the right arm , and with an automated oscillometric device ( Bosomat ) at the left arm . BP and HR readings obtained in the two positions were then compared . In a second group of 25 normo- and hypertensive persons , two sessions of BP and HR readings were performed in supine with the arms in two different arm positions : ( a ) the arm placed precisely at right atrium level and ( b ) the other arm on the examination bed . The measurements were performed at both arms with two automated devices ( Bosomat ) . The readings taken in the two positions were compared . Both systolic BP ( SBP ; by 9.5±9.0 ( st and ard deviation , s.d . ) ; right arm ) and diastolic BP ( DBP ; by 4.8±6.0 mmHg ; right arm ) were significantly higher in the supine than in the sitting position . When the two different arm positions ( body continously supine ) were compared in the second part of the study , significantly higher SBP ( by 4.6±6.1 mmHg ) and DBP ( by 3.9±2.8 mmHg ) were obtained when the arm of the patient was placed on the bed ( below the right atrium level ) , than when the arm was placed at the level of the right atrium . BP readings in sitting and supine positions are not the same . When according to guidelines the arm of the patient is meticulously placed at the right atrium level in both positions , the difference is even greater than when the arm rests on the desk or on the arm support of the chair . Moreover , in the supine position small but significant differences in BP are measured between arm on a 5 cm-high pillow and arm on the bed . In every study reporting BP values , the position of both the body and especially the arm should be precisely mentioned The relationship between sodium intake and blood pressure in adolescents was examined in a dietary intervention study . One hundred schoolchildren aged 11 - 14 years and representing the top , middle and bottom deciles of the blood pressure range completed a crossover protocol requiring them to raise and lower their sodium intake for alternate periods of 4 weeks . Blood pressure and urinary sodium excretion were assessed weekly and diet diaries were recorded at the end of each 4-week diet period . Diet-diary analysis confirmed that sodium intake was selectively affected by the intervention . Estimates of average urinary sodium excretion at the end of each diet period differed by more than 80 mmol/day . However , there was no significant change of either systolic or diastolic blood pressure , measured supine in the whole study group , in either sex or in any of the sub-groups , even in those children representing the highest blood pressure decile . Furthermore , the blood pressure changes seen in individuals during the crossover did not correlate with their changes in sodium excretion . This lack of effect of sodium on blood pressure is consistent with other dietary intervention studies in children and supports the hypothesis that the sodium sensitivity of blood pressure is age-related . We conclude that dietary sodium restriction alone has little potential for lowering blood pressure at an early age , even in children with higher than average blood pressure OBJECTIVE This study examined the impact of the Transcendental Meditation ( TM ) program on cardiovascular ( CV ) reactivity in adolescents with high normal BP . METHOD Thirty-five adolescents [ 34 African Americans ( AAs ) , 1 Caucasian American ( CA ) ; ages 15 - 18 years ] with resting systolic blood pressure ( SBP ) between the 85th and 95th percentile for their age and gender on three consecutive occasions , were r and omly assigned to either TM ( n=17 ) or health education control ( CTL , n=18 ) groups . The TM group engaged in 15-min meditation twice each day for 2 months including sessions during school lunch break . Primary CV outcome measures were changes in blood pressure ( BP ) , heart rate ( HR ) , and cardiac output ( CO ) at rest and in response to two laboratory stressors , a simulated car driving stressor and an interpersonal social stressor interview . RESULTS The TM group exhibited greater decreases in resting SBP ( P<.03 ) from pre- to postintervention , compared to the CTL group . The TM group exhibited greater decreases from pre- to postintervention in SBP , HR , and CO reactivity ( P's<.03 ) to the simulated car driving stressor , and in SBP reactivity ( P<.03 ) to the social stressor interview . CONCLUSION The TM program appears to have a beneficial impact upon CV functioning at rest and during acute laboratory stress in adolescents at-risk for hypertension Delineating the role that diet plays in blood pressure levels in children is important for guiding dietary recommendations for the prevention of hypertension . The purpose of this study was to investigate relationships between dietary nutrients and blood pressure in children . Data were analyzed from 662 participants in the Dietary Intervention Study in Children who had elevated low-density lipoprotein cholesterol and were aged 8 to 11 years at baseline . Three 24-hour dietary recalls , systolic pressure , diastolic pressure , height , and weight were obtained at baseline , 1 year , and 3 years . Nutrients analyzed were the micronutrients calcium , magnesium , and potassium ; the macronutrients protein , carbohydrates , total fat , saturated fat , polyunsaturated fat , and monounsaturated fat ; dietary cholesterol ; and total dietary fiber . Baseline and 3-year longitudinal relationships were examined through multivariate models on diastolic and systolic pressures separately , controlling for height , weight , sex , and total caloric intake . The following associations were found in longitudinal analyses : analyzing each nutrient separately , for systolic pressure , inverse associations with calcium ( P < .05 ) ; magnesium , potassium , and protein ( all P < .01 ) ; and fiber ( P < .05 ) , and direct associations with total fat and monounsaturated fat ( both P < .05 ) ; for diastolic pressure , inverse associations with calcium ( P < .01 ) ; magnesium and potassium ( both P < .05 ) , protein ( P < .01 ) ; and carbohydrates and fiber ( both P < .05 ) , and direct associations with polyunsaturated fat ( P < .01 ) and monounsaturated fat ( P < .05 ) . Analyzing all nutrients simultaneously , for systolic pressure , direct association with total fat ( P < .01 ) ; for diastolic pressure , inverse associations with calcium ( P < .01 ) and fiber ( P < .05 ) , and direct association with total and monounsaturated fats ( both P < .05 ) . Results from this sample of children with elevated low-density lipoprotein cholesterol indicate that dietary calcium , fiber , and fat may be important determinants of blood pressure level in children The objective of this study was to examine whether a protein-sparing modified fast diet and a hypocaloric balanced diet are effective in a clinic-based dietary intervention implemented in a school setting high-risk weight loss program for superobese ( > or = 140 % of their ideal body weight for height [ IBW ] children . A group of children from two suburban public schools in New Orleans , Louisiana were r and omized to either dietary-intervention group and control group . Children were followed for 6 months . In the dietary-intervention-group , 12 of 44 superobese children [ ages 8.8 to 13.4 years , weight 144 % to 212 % of IBW ] volunteered to participate . In the control group , 7 of 19 superobese children [ ages 9.4 to 12.9 years , weight 140 % to 195 % of IBW ] volunteered to participate . During the first 9 weeks , 12 superobese children were placed on a 2520 to 3360 J ( 600 to 800 Cal ) protein-sparing modified fast diet . Subsequently , the diets of all children were increased in a 3-month period 420 J ( 100 Cal ) every 2 weeks until a 5040 J ( 1200 Cal ) per day balanced diet was attained . In both groups , height and weight were obtained at baseline , 10 weeks , and 6 months ; and biochemical measurements were performed at baseline and 6 months . At 6 months the 12 superobese children on protein-sparing modified fast diet had a significant weight loss from baseline ( -5.6 + /- 7.1 kg , ANOVA p < 0.02 ) ; a significant decrease in percentage IBW ( -24.3 + /- 20 % , ANOVA p < 0.002 ) ; and had positive growth velocity Z-score ( 1.3 + /- 1.6 , ANOVA p < 0.05 ) . Six children were not superobese at 6 months . At 6 months eight of 12 children were active participants and 11 of 12 children were followed . Decrease in blood pressure , as well as , downward trends in serum lipids were observed at 6 months . No clinical complications were observed . At 6 months , the 7 control superobese children , when compared with baseline had gained weight ( 2.8 + /- 3.1 kg , ANOVA p < 0.008 ) ; but had no significant change in percentage IBW ( -0.3 + /- 5.9 % , ANOVA p = 0.61 ) ; and had no changes in growth velocity Z-score ( 0.1 + /- 1.3 , ANOVA p = 0.83 ) . These children did not have any change in blood pressure and an upward trend in serum lipids were observed at 6 months . Protein-sparing modified fast diet and a hypocaloric balanced diet appear to be effective in a group of superobese-school-age children in a medically supervised clinic-based program implemented in a school setting over a 6-month period . The efforts of committed clinic staffs , school officials , peers , and family involvement were crucial to the success of this intervention program in promoting and maintaining weight loss over a 6-month period . Further research with a specific comparison of the hypocaloric diets with longer follow-up periods in the school setting is necessary . In the meantime , these diets should be used only with close medical supervision OBJECTIVES To determine the association between carotid artery intimal-medial thickness ( cIMT ) and left ventricular mass index ( LVMI ) in children with elevated blood pressure . METHODS Study subjects ( n = 32 ; mean age : 13.9 + /- 2.7 years ) were untreated new referrals to a pediatric hypertension clinic with confirmed elevated blood pressure . LVM was calculated from 2-dimensionally guided m-mode echocardiographic measurements of the left ventricle . LVMI was calculated as LVM (g)/height (m)2.7 , and left ventricular hypertrophy ( LVH ) was defined as LVMI > 95th percentile . Carotid artery duplex ultrasound was performed by protocol by experienced vascular sonographers who were unaware of the echocardiography results . The thickest IMT complex of the far wall of the distal common carotid artery was measured in longitudinal B-mode section using a high-resolution linear array of 8 MHz . RESULTS The prevalence of LVH and increased cIMT was 41 % and 28 % , respectively . Subjects with increased cIMT had higher LVMI ( 46.8 g/m2.7 vs 31.4 g/m2.7 ) than those with normal cIMT . The LVH prevalence was 89 % ( 8 of 9 ) among subjects with increased cIMT as compared with 22 % ( 5 of 23 ) in subjects with normal cIMT . cIMT was positively correlated with body mass index ( r = 0.43 ) , interventricular septal thickness ( r = 0.58 ) , posterior wall thickness ( r = 0.54 ) , and LVMI ( r = 0.54 ) . cIMT and LVMI were positively associated after accounting for age , gender , and body mass index . CONCLUSIONS These findings raise the possibility that carotid duplex ultrasound , by indicating the presence of early arterial wall changes , may be useful for predicting other cardiovascular sequelae in hypertensive children Background —Children with chronic renal disease have a high prevalence of left ventricular hypertrophy ( LVH ) , which is thought to be adaptive to improve contractility and lower wall stress in the face of increased afterload and preload . The aim of this study was to determine the association between LV mass , LV performance , and LV contractility in children with chronic renal insufficiency ( CRI ) and children undergoing chronic dialysis . Methods and Results —Twenty-five children with CRI , 12 undergoing chronic dialysis , and 24 controls had echocardiographic evaluation during rest and peak exercise . LV performance was assessed by calculation of shortening fraction and heart rate – corrected velocity of circumferential fiber shortening ( VCF ) . Contractility ( VCF difference ) was determined based on the relation between VCF and end-systolic wall stress . Contractile reserve was assessed by the difference between contractility at rest and peak exercise . The dialysis group had higher LVM index than the group with CRI ( 42.9±10.3 versus 29.9±9.4 g/m2.7 , P < 0.001 ) . Both groups had higher LVM index compared with controls ( 22.2±6.1 g/m2.7 , P < 0.001 ) . At rest , the CRI and dialysis groups had significantly higher VCFc ( P < 0.001 ) and VCF difference ( P < 0.05 ) and significantly lower wall stress ( P < 0.01 ) compared with the control group . Dialysis patients had significantly lower contractile reserve compared with the control group ( P < 0.03 ) . Conclusions —These results indicate that children with CRI and undergoing chronic dialysis have increased LVM , LV performance , and contractility at rest . However , dialysis patients have diminished contractile reserve during exercise , which might be an indicator for the development of more severe systolic dysfunction over time Abstract Objective : To investigate the relation of infant feeding practice to childhood respiratory illness , growth , body composition , and blood pressure . Design : Follow up study of a cohort of children ( mean age 7.3 years ) who had detailed infant feeding and demographic data collected prospect ively during the first two years of life . Setting : Dundee . Subjects : 674 infants , of whom 545 ( 81 % ) were available for study . Data on respiratory illness were available for 545 children ( mean age 7.3 ( range 6.1- 9.9 ) years ) ; height for 410 children ; weight and body mass index for 412 children ; body composition for 405 children ; blood pressure for 301 children ( mean age 7.2 ( range 6.9 - 10.0 ) years ) . Main outcome measures : Respiratory illness , weight , height , body mass index , percentage body fat , and blood pressure in relation to duration of breast feeding and timing of introduction of solids . Results : After adjustment for the significant confounding variables the estimated probability of ever having respiratory illness in children who received breast milk exclusively for at least 15 weeks was consistently lower ( 17.0 % ( 95 % confidence interval 15.9 % to 18.1 % ) for exclusive breast feeding , 31.0 % ( 26.8 % to 35.2 % ) for partial breast feeding , and 32.2 % ( 30.7 % to 33.7 % ) for bottle feeding . Solid feeding before 15 weeks was associated with an increased probability of wheeze during childhood ( 21.0 % ( 19.9 % to 22.1 % ) v 9.7 % ( 8.6 % to 10.8 % ) ) . It was also associated with increased percentage body fat and weight in childhood ( mean body fat 18.5 % ( 18.2 % to 18.8 % ) v 16.5 % ( 16.0 % to 17.0 % ) ; weight st and ard deviation score 0.02 ( −0.02 to 0.06 ) v −0.09 ( −0.16 to 0.02 ) . Systolic blood pressure was raised significantly in children who were exclusively bottle fed compared with children who received breast milk ( mean 94.2 ( 93.5 to 94.9 ) mm Hg v 90.7 ( 89.9 to 91.7 ) mm Hg ) . Conclusions : The probability of respiratory illness occurring at any time during childhood is significantly reduced if the child is fed exclusively breast milk for 15 weeks and no solid foods are introduced during this time . Breast feeding and the late introduction of solids may have a beneficial effect on childhood health and subsequent adult disease . Key messages Current guidelines in the United Kingdom recommend that babies are exclusively breast fed for the first 4 months of life , with solids being introduced thereafter This study found that exclusive breast feeding is associated with a significant reduction in childhood respiratory illness The early introduction of solids is associated with increased body fat and weight in childhood Exclusive bottle feeding is associated with higher systolic blood pressure in childhood Breast feeding and delaying the introduction of solids until after 15 weeks may have a beneficial effect on childhood health and subsequent adult Background —Breast-feeding in infancy has been associated with decreased coronary heart disease mortality , but the underlying mechanisms are unclear . We investigated the association of breast-feeding with blood pressure in a contemporary cohort . Methods and Results —In a prospect i ve cohort study ( ALSPAC , United Kingdom ) , a total of 7276 singleton , term infants born in 1991 and 1992 were examined at 7.5 years . Complete data were available for 4763 children . The systolic and diastolic blood pressures of breast-fed children were 1.2 mm Hg lower ( 95 % CI , 0.5 to 1.9 ) and 0.9 mm Hg lower ( 0.3 to 1.4 ) , respectively , compared with children who were never breast-fed ( models controlled for age , sex , room temperature , and field observer ) . Blood pressure differences were attenuated but remained statistically significant in fully adjusted models controlling for social , economic , maternal , and anthropometric variables ( reduction in systolic blood pressure : 0.8 mm Hg [ 0.1 to 1.5 ] ; reduction in diastolic blood pressure : 0.6 mm Hg [ 0.1 to 1.0 ] ) . Blood pressure differences were similar whether breast-feeding was partial or exclusive . We examined the effect of breast-feeding duration . In fully adjusted models , there was a 0.2-mm Hg reduction ( 0.0 to 0.3 ) in systolic pressure for each 3 months of breast-feeding . Conclusions —Breast-feeding is associated with a lowering of later blood pressure in children born at term . If the association is causal , the wider promotion of breast-feeding is a potential component of the public health strategy to reduce population levels of blood pressure Objective Tracking of blood pressure ( BP ) from childhood occurs in population s but , for individuals , prediction of adult BP from childhood levels is poor . We examined factors that may influence tracking of BP to identify better predictors of higher BP in early adult life . Design A prospect i ve study of children recruited at the age of 9 years by r and om sampling of Perth metropolitan schools stratified by socio-economic status . Setting Community based with re-surveys 3-yearly for 9 years . Participants A total of 516 boys and 520 girls at 9 years ; 680 boys and 630 girls at 12 years ; 318 boys and 300 girls at 15 years ; 330 men and 326 women at 18 years . Main outcome measures Systolic ( SBP ) and diastolic ( DBP ) BP . Results Persistence in the highest quartile for SBP between surveys was seen in 34–48 % of subjects and in 37 % between the ages of 9 and 18 years . The proportion increased to around 60 % in those in the highest quartile for body mass index ( BMI ) , to 70 % in those in the highest quartile for change in BMI and to 60 % if there was a family history of hypertension . In log-linear models , persistence in a quartile for SBP was significantly related to a family history of hypertension , previous SBP , BMI and change in BMI . Relationships were similar for DBP . Conclusions Excessive weight gain in adolescence and a family history of hypertension substantially increase the risk of higher BP persisting into early adult life . Recognition of children at risk would allow early intervention emphasizing weight control with potential long-term benefits OBJECTIVE Recent reports have suggested that a low glycemic index ( GI ) diet may have a role in the management of obesity through its ability to increase the satiety value of food and modulate appetite . To date , no long-term clinical trials have examined the effect of dietary GI on body weight regulation . The majority of evidence comes from single-day studies , most of which have been conducted in adults . The purpose of this study was to investigate the effect of 3 test breakfasts-low-GI , low-GI with 10 % added sucrose , and high-GI-on ad libitum lunch intake , appetite , and satiety and to compare these with baseline values when habitual breakfast was consumed . METHODS A 3-way crossover study using block r and omization of breakfast type was conducted in a school that already ran a breakfast club . A total of 37 children aged 9 to 12 years ( 15 boys and 22 girls ) completed the study . The proportion of nonoverweight to overweight/obese children was 70:30 . Children were divided into 5 groups , and a rolling program was devised whereby , week by week , each group would r and omly receive 1 of 3 test breakfasts for 3 consecutive days , with a minimum of 5 weeks between the test breakfasts . Participants acted as their own control . The 3 test breakfasts were devised to match the energy and nutritional content of an individual 's habitual breakfast as far as possible . All test breakfasts were composed of fruit juice , cereal , and milk with/without bread and margarine ; foods with an appropriate GI value were selected . After each test breakfast , children were instructed not to eat or drink anything until lunchtime , except water and a small serving of fruit supplying approximately 10 g of carbohydrate , which was provided . Breakfast palatability , satiation after breakfast , and satiety before lunch were measured using rating scales based on previously used tools . Lunch was a buffet-style meal , and children were allowed free access to a range of foods . Lunch was served in the school hall where the rest of the schoolchildren were eating . Food intake at lunch was unobtrusively observed and recorded . Leftovers and food swapping were recorded , and plate waste was estimated . Lunch intakes were analyzed using a multilevel regression model for repeated measures data . The likelihood ratio statistic was used to determine whether the type of breakfast eaten had a significant effect on lunch intake after allowing for sex and weight status . RESULTS The type of breakfast eaten had a statistically significant effect on mean energy intake at lunchtime : lunch intake was lower after low-GI and low-GI with added sucrose breakfasts compared with lunch intake after high-GI and habitual breakfasts ( which were high-GI ) . Overweight and sex did not have a significant effect on lunch intake . Pairwise comparisons among the 3 types of test breakfasts and between each test breakfast and habitual breakfast were made . Lunch intake after the high-GI breakfast was significantly higher than after the low-GI breakfast and low-GI breakfast with added sucrose . The details of the pairwise comparisons were as follows : high-GI versus low-GI = 145 + /- 54 kcal ; high-GI versus low-GI plus sucrose = 119 + /- 53 kcal ; low-GI plus sucrose versus low-GI = 27 + /- 54 kcal . Lunch intake after the low-GI breakfast and the low-GI breakfast with added sucrose was significantly lower than after the habitual breakfast . The details of the pairwise comparisons were as follows : low-GI versus habitual = -109 + /- 75 kcal ; low-GI plus sucrose versus habitual = -83 + /- 75 kcal ; high-GI versus habitual = 36 + /- 75 kcal . There were no significant differences between the test breakfasts in immediate satiation . The high-GI breakfasts were rated to be more palatable than the low-GI breakfasts . At lunchtime , hunger ratings were greater after the high-GI breakfast compared with the other 2 test breakfasts on 2 of the 3 experimental days . Prelunch satiety scales were inversely related to subsequent food intake . CONCLUSIONS These results suggest that low-GI foods eaten at breakfast have a significant impact on food intake at lunch . This is the first study to observe such an effect in a group of normal and overweight children and adds to the growing body of evidence that low-GI foods may have an important role in weight control and obesity management . The potentially confounding effect of differences in the macronutrient and dietary fiber content of the test breakfasts warrants additional study . In addition , the impact of GI on food intake and body weight regulation in the long term needs to be investigated BACKGROUND The effect of dietary composition on blood pressure is a subject of public health importance . We studied the effect of different levels of dietary sodium , in conjunction with the Dietary Approaches to Stop Hypertension ( DASH ) diet , which is rich in vegetables , fruits , and low-fat dairy products , in persons with and in those without hypertension . METHODS A total of 412 participants were r and omly assigned to eat either a control diet typical of intake in the United States or the DASH diet . Within the assigned diet , participants ate foods with high , intermediate , and low levels of sodium for 30 consecutive days each , in r and om order . RESULTS Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg ( P<0.001 ) during the control diet and by 1.3 mm Hg ( P=0.03 ) during the DASH diet . Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet ( P<0.001 ) and 1.7 mm Hg during the DASH diet ( P<0.01 ) . The effects of sodium were observed in participants with and in those without hypertension , blacks and those of other races , and women and men . The DASH diet was associated with a significantly lower systolic blood pressure at each sodium level ; and the difference was greater with high sodium levels than with low ones . As compared with the control diet with a high sodium level , the DASH diet with a low sodium level led to a mean systolic blood pressure that was 7.1 mm Hg lower in participants without hypertension , and 11.5 mm Hg lower in participants with hypertension . CONCLUSIONS The reduction of sodium intake to levels below the current recommendation of 100 mmol per day and the DASH diet both lower blood pressure substantially , with greater effects in combination than singly . Long-term health benefits will depend on the ability of people to make long-lasting dietary changes and the increased availability of lower-sodium foods This study was intended to clarify the relation between fasting insulin , lipids , and blood pressure in adolescents before the onset of hypertension and to examine the association of these data with similar data obtained in their parents . The participants in this study were 183 adolescents 14 to 18 years old ( 96 girls ) completing a 4-year intervention trial and their parents ( 164 mothers , 122 fathers ) . Blood pressure was measured twice on the right arm in a seated position using a r and om-zero sphygmomanometer . Fasting blood sample s were obtained for lipid and insulin analyses . Fasting insulin was significantly correlated with systolic blood pressure in the adolescents and also in the parents before and after adjustment for body mass index . Fasting insulin was correlated significantly with levels of cholesterol , triglycerides , and HDL and LDL cholesterol in the adolescents . It was correlated only with triglycerides and HDL-cholesterol in mothers and fathers . After adjustment for body mass index , the correlations between fasting insulin and lipids in the children were not significant . A significant relation was shown between children 's systolic blood pressure and mothers ' fasting insulin and systolic blood pressure . Significant correlations were found between the children 's and fathers ' triglycerides and HDL-cholesterol , whereas significant correlations were found for fasting insulin and all lipids between mothers and children , and these remained significant after adjustment for body mass index . These results show ( 1 ) a significant relation between fasting insulin and both lipids and systolic blood pressure in adolescents and ( 2 ) a significant relation for these factors between adolescents and their parents . Although weight appears to play an important role in this relation during adolescence , genetic and environmental factors other than those mediated via weight may control insulin metabolism within families . The data support a role for studies during early biological development to address these issues Objective To determine the relation between blood pressure and insulin resistance in children and the differences between fasting insulin and the insulin clamp in that relation . Methods Children were r and omly selected after blood pressure screening of 12 043 fifth – eigth grade Minneapolis , Minnesota , students , with stratification by systolic blood pressure ( SBP ) percentile [ half from the upper 25th percentile ( high blood pressure ) and half from the lower 75th percentile ( low blood pressure ) ] . Euglycemic insulin clamps were performed with an insulin infusion rate of 1 mU/kg per min and a variable infusion of 20 % glucose to maintain plasma glucose at 5.6 mmol/l ( 100 mg/dl ) . Insulin sensitivity ( Mlbm ) is defined as the amount of glucose required to maintain euglycemia ( mg glucose infused/kg lean body mass (LBM)/min . Results Diastolic blood pressure was not significantly correlated with any of the body measurements or laboratory data . SBP was significantly correlated with virtually all measures of body size in males and females . SBP and Mlbm were not significantly correlated in either sex . The correlation between SBP and fasting insulin was significant for boys and girls , but became non-significant after adjustment for BMI . All measures of body fatness were significantly greater in the high blood pressure group , and a significant clustering effect for fasting insulin , BMI , triglycerides , and HDL-C was related to blood pressure . The clustering effect was similar when Mlbm was substituted for fasting insulin and was similar for boys , girls , blacks and whites . Conclusions These results suggest that level of blood pressure in children is mediated through body fat and that insulin resistance , as determined by the insulin clamp , does not play a primary role at this age of development . Nevertheless , the clustering effect of the risk factors according to SBP grouping is consistent with an early relation of blood pressure to the insulin resistance syndrome OBJECTIVE To evaluate the effect of calcium supplementation on blood pressure in children . DESIGN R and omized , double-masked , placebo-controlled trial . SETTING AND PARTICIPANTS One hundred one fifth- grade students in one inner-city school . INTERVENTION Each child consumed 480 ml of juice beverages , containing either no calcium or 600 mg calcium ( as calcium citrate malate ) daily for 12 weeks . MEASUREMENTS At baseline we obtained nutrient data from three sets of 2-day food records on each subject . We measured blood pressure four times on each of three weekly sittings at baseline and at follow-up . Using multiple linear regression analysis , we compared mean blood pressure change in the intervention group with that in the placebo group . RESULTS There were 50 girls and 51 boys ; 61 subjects were black . At baseline , mean age was 11.0 years , systolic and diastolic blood pressures were 101.7 and 57.7 mm Hg , daily total energy intake was 1966 kcal , and calcium intake was 827 mg . With control for age , height , hours of television watched , and baseline blood pressure , systolic blood pressure increased 1.0 mm Hg in the intervention group and 2.8 mm Hg in the placebo group ( effect estimate = -1.8 mm Hg ; 95 % confidence interval -4.0 , 0.3 ) . In black subjects the intervention effect estimate was -2.0 mm Hg ( 95 % confidence interval -4.4 , 0.4 ) . From lowest to highest quartile of baseline calcium intake ( per 1000 kcal ) , the intervention effect estimates were -3.5 , -2.8 , -1.3 , and 0.0 mm Hg ( p for trend = 0.009 ) . There was little effect on diastolic blood pressure . CONCLUSION These data suggest a blood pressure-lowering effect of calcium supplementation in children , especially in subjects with low baseline calcium intake BACKGROUND The Tucson Children 's Assessment of Sleep Apnea study ( TuCASA ) was design ed to investigate the prevalence and correlates of objective ly measured sleep-related breathing disorder ( SBD ) in preadolescent Hispanic and white children . OBJECTIVE To describe the associations of SBD and elevation in resting blood pressure in the first 239 children enrolled in TuCASA . DESIGN Children between the ages of 6 and 11 years ( 45 % girls and 51 % Hispanic ) from elementary schools of the Tucson Unified School District were enrolled in this prospect i ve cohort study . Resting systolic and diastolic blood pressure , sleep symptoms , and parental smoking status were obtained during evening home visits , followed by overnight unattended home polysomnography . RESULTS The mean ( SD ) systolic and diastolic blood pressures were 98.4 ( 10.6 ) mm Hg and 62.0 ( 8.9 ) mm Hg , respectively . Fifteen children had hypertension . The mean ( SD ) respiratory disturbance index ( 2 % ) , defined as the number of apneas and hypopneas per hour of sleep associated with a 2 % oxygen desaturation , was 2.3 ( 3.8 ) events per hour . Factors independently associated with systolic and diastolic blood pressure elevation were obesity , sleep efficiency , and respiratory disturbance index ( 2 % ) . CONCLUSIONS In preadolescent children , elevated blood pressure is associated with SBD and obesity , as previously noted in adults . The control of obesity in childhood may be important to reduce the daytime consequences of SBD and to reduce the risks of life-long hypertension SUMMARY To assess the effects of modifying dietary sodium intake , 80 school children with blood pressures abore the 95th percentile for age and sex but below 130/90 mm Hg at school screening were r and omized to a family intervention program or a control group . Twenty children aged 6 to 9 years and their families began a program to modify the family diet toward a goal of 70 mEq sodium per person per day . Adherence was assessed by 3-day food records and urine collection s in children and adults . The sodium intakes and blood pressures of the interrention and control group were compared 1 year after r and omization . Sodium intake was significantly lower in the intervention group only in the actire participants as compared to dropouts and controls ( 87 vs 130 and 133 mmoles/24 hr ) . There were no significant differences between the groups in height , weight , or blood pressure Antihypertensive medications are used extensively in children despite a paucity of r and omized , placebo-controlled trials . This study was among the first r and omized , controlled pediatric antihypertensive medication trials , in which the combination drug bisoprolol fumarate/hydrochlorothiazide ( B/HT ) was compared with placebo . The study comprised a 2-week single-blind placebo screening period , a 6-week double-blind dose titration period , a 4-week double-blind dose maintenance period , and a 2-week double-blind dose-tapering period . One hundred and forty subjects were enrolled to achieve 94 r and omized subjects treated either with B/HT ( n=62 ) or placebo ( n=32 ) . B/HT induced significant reductions compared with placebo for average sitting systolic blood pressure ( SiSBP ) ( 9.3 vs. 4.9 mmHg , P<0.05 ) and sitting diastolic blood pressure ( SiDBP ) ( 7.2 vs. 2.7 mmHg , P<0.05 ) . The placebo-subtracted BP reductions were greater in younger children and those with more-severe baseline hypertension . The percentage of subjects with BP less than the 90th percentile at study completion was 45 % for B/HT and 34 % for placebo ( P = NS ) . Although the study demonstrated that B/HT reduced BP safely compared with placebo , the large placebo effect and failure of most subjects to achieve target BP control make it uncertain whether B/HT is appropriate first-line therapy for pediatric hypertension , particularly in adolescents with mild-to-moderate BP elevation The associations of diastolic blood pressure ( DBP ) with stroke and with coronary heart disease ( CHD ) were investigated in nine major prospect i ve observational studies : total 420,000 individuals , 843 strokes , and 4856 CHD events , 6 - 25 ( mean 10 ) years of follow-up . The combined results demonstrate positive , continuous , and apparently independent associations , with no significant heterogeneity of effect among different studies . Within the range of DBP studied ( about 70 - 110 mm Hg ) , there was no evidence of any " threshold " below which lower levels of DBP were not associated with lower risks of stroke and of CHD . Previous analyses have described the uncorrected associations of DBP measured just at " baseline " with subsequent disease rates . But , because of the diluting effects of r and om fluctuations in DBP , these substantially underestimate the true associations of the usual DBP ( ie , an individual 's long-term average DBP ) with disease . After correction for this " regression dilution " bias , prolonged differences in usual DBP of 5 , 7.5 , and 10 mm Hg were respectively associated with at least 34 % , 46 % , and 56 % less stroke and at least 21 % , 29 % , and 37 % less CHD . These associations are about 60 % greater than in previous uncorrected analyses . ( This regression dilution bias is quite general , so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths . ) The DBP results suggest that for the large majority of individuals , whether conventionally " hypertensive " or " normotensive " , a lower blood pressure should eventually confer a lower risk of vascular disease CONTEXT Antihypertensive therapy is well established to reduce hypertension-related morbidity and mortality , but the optimal first-step therapy is unknown . OBJECTIVE To determine whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of coronary heart disease ( CHD ) or other cardiovascular disease ( CVD ) events vs treatment with a diuretic . DESIGN The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) , a r and omized , double-blind , active-controlled clinical trial conducted from February 1994 through March 2002 . SETTING AND PARTICIPANTS A total of 33 357 participants aged 55 years or older with hypertension and at least 1 other CHD risk factor from 623 North American centers . INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n = 15 255 ) ; amlodipine , 2.5 to 10 mg/d ( n = 9048 ) ; or lisinopril , 10 to 40 mg/d ( n = 9054 ) for planned follow-up of approximately 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome was combined fatal CHD or nonfatal myocardial infa rct ion , analyzed by intent-to-treat . Secondary outcomes were all-cause mortality , stroke , combined CHD ( primary outcome , coronary revascularization , or angina with hospitalization ) , and combined CVD ( combined CHD , stroke , treated angina without hospitalization , heart failure [ HF ] , and peripheral arterial disease ) . RESULTS Mean follow-up was 4.9 years . The primary outcome occurred in 2956 participants , with no difference between treatments . Compared with chlorthalidone ( 6-year rate , 11.5 % ) , the relative risks ( RRs ) were 0.98 ( 95 % CI , 0.90 - 1.07 ) for amlodipine ( 6-year rate , 11.3 % ) and 0.99 ( 95 % CI , 0.91 - 1.08 ) for lisinopril ( 6-year rate , 11.4 % ) . Likewise , all-cause mortality did not differ between groups . Five-year systolic blood pressures were significantly higher in the amlodipine ( 0.8 mm Hg , P = .03 ) and lisinopril ( 2 mm Hg , P<.001 ) groups compared with chlorthalidone , and 5-year diastolic blood pressure was significantly lower with amlodipine ( 0.8 mm Hg , P<.001 ) . For amlodipine vs chlorthalidone , secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine ( 10.2 % vs 7.7 % ; RR , 1.38 ; 95 % CI , 1.25 - 1.52 ) . For lisinopril vs chlorthalidone , lisinopril had higher 6-year rates of combined CVD ( 33.3 % vs 30.9 % ; RR , 1.10 ; 95 % CI , 1.05 - 1.16 ) ; stroke ( 6.3 % vs 5.6 % ; RR , 1.15 ; 95 % CI , 1.02 - 1.30 ) ; and HF ( 8.7 % vs 7.7 % ; RR , 1.19 ; 95 % CI , 1.07 - 1.31 ) . CONCLUSION Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive . They should be preferred for first-step antihypertensive therapy The influence of 4 months of physical training ( PT ) and detraining on body composition , and risk factors for coronary artery disease ( CAD ) and noninsulin‐dependent diabetes mellitus ( NIDDM ) was examined . The subjects were 81 obese 7–11‐year‐olds . At baseline , visceral adipose tissue ( VAT ) was the main adiposity variable cross‐sectionally associated with unfavorable levels of the lipid‐lipoprotein risk factors , while fat mass was more highly correlated with insulin , systolic blood pressure , and leptin . Adiposity measures were associated with unfavorable concentrations of clotting‐fibrinolysis factors . Subjects were r and omly assigned to engage in PT for the first or second 4‐month period of the study ; for most variables , tests were done at 0 , 4 , and 8‐month time points . The PT program was offered 5 days a week for 40 min/session . For the 73 children who completed 4 months of PT , attendance was 80 % and heart rate during the sessions was 157 bpm . PT had a favorable influence on percent fat , VAT , subcutaneous abdominal adipose tissue , insulin , triacylglycerol , and cardiac parasympathetic activity . Detraining generally led to unfavorable changes in percent fat and associated risk factors . Leptin decreased during periods of PT and increased following cessation of PT . No significant changes due to PT were found for diet , hemodynamic , left ventricular , or most lipid parameters . Thus , 4 months of controlled PT , without dietary intervention , had a favorable impact on body composition and some obesity‐associated CAD/NIDDM risk factors . Am . J. Hum . Biol . 11:237–247 , 1999 . © 1999 Wiley‐Liss , ABSTRACT . As part of a prospect i ve population study of cardiovascular disease , ophthalmoscopic examination was performed in 855 r and omly selected 50-year-old men in 1963 . The examination was repeated four years later , in 1967 . On both occasions haemorrhages , exu date s and papillary aedema were rarely seen . Attenuating arterioles , focal narrowing , crossing phenomena and broadened light reflex were all related to BP but attenuating arterioles and /or focal narrowing discriminated BP best . Isolated broadened reflex and /or crossing phenomena were not related to BP . The change in BP over four and ten years was the same in those who had and those who did not have hypertensive eye ground changes at the initial examination , indicating that eye ground changes do not precede hypertension . Mortality data and the morbidity in myocardial infa rct ion and stroke were followed up until 1975 . The importance of the separate eye ground variables for these mortality and morbidity end-points was analyzed , taking into account the importance of BP , serum cholesterol and smoking . Focal narrowings were of importance for mortality , regardless of its cause , for stroke and for death from malignancy . Crossing phenomena were of importance for mortality , regardless of cause , for fatal coronary heert disease , for stroke and for deaths other than cardiovascular and cancer deaths . The eye ground variables are thus of differing importance for different end-points . Grouping them as in Keith and Wagener 's or other classification systems , means a loss of information and should be avoided Left ventricular ( LV ) mass has been established as an independent risk factor for cardiovascular disease morbidity and mortality . To account for differences in body size , a variety of factors have been proposed for indexing LV mass . Dual energy x-ray absorptiometry provides a measure of lean body mass which can be used as a comparison with other more clinical ly applicable methods of st and ardization . The study included 192 subjects ( 100 male , 103 white ) aged 6 to 17 years . Lean body mass was determined by dual energy x-ray absorptiometry and LV mass was calculated from M-mode echocardiographic measurements . There were significant differences by gender ( males 98.7 g , females 80.3 g , p < 0.001 ) , but not race , for unindexed LV mass . Indexing LV mass by lean body mass eliminated the difference by gender . Log-log regression analysis revealed that the optimal height exponent for indexing LV mass was height3 ( 95 % confidence interval , 2.8 to 3.1 ) . LV mass/height3 provided the most consistently high intraclass correlation with LV mass/lean body mass versus indexing with body surface area , height , height2 , and height2.7 across the 4 race/gender groups . LV mass indexed by height3 eliminated differences in LV mass by gender ( males 26.1 + /- 4.72 g/m3 , females 25.5 + /- 4.8 g/m3 , p = NS ) . The proposed method for indexing LV mass by height3 should be useful in the clinical setting . The 90th and 95th percentiles of LV mass/height3 provide cutpoints for determining the presence of LV hypertrophy in children and adolescents Objective : To estimate the independent contribution of the blood pressure cuff bladder width : mid-upper arm circumference ( CW : AC ) ratio to the variability in systolic blood pressure ( SBP ) , diastolic blood pressure phase 4 ( DBP4 ) and diastolic blood pressure phase 5 ( DBP5 ) in children and adolescents , and its impact upon the estimate of prevalence of high blood pressure derived at screening . Design : Use of cuffs with a CW : AC ratio below 40 % causes overestimation of the true blood pressure level . With higher CW : AC ratios the level is underestimated . National recommendations for adults state that the CW : AC ratio is optimal at approximately 40 % , but no consistent recommendations exist for children . Methods : We measured SBP and diastolic blood pressure phases 4 and 5 in 811 boys and 771 girls aged 10—17 years ( 93 % participation rate ) . In each subject the blood pressure was measured with a cuff conforming to the 40 % rule ( recommended cuff ) , with one smaller ( mean decrease in the CW : AC ratio : 7.4 % ) , and with one larger ( mean increase in the CW : AC ratio : 10.2 % ) . Cuffs were used in r and om order . Results : Smaller cuffs gave significantly higher blood pressure readings . With the larger cuff there were significant mean decreases . The differences were independent of the blood pressure level obtained with the recommended cuff . The impact upon the estimate of the prevalence of high blood pressure was substantial . Conclusions : Selection of the proper cuff size is important for children and adolescents , in order to avoid both over- and underdiagnosis of hypertension We compared the efficacy of MR angiography with that of conventional angiography for visualizing the renal arteries and detecting renovascular disease . Thirty-three MR angiographic studies , consisting of axial two-dimensional ( 2-D ) phase-contrast , coronal 2-D phase-contrast , and coronal 2-D time-of-flight acquisitions , were performed within 48 hr of conventional arteriography . The studies were done to evaluate possible renovascular hypertension ( n = 25 ) or potential donor nephrectomy ( n = 8) . The three MR image sets were interpreted independently , in r and om order by three observers , with regard to the number of renal arteries , degree of vessel visualization , arteriovenous overlap , and presence of renovascular disease . A fourth interpretation was based on the combined axial and coronal phase-contrast image sets . Evaluation was limited to the proximal 35 mm of each renal artery . Renal artery visualization and detection of renovascular disease were more complete with coronal phase-contrast ( 80 % sensitivity , 91 % specificity ) than with time-of-flight ( 53 % sensitivity , 97 % specificity ) images . Combined axial and coronal phase-contrast images permitted visualization of the proximal 35 mm of all dominant renal arteries and detection of 13 of 15 stenoses ( 87 % sensitivity , 97 % specificity ) . Our data suggest that biplanar MR angiography has considerable potential as a noninvasive screening technique for the evaluation of renovascular disease An open-label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children ( 1 - 12 years ) and adolescents ( 13 - 16 years ) with hypertension . Patients received single once-daily oral doses of irbesartan 2 mg/kg ( maximum of 150 mg once daily ) for 2 to 4 weeks ( + /- nifedipine or hydrochlorothiazide ) . Plasma irbesartan concentrations were determined by a vali date d high-performance liquid chromatography/fluorescence method from blood sample s taken predose , up to 24 hours after dosing on Day 1 , and up to 48 hours after the final dose . The plasma concentration-time profiles were similar between the 6- to 12-year and the 13- to 16-year age groups and to that previously determined from a study of adult subjects receiving approximately 2 mg/kg ( i.e. , 150 mg ) oral irbesartan once daily . Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy ( n = 8) . Irbesartan was well tolerated and may be a treatment option for pediatric hypertensive patients The BP distribution of a group of 72 obese adolescents was determined both before and after weight loss . Weight loss was produced by a program of caloric restriction and behavior change alone ( n = 26 ) or with a combination of caloric restriction , behavior change , and exercise ( n = 25 ) . It was demonstrated that obese adolescents have a BP distribution that is skewed 1 SD to the right of normal ( P less than .01 ) , and that with weight loss this distribution was no longer different from that of the general population . It was also shown that a weight loss program that incorporates exercise and caloric restriction produces the most desirable effect on BP reduction ( ie , greatest decrease in resting systolic BP and greatest decrease in exercise diastolic and mean BP ) . Finally , it was demonstrated that obese adolescents have structural changes present in the forearm resistance vessels and that these structural changes are reversed to the greatest extent in the weight loss program that includes exercise BACKGROUND Despite widespread use in hypertensive children , the safety and effectiveness of lisinopril had not been previously tested in a controlled study . METHODS This study explored the dose-response relationship and safety of lisinopril in 115 hypertensive children , aged 6 to 16 years . Patients were r and omized in a double-blind fashion for 2 weeks to one of three doses by body weight at baseline : < 50 kg : low ( 0.625 mg ) , middle ( 2.5 mg ) , high ( 20 mg ) , and > or = 50 kg : low ( 1.25 mg ) , middle ( 5 mg ) , high ( 40 mg ) . The dose-response for lisinopril was evaluated by analyzing the change in slope in sitting diastolic and systolic blood pressure ( BP ) by dose after 2 weeks of therapy compared to baseline . Patients then entered a double-blind withdrawal , where patients were either switched to placebo or continued their current lisinopril treatment for up to 2 weeks . Patients completed period II when their BP returned to baseline . Antihypertensive effectiveness , between placebo and lisinopril was determined for all doses . Adverse events were carefully monitored . RESULTS There was a dose-response relationship between the lowest and each of the higher doses of lisinopril . Blood pressure in the placebo group increased after withdrawal of lisinopril . The dose-response relationship was consistent across all subgroups ( ie , age , Tanner stage , ethnicity , gender ) . CONCLUSIONS Lisinopril , once daily , is an effective and well-tolerated antihypertensive in children aged 6 to 16 years . An initial dose of 0.07 mg/kg , administered once daily , effectively lowered BP within 2 weeks . Blood pressure was reduced in a dose-dependent fashion Abstract . Blood pressure ( BP ) levels were recorded in 2 223 male and 2 205 female children and adolescents ranging in age from 7 to 18 years . In addition , 521 male adults ( soldiers ) ranging in age from 21 to 25 years were included in the study . Children and adolescents who participated in the survey were selected at r and om from the Elementary and High Schools . The results of the study showed that a gradual increase occurred in the systolic , as well as in the diastolic component of blood pressure from 7 to 18 years of age . By contrast , there was no increase with age in the systolic and diastolic blood pressure in the young male adult subjects , who had BP measurements comparable to those observed in children . A child was characterized as hypertensive according to the criteria outlined by Master et al. Children with BP between the 90th and the 95th percentile were considered as suspect hypertensive , whereas those with BP exceeding the 95th percentile were considered definitely hypertensive . The overall incidence of hypertension in children in this survey was 3.1 % Although epidemiologic data show a direct relation between dietary sodium intake and blood pressure at the population level ( 1 , 2 ) , some experts question the universality of the findings and oppose public health recommendations to decrease sodium intake in the general population ( 3 ) . Certainly , results from reports on the relationship between sodium and blood pressure among major subgroups vary considerably . Several studies suggest that African Americans and older adults have heightened salt sensitivity ( greater blood pressure response to sodium intake ) ( 4 - 6 ) . Some evidence also indicates increased salt sensitivity in women ( 7 ) , although other studies do not support this cl aim ( 4 , 5 ) . The association of sodium intake with cardiovascular morbidity and mortality varies by overweight status ( 8) , perhaps reflecting a differential effect of sodium on blood pressure in overweight persons . Finally , higher dietary intakes of potassium and calcium have been shown to blunt the pressor effects of dietary sodium ( 9 , 10 ) . Dietary factors other than sodium also directly affect blood pressure , and these effects also appear to vary across subgroups . In the Dietary Approaches to Stop Hypertension ( DASH ) Trial , for example , a diet that had reduced total and saturated fat and was rich in fruits , vegetables , and low-fat dairy foods ( the DASH diet ) substantially decreased blood pressure compared with a more typical U.S. diet , in the absence of weight change and at sodium intakes approximating current U.S. consumption ( 11 , 12 ) . These effects persisted across all subgroups and were especially pronounced among hypertensive persons , African Americans , and persons who did not drink alcohol ( 13 ) . The DASH-Sodium Trial examined the effects of reduced sodium intake in the context of the DASH diet and a more typical U.S. diet ( 14 ) . In that study , highly significant decreases in blood pressure were observed with decreased sodium intake in participants following either diet , and the DASH diet decreased blood pressure at sodium intakes well below the current U.S. average . These results were observed overall and in subgroups defined by ethnicity , sex , and hypertension status ( 15 ) . We report on more detailed subgroup analyses from the DASH-Sodium Trial , including results for subgroups defined by age , obesity , waist circumference , alcohol intake , and baseline sodium intake . We also report the results of multivariate analyses that demonstrate how these effects vary across subgroups defined jointly by age , ethnicity , sex , and hypertension status . Methods Study Design The DASH-Sodium Trial was a multicenter , r and omized feeding trial comparing the effects on blood pressure of three levels of sodium intake and two dietary patterns . The 412 participants were 22 years of age or older and had systolic blood pressures of 120 to 159 mm Hg and diastolic blood pressures of 80 to 95 mm Hg ( 15 ) . The three levels of sodium intake ( lower , intermediate , and higher ) varied according to energy intake in a ratio of 1:2:3 ; target intakes were 50 , 100 , and 150 mmol/d , respectively , for a 2100-kcal diet . The dietary patterns were a control diet , typical of what many Americans eat , and the DASH diet , which emphasizes fruits , vegetables , and low-fat dairy foods ; includes whole grains , poultry , fish , and nuts ; and is reduced in fats , red meat , sweets , and sugar-containing beverages ( 11 , 14 ) . Participants were recruited in four separate feeding cohorts and were r and omly assigned to one of the two dietary patterns by using a parallel-group design . They then ate their assigned diet for three consecutive 30-day intervention feeding periods , during which sodium intake varied among the three levels by a r and omly assigned sequence ( Figure ) . Participants ate the control diet at the higher sodium intake during a 2-week run-in period . During the three intervention periods , participants received all their food in the context of the study and were asked not to eat any non study food . Individual energy intake was adjusted to keep body weight stable . Figure . Design of the Dietary Approaches to Stop Hypertension (DASH)-Sodium Trial . Exclusion criteria were heart disease , renal insufficiency , poorly controlled hyperlipidemia or diabetes mellitus , diabetes requiring insulin , special dietary requirements , intake of more than 14 alcoholic drinks/wk , or use of antihypertensive drugs or other medications that would affect blood pressure or nutrient metabolism . The study was approved by the human subjects committees of the clinical centers and coordinating center , and participants gave informed consent . Measurement Protocol Trained staff measured blood pressure at each of three screening visits , on 2 days during the run-in period , and on 5 of the last 9 days of each intervention feeding period . Interim blood pressures were assessed once during each of the first 3 weeks of each intervention feeding period . During screening and the last week of each intervention feeding period , a 24-hour urine collection was obtained . Height and weight were measured , and body mass index was calculated . Baseline physical activity was measured by using a 7-day physical activity recall interview ( 16 ) . Information on education level , income , alcohol consumption , and family history was obtained by using a question naire . Baseline blood pressure was defined as the average of the five preintervention blood pressures . End-of-feeding blood pressures were defined as the average of the five blood pressures at the end of each 30-day intervention feeding period . If no end-of-feeding blood pressure values were available ( 49 of 1236 possible cases ) , interim ( n = 9 ) or screening ( n = 40 ) blood pressures were used to impute end-of-feeding blood pressures . Definitions of Subgroups Ethnicity was categorized as African American versus other ( primarily non-Hispanic white ) . Participants were considered hypertensive if their untreated baseline systolic blood pressure was 140 mm Hg or greater and their diastolic blood pressure was 90 mm Hg or greater . ( Use of antihypertensive agents was an exclusion criterion [ 17 ] . ) Obesity was defined as body mass index of 30 kg/m2 or greater , and high-risk waist circumference was defined as greater than 102 cm in men and greater than 88 cm in women ( 18 ) . Age , physical activity , baseline alcohol intake , baseline 24-hour urinary sodium level , and family income were dichotomized at the approximate median . Level of education was dichotomized as high school or less versus more than high school . Statistical Analysis The data were analyzed on an intention-to-treat basis . Given the differential effects of sodium on blood pressure observed in previous analyses among participants eating the DASH diet versus the control diet ( 15 ) and because power for subgroup analyses is more limited than for overall analysis , we focused our comparisons on the maximum contrasts ( higher versus lower sodium intake with the control diet , DASH diet versus control diet at the higher sodium intake , and the combined effect of DASH diet and lower sodium intake versus control diet and higher sodium intake ) . We used generalized estimating equations ( 19 ) to fit linear models that predicted baseline and end-of-feeding blood pressures as a function of diet ( DASH vs. control ) , sodium level , and subgroup indicators . Different ways of modeling the dietsodium effects and their interactions with the subgroup indicators were used to test specific hypotheses . In particular , two-way interactions of the various dietsodium effects with ethnicity , sex , hypertension status , and age were analyzed to determine the incremental effect on blood pressure in each of these subgroups while controlling for the main and incremental effects of the other subgroups . This model allowed us to estimate various diet-sodium contrasts for each of the 16 subgroups defined by hypertension status , ethnicity , sex , and age . A second set of models examined subgroup variables in a bivariate manner and did not assume simple additivity of subgroup effects . Finally , unadjusted subgroup analyses included main effects and interactions for a single subgroup indicator . All analyses were performed by using the xtgee procedure in Stata software , version 5 ( Stata Corp. , College Station , Texas ) ( 20 ) and included adjustment for baseline blood pressure , site , feeding cohort , and carryover effects . An exchangeable covariance matrix was assumed for the repeated measurements for each participant . Unless otherwise stated , a P value less than 0.05 was significant , and all confidence intervals are 95 % confidence intervals . Because subgroup analyses were planned to interpret and eluci date the overall study results , they are not adjusted for multiple comparisons . Results Of the 412 participants who underwent r and omization , 390 ( 95 % ) completed the 12-week intervention feeding period . Adherence to the study diets seemed excellent , and body weight remained stable over time ( 15 ) . Table 1 shows baseline characteristics of the 412 participants . Mean urinary sodium excretion at screening was 155 mmol/d , a value higher than that found while participants ate higher-sodium diets ( 142 mmol/d ) . Table 1 . Characteristics of Study Sample Several key subgroups were highly interrelated . Women made up 70 % of African-American participants but only 39 % of non-African-American participants . Women were more likely to be hypertensive than were men . The percentage of both men and women with hypertension increased sharply with age among non-African-American participants ( 21 % of those 45 years of age vs. 47 % of those > 45 years of age ) but was equally high among older and younger African Americans ( 43 % of those 45 years of age vs. 45 % of those > 45 years of age ) . These correlations highlight the potential for confounding in our results and , hence , the importance of the multivariate-adjusted analyses . Effects of the DASH Diet Table 2 shows the effect on systolic blood pressure of the DASH diet compared with the control diet

Conclusion This systematic review shows a significant association between the number of key elements of the intervention reflecting collaborative aspects in medication review and the implementation rate of recommendations

Background Many studies have investigated the effect of medication review on a variety of outcomes , but the elements of the interventions have been quite diverse . Moreover , implementation rates of recommendations also vary widely between studies . Objective The objective of this study was to investigate how the extent of collaboration between the general practitioner ( GP ) and the pharmacist impacts on the implementation of recommendations arising from medication review .

BACKGROUND Collaboration between physicians and pharmacists is one approach to address drug-related morbidity and achieve therapeutic goals . A collaborative practice of pharmaceutical care has been used in the Fairview Clinics System of Minneapolis-St Paul since 1999 . METHODS The quality of therapeutic determinations made by pharmacists within this collaborative practice of pharmaceutical care was studied by a 12-member panel of physicians and pharmacists who used r and omly selected patient records . This was a quality improvement and care process validation component of a study evaluating the effects of drug therapy management in patients receiving prepaid medical assistance . An implicit review process was used to evaluate the clinical credibility of therapeutic determinations made by pharmaceutical care practitioners . RESULTS A total of 5780 drug therapy problems were resolved for 2524 patients receiving pharmaceutical care . The rate of therapeutic goals achieved increased from 74 % at the time of patients ' initial pharmaceutical care encounters to 89 % at patients ' latest encounters . In this quality assessment analysis panel members performed a total of 4779 evaluations of clinical decisions . Panelists indicated agreement with the evaluations in 94.2 % of cases , expressed a neutral opinion in 3.6 % of cases , and disagreed in 2.2 % of cases . Intraclass correlation coefficients ranged from 0.73 to 0.85 . CONCLUSIONS The decisions made by pharmaceutical care practitioners working in collaboration with physicians to provide drug therapy management services are clinical ly credible based on the evaluations and comments of a peer review panel . This study provides information on the quality of care provided by pharmacists when collaborating with physicians to provide drug therapy management services OBJECTIVES To evaluate the effect of pharmaceutical care provided in addition to acute Geriatric Evaluation and Management ( GEM ) care on the appropriateness of prescribing . DESIGN R and omized , controlled trial , with the patient as unit of r and omization . SETTING Acute GEM unit . PARTICIPANTS Two hundred three patients aged 70 and older . INTERVENTION Pharmaceutical care provided from admission to discharge by a specialist clinical pharmacist who had direct contacts with the GEM team and patients . MEASUREMENTS Appropriateness of prescribing on admission , at discharge , and 3 months after discharge , using the Medication Appropriateness Index ( MAI ) , Beers criteria , and Assessing Care of Vulnerable Elders ( ACOVE ) underuse criteria and mortality , readmission , and emergency visits up to 12 months after discharge . RESULTS Intervention patients were significantly more likely than control patients to have an improvement in the MAI and in the ACOVE underuse criteria from admission to discharge ( odds ratio (OR)=9.1 , 95 % confidence interval (CI)=4.2 - 21.6 and OR=6.1 , 95 % CI=2.2 - 17.0 , respectively ) . The control and intervention groups had comparable improvements in the Beers criteria . CONCLUSION Pharmaceutical care provided in the context of acute GEM care improved the appropriate use of medicines during the hospital stay and after discharge . This is an important finding , because only limited data exist on the effect of various strategies to improve medication use in elderly in patients . The present approach has the potential to minimize risk and improve patient outcomes OBJECTIVES To determine whether a medication review by a specialized team would promote regimen changes in elders taking multiple medications and to measure the effect of regimen changes on monthly cost and functioning . DESIGN A r and omized-controlled trial . SETTING Health center ambulatory clinic . PARTICIPANTS Community-dwelling older adults taking five or more medications were assessed at baseline and 6 weeks . A medication-change intervention group of 57 elders was compared with a control group of 76 elder adults . INTERVENTION The primary intervention was a comprehensive review and recommended modification of a patient 's medication regimen . Changes were endorsed by each patient 's primary physician and discussed with each patient . MEASUREMENTS Measures were the Timed Manual Performance Test , Physical Performance Test , Functional Reach Assessment , subtests from the Wechsler Adult Intelligence Scale , a modified R and t Memory Test , the Center for Epidemiological Studies -Depression Scale , the Self-Rating Anxiety Scale , and the R and 36-item Health Survey 1.0 . Comorbidity was determined using the International Classification of Diseases , Ninth Revision , Clinical Modification . Medication usage was determined using brown bag review . RESULTS Intervention subjects decreased their medications by an average of 1.5 drugs . No differences in functioning were observed between groups . Intervention subjects saved an average $ 26.92 per month in wholesale medication costs ; control subjects saved $ 6.75 per month ( P<.006 ) . CONCLUSION Although the intervention significantly reduced the medications taken and monthly cost , most patients were resistant to reducing medications to the recommended level . Further study is needed to underst and patient resistance to reducing adverse polypharmacy and to devise better strategies for addressing this important problem in geriatric health . Greater focus on prescriber behavior is recommended Aim : To measure the outcomes of a harmonised , structured pharmaceutical care programme provided to elderly patients by community pharmacists . Method : A r and omised , controlled , longitudinal , clinical trial with repeated measures was performed over an 18‐month period , involving community pharmacies ( 5 intervention and 5 control ) in Northern Irel and . Elderly , ambulatory patients ( ≥ 65 years ) , taking 4 or more prescribed medications were eligible for participation . Patients attending an intervention pharmacy received education on medical conditions , implementation of compliance strategies , rationalising of drug regimens and appropriate monitoring ; patients attending control sites received normal services . A battery of clinical , humanistic and economic outcomes were assessed . Results : A significantly higher proportion of intervention patients were compliant at the end of the 18‐month study and experienced fewer problems with medication compared to control patients ( P < 0.05 ) . There was little impact on quality of life and health care utilisation . Conclusions : Pharmaceutical care provision to community‐dwelling patients result ed in an improvement in medication compliance and evidence of cost‐savings . Future pharmaceutical care studies may benefit from a more focussed selective approach to data collection and outcomes measurement OBJECTIVE To compare patients ' adherence to therapy , expectations , satisfaction with pharmacy services , and health-related quality of life ( HRQOL ) after the provision of pharmaceutical care with those of patients who received traditional pharmacy care . DESIGN R and omized controlled cluster design . SETTING Sixteen community pharmacies in Alberta , Canada . PATIENTS AND OTHER PARTICIPANTS Ambulatory elderly ( > or = 65 years of age ) patients covered under Alberta Health & Wellness 's senior drug benefit plan and who were concurrently using three or more medications according to pharmacy profiles . INTERVENTION Pharmacies were r and omly assigned to either treatment ( intervention ) or control ( traditional pharmacy care ) groups . Patients at treatment pharmacies were recruited into the study , and pharmacists provided comprehensive pharmaceutical care services . Pharmacists at control pharmacies continued to provide traditional pharmacy care . MAIN OUTCOME MEASURES Study participants ' opinions , adherence to therapy , and scores on the Medical Outcomes Study 36-Item Short Form Health Survey ( SF-36 ) . RESULTS Compared with those of patients receiving traditional care , treatment patients ' expectations that their pharmacist would perform activities congruent with pharmaceutical care changed over the study period . Treatment patients ' satisfaction with the constructs " trust , " " evaluation and goal setting , " and " communicates with doctor " were also positively affected . HRQOL and patient adherence were not significantly affected by pharmaceutical care interventions . CONCLUSION Successful implementation of a pharmaceutical care practice model has the potential to increase patients ' satisfaction with their pharmacists ' activities and may increase patients ' expectations that pharmacists will work on their behalf to assist them with their health care needs . If pharmaceutical care affects patients ' HRQOL , instruments more specific than the SF-36 may be needed to detect the differences Abstract Objective : To determine whether a pharmacist can effectively review repeat prescriptions through consultations with elderly patients in general practice . Design : R and omised controlled trial of clinical medication review by a pharmacist against normal general practice review . Setting : Four general practice s. Participants : 1188 patients aged 65 or over who were receiving at least one repeat prescription and living in the community . Intervention : Patients were invited to a consultation at which the pharmacist review ed their medical conditions and current treatment . Main outcome measures : Number of changes to repeat prescriptions over one year , drug costs , and use of healthcare services . Results : 590 ( 97 % ) patients in the intervention group were review ed compared with 233 ( 44 % ) in the control group . Patients seen by the pharmacist were more likely to have changes made to their repeat prescriptions ( mean number of changes per patient 2.2 v 1.9 ; difference=0.31 , 95 % confidence interval 0.06 to 0.57 ; P=0.02 ) . Monthly drug costs rose in both groups over the year , but the rise was less in the intervention group ( mean difference £ 4.72 per 28 days , −£7.04 to -£2.41 ) ; equivalent to £ 61 per patient a year . Intervention patients had a smaller rise in the number of drugs prescribed ( 0.2 v 0.4 ; mean difference −0.2 , −0.4 to −0.1 ) . There was no evidence that review of treatment by the pharmacist affected practice consultation rates , outpatient consultations , hospital admissions , or death rate . Conclusions : A clinical pharmacist can conduct effective consultations with elderly patients in general practice to review their drugs . Such review results in significant changes in patients ' drugs and saves more than the cost of the intervention without affecting the workload of general practitioners . What is already known on this topic Review of patients on long term drug treatment is important but is done inadequately Evidence from the United States shows that pharmacists can improve patient care by review ing drug treatment What this study adds Consultations with a clinical pharmacist are an effective method of review ing the drug treatment of older patients Review by a pharmacist results in more drug changes and lower prescribing costs than normal care plus a much higher review rate Use of healthcare services by patients is not OBJECTIVES To describe the processes of care used by community pharmacists participating in the Pharmaceutical Care Research and Education Project ( PREP ) in terms of drug-related problems ( DRPs ) , pharmacists ' recommendations , and status of DRPs at follow-up , and to determine characteristics associated with DRPs . DESIGN Descriptive analysis of the treatment group from a larger r and omized , controlled cluster design . SETTING Five independent community pharmacies in Alberta . PARTICIPANTS One hundred fifty-nine patients who were covered under Alberta Health and Wellness 's senior drug benefit plan ( i.e. , 65 years or older ) , were taking three or more medications concurrently according to pharmacy records , were able to complete telephone interviews as determined by pharmacists , maintained residence in Alberta for 12 of the 15 study months , agreed to receive their prescription medications only from the study pharmacy during the study period , and provided informed consent . MAIN OUTCOME MEASURES Frequency of DRPs , recommendations , status of DRPs , and analysis of clinical results as determined during pharmacists ' follow-up care . RESULTS In telephone surveys , patients reported taking 4.7 prescription medications per day , but pharmacists documented 8.7 prescription medications per day in their records . Pharmacists documented 559 DRPs , a mean ( + /- SD ) of 3.9+/-3.2 problems per patient . Approximately 39 % of problems were actual DRPs , while 60 % were potential DRPs . Medical conditions associated most frequently with a DRP involved the respiratory , cardiovascular , and musculoskeletal systems . The most common DRP categories were " patient requires drug therapy " or " patient requires influenza or pneumococcal vaccination . " Pharmacists wrote 551 initial clinical notes using the subjective , objective , assessment , plan ( SOAP ) format , and they recorded 346 follow-up interventions , also using SOAP notes . Counseling , preventive consultations , and clinical monitoring represented 40 % of their recommendations . In 80 % of situations , the pharmacist made the recommendation directly to the patient . On follow-up , 40 % of the 559 DRPs identified were resolved , controlled , or improved . Patients accepted 76 % of pharmacists ' recommendations , and physicians accepted 72 % of pharmacists ' suggested resolutions of DRPs . Pharmacists were more likely to follow up about actual DRPs , as compared with potential ones ; overall , they followed up on 62 % of identified DRPs . CONCLUSION Pharmacists identified more DRPs for study patients than previous community-based , observational studies have reported . Undertreatment appears to be a prevalent DRP . Community pharmacists ' recommendations to prevent and resolve DRPs were made primarily to patients and were well accepted . More follow-up was needed for all DRPs . When follow-up occurred , the DRP results generally showed improvement BACKGROUND Patients 80 years or older are underrepresented in scientific studies . The objective of this study was to investigate the effectiveness of interventions performed by ward-based pharmacists in reducing morbidity and use of hospital care among older patients . METHODS A r and omized controlled study of patients 80 years or older was conducted at the University Hospital of Uppsala , Uppsala , Sweden . Four hundred patients were recruited consecutively between October 1 , 2005 , and June 30 , 2006 , and were r and omized to control ( n = 201 ) and intervention ( n = 199 ) groups . The interventions were performed by ward-based pharmacists . The control group received st and ard care without direct involvement of pharmacists at the ward level . The primary outcome measure was the frequency of hospital visits ( emergency department and readmissions [ total and drug-related ] ) during the 12-month follow-up period . RESULTS Three hundred sixty-eight patients ( 182 in the intervention group and 186 in the control group ) were analyzed . For the intervention group , there was a 16 % reduction in all visits to the hospital ( quotient , 1.88 vs 2.24 ; estimate , 0.84 ; 95 % confidence interval [ CI ] , 0.72 - 0.99 ) and a 47 % reduction in visits to the emergency department ( quotient , 0.35 vs 0.66 ; estimate , 0.53 ; 95 % CI , 0.37 - 0.75 ) . Drug-related readmissions were reduced by 80 % ( quotient , 0.06 vs 0.32 ; estimate , 0.20 ; 95 % CI , 0.10 - 0.41 ) . After inclusion of the intervention costs , the total cost per patient in the intervention group was $ 230 lower than that in the control group . CONCLUSION If implemented on a population basis , the addition of pharmacists to health care teams would lead to major reductions in morbidity and health care costs BACKGROUND regular medication review has been recommended for those over 75 and those on multiple drug therapy . Pharmacists are a potential source of assistance in review ing medication . Evidence of the benefits of this process is needed . OBJECTIVE to study the effect of medication review led by a pharmacist on resolution of pharmaceutical care issues , medicine costs , use of health and social services and health-related quality of life . DESIGN r and omized , controlled trial . SETTING general medical practice s in the Grampian region of Scotl and . SUBJECTS patients aged at least 65 years , with at least two chronic disease states who were taking at least four prescribed medicines regularly . METHODS pharmacists review ed the drug therapy of 332 patients , using information obtained from the practice computer , medical records and patient interviews . In 168 patients , a pharmaceutical care plan was then drawn up and implemented . The 164 control patients continued to receive normal care . All outcome measures were assessed at baseline and after 3 months . RESULTS all patients had at least two pharmaceutical care issues at baseline . Half of these were identified from the prescription record , the rest from notes and patient interview . Of all the issues , 21 % were resolved by information found in notes and 8.5 % by patient interview . General practitioners agreed with 96 % of all care issues documented on the care plans in the intervention group . At the time of follow-up , 70 % of the remaining care issues had been resolved in the intervention group , while only 14 % had been resolved in the control group . There were no changes in medicine costs or health-related quality of life in either group . There were small increases in contacts with health-care professionals and slightly fewer hospital admissions among the intervention group than the control group . CONCLUSIONS pharmacist-led medication review has the capacity to identify and resolve pharmaceutical care issues and may have some impact on the use of other health services BACKGROUND Pharmacists can improve patient outcomes in institutional and pharmacy setting s , but little is known about their effectiveness as consultants to primary care physicians . We examined whether an intervention by a specially trained pharmacist could reduce the number of daily medication units taken by elderly patients , as well as costs and health care use . METHODS We conducted a r and omized controlled trial in family practice s in 24 sites in Ontario . We r and omly allocated 48 r and omly selected family physicians ( 69.6 % participation rate ) to the intervention or the control arm , along with 889 ( 69.5 % participation rate ) of their r and omly selected community-dwelling , elderly patients who were taking 5 or more medications daily . In the intervention group , pharmacists conducted face-to-face medication review s with the patients and then gave written recommendations to the physicians to resolve any drug-related problems . Process outcomes included the number of drug-related problems identified among the senior citizens in the intervention arm and the proportion of recommendations implemented by the physicians . RESULTS After 5 months , seniors in the intervention and control groups were taking a mean of 12.4 and 12.2 medication units per day respectively ( p = 0.50 ) . There were no statistically significant differences in health care use or costs between groups . A mean of 2.5 drug-related problems per senior was identified in the intervention arm . Physicians implemented or attempted to implement 72.3 % ( 790/1093 ) of the recommendations . INTERPRETATION The intervention did not have a significant effect on patient outcomes . However , physicians were receptive to the recommendations to resolve drug-related problems , suggesting that collaboration between physicians and pharmacists is feasible BACKGROUND The administration of many drugs concurrently to elderly patients is a well-known problem in geriatrics and involves numerous risks . One way to reduce polypharmacy is to provide information to physicians in order to modify their prescribing practice s. The main objective of this study was to evaluate the impact of an intervention program that targeted physicians with the aim of reducing the number of potentially inappropriate prescriptions ( PIPs ) given to elderly patients . METHODS A r and omized controlled trial was carried out among community-dwelling elderly people in Sherbrooke , Que . The participants were 266 patients over 75 years of age ( experimental group : n = 136 , control group : n = 130 ) . A team comprising 2 physicians , a pharmacist and a nurse review ed the list of drugs and the diagnoses of a subgroup of the experimental group in a case conference . Suggestions were formulated and mailed to the patients ' physicians together with relevant scientific documentation justifying the recommendations . The main outcome measure was the number of PIPs . RESULTS The mean number of PIPs per patient declined by 0.24 in the experimental group ( n = 127 ) and by 0.15 in the control group ( n = 116 ) . The decline in PIPs was even larger in the experimental group that had case conferences ( n = 80 ) , in which the mean number of PIPs per patient declined by 0.31 . However , this difference between the experimental group and the control group was not statistically significant in the intent-to-treat analysis . The number of drugs prescribed was not modified by the intervention , nor were the results of the global assessment of the patients ' drug profiles . INTERPRETATION This study suggests that the intervention program had no effect on the prescribing of PIPs Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists BACKGROUND Older people are prone to problems related to use of medicines . As they tend to use many different medicines , monitoring pharmacotherapy for older people in primary care is important . AIM To determine which procedure for treatment review s ( case conferences versus written feedback ) results in more medication changes , measured at different moments in time . To determine the costs and savings related to such an intervention . DESIGN OF STUDY R and omised , controlled trial , r and omisation at the level of the community pharmacy . SETTING Primary care ; treatment review s were performed by 28 pharmacists and 77 GPs concerning 738 older people ( > or = 75 years ) on polypharmacy ( > five medicines ) . METHOD In one group , pharmacists and GPs performed case conferences on prescription-related problems ; in the other group , pharmacists provided results of a treatment review to GPs as written feedback . Number of medication changes was counted following clinical ly-relevant recommendations . Costs and savings associated with the intervention at various times were calculated . RESULTS In the case-conference group significantly more medication changes were initiated ( 42 versus 22 , P = 0.02 ) . This difference was also present 6 months after treatment review s ( 36 versus 19 , P = 0.02 ) . Nine months after treatment review s , the difference was no longer significant ( 33 versus 19 , P = 0.07 ) . Additional costs in the case-conference group seem to be covered by the slightly greater savings in this group . CONCLUSION Performing treatment review s with case conferences leads to greater uptake of clinical ly-relevant recommendations . Extra costs seem to be covered by related savings . The effect of the intervention declines over time , so performing treatment review s for older people should be integrated in the routine collaboration between GPs and pharmacists OBJECTIVE To assess whether home-based medication review by a pharmacist for at-risk older patients in a primary care setting can reduce hospital admissions . DESIGN R and omised controlled trial comparing home-based medication review with st and ard care . SETTING Home-based medication review of 136 patients registered with one general practice . METHOD Study participants were over 80 years of age , living at home , taking four or more medicines , and had at least one additional medicines-related risk factor . The intervention comprised two home visits by a community pharmacist who educated the patient/carer about their medicines , noted any pharmaceutical care issues , assessed need for an adherence aid , and subsequently met with the lead GP to agree on actions . MAIN OUTCOME MEASURE Total non-elective hospital admissions within 6 months . Secondary outcomes included number of deaths , care home admissions and quality of life ( EQ-5d ) . Impact on number of medicines prescribed was also assessed . RESULTS At 6 months , no difference in hospital admissions ( 21 intervention versus 20 control P = 0.80 ) , and no difference in care home admissions or deaths were detected between groups . There was a small ( non-significant ) decrease in quality of life in the intervention group . There was a statistically significant reduction in the mean number of medicines prescribed ( -0.87 items in favour of the intervention group , 95 % confidence interval -1.66 to -0.08 , P = 0.03 ) . CONCLUSIONS No positive impact on clinical outcomes or quality of life was demonstrated , however , this intervention did appear to reduce prescribing . This is in line with other evidence and suggests that this form of intervention may not have a clear health gain , but may lead to modest savings in terms of reduced prescribing . Future research should focus on whether such a prescribing effect would make this type of intervention cost effective Background : Medical in patients are at risk for suboptimal health outcomes from adverse drug events and under-use of evidence -based therapies . We sought to determine whether collaborative care including a team-based clinical pharmacist improves the quality of prescribed drug therapy and reduces hospital readmission . Methods : Multicenter , quasi-r and omized , controlled clinical trial . Consecutive patients admitted to 2 internal and 2 family medicine teams in 3 teaching hospitals between January 30 , 2006 and February 2 , 2007 were included . Team care patients received proactive clinical pharmacist services ( medication history , patient-care round participation , resolution of drug-related issues , and discharge counseling ) . Usual care patients received traditional reactive clinical pharmacist services . The primary outcome was the overall quality score measured retrospectively by a blinded chart review er using 20 indicators targeting 5 conditions . Secondary outcomes included 3- and 6-month readmission . Results : A total of 452 patients ( 220 team care , 231 usual care , mean age : 74 years , 46 % male ) met eligibility criteria . Team care patients were more likely than usual care patients to receive care specified by the indicators overall ( 56.4 % vs. 45.3 % ; adjusted mean difference : 10.4 % ; 95 % confidence interval [ CI ] : 4.9 % , 15.7 % ) and for each targeted disease state except for heart failure . Team care patients experienced fewer readmissions at 3 months ( 36.2 % vs. 45.5 % ; adjusted OR : 0.63 ; 95 % CI : 0.42 , 0.94 ) but not at 6 months ( 50.7 % vs. 56.3 % ; adjusted OR ; 0.78 ; 95 % CI : 0.53 , 1.15 ) . Conclusions : In patients admitted to internal and family medicine teams , team-based care including a clinical pharmacist , improved the overall quality of medication use and reduced rates of readmission AIMS To examine the effectiveness of a multidisciplinary service model delivering medication review to patients at risk of medication misadventure in the community . METHODS The study was carried out in three Australian states ; Queensl and , New South Wales and Western Australia , and conducted as a r and omized , controlled effectiveness trial with the general practitioner ( GP ) as the unit of r and omization . In total , 92 GPs , 53 pharmacists and 400 patients enrolled in the study . The multidisciplinary service model consisted of GP education , patient home visits , pharmacist medication review s , primary healthcare team conferences , GP implementation of action plans in consultation with patients , and follow-up surgery visits for monitoring . Effectiveness was assessed using the four clinical value compass domains of ( i ) functional status , ( ii ) clinical outcomes , ( iii ) satisfaction and ( iv ) costs . The domains of functional status ( assessed by the health-related quality of life measure SF-36 subscales ) and clinical outcomes ( as assessed by adverse drug events ( ADEs ) , number of GP visits , hospital services and severity of illness ) were measured at baseline and endpoint . Satisfaction was measured by success in implementation and by participant satisfaction at endpoint , and costs ( as assessed using medication and healthcare service costs , less intervention costs ) were measured preintervention and during the trial . In addition , process evaluation was conducted for intervention patients , in which problems and recommendations from the medication review s were described . RESULTS The model was successfully implemented with 92 % of intervention GPs suggesting that the model had improved the care of participating patients , a view shared by 94 % of pharmacists . In addition , positive trends in clinical outcomes ( ADEs and severity of illness ) and costs ( an ongoing trend towards reduction in healthcare service costs ) were evident , although the trial was limited to a 6-month intervention time . No differences between intervention and control groups were identified for the health-related quality of life domain . The cost-effectiveness ratio for the intervention based on cost savings , reduced adverse events and improved health outcomes was small . The most common problems identified in the medication review s were potential adverse drug reactions , suboptimal monitoring and adherence/lack of concordance issues . In total , 54.4 % of recommendations were enacted , and 23.9 % were implemented precisely as recommended in the medication review . Follow-up evaluation showed that 70.9 % of actions had a positive outcome , 15.7 % no effect and 3.7 % had a negative outcome . CONCLUSIONS Most studies emphasize efficacy and the best achievable clinical outcomes rather than whether an intervention will be effective in practice . The current trial showed that three of the four domains in the clinical value compass showed trends of improvement or were indeed improved in the relatively short follow-up period of the trial , suggesting that a service based on this model could achieve similar benefits in practice . A domiciliary medication review programme similar to this model has now been implemented into national Australian practice , where GPs and pharmacists are reimbursed by the Australian government for the provision of these services BACKGROUND Drug-related problems ( DRPs ) in Australian aged care homes have been studied previously . However , little is known about the acceptance and implementation of pharmacists ' recommendations by general practitioners ( GPs ) to resolve DRPs . OBJECTIVES The primary objective of this study was to investigate the number and nature of DRPs identified by accredited clinical pharmacists . The secondary objective was to study the GP acceptance and implementation of pharmacist recommendations to resolve DRPs . METHODS This was a retrospective study of 500 r and omly selected , de-identified medication review s performed by 10 accredited clinical pharmacists over 6 months across 62 aged care homes . The DRPs identified by pharmacists were subsequently classified by the drugs involved , types of problem ( indication , effectiveness and safety ) and medical diagnoses of the patient . GP written feedback on the medication review reports determined implementation of pharmacists ' recommendations to resolve the DRPs . RESULTS A total of 1433 DRPs were identified in 480 of the 500 residents . Potential DRPs were frequently classified as risk of adverse drug reactions , need for additional monitoring and inappropriate choice of a drug . Alimentary , cardiovascular , central nervous system and respiratory drugs were most frequently implicated , accounting for more than 75 % of the DRPs . GPs ' acceptance and implementation of pharmacists recommendations were 72.5 % ( 95 % CI ; 70.2 , 74.8 ) and 58.1 % ( 95 % CI ; 55.5 , 60.6 ) , respectively . CONCLUSIONS Over 96 % of the residents had potential DRPs identified by pharmacists . GP acceptance of pharmacists ' recommendations was independent of the drug category , but not independent of the disease category BACKGROUND There have been recent moves to extend the role of the community pharmacist to include medicine management . METHODS A r and omized controlled trial was conducted in nine sites in Engl and . Patients with coronary heart disease were identified from general practice computer systems , recruited and r and omized ( 2:1 ) to intervention or control . The 12-month intervention comprised an initial consultation with a community pharmacist to review appropriateness of therapy , compliance , lifestyle , social and support issues . Control patients received st and ard care . The primary outcome measures were appropriate treatment [ derived from the National Service Framework ( NSF ) ] , health status ( SF-36 , EQ-5D ) and an economic evaluation . Secondary outcome measures were patient risk of cardiovascular death and satisfaction . RESULTS The study involved 1493 patients ( 980 intervention and 513 control ) , 62 pharmacists and 164 GPs . No statistically significant differences between intervention and control groups were shown at follow-up for any of the primary outcome measures such as numbers on aspirin or lifestyle measures . There were few differences in quality of life ( SF-36 ) between the intervention and control groups at baseline or follow-up or with overall EQ-5D score over time . The total National Health Service cost increased between baseline and at 12 months in both groups but to a greater extent in the intervention group . Significant improvements were found in the satisfaction score for patients ' most recent pharmacy visit for prescription medicines among the intervention group , compared with control group . Self-reported compliance was good for both groups at baseline and no significant differences were shown at follow-up . CONCLUSION There was no change in the proportion of patients receiving appropriate medication as defined by the NSF . The pharmacist-led service was more expensive than st and ard care Objective This study aim ed to measure the outcomes of a harmonised , structured pharmaceutical care programme provided to elderly patients ( ≥65 years of age ) by community pharmacists in a multicentre international study performed in 7 European countries . Design and setting The study was a r and omised , controlled , longitudinal , clinical trial with repeated measures performed over an 18-month period . A total of 104 intervention and 86 control pharmacy sites participated in the research and 1290 intervention patients and 1164 control patients were recruited into the study .Main outcome measures and results A general decline in health-related quality of life over time was observed in the pooled data ; however , significant improvements were achieved in patients involved in the pharmaceutical care programme in some countries . Intervention patients reported better control of their medical conditions as a result of the study and cost savings associated with pharmaceutical care provision were observed in most countries . The new structured service was well accepted by intervention patients and patient satisfaction with the services improved during the study . The pharmacists involved in providing pharmaceutical care had a positive opinion on the new approach , as did the majority of general practitioners surveyed . The positive effects appear to have been achieved via social and psychosocial aspects of the intervention , such as the increased support provided by community pharmacists , rather than via biomedical mechanisms . Conclusions This study is the first large-scale , multicentre study to investigate the effects of pharmaceutical care provision by community pharmacists to elderly patients . Future research methodology and implementation will be informed by the experience gained from this challenging trial OBJECTIVES There are conflicting results in studies of pharmacists undertaking medication review s for older people . With increasing promotion and funding for ' medication review s ' there is a need for them to be st and ardised , and to determine their effectiveness and the feasibility of providing them from a community pharmacy . The objective was to determine whether involvement of community pharmacists undertaking clinical medication review s , working with general practitioners , improved medicine-related therapeutic outcomes for patients . METHODS A r and omised controlled trial was carried out in people 65 years and older on five or more prescribed medicines . Community pharmacists undertook a clinical medication review ( Comprehensive Pharmaceutical Care ) and met with the patient 's general practitioner to discuss recommendations about possible medicine changes . The patients were followed-up 3-monthly . The control group received usual care . The main outcome measures were Quality of Life ( SF-36 ) and Medication Appropriateness Index . KEY FINDINGS A total of 498 patients were enrolled in the study . The quality -of-life domains of emotional role and social functioning were significantly reduced in the intervention group compared to the control group . The Medication Appropriateness Index was significantly improved in the intervention group . Only 39 % of the 44 pharmacists who agreed to participate in the study provided adequate data , which was a limitation of the study and indicated potential barriers to the generalisability of the study . CONCLUSION Clinical medication review s in collaboration with general practitioners can have a positive effect on the Medication Appropriateness Index . However , pharmacist withdrawal from the study suggests that community pharmacy may not be an appropriate environment from which to exp and clinical medication review s in primary care Background : There are concerns that automated drug dispensing may increase inappropriate drug use . Automated dispensing could lead to perpetual repeating of drug therapies without the necessary re-evaluation . Objectives : The aim of this study was to examine the effect of a pharmacist-led medication review on drug-related problems ( DRPs ) in older patients receiving their drugs via automated dispensing . Methods : This was a pragmatic r and omized controlled study conducted in primary care . Patients were recruited from six Dutch community pharmacies . They were eligible if they lived at home , were aged ≥65 years , and used five or more different drugs , of which at least one had to be dispensed via an automated system . Patients were r and omly allocated to receive a medication review at the start of the study ( intervention group ) or after 6 months ( waiting-list group ) . Each patient was independently review ed by two pharmacist review ers . The results of these medication review s were sent to the community pharmacist to be discussed with the patient ’s general practitioner ( GP ) . The primary outcome measure was the number of DRPs leading to a recommendation for drug change . Secondary outcomes were the total number of drug changes and the number of drug changes related to a recommendation . In order to analyse drug changes , medication records were collected 6 months after the medication review or index date in the waiting-list group . Potential DRPs were classified using the DOCUMENT classification . Results : There were no baseline differences between the 63 patients in the intervention group and the 55 patients in the waiting-list group with respect to age , sex , number of drugs per patient and type of drug prescribed . The mean number of DRPs per patient at baseline in the intervention group and waiting list combined was 8.5 , with no difference between the groups . At baseline , the mean number of DRPs leading to a recommendation for drug change was 4.5 per patient and did not differ between the two groups . After 6 months , the number of DRPs leading to a recommendation for drug change decreased by 29 % in the intervention group versus 5 % in the waiting-list group ( p < 0.01 ) . Recommendations for cessation of a drug were more frequently accepted than recommendations to add a new drug ( 82 % vs 44 % , p = 0.01 ) . Conclusions : This study shows that patients using automated drug dispensing have a high number of DRPs . Medication review decreases the number of DRPs among these patients . We recommend that all patients with automatic drug dispensing should have a thorough medication review by pharmacists and prescribers

Uptake of therapeutic agents for the prevention of breast cancer is low , and long-term persistence is often insufficient for women to experience the full preventive effect .

BACKGROUND Preventive therapy is a risk reduction option for women who have an increased risk of breast cancer . The effectiveness of preventive therapy to reduce breast cancer incidence depends on adequate levels of uptake and adherence to therapy . We aim ed to systematic ally review articles reporting uptake and adherence to therapeutic agents to prevent breast cancer among women at increased risk , and identify the psychological , clinical and demographic factors affecting these outcomes .

OBJECTIVE To investigate how ethnically diverse women who are eligible for tamoxifen prophylaxis because of their breast cancer risk decide about tamoxifen use for risk reduction . DESIGN A qualitative intervention pilot study used focus groups to discuss the use of tamoxifen and to identify the concerns of ethnically diverse women about the preventive use of this drug . Focus group discussion involved exploration of the benefits and risks of tamoxifen prophylaxis , presentation of a st and ardized educational intervention , and focused discussion on attitudes about tamoxifen for prevention . Prominent themes emerged from iterative review of focus group transcripts . RESULTS Fear of breast cancer was not prominent , and participants were less inclined to take tamoxifen as preventive therapy after receiving information . Decisions were based on participants ' underst and ings of competing risks and benefits . Specifically , participants expressed limited willingness to take medication with potential serious side effects for risk reduction and were unwilling to discontinue hormone replacement therapy . Uneasiness about the reliability of scientific studies surfaced in the focus groups comprised of White and Latina women . African-American women described faith as important to prevention . CONCLUSIONS Women were wary of taking a drug for a disease they might not develop . Women felt they had options other than tamoxifen to reduce their risk of breast cancer , including early detection , diet , faith , and complementary and alternative therapies Women with germline BRCA1 or BRCA2 ( BRCA1/2 ) mutations are considered as an extreme risk population for developing breast cancer . Prophylactic mastectomy provides a valid option to reduce such risk , impacting however , the quality of life . Medical prevention by aromatase inhibitor that has also recently shown to have preventive effect may thus be considered as an alternative . LIBER is an ongoing double-blind , r and omized phase III trial to evaluate the efficacy of 5-year letrozole versus placebo to decrease breast cancer incidence in post-menopausal BRCA1/2 mutation carriers ( NCT00673335 ) . We present data on the uptake of this trial . We compared characteristics of women in the LIBER trial ( n = 113 ) to those of women enrolled in the prospect i ve ongoing national GENEPSO cohort ( n = 1,505 ) . Uptake was evaluated through a survey sent to all active centres , with responses obtained from 17 to the 20 ( 85 % ) centres . According to the characteristics of the women enrolled in the GENEPSO cohort and the survey , approximately one-third of BRCA1/2 mutation carriers were eligible for the trial . Five hundred and thirty-four women eligible from chart review have been informed by mail about the prevention trial and were invited to an oral information by participating centres . Forty-four percentage of them came to the dedicated medical visit . Uptake of drug prevention trial was 32 % among women informed orally and 15 % of all the eligible women . The main reasons of refusal were : potential side effects , probability to receive the placebo and lack of support from their physicians . Additionally , we noticed that prior prophylactic oophorectomy and previous unilateral breast cancer were more frequent in women enrolled in the LIBER trial than in the French cohort ( 93 % vs. 60 % and 50 % vs. 39 % , respectively ) . Based on an overall 15 % uptake among all eligible subjects , greater and wider information of the trial should be offered to women with BRCA1/2 mutation to improve recruitment . Women with previous unilateral breast cancer or prior prophylactic oophorectomy are more likely to enter a medical prevention trial Background Adherence to preventive medication is often poor , and current interventions have had limited success . Purpose This study was conducted to pilot a r and omised controlled trial aim ed at increasing adherence to preventive medication in stroke survivors using a brief , personalised intervention . Methods Sixty-two stroke survivors were r and omly allocated to either a two-session intervention aim ed at increasing adherence via ( a ) introducing a plan linked to environmental cues ( implementation intentions ) to help establish a better medication-taking routine ( habit ) and ( b ) eliciting and modifying any mistaken patient beliefs regarding medication/stroke or a control group . Primary outcome was adherence to antihypertensive medication measured objective ly over 3 months using an electronic pill bottle . Results Fifty-eight people used the pill bottle and were analysed as allocated ; 54 completed treatment . The intervention result ed in 10 % more doses taken on schedule ( intervention , 97 % ; control , 87 % ; 95 % CI for difference ( 0.2 , 16.2 ) ; p = 0.048 ) . Conclusions A simple , brief intervention increased medication adherence in stroke survivors , over and above any effect of increased patient contact or mere measurement . ( http://controlled-trials.com , number IS RCT N38274953 . Background Asthma is a common medical condition caused by chronic inflammation of the airways . Characteristic symptoms of the illness include attacks of shortness of breath , wheezing , tightness in the chest , and cough . Asthma is commonly treated by inhaled corticosteroids , which help to suppress inflammation of the airways and reduce the frequency of severe symptoms and attacks . This medication in the form of inhalers is known as preventer or controller medication and many patients also take short-acting bronchodilators to control acute symptoms ( reliever medication ) . In order to provide therapeutic benefit , preventer medication needs to be taken regularly on a daily basis . However , non-adherence to preventer medication is a common problem in patients diagnosed with asthma and these results in the overuse of reliever medication , increased asthma symptoms , more frequent asthma attacks , and hospital admissions ( Stern et al. , 2006 ) . Optimal adherence to inhaled corticosteroids requires patients to take their preventer medication on 80 % or more occasions , as this is associated with greatest asthma control ( Lasmar et al. , 2009 ) . Objective While effective preventative medication is readily available for asthma , adherence is a major problem due to patients ’ beliefs about their illness and medication . We investigated whether a text message programme targeted at changing patients ’ illness and medication beliefs would improve adherence in young adult asthma patients . Methods Two hundred and sixteen patients aged between 16 and 45 on asthma preventer medication were recruited from pamphlets dispensed with medication and e-mails sent to members of a targeted marketing website . Participants were r and omized to receive individually tailored text messages based on their illness and medication beliefs over 18 weeks or no text messages . Illness and medication beliefs were assessed at baseline and at 18 weeks . Adherence rates were assessed by phone calls to participants at 6 , 12 , and 18 weeks and at 6 and 9 months . Results At 18 weeks , the intervention group had increased their perceived necessity of preventer medication , increased their belief in the long-term nature of their asthma , and their perceived control over their asthma relative to control group ( all p<0.05 ) . The intervention group also significantly improved adherence over the follow-up period compared to the control group with a relative average increase in adherence over the follow-up period of 10 % ( p<0.001 ) . The percentage taking over 80 % of prescribed inhaler doses was 23.9 % in the control group compared to 37.7 % in the intervention group ( p<0.05 ) . Conclusion A targeted text message programme increases adherence to asthma preventer inhaler and may be useful for other illnesses where adherence is a major issue BACKGROUND Exemestane can prevent breast cancer in postmenopausal women . Because of potential widespread use , we examined the safety of exemestane on bone health . METHODS In this nested safety sub study of the MAP.3 trial ( a r and omised , placebo-controlled , double-blind trial of exemestane 25 mg a day for the primary prevention of breast cancer ) , we included postmenopausal women from five centres who were eligible to participate in MAP.3 , not osteoporotic , not receiving drugs for bone-related disorders , with baseline lumbar spine , total hip , and femoral neck T-scores above -2·0 . The primary endpoint was percent change from baseline to 2 years in total volumetric bone mineral density ( BMD ) at the distal radius by high-resolution peripheral quantitative CT . The primary analysis was per protocol using a non-inferiority margin . This analysis was done earlier than originally planned because of the impending announcement of MAP.3 results and subsequent unmasking of patients to treatment assignment . This study is registered with Clinical Trials.gov , number NCT01144468 , and has been extended to 5 years of unmasked follow-up . FINDINGS 351 women ( 176 given exemestane , 175 given placebo ; median age 61·3 years [ IQR 59·2 - 64·9 ] ) met our inclusion criteria and completed baseline assessment . At the time of clinical cutoff , 242 women had completed 2-year follow-up ( 124 given exemestane , 118 given placebo ) . From baseline to 2 years , the mean percent change in total volumetric BMD at the distal radius was -6·1 % ( 95 % CI -7·0 to -5·2 ) in the exemestane group and -1·8 % ( -2·4 to -1·2 ) in the placebo group ( difference -4·3 % , 95 % CI -5·3 to -3·2 ; p<0·0001 ) . The lower limit of the 95 % CI was lower than our non-inferiority margin of negative 4 % ( one-sided test for non-inferiority p=0·70 ) , meaning the hypothesis that exemestane was inferior could not be rejected . At the distal tibia , the mean percent change in total volumetric BMD from baseline to 2 years was -5·0 % ( 95 % CI -5·5 to -4·4 ) in the exemestane group and -1·3 % ( -1·7 to -1·0 ) in the placebo group ( difference -3·7 % , 95 % CI -4·3 to -3·0 ; p<0·0001 ) . The mean percent change in cortical thickness was -7·9 % ( SD 7·3 ) in the exemestane group and -1·1 % ( 5·7 ) in the placebo group at the distal radius ( difference -6·8 % , 95 % CI -8·5 to -5·0 ; p<0·0001 ) and -7·6 % ( SD 5·9 ) in the exemestane group and -0·7 % ( 4·9 ) in the placebo group at the distal tibia ( difference -6·9 % , -8·4 to -5·5 ; p<0·0001 ) . Decline in areal BMD , as measured by dual-energy x-ray absorptiometry , in the exemestane group compared with the placebo group occurred at the lumbar spine ( -2·4 % [ 95 % CI -3·1 to -1·7 ] exemestane vs -0·5 % [ -1·1 to 0·2 ] placebo ; difference -1·9 % , 95 % CI -2·9 to -1·0 ; p<0·0001 ) , total hip ( -1·8 % [ -2·3 to -1·2 ] exemestane vs -0·6 % [ -1·1 to -0·1 ] placebo ; difference -1·2 % , -1·9 to -0·4 ; p=0·004 ) , and femoral neck ( -2·4 % [ -3·2 to -1·7 ] exemestane vs -0·8 % [ -1·5 to 0·1 ] placebo ; difference -1·6 % , -2·7 to -0·6 ; p=0·002 ) . INTERPRETATION 2 years of treatment with exemestane worsens age-related bone loss in postmenopausal women despite calcium and vitamin D supplementation . Women considering exemestane for the primary prevention of breast cancer should weigh their individual risks and benefits . For women taking exemestane , regular bone monitoring plus adequate calcium and vitamin D supplementation are important . To assess the effect of our findings on fracture risk , long-term follow-up is needed . FUNDING Canadian Breast Cancer Research Alliance ( Canadian Institutes of Health Research /Canadian Cancer Society ) Abstract Objective To investigate the effects of compliance and periodic telephone counselling by a pharmacist on mortality in patients receiving polypharmacy . Design Two year r and omised controlled trial . Setting Hospital medical clinic . Participants 502 of 1011 patients receiving five or more drugs for chronic disease found to be non-compliant at the screening visit were invited for r and omisation to either the telephone counselling group ( n = 219 ) or control group ( n = 223 ) at enrolment 12 - 16 weeks later . Main outcome measures Primary outcome was all cause mortality in r and omised patients . Associations between compliance and mortality in the entire cohort of 1011 patients were also examined . Patients were defined as compliant with a drug if they took 80 - 120 % of the prescribed daily dose . To calculate a compliance score for the whole treatment regimen , the number of drugs that the patient was fully compliant with was divided by the total number of prescribed drugs and expressed as a percentage . Only patients who complied with all recommended drugs were considered compliant ( 100 % score ) . Results 60 of the 502 eligible patients defaulted and only 442 patients were r and omised . After two years , 31 ( 52 % ) of the defaulters had died , 38 ( 17 % ) of the control group had died , and 25 ( 11 % ) of the intervention group had died . After adjustment for confounders , telephone counselling was associated with a 41 % reduction in the risk of death ( relative risk 0.59 , 95 % confidence interval 0.35 to 0.97 ; P = 0.039 ) . The number needed to treat to prevent one death at two years was 16 . Other predictors included old age , living alone , rate of admission to hospital , compliance score , number of drugs for chronic disease , and non-treatment with lipid lowering drugs at screening visit . In the cohort of 1011 patients , the adjusted relative risk for death was 1.61 ( 1.05 to 2.48 ; P = 0.029 ) and 2.87 ( 1.80 to 2.57 ; P < 0.001 ) in patients with compliance scores of 34 - 66 % and 0 - 33 % , respectively , compared with those who had a compliance score of 67 % or more . Conclusion In patients receiving polypharmacy , poor compliance was associated with increased mortality . Periodic telephone counselling by a pharmacist improved compliance and reduced mortality . Trial registration International St and ard R and omised Controlled Trial Number Register : S RCT N48076318 CONTEXT Tamoxifen is approved for the reduction of breast cancer risk , and raloxifene has demonstrated a reduced risk of breast cancer in trials of older women with osteoporosis . OBJECTIVE To compare the relative effects and safety of raloxifene and tamoxifen on the risk of developing invasive breast cancer and other disease outcomes . DESIGN , SETTING , AND PATIENTS The National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene trial , a prospect i ve , double-blind , r and omized clinical trial conducted beginning July 1 , 1999 , in nearly 200 clinical centers throughout North America , with final analysis initiated after at least 327 incident invasive breast cancers were diagnosed . Patients were 19,747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk ( mean risk , 4.03 % [ SD , 2.17 % ] ) . Data reported are based on a cutoff date of December 31 , 2005 . INTERVENTION Oral tamoxifen ( 20 mg/d ) or raloxifene ( 60 mg/d ) over 5 years . MAIN OUTCOME MEASURES Incidence of invasive breast cancer , uterine cancer , noninvasive breast cancer , bone fractures , thromboembolic events . RESULTS There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 in those assigned to raloxifene ( incidence , 4.30 per 1000 vs 4.41 per 1000 ; risk ratio [ RR ] , 1.02 ; 95 % confidence interval [ CI ] , 0.82 - 1.28 ) . There were fewer cases of noninvasive breast cancer in the tamoxifen group ( 57 cases ) than in the raloxifene group ( 80 cases ) ( incidence , 1.51 vs 2.11 per 1000 ; RR , 1.40 ; 95 % CI , 0.98 - 2.00 ) . There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene ( RR , 0.62 ; 95 % CI , 0.35 - 1.08 ) . No differences were found for other invasive cancer sites , for ischemic heart disease events , or for stroke . Thromboembolic events occurred less often in the raloxifene group ( RR , 0.70 ; 95 % CI , 0.54 - 0.91 ) . The number of osteoporotic fractures in the groups was similar . There were fewer cataracts ( RR , 0.79 ; 95 % CI , 0.68 - 0.92 ) and cataract surgeries ( RR , 0.82 ; 95 % CI , 0.68 - 0.99 ) in the women taking raloxifene . There was no difference in the total number of deaths ( 101 vs 96 for tamoxifen vs raloxifene ) or in causes of death . CONCLUSIONS Raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer . The risk of other cancers , fractures , ischemic heart disease , and stroke is similar for both drugs . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00003906 Epidemiological and experimental evidence indicates that oestrogens are involved in the carcinogenic promotion of human breast cancer . We have undertaken a pilot trial of tamoxifen , an anti-oestrogen , compared to placebo given to 200 women at a high risk of developing breast cancer . The results of this trial show that acute toxicity is low and that accrual and compliance are satisfactory . Furthermore , biochemical monitoring of lipids and clotting factors indicate that tamoxifen may reduce the risk of cardiovascular deaths . At this stage no untoward long-term risks have been identified , and it is therefore proposed that a large multicentre trial should be started It has been shown in several studies that antihormonal compounds can offer effective prophylactic treatment to prevent breast cancer . In view of the low participation rates in chemoprevention trials , the purpose of this study was to identify the characteristics of women taking part in a population -based mammography screening program who wished to obtain information about the risk of breast cancer and then participate in the the International Breast Cancer Intervention Study II ( IBIS-II ) trial , a r and omized double-blind controlled chemoprevention trial comparing anastrozole with placebo . A paper-based survey was conducted in a population -based mammography screening program in Germany between 2007 and 2009 . All women who met the criteria for the mammography screening program were invited to complete a question naire . A total of 2,524 women completed the question naire , and 17.7 % ( n = 446 ) met the eligibility criteria for the IBIS-II trial after risk assessment . The women who wished to receive further information about chemoprevention were significantly younger ( P < 0.01 ) and had significantly more children ( P = 0.03 ) and significantly more relatives with breast cancer ( P < 0.001 ) . There were no significant differences between the participants with regard to body mass index or hormone replacement therapy . Normal mammographic findings at screening were the main reason ( 42 % ) for declining to participate in the IBIS-II trial or attend risk counseling . The ultimate rate of recruitment to the IBIS-II trial was very low ( three women ) . Offering chemoprevention to women within a mammography screening unit as part of a paper-based survey result ed in low participation rates for both , the survey and the final participation in the IBIS-II trial . More individualized approaches and communication of breast cancer risk at the time of the risk assessment might be helpful to increase the participation and the underst and ing of chemopreventive approaches The selective estrogen-receptor modulator ( SERM ) tamoxifen became the first U.S. Food and Drug Administration ( FDA ) –approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention , largely because it increased endometrial cancer and thromboembolic events . The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene ( STAR ) . Raloxifene caused less toxicity ( versus tamoxifen ) , including reduced thromboembolic events and endometrial cancer . In this report , we present an up date d analysis with an 81-month median follow-up . STAR women were r and omly assigned to receive either tamoxifen ( 20 mg/d ) or raloxifene ( 60 mg/d ) for 5 years . The risk ratio ( RR ; raloxifene : tamoxifen ) for invasive breast cancer was 1.24 ( 95 % confidence interval [ CI ] , 1.05–1.47 ) and for noninvasive disease , 1.22 ( 95 % CI , 0.95–1.59 ) . Compared with initial results , the RRs widened for invasive and narrowed for noninvasive breast cancer . Toxicity RRs ( raloxifene : tamoxifen ) were 0.55 ( 95 % CI , 0.36–0.83 ; P = 0.003 ) for endometrial cancer ( this difference was not significant in the initial results ) , 0.19 ( 95 % CI , 0.12–0.29 ) for uterine hyperplasia , and 0.75 ( 95 % CI , 0.60–0.93 ) for thromboembolic events . There were no significant mortality differences . Long-term raloxifene retained 76 % of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease , with far less toxicity ( e.g. , highly significantly less endometrial cancer ) . These results have important public health implication s and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer . Cancer Prev Res ; 3(6 ) ; 696–706 . © 2010 AACR Pre- clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention . We conducted a single-arm , biomarker modulation trial of lovastatin among women with increased risk of breast cancer . Eligibility criteria included a deleterious germline mutation in BRCA1 , BRCA2 , CDH1 , or TP53 ; lifetime breast cancer risk of ≥20 % as estimated by the Claus model ; or personal history of estrogen receptor and progesterone receptor-negative breast cancer . Participants received 40 mg of lovastatin orally twice daily for 6 months . We evaluated the following biomarkers before and after lovastatin use : breast duct cytology ( primary endpoint ) , serum lipids , C-reactive protein , insulin-like growth factor-1 , IGF binding protein-3 , lipid peroxidation , oxidative DNA damage , 3-hydroxy-3-methylglutaryl CoA reductase genotype , and mammographic density . Thirty women were enrolled , and 26 ( 86.7 % ) completed the study . For the primary endpoint of changes in breast duct cytology sample d by r and om periareolar fine needle aspiration , most participants [ 57.7 % , 95 % confidence interval ( CI ) 38.9–74.5 % ] showed no change after lovastatin ; 19.2 % ( CI 8.1–38.3 % ) had a favorable change in cytology , 7.7 % ( 95 % CI 1.0–25.3 % ) had an unfavorable change , and 15.4 % ( 95 % CI 5.5–34.2 % ) had equivocal results due to acellular specimens , usually after lovastatin . No significant changes were observed in secondary biomarker endpoints . The study was generally well-tolerated : 4 ( 13.3 % ) participants did not complete the study , and one ( 3.8 % ) required a dose reduction . This trial was technically feasible , but demonstrated no significant biomarker modulation ; contributing factors may include insufficient sample size , drug dose and /or duration . The results are inconclusive and do not exclude a favorable effect on breast cancer risk Background / Objectives : The antiestrogen , Raloxifene ( Ral ) is an effective breast cancer chemopreventive agent . Omega-3 fatty acids ( n-3FA ) may inhibit mammary carcinogenesis . On the basis of their mechanisms of action , we test the hypothesis that a combination of n-3FA and Ral may be superior in reducing select biomarkers of breast cancer risk in women . Subjects/ Methods : Postmenopausal women at increased risk for breast cancer ( breast density ⩾25 % ) were r and omized to : ( 1 ) no intervention ; ( 2 ) Ral 60 mg ; ( 3 ) Ral 30 mg ; ( 4 ) n-3FA ( Lovaza ) 4 g and ( 5 ) Lovaza 4 g+Ral 30 mg for 2 years . Reduction in breast density is the primary end point of the study . We report preliminary data on feasibility , compliance and changes in secondary end points related to IGF-I signaling , estrogen metabolism , oxidative stress and inflammation in the first group of 46 women who completed 1 year of the study . Results : All interventions were well tolerated with excellent compliance ( 96±1 % overall ) by pill count and also supported by the expected rise in both serum n-3FA and n-3FA/Omega-6 fatty acids ( n-6FA ) ratio in women r and omized to groups 4 and 5 ( P<0.05 ) . Lovaza decreased serum triglycerides and increased high-density lipoprotein ( HDL ) cholesterol compared with control ( P<0.05 for both ) . Ral reduced serum IGF-1 in a dose-dependent manner ( P<0.05 ) while Lovaza did not . Lovaza had no effect on IGF-1 or IGFBP-3 . None of the other biomarkers were affected by our treatment . Conclusion : The combination of Lovaza and Ral is a feasible strategy that may be recommended in future breast cancer chemoprevention trials Little is known about the cognitive factors associated with adherence to antiestrogen therapy . Our objective was to investigate the association between domain-specific cognitive function and adherence among women in a clinical prevention trial of oral antiestrogen therapies . We performed a secondary analysis of Co-STAR , an ancillary study of the STAR breast cancer prevention trial in which postmenopausal women at increased breast cancer risk were r and omized to tamoxifen or raloxifene . Co-STAR enrolled nondemented participants ≥65 years old to compare treatment effects on cognition . The cognitive battery assessed global cognitive function ( Modified Mini-Mental State Exam ) , and specific cognitive domains of verbal knowledge , verbal fluency , figural memory , verbal memory , attention and working memory , spatial ability , and fine motor speed . Adherence was defined by a ratio of actual time taking therapy per protocol ≥80 % of expected time . Logistic regression was used to evaluate the association between cognitive test scores and adherence to therapy . The mean age of the 1,331 Co-STAR participants was 67.2 ± 4.3 years . Mean 3MS score was 95.1 ( 4.7 ) and 14 % were nonadherent . In adjusted analyses , the odds of nonadherence were lower for those with better scores on verbal memory [ OR ( 95 % confidence interval ) : 0.75 ( 0.62–0.92 ) ] . Larger relative deficits in verbal memory compared with verbal fluency were also associated with nonadherence [ 1.28 ( 1.08–1.51 ) ] . Among nondemented older women , subtle differences in memory performance were associated with medication adherence . Differential performance across cognitive domains may help identify persons at greater risk for poor adherence . Cancer Prev Res ; 7(1 ) ; 161–8 . © 2013 AACR Chemoprevention for women at risk for breast cancer has been shown to be effective , but in actual practice , women 's uptake of chemoprevention has been poor . We explored factors that influence acceptability , adherence , and dropout in the International Breast ( Prevention ) Intervention Study during our first 3 years of activity at the Modena Familial Breast and Ovarian Cancer Center . We evaluated socio-demographic characteristics , health status , adherence , and side effect intensity . Semi-structured interviews analyzed reasons for accepting/refusing/stopping the trial . A total of 471 postmenopausal women were invited to participate , of which 319 declined to participate ( 68 % ) , 137 accepted to participate ( 29 % ) , and 15 participants did not make a final decision ( 3 % ) . Breast cancer-related worries and trust in our preventive and surveillance programs were the most frequent reasons for accepting . Side effect-related worry was the most frequent reason for refusing . General practitioners ' and family members ' opinions played an important role in the decision-making process . Adherence significantly decreased after a 12-month follow-up , but it remained unchanged after 24- and 36-month follow-ups . Mild/moderate side effects reported by women did not change after 12 months of treatment . Forty percent of women withdrew from the study due to complaints of side effects . We concluded that chemoprevention trials are difficult medical experiments and that the process of deciding about whether or not to participate is based mainly on beliefs and values . This study has important clinical implication s. During counselling with prospect i ve participants , it is important to emphasize the potential benefits and to promote an informed choice . How participants make decisions , their belief systems , and their perception of risk are all factors that should be investigated in future research Treatment with the selective estrogen receptor modulator ( SERM ) tamoxifen for 5 years has produced dramatic breast cancer – related benefits in ( a ) the adjuvant setting , with 30 % to 50 % reductions in recurrence , contralateral disease , and mortality and ( b ) the prevention setting of healthy high-risk women , where tamoxifen reduces the risk of invasive and noninvasive breast cancer by 50 % . Despite these striking data , adherence to tamoxifen is low , and low adherence is associated with poor survival . Although toxicity is a major predictor of poor adherence after starting therapy , pretreatment ( baseline ) predictors of poor tamoxifen adherence have been minimally studied . The adherence – survival link underscores the critical need to identify early predictors of poor adherence , and recent work is beginning to address this need . A major baseline predictor of poor adherence to prevention is current smoking , which is interestingly absent from studies of adherence to adjuvant therapy . Other important prevention adherence factors include breast cancer risk , extremes of age , non-white ethnicity , low socioeconomic status , and alcohol use . The strongest adjuvant therapy predictors are age ( especially very young ) , ethnicity , and socioeconomic status . Future studies involving prospect i ve systematic evaluation of these and other potential predictors in endocrine chemoprevention ( e.g. , other SERMs and aromatase inhibitors ) are critical , as is the development of effective/targeted interventions to improve adherence and thus treatment outcomes in at-risk women . Cancer Prev Res ; 4(9 ) ; 1360–5 . © 2011 AACR CONTEXT Tamoxifen has been approved for breast cancer risk reduction in high-risk women , but how raloxifene compares with tamoxifen is unknown . OBJECTIVE To compare the differences in patient-reported outcomes , quality of life [ QOL ] , and symptoms in Study of Tamoxifen and Raloxifene ( STAR ) participants by treatment assignment . DESIGN , SETTING , PARTICIPANTS , AND INTERVENTIONS STAR was a double-blind , r and omized phase 3 prevention trial design ed to evaluate the relative efficacy of raloxifene vs tamoxifen in reducing the incidence of invasive breast cancer in high-risk postmenopausal women . Between July 1 , 1999 , and November 4 , 2004 , 19,747 participants were enrolled at centers throughout North America , with a median potential follow-up time of 4.6 years ( range , 1.2 - 6.5 years ) . Patient-reported symptoms were collected from all participants using a 36-item symptom checklist . Quality of life was measured with the Medical Outcomes Study Short-Form Health Survey ( SF-36 ) , the Center for Epidemiologic Studies -Depression ( CES-D ) , and the Medical Outcomes Study Sexual Activity Question naire in a sub study of 1983 participants , median potential follow-up 5.4 years ( range , 4.6 - 6.0 years ) . Question naires were administered before treatment , every 6 months for 60 months and at 72 months . MAIN OUTCOME MEASURES Primary QOL end points were the SF-36 physical ( PCS ) and mental ( MCS ) component summaries . RESULTS Among women in the QOL analysis , mean PCS , MCS , and CES-D scores worsened modestly over the study 's 60 months , with no significant difference between the tamoxifen ( n = 973 ) and raloxifene ( n = 1010 ) groups ( P>.2 ) . Sexual function was slightly better for participants assigned to tamoxifen ( age-adjusted repeated measure odds ratio , 1.22 % ; 95 % CI , 1.01 - 1.46 ) . Of the women in the symptom assessment analyses , the 9769 in the raloxifene group reported greater mean symptom severity over 60 months of assessment s than the 9743 in the tamoxifen group for musculoskeletal problems ( 1.15 vs 1.10 , P = .002 ) , dyspareunia ( 0.78 vs 0.68 , P<.001 ) , and weight gain ( 0.82 vs 0.76 , P<.001 ) . Women in the tamoxifen group reported greater mean symptom severity for gynecological problems ( 0.29 vs 0.19 , P<.001 ) , vasomotor symptoms ( 0.96 vs 0.85 , P<.001 ) , leg cramps ( 1.10 vs 0.91 , P<.001 ) , and bladder control symptoms ( 0.88 vs 0.73 , P<.001 ) . CONCLUSIONS No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health , mental health , and depression , although the tamoxifen group reported better sexual function . Although mean symptom severity was low among these postmenopausal women , those in the tamoxifen group reported more gynecological problems , vasomotor symptoms , leg cramps , and bladder control problems , whereas women in the raloxifene group reported more musculoskeletal problems , dyspareunia , and weight gain . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00003906 R and om periareolar fine-needle aspiration ( RPFNA ) is a research procedure design ed to ( a ) evaluate short-term breast cancer risk in women at high risk for developing breast cancer , and ( b ) track response to chemoprevention . Of import , cellular atypia in breast RPFNA is prospect ively associated with a 5.6-fold increase in breast cancer risk in women at high risk . Among 99 women attending a clinic for high-risk breast cancer , we explored the effects of RPFNA cytology results on decision making pertaining to the use of tamoxifen for breast cancer chemoprevention . No patient with nonproliferative or hyperplastic cytology subsequently elected to take tamoxifen . Only 7 % of subjects with borderline atypia elected to take tamoxifen . In contrast , 50 % with atypia elected to take tamoxifen . These results suggest that the provision of a biomarker of short-term risk can affect the motivation to take tamoxifen for chemoprevention . This conclusion is informative given that tamoxifen , due to its side effects , is often underused by women at high risk of developing breast cancer . Further research is needed to determine the mechanisms through which RPFNA results affect the decision to use tamoxifen , or any other breast cancer chemopreventive agent . ( Cancer Epidemiol Biomarkers Prev 2007;16(5):1032–4 Background : Decision aids may improve informed consent in clinical trial recruitment , but have not been evaluated in this context . This study investigated whether decision aids ( DAs ) can reduce decisional difficulties among women considering participation in the International Breast Cancer Intervention Study -II ( IBIS-II ) trial . Methods : The IBIS-II trial investigated breast cancer prevention with anastrazole in two cohorts : women with increased risk ( Prevention ) , and women treated for ductal carcinoma in situ ( DCIS ) . Australia , New Zeal and and United Kingdom participants were r and omised to receive a DA ( DA group ) or st and ard trial consent material s ( control group ) . Question naires were completed after deciding about participation in IBIS-II ( post decision ) and 3 months later ( follow-up ) . Results : Data from 112 Prevention and 34 DCIS participants were analysed post decision ( 73 DA ; 73 control ) ; 95 Prevention and 24 DCIS participants were analysed at follow-up ( 58 DA ; 61 control ) . There was no effect on the primary outcome of decisional conflict . The DCIS – DA group had higher knowledge post decision , and the Prevention-DA group had lower decisional regret at follow-up . Conclusions : This was the first study to evaluate a DA in the clinical trial setting . The results suggest DAs can potentially increase knowledge and reduce decisional regret about clinical trial participation The double-blind , prospect i ve , National Surgical Adjuvant Breast and Bowel Project ( NSABP ) Breast Cancer Prevention Trial ( BCPT ) showed a 50 % reduction in the risk of breast cancer for tamoxifen versus placebo , yet many women at risk of breast cancer do not adhere to the 5-year course . This first report of the rich BCPT drug adherence data examines predictors of adherence . Between June , 1992 and September , 1997 13,338 women at high risk of breast cancer were r and omly assigned to 20 mg/d tamoxifen versus placebo ; we analyzed the 11,064 enrolled more than 3 years before trial unblinding . Primary endpoint was full drug adherence ( 100 % of assigned pills per staff report , excluding protocol -required discontinuation ) at 1 and 36 months ; secondary was adequate adherence ( 76%–100 % ) . Protocol -specified multivariable logistic regression tested lifestyle factors , controlling for demographic and medical predictors . About 13 % were current smokers ; 60 % were overweight/obese ; 46 % had moderate/heavy physical activity ; 21 % , 66 % , 13 % drank 0 , 0–1 , 1 + drinks per day , respectively ; 91 % were adequately adherent at 1 month ; and 79 % were at 3 years . Alcohol use was associated with reduced full adherence at 1 month ( P = 0.016 ; OR = 0.79 1 + vs. 0 ) , as was college education ( P < 0.001 ; OR = 0.78 vs. high school ) ; age ( P < 0.001 ; OR = 1.4 age 60 + ) and per capita household annual income ( P < 0.001 ; OR = 1.2 per $ 30,000 ) with increased adherence . Current smoking ( P = 0.003 ; OR = 0.75 ) , age ( P = 0.024 , OR = 1.1 ) , college education ( P = 0.037 ; OR = 1.4 ) , tamoxifen assignment ( P = 0.031 ; OR = 0.84 ) , and breast cancer risk ( P < .001 ; OR = 1.5 high vs. low ) predicted adequate adherence at 36 months . There were no significant associations with obesity or physical activity . Alcohol use and smoking might indicate a need for greater adherence support . Cancer Prev Res ; 4(9 ) ; 1393–400 . © 2011 AACR Background : R and omised trials of tamoxifen versus placebo indicate that tamoxifen reduces breast cancer risk by approximately 33 % , yet uptake is low . Approximately 10 % of women in our clinic entered the IBIS-I prevention trial . We assess the uptake of tamoxifen in a consecutive series of premenopausal women not in a trial and explore the reasons for uptake through interviews . Methods : All eligible women between 33 and 46 years at ⩾17 % lifetime risk of breast cancer and undergoing annual mammography in our service were invited to take a 5-year course of tamoxifen . Reasons for accepting ( n=15 ) or declining ( n=15 ) were explored using semi-structured interviews . Results : Of 1279 eligible women , 136 ( 10.6 % ) decided to take tamoxifen . Women > 40 years ( 74 out of 553 ( 13.4 % ) ) and those at higher non-BRCA-associated risk were more likely to accept tamoxifen ( 129 out of 1109 ( 11.6 % ) ) . Interviews highlighted four themes surrounding decision making : perceived impact of side effects , the impact of others ’ experience on beliefs about tamoxifen , tamoxifen as a ‘ cancer drug ’ , and daily reminder of cancer risk . Conclusions : Tamoxifen uptake was similar to previously ascertained uptake in a r and omised controlled trial ( IBIS-I ) . Concerns were similar in women who did or did not accept tamoxifen . Decision making appeared to be embedded in the experience of significant others AIMS OF THE STUDY This prospect i ve study was performed to investigate the effects of 5-year 's use of tamoxifen in preventive setting on endometrium and gynaecological symptoms . MATERIAL AND METHODS Altogether 96 women were treated either with tamoxifen ( TAM , n=45 ) or placebo ( PLA , n=51 ) for up to 5 years in a r and omised , double-blind IBIS I breast cancer prevention trial , clinical ly followed-up for an additional year and for the occurrence of malignancies at least 9 years between 2/1995 and 7/2009 in Finl and . The gynaecological follow-up with trans-vaginal ultrasound and endometrial biopsies were performed at baseline , at 2.5 and 5 years and at the 6 years follow-up visit . RESULTS Women in the TAM group discontinued the treatment significantly more often ( 44 % versus 22 % ; p=0.017 ) and earlier ( at 15 versus 30 months ; p=0.044 ) , than those in the PLA group . In postmenopausal women the median endometrial thickness was significantly increased at five years in the TAM group ( median 4.3 versus 2.0 mm , p=0.011 ) , but there was no difference between the groups at one year after the treatment . There were also statistically significantly more referrals to hospitals due to gynaecological findings in the TAM group ( risk rates ( RR ) 3.15 ; 95 % confidence intervals ( CI ) 1.12 - 10.10 ) , but no differences in hysterectomy rates or other serious adverse event rates were observed . CONCLUSIONS The discontinuation rate in the TAM group was high , and the discontinuations also occurred early . Even though there were significantly more non-serious gynaecological events during the TAM treatment , routine gynaecological follow-up can not be recommended Background : Epidemiologic studies suggest a reduced risk of breast cancer among women who regularly use aspirin ; a plausible mechanism is through aspirin effect on mammographic breast density , a breast cancer risk factor , possibly mediated through aspirin interference with estrogen synthesis . Methods : In a 2-arm r and omized placebo-controlled clinical trial , we evaluated the effects of 6-month administration of 325 mg/day aspirin on total mammographic breast dense area and percent of the mammographic breast image occupied by dense areas ( % density ) in 143 postmenopausal women . Eligible women , recruited from 2005 to 2007 , were healthy , not taking hormone therapy , with elevated mammographic breast density ( American College of Radiology Breast Imaging Reporting and Data System density category 2 , 3 , or 4 ) within 6 months before enrollment . Results : Women were a mean ( SD ) 59.5 ( 5.5 ) years . Geometric mean baseline percent density was 17.6 % ( 95 % confidence interval , 14.8 - 20.9 ) in women r and omized to aspirin and 19.2 % ( 95 % confidence interval , 16.3 - 22.7 ) in women r and omized to placebo . Percent density decreased in women r and omized to aspirin by an absolute 0.8 % versus an absolute decrease of 1.2 % in controls ( P = 0.84 ) . Total breast area and dense area decreased to a similar degree in women assigned to aspirin and in those assigned to placebo , with no statistically significant differences between trial arms . Conclusions : A single daily administration of adult-dose aspirin for 6 months had no effect on mammographic density in postmenopausal women . If aspirin affects breast cancer risk in postmenopausal women , it may do so through alternative pathways than mammographic breast density . ( Cancer Epidemiol Biomarkers Prev 2009;18(5):1524–30 BACKGROUND Women with a family history of breast cancer have several menopausal therapy options , including tamoxifen , hormone therapy ( HT ) , alternative medications , or no treatment . This complex decision should be based on each woman 's risk to develop breast cancer , menopausal symptoms , preferences , and risks for other conditions . The authors determined the effects of a personalized risk assessment and genetic counseling intervention on knowledge , risk perception , and decision making in a group of healthy women who had a first-degree relative with breast cancer . METHODS Forty-eight cancer-free menopausal women age > or = 40 years who had at least one first-degree relative with breast cancer were r and omized to a genetic counseling intervention or control . Intervention participants were given a personalized risk assessment for breast cancer , heart disease , osteoporosis , and uterine cancer based on family history and personal health data . Knowledge , risk perception , and medication usage were measured at baseline , 1 month , and 6 months . RESULTS Knowledge was higher in the intervention group at both follow-up time points postintervention . Perceived risk for developing breast cancer was significantly lower and more accurate in the intervention group at 1 and 6 months postintervention than at baseline , as was perceived risk of developing heart disease . Although the counseling intervention did affect both knowledge and risk perception , overall , both groups were reluctant to take any form of menopausal therapy . CONCLUSIONS A personalized risk assessment and genetic counseling intervention improves patient knowledge and risk perception ; however , it is unclear that the intervention influenced menopausal treatment decisions This study prospect ively evaluated the utilization of cancer risk management strategies in a multi‐institutional cohort of BRCA1 and BRCA2 mutation carriers using a self‐report question naire . Of 142 unaffected female mutation carriers , 70 ( 49 % ) had elected to receive their mutation result . Of those who knew their mutation result , 11 % underwent bilateral mastectomy ( BM ) , 29 % had bilateral oophorectomy ( BO ) , 78 % performed regular breast self‐examination ( BSE ) , and 80 % , 89 % , 67 % , and 0 % had at least annual clinical breast examination ( CBE ) , mammography , transvaginal ultrasound ( TVU ) , and CA125 , respectively . A further 20 % , 7 % , 0 % , 21 % , and 75 % , respectively , reported never having had these tests . For women who elected not to receive their mutation result , 0 % underwent BM , 6 % underwent BO , and 77 % , 42 % , 56 % , 7 % , and 0 % had regular BSE , CBE , mammography , TVU , and CA125 , respectively . Only one woman used chemoprevention outside a clinical trial . Uptake of prophylactic surgery and screening was associated with knowing one ’s mutation status ( for all behaviors except BSE ) , age ( for BO and CBE ) and residence ( for mammography ) . In this cohort , the minority of mutation carriers utilized risk‐reducing surgery or chemoprevention and a substantial minority were not undergoing regular cancer‐screening tests BACKGROUND Tamoxifen is a c and i date chemopreventive agent in breast cancer , although the drug may be associated with the development of endometrial cancer . Therefore we did a trial in hysterectomised women of tamoxifen as a chemopreventive . METHODS In October , 1992 , we started a double-blind placebo-controlled , r and omised trial of tamoxifen in women ( mainly in Italy ) who did not have breast cancer and who had had a hysterectomy . Women were r and omised to receive tamoxifen 20 mg per day or placebo , both orally for 5 years . The original plan was to follow the intervention phase by 5 years ' follow-up . In June , 1997 , the trialists and the data -monitoring committee decided to end recruitment primarily because of the number of women dropping out of the study . Recruitment ended on July 11 , 1997 , and the study will continue as planned . The primary endpoints are the occurrence of and deaths from breast cancer . This preliminary interim analysis is based on intention-to-treat . FINDINGS 5408 women were r and omised ; participating women have a median follow-up of 46 months for major endpoints . 41 cases of breast cancer occurred so far ; there have been no deaths from breast cancer . There is no difference in breast-cancer frequency between the placebo ( 22 cases ) and tamoxifen ( 19 ) arms . There is a statistically significant reduction of breast cancer among women receiving tamoxifen who also used hormone-replacement therapy during the trial : among 390 women on such therapy and allocated to placebo , we found eight cases of breast cancer compared with one case among 362 women allocated to tamoxifen . Compared with the placebo group , there was a significantly increased risk of vascular events and hypertriglyceridaemia among women on tamoxifen . INTERPRETATION Although this preliminary analysis has low power , in this cohort of women at low-to-normal risk of breast cancer , the postulated protective effects of tamoxifen are not yet apparent . Women using hormone-replacement therapy appear to have benefited from use of tamoxifen . There were no deaths from breast cancer recorded in women in the study . It is essential to continue follow-up to quantify the long-term risks and benefits of tamoxifen therapy BACKGROUND Despite the results of prospect i ve r and omized placebo controlled studies , endorsement from various professional societies , and approval by the FDA , the chemoprevention of breast cancer is limited . This is attributable to the perceived risks of complications with tamoxifen . Individualized risk-benefit calculation regarding the use of tamoxifen is burdensome for practical clinical use . We propose a Chemoprevention Indication Score ( CIS ) that is easy to compute and reliable to identify women suitable for chemoprevention . MATERIAL AND METHODS Chart- review of all patients attending a university-based high-risk breast clinic identified the women offered chemoprevention and those who accepted it . Age , Gail risk score , past medical history and physician 's reasons for not offering tamoxifen were recorded . CIS was developed weighing risks and benefits of tamoxifen ; high , moderate and low indication score categories were defined for recommendation of tamoxifen . CIS was vali date d by cross-tabulating with the rate of physician recommendation of tamoxifen and by agreement with Gail 's risk-benefit index . RESULTS Between 2004 and 2006,105 women attended the high-risk clinic . Median ( interquartile ) age was 47 ( 42 - 53 ) yrs ; 142(90 % ) were Caucasian . Median ( interquartile ) Gail score was 2.3 ( 1.0 - 3.2 ) . Forty-eight ( 46 % ) women were offered tamoxifen while 15(14 % ) complied . Tamoxifen was offered to 1 of 5(20 % ) women with low ; 32 of 82(39 % ) women with moderate and 15 of 18(83 % ) women with high CIS [ p=0.0008 ] . The McNemar 's test for agreement between CIS ( < 6 vs. > or=6 ) and Gail 's risk-benefit index was significant at p<0.0001 and Kruskal-Wallis test comparing median Gail 's risk-benefit index across CIS was significant at p<0.0001 . CONCLUSION Inability to identify appropriate c and i date s has been a great barrier towards acceptance of chemoprevention for breast cancer . The CIS can be used for individual risk-benefit analysis for recommendation of breast cancer chemoprevention . However , CIS needs to be vali date d on a larger scale with method ologically more rigorous studies before proposing generalized use in the community Aim The aim of this study was to investigate whether tamoxifen toxicity and treatment discontinuations differred in the adjuvant versus chemopreventive setting . Methods At our Institutions 119 postmenopausal breast cancer patients were r and omized from August 1987 to March 1995 to tamoxifen only within adjuvant studies ( International Breast Cancer Study Group studies VII and IX ) and 202 healthy hysterectomized women aged 35 - 70 years were r and omized from November 1993 to May 1996 in a multicenter , double-blind , placebo-controlled chemoprevention study ( Italian Tamoxifen Prevention Study ) . The tamoxifen dose was 20 mg/day for 5 years in all studies . Median age was 66 years ( 54 - 85 ) in the adjuvant studies and 53 years ( 37 - 69 ) in the chemoprevention study . Median treatment duration was 238 and 120 weeks , respectively . Results Patients treated within adjuvant studies experienced more hot flashes , vaginal discharge and /or bleeding , bone marrow depression and weight gain than those treated in the chemoprevention study , consistent with the fact that a proportion of women in the latter study were receiving placebo . Temporary discontinuation occurred in 2.5 % of patients in the adjuvant studies and in 5.4 % of women in the chemoprevention study ( difference not statistically significant ) . Permanent discontinuation was more frequent in the chemoprevention study than in the adjuvant ones ( 26.7 % vs 15.1 % - P < 0.05 ) . Conclusions In summary , our data show that , although the toxicity of tamoxifen is superimposable in the two setting s , a larger proportion of women treated as chemoprevention discontinue treatment spontaneously . Due to the double-blind nature of the chemoprevention study , the impact of the toxicity of tamoxifen upon compliance in the chemopreventive setting can not be ascertained PURPOSE The purpose of this study was to evaluate the psychosocial implication s of tamoxifen versus placebo in women who are at increased risk of breast cancer . PATIENTS AND METHODS The 488 women in the psychosocial study were recruited from participants in two placebo-controlled , double-blind , r and omized , controlled trials that investigated the efficacy of tamoxifen in the prevention of breast cancer in women who are at high familial risk . During a 5-year period , repeated assessment s were made of anxiety , psychological distress , and sexual functioning using st and ardized question naires before treatment at baseline and at 6-month intervals during the trial . RESULTS Question naire completion over 5 years was good , with 71.1 % of women returning at least 8 of 10 follow-up assessment s. Although scores from individuals showed considerable fluctuation and variation over time , changes in anxiety , mood , and sexual functioning were not associated with treatment group . The number of symptoms reported at 48 months via a self-report checklist were not associated with treatment group , but vasomotor symptoms were more frequent among tamoxifen-treated women . Symptoms of low energy , breast sensitivity , and visual blurring were reported most frequently in the placebo group . CONCLUSION In general , these results are comparable to those from the National Surgical Adjuvant Breast and Bowel Project psychosocial study despite differences in study population s , methodology , and instruments . The long-term use of tamoxifen and other selective estrogen response modulators as preventive agents in high-risk groups has been question ed , but we found no evidence of treatment-related side effects that affect women 's psychosocial and sexual functioning Background . Using an a priori theoretic model of behavior change , factors predicting enrollment in a r and omized chemoprevention trial during the first year of recruitment were assessed prospect ively Introduction Tamoxifen and raloxifene are chemopreventive drugs that can reduce women 's relative risk of primary breast cancer by 50 % ; however , most women eligible for these drugs have chosen not to take them . The reasons for low uptake may be related to women 's knowledge or attitudes towards the drugs . We aim ed to examine the impact of an online breast cancer chemoprevention decision aid ( DA ) on informed intentions and decisions of women at high risk of breast cancer . Methods We conducted a r and omized clinical trial , assessing the effect of a DA about breast cancer chemoprevention on informed choices about chemoprevention . Women ( n = 585 ) , 46- to 74-years old old , completed online baseline , post-test , and three-month follow-up question naires . Participants were r and omly assigned to either an intervention group , a st and ard control group that answered questions about chemoprevention at baseline , or a three-month control group that did not answer questions about chemoprevention at baseline . The main outcome measures were whether women 's intentions and decisions regarding chemoprevention drugs were informed , and whether women who viewed the DA were more likely to make informed decisions than women who did not view the DA , using a dichotomous composite variable ' informed choice ' ( yes/no ) to classify informed decisions as those reflecting sufficient knowledge and concordance between a woman 's decision and relevant attitudes . Results Analyses showed that more intervention than st and ard control participants ( 52.7 % versus 5.9 % ) made informed decisions at post-test , P < 0.001 . At the three-month follow-up , differences in rates of informed choice between intervention ( 16.9 % ) and both control groups ( 11.8 % and 8.0 % ) were statistically non-significant , P = 0.067 . Conclusions The DA increased informed decision making about breast cancer chemoprevention , although the impact on knowledge diminished over time . This study was not design ed to determine how much knowledge decision makers must retain over time . Examining informed decisions increases underst and ing of the impact of DAs . A st and ard for defining and measuring sufficient knowledge for informed decisions is needed . Trial registration Clinical Trials.gov : Two selective estrogen receptor modulators , tamoxifen and raloxifene , have been shown in r and omized clinical trials to reduce the risk of developing primary invasive breast cancer in high-risk women . In 1998 , the U.S. Food and Drug Administration ( FDA ) used these studies as a basis for approving tamoxifen for primary breast chemoprevention in both premenopausal and postmenopausal women at high risk . In 2007 , the FDA approved raloxifene for primary breast cancer chemoprevention for postmenopausal women . Data from the year 2010 National Health Interview Survey were analyzed to estimate the prevalence of tamoxifen and raloxifene use for chemoprevention of primary breast cancers among U.S. women . Prevalence of use of chemopreventive agents for primary tumors was 20,598 ( 95 % CI , 518–114,864 ) for U.S. women aged 35–79 for tamoxifen . Prevalence was 96,890 ( 95 % CI , 41,277–192,391 ) for U.S. women aged 50–79 for raloxifene . Use of tamoxifen and raloxifene for prevention of primary breast cancers continues to be low . In 2010 , women reporting medication use for breast cancer chemoprevention were primarily using the more recently FDA approved drug raloxifene . Multiple possible explanations for the low use exist , including lack of awareness and /or concern about side effects among primary care physicians and patients BACKGROUND Initial results from the first International Breast Cancer Intervention Study ( IBIS-I ) found that tamoxifen reduced the risk of invasive estrogen receptor (ER)-positive tumors by 31 % in women at increased risk for breast cancer , but most of the follow-up at this time was during the active treatment phase . We report an up date d analysis of IBIS-I that focuses on the period after active treatment was completed , a time for which little evidence from other trials is available . METHODS A total of 7145 women who were aged 35 - 70 years and at increased risk of breast cancer were r and omly assigned to receive either tamoxifen ( 20 mg/day ) or placebo for 5 years . The primary outcome measure was the incidence of breast cancer ( including ductal carcinoma in situ ) , but side effects were also investigated . Relative risks were computed as the ratio of incidence rates . All statistical tests were two-sided . RESULTS After a median follow-up of 96 months after r and omization , 142 breast cancers were diagnosed in the 3579 women in the tamoxifen group and 195 in the 3575 women in the placebo group ( 4.97 versus 6.82 per 1000 woman-years , respectively ; risk ratio [ RR ] = 0.73 , 95 % confidence interval [ CI ] = 0.58 to 0.91 , P = .004 ) . The prophylactic effect of tamoxifen was fairly constant for the entire follow-up period , and no diminution of benefit was observed for up to 10 years after r and omization . However , side effects in the tamoxifen group were much lower after completion of the active treatment period than during active treatment . For example , deep-vein thrombosis and pulmonary embolism were statistically significantly higher in the tamoxifen arm than in the placebo arm during active treatment ( 52 versus 23 cases , RR = 2.26 , 95 % CI = 1.36 to 3.87 ) but not after tamoxifen was stopped ( 16 versus 14 cases , RR = 1.14 , 95 % CI = 0.52 to 2.53 ) . The two arms did not differ in the risk of ER-negative invasive tumors ( 35 in each arm , RR = 1.00 , 95 % CI = 0.61 to 1.65 ) across the entire follow-up period , but the risk of ER-positive invasive breast cancer was 34 % lower in the tamoxifen arm ( 87 versus 132 cases , RR = 0.66 , 95 % CI = 0.50 to 0.87 ) . CONCLUSIONS The risk-reducing effect of tamoxifen appears to persist for at least 10 years , but most side effects of tamoxifen do not continue after the 5-year treatment period A pilot r and omised placebo controlled trial using tamoxifen in healthy women at increased risk of developing breast cancer , has been undertaken in order to evaluate the problems of accrual , acute symptomatic toxicity , compliance , and safety as a basis for subsequent large national multicentre trials design ed to test whether tamoxifen can chemoprevent breast cancer . From October 1986 until June 1993 , 2012 healthy women with an increased risk of developing breast cancer , usually because of a strong family history , were r and omly allocated to receive tamoxifen 20 mgs/day or placebo for up to 8 years if possible . Accrual remained high in spite of extensive informed consent regarding potential risk . Acute symptomatic toxicity was low for participants on tamoxifen or placebo and compliance remained correspondingly high with a predicted 77 % of women on tamoxifen and 82 % of women on placebo continuing medication at 5 years . There was a significant increase in hot flushes ( 34 % versus 20 % ) mostly in premenopausal women ( p < 0.005 ) , vaginal discharge ( 16 % versus 4 % , p < 0.005 ) , and menstrual irregularities ( 14 % versus 9 % , p < 0.005 ) . The requirements for hormone replacement therapy for women on tamoxifen or placebo were the same . Safety monitoring indicates no adverse anti oestrogenic effects of tamoxifen . There was no obvious effect of tamoxifen on bone mineral densities ( single photon radial absorption ) . The fibrinogen and antithrombin III were both lowered , result ing in no observed detrimental effect on the ratio of these clotting factors . There was a significant reduction in the serum cholesterol maintained out to 5 years . Annual pelvic assessment using transvaginal ultrasound indicates an increased incidence of uterine fibromata and benign ovarian cysts . These results have encouraged the commencement of the NSABP national trial in the USA , and the subsequent start of national trials in Italy and the UK , which together should provide sufficient evidence to evaluate the efficacy of tamoxifen for prevention of breast cancer BACKGROUND The purpose of this study was to evaluate the effect of physician recommendation on whether to enroll in a r and omized controlled chemoprevention trial for breast cancer . METHODS We surveyed 360 women who were at increased risk for breast cancer regarding social and behavioral factors that could influence their decision to enroll or not to enroll in the Breast Cancer Prevention Trial ( BCPT ) . Respondents completed a question naire following attendance at an informational session about the trial . The analysis was restricted to 175 women who discussed the possibility of their participation in the trial with their primary care physician ( PCP ) and who reported what their physician advised them to do regarding participation . RESULTS Logistic regression modeling showed that among women who discussed the trial with their physician , physician recommendation was the most important factor that influenced the respondent 's decision to enroll in the BCPT . Women who reported that their physician advised them to enroll in the trial were 13 times more likely to participate than were women who reported that their physicians advised them not to participate . CONCLUSIONS The results of our study show that PCPs play an important role in influencing preventive health behavior , specifically , regarding enrollment in a r and omized breast cancer chemoprevention trial . Efforts to increase recruitment to a trial should include enlisting the support of PCPs Objectives To investigate the knowledge and views of a range of healthcare professionals ( consultant paediatricians , general practitioners ( GPs ) , community pharmacists and paediatric nurses ) regarding the use of unlicensed/off-label medicines in children and the participation of children in clinical trials . Methods A regional study in which a survey instrument with 39 items was issued to 500 r and omly selected GPs , all community pharmacists ( n = 512 ) , 50 hospital consultants and 150 paediatric nurses in Northern Irel and . Results Approximately half ( 46.5 % ) of the 1,212 healthcare professionals approached responded to the question naire . The majority of respondents indicated their familiarity with the term unlicensed ( 82.9 % ) or off-label ( 58.6 % ) prescribing with the most frequently quoted reason for such prescribing being younger age ( 33.6 % ) . Apart from community pharmacists , most respondents reported having gained their knowledge through personal experience . Even though a large percentage of respondents expressed concerns about the safety ( 77.8 % ) or efficacy ( 87.9 % ) of unlicensed/off-label prescribing in children , only 30.7 % reported informing parents/guardians of these concerns on the use of such medicines in children . In addition , only 56 % of respondents believed that unlicensed/off-label medicines should undergo clinical trials in children . Overall , 28.4 % of respondents ( 20.1 % of GPs , 41.4 % of community pharmacists , 27.7 % of paediatric nurses and 94 % of consultant paediatricians ) indicated their willingness to be actively involved in , and recruit their patients for paediatric clinical research . Conclusion The use of unlicensed and off-label medicines remains a major issue in paediatric medicine . Until such times as more licensed medicines are available for children , clear guidance should be developed to allow consistency in practice across the spectrum of healthcare professionals who are involved with such medicines in their routine practice Although tamoxifen can prevent primary breast cancer , few women use it as a preventive measure . A second option , raloxifene , has recently been approved . The objective of the study was to determine women ’s interest in tamoxifen and raloxifene after reading a decision aid ( DA ) describing the risks and benefits of each medication . Women with 5-year risk of breast cancer ≥ 1.66 from two large health maintenance organizations were r and omized to receive a DA versus usual care . After reading an on-line DA that discussed the risks and benefits of tamoxifen and raloxifene , women completed measures of risk perception , decisional conflict , behavioral intentions , and actual behavior related to tamoxifen and raloxifene . 3 months following the intervention , 8.1 % of participants had looked for additional information about breast cancer prevention drugs , and 1.8 % had talked to their doctor about tamoxifen and /or raloxifene . The majority , 54.7 % , had decided to not take either drug , 0.5 % had started raloxifene , and none had started tamoxifen . Participants were not particularly worried about taking tamoxifen or raloxifene and did not perceive significant benefits from taking these drugs . Over 50 % did not perceive a change in their risk of getting breast cancer if they took tamoxifen or raloxifene . After reading a DA about tamoxifen and raloxifene , few women were interested in taking either breast cancer prevention drug BACKGROUND Tamoxifen , a drug with antioestrogenic effects , is predicted to prevent the occurrence of breast cancer . We have undertaken a trial of tamoxifen in healthy women who are at increased risk of breast cancer because of family history . We report a planned interim analysis . METHODS Between October , 1986 , and April , 1996 , we accrued 2494 healthy women aged between 30 and 70 with a family history of breast cancer . They have been r and omised ( double blind ) to receive tamoxifen 20 mg per day orally or placebo for up to 8 years . Follow-up included clinical assessment , annual mammography , and assessment of toxicity and compliance . The primary endpoint was the occurrence of breast cancer , which was analysed on an intention-to-treat basis with a survival curve . FINDINGS With a median follow-up of 70 months , 2471 women ( tamoxifen 1238 , placebo 1233 ) were suitable for analysis . The groups were evenly matched at baseline , and compliance was good . The overall frequency of breast cancer is the same for women on tamoxifen or placebo ( tamoxifen 34 , placebo 36 , relative risk 1.06 [ 95 % CI 0.7 - 1.7 ] , p=0.8 ) . Participants who were already on hormone-replacement therapy when they entered the study had an increased risk of breast cancer compared with non-users . Those participants who started such therapy while on trial had a significantly reduced risk . The safety profile of tamoxifen was as expected . INTERPRETATION We have been unable to show any effect of tamoxifen on breast-cancer incidence in healthy women , contrary to the report from the NSABP-P1 study showing a 45 % reduction in healthy women given tamoxifen versus placebo . Differences in the study population s for the two trials may underlie these conflicting findings : eligibility in our trial was based predominantly on a strong family history of breast cancer whereas in the NSABP trial was mostly based on non-genetic risk factors . The importance of oestrogen promotion may vary between such population Summary Background Four previously published r and omised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up . We report the long-term follow-up of the IBIS-I trial , in which the participants and investigators remain largely masked to treatment allocation . Methods In the IBIS-I r and omised controlled trial , premenopausal and postmenopausal women 35–70 years of age deemed to be at an increased risk of developing breast cancer were r and omly assigned ( 1:1 ) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years . Patients were r and omly assigned to the two treatment groups by telephone or fax according to a block r and omisation schedule ( permuted block sizes of six or ten ) . Patients and investigators were masked to treatment assignment by use of central r and omisation and coded drug supply . The primary endpoint was the occurrence of breast cancer ( invasive breast cancer and ductal carcinoma in situ ) , analysed by intention to treat . Cox proportional hazard models were used to assess breast cancer occurrence and mortality . The trial is closed to recruitment and active treatment is completed , but long-term follow-up is ongoing . This trial is registered with controlledtrials.com , number IS RCT N91879928 . Findings Between April 14 , 1992 , and March 30 , 2001 , 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were r and omly allocated to the two treatment groups : 3579 to tamoxifen and 3575 to placebo . After a median follow up of 16·0 years ( IQR 14·1–17·6 ) , 601 breast cancers have been reported ( 251 [ 7·0 % ] in 3579 patients in the tamoxifen group vs 350 [ 9·8 % ] in 3575 women in the placebo group ; hazard ratio [ HR ] 0·71 [ 95 % CI 0·60–0·83 ] , p<0·0001 ) . The risk of developing breast cancer was similar between years 0–10 ( 226 [ 6·3 % ] in 3575 women in the placebo group vs 163 [ 4·6 % ] in 3579 women in the tamoxifen group ; hazard ratio [ HR ] 0·72 [ 95 % CI 0·59–0·88 ] , p=0·001 ) and after 10 years ( 124 [ 3·8 % ] in 3295 women vs 88 [ 2·6 % ] in 3343 , respectively ; HR 0·69 [ 0·53–0·91 ] , p=0·009 ) . The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer ( HR 0·66 [ 95 % CI 0·54–0·81 ] , p<0·0001 ) and ductal carcinoma in situ ( 0·65 [ 0·43–1·00 ] , p=0·05 ) , but no effect was noted for invasive oestrogen receptor-negative breast cancer ( HR 1·05 [ 95 % CI 0·71–1·57 ] , p=0·8 ) . Interpretation These results show that tamoxifen offers a very long period of protection after treatment cessation , and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention . Funding Cancer Research UK ( UK ) and the National Health and Medical Research Council ( Australia ) This study sought to evaluate a shared decision-making aid for breast cancer prevention care design ed to help women make appropriate prevention decisions by presenting information about risk in context . The decision aid was implemented in a high-risk breast cancer prevention program and pilot-tested in a r and omized clinical trial comparing st and ard consultations to use of the decision aid . Physicians completed training with the decision aid prior to enrollment . Thirty participants enrolled ( 15 per group ) and completed measures of clinical feasibility and effectiveness prior to , immediately after , and at 9 months after their consultations . The decision aid was feasible to use during the consultations as measured by consultation duration , user satisfaction , patient knowledge , and decisional conflict . The mean consultation duration was not significantly different between groups ( 24 minutes for intervention group versus 21 minutes for control group , p = 0.42 ) . The majority found the decision aid acceptable and useful and would recommend it to others . Both groups showed an improvement in breast cancer prevention knowledge postvisit , which was significant in the intervention group ( p = 0.01 ) but not the control group ( p = 0.13 ) . However , the knowledge scores returned to baseline at follow-up in both groups . Decision preference for patients who chose chemoprevention post consultations remained constant at follow-up for the intervention group , but not for the control group . The decision framework provides access to key information during consultations and facilitates the integration of emerging biomarkers in this setting . Initial results suggest that the decision aid is feasible for use in the consultation room . The tendency for the decision choices and knowledge scores to return to baseline at follow-up suggests the need for initial and ongoing prevention decision support OBJECTIVE To estimate the prevalence of the use of cancer risk-reducing measures among Australian BRCA1 and BRCA2 mutation carriers . DESIGN , SETTING AND PARTICIPANTS Prospect i ve follow-up of female carriers of BRCA1 or BRCA2 mutations who had no personal history of cancer and were enrolled in a multiple-case breast cancer family cohort study ( kConFab ) . Data , including cancer events and uptake of risk-reducing surgery and medication were collected by self-report at cohort entry and 3 yearly thereafter . Surgery was confirmed from pathology and medical records . Women were followed up from enrolment until cancer diagnosis , date of last follow-up , or death . Data were collected from 3 November 1997 to 21 May 2012 . MAIN OUTCOME MEASURES Uptake of risk-reducing surgery and /or medication . RESULTS Of 175 BRCA1 and 150 BRCA2 mutation carriers ( median age , 37 years at cohort enrolment ) , 69 ( 21 % ) underwent risk-reducing mastectomy , 125 ( 38 % ) underwent risk-reducing bilateral salpingo-oophorectomy and nine ( 3 % ) participated in a clinical trial of risk-reducing medication , during 2447 person-years of follow-up ( median follow-up , 9 years ) . Sixty-eight women ( 21 % ) reported incident cancers , including 52 breast cancers and nine ovarian cancers ( defined in this article as high- grade serous cancers of the ovary , fallopian tube or peritoneum ) . CONCLUSIONS There is considerable scope to increase the uptake of cancer risk-reducing measures in Australian BRCA1 and BRCA2 mutation carriers . These findings should drive ( i ) future research into the factors contributing to low uptake in Australia and ( ii ) changes to policy and practice to help better translate genetic knowledge into reductions in cancer incidence BACKGROUND Concerns have been raised that tamoxifen may be associated with depression . To investigate this question , we examined the psychological effects of tamoxifen treatment for breast cancer prevention on women at different levels of risk for clinical depression who were enrolled in the National Surgical Adjuvant Breast and Bowel Project 's Breast Cancer Prevention ( P-1 ) Study . METHODS A total of 11 064 women were r and omly assigned to receive for 5 years daily doses of 20 mg of tamoxifen or placebo in the P-1 study , a multicenter , double-blind , placebo-controlled chemoprevention trial . Each woman was prospect ively assessed for depression risk on the basis of medical history items collected at the baseline examination and placed in a high- , medium- , or low-risk group . Every 6 months , for a total of 36 months , the participants were assessed for depressive symptoms by completing the Center for Epidemiological Studies -Depression ( CES-D ) question naire . Scores of 16 or higher were indicative of an episode of affective distress . Differences between the risk groups and treatment arms were analyzed by logistic regression . All statistical tests were two-sided . RESULTS Women in the higher risk depression groups were more likely to score 16 or higher on the CES-D ( percent follow-up examinations with a score of > or = 16 : high-risk group = 35.7 % , with 95 % confidence interval [ CI ] = 32.5 % to 38.9 % ; medium-risk group = 19.2 % , with 95 % CI = 18.1 % to 20.3 % ; and low-risk group = 8.7 % , with 95 % CI = 8.3 to 9.1 % ) and to have these scores more frequently and for longer periods than women in the lower risk groups . Within each depression risk group , there was no difference in the proportion of women scoring 16 or higher by treatment assignment ( tamoxifen versus placebo ) ( odds ratio = 0.98 ; 95 % CI = 0.93 to 1.02 ) . A post-hoc analysis indicated that the lack of a tamoxifen effect was not a result of differential missing data . CONCLUSIONS Physicians need not be overly concerned that treatment with tamoxifen will increase the risk for or exacerbate existing depression in women . Nevertheless , physicians should continue to screen for and treat or refer potential cases of depression encountered in routine clinical practice PURPOSE This is the initial report from the health-related quality of life ( HRQL ) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial . This report provides an overview of HRQL findings , comparing tamoxifen and placebo groups , and advice to clinicians counseling women about the use of tamoxifen in a prevention setting . PATIENTS AND METHODS This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study . Findings are presented from the Center for Epidemiological Studies -Depression Scale ( CES-D ) , the Medical Outcomes Study 36-Item Short Form Health Status Survey ( MOS SF-36 ) and sexual functioning scale , and a symptom checklist . RESULTS No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinical ly significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores . The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms . Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level , although overall rates of sexual activity remained similar . CONCLUSION Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use . Weight gain and depression , two clinical problems anecdotally associated with tamoxifen treatment , were not increased in frequency in this trial in healthy women , which is good news that also needs to be communicated Objective : To assess current attitudes of hospital based paediatricians to off label prescribing , and the performance of clinical trials in children . Design : A prospect i ve , question naire based study . Setting : 257 hospital based consultants and specialist registrars in paediatric practice in Scotl and during 2003–2004 . Results : A 25 item question naire was sent to 257 hospital based paediatricians and 151 ( 59 % ) were returned completed . Over 90 % of responders were familiar with the concept of , and knowingly prescribed , off label drugs ; 55 % of responders stated that such prescribing disadvantaged children , and 47 % expressed concerns about the efficacy of off label medicines . Although 70 % of responders expressed concerns about safety , only 17 % had observed an adverse event , and 47 % a treatment failure , while 69 % did not obtain informed consent or tell parents they were prescribing off label , and 67 % did not inform the family ’s general practitioner . Many respondents did not believe it was necessary to carry out clinical trials in children for new ( 46 % ) or generic ( 64 % ) medicines . However , 52 % of respondents stated that they would be willing to undertake clinical studies and recruit their own patients ( 61 % ) or children ( 73 % ) to take part in such studies . Conclusions : Among Scottish paediatricians there is concern about off label prescribing , although the majority do not consider it necessary to inform parents or GP colleagues . The need for clinical trials in children was recognised but there was a less than wholehearted acceptance of the need for such studies , at variance with the current drive to promote clinical trials in this age group The impact of chemoprevention trials can be hampered by poor participant compliance with the study medication . We used medication monitoring systems and pill count data to try to establish factors that may predict compliance with the International Breast Intervention Study ( IBIS ) and whether the participants went on to complete or benefit the trial . Women who took their trial medication in a regular pattern rather than r and omly were more likely to be of benefit to the study ( p = 0.003 ) . For those women who failed to complete the study , compliance was shown to gradually reduce at each follow-up appointment . The taking of additional prescribed medication and not smoking were important factors in predicting completion ( p = 0.04 and p = 0.047 , respectively ) and benefit ( p = 0.037 and p = 0.031 , respectively ) to the study . Taking these factors into account when advising women at the start of a chemoprevention trial may be helpful in improving compliance Background Uptake of cancer trials and in particular prevention trials has been disappointing globally . Methods Uptake to three r and omised chemotherapy breast cancer prevention trials and two dietary prevention trials in women at increased familial risk were assessed and compared with uptake of screening trials across a range of risk categories . Results Uptake of drug prevention trials remains low at 5.3–13.6 % , but is significantly higher in the high ( 12 % ) compared to very high risk group ( 8.4 % ) for IBIS1 and IBIS2 combined ( p=0.004 ) . Recruitment to two dietary prevention studies via mail shot was also disappointingly low at 6.2 % and 12.5 % . In contrast uptake to two mammography screening trials was > 90 % in all risk categories . Conclusions More work must be done to improve recruitment to prevention trials if they are to be seen as viable alternatives to risk reducing surgery . Impact Trial design s and decision aids need to be developed to improve recruitment OBJECTIVE To assess the effect of a group-based intervention on the balance between necessity beliefs and concern beliefs about medication and on medication non-adherence in patients with rheumatoid arthritis ( RA ) . METHODS Non-adherent RA patients using disease-modifying anti-rheumatic drugs ( DMARDs ) were r and omized to an intervention or control arm . The intervention consisted , amongst others , of two motivational interviewing-guided group sessions led by the same pharmacist . Control patients received brochures about their DMARDs . Question naires were completed up to 12 months follow-up . RESULTS 123 patients ( mean age : 60 years , female : 69 % ) were r and omized . No differences in necessity beliefs and concern beliefs about medication and in medication non-adherence were detected between the intervention and control arm , except at 12 months ' follow-up : participants in the intervention arm had less strong necessity beliefs about medication than participants in the control arm ( b : -1.0 ( 95 % CI : -2.0 , -0.1 ) ) . CONCLUSION This trial did not demonstrate superiority of our intervention over the control arm in changing beliefs about medication or in improving medication adherence over time . PRACTICE IMPLICATION S Absent intervention effects might have been due to , amongst others , selection bias and a suboptimal treatment integrity level . Hence , targeting beliefs about medication in clinical practice should not yet be ruled out

For diagnostic purpose s , the most independently vali date d genes to study further are VIM , SEPT9 , ITGA4 , OSM4 , GATA4 and NDRG4 . In terms of prognostic markers , myopodin , KISS1 , TMEFF2 , HLTF , hMLH1 , APAF1 , BCL2 and p53 are independently vali date d. Most prognostic markers published lack both a multivariate analysis in comparison to clinical risk factors and the appropriate patient group who will benefit by adjuvant chemotherapy . Methylation of IGFBP3 , mir148a and PTEN are found to be predictive markers for 5-FU and EGFR therapy respectively .

Since genetic and epigenetic alterations influence the development of colorectal cancer ( CRC ) , huge potential lies in the use of DNA methylation as biomarkers to improve the current diagnosis , screening , prognosis and treatment prediction . Here we performed a systematic review on DNA methylation-based biomarkers published in CRC , and discussed the current state of findings and future challenges . Based on the findings , we then provide a perspective on future studies .

Genome-wide DNA hypomethylation plays has an important role in genomic instability and colorectal carcinogenesis . However , the relationship between cellular DNA methylation level and patient outcome remains uncertain . Using 643 colon cancers in two independent prospect i ve cohorts , we quantified DNA methylation in repetitive long interspersed nucleotide element-1 ( LINE-1 ) elements using pyrosequencing , which is a good indicator of global DNA methylation level . We used Cox proportional hazard models to calculate hazard ratios ( HRs ) of colon cancer-specific and overall mortality , adjusting for patient and tumoral features , including CpG isl and methylator phenotype ( CIMP ) . Statistical tests were two-sided . LINE-1 hypomethylation was linearly associated with a statistically significant increase in colon cancer-specific mortality ( for a 30 % decrease in LINE-1 methylation : multivariable HR = 2.37 , 95 % confidence interval [ CI ] = 1.42 to 3.94 ; P(trend ) < .001 ) and overall mortality ( multivariable HR = 1.85 , 95 % CI = 1.25 to 2.75 ; P(trend ) = .002 ) . The association was consistent across the two independent cohorts and strata of clinical and molecular characteristics , including sex , age , tumor location , stage , and CIMP , microsatellite instability , KRAS , BRAF , p53 , and chromosomal instability status . In conclusion , tumoral LINE-1 hypomethylation is independently associated with shorter survival among colon cancer patients Responses of patients with gliomas to temozolomide are determined by O6-methylguanine-DNA methyltransferase ( MGMT ) and mismatch repair ( MMR ) pathways . This phase II study ( NCT00423150 ) investigated whether MGMT promoter methylation predicts response in patients with advanced aerodigestive tract and colorectal cancers ( CRC ) . Tumor and serum sample s were screened for MGMT promoter methylation . In methylation-positive patients , 150 mg/m2 temozolomide was administered daily on a seven-day-on , seven-day-off schedule for each 28-day cycle . The primary efficacy endpoint was response rate ( RR ) . MMR status was determined by a microsatellite instability assay . Among 740 patients screened , 86 were positive for MGMT promoter methylation and enrolled . Nineteen percent of the screened population ( 137/740 ) had confirmed tissue and /or serum MGMT promoter methylation , including 25 % ( 57 of 229 ) for CRC , 36 % ( 55 of 154 ) for esophageal cancer , 11 % ( 12 of 113 ) for head and neck cancer , and 5 % ( 13 of 242 ) for non – small cell lung carcinoma . Among patients with valid methylation results in both tissue and serum sample s , concordance was 81 % ( 339 of 419 ) . The majority of enrolled patients ( 69 of 86 ; 80 % ) had microsatellite stable cancer . Overall RR was 6 % ( 5 of 86 partial responses ) ; all responders had microsatellite stable cancer . Temozolomide result ed in low RRs in patients enriched for MGMT methylation . MGMT methylation status varied considerably in the patient population . Although serum methylation assay is an option for promoter methylation detection , tissue assay remains the st and ard for methylation detection . The low RR of this cohort of patients indicates that MGMT methylation as a biomarker is not applicable to heterogeneous tumor types , and tumor-specific factors may override vali date d biomarkers . Mol Cancer Ther ; 12(5 ) ; 809–18 . © 2013 AACR Purpose : Radiotherapy followed by total mesorectal excision surgery has been shown to significantly reduce local recurrence rates in rectal cancer patients . Radiotherapy , however , is associated with considerable morbidity . The present study evaluated the use of biochemical detection of enzymatic caspase-3 activity as preoperative marker for apoptosis to preselect patients that are unlikely to develop a local recurrence to spare these patients from overtreatment and the negative side effects of radiotherapy . Experimental Design : Nonirradiated freshly frozen tissue sample s from 117 stage III rectal cancer patients were collected from a r and omized clinical trial that evaluated preoperative radiotherapy in total mesorectal excision surgery . Additional frozen archival tissues from 47 preoperative biopsies and corresponding resected colorectal tumors were collected . Level of apoptosis was determined by measuring the enzymatic activity of caspase-3 in a biochemical assay . Results : In tumor tissue , caspase-3 activity lower than the median was predictive of 5-year local recurrence ( hazard ratio , 7.4 ; 95 % confidence interval , 1.7 - 32.8 ; P = 0.008 ) , which was unaffected by adjustment for type of resection , tumor location , and T status ( adjusted hazard ratio , 7.5 ; 95 % confidence interval , 1.7 - 34.1 ; P = 0.009 ) . Caspase-3 activity in preoperative biopsies was significantly correlated with caspase-3 activity in corresponding resected tumors ( r = 0.56 ; P < 0.0001 ) . Conclusion : Detection of tumor apoptosis levels by measuring caspase-3 activity , for which a preoperative biopsy can be used , accurately predicted local recurrence in rectal cancer patients . These findings indicate that caspase-3 activity is an important denominator of local recurrence and should be evaluated prospect ively to be added to the criteria to select rectal cancer patients in which radiotherapy is redundant BACKGROUND & AIMS Despite poor performance , guaiac-based fecal occult blood tests ( G-FOBT ) are most frequently implemented for colorectal cancer screening . Immunochemical fecal occult blood tests ( I-FOBT ) are cl aim ed to perform better , without r and omized comparison in screening population s. Our aim was to r and omly compare G-FOBT with I-FOBT in a screening population . METHODS We conducted a population -based study on a r and om sample of 20,623 individuals 50 - 75 years of age , r and omized to either G-FOBT ( Hemoccult-II ) or I-FOBT ( OC-Sensor ) . Tests and invitations were sent together . For I-FOBT , the st and ard cutoff of 100 ng/ml was used . Positive FOBTs were verified with colonoscopy . Advanced adenomas were defined as > or=10 mm , high- grade dysplasia , or > or=20 % villous component . RESULTS There were 10,993 tests returned : 4836 ( 46.9 % ) G-FOBTs and 6157 ( 59.6 % ) I-FOBTs . The participation rate difference was 12.7 % ( P < .01 ) . Of G-FOBTs , 117 ( 2.4 % ) were positive versus 339 ( 5.5 % ) of I-FOBTs . The positivity rate difference was 3.1 % ( P < .01 ) . Cancer and advanced adenomas were found , respectively , in 11 and 48 of G-FOBTs and in 24 and 121 of I-FOBTs . Differences in positive predictive value for cancer and advanced adenomas and cancer were , respectively , 2.1 % ( P = .4 ) and -3.6 % ( P = .5 ) . Differences in specificities favor G-FOBT and were , respectively , 2.3 % ( P < .01 ) and -1.3 % ( P < .01 ) . Differences in intention-to-screen detection rates favor I-FOBT and were , respectively , 0.1 % ( P < .05 ) and 0.9 % ( P < .01 ) . CONCLUSIONS The number-to-scope to find 1 cancer was comparable between the tests . However , participation and detection rates for advanced adenomas and cancer were significantly higher for I-FOBT . G-FOBT significantly underestimates the prevalence of advanced adenomas and cancer in the screening population compared with I-FOBT

Further , it was found in a meta- analysis in subsets of patients with diabetic foot ulcers ( neuropathic ) that HA derivatives healed these types of wounds significantly faster than st and ard of care . These studies in aggregate show that HA derivatives accelerate the healing process in burns , epithelial surgical wounds , and chronic wounds

Hyaluronic acid ( HA ) is a polysaccharide common to most species and is found in many sites in the human body , including the skin and soft tissue .

ABSTRACT This study was design ed to assess the efficacy and tolerability of MAS065D ( Xclair ™ ) compared to a vehicle control in the management of radiation dermatitis in patients receiving radiotherapy for breast cancer . Twenty patients were r and omized blindly to use the two study substances , three times daily , on separate sections of irradiated skin throughout the duration of radiotherapy and for two weeks afterwards . Patients were monitored before therapy , weekly during therapy , and for 2 weeks after radiotherapy was completed . Skin appearance according to National Cancer Institute ( NCI ) toxicity criteria , erythema rating , transepidermal water loss ( TEWL ) , skin hydration , patients ' view of itch , pain , acceptance , and view of each cream and adverse events , were monitored ; at the final visit patients and investigators expressed their preference for one of the creams . MAS065D showed statistically significant superiority in the outcomes of NCI grading for radiation dermatitis and erythema . Patients ' and investigators ' preferences for one of the study substances were statistically in favor of MAS065D . Very few patients recorded nonzero itch and pain scales , so no significant differences emerged between the two groups . It was concluded that MAS065D can provide an effective option for managing radiation dermatitis although further studies are needed to assess its effect on pain and itch Objective : To determine if a hyaluronic acid/carboxymethylcellulose ( HA/CMC ) sinus dressing reduces the rate of postoperative scarring . Methods : In a r and omized , matched-controlled , single-blinded study , following the completion of surgery , an HA/CMC dressing was r and omly assigned to one side with the opposite unpacked side serving as a control . Results : Fifty-three patients underwent surgery for chronic rhinosinusitis ( CRS ; 39 patients ) or CRS with nasal polyposis ( 14 patients ) . At the 8-week follow-up , there was no difference in synechiae on the HA/CMC side compared to the control ( p = 0.09 ) . HA/CMC-treated sinuses , however , demonstrated fewer synechiae in the first 2 weeks postoperatively compared to the control ( p = 0.01 ) , and were associated with significantly less nasal congestion at the 4-week ( p = 0.02 ) and 8-week follow-up visits ( 0.03 ) . Conclusion : There was no long-term difference in the rate of synechiae in the HA/CMC-treated sinus compared to the control . However , less severe nasal congestion and synechiae in the initial postoperative period may reduce the need for aggressive sinus debridement The purpose of this study was to evaluate outcomes of persons with neuropathic diabetic foot wounds treated with a hyaluronan-containing dressing . Data were abstract ed for 36 patients with diabetes , 72.2 % male , aged 60.0+/-10.7 years and a mean glycated hemoglobin ( HbA(1c ) ) of 9.5+/-2.5 % presenting for care at two large , multidisciplinary wound care centers . All patients received surgical debridement for their diabetic foot wounds and were placed on therapy consisting of hyaluronan dressing ( Hyalofill , Convatec , USA ) with dressing changes taking place every other day . Outcomes evaluated included time to complete wound closure and proportion of patients achieving wound closure in 20 weeks . Hyalofill therapy was used until the wound bed achieved 100 % granulation tissue . Therapy was then followed by a moisture-retentive dressing until complete epithelialization . In total , 75.0 % of wounds measuring a mean 2.2+/-2.2 cm(2 ) healed in the 20-week evaluation period . Of those that healed in this period , healing took place in a mean 10.0+/-4.8 weeks . The average duration of Hyalofill therapy in all patients was 8.6+/-4.2 weeks . Deeper ( UT Grade 2A ) wounds were over 15 times less likely to heal than superficial ( 1A ) wounds ( 94.7 vs. 52.9 % , Odds Ratio=15.9 , 95 % Confidence Interval=1.7 - 142.8 , P=0.006 ) . We conclude that a regimen consisting of moist wound healing using hyaluronan-containing dressings may be a useful adjunct to appropriate diabetic foot ulcer care . We await the completion of a multicenter r and omized controlled trial in this area to either support or refute this initial assessment Neuropathic leg ulcers ( NLUs ) affect more than 10 % of diabetic patients with peripheral neuropathy and represent the most common cause of ulceration of the leg in these patients . Though their pathogenesis is well known , related to the chronic neuropathic edema , the management of NLUs , mainly based on elastocompression , is still controversial , with lower healing rates than nondiabetic venous leg ulcers . The authors tested if a novel gel formulation , containing amino acids and hyaluronic acid ( Vulnamin ® gel ; Errekappa , Milan , Italy ) , will improve the outcomes of NLUs when used together with elastocompression . Thirty patients affected by NLU were r and omized into 2 groups , both treated with 4-layer elastocompressive b and aging : patients in group A were topically treated with the application of Vulnamin ® gel , whereas patients in group B received only the inert gel vehicle . The healing rate at 3 months was evaluated as the primary endpoint , whereas the secondary endpoints were healing time , reduction in ulcer area and ulceration score in 4 weeks , number of infective complications , and overall satisfaction of patients . Healing rate was significantly ( P < .05 ) higher in patients in group A when compared with those in group B ; healing time , patients ’ satisfaction , and reduction in ulcer area and ulceration score in 4 weeks were also higher in patients in group A. However , no significant differences were found in the prevalence of infections and other adverse events . The use of Vulnamin ® gel with elastocompression is safe and effective in the management of NLUs of diabetic patients BACKGROUND The aim of this study was to evaluate the efficacy of a topical hyaluronic acid ( HA ) gel preparation ( 0.2 % ) in the management of oral lichen planus ( OLP ) . METHODS A total of 124 patients with erosive OLP participated in a r and omized , placebo-controlled , double-blind trial to evaluate the efficacy of a topical HA preparation . Outcome measures included soreness relief following immediate application , oral function and size of erosive/ulcerative area . Patients were medicated for 28 days and completed a log diary recording oral function and soreness scores . RESULTS Application of topical HA produced a significant reduction ( P < 0.05 ) in soreness scores when compared with placebo for up to 4 h post-application . There was no difference between treatment groups ( P > 0.05 ) with respect to oral function . Patients treated with 0.2 % HA showed a significant reduction ( P < 0.05 ) in the size of the erosive/ulcerated area after 28 days of treatment when compared with baseline . There was no significant difference in changes in ulcerative areas between treatment groups . CONCLUSIONS Topical HA ( 0.2 % ) does appear to be of some benefit in the management of erosive lichen planus providing efficacy for up to 4 h after administration . Very frequent applications should be considered to obtain a more significant clinical benefit . Topical HA gel may be a useful addition to the treatment option for OLP Prior studies have suggested that hyaluronic acid ( HA ) , a naturally occurring glycosaminoglycan , may accelerate the healing of superficial burn wounds . To objective ly assess whether exogenous HA could accelerate the rate of healing and limit scar formation in superficial wounds , 11 patients with burn injuries who were undergoing skin grafting were given two separate skin graft donor sites of similar size and depth ( 1 " x 1 " x 0.016 " ) . In a r and omized , double-blind fashion , one of these partial-thickness wounds had repeated application with 1.5 % HA ; 100 % glycerin , which served as a control of similar viscosity , was applied to the other wound . On alternating days , photographs were taken and then analyzed with computerized digital planimetry to objective ly quantitate the rate of reepithelialization . In contrary to our hypothesis , HA significantly delayed wound healing compared to the glycerin control ( time to > 95 % reepithelialization : 10.3 + /- 2 days HA vs. 9.1 + /- 1.6 days control ; mean + /- SD ) . Furthermore , no difference in the result ant scar at 6 weeks and at 3 months after wounding was evident . These results demonstrate that HA retards healing of partial thickness wounds in adults OBJECTIVE To evaluate the clinical efficacy and safety of HYAFF 11-based autologous dermal and epidermal grafts in the management of diabetic foot ulcers . RESEARCH DESIGN AND METHODS A total of 79 patients with diabetic dorsal ( n = 37 ) or plantar ( n = 42 ) ulcers were r and omized to either the control group with nonadherent paraffin gauze ( n = 36 ) or the treatment group with autologous tissue-engineered grafts ( n = 43 ) . Weekly assessment , aggressive debridement , wound infection control , and adequate pressure relief ( fiberglass off-loading cast for plantar ulcers ) were provided in both groups . Complete wound healing was assessed within 11 weeks . Safety was monitored by adverse events . RESULTS Complete ulcer healing was achieved in 65.3 % of the treatment group and 49.6 % of the control group ( P = 0.191 ) . The Kaplan-Meier mean time to closure was 57 and 77 days , respectively , for the treatment versus control groups . Plantar foot ulcer healing was 55 % and 50 % in the treatment and control groups , respectively . Dorsal foot ulcer healing was significantly different , with 67 % in the treatment group and 31 % in the control group ( P = 0.049 ) . The mean healing time in the dorsal treatment group was 63 days , and the odds ratio for dorsal ulcer healing compared with the control group was 4.44 ( P = 0.037 ) . Adverse events were equally distributed between the two groups , and none were related to the treatments . CONCLUSIONS The autologous tissue-engineered treatment exhibited improved healing in dorsal ulcers when compared with the current st and ard dressing . For plantar ulcers , the off-loading cast was presumably paramount and masked or nullified the effects of the autologous wound treatment . This treatment , however , may be useful in patients for whom the total off-loading cast is not recommended and only a less effective off-loading device can be applied Intra-articular injections of hyaluronic acid products may eliminate pain , improve mobility and quality of life , and delay osteoarthritis progression . In this study , we evaluated the safety and efficacy of sodium hyaluronate injections given after knee arthroscopy . Forty-six patients with early osteoarthritis and a symptomatic meniscus tear were prospect ively r and omized into study ( injection ) and control groups and underwent knee arthroscopy . Study patients received 3 sodium hyaluronate injections after surgery . Study and control outcomes were compared 3 and 6 months after surgery . The injection patients had significantly less pain ( visual analog scale ) at 3-month follow-up and more flexion at 6-month follow-up . Tenderness , pain on motion , and crepitus were significantly more likely to be absent from injection patients at the 3- and 6-month follow-ups . Patients with osteoarthritis and a symptomatic meniscus tear may experience more pain relief and functional mobility after arthroscopic surgery plus hyaluronic acid injections than after arthroscopy alone This study evaluated the efficacy and tolerability of an autologous tissue-engineered graft — a 2-step HYAFF autograft — in the treatment of diabetic foot ulcers compared with st and ard care . In all , 180 patients with dorsal or plantar diabetic foot ulcers ( unhealed for ≥1 month ) were r and omized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks ( n = 90 ; treatment group ) or nonadherent paraffin gauze ( n = 90 ; control group ) . Efficacy and adverse events were assessed weekly for 12 weeks , at 20 weeks , and at 18 months . The primary efficacy outcome was complete ulcer healing at 12 weeks . Wound debridement , adequate pressure relief , and infection control were provided to both groups . At 12 weeks , complete ulcer healing was similar in both groups ( 24 % of treated vs 21 % controls ) . A 50 % reduction in ulcer area was achieved significantly faster in the treatment group ( mean 40 vs 50 days ; P = .018 ) . Weekly percentage ulcer reduction was consistently higher in the treatment group . At 20 weeks , ulcer healing was achieved in 50 % of the treated group as compared with 43 % of controls . Dorsal ulcers had a 2.17-fold better chance of wound healing per unit time following autograft treatment ( P = .047 ) . In a subgroup with hard-to-heal ulcers , there was a 3.65-fold better chance of wound healing following autograft treatment of dorsal ulcers ( P = .035 ) . Adverse events were similar in both groups . The study results demonstrated the potential of this bioengineered substitutes to manage hard-to-heal dorsal foot ulcers An open r and omized controlled study was carried out of 44 diabetic patients with necrotic foot ulcers treated with adhesive zinc oxide tape ( MeZinc ) or with an adhesive occlusive hydrocolloid dressing ( DuoDerm ) . Fourteen of the 21 patients treated with MeZinc had their necrotic ulcers improved by at least 50 % compared to six out of 21 with the hydrocolloid dressing ( P < 0·025 ) . Fifteen patients showed an increase in the area of necrosis during the course of the 5‐week study and of these , 10 had been treated with the hydrocolloid dressing BACKGROUND Intra-articular injections of hyaluronans have been shown to be safe and effective for the treatment of pain associated with osteoarthritis of the knee . This pilot study was undertaken to gather preliminary data on the efficacy and safety of five weekly intra-articular injections of Hyalgan ( sodium hyaluronate ; molecular weight , 500 to 730 kDa ) as compared with saline solution for the treatment of pain associated with osteoarthritis of the ankle . METHODS Twenty patients at two test sites were r and omized with use of a double-blind ( blinded observer ) , saline solution-controlled , parallel experimental design . Patients were r and omized to receive five weekly intra-articular injections of either 1 mL of sodium hyaluronate ( 10 mg/mL ) or 1 mL of phosphate-buffered saline solution into the ankle joint . The primary outcome measurement was the ankle osteoarthritis score . Several secondary outcome measures also were assessed . RESULTS Significant improvement in the mean ankle osteoarthritis score from baseline was seen at all follow-up visits from one to six months in both the sodium hyaluronate group and the saline solution group ( p < 0.0001 ) . In addition , five of nine patients in the sodium hyaluronate group had > 30 mm of improvement in this score , compared with one of eight patients in the control group . No withdrawals were directly attributable to the injections of sodium hyaluronate or saline solution , and no severe medication-related adverse events were observed . CONCLUSIONS The present study suggests that five weekly intra-articular injections of sodium hyaluronate ( molecular weight , 500 to 730 kDa ) are well tolerated , can provide sustained relief of pain , and can improve function in patients with osteoarthritis of the ankle . These findings are consistent with those of previously published studies involving intra-articular injections of sodium hyaluronate in other joints , but they require confirmation in a large , r and omized , saline solution-controlled study OBJECTIVE To compare the effectiveness of total-contact casts ( TCCs ) , removable cast walkers ( RCWs ) , and half-shoes to heal neuropathic foot ulcerations in individuals with diabetes . RESEARCH DESIGN AND METHODS In this prospect i ve clinical trial , 63 patients with superficial noninfected , nonischemic diabetic plantar foot ulcers were r and omized to one of three off-loading modalities : TCC , half-shoe , or RCW . Outcomes were assessed at wound healing or at 12 weeks , whichever came first . Primary outcome measures included proportion of complete wound healing at 12 weeks and activity ( defined as steps per day ) . RESULTS The proportions of healing for patients treated with TCC , RCW , and half-shoe were 89.5 , 65.0 , and 58.3 % , respectively . A significantly higher proportion of patients were healed by 12 weeks in the TCC group when compared with the two other modalities ( 89.5 vs. 61.4 % , P = 0.026 , odds ratio 5.4 , 95 % CI 1.1 - 26.1 ) . There was also a significant difference in survival distribution ( time to healing ) between patients treated with a TCC and both an RCW ( P = 0.033 ) and half-shoe ( P = 0.012 ) . Patients were significantly less active in the TCC ( 600.1 + /- 320.0 daily steps ) compared with the half-shoe ( 1,461.8 + /- 1,452.3 daily steps , P = 0.04 ) . There was no significant difference in the average number of steps between the TCC and the RCW ( 767.6 + /- 563.3 daily steps , P = 0.67 ) or the RCW and the half-shoe ( P = 0.15 ) . CONCLUSIONS The TCC seems to heal a higher proportion of wounds in a shorter amount of time than two other widely used off-loading modalities , the RCW and the half-shoe Two occlusive dressings -- one zinc oxide medicated ( Mezinc ) and one hydrocolloid (Duoderm)--were compared in a prospect i ve , r and omized trial over a period of 8 weeks to determine their healing ability and effect on pain for venous and arterial leg ulcers . All patients were patch-tested before the study and colophony allergy was an exclusion criterion . Of the 43 out patients included , 31 completed the trial and 6 patients r and omized to each treatment group were withdrawn . The initial ulcer areas decreased after 8 weeks of treatment with Mezinc by 64 % and by 48 % after treatment with Duoderm . Ulcer pain was relieved in 50 % of the patients --with a similar analgesic effect for the two dressings . Mezinc treatment was discontinued in 2 cases due to sensitization to colophony ( one ingredient of Mezinc ) which indicated a risk of contact allergy to colophony due to Mezinc treatment . 1103 consecutive eczema patients were patch-tested on the back with Mezinc and colophony 20 % in petrolatum simultaneously . It was found that 42 ( 4 % ) of the patients showed allergic skin reactions to colophony and 19 ( 2 % ) to Mezinc . Both dressings were well tolerated by leg ulcer patients and there appeared to be no major differences in the efficacy of the two occlusive dressings The derivatives of hyaluronic acid ( hyaluronan ) have been extensively studied in the field of tissue engineering . Several forms of the material are available ( benzyl esters of hyaluronic acid , HYAFF ) , with differing degradation profiles . This study compared 2 such products used for dermal regeneration ( HYAFF p80 and HYAFF p100 , the partial and total benzyl ester of hyaluronan , respectively ) , in a human model . In a prospect i ve , r and omized , controlled trial , 20 tattoos were tangentially excised and 1 of 2 hyaluronic acid-derived dermal matrices were applied to the wound bed . The partial ester was changed after 1 week and the total ester was kept for 2 weeks . After 2 weeks , cultured epidermal autograft was applied using the Laserskin method . Wounds were subsequently assessed by several modalities and by such features as rate of epithelialization , wound contraction , and histologic and immunohistologic appearances . Subtle differences were seen between the 2 groups , indicating that the total ester , which showed better clinical performance , could be used , especially in burns . This has the advantage of a single application for a 2-week period , rather than the comparison material , a partial ester , which requires weekly changing and de grade s faster . Further , the method of epidermal grafting with a dermal substitute shows excellent results and adds to the armory for the treatment of both chronic and acute wounds HYPOTHESIS A r and omized , double-blind , placebo-controlled study of sodium hyaluronate ( ARTZ Dispo ) treatment was performed in 51 patients with rotator cuff lesions without complete tears . We hypothesized that ARTZ Dispo would render better results than the placebo . MATERIAL S AND METHODS Twenty-five patients ( ARTZ Dispo group ) had injections of 25 mg/wk of sodium hyaluronate into the subacromial bursa for 5 consecutive weeks . Twenty-six patients ( placebo group ) were given 2.5 mL of normal saline solution with the same injection protocol as the ARTZ Dispo group . No significant difference in age , height , weight , gender , vocation , involved shoulder , duration of symptoms , baseline Constant score , or visual analog scale ( VAS ) score existed between the 2 groups . RESULTS The 2 groups did not significantly differ with regard to Constant scores , VAS scores , or global improvement assessment s 1 week after injections . The ARTZ Dispo group had a better Constant score ( P = .0095 ) and VAS score ( P = .0018 ) than the placebo group 6 weeks after treatment . Patients in the placebo group were given 5 sodium hyaluronate injections , rather than placebo , after disclosure of the blind list , if they wished . Forty-one patients who underwent hyaluronate injection exhibited a significantly improved Constant score , from 64.0 + /- 11.7 at baseline to 88.9 + /- 10.4 ( P < .0001 ) , and a significantly improved VAS score , from 6.4 + /- 1.3 to 1.5 + /- 1.6 ( P < .0001 ) , at a mean follow-up of 33.1 months . No significant adverse effect was noted . CONCLUSIONS Subacromial injections of sodium hyaluronate are effective in treating rotator cuff lesions without complete tears ABSTRACT Aims : This multicenter , multinational , r and omized , double-blind , controlled , parallel-group study , was design ed to assess the efficacy and safety of a fixed combination topical medicinal product , containing 0.2 % hyaluronic acid and 1 % silver sulfadiazine ( HA‐SSD ) ( Connettivina * Plus cream ) versus 1 % silver sulfadiazine cream alone ( SSD ) , in the treatment of second-degree burns . * Connettivina is a registered trade name of Fidia Farmaceutici SpA , Abano Terme ( PD ) , Italy Methods : 111 adult patients ( age 18–75 years ) of both sexes , with IIa-degree ( superficial ) and IIb-degree ( deep dermal ) burns , were r and omized to receive HA‐SSD or SSD . Treatments ( approximately 5 g/100 cm2 ) were applied once a day until the wounds healed , but for no longer than 4 weeks . Burns had to have occurred within 48 hours from the start of treatment , be caused by thermal injury , and be confined to the trunk and /or upper and lower extremities . Results : Results showed that both the fixed combination HA‐SSD , and SSD alone , were effective and well tolerated topical agents for the treatment of second-degree burns . All burns were healed except in one patient treated with SSD . It was also observed that the fixed combination HA‐SSD caused a significantly more rapid re-epithelialization of burns , i.e. a shorter time to healing , than SSD alone . The difference recorded – 4.5 days – was statistically significant ( p = 0.0073 ) . Conclusion : The observed shorter time to healing caused by the fixed combination is clinical ly relevant and further demonstrates the wound healing activity of HA OBJECTIVE To investigate the efficacy and tolerability of a course of 5 injections of hyaluronan ( HA ) given at intervals of one week in patients with symptomatic , mild to moderate osteoarthritis ( OA ) of the knee . METHODS A double blind , r and omized , parallel group , multicenter ( 17 centers ) , saline vehicle-controlled study was conducted over 18 weeks . Patients received either 25 mg ( 2.5 ml ) HA in a phosphate buffered solution or 2.5 ml vehicle containing only the buffer by intraarticular injection . Five injections were given at one week intervals and the patients were followed for a further 13 weeks . The Western Ontario McMaster ( WOMAC ) OA instrument was used as the primary efficacy variable and repeated measures analysis of covariance was used to compare the 2 treatments over Weeks 6 , 10 , 14 , and 18 . RESULTS Of 240 patients r and omized for inclusion in the study , 223 were evaluable for the modified intention to treat analysis . The active treatment and control groups were comparable for demographic details , OA history , and previous treatments . Scores for the pain and stiffness subscales of the WOMAC were modestly but significantly lower in the HA-treated group overall ( Weeks 6 to 18 ; p < 0.05 ) and the statistically significant difference from the control was not apparent until after the series of injections was complete . The physical function subscale did not reach statistical significance ( p = 0.064 ) . Tolerability of the procedure was good and there were no serious adverse events that were considered to have a possible causal relationship with the study treatment . CONCLUSION Intraarticular HA treatment was significantly more effective than saline vehicle in mild to moderate OA of the knee for the 13 week postinjection period of the study OBJECTIVE To determine efficacy and safety of intraarticular ( IA ) hyaluronic acid ( HA ; Hyalgan ) versus placebo and a nonsteroidal antiinflammatory drug for osteoarthritis ( OA ) of the knee . METHOD A series of 5 weekly IA injections of HA ( 20 mg each ) was compared to placebo or oral naproxen in a 26 week , double blind , masked observer , multicenter trial of 495 patients with idiopathic OA . Acetaminophen was permitted for escape analgesia . The primary measurement was pain experienced on a 50 foot walk test for those completing the study ( completers ) as measured on a 10 cm visual analog scale ( VAS ) . Also measured were the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index ( pain , stiffness , function ) and categorical assessment s of pain . RESULTS Patients receiving HA improved more with respect to pain on the 50 foot walk compared to placebo at Week 26 ( HA vs placebo difference 8.8 mm ; p < 0.005 ) ; 56 % of HA treated patients compared to 41 % of placebo treated patients had > or = 20 mm reduction in the VAS from Week 5 continuously through Week 26 ( p=0.031 ) . At 26 weeks , more HA treated patients ( 47.6 % ) had slight pain or were pain-free in contrast to placebo treated ( 33.1 % ; p=0.039 ) or naproxen treated ( 36.9 % ; p=0.22 ) [ corrected ] patients . Improvement in secondary outcome variables was generally superior in the HA group compared to those receiving placebo and was significantly better at Week 26 with respect to the WOMAC pain ( p=0.041 ) and WOMAC physical function ( p=0.047 ) subscales . The HA group also tended to have better results relative to the naproxen group in both primary and secondary assessment s. For all r and omized patients , there was a > or = 20 mm improvement in pain experienced on the 50 foot walk in 28 % [ corrected ] of placebo treated patients vs 36 % [ corrected ] of the HA treated patients ( p=0.127 ; 67 % of patients completed the trial ) . Injection site pain , more commonly reported in the HA group ( 38/164=23 % ) than in the placebo group ( 22/168=13 % ; p < 0.001 ) , result ed in withdrawal in 6 patients ( 4 % ) . One withdrawal was associated with the HA injection ( < 1 % ) . Gastrointestinal adverse events were significantly more common in the naproxen group than the HA or the placebo groups and 14 naproxen treated patients ( 8.3 % ) discontinued prematurely due to these events . CONCLUSION This large , controlled r and omized clinical trial confirms that 5 weekly IA injections of HA ( Hyalgan ) in patients with OA of the knee are generally well tolerated , provide sustained relief of pain and improved patient function , and were at least as effective with fewer adverse reactions as continuous treatment with naproxen for 26 weeks AIM The goal of this study was to determine whether or not the intraarticular administration of hyaluronic acid can improve functional parameters , such as isokinetic muscle strength or total work and clinical test results in patients with osteoarthritis ( OA ) of the knee . METHOD As part of a prospect i ve , controlled study 43 patients with osteoarthritic changes of both knees ( radiographic Kellgren stage II-III ) were followed in a right/left comparison . The influence of intraarticularly injected hyaluronic acid ( 20 mg hyaluronic acid/2ml Hyalart ) on functional and clinical parameters was analysed . We used the isokinetic system Cybex 600 for measuring maximal isokinetic muscle strength and total work . A total of 20 males and 23 females fulfilled the inclusion criteria with an age between 55 - 78 years and underwent five injections of hyaluronic acid ( one injection per week ) . The injected knee represented the treatment group , while the contralateral knee served as the control . RESULTS The maximum peak torque of the knee extensors in the treatment group was measured between 57+/-26.15/32.33+/-19.63Nm prior to the injections and 77.17+/-32.54/47.83+/-21.43Nm following the hyaluronic acid therapy ( P < 0.01 ) . The analysis of the knee flexors at angular velocities of 60 degrees /s and 180 degrees /s revealed values of 40.44+/-21.58/22.89+/-16.64Nm and 53.55+/-24.26/34.05+/-17.37Nm ( P < 0.01 ) respectively . The evaluation of the total work of the knee flexors and extensors revealed a significant difference ( P < 0.01 ) between the treatment and control group . The Lequesne score was reduced from 13.57+/-1.88 prior to the injections to 7.94+/-2.53 after the treatment ( P < 0.01 ) . The pain score was documented with the help of a visual analog scale . The VAS values were reduced at rest from 3.83+/-1.72 cm to 1.36+/-1.42 cm and during weight bearing from 7.57+/-1.34 cm to 3.75+/-1.32 cm in the treatment group ( P < 0.01 ) . CONCLUSIONS This controlled prospect i ve clinical trial confirmed that 5 weekly intraarticular injections of HA ( Hyalart ) in patients with OA of the knee provide pain relief and functional improvements PURPOSE The effect of hyaluronic acid ( Ialugen cream ) on acute skin reactions after radiotherapy , was assessed in a r and omized , double-blind , placebo-controlled study . MATERIAL AND METHODS Out of the 152 patients presenting with head and neck , breast or pelvic carcinomas and registered in the study , 134 cases-70 in the Ialugen group ( IA ) and 64 in the placebo group (PBO)-completed their IA or PBO treatment . At the time of r and omisation , these two groups were balanced for sex , age , weight and height . The mean total dose of radiation given during the study was 60.6 + /- 10.9 Gy in the IA group and 64.3 + /- 10.8 Gy in the PBO group ( P = 0.47 ) . RESULTS Acute radio-epithelitis scores were significantly higher in the PBO group than in the IA group , starting from the control at week 3 and throughout the 6 weeks of treatment ( P < 0.01 from week 3 to week 7 ; P < 0.05 at weeks 8 and 10 ) . Likewise , the global efficacy judgement expressed , at the end of treatment , by both the physician and the patient showed a significant difference in favour of Ialugen ( P < 0.01 and P < 0.05 , respectively ) . There was no significant difference of tolerance between the IA and PBO treatments ( P = 0.18 according to the physician and P = 0.42 from the patient 's viewpoint ) . CONCLUSION The prophylactic use of a cream with hyaluronic acid is shown to reduce the incidence of high grade radio-epithelitis , suggesting an interesting role of the hyaluronic acid cream as supportive treatment to improve compliance and quality of life in patients undergoing radiation therapy Our aim was to assess the efficacy of MAS065D , a non-steroidal water-in-oil cream , in preventing and limiting skin reactions caused by radiation therapy ( RT ) . 40 women treated with conservative breast cancer surgery followed by radiotherapy , were r and omised to receive MAS065D ( 22 pts ) or vehicle ( 18 pts ) . Radiotherapy was delivered in 20 fractions : 2.25 Gy to the whole breast plus a concomitant boost of 0.25 Gy to the tumour bed up to a total dose of 50 Gy . Evaluations of skin toxicity , erythema , and subjective symptoms were carried out weekly and 3 weeks after treatment completion . A statistically significant difference between vehicle and MAS065D groups was recorded regarding the maximum severity of skin toxicity ( p < 0.0001 ) , burning within the radiation field ( p = 0.039 ) and desquamation ( p = 0.02 ) , in favour of the latter . We conclude that MAS065D may be considered a safe and effective treatment in the prevention and minimization of skin reactions and associated symptoms OBJECTIVE Hyaluronan , a component of the extracellular matrix , plays a significant role in several aspects of tissue repair and the wound healing process . METHOD In this Italian study Hyalofill-F , a partial benzyl ester derivative of hyaluronan , used in combination with compression b and aging , was compared with the well-established therapy in Italy of non-adherent gauze plus compression therapy in the treatment of chronic venous leg ulcers . RESULTS Hyalofill-F plus compression b and aging performed significantly better than non-adherent gauze plus compression b and age in all of the clinical ly relevant efficacy parameters . Mean reduction in ulcer area in the hyaluronan-derivative group was 8.1 cm2 after eight weeks of treatment , compared with 0.4 cm2 in the comparator group . The result ing difference of 7.7 cm2 between the two groups was statistically significant ( p = 0.0019 ) . Furthermore , statistically significant results in favour of the hyaluronan-derivative group were obtained in the following : speed of epithelialisation ; leveling of the margins ; degree of maceration ; pain intensity and frequency . CONCLUSION Hyalofill-F plus compression b and aging result ed in an earlier and greater decrease in ulcer area compared with non-adherent gauze plus compression b and aging , therapy supporting its use in the treatment of chronic venous ulcers

However , this risk reduction may not be clinical ly important . The investigated interventions to prevent OIHD probably cause few or no serious adverse effects . AUTHORS ' CONCLUSIONS Moisturisers used alone or in combination with barrier creams may result in a clinical ly important protective effect , either in the long- or short-term , for the primary prevention of OIHD . Barrier creams alone may have slight protective effect , but this does not appear to be clinical ly important . For skin protection education , the results varied substantially across the trials , the effect was imprecise , and the pooled risk reduction was not large enough to be clinical ly important . The very low quality of the evidence means that we are unsure as to whether skin protection education reduces the risk of developing OIHD . The interventions probably cause few or no serious adverse effects . We conclude that at present there is insufficient evidence to confidently assess the effectiveness of interventions used in the primary prevention of OIHD . This does not necessarily mean that current measures are ineffective .

BACKGROUND Occupational irritant h and dermatitis ( OIHD ) causes significant functional impairment , disruption of work , and discomfort in the working population . Different preventive measures such as protective gloves , barrier creams and moisturisers can be used , but it is not clear how effective these are . This is an up date of a Cochrane review which was previously published in 2010 . OBJECTIVES To assess the effects of primary preventive interventions and strategies ( physical and behavioural ) for preventing OIHD in healthy people ( who have no h and dermatitis ) who work in occupations where the skin is at risk of damage due to contact with water , detergents , chemicals or other irritants , or from wearing gloves .

The object of this study was to compare the protective action of a new barrier cream ( Excipial Protect ® , Spirig Pharma AG , Egerkingen , Switzerl and ) to its vehicle in the context of h and irritation of apprentice hairdressers caused by repeated shampooing and exposure to hair‐care products . This was a double‐blind cross‐over comparing Excipial Protect ® ( containing aluminium chlorohydrate 5 % as active ingredient ) against its vehicle alone . The efficacy of the creams was evaluated taking into account : ( 1 ) clinical scores by research ers , ( 2 ) biometric measurements , ( 3 ) subjective opinions of the subjects . An analysis of variance was performed considering order of application , degree of atopy , and reported number of shampoos . We observed very little difference in efficacy between the protective cream and its vehicle . The presence , however , of aluminium chlorhydrate in the protective cream was shown to have a positive effect against work‐related irritation . The cosmetic qualities of the creams seemed , to the participants , to be as important as their real protective and hydrating properties , an important factor in compliance issues The purpose of this study was to develop a new model for the induction of chronic irritant contact dermatitis , which would reflect well the conditions of daily practice . Various weak irritant agents were tested for irritating potency on the skin and the sensitivity of transepidermal water loss ( TEWL ) measurements in the detection of early skin changes was also studied . 10 widely used surfactants and 1 solubilizer were applied to the skin of the forearms of healthy volunteers in aqueous solutions of 12.5 millimoles/1 for 45 min twice daily for 3 weeks . The effect on the skin was evaluated daily by means of TEWL measurements and by a visual scoring system . Each solution caused an increase in TEWL value over time due to the cumulative irritating action on the epidermal barrier . This increase in TEWL was different for the various solutions , result ing in different mean TEWL values on the last day of the experiment . Thus , it was possible to rank the agents according to irritating potency . This ranking order was the same in almost every individual and remained constant during the 3 weeks . In comparison with the visual scoring system , the TEWL measurements were more sensitive in the detection of early changes in the skin BACKGROUND Limited information documents the prevention and treatment benefits of a h and care regimen using moisturizer in a controlled manner for employees in typical manufacturing situations . OBJECTIVE The objective was to assess the effectiveness of a comprehensive skin care program including skin conditioning lotion in multiple manufacturing environments where employees are at high risk for skin disease . METHODS A r and omized trial test design with multiple measures , including skin bioengineering measurement techniques , visual grading , and self- assessment question naires , was used to broadly characterize skin condition . RESULTS Comparison of the change in the skin condition of workers using the full h and care regimen with moisturizer versus a control group using a regimen without moisturizer demonstrated significant ( p < .05 ) improvements in multiple measures after 1 to 2 weeks . Corneometer readings consistently showed significant improvement for employees using moisturizer , regardless of their work location . CONCLUSION Improved skin condition result ed from the regular use of an effective skin conditioning h and moisturizer as part of a skin care regimen in work environments in which workers were prone to experiencing occupational irritant contact dermatitis An in vivo method was developed to measure the effectiveness of skin protective creams against 2 dye indicator solutions : methylene blue in water and oil red O in ethanol , representative of model hydrophilic and lipophilic compounds , 3 representative barrier creams commercialized as effective against lipophilic , hydrophilic , or lipophilic and hydrophilic substances were assayed by measurements of the dye in cyanoacrylate strips of protected skin sample s after various application limes . The flexural surfaces of the forearms of 6 normal volunteers ( 3 female and 3 male , mean age 26.8±4.1 years ) were treated . The method was as follows : solutions of 5 % methylene blue in water and 5 % oil red O in ethanol were prepared , and applied to untreated skin and protective‐cream‐pretreated skin with the aid of aluminum occlusive chambers , for 0 h and 4 h , respectively . At the end of the application time , the creams were removed . Consecutive skin surface biopsies ( SSB ) from 1 to 4 strips were taken . The amount of stain in each strip was determined by colorimetry , and the cumulative amount of stain from 1 to 4 strips in each measurement was calculated . The cumulative amount represents the amount of permeation of each solution at each time point , and the efficacy of skin barrier cream . The results showed one formulation at both 0 h and 4 h reduced the amount of permeation of melhylene blue ( p<0.0l ) and oil red O ( p<0.01 ) compared with the control group . Another formulation was protective against the permeation of oil red O ( p < 0.0l ) . but not against methylene blue at 0 h and 4 h ; it was not significantly different at 0 h versus 4 h. The 3rd formulation produced increased cumulative amounts to oil red O at both 0 h and 4 h ( p<0.05 ) ; it also increased permeation amounts to methylene blue ( p<0.05 ) after 4 h. This model appears a facile , rapid and objective early screen to evaluate the efficacy of skin barrier creams in vivo , as well as their individual ingredients A total of 942 workers of 13 dyeing and printing factories in the area of Como ( N. Italy ) were examined in order to detect skin complaints on the h and s and forearms . Of these , 868 were eligible for and consented to participate in a controlled and r and omized experiment aim ed at assessing the efficacy of using barrier creams in practical circumstances . 657 workers underwent all three control examinations arranged over about one year . In the r and omized group for treatment with barrier creams the cumulative incidence of objective skin lesions was significantly lower than in the group in which no particular recommendation of use was made ( 44.5 % versus 54.4 % positive for objective examination in at least one of the three control examinations after recruitment : 95 % confidence limits of the difference between 2%-17 % percentages ; 39.9 % versus 47.0 % in subjects who were negative at the recruitment examination , 59.0 % versus 76.8 % in subjects who were positive at the recruitment examination ) . The use of a hydrocarbon cream was significantly more effective than using a silicone cream ( 95 % confidence limits of the differences of cumulative incidences : -10.9 % + 20.7 % comparing silicone creams with non-treatment ; 2.8%-20.2 % comparing hydrocarbon creams with non-treatment ) The effect on the skin of housewives of using a washing product in the home for all cleaning purpose s under conditions of maximal exposure has been studied . Tests conducted on over 4,000 housewives showed that detergents containing proteolytic enzymes had no greater effect on the skin than conventional detergents , even when the h and skin condition was initially poor . The same was true in a further test on 130 housewives with “ dishpan ” h and s. No adverse reactions attributable specifically to the enzyme products were seen . No eruptions from contact with clothes washed in enzyme products were reported from any of the families involved in these tests Objective . The objective of this controlled intervention study was to quantify the efficacy of skin protection ( SP ) measures and ultraviolet B ( UVB ) hardening in the prevention of h and dermatitis in bakers ' apprentices . Method . SP measures were compared against UVB hardening in a controlled clinical trial of 94 apprentices . The apprentices were assigned to the intervention arms class-wise . Bakers ' apprentices involved in a previous follow-up study served as additional controls representing no intervention . The apprentices were interviewed and examined in a st and ardised way at the beginning of the training and at 4 monthly follow-ups . Transepidermal water loss ( TEWL ) was measured at the back of the h and s. Results . Demographic profile and atopy criteria were equally distributed in the two intervention arms and the control group . Point prevalence of h and dermatitis after 6 months was highest in the controls ( 29.1 % ) followed by the UVB ( 19.4 % ) and the SP group ( 13.3 % ) . UVB hardening and SP measures reduced h and dermatitis prevalence by 9.7 % ( 95%CI : –8.5 to 28.1 ) and 15.7 % ( 95%CI : –2.4 to 33.9 ) , respectively . Application of SP measures reduced the odds ratios ( ORs ) for h and dermatitis 0.8-fold ( 95%CI : 0.17–3.70 ) and 0.33-fold ( 95%CI : 0.09–1.23 ) compared with the UVB group and the controls , respectively . These clinical trends were confirmed by statistically significant differences in TEWL values . TEWL values were consistently higher in the UVB group than in the SP group ( P=0.002 ) . Conclusions . This study provided evidence , based on significant differences in TEWL levels , that general SP measures may be more effective than UV light hardening of the skin , which in turn was more effective than no intervention . This trend was supported by the frequency of development of clinical h and dermatitis , although differences did not reach statistical significance . A multi-centre trial is recommended to confirm the efficacy of SP measures in a larger r and omised study Aims : To evaluate the effect of implementation of an evidence based skin care programme for wet work employees as part of an occupational health and safety management system . Methods : 375 wet work employees were included in a prospect i ve r and omised controlled trial , allocated to either intervention ( n = 207 ) or control ( n = 168 ) . The intervention group was exposed to a skin care programme during the five month study period . The intervention included an educational programme for a group of frontline employees , who underwent formalised training , and subsequently introduced the information to their colleagues . As part of the intervention a skin care policy including written instructions was established at each workplace . Both groups answered a test quiz , completed question naires on behaviour and symptoms , and underwent clinical examination of their h and s before and after the five month period . Results : No difference between the intervention and the control group was found at baseline with respect to clinical symptoms or behaviour . Evaluation after the five months of intervention revealed a significantly higher information level on skin care in the intervention group compared to the control group , a significant change in behaviour in the intervention group but not in the control group , and significantly less skin symptoms as evaluated clinical ly in the intervention group but not in the control group . No significant difference was found for self reported skin problems . Conclusions : The intervention was successful with respect to information level ( knowledge ) , behaviour , and clinical symptoms . Implementation of a skin care programme as part of an occupational health and safety management system is recommended as a prophylactic measure for employees in wet occupations Objectives : The objective of the present implementation study is to document how an intervention to reduce work-related skin problems by means of implementing an evidence -based skin protection programme in six gut-cleaning departments in swine slaughterhouses was understood , accepted and carried out . The association between the degree of implementation and the reduction of work-related skin problems in each department is examined . The intervention included a top-down strategy with establishment of a management system focusing on skin risks and a bottom-up strategy with participation of a selected group of shop floor workers and the safety representative , as change agents , as well as an empowerment-based educational programme , where the middle management and representatives from the top management also participated . Methods : The study design was a r and omized controlled intervention study with a 1-year study period . The outcome of the intervention was evaluated by telephone interviews . Data on the implementation process consisted of self-administered question naires , focus interviews and compiled written material s. Four indexes referring to the management system and the change agents ’ intervention activities were constructed . Finally , the Pearson correlation coefficient was used to test the correlation between the degree of implementation and the eczema frequency at 1-year follow-up . Results : There was a statistically significant association ( p < 0.05 ) between both the index for the combined implementation method and the eczema frequency after 1 year of intervention , and between the activities of the change agents and the eczema frequency . In contrast to this there was only a weak association between the establishment of a formal management system alone and the outcome . Conclusion : The study evidence s that a combination of a top-down and a bottom-up implementation method is effective to reduce work-related skin problems , and that the process of implementation is a significant determinant of the overall results The effect of three industrial h and cleansers on transepidermal water loss ( TWL ) was evaluated in groups of healthy volunteers . After 2 weeks , subjects using Baracaide averaged 47 % less TWL than those using Swarfega und 35 % less than with Go‐Jo . In a second study in printers , the use of Baracaide decreased TWL by 20 % after 2 weeks . Because it contains no volatile solvents , Baracaide may be less injurious to the barrier layer OBJECTIVE To examine the impact of introduction of an alcohol-based h and rub on h and hygiene knowledge and compliance and h and colonization of healthcare workers ( HCWs ) in a long-term-care facility ( LTCF ) . METHODS Two floors of an LTCF participated . Ward A used the h and rub as an adjunct to soap and water ; ward B was the control . HCWs ' h and s were cultured using the bag-broth technique for Staphylococcus aureus , gram-negative bacilli ( GNB ) , C and ida , and vancomycin-resistant enterococci ( VRE ) . HCWs completed a question naire at baseline and after an educational intervention and introduction of rub . RESULTS H and hygiene practice s , knowledge , and opinions did not change after the educational or rub intervention . Ward A HCWs thought that the rub was faster ( P = .002 ) and less drying ( P = .04 ) than soap . H and hygiene frequency did not differ at baseline between the two floors , but increased on ward A by the end of the study ( P = .04 ) . HCWs were colonized frequently with GNB ( 66 % ) , C and ida ( 41 % ) , S. aureus ( 20 % ) , and VRE ( 9 % ) . Although colonization did not change from baseline on either ward , the rub was more effective in clearing GNB P = .03 ) and S. aureus ( P = .003 ) . Nosocomial infection rates did not change . CONCLUSION The alcohol-based h and rub was a faster , more convenient , less drying method of h and hygiene for HCWs in an LTCF , and it improved compliance . Although microbial colonization did not change , the rub was more efficacious in removing pathogens already present on the h and s of HCWs An improved human model for the quantification of skin barrier creams ( BCs ) is described . In contrast to the previously published procedure , the back , instead of the forearm , and a total of 4 irritants are used . Due to the larger area , 3 BC formulations can be simultaneously compared to the control field , which receives the irritant only , without BC‐pretreatment . On 10 human volunteers , the irritants 10 % sodium lauryl sulfate ( SLS ) , 1 % sodium hydroxide ( NaOH ) , 30 % lactic acid ( LA ) and undiluted toluene ( TOL ) were applied via large Finn Chambers for 30 min , 5 × during the 1st week and 4 × during the 2nd week . Taktosan Salbe ( water‐in‐oil emulsion ) and RAWI Speerschutzcreme ( oil‐in‐water emulsion ) were applied 30 min before contact with the irritants . In order to asses reproducibility and interindividual variation , the BC RAWI was tested in duplicate . Irritant cutaneous reactions were quantified by 4 parameters : erythema score , transepidermal water loss , blood flow volume and stratum corneum hydration by measuring capacitance . The results showed marked differences in efficacy . Taktosan significantly suppressed irritation by SLS , NaOH and LA , which was apparent in nearly all parameters . RAWI caused significant inhibition of SLS irritation , and a positive trend against NaOH and LA was observed . Both BCs failed against TOL . The results of duplicate testing with RAWI showed good reproducibility . The dogma that oil‐in‐water emulsions are primarily effective against lipophilic irritants , and water‐in‐oil emulsions against hydrophilic irritants , needs to be re‐evaluated on the basis of our findings . This model seems to have potential for further studies on BCs and might eluci date the complex interaction of BCs with irritants Background H and decontamination is crucial to control nosocomial infections . The utility of h and decontamination is related not only to its antimicrobial effectiveness , but also to its acceptability by hospital staff . Objectives We aim ed to assess skin tolerance and antimicrobial effects of two widely accepted h and hygiene measures under in‐use conditions . Methods Fifty‐two nurses were r and omly assigned for an 8‐day period to either an alcohol‐based disinfectant or a h and wash with a non‐antiseptic soap . At baseline and at the end of the test period , microbiological h and sample s were obtained both before and after a h and hygiene procedure , and skin tolerance was assessed using clinical scores and measurement of transepidermal water loss . Results Self‐ assessment of skin condition and grade of skin damage worsened significantly more in the group using soap than in the group using alcoholic disinfectant ( P = 0·004 and P = 0·01 , respectively ) . The alcohol‐based rinse was significantly more effective than liquid soap in removing transient contaminant micro‐organisms ( P = 0·016 ) . Twenty of 50 h and washes with non‐antiseptic soap apparently result ed in bacterial contamination of the h and s. At the end of the study , the total bacterial count increased with the increasing number of h and washes in the soap group ( P = 0·003 ) , and with the degree of skin damage ( P = 0·005 ) in the antiseptic group . Conclusions In everyday hospital practice , alcohol‐based disinfectant is more effective and better tolerated than non‐antiseptic soap ; soap is at risk of spreading contamination ; and skin comfort strongly influences the number and the quality of h and hygiene procedures Objective : The aim of this prospect i ve follow-up study was to quantify the impact of h and dermatitis ( HD ) in bakers , confectioners and bakery shop assistants , and to investigate related risk factors . Method : Bakers ' , confectioners ' and bakery-shop assistants were included in a prospect i ve follow-up study in the region of East Thuringia starting in August 1996 . At the beginning of their vocational training 91 apprentices were interviewed and examined in a st and ardised way . Follow-up examinations and interviews were done after 6 months ( n=79 ) , 12 months ( n=63 ) and at the end of the training ( n=69 ) after 36 months . Results : In their case histories 3.3 % ( n=3 ) of the apprentices reported previous HD in childhood and adolescence . The first assessment after 2 to 4 weeks of vocational training revealed HD in 17.5 % ( n=16 ) of the individuals . At the follow-up examination after 6 months , point prevalence of HD was 29.1 % ( n=23 ) , after 12 months 27.0 % ( n=17 ) and after 36 months 27.5 % ( n=19 ) . Mild to moderate irritant contact dermatitis was the most frequent finding . Finally , an atopic skin diathesis ( > 10 points , “ atopy score ” ) ( OR=4.89 ; CI 95 % 1.15–20.79 ) , previous HD ( OR=41.1 ; CI 95 % 4.99–339.13 ) as well as flexural dermatitis ( OR=6.8 ; CI 95 % 1.72–27.22 ) proved to be predictive factors for the development of HD . No association was found to respiratory atopy ( OR=1.29 ; CI 95 % 0.35–4.7 ) and metal sensitisation ( OR=1.1 ; CI 95 % 0.29–4.35 ) . Exogenous irritant factors did not show a strong association towards a risk increase . Wet work in general , as well as distinct occupational tasks showed only a tendency for being a risk factor for HD . However , leisure time activities , especially house building and rebuilding ( OR=5.4 ; CI 95 % 1.05–27.81 ) , were associated with an elevated risk . Conclusions : Endogenous and exogenous factors contribute to the development of HD in bakers ' and confectioners ' apprentices Skin harrier function was studied after use of occlusive gloves on normal and compromised skin . 2 studies were performed ( Study A and B ) , and the effects were evaluated by non‐invasive methods . Participants in the studies were instructed to wear an occlusive glove on one h and , while the other h and served as control . The gloves used were hypoallergenic , non‐latex . Study A : 20 volunteers wore a glove on normal skin 6 h/day for 3 days . Study B : 20 volunteers wore a glove on sodium fauryl sulfa lei S LSI‐compromised skin 6 h/day for 3 days . Skin harrier function was evaluated by measurement of transepidermal water loss ( TEWL ) ( Evaporimeter ) , skin hydration by electrical capacitance ( Corneometer ) and inflammation was evaluated by erythema index ( DermaSpetrometer ) . Results : Study A. Glove occlusion on normal skin 6 h/day for 3 days caused no significant influence on the water barrier function . Study B : Glove occlusion on SLS‐compromised skin for the same period of time had a significantly negative effect on the water barrier function . It is concluded that occlusion may be an additional factor in the pathogenesis of cumulative irritant contact dermatitis Moisturizers are used daily by many people to alleviate symptoms of clinical ly and subjectively dry skin . Recent studies suggest that certain ingredients in creams may accelerate the recovery of a disrupted barrier and decrease the skin susceptibility to irritant stimuli . In the present single‐blind study , a moisturizing cream was tested for its influence both on barrier recovery in surfuctant‐damaged skin and on the susceptibility of normal skin to exposure to the irritant sodium lauryl sulphate ( SLS ) . Parameters measured were transepidermal water loss ( TEWL ) and skin corneometer values , indicating degree of hydration . Treatment of surfactant‐damaged skin with the test cream for 14 days promoted barrier recovery , as observed as a decrease in TEWL . Skin corneometer values also normalized more rapidly during the treatment . In normal skin , use or the test cream significantly reduced TFWL after 14 days of treatment , and irritant reactions to SLS were , significantly decreased . Skin corneometer values increased after only 1 application and remained elevated after 14 days . In conclusion , the accelerated rate of recovery of surfactant‐damaged skin and the lower degree of SLS‐induced irritation in normal skin treated with the test cream may be of clinical relevance in attempts to reduce contact dermatitis due to irritant stimuli Baker and confectioner apprentices have been included in a prospect i ve follow‐up study in the region of East Thuringia , to evaluate risk factors for the development of h and dermatitis . Starting in August 1996 , the apprentices have been interviewed and examined in a st and ardized way right at the beginning ( n=91 ) of their vocational training , 6 ( n=79 ) and 12 months ( n=63 ) later . To gain objective data , TEWL score was also assessed at 3 st and ardized sites on the h and s. In their case histories , 3.3 % ( n=3 ) of the apprentices reported h and dermatitis . The 1st assessment after 2 to 4 weeks vocational training revealed h and eczema in 17.5 % ( n=16 ) of the individuals . At the follow‐up after 6 months of training 29.1 % ( n=23 ) , and after 12 month of training 27.0 % ( n=17 ) , of the apprentices had h and dermatitis of mild to moderate severity . Within 6 months , the TEWL score rose significantly ( p<0.001 ) from 11.9 g m−2 h−1 ( ± 5.4 ) to 16.8 g m−2 h−1 ( ± 9.5 ) . After 12 months , the TEWL score was 14.9 g m−2 h−1 ( ± 4.6 ) . For the atopic skin diathesis ( > 10 points of Diepgen 's atopy score ) , there was a significant tendency to be a predictive factor for the development of occupational h and dermatitis . TEWL score failed to correlate with the development of skin damage in our study . The same was true for respiratory atopy and metal sensitization The occurrence of h and eczema in an industrial city was studied . Question naires were sent to 20000 individuals aged 20–65 years , r and omly selected from the population register of the city . After two reminders , a response rate of 83 % was obtained . Analysis of the drop‐outs did not indicate that the presence of h and eczema was an important selection factor for response to the question naire . Those subjects considering themselves to have had h and eczema within the previous 12 months were invited to a dermatological examination to verify the diagnosis and for further investigation . Seventy‐one per cent accepted the invitation . Analysis of drop‐outs showed that willingness to attend the dermatological examination was to some extent dependent on the severity of the h and eczema Thirty-one health care workers , of whom 24 ( 77 % ) were perioperative nurses , evaluated a new nonlatex surgical glove with a coating consisting of ingredients clinical ly proven to have beneficial effects on skin health . In this one-day , clinical self- assessment study , nurses and other health care workers compared the condition of the skin on their h and s before and after wearing these surgical gloves . Eighty-one percent of the perioperative nurses and health care workers rated the skin on the h and that had worn the glove as less dry than it had been at baseline . Sixty-five percent rated their skin as more hydrated , and 58 % rated their skin as smoother and more supple after wearing a surgical glove coated with a dermal therapy formulation Aims : To evaluate the effect of an intervention to reduce work related skin problems in gut cleaning departments in Danish swine slaughterhouses . The intervention consisted of an evidence based prevention programme and a documented method for implementation . Methods : R and omised controlled intervention study with a one year follow up . The intervention included educational activities and evidence based recommendations . The effect of the intervention was evaluated by telephone interviews using a st and ardised question naire based on the Nordic Occupational Skin Question naire ( NOSQ-2002 ) with modified and additional questions on exposure , preventive measures , information , and discussion s on prevention of skin problems , etc . Results : A total of 644 ( 87.5 % ) responded at the baseline interview and 622 ( 71.6 % ) at the one year follow up interview . A total of 495 participated in both interviews ( 67.3 % ) . In the intervention departments the frequency of eczema on h and s or forearms within the past three months at follow up was reduced significantly from 56.2 % at baseline to 41.0 % at follow up , while a slight non-significant increase was observed in the comparison departments ( from 45.9 % to 50.2 % ) . The intervention activities result ed in more frequent use of protective gloves in general and the use of cotton gloves worn underneath rubber and plastic gloves . At follow up three times as many in the intervention departments used the recommended high fat skin care products introduced as part of the intervention activities . At follow up , discussion of skin problems was increased in the intervention group while no changes were observed in the comparison group . Conclusions : A significant 27 % relative reduction of occupational eczema in a high risk group was feasible through implementation of an evidence based prevention programme In order to protect the h and s of dentists , dental technicians and dental nurses from direct contacts with acrylic monomer , a new type of protective monoglyceride containing ointment has been introduced . The monoglyceride-based ointment was found to prevent penetration of the monomeric part of an autopolymerising acrylic resin and was also shown to have significantly smaller decreasing influence on the ability to manipulate instruments and material s than a compared silicone-based ointment . Furthermore , even with addition of 1 % by volume of the monoglyceride-based ointment there was no marked influence on the mechanical properties ( elastic modulous and ultimate tensile strength ) of an investigated acrylic tray material Eczematous skin disease is a serious work-related illness . Since 1995 , reimbursement by insurance companies for treatment of skin diseases has become the largest cost source in some countries . This study was a r and omized controlled trial ( N = 20 ) of the efficacy of Pro-Q , a skin protectant product , in the prevention of contact dermatitis from sodium lauryl sulfate and urushiol , the resinous sap of poison ivy and poison oak . Pro-Q was significantly effective in reducing the irritation from sodium lauryl sulfate but did not prevent the allergic reaction to urushiol The actual advantage of barrier creams over bl and emollients for skin protection is still hotly debated . In a r and omized , double‐blinded study , a newly‐introduced barrier cream and its moisturizing vehicle were compared regarding their skin compatibility , efficacy and result ing acceptance . Thus , 2 panels of 25 hospital nurses with mild signs of skin irritation were asked to use 1 of the test products provided ( verum or vehicle ) over a period of 4 weeks . Effects of both types of preparations were studied weekly by clinical examination and the instrumental assessment of bioengineering parameters . Results showed no significant differences between barrier cream and vehicle . In both groups , clinical skin status improved and stratum corneum hydration increased significantly during the study period . Both preparations were tolerated and accepted well , thus showing both skin protection and skin care . These results contribute to the debate as to whether a strict distinction between “ skin care ” and “ skin protection ” products is justified . The vehicle alone is capable of positively influencing skin status . Emphasis must be laid on regular , frequent , and correct application of a product for it to be effective In the present work a practical cl aim substantiation study is shown by the example of 5 commercially available body lotions . Their efficacy with respect to effects on transepidermal water loss ( TEWL ) and stratum corneum ( SC ) hydration of ageing skin has been examined . Results were obtained after single and repeated application ( 14 days , 2 × a day ) . The best performing product was then selected and further tested for its potential effects on sodium lauryl sulfate (SLS)‐damaged skin . This was done in a younger population and the recovery of the impaired barrier function was followed by TEWL measurements . The selected body lotion had a high efficacy , improving both the TEWL and SC hydration of ageing skin by more than 30 % . When applied to SLS‐damaged skin , the product was able to improve skin barrier repair in comparison with physiological barrier repair . The results of this study show that a combination of non‐invasive objective measurements can be used to substantiate product cl aims . Cl aims can be made with respect to protective and preventive properties of products , but also as to effectiveness of topical skin treatment in the case of abnormal barrier function or barrier restoration Irritant contact dermatitis is a mayor problem in health care employees . Because educational programs have shown convincing success in certain occupations ( e.g. in hairdressers ) , this study investigates the effect of a special training program in health care trainees . 521 trainees from 14 nursing schools in Central Germany were r and omly divided in 2 groups , ( i ) an intervention group with a regular teaching protocol regarding all aspects of primary prevention and ( ii ) a control group without any further teaching . Morphological changes of the h and s , use of h and care creams and knowledge regarding skin care were evaluated regularly during their 3 years lasting training period ( 1999–2002 ) . In the intervention group , we found at the end of the 3‐year training period a significant better skin condition of the h and s than in the control group : a 3‐year prevalence of morphological skin changes of 66.7 % versus 89.3 % . The unteached trainees ( control group ) had an odds ratio ( OR ) of 4.8 [ 95 % confidential interval ( CI ) : 2.9–7.8 ] for developing any skin changes on the h and s after 3 years . Besides the effect of the teaching , the history of h and dermatitis before the study start was an independent risk factor for development of further h and dermatitis [ OR 1.9 , 95 % CI : 1.0–3.6 ) . Age and sex showed no influence on the skin condition . Atopic constitution had an influence on the development of skin changes only at the evaluation after 18 month . The observed effect in the intervention group may best be explained by different behaviour of the trainees , e.g. the amount of h and washing was reduced , while procedure of h and disinfection remained unchanged compared with the control group . However , the amount of used skin care cream did not differ between the both groups . This study shows that primary prevention of skin disease by regularly teaching during the training period of medical employees can effectively reduce the risk of development of irritant skin changes of the h and s. Therefore , teaching and continuous motivation regarding preventive individual and collective measures during the training of medical staff should be an obliged part of the curriculum The effect of a moisturizer was tested on experimentally irritated human skin in two studies . In a prevention study , 12 volunteers had both h and s immersed into a 0.375 % sodium lauryl sulphate solution , 10 min twice daily for 2 days . Before each immersion one h and was treated with the moisturizer ; the other h and served as control . In a therapeutic study , 12 volunteers had both h and s immersed in the same way as mentioned above . After the last immersion one h and was treated for 5 days with the moisturizer ; the other h and served as control . Skin barrier function was evaluated by transepidermal water loss ( Evaporimeter ) , and blood flow was evaluated by laser Doppler flowmetry and skin hydration by electrical capacitance ( Corneometer ) . A significant preventive effect was obtained on the treated h and , compared to the control h and , judged by all measured parameters . A significant therapeutic effect was observed on skin barrier function and on skin hydration on the treated h and , compared to the control h and , while no difference between the h and s in blood flow was observed after the end of treatment . The moisturizer could prevent irritant skin reactions induced by a detergent , and it could also accelerate regeneration of the barrier function of irritated skin CONTEXT Many health care workers suffer severe h and irritation , with cracking and bleeding , as a consequence of frequent h and washing and glove use . Integumentary breakdown has major implication s for nosocomial infection control and promotes the spread of bloodborne viruses . The potential benefits of scheduled use of h and -care agents-lotions or creams-in health care workers has not been established by controlled trial . OBJECTIVE To compare the value of an oil-containing lotion with a novel barrier skin cream in health care workers with severe h and irritation . DESIGN Prospect i ve , r and omized , double-blind trial . SETTING University medical center . PARTICIPANTS Fifty-four health care workers from multiple departments with severe h and irritation , 74 % with one or more full-thickness cracks or other integumentary breaks . MAIN OUTCOME MEASURES Objective and subjective parameters for scaling , cracking , weeping , bleeding , and pain were scored by two blinded investigators weekly for 4 weeks , and the h and s of subjects were cultured quantitatively at the onset and after 2 weeks and 4 weeks . RESULTS Subjects in both groups experienced marked improvement in overall h and condition ( each , P < .02 ) , particularly in scaling , cracking , and pain . Persons r and omized to use of the oil-containing lotion showed greater improvement ( mean score , from 6.5 to 2.7 vs 6.8 to 4 . 7 , P = .006 ) . In 18 ( 69 % ) of 26 persons who used the control lotion , all full-thickness integumentary breaks were healed and pain was totally resolved , compared with 14 ( 52 % ) of 27 persons who used the barrier cream ( P = .26 ) . Use of the two agents in a scheduled fashion had no effect on the levels or profile of the transient h and flora . However , by the fourth week of use , h and washing frequency was 50 % higher in subjects r and omized to use the control lotion than it was in subjects r and omized to use the barrier cream ( 17.8 vs 11.7 times per day , P = .04 ) . CONCLUSION Use of an oil-containing lotion or a barrier cream on a scheduled basis can substantially protect the h and s of vulnerable health care workers against drying and chemical irritation , preventing skin breakdown and promoting more frequent h and washing Objectives The aim of the trial was to investigate whether the publicized effects of skin protection creams can be replicated in a real occupational setting during activities that expose the skin . Methods A prospect i ve , r and omized , four-tailed controlled pilot trial was performed to compare the effect of skin protection and skin care alone or in combination with cleansing against a control group ( only cleansing ) . Two branches were selected for the investigation : the building industry and the timber industry . A total of 1,006 workers from these two branches were recruited , and out of these 485 workers were examined longitudinally for at least three time points over 1 year ( lost for follow-up : 430 workers , exclusion : 91 workers ) . At each time point , as a primary outcome measure , we assessed the condition of the skin at both h and s in a blinded manner and the individual was assigned to one of the following categories : no eczema , mild , moderate and severe eczema . As a secondary outcome measure , the worker ’s transepidermal water loss ( TEWL ) was measured under st and ardized conditions at the back of both h and s. In addition , the workers were asked to evaluate their skin condition during the study . Results With regard to differences in the occurrence of eczemas , we found only in workers in building industry without application of skin protection or skin care creams a statistical significant increase in the incidence between the first and the second visit and a statistical significant decrease in the incidence between the second and third visit . When evaluating the secondary outcome -measurement changes in the TEWL values , an improvement was found for the group skin protection and skin care in combination and by skin care alone . Females in the timber industry started with better TEWL values than males , which may be due to better overall skin care . In this group we found an improvement for the group skin protection and skin care in combination and by skin protection alone . For skin protection alone , we noted a slight , but not significant improvement in all other groups . The subjective improvement of skin condition was reported from the participants who used skin protection and skin care in combination . Conclusions Taking all these secondary - outcome measurements together , the main result of this study was that skin protection creams alone have a small effect on the skin barrier in workers in the building and timber industries compared with skin care alone or in combination with skin protection The present study was design ed as an intervention study to investigate whether an educational programme was efficient in preventing work‐related skin problems on the h and s. 107 student auxiliary nurses ( 61 in the intervention group and 46 in the control group ) were followed during the first 10 weeks of their initial practical training in county hospitals . The intervention group was given an educational programme before the practical training started . For evaluation the participants had question naires , clinical examination of the h and s , measurement of transepidermal water loss ( TEWL ) and patch testing . The use of h and disinfectants , which was discouraged in the educational programme , was significantly lower in the intervention group as compared to the control group ( p=0.002 ) . 48 % of the intervention group and 58 % of the control group had aggravation of skin problems during practical training ( p>0.05 ) . Use of h and disinfectant agents was significantly associated with aggravation of skin problems ( p=0.016 ) . A significant increase in TEWL for the control group ( p<0.005 ) , but not for the intervention group , was seen after 10 weeks of practical training . In conclusion , the present intervention study shows promising results from the use of an educational programme OBJECTIVES The role of atopic constitution , contact sensitization , transepidermal water loss , and dry skin in the development of h and dermatitis was investigated in a prospect i ve study of 74 apprentice hairdressers and 111 apprentice nurses . METHODS Base-line measurements included a question naire on personal characteristics and anamnestic information , examination of h and skin , measurements of transepidermal water loss , patch tests , and prick tests . The condition of the h and s , previous exposure , and transepidermal water loss were followed at intervals of four to six weeks . Cox proportional hazard models were used in the statistical analysis . RESULTS The average incidence rate of h and dermatitis was 32.8 cases per 100 person-years for the hairdressers and 14.5 cases per 100 person-years for the nurses . The rate ratio of having a dry versus normal skin type was 7.3 for the hairdressers [ 95 % confidence interval ( 95 % CI ) 2.2 - 24.3 ] and 1.7 for the nurses ( 95 % CI 0.5 - 6.4 ) . Apprentice nurses with a history of ( atopic ) mucosal symptoms had a 3.4-fold increased incidence rate of h and dermatitis ( 95 % CI 1.05 - 11.2 ) . The rate ratio of mucosal atopy for the apprentice hairdressers was 2.2 ( 95 % CI 0.7 - 6.7 ) . Graphic display of the results suggested an increased risk of h and dermatitis among the apprentice hairdressers with transepidermal water loss on the h and greater than 15 g.m-2.h , but the relative risk of increased transepidermal water loss was not statistically significant . CONCLUSION The most important endogenous risk factors for h and dermatitis among the apprentice hairdressers and nurses were the presence of dry skin and a history of mucosal atopy . No relationship between increased transepidermal water loss and the risk of h and dermatitis was observed 56 builder 's labourers manipulating lime cement applied a protective cream on their h and s and 57 used a placebo in a double blind test of two months ' duration . The labourers , the doctors who surveyed the condition of their h and s , and the statistician who analyzed the results knew only that one cream had a blue label , and the other a green one . Before and after the test , the presence or the absence of certain symptoms on the h and s were objective ly examined , while the subjective opinion of the labourers was registered at the end of the test . As usual in tests of that kind , the great majority of the labourers ( more than 75 % ) were satisfied , 62 % of them acknowledged an improvement . That percentage justified a comparative double-blind study that revealed a much higher quota ( 86 % of the test persons ) of satisfaction among the labourers treated with Ivosin than in the placebo group ( 66 % ) . That difference was statistically significant . On the other h and , no objective difference could be revealed between the two groups . It was impossible to discover among the symptoms studied , any objective cause of that subjective difference

CONCLUSIONS More research on the effectiveness of KT interventions regarding genetic testing in the clinical context may contribute to patients making informed value-based decisions and drawing the maximum benefit from clinical applications of genetic and genomic innovations

BACKGROUND Knowledge translation ( KT ) interventions are attempts to change behavior in keeping with scientific evidence . While genetic tests are increasingly available to healthcare consumers in the clinic , evidence about their benefits is unclear and decisions about genetic testing are thus difficult for all parties . OBJECTIVE We sought to identify KT interventions that involved decisions about genetic testing in the clinical context and to assess their effectiveness for improving decision making in terms of behavior change , increased knowledge and wellbeing .

ABSTRACT Despite increased interest among the public in breast cancer genetic risk and genetic testing , there are limited services to help women make informed decisions about genetic testing . This study , conducted with female callers ( N = 279 ) to the National Cancer Institute 's ( NCI 's ) Atlantic Region Cancer Information Service ( CIS ) , developed and evaluated a theory-based , educational intervention design ed to increase callers ' underst and ing of the following : ( a ) the kinds of information required to determine inherited risk ; ( b ) their own personal family history of cancer ; and ( c ) the benefits and limitations of genetic testing . Callers requesting information about breast/ovarian cancer risk , risk assessment services , and genetic testing were r and omized to either : ( 1 ) st and ard care or ( 2 ) an educational intervention . Results show that the educational intervention reduced intention to obtain genetic testing among women at average risk and increased intention among high-risk women at 6 months . In addition , high monitors , who typically attend to and seek information , demonstrated greater increases in knowledge and perceived risk over the 6-month interval than low monitors , who typically are distracted from information . These findings suggest that theoretically design ed interventions can be effective in helping women underst and their cancer risk and appropriate risk assessment options and can be implemented successfully within a service program like the CIS Abstract Objective : To investigate the feasibility of improving screening for carriers of haemoglobin disorders in general practice by using a nurse facilitator to work with primary care teams and the relevant haematology laboratories ; to identify problems in communication between all those involved in delivering the service , and to implement solutions . Design : Two year , practice based r and omised controlled trial . Setting : North London area where 29 % of residents and 43 % of births are in ethnic groups at risk for haemoglobin disorders . Subjects : 26 of the 93 practice s using the services of the area 's haematology laboratory agreed to take part and were r and omly divided into control and intervention practice s. Main outcome measure : Change in number of requests for screening tests for haemoglobin disorders made by control and intervention practice s in baseline and intervention years . Results : The number of screening tests requested varied from 0 - 150 in the 93 practice s in the baseline year . Study practice s tended to have made a moderate number of requests ( 10 - 50 ) during this period . During the intervention year intervention practice s made 292 more requests ( 99 % increase ) and control practice s made 74 fewer requests ( 23 % decrease ; P=0.001 for difference in median change ) . Four practice s , three of which were singleh and ed , accounted for 75 % of the increase . The number of requests from intervention practice s , adjusted for baseline requests , was 3.2 times higher than control practice s ( P<0.0001 ) . Conclusion : General practitioners and practice nurses are willing to undertake a new genetic screening service ( or exp and an existing one ) if they are persuaded that it benefits the health of a significant proportion of their practice population . They need appropriate tools ( for example , information material s for carriers and groups at risk ) , and the laboratory must be sensitive to their needs . Preconceptional carrier screening and counselling need to be coupled with antenatal screening OBJECTIVE Genetic testing is increasingly part of routine clinical care for women with a family history of breast cancer . Given their substantially elevated risk for breast cancer , BRCA1/BRCA2 mutation carriers must make the difficult decision whether or not to opt for risk reducing mastectomy . To help BRCA1/2 carriers make this decision , the authors developed a computer-based interactive decision aid that was tested against usual care in a r and omized controlled trial . DESIGN After the completion of genetic counseling , 214 female ( aged 21 - 75 ) BRCA1/BRCA2 mutation carriers were r and omized to Usual Care ( UC ; N = 114 ) or Usual Care plus Decision Aid ( DA ; N = 100 ) arms . UC participants received no additional intervention . DA participants were sent the CD-ROM DA to view at home . MAIN OUTCOME MEASURES The authors measured final management decision , decisional conflict , decisional satisfaction , and receipt of risk reducing mastectomy at 1- , 6- , and 12-months postr and omization . RESULTS Longitudinal analyses revealed that the DA was effective among carriers who were initially undecided about how to manage their breast cancer risk . Within this group , the DA led to an increased likelihood of reaching a management decision ( OR = 3.09 , 95 % CI = 1.62 , 5.90 ; p < .001 ) , decreased decisional conflict ( B = -.46 , z = -3.1 , p < 002 ) , and increased satisfaction ( B = .27 , z = 3.1 , p = .002 ) compared to UC . Among carriers who had already made a management decision by the time of r and omization , the DA had no benefit relative to UC . CONCLUSION These results demonstrate that BRCA1/BRCA2 mutation carriers who are having difficulty making a breast cancer risk management decision can benefit from adjunct decision support PURPOSE To evaluate the predictors of and time taken for the translation of highly promising basic research into clinical experimentation and use . METHODS We identified 101 articles , published between 1979 and 1983 in six major basic science journals , which clearly stated that the technology studied had novel therapeutic or preventive promises . Each case was evaluated for whether the promising finding result ed in relevant r and omized controlled trials and clinical use . Main outcomes included the time to published trials , time to published trials with favorable results ( " positive " trials ) , and licensed clinical use . RESULTS By October 2002 , 27 of the promising technologies had result ed in at least one published r and omized trial , 19 of which had led to the publication of at least one positive r and omized trial . Five basic science findings are currently licensed for clinical use , but only has been used extensively for the licensed indications . Promising technologies that did not lead to a published human study within 10 to 12 years were unlikely to be tested in humans subsequently . Some form of industry involvement in the basic science publication was the strongest predictor of clinical experimentation , accelerating the process by about eightfold ( 95 % confidence interval : 3 to 19 ) when an author had industry affiliations . CONCLUSION Even the most promising findings of basic research take a long time to translate into clinical experimentation , and adoption in clinical practice is rare PURPOSE Markers of genetic susceptibility to tobacco-related cancers could personalize harms of smoking and motivate cessation . Our objective was to assess whether a multicomponent intervention that included feedback about genetic susceptibility to lung cancer increased risk perceptions and rates of smoking cessation compared with a st and ard cessation intervention . EXPERIMENTAL DESIGN Our design was a two-arm trial with eligible smokers r and omized in a 1:2 ratio to Enhanced Usual Care or Biomarker Feedback ( BF ) . Surveys were conducted at baseline , 6 , and 12 months later . The setting was an inner city community health clinic . African-American patients who were current smokers ( n = 557 ) were identified by chart abstract ion and provider referral . All smokers received a self-help manual and , if appropriate , nicotine patches . Smokers in the BF arm also were offered a blood test for genotyping the GST(3 ) gene ( GSTM1 ) , sent a test result booklet , and called up to four times by a health educator . Prevalent abstinence was assessed by self-report of having smoked no cigarettes in the prior 7 days at the 6- and 12-month follow-ups and sustained abstinence , i.e. , not smoking at either follow-up or in-between . RESULTS Smoking cessation was greater for the BF arm than the Enhanced Usual Care arm ( 19 % versus 10 % , respectively ; P < 0.006 ) at 6 months but not at 12 months . CONCLUSIONS Smokers agreed to genetic feedback as part of a multicomponent cessation program . Although the program increased short-term cessation rates compared with st and ard intervention , genetic feedback of susceptibility may not benefit smokers with high baseline risk perceptions Prenatal diagnosis ( PND ) is offered routinely as part of pregnancy care to a large number of women at increased risk of fetal anomalies . Despite an extraordinary growth in the use of PND and significant re source allocation , few studies have examined outcomes of PND counseling , and virtually no research has evaluated the relative efficacy of various approaches to genetic counseling . This study was a r and omized trial that compared which counseling methods – individual , group , and use of a decision aid – are effective in PND counseling for women of advanced maternal age ( ≥35 years ) and their partners . Three hundred and fifty‐two women and 225 partners completed pre‐ and post‐intervention question naires assessing changes in knowledge , decisional conflict , state anxiety , satisfaction , use of PND , and pregnancy outcomes . All participants showed a significant increase in knowledge and a decrease in decisional conflict post intervention . Those in the group intervention showed a significantly greater increase in knowledge than those in the individual counseling intervention . While high levels of satisfaction were reported by all , those in individual counseling were significantly more satisfied than those receiving group counseling or the decision aid . This study has shown unique benefits with each type of intervention such that women and their partners preferred individual genetic counseling , while they learned best in group‐counseling sessions , and experienced the least decisional conflict regarding genetic testing with a decision aid OBJECTIVES (1)To compare an interactive multimedia decision aid ( IMDA ) with a leaflet and a video to give information about prenatal screening for Down syndrome and ( 2 ) to determine the women 's acceptance of IMDA . METHODS Two hundred and one women were recruited from the prenatal clinic of a university teaching hospital and r and omised into the intervention group ( IMDA , video , and information leaflet ) or the control group ( video and information leaflet ) . RESULTS There were no significant differences in the initial decision for and the final uptake of the prenatal screening test between the control and intervention groups . The proportion of women who were undecided was less than 10 % in both groups . Of the women in the intervention group , 86.6 % and 78.9 % agreed that IMDA was user-friendly and acceptable , respectively . Significantly more women aged < 35 ( 88.1 % ) accepted IMDA than women aged > or = 35 ( 68.3 % ) ( P = 0.030 ) , but the logistic regression analysis did not confirm this finding after adjusting for other factors ( computer knowledge and usage of computer ) . CONCLUSION The use of IMDA did not affect the women 's overall uptake rate of the prenatal screening test for Down syndrome . More women less than 35 years accepted IMDA probably because they used computer more frequently and had more computer knowledge BACKGROUND In response to the isolation of the BRCA1 gene , a breast-ovarian cancer-susceptibility gene , biotechnology companies are already marketing genetic tests to health care providers and to the public . Initial studies indicate interest in BRCA1 testing in the general public and in population s at high risk . However , the optimal strategies for educating and counseling individuals have yet to be determined . PURPOSE Our goal was to evaluate the impact of alternate strategies for pretest education and counseling on decision-making regarding BRCA1 testing among women at low to moderate risk who have a family history of breast and /or ovarian cancer . METHODS A r and omized trial design was used to evaluate the effects of education only ( educational approach ) and education plus counseling ( counseling approach ) , as compared with a waiting-list ( control ) condition ( n = 400 for all groups combined ) . The educational approach review ed information about personal risk factors , inheritance of cancer susceptibility , the benefits , limitations , and risks of BRCA1 testing , and cancer screening and prevention options . The counseling approach included this information , as well as a personalized discussion of experiences with cancer in the family and the potential psychological and social impact of testing . Data on knowledge of inherited cancer and BRCA1 test characteristics , perceived risk , perceived benefits , limitations and risks of BRCA1 testing , and testing intentions were collected by use of structured telephone interviews at baseline and at 1-month follow-up . Provision of a blood sample for future testing served as a proxy measure of intention to be tested ( in the education and counseling arms of the study ) . The effects of intervention group on study outcomes were evaluated by use of hierarchical linear regression modeling and logistic regression modeling ( for the blood sample outcome ) . All P values are for two-sided tests . RESULTS The educational and counseling approaches both led to significant increases in knowledge , relative to the control condition ( P < .001 for both ) . The counseling approach , but not the educational approach , was superior to the control condition in producing significant increases in perceived limitations and risks of BRCA1 testing ( P < .01 ) and decreases in perceived benefits ( P < .05 ) . However , neither approach produced changes in intentions to have BRCA1 testing . Prior to and following both education only and education plus counseling , approximately one half of the participants stated that they intended to be tested ; after the session , 52 % provided a blood sample . CONCLUSIONS St and ard educational approaches may be equally effective as exp and ed counseling approaches in enhancing knowledge . Since knowledge is a key aspect of medical decision-making , st and ard education may be adequate in situations where genetic testing must be streamlined . On the other h and , it has been argued that optimal decision-making requires not only knowledge , but also a reasoned evaluation of the positive and negative consequences of alternate decisions . Although the counseling approach is more likely to achieve this goal , it may not diminish interest in testing , even among women at low to moderate risk . Future research should focus on the merits of these alternate approaches for subgroups of individuals with different background s who are being counseled in the variety of setting s where BRCA1 testing is likely to be offered This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia ( FH ) by finding a genetic mutation reduces patients ' perceptions of control over the disease and adherence to risk‐reducing behaviors . Three hundred forty‐one families , comprising 341 hypercholesterolemia prob and s and 128 adult relatives , were r and omized to one of two groups : ( a ) routine clinical diagnosis ; ( b ) routine clinical diagnosis plus genetic testing ( mutation search ing in prob and s and direct gene testing in relatives ) . The main outcome measures were perceptions of control over hypercholesterolemia , adherence to cholesterol‐lowering medication , diet , physical activity , and smoking . There was no support for the main hypothesis : finding a mutation had no impact on perceived control or adherence to risk‐reducing behavior ( all P‐values > 0.10 ) . While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack , participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level ( P = 0.02 at 6 months ) and showed a trend in believing more strongly in the efficacy of cholesterol‐lowering medication ( P = 0.06 at 6 months ) . In conclusion , finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk‐reducing behaviors . The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition , but does affect their perceptions of how control is most effectively achieved . Further work is needed to determine whether similar results will be obtained in population s with little previous awareness of their risks . © 2004 Wiley‐Liss , CONTEXT As the availability of and dem and for genetic testing for hereditary cancers increases in primary care and other clinical setting s , alternative or adjunct educational methods to traditional genetic counseling will be needed . OBJECTIVE To compare the effectiveness of a computer-based decision aid with st and ard genetic counseling for educating women about BRCA1 and BRCA2 genetic testing . DESIGN R and omized controlled trial conducted from May 2000 to September 2002 . SETTING AND PARTICIPANTS Outpatient clinics offering cancer genetic counseling at 6 US medical centers enrolled 211 women with personal or family histories of breast cancer . INTERVENTIONS St and ard one-on-one genetic counseling ( n = 105 ) or education by a computer program followed by genetic counseling ( n = 106 ) . MAIN OUTCOME MEASURES Participants ' knowledge , risk perception , intention to undergo genetic testing , decisional conflict , satisfaction with decision , anxiety , and satisfaction with the intervention . Counselor group measures were administered at baseline and after counseling . Computer group measures were administered at baseline , after computer use , and after counseling . Testing decisions were assessed at 1 and 6 months . Outcomes were analyzed by high vs low risk of carrying a BRCA1 or BRCA2 mutation . RESULTS Both groups had comparable demographics , prior computer experience , medical literacy , and baseline knowledge of breast cancer and genetic testing , and both counseling and computer use were rated highly . Knowledge scores increased in both groups ( P<.001 ) regardless of risk status , and change in knowledge was greater in the computer group compared with the counselor group ( P = .03 ) among women at low risk of carrying a mutation . Perception of absolute risk of breast cancer decreased significantly after either intervention among all participants . Intention to undergo testing decreased significantly after either intervention among low-risk but not high-risk women . The counselor group had lower mean scores on a decisional conflict scale ( P = .04 ) and , in low-risk women , higher mean scores on a satisfaction-with-decision scale ( P = .001 ) . Mean state anxiety scores were reduced by counseling but were within normal ranges for both groups at baseline and after either intervention , regardless of risk status . CONCLUSIONS An interactive computer program was more effective than st and ard genetic counseling for increasing knowledge of breast cancer and genetic testing among women at low risk of carrying a BRCA1 or BRCA2 mutation . However , genetic counseling was more effective than the computer at reducing women 's anxiety and facilitating more accurate risk perceptions . These results suggest that this computer program has the potential to st and alone as an educational intervention for low-risk women but should be used as a supplement to genetic counseling for those at high risk OBJECTIVES It is well-known that smoking causes many diseases including cancers . Informing smokers of their genotypes associated with the vulnerability to the harms of smoking may be effective measures for smoking cessation . The present study examined the effects of genotype notification of an oncogene ( L-myc ) genotype to smokers on their behavior to quit smoking . METHODS Subjects were 562 employees of a bank who answered to be a smoker for a question naire used at annual health checkup at workplace from July to December 2002 . Those enrolled on August , October , and December were allocated into the genotype notification group ( intervention group ) , and the rest into the controls . Among 286 smokers allocated into the intervention group , 257 participants ( 89.9 % ) agreed to genotype testing . One year after the enrollment , a follow-up question naire survey was conducted for all smokers including controls . RESULTS Those who stated to have quitted smoking were 22 ( 8.0 % ) among the 276 controls and 15 ( 5.8 % ) among the 257 genotype notified participants , providing that the odds ratio ( OR ) of cessation for the intervention was 0.64 ( 95 % confidence interval , 0.32 - 1.28 ) . No psychological problems associated with genotype notification were observed . CONCLUSION The present study did not show positive effects of genotype notification on smoking cessation rate . To elevate the cessation rate , methods to explain and notify genotypes should be improved PURPOSE To evaluate a shared decision-making intervention ( SDMI ) for BRCA1/2 mutation carriers who have to make a choice between screening and prophylactic surgery for breasts and /or ovaries . PATIENTS AND METHODS The SDMI consisted of two value assessment sessions , using the time trade-off method , followed by individualized treatment information based on ( quality -adjusted ) life expectancy . After the baseline assessment ( 2 weeks after a positive DNA test result ) , women were r and omly assigned to the SDMI group ( n = 44 ) , receiving the SDMI 2 months after the test result , or to the control group ( n = 44 ) . The short- and long-term effects , 3 and 9 months after the test result , were assessed using question naires . Data were collected on well-being , treatment choice , and decision-related outcomes . RESULTS In the short term , the SDMI had no effect . In the long term , with respect to well-being , patients in the SDMI group had less intrusive thoughts ( P = .05 ) and better general health ( P = .01 ) and tended to be less depressed ( P = .07 ) . With respect to decision-related outcomes for the breasts , the SDMI group held stronger preferences ( P = .02 ) and agreed more strongly to having weighed the pros and cons ( P = .01 ) . No effect was found on treatment choice . In the long term , interaction effects between the SDMI and cancer history were found . The SDMI showed an overall beneficial effect for unaffected women , whereas affected women tended to experience detrimental effects . CONCLUSION We conclude that the SDMI improved decision making in unaffected BRCA1/2 mutation carriers . Supporting decision making in a systematic way using trade-offs is beneficial for these women Purpose To measure the effectiveness of a tailored decision aid ( DA ) design ed to help women make informed decisions about genetic testing for breast/ovarian cancer risk . Methods A total of 145 women were r and omized to receive the DA or a control pamphlet at the end of their first genetic counseling consultation . Of these , 120 ( 82.8 % ) completed two question naires , 1 week and 6 months post-consultation . Results While the DA had no effect on informed choice , post-decisional regret or actual genetic testing decision , the trial showed that women who received the DA had higher knowledge levels and felt more informed about genetic testing than women who received the control pamphlet ( χ2(2 ) = 6.82 ; P = 0.033 ; χ2(1 ) = 4.86 ; P = 0.028 respectively ) . The DA also helped women who did not have blood drawn at their first consultation to clarify their values with regards to genetic testing ( χ2(1 ) = 5.27 ; P = 0.022 ) . Women who received the DA were less likely to share the information with other family members than women in the control condition ( χ2(1 ) = 8.78 ; P = 0.003 ) . Conclusions Decision aids are an effective decision-support strategy for women considering genetic testing for breast/ovarian cancer risk , and are most effective before the patient has made a decision , which is generally at the point of having blood drawn OBJECTIVE To evaluate decision analysis as a technique to facilitate women 's decision-making about prenatal diagnosis for Down syndrome using measures of effective decision-making . DESIGN R and omised controlled trial in a UK hospital 's prenatal diagnosis clinic . INTERVENTION Routine versus routine consultation structured by decision analysis . PARTICIPANTS 117/132 women receiving a screen-positive maternal serum screening result participated ( 58 routine , 59 decision analysis ) . METHODS Consultations were audio tape-recorded , transcribed and coded ; question naires were completed after the consultation and one month later after receipt of a diagnostic test and /or the 19-week scan result . MAIN MEASURES Test decision , subjective expected utilities , knowledge , informed decision-making , risk perception , decisional conflict , anxiety , perceived usefulness and directiveness of consultation information . RESULTS 48/59 in the decision-aided group and 47/58 in the routine group underwent prenatal diagnosis . Informed decision-making was higher , perceived risk more realistic and decisional conflict over time lower in the decision analysis group . Decision analysis had no impact on knowledge or SEU scores , and was no more or no less directive , useful or anxiety provoking than the routine care . Consultations were six minutes longer . CONCLUSIONS Decision analysis consultations enable women to make more informed prenatal diagnosis decisions . Professionals will need training to use this technique effectively As genetic testing for susceptibility to breast cancer becomes more widespread , alternative methods for educating individuals prior to testing will be needed . Our objective was to compare face-to-face education and counseling by a genetic counselor with education by an interactive computer program , assessing the effects of each on knowledge of breast cancer genetics and intent to undergo genetic testing . We used a r and omized , controlled trial . Seventy-two self-referred women with a first-degree relative with breast cancer received outpatient education and counseling at the Clinical Center of the National Institutes of Health ( NIH ) . Twenty-nine received individualized counseling from a genetic counselor ( counseling group ) , 29 received education from an interactive computer program followed by individualized counseling ( computer group ) , and 14 were controls . Both pre- and postintervention assessment of knowledge about breast cancer genetics and intent to undergo genetic testing were measured . The control group participants correctly answered 74 % of the knowledge questions ; the counselor group , 92 % ; and the computer group , 96 % ( P < .0001 ) . Unadjusted mean knowledge scores were significantly higher in the computer group than the counselor group ( P = .048 ) , but they were equivalent when adjusted for demographic differences ( P = 0.34 ) . Intent to undergo genetic testing was influenced by the interventions : preintervention , a majority in all groups ( 69 % ) indicated that they were likely ( definitely and most likely ) to undergo testing ; after either intervention coupled with counseling , only 44 % indicated that they were likely to do so ( P = .0002 ; odds ratio = 2.8 , 95 % CI = 1.7 - 4.9 ) . We concluded that a computer program can successfully educate patients about breast cancer susceptibility , and , along with genetic counseling , can influence patients ' intentions to undergo genetic testing Purpose : A r and omized trial was conducted to test the effects of two counseling methods ( genetic counseling and group counseling ) against a control no-intervention condition on interest in genetic testing in lower risk women . Methods : After completing baseline surveys , women ( N = 357 ) were r and omized to one of three conditions : to receive individual genetic risk counseling , to receive a group psychosocial group counseling , or to serve as a control group . Participants completed follow-up question naires 6 months after r and omization . Results : All participants had some familial history of breast cancer , but none had a family history indicative of autosomal dominant genetic mutation . At baseline over three fourths of the sample judged themselves to be appropriate c and i date s for testing . By the end of the survey , two thirds ( 70 % ) of the women in the counseling group still judged themselves to be appropriate c and i date s for testing . Findings were similar for interest in genetic testing . Changes in beliefs about genetic testing ( e.g. , beliefs about potential stigma associated with testing ) altered the effects of counseling . Conclusion : These results indicate that counseling can change interest in genetic testing only slightly and that changing women ’s beliefs about the properties of testing might be one mechanism of doing so OBJECTIVE To provide a review of published studies on the use of cell-free fetal DNA in maternal plasma for the non-invasive diagnosis of Down syndrome , trisomy 18 , and trisomy 13 . EVIDENCE PubMed was search ed for articles published between 2006 and October 2012 , using appropriate key words ( e.g. , non-invasive prenatal diagnosis , Down syndrome , cell-free fetal DNA , aneuploidy screening ) . Results were restricted to systematic review s , r and omized control trials/controlled clinical trials , and observational studies . Search es were up date d on a regular basis and incorporated in the guideline to October 31 , 2012 . Grey ( unpublished ) literature was identified through search ing the websites of health technology assessment and health technology assessment -related agencies , clinical practice guideline collection s , clinical trial registries , and national and international medical specialty societies . VALUES The studies review ed were classified according to criteria described by the Canadian Task Force on Preventive Health Care , and the recommendations for practice were ranked according to this classification ( Table 1 ) . Recommendations 1 . Non-invasive prenatal testing using massive parallel sequencing of cell-free fetal DNA to test for trisomies 21 , 18 , and 13 should be an option available to women at increased risk in lieu of amniocentesis . Pretest counselling of these women should include a discussion of the limitations of non-invasive prenatal testing . ( II-2A ) 2 . No irrevocable obstetrical decision should be made in pregnancies with a positive non-invasive prenatal testing result without confirmatory invasive diagnostic testing . ( II-2A ) 3 . Although testing of cell-free fetal DNA in maternal plasma appears very promising as a screening test for Down syndrome and other trisomies , studies in average-risk pregnancies and a significant reduction in the cost of the technology are needed before this can replace the current maternal screening approach using biochemical serum markers with or without fetal nuchal translucency ultrasound . ( III-A ) OBJECTIVE Women of all risk levels have reported high interest in obtaining genetic testing for breast cancer risk . Breast cancer risk counseling may help women to learn about their risk and appropriate options of testing . This study measured the effects of an intervention in-person and by telephone , compared to a control group . METHODS Participants were 340 women , recruited through a network of primary care physicians . They received a baseline question naire in the mail , were r and omized to one of the three study arms , and completed a follow-up survey 3 months later . RESULTS Both types of counseling were very well received . The counseling decreased women 's cancer worry , risk perceptions , and intentions to pursue genetic testing . There were similar effects for both in-person and telephone counseling . CONCLUSION Genetic counseling can be used to inform women at all risk levels about their breast cancer risk . PRACTICE IMPLICATION S Breast cancer risk counseling can be done in-person and by telephone -- thereby reaching women in remote areas The recent identification of several BRCA1/BRCA2 founder mutations among Ashkenazi Jewish individuals has led to increased salience of BRCA1/BRCA2 testing for Jewish individuals . Little is known about interest in BRCA1/BRCA2 testing among Ashkenazi Jews from the general population . Furthermore , previous research has not generally evaluated the impact of education on interest in testing among individuals from the general population . The goal of the current study was to examine whether a brief educational booklet regarding BRCA1/BRCA2 testing would influence knowledge , attitudes , and interest in testing among Ashkenazi Jewish women from the general population Risk information for Alzheimer disease ( AD ) may be communicated through susceptibility gene disclosure , even though this is not currently in clinical use . The REVEAL Study is the first r and omized clinical trial of risk assessment for AD with apolipoprotein E ( APOE ) genotype and numerical risk estimate disclosure . We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors . One hundred sixty-two participants were r and omized to either intervention ( APOE disclosure ) or control ( no genotype disclosure ) groups . Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD . The intervention group received their APOE genotype . Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation . Participants who learned they were ϵ4 positive were significantly more likely than ϵ4 negative participants to report AD-specific health behavior change 1 year after disclosure ( adjusted odds ratio : 2.73 ; 95 % confidence interval : 1.14 , 6.54 ; P=0.02 ) . Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change . Despite lack of preventive measures for AD , knowledge of APOE genotype , numerical lifetime risk , or both , influences health behavior BACKGROUND To evaluate whether feedback of genetic information regarding an L-myc polymorphism , identified as impacting on tobacco-related cancer risk , has an influence on smoking cessation , an intervention study was conducted . METHODS We recruited smokers from first-visit out patients at Aichi Cancer Center Hospital . Six hundred and seventeen participated and were allocated into two groups : the biomarker feedback group ( BF ) and the follow-up smoking status group ( FS ) . The subjects were asked for their smoking status at enrolment and at 3- and 9-month follow-ups . BF subjects were notified about their L-myc genotype . RESULTS The smoking cessation rate at 9-month follow-up was essentially the same for both BF and FS cases , at 18.8 % and 17.0 % , respectively ( P = 0.798 ) . However , a difference in the rate was evident with non-cancer subjects ( 12.7 % and 8.4 % , respectively , P = 0.237 ) , especially in females ( 15.0 % and 4.2 % , respectively , P = 0.024 ) . The non-cancer subjects informed of their genotype were more likely to quit smoking than the FS patients ; particularly in those having a risky genotype , this was significant ( odds ratio : 2.87 , P = 0.003 ) . Again it was most prominent in females . CONCLUSION Feedback regarding an L-myc polymorphism did not impact on smoking cessation overall but appeared to benefit smokers without cancer . In addition , gender could affect the response to the feedback The behavioural and psychological impact of genetic testing for lung cancer susceptibility was examined among smokers ( N = 61 ) who were r and omly allocated to a GSTM1 genetic testing group ( with GSTM1-missing or GSTM1-present result ) or no-test control group . The GSTM1-missing ( higher risk ) group reported greater motivation to quit smoking , and both genetic testing groups reported lower depression than the control group at one-week follow-up ( p < .05 for all ) . Differences were not significant at two months follow-up . This study indicates the feasibility of much-needed research into the risks and benefits for individuals of emerging lifestyle-related genetic susceptibility tests OBJECTIVE : Guidelines for fetal aneuploidy testing recommend that screening and diagnostic testing be made available to pregnant women of all ages and that providers explain the differences between these tests to help their patients make informed testing decisions . We sought to estimate the effect of a computerized , interactive prenatal testing decision tool on prenatal testing decision making . METHODS : Four hundred ninety-six English- or Spanish-speaking women at 20 or fewer weeks of gestation were r and omly assigned to view the interactive prenatal testing decision tool or the California Department of Health Services ’ educational booklet . Primary outcomes were knowledge , risk awareness , intervention satisfaction , decisional conflict , and among women aged at least 35 years , use of invasive diagnostic testing . RESULTS : Women assigned to the interactive prenatal testing decision tool had higher knowledge scores ( 79.5 % compared with 64.9 % , P<.001 ) , were more likely to correctly estimate their risk of procedure-related miscarriage ( 64.9 % compared with 48.1 % , P=.002 ) and carrying a Down syndrome-affected fetus ( 63.5 % compared with 15.1 % , P<.001 ) , were more satisfied with the intervention ( P<.001 ) , and had less decision uncertainty ( P<.001 ) than controls after viewing the intervention . Most of these differences persisted over time . Among women aged at least 35 years , the interactive prenatal testing decision tool viewers who were originally less inclined to undergo invasive testing were ultimately more likely than similarly inclined controls to have amniocentesis or chorionic villus sampling ( 44.8 % compared with 29.2 % ) , whereas those who were originally more inclined to undergo an invasive procedure ultimately were less likely than similarly inclined controls to have a diagnostic procedure ( 84.6 % compared with 94.9 % ; P=.015 for interaction ) . CONCLUSION : Using an interactive prenatal testing decision tool results in more informed prenatal genetic testing decisions than viewing st and ard educational booklets . CLINICAL TRIAL REGISTRATION : Clinical trials.gov , www . clinical trials.gov , NCT00686062 LEVEL OF EVIDENCE : Although tailored print material s ( TPMs ) have been assessed for a variety of behavioral targets , their effectiveness as decision aids for genetic testing had not been evaluated at the time this study began . We compared TPMs and non-tailored print material ( NPMs ) that included similar content about genetic testing for breast and ovarian cancer susceptibility . TPMs were prepared especially for an individual based on information from and about her . We mailed baseline surveys to 461 women referred by physicians or identified through a tumor registry . All had personal and family histories of breast and /or ovarian cancer and , on the basis of these histories , an estimated > or = 10 % probability of carrying a mutation in the breast/ovarian cancer genes BRCA1 or BRCA2 . The 325 ( 70 % ) who responded were r and omly assigned to receive TPM or NPM . Followup surveys , mailed 2 weeks following receipt of print material s , were returned by 262 women ( 81 % of baseline responders ) . Participants were predominately white ( 94 % ) and well-educated ( 50 % college graduates ) . The mean age was 49 years . At follow-up , TPM recipients exhibited significantly greater improvement in percent of correct responses for the 13-item true/false measure of knowledge ( 24 % increase for TPM vs. 16 % for NPM ; p < 0.0001 ) and significantly less over-estimation of risk of being a mutation carrier ( 40 % TPM group overestimated vs. 70 % NPM ; p < 0.0001 ) . Anxiety did not differ significantly between groups . Reactions to material s differed on two items : " seemed to be prepared just for me " ( 76 % TPM vs. 52 % NPM ; p < 0.001 ) and " told me what I wanted to know about BRCA1 and 2 testing " ( 98 % TPM vs. 91 % NPM ; p < 0.05 ) . TPMs showed an advantage in increasing knowledge and enhancing accuracy of perceived risk . Both are critical components of informed decision making OBJECTIVES To evaluate the impact of a decision aid for women considering genetic testing for breast/ovarian cancer risk given during genetic counseling . METHODS One hundred and forty-eight women were r and omized to receive the decision aid or a control pamphlet at the beginning of their first consultation with a genetic counselor . When the patient received the decision aid , it was used to complement consultation discussion s about genetic testing . One hundred and ten ( 74.3 % ) women completed the first question naire design ed to elicit information about women 's levels of decisional conflict and knowledge about genetic testing . Of these , 105 ( 70.9 % ) completed a second question naire to assess longer-term outcomes , 6 months postconsultation . RESULTS Results showed that women who received the decision aid felt more informed about genetic testing ( chi(2)(1)=8.69 ; P=0.003 ) , had clearer values ( chi(2)(1)=6.90 ; P=0.009 ) and had higher knowledge levels ( chi(2)(2)=6.49 ; P=0.039 ) than women who received the control pamphlet . CONCLUSIONS The developed decision aid improved patient outcomes better than a control pamphlet when implemented during genetic counseling and given to the patient to take home This study evaluated the long-term impact of genetic susceptibility biomarker feedback on smoking behavior change and symptoms of depression in 426 male and female smokers . Smokers were r and omized to one of three smoking-cessation interventions : minimal contact quit-smoking counseling ( QSC ) , QSC + exposure biomarker feedback ( EBF ) , and QSC + EBF + biomarker feedback about genetic susceptibility to lung cancer ( SBF ) . The logistic regression model for quit attempt revealed a significant main effect for treatment such that participants in the SBF group were more than two times more likely to make a quit attempt than participants in the QSC group . There was not a significant difference between EBF and QSC participants . The results also revealed a significant effect for baseline stage of change . Those smokers in the preparation stage at baseline were more than three times more likely to make a quit attempt over the 12 months following treatment . The models for 30-day cessation and follow-up smoking rate revealed no significant main or interacting effects for treatment . A repeated measures analysis of variance revealed a significant main effect for time , indicating that an initial increase in depression in the genetic susceptibility group was not maintained over time . Genetic susceptibility feedback has the intended effects on motivation to quit , but it may need to be delivered within a more intensive smoking-cessation treatment for the heightened motivation to translate into smoking cessation OBJECTIVE To evaluate the effects of an information film on making an informed choice regarding Down syndrome screening , and women 's knowledge and experiences of information . METHODS R and omized controlled trial including 184 women in the intervention group and 206 controls recruited from maternity units in Stockholm , Sweden . The intervention was an information film presented as a complement to written and verbal information . Data were collected via a question naire in gestational week 27 . Three different measures were combined to measure informed choice : attitudes towards Down syndrome screening , knowledge about Down syndrome and Down syndrome screening , and uptake of CUB ( combined ultrasound and biochemical screening ) . RESULTS In the intervention group 71.5 % made an informed choice versus 62.4 % in the control group . Women in the intervention group had significantly increased knowledge , and to a greater extent than the control group , experienced the information as being sufficient , comprehensible , and correct . CONCLUSIONS An information film tended to increase the number of women who made an informed choice about Down syndrome screening . Participants were more satisfied with the information received . PRACTICE IMPLICATION S Access to correct , nondirective , and sufficient information is essential when making a choice about prenatal diagnostics . It is essential with equivalent information to all women The objective of this study was to assess the effects of two brief training interventions to improve obstetricians ' and midwives ' explanations to patients of a routine prenatal screening test . Health professionals were r and omly allocated to one of two intervention groups or a control group . Information-giving about the test and communication skills were assessed at baseline , post-training and 3-month follow-up from audiotaped consultations . Both intervention groups received a 1-h training session involving small group discussion s focused around a video . In addition , one group received individual feedback on their baseline and post-training consultations . Twenty-six midwives and nine obstetricians completed the study according to the protocol . Changes between baseline and post-training , and between baseline and follow-up , were computed . Information-giving and communication skills improved significantly in subjects receiving training and feedback on their performance , with the greatest improvements occurring before feedback was given . Those receiving training without feedback significantly improved their communication skills and showed some improvement in information-giving . These results show that modest improvements in communication can be made with relatively brief training . Greater and more sustained improvements may be found if all staff were trained , and trained on a regular basis OBJECTIVE To study the effect of fast reporting by mobile phone short-message service ( SMS ) on anxiety levels in women undergoing prenatal biochemical screening for Down syndrome . METHOD From January 2005 to December 2006 , 2782 women undergoing prenatal biochemical serum screening were r and omized into fast reporting by SMS ( group A ) or without mobile phone reporting ( group B ) . Anxiety levels were measured with the Spielberger State-Trait Anxiety Inventory ( STAI ) before prenatal screen testing , before the appointed clinic ( when the SMS report had already been given to group A ) , and 3 days after the appointed clinic ( when the full screening report had been given to groups A and B ) . RESULTS For screen-negative women , anxiety scores did not differ between groups before prenatal screen testing and 3 days after the appointed clinic . The state-anxiety scores measured on the second occasion had declined significantly in group A. The state-anxiety scores in both groups increased over the 3-week period after being informed of positive screen results . The trait- and state-anxiety scores at all points did not differ between the two groups of screen-positive women . CONCLUSIONS The provision of a routine reporting system plus additional SMS report revealed some overall benefits in reducing anxiety among women with screen-negative result

In conclusion , the results suggest minor differences in the associations of BMI and the risk of cancer between the colorectal subsites . For physical activity , the association does not seem to differ between the colonic subsites , but a difference was observed between the colon and the rectum , perhaps indicating that different mechanisms are operating in the development of colon and rectal cancer

Several studies report varying incidence rates of cancer in subsites of the colorectum , as an increasing proportion appears to develop in the proximal colon . Varying incidence trends together with biological differences between the colorectal segments raise questions of whether lifestyle factors impact on the risk of cancer differently at colorectal subsites . We provide an up date d overview of the risk of cancer at different colorectal subsites ( proximal colon , distal colon , and rectum ) according to BMI and physical activity to shed light on this issue .

Background : Existing data suggest that physical activity reduces colon cancer risk , but the association is not consistently observed in women . One potential explanation for this inconsistency is that hormone therapy , which is associated with lower colon cancer risk , acts as a modifier of the physical activity/colon cancer relationship . Methods : Participants in the California Teachers Study ( N = 120,147 ) , a prospect i ve cohort of female teachers and administrators residing in California , ages 22 to 84 years at baseline and with no prior history of colon cancer were eligible for study . Between 1996 and 2002 , 395 patients were diagnosed with invasive colon cancer . The relative risks ( RR ) associated with lifetime ( high school through age 54 years or current age ) and recent ( past 3 years ) strenuous and moderate recreational physical activity were estimated using Cox proportional hazards regression models . Results : Combined lifetime moderate and strenuous recreational physical activity was only modestly associated with colon cancer risk in the cohort [ ≥4 versus ≤0.5 h/wk/y : RR , 0.75 ; 95 % confidence interval , 0.57 - 1.00 ; Ptrend = 0.23 ] . Lifetime physical activity reduced colon cancer risk among postmenopausal women who had never taken hormone therapy ( ≥4 versus ≤0.5 h/wk/y : RR , 0.51 ; 95 % confidence interval , 0.31 - 0.85 ; Ptrend = 0.02 ) . Postmenopausal women with histories of hormone therapy use had lower colon cancer risk , but their risk was not associated with physical activity . The likelihood ratio test for interaction between hormone use and lifetime moderate plus strenuous physical activity was of borderline statistical significance ( P = 0.05 ) . We observed no effect modification by age , body mass index , smoking status , menopausal status , or folate intake . Conclusions : Lifetime recreational physical activity may protect against colon cancer among postmenopausal women who have never used hormone therapy . Among hormone therapy users , who have lower risk of colon cancer , recreational physical activity does not seem to provide any additional benefit . With declining rates of hormone therapy use , physical activity offers one possible means for reducing women 's colon cancer risk . ( Cancer Epidemiol Biomarkers Prev 2007;16(3):517–25 Physical activity may reduce colon cancer risk , but the underlying mechanisms remain unclear . Relating physical activity to cancer risk in anatomic segments of the colon may advance our underst and ing of possible mechanisms . We conducted a prospect i ve study of 59,369 Norwegian men and women who were followed up for cancer incidence and mortality . Cox proportional hazards models were used to estimate multivariably adjusted hazard ratios ( HR ) and 95 % confidence intervals ( 95 % CI ) . All statistical tests were two sided . During 17 years of follow-up , 736 colon cancers and 294 rectal cancers were diagnosed . Overall , we found an inverse association between recreational physical activity and colon cancer risk , but subsite analyses showed that the association was confined to cancer in the transverse and sigmoid colon . The adjusted HR , comparing people who reported high versus no physical activity , was 0.44 ( 95 % CI , 0.25 - 0.78 ) for cancer in the transverse colon and 0.48 ( 95 % CI , 0.31 - 0.75 ) for cancer in the sigmoid colon . The corresponding HR for cancer mortality was 0.33 ( 95 % CI , 0.14 - 0.76 ) for the transverse colon and 0.29 ( 95 % CI , 0.15 - 0.56 ) for the sigmoid colon . For rectal cancer , there was no association with physical activity in these data . In conclusion , the inverse association of recreational physical activity with cancer risk and mortality in the transverse and sigmoid segments of the colon may point at increased colon motility and reduced fecal transit time as possible underlying mechanisms . ( Cancer Epidemiol Biomarkers Prev 2008;17(1):183–8 Studies of colon cancer risk in males have reported strong positive associations with obesity , particularly with central adiposity . The association has been weaker and less consistent for women . In a prospect i ve cohort study of women , body measurements were taken directly ; fat mass and fat‐free mass being estimated by bioelectrical impedance analysis and central adiposity by waist circumference and waist‐to‐hip ratio ( WHR ) . Among 24,072 women followed on average for 10.4 years , 212 colon cancers were ascertained via the population cancer registry . We review ed medical records of all cases and classified them according to anatomic site and stage . The central adiposity measures of WHR ( hazard ratio per 0.1 unit increase = 1.31 , 95 % confidence interval ( CI ) 1.08–1.58 ) and waist circumference ( hazard ratio per 10 cm increase = 1.14 , 95 % CI 1.02–1.28 ) were positively associated with colon cancer risk . There was little or no association between other anthropometric measures and risk of colon cancer . There was some evidence that the associations were stronger for proximal tumors , but no evidence that risk differed by stage for any of the anthropometric measures . Central adiposity appears to be associated with colon cancer risk in women . © 2005 Wiley‐Liss , Physical activity is protective against colon cancer , whereas colonic bile acid exposure is a suspected risk factor . Although likely related , the association between physical activity and bile acid levels has not been well-studied . Furthermore , the effect of triglycerides , which are known to modify bile acid levels , on this relationship has not been investigated . We conducted a cross-sectional analysis of baseline fecal bile acid levels for 735 colorectal adenoma formers obtained from participants in a phase III ursodeoxycholic acid chemoprevention trial . Compared with the lowest quartile of recreational physical activity duration , the highest quartile was associated with a 17 % lower fecal bile acid concentration , adjusted for age , sex , dietary fiber intake , and body mass index ( P = 0.042 ) . Furthermore , consistent with a previously established relationship between serum triglyceride levels and bile acid metabolism , we stratified by triglyceride level and observed a 34 % lower fecal bile acid concentration ( highest versus lowest quartiles of physical activity ) in individuals with low triglycerides ( < 136 mg/dL ; P = 0.002 ) . In contrast , no association between physical activity and fecal bile acid concentration was observed for subjects with high triglycerides ( ≥136 mg/dL ) . Our results suggest that the biological mechanism responsible for the protective effect of physical activity on the incidence of colon cancer may be partially mediated by decreasing colonic bile acid exposure . However , this effect may be limited to individuals with lower triglyceride levels . ( Cancer Epidemiol Biomarkers Prev 2009;18(5):1591–8 BACKGROUND Several studies of male colon cancer have found positive associations with body size and composition . It is uncertain whether this relationship is due to non-adipose mass , adipose mass , distribution of adipose mass such as central adiposity , or all three . METHODS In a prospect i ve cohort study of men aged 27 - 75 at recruitment in 1990 - 1994 , body measurements were taken by interviewers . Fat mass and fat-free mass ( FFM ) were estimated from bioelectrical impedance analysis . Waist circumference and waist-to-hips ratio ( WHR ) estimated central adiposity . Incident colon cancers were ascertained via the population cancer registry . Altogether , 16,556 men contributed 145,433 person-years and 153 colon cancers . RESULTS Rate ratios ( RRs ) comparing men in the fourth quartile with those in the first quartile were as follows : FFM 2.3 [ 95 % confidence interval ( CI ) 1.4 - 3.7 ] ; height 1.9 ( 95 % CI 1.1 - 3.1 ) ; waist circumference 2.1 ( 95 % CI 1.3 - 3.5 ) ; WHR 2.1 ( 95 % CI 1.3 - 3.4 ) ; fat mass 1.8 ( 95 % CI 1.1 - 3.0 ) ; and body mass index 1.7 ( 95 % CI 1.1 - 2.8 ) . When continuous measures of FFM and WHR were modeled together , the RR for FFM per 10 kg was 1.37 ( 95 % CI 1.04 - 1.80 ) and the RR for WHR per 0.1 unit was 1.65 ( 95 % CI 1.28 - 2.13 ) . After adjustment for FFM and WHR , the RRs for fat mass and body mass index were no longer statistically significant . CONCLUSION Male colon cancer appears to be related to body size and composition by two different pathways , via central adiposity and via non-adipose mass Objective To prospect ively examine the association between physical activity and the risk of developing colorectal cancer in a large population -based cohort study of Japanese men and women , and to investigate whether the effects of physical activity on colorectal cancer risk differ by sex and subsite . Methods We analyzed data from a population -based cohort of 65,022 subjects . A total of 486 incident colorectal cancers ( 154 proximal colon , 166 distal colon and 149 rectal cancers ) was identified during 6 years of follow-up . Results We observed a significant inverse association between physical activity and the risk of developing colorectal cancer , particularly colon cancer , among men . Relative to men in the lowest level of metabolic equivalent ( MET ) hours per day , those in the highest level had a RR of 0.69 ( 95 % CI = 0.49–0.97 ) . A significant decrease in risk of colorectal cancer was associated with increasing MET hours per day among men . This inverse association was essentially limited to colon cancer . A significant decrease in risk with increasing MET-hour score was observed predominantly for proximal colon cancer among men . In contrast , no significant decrease was seen among women . Conclusion These findings suggest that physical activity may prevent colon cancer among Japanese men Abstract Objective : Epidemiologic data relating obesity to risk of colorectal cancer in women have been inconclusive . Two recent studies have suggested that the association may be modified by estrogen status ; BMI was positively associated with colorectal cancer risk among women with high estrogen exposures [ premenopausal women , and postmenopausal women who currently received postmenopausal hormone therapy ( PMH ) ] . We prospect ively investigated the role of BMI in colorectal cancer risk along with the modifying effects of estrogen in a large cohort from the Women 's Health Study . Methods : Among 39,876 apparently healthy women aged ≥45 years at baseline ( 54 % of them were postmenopausal ) , 37,671 were eligible for the present study . During an average of 8.7 years of follow-up , 202 women had a confirmed diagnosis of colorectal cancer . Baseline BMI was calculated by dividing self-reported weight in kilograms by height in meters squared . Results : The multivariate relative risks ( RRs ) and 95 % confidence interval ( CI ) of colorectal cancer were 1.72 ( 1.12–2.66 ) for 27–29.9 kg/m2 , and 1.67 ( 1.08–2.59 ) for ≥30 kg/m2 , as compared with BMI < 23 kg/m2(p for trend = 0.02 ) . This positive association was seen primarily in the proximal colon ( p for trend = 0.004 ) . When the association was further examined according to PMH use among postmenopausal women , we found that both current and never users with higher BMI were at a greater risk of colorectal cancer ( p for interaction between BMI and PMH use = 0.33 ) . As compared with BMI < 23 kg/m2 , the multivariate RRs and 95 % CI for 27–29.9 and ≥30 kg/m2 were 1.98 ( 0.98–3.99 ) and 1.41 ( 0.65–3.06 ) among current users , and 1.05 ( 0.42–2.65 ) and 2.91 ( 1.40–6.06 ) among never users . Conclusions : These data suggest that higher BMI was associated with an elevated risk of colorectal cancer , and the positive relationship was not altered by estrogen exposure among postmenopausal women Anthropometric factors have been associated with colorectal cancer and adenomas but with conflicting results in women or regarding adenoma characteristics . The authors aim ed to explore associations between anthropometric factors ( height , weight , body mass index , waist and hip circumferences , and weight changes ) and adenoma risk . They analyzed the 17,391 women of the French Etude épidémiologique des femmes de la Mutuelle Générale de l'Education Nationale (E3N)-European Prospect i ve Investigation into Cancer and Nutrition ( EPIC ) cohort who underwent a colonoscopy during follow-up ( 1993 - 2002 ) , including 1,408 who developed a first colorectal adenoma . In Cox multivariate proportional hazard regression models , obesity was associated with an increased colorectal adenoma risk ( hazard ratio = 1.53 , 95 % confidence interval : 1.21 , 1.94 ) . This association was restricted to left colon adenomas ( P(homogeneity ) = 0.05 and 0.01 for colon vs. rectum and right vs. left colon , respectively ) , with a dose-effect relation observed from 22 kg/m² . A high waist circumference was also associated with left colon adenoma risk ( hazard ratio = 1.81 , 95 % confidence interval : 1.36 , 2.41 ) . Mean weight gain over 0.5 kg/year was associated with a 23 % increased colorectal adenoma risk . Associations did not differ between advanced and nonadvanced adenomas . In conclusion , study findings suggest that obesity and weight gain are associated with early colorectal carcinogenesis in women , and specifically regarding the distal colon Objective To examine the relation between body mass index ( kg/m2 ) and cancer incidence and mortality . Design Prospect i ve cohort study . Participants 1.2 million UK women recruited into the Million Women Study , aged 50 - 64 during 1996 - 2001 , and followed up , on average , for 5.4 years for cancer incidence and 7.0 years for cancer mortality . Main outcome measures Relative risks of incidence and mortality for all cancers , and for 17 specific types of cancer , according to body mass index , adjusted for age , geographical region , socioeconomic status , age at first birth , parity , smoking status , alcohol intake , physical activity , years since menopause , and use of hormone replacement therapy . Results 45 037 incident cancers and 17 203 deaths from cancer occurred over the follow-up period . Increasing body mass index was associated with an increased incidence of endometrial cancer ( trend in relative risk per 10 units=2.89 , 95 % confidence interval 2.62 to 3.18 ) , adenocarcinoma of the oesophagus ( 2.38 , 1.59 to 3.56 ) , kidney cancer ( 1.53 , 1.27 to 1.84 ) , leukaemia ( 1.50 , 1.23 to 1.83 ) , multiple myeloma ( 1.31 , 1.04 to 1.65 ) , pancreatic cancer ( 1.24 , 1.03 to 1.48 ) , non-Hodgkin 's lymphoma ( 1.17 , 1.03 to 1.34 ) , ovarian cancer ( 1.14 , 1.03 to 1.27 ) , all cancers combined ( 1.12 , 1.09 to 1.14 ) , breast cancer in postmenopausal women ( 1.40 , 1.31 to 1.49 ) and colorectal cancer in premenopausal women ( 1.61 , 1.05 to 2.48 ) . In general , the relation between body mass index and mortality was similar to that for incidence . For colorectal cancer , malignant melanoma , breast cancer , and endometrial cancer , the effect of body mass index on risk differed significantly according to menopausal status . Conclusions Increasing body mass index is associated with a significant increase in the risk of cancer for 10 out of 17 specific types examined . Among postmenopausal women in the UK , 5 % of all cancers ( about 6000 annually ) are attributable to being overweight or obese . For endometrial cancer and adenocarcinoma of the oesophagus , body mass index represents a major modifiable risk factor ; about half of all cases in postmenopausal women are attributable to overweight or obesity The relation between relative body weight and colorectal cancer among women is unclear . In a large prospect i ve cohort study , we found a positive association only for distal cancers among younger women that became attenuated at older ages . These results support previous reports in which results were stratified by age or colorectal cancer site . © 2001 Cancer Research We investigated several aspects of the role of physical activity in colon and rectal cancer etiology that remain unclear in the European Prospect i ve Investigation into Nutrition and Cancer . This cohort of 413,044 men and women had 1,094 cases of colon and 599 cases of rectal cancer diagnosed during an average of 6.4 years of follow-up . We analyzed baseline data on occupational , household , and recreational activity to examine associations by type of activity , tumor subsite , body mass index ( BMI ) , and energy intake . The multivariate hazard ratio for colon cancer was 0.78 [ 95 % confidence interval ( 95 % CI ) , 0.59 - 1.03 ] among the most active participants when compared with the inactive , with evidence of a dose-response effect ( Ptrend = 0.04 ) . For right-sided colon tumors , the risk was 0.65 ( 95 % CI , 0.43 - 1.00 ) in the highest quartile of activity with evidence of a linear trend ( Ptrend = 0.004 ) . Active participants with a BMI under 25 had a risk of 0.63 ( 95 % CI , 0.39 - 1.01 ) for colon cancer compared with the inactive . Finally , an interaction between BMI and activity ( Pinteraction = 0.03 ) was observed for right-sided colon cancers ; among moderately active and active participants with a BMI under 25 , a risk of 0.38 ( 95 % CI , 0.21 - 0.68 ) was found as compared with inactive participants with BMI > 30 . No comparable decreased risks were observed for rectal cancer for any type of physical activity for any subgroup analyses or interactions considered . We found that physical activity reduced colon cancer risk , specifically for right-sided tumors and for lean participants , but not rectal cancer . ( Cancer Epidemiol Biomarkers Prev 2006;15(12):2398–407 BACKGROUND Physical inactivity and high body mass index ( weight in kilograms divided by height in square meters ) have been linked to increased risk of colon cancer . However , none of the few prospect i ve studies in women has shown a statistically significant reduction in colon cancer incidence or mortality associated with increased leisure-time physical activity . PURPOSE In this prospect i ve study , we asked whether leisure-time physical activity , body mass index , or body fat distribution could significantly influence the risk of colon cancer in women . METHODS The participants in this study were enrolled in the Nurses ' Health Study , which began in 1976 . Every 2 years , the women provided additional personal information and information on medical risk factors and major medical events . The time spent per week at a variety of leisure-time physical activities was determined , and the time spent at each activity was multiplied by its typical energy expenditure , expressed in terms of metabolic equivalents or METs . The result ing values for each woman were added to yield an MET-hours-per-week score . Reported diagnoses of colon cancer were confirmed by review of hospital records and pathology reports . Relative risks and associated 95 % confidence intervals were calculated . RESULTS In multivariate analyses that included body mass index , women who expended more than 21 MET-hours per week on leisure-time physical activity had a relative risk of colon cancer of 0.54 ( 95 % confidence interval [ CI ] = 0.33 - 0.90 ) in comparison with women who expended less than 2 MET-hours per week . Women who had a body mass index greater than 29 kg/m2 had a relative risk of colon cancer of 1.45 ( 95 % CI = 1.02 - 2.07 ) in comparison with women who had a body mass index less than 21 kg/m2 . A tendency toward higher colon cancer risk was observed for increasing waist-to-hip ratio ( relative risk = 1.48 [ 95 % CI = 0.88 - 2.49 ] for comparison of the highest quintile ratio [ > 0.833 ] to the lowest [ < 0.728 ] ) . CONCLUSIONS AND IMPLICATION S The significant inverse association between leisure-time physical activity and incidence of colon cancer in women in this study is consistent with what has been found in men . Recommendations to increase physical activity and maintain lean body weight should receive greater emphasis as part of a feasible approach to the prevention of colon cancer Westernization or industrialization leads to an increase in rates of colon cancer , which is the second leading cause of malignant death in the United States [ 1 ] . Although the precise causes of colon cancer remain unclear , a diet high in red meat or animal fat and low in fruits and vegetables appears to increase the risk for this malignancy [ 2 , 3 ] . It is perhaps less well recognized that an inverse association between physical activity and risk for colon cancer has been seen in studies of occupational activity only [ 4 - 12 ] and of both job-related and recreational activity [ 13 - 23 ] . In addition , many studies have found an association between body mass and elevated risk for colon cancer in men ; this association is weaker in women [ 24 - 33 ] . The fact that the association is stronger in men suggests that the abdominal distribution of adiposity typical in men may be an important component of enhanced risk . More limited evidence suggests that height , which may be a proxy for a person 's net energy intake during childhood and adolescence , is related to a higher risk for colon cancer [ 33 - 35 ] . We examine the association between physical activity , obesity , and attained height in relation to risk for colon cancers and their precursory adenomas in a large cohort of male health professionals in the United States . Waist and hip circumferences were available for a subcohort of the study population . We address the hypotheses that physical inactivity , obesity , and height increase the risk for colon cancer and adenoma independently of each other and of diet , and that the abdominal pattern of obesity is an additional independent risk factor . Methods Study Population The Health Professionals Follow-up Study [ 36 ] was started in 1986 ; in that year , 51 529 male dentists , optometrists , osteopaths , podiatrists , pharmacists , and veterinarians in the United States between 40 and 75 years of age responded to a mailed question naire . They reported on their leisure-time physical activity ( described below ) ; current body weight ; weight at age 21 years ; height ; history of cancer and other medical conditions ; parental history of various diseases , including colorectal cancer ; and use of aspirin and other nonsteroidal anti-inflammatory medications . They also reported dietary and alcohol intake using a vali date d [ 37 , 38 ] , semi-quantitative food-frequency question naire . We mailed an optional question naire in 1987 to assess waist and hip circumferences . In 1988 , 1990 , and 1992 , we up date d exposure information and ascertained newly diagnosed medical conditions and history of colonoscopy or sigmoidoscopy , including the indications for endoscopy : bleeding in stool , positive results from tests for occult fecal blood , abdominal pain , diarrhea or constipation , family history of colorectal cancer , routine screening without symptoms , or follow-up [ 39 ] . Most of the deaths in the cohort were reported by family members or by the postal system in response to the follow-up question naires . We also used the National Death Index to identify deaths among nonrespondents [ 40 ] . Assessment of Physical Activity The 1986 question naire included a section about mainly recreational or leisure-time physical activity . The reliability and validity of question naires design ed to assess physical activity have been investigated [ 41 - 43 ] . A question naire such as the one used in our cohort was evaluated in a cohort of U.S. nurses and was found to provide useful information [ 44 ] , and similar results were found during a similar validation study done within the Health Professionals cohort ( Chasan-Taber S. Personal communication ) . Participants reported the average time per week spent doing each of eight moderate and vigorous activities , choosing from among 10 possible responses that ranged from 0 minutes to 11 or more hours per week . The specific activities listed were walking or hiking outdoors ( including walking during golf ) ; jogging ( slower than 10 minutes/mile ) ; running ( 10 minutes/mile or faster ) ; bicycling ( including that done on a stationary machine ) ; lap swimming ; tennis , squash , or racquetball ; and calisthenics or rowing . In addition , each respondent reported the number of flights of stairs he climbed daily and his usual walking pace . The reported time spent at each activity per week was multiplied by its typical energy expenditure requirements expressed in metabolic equivalents ( METs ) [ 45 ] to yield a MET-hour score . One MET , which is the energy expended by sitting quietly , is equivalent to 3.5 mL of oxygen uptake per kilogram of body weight per minute for a 70-kg adult . For example , 1 hour per week of running contributed 10.2 MET-hours , 1 hour of tennis contributed 6 MET-hours , and 1 hour of walking at a moderate pace contributed 3.2 MET-hours . Body weight was excluded from the derivation of energy expenditure from physical activity to avoid confounding the expenditure variable by body weight . If more than one published intensity level was available for a given activity , the moderate or general MET value was chosen . An average MET value was assigned to the categories that listed more than one activity , such as rowing or calisthenics , and squash or racquetball . Assessment of Anthropometric Variables Each man reported his current weight and height and his weight at age 21 years on the 1986 question naire . In 1987 , we mailed an optional question naire once to obtain additional exposure information , including body circumference measurements . We instructed each participant to measure ( to the nearest quarter inch ) his waist at the umbilicus and his hips at the largest circumference between the waist and thighs while st and ing and without measuring over bulky clothing [ 46 ] . We provided a tape measure and an illustration to help st and ardize the measurements . Sixty-five percent of the cohort responded . We used the Quetelet index ( kilograms/height in meters2 ) as a measure of total adiposity , waist-to-hip ratio to measure relative distribution of fat , and waist circumference to estimate total abdominal fat . Although the waist-to-hip ratio has been used more widely , waist circumference provides an estimate of absolute abdominal adiposity , the component most closely related to important metabolic abnormalities , including hyperinsulinemia , hypertension , and high triglyceride levels . To remove extraneous variation in the waist circumference because of height ( taller men tend to have larger waist circumferences due to their larger body size rather than to obesity ) , we adjusted waist for height using residual analysis [ 47 ] . We first regressed waist on height using multiple linear regression and then added the residual to the average waist size ( 37.4 inches ) for a man of average height ( 70 inches ) to convert this measure back to the initial scale . This conversion created for each man a st and ardized waist circumference unconfounded by height . We evaluated the precision of self-reported anthropometric measures among 123 cohort members who were part of a dietary validation study [ 46 ] . Trained technicians paid the sub study participants two visits , approximately 6 months apart , to measure current weight and waist and hip circumferences . The Pearson correlation between self-report and the average of the technicians ' two measurements was 0.97 for weight , 0.95 for waist circumference , 0.88 for hip circumference , and 0.69 for waist-to-hip ratio . The men 's self- measurements of their waist circumferences were 0.36 inches greater , their self- measurements of hip circumferences were 0.78 inches smaller , and their self- measurements of weight were 2.3 pounds less than the technician 's measurements . Identification of Patients with Colorectal Cancers In 1988 , 1990 , and 1992 , we asked each participant whether cancer had been diagnosed during the previous 2 years . The response rate to the follow-up question naires was 94 % through 31 January 1992 . When a participant ( or a decedent 's next-of-kin ) reported a diagnosis of cancer of the colon or rectum , we sought permission to obtain hospital records and pathology reports . A study physician , blinded to exposure information , review ed all medical records received and extracted data about histologic type , anatomic location , and stage of the cancer . Proximal colon cancers were defined as those from the cecum to and including the splenic flexure , and distal colon cancers were defined as those in the descending and sigmoid colon . We confirmed 249 new cases of colorectal adenocarcinoma ( excluding carcinoma in situ ) , 90 % by medical records and the remainder with corroborating information about diagnosis and treatment from the cohort member . Two hundred three cancers were in the colon and 46 were in the rectum . Identification of Patients with Colorectal Adenomas and Controls Because more than 90 % of the adenomas were diagnosed during endoscopic procedures for screening or for unrelated gastrointestinal conditions , we restricted the adenoma analysis to men who had had a colonoscopy or sigmoidoscopy . This was done to reduce the potential for detection bias . Most procedures were sigmoidoscopies ; thus , we analyzed only adenomas of the distal colorectum . Although we did not examine proximal colon adenomas , this should not have biased inferences for the distal colorectum . However , different causes for proximal adenomas may exist . A total of 12 879 men who did not meet any of the exclusion criteria ( see Data Analysis ) reported having had an endoscopy between 1986 and 1992 . In 1993 , we sent a mailing to a r and om sample of 200 controls ( men who reported negative results from an endoscopy ) to confirm that they did not have adenomas . After one mailing , 140 ( 70 % ) controls granted us permission to review the medical records of their endoscopic procedure ; none had an unreported , histologically confirmed adenoma . We were able to recontact 96 % of the men who reported a diagnosis of polyp , and we received medical records in response to more than 96 % of the requests sent to medical record departments , Obesity is a controversial risk factor for colorectal cancer ( CRC ) in older women . We evaluated associations between multiple body size parameters and incident CRC in the prospect i ve , population -based Iowa Women 's Health Study ( IWHS ) . IWHS participants , ages 55 to 69 years , provided data regarding height ; weight ; weight at ages 50 , 40 , 30 , 18 years ; hip circumference ; and waist circumference at baseline ( 1986 ) . Derived variables included body mass index ( BMI ) , waist-to-hip ratio ( WHR ) , and “ overweight years ” ( OWY ; conceptually similar to cigarette pack-years ) . Incident CRC cases ( n = 1,464 ) were ascertained from the State Health Registry of Iowa , through 2005 . Multivariable Cox regression models were fit to estimate body size – associated CRC risks . Among 36,941 women ( 619,961 person-years ) , baseline height , weight , BMI , hip circumference , waist circumference , and WHR were all positively associated with incident CRC ( P trend ≤ 0.003 for each ) . Baseline BMI yielded the highest CRC risk estimates ( obese III versus normal , RR = 1.56 ; 95 % CI = 1.10–2.22 ; P trend < 0.001 ) and was more closely associated with distal than proximal tumors ( P trend < 0.001 versus 0.06 ) . Conversely , height was more closely associated with proximal than distal tumors ( P trend < 0.001 versus 0.04 ) . Other body size parameters were less predictive of incident CRC . These data strongly support a positive association between increased body size and CRC risk among older women . Further investigation of when increased body size has the greatest effect on CRC risk ( i.e. , early adulthood versus later adulthood ) might also be informative , particularly with respect to defining subsite-specific pathways of colorectal carcinogenesis . Cancer Prev Res ; 3(12 ) ; 1608–20 . © 2010 AACR Objective In order to prospect ively investigate physical activity at varying intensities and sedentary behavior in relation to colorectal cancer . Methods We considered 488,720 participants of the NIH-AARP Diet and Health Study who were aged 50–71 years at baseline in 1995–1996 . Through 31 December , 2003 , we identified 3,240 and 1,482 colorectal cancers among men and women , respectively . We estimated multivariable relative risks ( RR ) and 95 % confidence intervals ( CI ) of colorectal cancer using Cox regression . Results Engaging in exercise/sports five or more times per week compared to never or rarely exercising was associated with a reduced risk of colon cancer among men ( p = 0.001 ; RR = 0.79 , 95 % CI = 0.68–0.91 ) and a suggestive decrease in risk among women ( p = 0.376 ; RR = 0.85 , 95 % CI = 0.70–1.04 ) . Engaging in exercise/sports was also associated with a decreased risk of rectal cancer in men ( P = 0.074 ; RR comparing extreme categories = 0.76 , 95 % CI = 0.61–0.94 ) . In men , we observed inverse relations of both low intensity ( p = 0.017 ; RR = 0.81 , 95 % CI = 0.65–1.00 for ≥7 h/week ) and moderate to vigorous intensity activity ( p = 0.037 ; RR = 0.82 , 95 % CI = 0.67–0.99 for ≥7 h/week ) to colon cancer risk . In contrast , sedentary behavior ( time spent watching television/videos ) was positively associated with colon cancer ( p < 0.001 ; RR = 1.61 , 95 % CI = 1.14–2.27 for ≥9 h/day ) among men . Similar , but less pronounced relations were observed in women . Conclusion Engaging in physical activity of any intensity is associated with reductions in colon and rectal cancer risk . Conversely , time spent sedentary is associated with increased colon cancer risk Background Although body mass index has been shown to be associated with colon cancer , studies of rectal cancer risk have generally reported no association . The relationship between rectal cancer risk and central adiposity , overall fat mass , and fat-free mass is unknown . Methods In a prospect i ve cohort study of people aged 27–75 years , body measurements were taken directly ; fat mass and fat-free mass being estimated by bioelectrical impedance analysis and central adiposity by waist circumference and waist-to-hip ratio . Among 16,867 men and 24,247 women followed on average for 10.3 years , 229 rectal cancers were ascertained via the population cancer registry . Results When comparing the highest tertile with the lowest tertile , weight ( hazard ratio = 1.4 , 95 % confidence interval ( CI ) 1.1–2.0 ) , waist circumference ( hazard ratio = 1.4 , 95 % CI 1.0–1.9 ) , fat mass ( hazard ratio = 1.4 , 95 % CI 1.0–2.0 ) and percent fat ( hazard ratio = 1.4 , 95 % CI 1.0–2.0 ) were positively associated with rectal cancer risk . There was no evidence that risk differed by sex for any of the anthropometric measures . Conclusions Waist circumference and fat mass may be weakly related to risk of rectal cancer Predictors of colorectal cancer have been extensively studied with some evidence suggesting that risk factors vary by subsite . Using data from 2 prospect i ve cohort studies , we examined established risk factors to determine whether they were differentially associated with colon and rectal cancer . Our study population included 87,733 women from the Nurses ' Health Study ( NHS ) and 46,632 men from the Health Professionals Follow Up Study ( HPFS ) . Exposure information was collected via biennial question naires ( dietary variables were collected every 4 years ) . During the follow-up period ( NHS : 1980 to May 31 , 2000 ; HPFS : 1986 to January 31 , 2000 ) , we identified 1,139 cases of colon cancer and 339 cases of rectal cancer . We used pooled logistic regression to estimate multivariate relative risks for the 2 outcomes separately and then used polytomous logistic regression to compare these estimates . In the combined cohort , age , gender , family history of colon or rectal cancer , height , body mass index , physical activity , folate , intake of beef , pork or lamb as a main dish , intake of processed meat and alcohol were significantly associated with colon cancer risk . However , only age and sex were associated with rectal cancer . In a stepwise polytomous logistic regression procedure , family history and physical activity were associated with statistically significant different relative risks of colon and rectal cancer . Our findings support previous suggestions that family history and physical activity are not strong contributors to the etiology of rectal cancer . Future investigations of colon or rectal cancer should take into consideration risk factor differences by subsite Objective To investigate the association of body mass index ( BMI ) or body height with colorectal cancer incidence in a population -based prospect i ve study . Methods We identified 986 ( 626 men and 360 women ) newly diagnosed cases of colorectal cancer during the 9.4-year follow-up of a cohort consisting of 102,949 ( 49,158 male and 53,791 female ) middle-aged and elderly Japanese . Results Lower BMI groups ( lower than 23 ) were not associated with colorectal cancer compared with the 23–24.9 BMI group . Any categories of 25–26.9 , 27–29.9 , or 30 or more BMI were associated with an increased risk of colorectal cancer compared with the lower than 25 BMI ( RR , 1.2 for 25–26.9 , 1.4 for 27–29.9 , and 1.5 for 30 or more ; p for trend , 0.004 ) in men . These associations were more evident only in invasive-type cancer analysis . BMI was not associated with the risk of colorectal cancer in women . No significant association with height was obtained for either men or women . Conclusions The association of BMI with colorectal cancer was confirmed in a Japanese population as well as Western population s. Only invasive-cancer analysis suggested that BMI was important for tumor growth and proliferation . Approximately 6.7 % of colorectal cancer was attributable to a BMI of 25 or higher in middle-aged and elderly Japanese men Background : Several large studies of obesity and colorectal cancer risk have found no association among women but a reasonably consistent positive association among men . In women , a positive association that is stronger among , or limited to , those who are premenopausal has been suggested by studies that stratified analyses by age , although no previous study has examined the association by menopausal status . Methods : We used proportional hazards analyses to estimate hazard ratios relating obesity to colorectal cancer risk among 89 835 women aged 40–59 years at recruitment into the Canadian National Breast Screening Study , a multicentre r and omised controlled trial of mammography screening for breast cancer . During an average 10.6 years of follow up ( 936 433 person years ) , a total of 527 women were diagnosed with incident colorectal cancer ( 363 colon and 164 rectal ) . Results : We found that obesity ( body mass index ≥30 kg/m2 ) was associated with an approximately twofold increased risk of colorectal cancer among women who were premenopausal at baseline ( hazard ratio 1.88 , 95 % confidence interval 1.24–2.86 ) . There was no association among postmenopausal women ( p for interaction=0.01 ) , and there was only a weak positive association in the entire cohort . Conclusions : Our data suggest that obesity is associated with a twofold increased risk of colorectal cancer in premenopausal women but is not associated with altered risk in postmenopausal women . Effect modification by menopausal status may better explain the inconsistent or weak findings in previous studies than the presumed lack of an association among women We conducted a population -based prospect i ve cohort study in Japan to examine the relationship between body mass index ( BMI ) and the risk of incidence of any cancer and of cancer at individual sites . Body mass index was calculated from self-administered body weight and height at baseline . Relative risks ( RR ) and 95 % confidence intervals ( CI ) were calculated in multivariate proportional-hazards models . Among 27,539 persons ( 15,054 women and 12,485 men ) aged 40 years or older who were free of cancer at enrollment in 1984 , 1,672 ( 668 women and 1,004 men ) developed cancer during 9 years of follow-up . In women , after adjustment for potential confounders , the RR of all cancers associated with different BMI , relative to a BMI of 18.5 - 24.9 , were 1.04 ( 95 % CI = 0.85 - 1.27 ) for BMI = 25.0 - 27.4 , 1.29 ( 1.00 - 1.68 ) for BMI = 27.5 - 29.9 and 1.47 ( 1.06 - 2.05 ) for BMI > /=30.0 ( p for trend = 0.007 ) . Higher BMI was also significantly associated with higher risk of cancers of the colorectum , breast ( postmenopausal ) , endometrium and gallbladder in women . In men , we observed significantly increased all-cancer risk among only never-smokers . Overweight and obesity could account for 4.5 % ( all subjects ) or 6.2 % ( never-smokers ) of the risk of any cancer in women and -0.2 % ( all subjects ) or 3.7 % ( never-smokers ) in men . The value for women was within the range among women reported from Western population s ( 3.2%-8.8 % ) . Our data demonstrate that excess weight is a major cancer risk among Japanese women BACKGROUND Body weight and body mass index ( BMI ) are positively related to risk of colon cancer in men , whereas weak or no associations exist in women . This discrepancy may be related to differences in fat distribution between sexes or to the use of hormone replacement therapy ( HRT ) in women . METHODS We used multivariable adjusted Cox proportional hazards models to examine the association between anthropometric measures and risks of colon and rectal cancer among 368 277 men and women who were free of cancer at baseline from nine countries of the European Prospect i ve Investigation Into Cancer and Nutrition . All statistical tests were two-sided . RESULTS During 6.1 years of follow-up , we identified 984 and 586 patients with colon and rectal cancer , respectively . Body weight and BMI were statistically significantly associated with colon cancer risk in men ( highest versus lowest quintile of BMI , relative risk [ RR ] = 1.55 , 95 % confidence interval [ CI ] = 1.12 to 2.15 ; P(trend ) = .006 ) but not in women . In contrast , comparisons of the highest to the lowest quintile showed that several anthropometric measures , including waist circumference ( men , RR = 1.39 , 95 % CI = 1.01 to 1.93 ; P(trend ) = .001 ; women , RR = 1.48 , 95 % CI = 1.08 to 2.03 ; P(trend ) = .008 ) , waist-to-hip ratio ( WHR ; men , RR = 1.51 , 95 % CI = 1.06 to 2.15 ; P(trend ) = .006 ; women , RR = 1.52 , 95 % CI = 1.12 to 2.05 ; P(trend ) = .002 ) , and height ( men , RR = 1.40 , 95 % CI = 0.99 to 1.98 ; P(trend ) = .04 ; women , RR = 1.79 , 95 % CI = 1.30 to 2.46 ; P(trend)<.001 ) were related to colon cancer risk in both sexes . The estimated absolute risk of developing colon cancer within 5 years was 203 and 131 cases per 100,000 men and 129 and 86 cases per 100,000 women in the highest and lowest quintiles of WHR , respectively . Upon further stratification , no association of waist circumference and WHR with risk of colon cancer was observed among postmenopausal women who used HRT . None of the anthropometric measures was statistically significantly related to rectal cancer . CONCLUSIONS Waist circumference and WHR , indicators of abdominal obesity , were strongly associated with colon cancer risk in men and women in this population . The association of abdominal obesity with colon cancer risk may vary depending on HRT use in postmenopausal women ; however , these findings require confirmation in future studies

Regarding the repolarization changes on the ECG NSTEMI shows similarities with other clinical symptoms where increased intramyocardial microvascular resistance can be supposed without coronary artery disease : false positive exercise stress test , supraventricular tachycardia , left ventricular strain and conduction disturbances . CONCLUSION The acute treatment of NSTEMI should aim to improve the blood inflow to the stiff myocardium and /or impaired microvascular system and decrease the high microvascular resistance

UNLABELLED Non-ST elevation myocardial infa rct ion ( NSTEMI ) and ST elevation infa rct ion have many differences in their appearance and prognosis . A comprehensive search made us form a new hypothesis that a further cause also existsin NSTEMI : an acute , critical increase in the already existing high microvascular resistance in addition to the subtotal coronary artery occlusion . Various findings and studies can be interpreted only by our hypothesis : hemodynamic findings , ECG changes , autopsy reports and clinical observations ( different long-time prognosis and different result of acute revascularization therapy in NSTEMI , similarities of NSTEMI with other clinical symptoms where increased microvascular resistance can be supposed without coronary artery disease ) . OBJECTIVE Despite similarities in the underlying pathologic mechanism non-ST elevation myocardial infa rct ion(NSTEMI ) and ST elevation infa rct ion ( STEMI ) have many differences in their clinical presentation and prognosis . METHOD A systematic review of the literature about NSTEMI and the blood supply of the myocardium made us form a hypothesis that a further cause also exists in addition to the accepted cause of NSTEMI ( subtotal coronaryartery occlusion ) : an acute , critical increase in an already existing high intramyocardial microvascular resistance . EVIDENCE Knowledge about microcirculation disturbances in ischemic heart disease and development of microcirculation damage can be fitted in our hypothesis .

CONTEXT The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease ( CAD ) and normal blood pressure remains uncertain . OBJECTIVE To compare the effects of amlodipine or enalapril vs placebo on cardiovascular events in patients with CAD . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , multicenter , 24-month trial ( enrollment April 1999-April 2002 ) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD ( > 20 % stenosis by coronary angiography ) and diastolic blood pressure < 100 mm Hg . A sub study of 274 patients measured atherosclerosis progression by intravascular ultrasound ( IVUS ) . INTERVENTIONS Patients were r and omized to receive amlodipine , 10 mg ; enalapril , 20 mg ; or placebo . IVUS was performed at baseline and study completion . MAIN OUTCOME MEASURES The primary efficacy parameter was incidence of cardiovascular events for amlodipine vs placebo . Other outcomes included comparisons of amlodipine vs enalapril and enalapril vs placebo . Events included cardiovascular death , nonfatal myocardial infa rct ion , resuscitated cardiac arrest , coronary revascularization , hospitalization for angina pectoris , hospitalization for congestive heart failure , fatal or nonfatal stroke or transient ischemic attack , and new diagnosis of peripheral vascular disease . The IVUS end point was change in percent atheroma volume . RESULTS Baseline blood pressure averaged 129/78 mm Hg for all patients ; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups , respectively ( P<.001 for both vs placebo ) . Cardiovascular events occurred in 151 ( 23.1 % ) placebo-treated patients , in 110 ( 16.6 % ) amlodipine-treated patients ( hazard ratio [ HR ] , 0.69 ; 95 % CI , 0.54 - 0.88 [ P = .003 ] ) , and in 136 ( 20.2 % ) enalapril-treated patients ( HR , 0.85 ; 95 % CI , 0.67 - 1.07 [ P = .16 ] . Primary end point comparison for enalapril vs amlodipine was not significant ( HR , 0.81 ; 95 % CI , 0.63 - 1.04 [ P = .10 ] ) . The IVUS sub study showed a trend toward less progression of atherosclerosis in the amlodipine group vs placebo ( P = .12 ) , with significantly less progression in the subgroup with systolic blood pressures greater than the mean ( P = .02 ) . Compared with baseline , IVUS showed progression in the placebo group ( P<.001 ) , a trend toward progression in the enalapril group ( P = .08 ) , and no progression in the amlodipine group ( P = .31 ) . For the amlodipine group , correlation between blood pressure reduction and progression was r = 0.19 , P = .07 . CONCLUSIONS Administration of amlodipine to patients with CAD and normal blood pressure result ed in reduced adverse cardiovascular events . Directionally similar , but smaller and nonsignificant , treatment effects were observed with enalapril . For amlodipine , IVUS showed evidence of slowing of atherosclerosis progression The West of Scotl and Coronary Prevention Study ( WOSCOPS ) showed that pravastatin reduced the risk of coronary heart disease ( CHD ) events in 6,595 middle-aged hypercholesterolaemic men aged 45 - 64 years without prior myocardial infa rct ion followed for an average of 4.9 years . We hypothesised prospect ively ( a ) that baseline levels of haemorheological variables were related to baseline and incident CHD and to mortality ; and ( b ) that reduction in lipoproteins by pravastatin would lower plasma and blood viscosity , a potential contributory mechanism to CHD events . We therefore studied plasma and blood viscosity , fibrinogen , haematocrit , and blood cell counts at baseline and 1 year . At baseline , plasma and blood viscosity were related to risk factors , CHD measures , and claudication . On univariate analysis , baseline levels of all rheological variables ( except platelet count ) were related to incident CHD ; CHD mortality ; and total mortality . On multivariate analysis including baseline CHD and risk factors , plasma and blood viscosity , haematocrit and white cell count each remained significantly associated with incident CHD ; while fibrinogen remained an independent predictor of mortality ( all p < 0.03 ) . After one year , lipoprotein reduction by pravastatin was associated with significant reductions ( about one quarter of a st and ard deviation ) in plasma viscosity ( mean difference 0.02 mPa.s , p < 0.001 ) and in blood viscosity ( mean difference 0.06 mPa.s , p<0.001 ) , but was not associated with significant changes in other rheological variables . We therefore suggest that pravastatin therapy , which reduces elevated lipoproteins in hypercholesterolaemic men , may lower risks of CHD and mortality partly by lowering plasma and blood viscosity . Further studies are required to test this hypothesis To determine the effect of atorvastatin on blood rheology in patients with familial hypercholesterolemia ( FH ) on regular LDL apheresis , we prospect ively studied the rheological variables fibrinogen , plasma viscosity , red cell aggregation , whole blood viscosity , hematocrit and platelet aggregation in 12 patients ( two homozygous , ten heterozygous ) before and during treatment with atorvastatin . Baseline values of red cell aggregation and whole blood viscosity were increased in FH patients on regular LDL apheresis compared with healthy controls ( P<0.05 ) , whereas fibrinogen , plasma viscosity and hematocrit were similar in the two groups . Treatment with atorvastatin reduced red cell aggregation ( P<0.01 ) , whole blood viscosity ( P<0.01 ) , plasma viscosity ( P<0.01 ) and platelet aggregation ( P<0.05 ) , but caused a slight increase in plasma fibrinogen ( by 5 % ; P<0.01 ) . Our findings suggest that atorvastatin improves blood rheology in patients with FH on regular LDL-apheresis . This improvement in blood flow properties may contribute to the well-known beneficial effects of atorvastatin on cardiovascular risk in patients with severe hyperlipidemia and atherosclerotic vascular disease Background —The Clopidogrel in Unstable angina to prevent Recurrent Events ( CURE ) trial demonstrated that clopidogrel , given early and continued long term , was superior to placebo in patients with non-ST – elevation acute coronary syndromes receiving aspirin . The purpose of the present analysis was to estimate the treatment effect Zof clopidogrel in patients who were stratified according to their risk of future cardiovascular events . Methods and Results — Patients ( n=12 562 ) who presented within 24 hours after the onset of symptoms were r and omized to receive clopidogrel ( 300 mg followed by 75 mg daily ) or placebo in addition to aspirin for 3 to 12 months . Treatment effect was analyzed in various risk groups according to the Thrombolysis in Myocardial Infa rct ion ( TIMI ) risk score . The TIMI risk model was vali date d in the CURE population ( C statistic , 0.634 ) . The primary composite outcome of cardiovascular death , myocardial infa rct ion , or stroke increased proportionally with increasing risk according to the TIMI risk score . The impact of clopidogrel versus placebo on the rate of the primary outcome was as follows : low-risk group ( TIMI score 0 to 2 ) , 4.1 % versus 5.7 % ( relative risk [ RR ] , 0.71 ; 95 % confidence interval [ CI ] , 0.52 to 0.97;P < 0.04 ) , intermediate-risk group ( TIMI score 3 to 4 ) , 9.8 % versus 11.4 % ( RR , 0.85 ; 95 % CI , 0.74 to 0.98;P < 0.03 ) , and high-risk group ( TIMI score 5 to 7 ) , 15.9 % versus 20.7 % ( RR , 0.73 ; 95 % CI , 0.60 to 0.90;P < 0.004 ) . There was no evidence of statistical heterogeneity among the groups . Conclusions —The benefit of clopidogrel demonstrated in the CURE trial is consistent in low- , intermediate- , and high-risk patients with acute coronary syndromes ( as stratified by TIMI risk score ) , thus supporting its use in all patients with documented non – ST elevation acute coronary syndromes OBJECTIVES The Circadian Anti-ischemia Program in Europe ( CAPE II ) compared the efficacy of amlodipine and diltiazem ( Adizem XL ) and the combination of amlodipine/atenolol and diltiazem ( Adizem XL)/isosorbide 5-mononitrate on exercise and ambulatory myocardial ischemia during regular therapy and after omission of medication . BACKGROUND The optimal medical therapy for ischemia suppression and the impact of irregular dosing using agents with different pharmacologic properties has not been established in patients with coronary disease . METHODS Patients with > or = 4 ischemic episodes or > or = 20 min of ST segment depression on 72-h electrocardiogram were r and omized to amlodipine 10 mg once daily or diltiazem ( Adizem XL ) 300 mg once daily in a 14-week double-blind r and omized multicountry study . In the second phase , atenolol 100 mg was added to amlodipine and isosorbide 5-mononitrate 100 mg to diltiazem ( Adizem XL ) . Ambulatory monitoring ( 72 h ) and exercise testing were repeated after both phases , on treatment and after a 24-h drug-free interval . RESULTS Both monotherapy with amlodipine and diltiazem ( Adizem XL ) were effective on symptoms and ambulatory and exercise ischemia . Combination therapy reduced ischemia further , with amlodipine/atenolol superior to diltiazem ( Adizem XL)/isosorbide 5-mononitrate . Amlodipine/atenolol was significantly superior during the drug-free interval with maintenance of ischemia reduction . CONCLUSIONS Amlodipine , with its intrinsically long half-life alone or together with beta-blocker , is likely to produce superior ischemia reduction in clinical practice when patients frequently forget to take medication or dose irregularly BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure Summary Background : Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol ( LDL-C ) levels . However , there is no long-term survival study that evaluated this statin . Patients − Methods : To assess the effect of atorvastatin on morbidity and mortality ( total and coronary ) of patients with established coronary heart disease ( CHD ) , 1600 consecutive patients were r and omised either to atorvastatin or to ' usual ' medical care . The dose of atorvastatin was titrated from 10 to 80mg/day , in order to reach the National Cholesterol Education Program ( NCEP ) goal of LDL-C < 100mg/dl ( 2.6mmol/l ) . All patients were followed up for a mean period of 3 years . Main Outcome Measures : Primary endpoints of the study were defined as death , non-fatal myocardial infa rct ion , unstable angina , congestive heart failure , revascularisation ( coronary morbidity ) and stroke . Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin . Results : The mean dosage of atorvastatin was 24 mg/day . This statin reduced total cholesterol by 36 % , LDL-C by 46 % , triglycerides by 31 % , and non-high-density lipoprotein cholesterol ( non-HDL-C ) by 44 % , while it increased HDL-C by 7 % ; all these changes were significant . The NCEP LDL-C and non-HDL-C treatment goals were reached by 95 % ( n = 759 ) and 97 % ( n = 776 ) , respectively , of patients on atorvastatin . Only 14 % of the ' usual ' care patients received any hypolipidaemic drugs throughout the study and 3 % of them reached the NCEP LDL-C treatment goal . The cost per quality -adjusted life-year gained with atorvastatin was estimated at $ US 8350 . During this study 196 ( 24.5 % ) CHD patients on ' usual ' care had a CHD recurrent event or died vs. 96 ( 12 % ) CHD patients on atorvastatin ; risk ratio ( RR ) 0.49 , confidence interval ( CI ) 0.27 - 0.73 , p < 0.0001 . In detail , atorvastatin reduced , in comparison to ' usual ' care , total mortality ( RR 0.57 , CI 0.39 - 0.78 , p = 0.0021 ) , coronary mortality ( RR 0.53 , CI 0.29 - 0.74 , p = 0.0017 ) , coronary morbidity ( RR 0.46 , CI 0.25 - 0.71 , p < 0.0001 ) , and stroke ( RR 0.53 , CI 0.30 - 0.82 , p = 0.034 ) . All subgroups of patients ( women , those with diabetes mellitus , arterial hypertension , age 60 to 75 years , congestive heart failure , recent unstable angina or prior revascularisation ) benefited from treatment with atorvastatin . Withdrawal of patients because of side-effects from the atorvastatin group was low ( 0.75 % ) and similar to that of the ' usual ' care group ( 0.4 % ) . Conclusions : Long-term treatment of CHD patients with atorvastatin to achieve NCEP lipid targets significantly reduces total and coronary mortality , coronary morbidity and stroke , in comparison to patients receiving ' usual ' medical care . Treatment with atorvastatin is well tolerated and cost-effective BACKGROUND Although coronary thrombosis plays a critical role in the pathogenesis of unstable angina and non-Q-wave myocardial infa rct ion ( NQMI ) , the effects of thrombolytic therapy in these disorders is not clear . Also , the role of routine early coronary arteriography followed by revascularization has not been established . METHODS AND RESULTS Patients ( n = 1473 ) seen within 24 hours of ischemic chest discomfort at rest , considered to represent unstable angina or NQMI , were r and omized using a 2 x 2 factorial design to compare ( 1 ) TPA versus placebo as initial therapy and ( 2 ) an early invasive strategy ( early coronary arteriography followed by revascularization when the anatomy was suitable ) versus an early conservative strategy ( coronary arteriography followed by revascularization if initial medical therapy failed ) . All patients were treated with bed rest , anti-ischemic medications , aspirin , and heparin . The primary end point for the TPA-placebo comparison ( death , myocardial infa rct ion , or failure of initial therapy at 6 weeks ) occurred in 54.2 % of the TPA-treated patients and 55.5 % of the placebo-treated patients ( P = NS ) . Fatal and nonfatal myocardial infa rct ion after r and omization ( reinfa rct ion in NQMI patients ) occurred more frequently in TPA-treated patients ( 7.4 % ) than in placebo-treated patients ( 4.9 % , P = .04 , Kaplan-Meier estimate ) . Four intracranial hemorrhages occurred in the TPA-treated group versus none in the placebo-treated group ( P = .06 ) . The end point for the comparison of the two strategies ( death , myocardial infa rct ion , or an unsatisfactory symptom-limited exercise stress test at 6 weeks ) occurred in 18.1 % of patients assigned to the early conservative strategy and 16.2 % of patients assigned to the early invasive strategy ( P = NS ) . In the latter , the average length of initial hospitalization , incidence of rehospitalization within 6 weeks , and days of rehospitalization all were significantly lower . CONCLUSIONS In the overall trial , patients with unstable angina and NQMI were managed with low rates of mortality ( 2.4 % ) and myocardial infa rct ion or reinfa rct ion ( 6.3 % ) at the time of the 6-week visit . These results can be achieved using either an early conservative or early invasive strategy , the latter result ing in a reduced incidence of days of hospitalization and of rehospitalization and in the use of antianginal drugs . The addition of a thrombolytic agent is not beneficial and may be harmful AIMS To use the ten year follow-up of the Caerphilly and Speedwell studies to assess the contributions of fibrinogen and viscosity to the prediction of risk of ischaemic heart disease . METHODS AND RESULTS Caerphilly and Speedwell are prospect i ve studies based on representative sample s of middle-aged males . Ischaemic heart disease morbidity and mortality were defined using hospital notes , repeat electro-cardiographs and death certificates . There were 603 incident events among the 4860 men . Age-adjusted relative odds of ischaemic heart disease increased to 3.3 and 3.4 in the 20 % of men with the highest levels of fibrinogen and viscosity , respectively . After st and ardizing for the major cardiovascular risk factors , these relative odds were 2.2 ( 95 % confidence interval 1.6 to 3.1 ) for fibrinogen and 2.3 ( 95 % confidence interval 1.7 to 3.2 ) for viscosity . When fibrinogen and viscosity were entered jointly , both remained significant ( P < 0.01 ) predictors . Incidence of ischaemic heart disease increased with increasing fibrinogen at every level of viscosity , and vice versa . Interactions with lipids were also examined . There was no support for the suggestion that risk is independent of cholesterol level when fibrinogen is low . CONCLUSIONS Fibrinogen and viscosity are powerful , long term and independent predictors of the risk of ischaemic heart disease OBJECTIVES Our intent was to investigate the effect of the dihydropyridine calcium channel blocker amlodipine on restenosis and clinical outcome in patients undergoing percutaneous transluminal coronary angioplasty ( PTCA ) . BACKGROUND Amlodipine has sustained vasodilatory effects and relieves coronary spasm , which may reduce luminal loss and clinical complications after PTCA . METHODS In a prospect i ve , double-blind design , 635 patients were r and omized to 10 mg of amlodipine or placebo . Pretreatment with the study drug started two weeks before PTCA and continued until four months after PTCA . The primary angiographic end point was loss in minimal lumen diameter ( MLD ) from post-PTCA to follow-up , as assessed by quantitative coronary angiography ( QCA ) . Clinical end points were death , myocardial infa rct ion , coronary artery bypass graft surgery and repeat PTCA ( major adverse clinical events ) . RESULTS Angioplasty was performed in 585 patients ( 92.1 % ) ; 91 patients ( 15.6 % ) had coronary stents implanted . Follow-up angiography suitable for QCA analysis was done in 236 patients in the amlodipine group and 215 patients in the placebo group ( per- protocol group ) . The mean loss in MLD was 0.30 + /- 0.45 mm in the amlodipine group versus 0.29 + /- 0.49 mm in the placebo group ( p = 0.84 ) . The need for repeat PTCA was significantly lower in the amlodipine versus the placebo group ( 10 [ 3.1 % ] vs. 23 patients [ 7.3 % ] , p = 0.02 , relative risk ratio [ RR ] : 0.45 , 95 % confidence interval [ CI ] : 0.22 to 0.91 ) , and the composite incidence of clinical events ( 30 [ 9.4 % ] vs. 46 patients ( 14.5 % ) , p = 0.049 , RR : 0.65 , CI : 0.43 to 0.99 ) within the four months follow-up period ( intention-to-treat analysis ) . CONCLUSIONS Amlodipine therapy starting two weeks before PTCA did not reduce luminal loss , but the incidence of repeat PTCA and the composite major adverse clinical events were significantly reduced during the four-month follow-up period after PTCA with amlodipine as compared with placebo BACKGROUND Cardiovascular complications are the most important causes of perioperative morbidity and mortality among patients undergoing major vascular surgery . METHODS We performed a r and omized , multicenter trial to assess the effect of perioperative blockade of beta-adrenergic receptors on the incidence of death from cardiac causes and nonfatal myocardial infa rct ion within 30 days after major vascular surgery in patients at high risk for these events . High-risk patients were identified by the presence of both clinical risk factors and positive results on dobutamine echocardiography . Eligible patients were r and omly assigned to receive st and ard perioperative care or st and ard care plus perioperative beta-blockade with bisoprolol . RESULTS A total of 1351 patients were screened , and 846 were found to have one or more cardiac risk factors . Of these 846 patients , 173 had positive results on dobutamine echocardiography . Fifty-nine patients were r and omly assigned to receive bisoprolol , and 53 to receive st and ard care . Fifty-three patients were excluded from r and omization because they were already taking a beta-blocker , and eight were excluded because they had extensive wall-motion abnormalities either at rest or during stress testing . Two patients in the bisoprolol group died of cardiac causes ( 3.4 percent ) , as compared with nine patients in the st and ard-care group ( 17 percent , P=0.02 ) . Nonfatal myocardial infa rct ion occurred in nine patients given st and ard care only ( 17 percent ) and in none of those given st and ard care plus bisoprolol ( P<0.001 ) . Thus , the primary study end point of death from cardiac causes or nonfatal myocardial infa rct ion occurred in 2 patients in the bisoprolol group ( 3.4 percent ) and 18 patients in the st and ard-care group ( 34 percent , P<0.001 ) . CONCLUSIONS Bisoprolol reduces the perioperative incidence of death from cardiac causes and nonfatal myocardial infa rct ion in high-risk patients who are undergoing major vascular surgery CONTEXT Limited data are available evaluating how the timing and intensity of statin therapy following an acute coronary syndrome ( ACS ) event affect clinical outcome . OBJECTIVE To compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in patients with ACS . DESIGN , SETTING , AND PARTICIPANTS International , r and omized , double-blind trial of patients with ACS receiving 40 mg/d of simvastatin for 1 month followed by 80 mg/d thereafter ( n = 2265 ) compared with ACS patients receiving placebo for 4 months followed by 20 mg/d of simvastatin ( n = 2232 ) , who were enrolled in phase Z of the A to Z trial between December 29 , 1999 , and January 6 , 2003 . MAIN OUTCOME MEASURE The primary end point was a composite of cardiovascular death , nonfatal myocardial infa rct ion , readmission for ACS , and stroke . Follow-up was for at least 6 months and up to 24 months . RESULTS Among the patients in the placebo plus simvastatin group , the median low-density lipoprotein ( LDL ) cholesterol level achieved while taking placebo was 122 mg/dL ( 3.16 mmol/L ) at 1 month and was 77 mg/dL ( 1.99 mmol/L ) at 8 months while taking 20 mg/d of simvastatin . Among the patients in the simvastatin only group , the median LDL cholesterol level achieved at 1 month while taking 40 mg/d of simvastatin was 68 mg/dL ( 1.76 mmol/L ) and was 63 mg/dL ( 1.63 mmol/L ) at 8 months while taking 80 mg/d of simvastatin . A total of 343 patients ( 16.7 % ) in the placebo plus simvastatin group experienced the primary end point compared with 309 ( 14.4 % ) in the simvastatin only group ( 40 mg/80 mg ) ( hazard ratio [ HR ] , 0.89 ; 95 % confidence interval [ CI ] 0.76 - 1.04 ; P = .14 ) . Cardiovascular death occurred in 109 ( 5.4 % ) and 83 ( 4.1 % ) patients in the 2 groups ( HR , 0.75 ; 95 % CI , 0.57 - 1.00 ; P = .05 ) but no differences were observed in other individual components of the primary end point . No difference was evident during the first 4 months between the groups for the primary end point ( HR , 1.01 ; 95 % CI , 0.83 - 1.25 ; P = .89 ) , but from 4 months through the end of the study the primary end point was significantly reduced in the simvastatin only group ( HR , 0.75 ; 95 % CI , 0.60 - 0.95 ; P = .02 ) . Myopathy ( creatine kinase > 10 times the upper limit of normal associated with muscle symptoms ) occurred in 9 patients ( 0.4 % ) receiving simvastatin 80 mg/d , in no patients receiving lower doses of simvastatin , and in 1 patient receiving placebo ( P = .02 ) . CONCLUSIONS The trial did not achieve the prespecified end point . However , among patients with ACS , the early initiation of an aggressive simvastatin regimen result ed in a favorable trend toward reduction of major cardiovascular events PURPOSE No studies have been addressed to the differences in inflammation kinetics between ST-segment elevation myocardial infa rct ion ( STEMI ) and non-ST-segment elevation myocardial infa rct ion ( NSTEMI ) . PATIENTS AND METHODS Forty consecutive patients with acute coronary syndrome ( ACS ) ( n=23 STEMI , age=61.7+/-10.3 years ; n=17 NSTEMI , age=65.6+/-11.3 years ) were enrolled within 12h after symptoms . All patients received therapy according to the current Guidelines . Blood sample s were collected at admission ( t0 ) , on days 7 ( t1 ) and 30 ( t2 ) to evaluate CD40 lig and ( CD40L ) , transforming growth factor (TGF)-beta , interleukin (IL)-6 , tumor necrosis factor (TNF)-alpha and its receptors TNFRI and TNFRII , high sensitivity C-reactive protein ( hs-CRP ) , serum amyloid A ( SAA ) and white blood cells ( WBC ) . Echocardiographic parameters were also evaluated . RESULTS STEMI patients , at admission , had significantly higher median values of hs-CRP ( p<0.001 ) , WBC ( p<0.01 ) , ferritin ( p<0.0005 ) and IL-6 ( p<0.05 ) than NSTEMI . On the contrary , NSTEMI patients had lower median levels of every inflammatory marker except for CD40L ( p<0.05 ) that was significantly higher . Moreover , three out of four deceased patients presented levels of CD40L higher than the median . At admission , STEMI showed a reduced ejection fraction ( EF , p<0.01 ) and increased wall motion score index ( WMSI , p<0.001 ) and end-diastolic volume ( EDV , p<0.05 ) vs NSTEMI . An inverse correlation between admission values of inflammatory markers ( SAA and WBC ) and cardiac function was observed ( p<0.05 ) . Moreover , the necrosis marker troponin I was positively correlated with both WMSI ( p<0.05 ) and hs-CRP ( p<0.05 ) . Regarding the inflammation kinetics , a difference was observed in the two groups only for WBC ( p<0.05 ) and SAA ( p<0.05 ) . SAA showed higher values in STEMI at t0 and t1 . In both groups , TGF-beta had an increase at t1 and t2 with respect to admission , while IL-6 had a decreasing trend . The total incidence of major adverse clinical events ( MACE ) was 22.5 % at t2 , with a mortality rate of 10 % . CONCLUSION These observations suggest a differential inflammatory pattern in STEMI and NSTEMI patients . The absence of significant correlations between inflammatory indexes and myocardial infa rct ion in NSTEMI supports the hypothesis that a different pattern of inflammation occurs in these patients . CD40L may have an important role as a marker for risk stratification in patients with ACS

The results of published intervention trials are of insufficient quality to enable evidence -based recommendations to be developed for clinical practice in antenatal care

BACKGROUND Excessive weight gain during pregnancy is common in developed countries and increases the risk of complications during pregnancy , delivery and the postpartum period , which can affect both maternal and fetal outcome . Interventions to reduce excessive gestational weight gain have previously not been systematic ally evaluated using the Grading of Recommendations , Assessment , Development and Evaluation ( GRADE ) system . OBJECTIVES To determine whether published trials of interventions to reduce excessive gestational weight gain are of sufficient quality and provide sufficient data to enable evidence -based recommendations to be developed for clinical practice in antenatal care .

OBJECTIVE Our purpose was to measure the agreement , reliability , construct validity , and feasibility of a measurement tool to assess systematic review s ( AMSTAR ) . STUDY DESIGN AND SETTING We r and omly selected 30 systematic review s from a data base . Each was assessed by two review ers using : ( 1 ) the enhanced quality assessment question naire ( Overview of Quality Assessment Question naire [ OQAQ ] ) ; ( 2 ) Sacks ' instrument ; and ( 3 ) our newly developed measurement tool ( AMSTAR ) . We report on reliability ( interobserver kappas of the 11 AMSTAR items ) , intraclass correlation coefficients ( ICCs ) of the sum scores , construct validity ( ICCs of the sum scores of AMSTAR compared with those of other instruments ) , and completion times . RESULTS The interrater agreement of the individual items of AMSTAR was substantial with a mean kappa of 0.70 ( 95 % confidence interval [ CI ] : 0.57 , 0.83 ) ( range : 0.38 - 1.0 ) . Kappas recorded for the other instruments were 0.63 ( 95 % CI : 0.38 , 0.78 ) for enhanced OQAQ and 0.40 ( 95 % CI : 0.29 , 0.50 ) for the Sacks ' instrument . The ICC of the total score for AMSTAR was 0.84 ( 95 % CI : 0.65 , 0.92 ) compared with 0.91 ( 95 % CI : 0.82 , 0.96 ) for OQAQ and 0.86 ( 95 % CI : 0.71 , 0.94 ) for the Sacks ' instrument . AMSTAR proved easy to apply , each review taking about 15 minutes to complete . CONCLUSIONS AMSTAR has good agreement , reliability , construct validity , and feasibility . These findings need confirmation by a broader range of assessors and a more diverse range of review In ninety-four Dutch nulliparous women the effects of a low-Na diet in pregnancy on blood pressure , energy and nutrient intake , Ca metabolism , Zn and Mg status and body composition were studied longitudinally . The women were r and omly divided into an intervention group ( n 41 ) , which used a low-Na diet ( mean urinary Na excretion 61 mmol/24 h ) from week 14 of pregnancy until delivery and a control group ( n 53 ; mean urinary Na excretion 142 mmol/24 h ) . No effect of the diet on blood pressure was observed . The use of a low-Na diet result ed in significantly reduced intakes of energy , protein , carbohydrates , fat , Ca , Zn , Mg , Fe and cholesterol . However , the women on the low-Na diet appeared to be able to adapt quite well to the reduced intake since Ca , Zn and Mg homeostasis was maintained . In the case of Ca and Mg this was probably due to the observed reduced urinary excretions of these nutrients . Non-significant reductions in weight gain ( 1.5 kg ) and fat-mass gain ( 0.9 kg ) over pregnancy were found in the women on the low-Na diet . No significant effects of the diet on birth weight or placental weight were observed OBJECTIVE To investigate the relation between gestational weight gain in women of normal prepregnant weight and complications during pregnancy and delivery in a population with high gestational weight gain and birth weight . METHODS Healthy women ( n = 615 ) of normal weight before pregnancy ( body mass index 19.5–25.5 kg/m2 ) were r and omly selected . Maternity records gave information on age , height , prepregnant weight , gestational weight gain , parity , smoking , gestational hypertension and diabetes , preeclampsia , delivery complications , and infants ' birth size and health . RESULTS The mean weight gain in pregnancy was 16.8 ± 4.9 kg ( mean ± st and ard deviation ) . A total of 26.4 % of the women had complications , either in pregnancy ( 9.1 % ) or delivery ( 17.3 % ) . Women gaining weight according to the recommendation of the Institute of Medicine ( 11.5–16.0 kg ) had lower frequency of pregnancy‐delivery complications than women gaining more than 20.0 kg ( P = .017 ) , but did not differ significantly from those gaining 16–20 kg ( P > .05 ) . When dividing weight gain in pregnancy into quintiles , a relative risk of 2.69 ( 95 % confidence interval 1.01 , 7.18 , P = .048 ) was found for complications in pregnancy in the fourth quintile ( 17.9–20.8 kg ) , using the second quintile as reference ( 12.5–15.5 kg ) . The mean birth weight was 3778 ± 496 g. A low weight gain in pregnancy ( less than 11.5 kg ) was associated with an increased frequency of infants weighing less than 3500 g at birth ( P < .01 ) . CONCLUSION A gestational weight gain of 11.5–16.0 kg ( Institute of Medicine recommendation ) for women of normal prepregnant weight is related to the lowest risk for pregnancy‐delivery complications . In the population studied , the upper limit might be higher ( up to 18 kg ) , and low weight gain should be avoided to optimize birth outcome BACKGROUND : The Institute of Medicine ( IOM ) recommends that normal‐weight women ( BMI ( body mass index ) of 19.8–26.0 ) gain 25–35 lb ( 11.4–15.9 kg ) during pregnancy , and that overweight women ( BMI of 26.1–29.0 ) gain 15–25 lbs ( 6.8–11.4 kg ) . A significant number of normal‐weight women and an even greater proportion of overweight women exceed these guidelines , which increases postpartum weight retention and may contribute to the development of obesity . OBJECTIVE : To determine whether a stepped care , behavioral intervention will decrease the percentage of women who gain more than the IOM recommendation . DESIGN : R and omized controlled trial comparing a stepped-care behavioral intervention with usual care . Women ( n=120 ) who had a BMI > 19.8 , age>18 and < 20 weeks gestation were recruited from a hospital-based clinic serving low-income women and r and omized by race and BMI category to the intervention or control group . The intervention group received education about weight gain , healthy eating , and exercise and individual graphs of their weight gain . Those exceeding weight gain goals were given more intensive intervention . Women were followed through pregnancy to their first postpartum clinic visit . The main outcome measure was weight gain during pregnancy categorized as above the IOM recommendations vs below or within the IOM recommendations . RESULTS : The intervention significantly decreased the percentage of normal-weight women who exceeded the IOM recommendations ( 33 vs 58 % , P<0.05 ) . There was a non-significant ( P=0.09 ) effect in the opposite direction among overweight women ( 59 % of intervention and 32 % of control gained more than recommended ) . Postpartum weight retention was strongly related to weight gain during pregnancy ( r=0.89 ) . CONCLUSIONS : The intervention reduced excessive weight gain during pregnancy among normal weight women Summary : A r and omised controlled trial was design ed to determine the effect of moderate 30 % maternal dietary energy restriction on the requirement for maternal insulin therapy and the incidence of macrosomia in gestational diabetes . Although the control group restricted their intake to a level similar to that of the intervention group ( 6845 kiloJoules ( kJ ) versus 6579 kJ ) , the result ing cohort could not identify any adverse effect of energy restriction in pregnancy . Energy restriction did not alter the frequency of insulin therapy ( 17.5 % in the intervention group and 16.9 % in the control group ) . Mean birth weight ( 3461 g in the intervention group and 3267 g in the control group ) was not affected . There was a trend in the intervention group towards later gestational age at commencement of insulin therapy ( 33 weeks versus 31 weeks ) and lower maximum daily insulin dose ( 23 units versus 60 units ) which did not reach statistical significance . Energy restriction did not cause an increase in ketonemia BACKGROUND A high prevalence of gestational diabetes mellitus and type 2 diabetes has been observed among the Cree of James Bay , Quebec . To address this problem , a diet and activity intervention during pregnancy , which was based on social learning theory , was initiated in 4 Cree communities . METHODS A prospect i ve intervention compared dietary , weight and glycemic indicators for 107 control subjects and for 112 women who received the intervention during the course of their pregnancy . A control period in 4 communities ( July 1995-March 1996 ) was followed by an intervention period ( April 1996-January 1997 ) when subjects were offered regular , individual diet counselling , physical activity sessions and other activities related to nutrition . RESULTS The intervention and control groups did not differ at baseline regarding their mean age ( 24.3 years [ SD 6.29 ] v. 23.8 years [ SD 5.86 ] ) , mean prepregnancy weight ( 81.0 kg [ SD 19.46 ] v. 78.9 kg [ SD 17.54 ] ) and mean gestational age at recruitment ( 17.1 weeks [ SD 7.06 ] v. 18.5 weeks [ SD 6.92 ] ) . The intervention did not result in differences in diet measured at 24 - 30 weeks ' gestation , rate of weight gain over the second half of pregnancy ( 0.53 kg per week [ SD 0.32 ] v. 0.53 kg per week [ SD 0.27 ] ) or plasma glucose level ( 50 g oral glucose screen ) between 24 and 30 weeks ( 7.21 mmol/L [ SD 2.09 ] v. 7.43 mmol/L [ SD 2.10 ] ) . Mean birth weights were similar ( 3741 g [ SD 523 ] v. 3686 g [ SD 686 ] ) , as was maternal weight at 6 weeks post partum ( 88.1 kg [ SD 16.8 ] v. 86.4 kg [ SD 19.0 ] ) . The only changes in dietary intake were a reduction in caffeine ( pregnancy ) and an increase in folate ( post partum ) . INTERPRETATION This intervention had only a minor impact on diet ; finding ways of encouraging appropriate body weight and activity levels remains a challenge OBJECTIVE The research addresses two questions : Are potentially modifiable psychosocial and behavioral factors related to gestational weight gain ? Do the same factors relate to both excessive and insufficient weight gain ? DESIGN Prospect i ve cohort study that followed women from early pregnancy until two years postpartum . Data were collected through mailed question naires and an audit of the medical record . Subjects/ setting The sample included 622 healthy adult women who gave birth to live singleton infants . Subjects were recruited from all women who registered for prenatal care in a hospital and primary care clinic system serving a 10-county area of Upstate New York . Statistical analyses performed Multiple linear and logistic regression with adjustment for timing of measurements and length of gestation were performed . RESULTS Only 38 % of women gained an amount of weight in pregnancy that was within the range recommended by the Institute of Medicine . Valid and easily implemented measures of change in food intake and physical activity from prepregnancy and cigarette smoking during pregnancy were each significantly ( P<.05 ) and independently related to gestational weight gain . Along with other variables in a biopsychosocial regression model , these variables accounted for 27 % of the variance in gestational weight gain and were also significantly related to risk of inadequate and excessive gain . APPLICATIONS/ CONCLUSIONS The findings facilitate the design of more effective nutrition interventions to promote appropriate gestational weight gain and the long-term health of women and their infants Objective To determine whether the risk of maternal overweight associated with an excessive rate of gestational gain needs to be balanced against the risks of impaired fetal growth associated with a low rate of gain . Methods Rate of gestational weight gain was measured prospect ively in a sample of 274 young , low-income , and primarily minority women ( 12–29 years old ) with pregravid body mass indices ( BMI ) in the normal range ( 19.8–26.0 ) . We defined an excessive rate of gain between 20–36 weeks ' gestation as one greater than 0.68 kg/week , and a low rate of gain as one less than 0.34 kg/week . Women were followed-up at 4–6 weeks and 6 months postpartum . Results Rate of measured gestational gain between 20–36 weeks ' gestation was associated with total weight gain based on pregravid weight , with infant birth weight and gestation duration , and with maternal overweight ( BMI greater than 26 ) and weight retention postpartum . Infant birth weight and gestation duration were significantly reduced for women with low rates of gain , and there was no significant difference between women with excessive and moderate gains . Despite little difference in pregravid BMI , women with excessive rates of gain retained more weight overall , attained a greater postpartum BMI , and had higher levels of subcutaneous fat and overweight . Maternal anthropometric status showed little change between 4–6 weeks and 6 months postpartum . Conclusion Weight gained at an excessive rate by women with a pregravid BMI in the normal range does not greatly enhance fetal growth and gestation duration , contributing instead to postpartum maternal overweight

Miscarriage and multiple pregnancy rates were poorly reported . This review shows evidence supporting the effectiveness of the current first line treatment , clomiphene citrate . No evidence of a difference in effect was found between clomiphene and tamoxifen . The use of dexamethasone as an adjunct to clomiphene therapy appears promising as do combined oral contraceptives .

BACKGROUND Infertility due to anovulation is a common problem in women . The first line oral treatment is with anti-oestrogens , such as clomiphene citrate . Unfortunately there may be resistance and alternative and adjunctive treatments have been developed . These include tamoxifen , dexamethasone , bromocriptine and aromatase inhibitors ( AIs ) . OBJECTIVES To determine the relative effectiveness of anti-oestrogen agents , with or without medical adjuncts , in women with WHO group 2 anovulation .

OBJECTIVE To assess the efficacy of a clomiphene citrate ( CC ) and tamoxifen citrate ( CC/tamoxifen ) combination therapy in ovulation induction by comparing with a CC alone therapy . DESIGN A r and omized cross-over study with CC alone and CC/tamoxifen combination therapies for 20 normoprolactinemic anovulatory women . R and omly selected 10 of the 20 women ( group A ) underwent a CC alone therapy ( 100 mg CC during cycle days 5 to 9 ) for the initial three consecutive treatment cycles and a CC/tamoxifen combination therapy ( 50 mg CC and 20 mg tamoxifen during cycle days 5 to 9 ) for the subsequent three consecutive treatment cycles . The remaining 10 ( group B ) were treated similarly but with the inverse sequence . Ovulation was documented when a high BBT phase persisted for 11 days or more , when midluteal serum P levels exceeded 7 ng/mL ( 22.3 nmol/L ) , or when pregnancy ensued . RESULTS The rates of ovulatory/treated , pregnant/treated , and pregnant/ovulatory cycles were 42 of 56 ( 75.0 % ) , 3 of 47 ( 6.4 % ) , and 3 of 35 ( 8.6 % ) for CC/tamoxifen , respectively . Those were 25 of 57 ( 43.9 % ) , 1 of 48 ( 2.1 % ) , and 1 of 21 ( 4.8 % ) for CC , respectively . Clomiphene citrate/tamoxifen was more effective in ovulation induction than CC . All the pregnancies were normal and single . None of the treatments was accompanied by any remarkable side effects . CONCLUSION Clomiphene citrate/tamoxifen is a novel treatment modality of ovulation induction with high efficacy OBJECTIVE --To determine whether pituitary suppression before induction of ovulation reduces the rate of spontaneous abortion in women with polycystic ovarian disease and primary recurrent spontaneous abortions . DESIGN --Closed , r and omised , sequential trial . Pairs of women were allocated to each treatment by the toss of a coin . SETTING --Supraregional clinic for women who had had recurrent spontaneous abortions . SUBJECTS -- Forty two women with polycystic ovarian disease and primary recurrent spontaneous abortions . INTERVENTIONS --Ovulation was induced by clomiphene or pituitary suppression with buserelin followed by pure follicle stimulating hormone . MAIN OUTCOME MEASURES --Preference for a particular treatment was noted . A preference occurred when one woman in a pair had a successful pregnancy ( defined as one of over 12 weeks ' gestation ) and one had a spontaneous abortion ; the preference was for the treatment result ing in the successful pregnancy . RESULTS --Spontaneous abortions occurred in 11 of 20 women given clomiphene compared with two of 20 who had pituitary suppression . Eleven preferences were found for buserelin and two for clomiphene . In seven pairs both women had successful pregnancies . One pair was discarded because one of the women did not become pregnant . The ratio of luteinising hormone concentration to follicular diameter was found to be a possible diagnostic indicator of spontaneous abortion . CONCLUSION --Pituitary suppression before induction of ovulation significantly reduces the risk of spontaneous abortion in women with polycystic ovarian disease and primary recurrent spontaneous abortions Antiestrogens are widely used to treat eugonadal anovulation , luteal phase deficiency ( LPD ) and oligospermia . This paper review s the rationale s , endocrine effects , profertility effects and side effects of these treatments . Furthermore , we present our own experience of the use of antiestrogens in this field . We have compared the results of clomiphene citrate ( CC ) to those of tamoxifen ( TAM ) in a r and omized study including 66 infertile women presenting eugonadal anovulation ( n = 26 ) or LPD ( n = 40 ) . Both drugs obtained the same pregnancy rate of 80 % at 9 months in the anovulatory patients . Conversely , CC was superior to TAM in the LPD cases ( pregnancy rates at 6 months of respectively 40 and 11 % ) . The abortion rates were of 11 % on CC versus 36 % on TAM . Both drugs significantly increased the luteal phase length and plasma progesterone level to the same extent . The results of endometrial biopsies suggest that the difference in their effects on female fertility could result from a detrimental effect of TAM on endometrium . The rates of the side effects proved to be almost identical on both drugs . Thus the use of TAM is not justified as a first-step treatment in ovulation disturbances . TAM should be reserved for patients who experience severe visual side effects on CC . We have also tested TAM in 100 subfertile males . In the 92 oligospermic males , TAM significantly increased the mean sperm count only in the normogonadotropic patients , but as much whether oligospermia was idiopathic or not . Sperm improvement was not significantly related to any hormone criterion except basal serum FSH . The cumulative pregnancy rate was of 41.2 % at 1 year . Whether TAM actually improves male fertility , and is superior to CC in this indication , remains to be confirmed in controlled studies Abstract Purpose : To study the effect of CYP17a inhibitor , “ ketoconazole , ” on clomiphene responsiveness in PCOS patients . Methods : Prospect i ve analysis was employed with the setup at Alex and ria IVF/ICSI center . Ninety-seven insulin-resistant PCOS patients undergoing ovulation induction using clomiphene citrate were r and omly divided , by r and om number table , into two groups . The first group ( n = 49 ) received ketoconazole ( 400 mg daily ) till correction of metabolic syndrome followed by clomiphene ( 100 mg/day ) ; the second group ( n = 48 ) receiving clomiphene without ketoconazole pretreatment . Main outcome measures were incidence of clomiphene resistance , monofollicular response , fasting insulin/glucose ratio , serum testosterone , and pregnancy rates . Results : The ketoconazole group showed significantly ( p < 0.05 ) higher incidence of monofollicular response ( 38 % ) , higher pregnancy rates , and significantly less marked antiestrogenic manifestations than did the control group . They also had significantly lower incidence of clomiphene resistance ( 11.6 % ) , lower serum testosterone levels , less hyperinsulinaemia , than did the control group . Conclusion : Ketoconazole improved clomiphene responsivenss in PCOS patients and attenuated its untoward biological effects Objective To determine the efficacy of pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins in a stepwise approach for inducing ovulation in women with clomiphene-resistant polycystic ovary syndrome ( PCOS ) . Methods Eighty women with clomiphene-resistant anovulatory infertility and PCOS were given subcutaneous pulsatile GnRH ( 15 μg every 90 minutes ) using a portable infusion pump . If no follicular development was seen , clomiphene citrate ( 100 mg/day for 5 days ) was given concurrently with the hormone in the next cycle of treatment . Those who still failed to ovulate regularly were treated with combined pulsatile GnRH with intramuscular gonadotropins ( one ampule per day for 5–7 days ) . Results Sixty-six of 131 ( 50 % ) pulsatile GnRH cycles , 94 of 142 ( 66 % ) pulsatile GnRH with clomiphene cycles , and 48 of 69 ( 70 % ) pulsatile GnRH with gonadotropin cycles were ovulatory . Monofollicular response ( one follicle at least 14 mm on the day of ovulation ) occurred in 80.6 , 83.9 , and 53.6 % of cycles , and multifollicular response occurred in 4.8 , 3.1 , and 21.6 % of cycles in the three groups , respectively . Mild ovarian hyperstimulation occurred in one of the 342 cycles . The cumulative conception rate was 30 % after three cycles , 60 % after six cycles , and 73 % after nine cycles . The miscarriage rate was 22 % ( ten of 45 pregnancies ) , and 35 women ( 78 % ) had live births ( 33 singletons and two sets of twins ) . Conclusion The use of subcutaneous pulsatile GnRH alone and in combination with clomiphene citrate or gonadotropins for induction of ovulation in clomiphene-resistant PCOS in a stepwise approach produces a high cumulative conception rate associated with a low rate of multiple pregnancy and ovarian hyperstimulation syndrome OBJECTIVE To use aromatase inhibition for induction of ovulation in women in whom clomiphene citrate ( CC ) treatment was unsuccessful . DESIGN Prospect i ve trial in infertility patients treated with CC . SETTING Two tertiary-referral infertility clinics associated with the Division of Reproductive Sciences , University of Toronto . PATIENT(S ) Twelve patients with anovulatory polycystic ovary syndrome ( PCOS ) and 10 patients with ovulatory infertility , all of whom had previously received CC with an inadequate outcome ( no ovulation and /or endometrial thickness of < or = 0.5 cm ) . INTERVENTION(S ) The aromatase inhibitor letrozole was given orally in a dose of 2.5 mg on days 3 - 7 after menses . MAIN OUTCOME MEASURE(S ) Occurrence of ovulation , endometrial thickness , and pregnancy rates . RESULT ( S ) With CC treatment in patients with PCOS , ovulation occurred in 8 of 18 cycles ( 44.4 % ) , and all ovulatory cycles for the women included in this study had endometrial thickness of < or = 0.5 cm . In 10 ovulatory patients , 15 CC cycles result ed in a mean number of 2.5 mature follicles , but all cycles had endometrial thickness of < or = 0.5 cm on the day of hCG administration . With letrozole treatment in the same patients with PCOS , ovulation occurred in 9 of 12 cycles ( 75 % ) and pregnancy was achieved in 3 patients ( 25 % ) . In the 10 patients with ovulatory infertility , letrozole treatment result ed in a mean number of 2.3 mature follicles and mean endometrial thickness of 0.8 cm . Pregnancy was achieved in 1 patient ( 10 % ) . CONCLUSION ( S ) Oral administration of the aromatase inhibitor letrozole is effective for ovulation induction in anovulatory infertility and for increased follicle recruitment in ovulatory infertility . Letrozole appears to avoid the unfavorable effects on the endometrium frequently seen with antiestrogen use for ovulation induction Improved underst and ing of follicular dynamics has led to a reevaluation of suppression of adrenal and rogens in ovulation induction . To test whether adrenal suppression during clomiphene citrate ( CC ) therapy would improve ovulation/pregnancy rates , 64 anovulatory patients who had not previously received CC were r and omly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone ( CC + DEX ) . Patients were then screened for dehydroepi and rosterone sulfate ( DHEA-S ) ( normal range , 80 to 320 micrograms/dl ) , prolactin , testosterone , and semen analysis of the partner . Nine patients discontinued participation prior to completing the first treatment cycle , and ten patients were found to have either elevated prolactin ( 4 ) , severe male factors ( 3 ) , or tubal disease ( 3 ) and were discontinued . CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred . Once the patient was ovulatory on therapy , a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed . If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC , patients were crossed to the other arm of the treatment protocol . The results revealed a significantly higher rate of ovulation ( P less than 0.01 ) and conception ( P less than 0.05 ) in the CC + DEX-treated group . When correlated with DHEA-S levels , this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl ( P less than 0.05 ) OBJECTIVE To evaluate the role of ketoconazole in prevention of ovarian hyperstimulation syndrome ( OHSS ) in women with the polycystic ovary syndrome ( PCOS ) undergoing ovarian stimulation with gonadotropins . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled study . SETTING University hospitals . One hundred nine women with PCOS who were referred for treatment with gonadotropins . INTERVENTION(S ) Fifty patients were r and omly assigned to receive two ampoules of hMG beginning on day 2 or 3 of the cycle and ketoconazole ( 50 mg every 48 hours ) starting on the first day of hMG treatment . Fifty-one patients received the same amount of hMG plus one tablet of placebo every 48 hours . MAIN OUTCOME MEASURE(S ) Follicular development , E(2 ) level , and pregnancy rate . RESULT ( S ) The total number of hMG ampoules and duration of treatment to attain ovarian stimulation were higher among ketoconazole recipients . The serum E(2 ) level and number of patients with dominant follicles on day 9 of the cycle were greater in placebo recipients . Serum E(2 ) level and total number of follicles at the time of hCG administration did not differ between the two groups . The cancellation rate and OHSS rate were similar in the two groups . CONCLUSION ( S ) Ketoconazole does not prevent OHSS in patients with PCOS who are undergoing ovarian stimulation . It may reduce the rate of folliculogenesis and steroidogenesis Literature data have demonstrated that the chronic use of metoclopramide ( MCP ) , a dopamine antagonist , causes increased gonadotropin secretion in patients with hypothalamic amenorrhea but without triggering ovulation . It has also been observed that women with hypothalamic amenorrhea respond poorly to ovulation induction with clomiphene citrate ( CC ) . On this basis , the objective of the present study was to determine the effect of MCP on the response to CC in patients with hypothalamic amenorrhea in order to evaluate the validity of the simultaneous use of these drugs as ovulation inducers in this type of chronic anovulation . Twenty-two patients with amenorrhea of hypothalamic origin were su bmi tted to a r and omized double blind study in which one tablet of 5 mg MCP or placebo was administered every 8 hours for 2 months . After the 30th day of medication ( MCP or placebo ) , CC , 100 mg orally , was additionally administered to both groups for 5 days . Blood sample s were collected on days 1 , 15 and 30 during the first month of the study and on days 7 , 14 and 21 after the last CC tablet during the second month , for later measurement of follicle-stimulating hormone ( FSH ) , luteinizing hormone ( LH ) , prolactin , estradiol and progesterone by radioimmunoassay . The group that received MCP showed a significant increase in LH and FSH during the first month of the study , as well as a slighter increase in estradiol . Prolactin increased only during the second stage of treatment . No significant increases in gonadotropins , prolactin or estradiol occurred in the placebo group . In the group treated with MCP , 40 % of the patients ovulated after CC , with menstruation occurring in 60 % of them . In the placebo group , 33.3 % of the women ovulated after CC and 44.4 % menstruated at the end of the study . We conclude that MCP increases the circulating levels of LH , FSH , estradiol and prolactin in patients with hypothalamic amenorrhea and low estrogen levels , supporting the hypothesis that an increase in hypothalamic dopaminergic tonus occurs in these patients . On the other h and , the combination of MCP and CC does not improve the rate of ovulation compared to placebo OBJECTIVE To compare the rates of ovulation and pregnancy after tamoxifen citrate ( TMX ) or clomiphene citrate ( CC ) among anovulatory women with infertility . DESIGN Prospect i ve r and omized trial . SETTING Infertility clinic in a university teaching hospital . PATIENT(S ) Eighty-six anovulatory women under 40 years of age undergoing ovulation induction . INTERVENTION(S ) The women were assigned r and omly to receive either TMX or CC on cycle days 5 - 9 . MAIN OUTCOME MEASURE(S ) Rates of ovulation and pregnancy for the two treatment modalities . RESULTS ( S ) The overall rate of ovulation in the TMX group was 50 of 113 ( 44.2 % ) and in the CC group , 41 of 91 ( 45.1 % ) . There were 10 pregnancies in the TMX group and 6 pregnancies in the CC group . The cycle fecundity per ovulatory cycle was 20.0 % in the TMX group and 14.6 % in the CC group . CONCLUSION ( S ) The overall rate of ovulation and pregnancy were similar with TMX and CC . TMX is a suitable alternative agent to CC in the management of anovulatory infertility The effects of clomiphene and tamoxifen treatment on the concentrations of oestradiol and progesterone in plasma were compared in the same infertile women . Nine patients , three with anovulation and six with suspected luteal phase deficiency , were given clomiphene during 2 months and tamoxifen during 2 months . Placebo treatment was given in the month before the first drug and during a month between drug treatments . The concentrations of oestradiol and progesterone were determined by radioimmunoassay in three sample s collected each month between days 6 and 8 , 11 and 13 , and 18 and 20 Abstract . Objective : The purpose of this study was to examine the effects of of bromocriptin combined with clomiphene citrate in clomiphene-resistant patients with polycystic ovary syndrome and normal prolactin level . Design : Prospect i ve , double-blind , controlled study . Setting : University teaching hospital . Patients : One hundred polycystic ovary patients and normal prolactin ( PRL ) who were clomiphene citrate resistant . Interventions : Treatment group received 150 mg clomiphene citrate on days 5–9 and 7.5 mg bromocriptin continuously . Control group received the same protocol of clomiphene citrate combined with placebo . Main outcome measures : Hormonal status , follicular monitoring , ovulation rate . Results : Follicular development ( follicular size greater than 15 mm ) was observed in 12 ( 25.5 % ) and eight ( 15.1 % ) women in treatment and placebo group respectively ( P=0.29 ) . The serum prolactin level was within normal limits in all patients before treatment . After 3 and 6 months of treatment with bromocriptin , there was a significant decrease in serum level of prolactin (P=0.000001).No any significant differences was seen in ovulation , and serum levels of follicle-stimulating hormone ( FSH ) , luteinizing hormone ( LH ) , dehydroepi and rosterone sulfate ( DHEAS ) , progesterone ( P ) between treatment and placebo group after treatment . Conclusions : The only significant effect of long-term bromocriptin therapy in clomiphene citrate resistant polycystic ovary women was to lower the serum prolactin concentration . It was also concluded that 10–15 % of patients with polycystic ovaries experienced occasional ovulatory cycles and pregnancy whether or not they were on treatment BACKGROUND The quality of clinical trials has received increasing attention with the growth of evidence -based medicine and systematic review s. We aim ed to identify whether errors and omissions commonly encountered when undertaking Cochrane review s in this field are still passing peer review . METHODS We undertook a review of trials published in 2001 by two major journals . We selected from Medline only trials in which authors compared pregnancy rates under two interventions by allocating women to different groups . RESULTS We identified 39 trials meeting our criteria . Six trials were fatally flawed by design , either by inappropriate use of a cross-over design or by systematic allocation described by the authors as ' r and om ' . Only six reports cl aim ed to apply the intention-to-treat principle , and the principle was misunderstood by four of these . Only five trials reported live birth rates sufficiently to allow valid meta- analysis . Most trials ( 82 % ) included at least one ' unit of analysis ' error . CONCLUSIONS We selected simple trials from respected journals , assuming that our sample would represent trials of highest method ological quality in the field . Nevertheless , the st and ards of design , analysis and reporting of many subfertility trials are not sufficient to allow reliable interpretation of results , or inclusion in meta-analyses OBJECTIVE The purpose of this study was to evaluate the effectiveness and endocrine response of oral contraceptive ovarian suppression followed by clomiphene citrate in patients who previously were clomiphene citrate resistant . STUDY DESIGN Forty-eight patients from a private tertiary infertility clinic were assigned r and omly prospect ively to either group 1 ( oral contraceptive/clomiphene citrate ) , which received continuous oral contraceptives followed by clomiphene citrate , or to group 2 ( control ) received no treatment in the cycle before clomiphene citrate treatment . On day 3 , 17 beta-estradiol , follicle-stimulating hormone , luteinizing hormone , and and rogens were assayed before and after treatment . Follicle growth , ovulation , and pregnancy were evaluated . The Student t test and analysis of variance were used for statistical significance . RESULTS The oral contraceptive/clomiphene citrate group had a significantly higher percentage of patients who ovulated and of ovulatory cycles and pregnancies . Significantly lower levels of 17 beta-estradiol , luteinizing hormone , and and rogen levels were seen in the oral contraceptive/clomiphene citrate group , with no significant changes in group 2 . CONCLUSION Suppression of the ovary with oral contraceptives results in excellent rates of ovulation and pregnancy in patients who previously were resistant to clomiphene citrate . The decreases in ovarian and rogens , luteinizing hormone , and 17 beta-estradiol may be responsible for the improved response Patients suffering from normogonadotrophic anovulation and infertility are initially treated with clomiphene citrate . Those who do not respond to clomiphene citrate usually receive gonadotrophin treatment which is labour-intensive , expensive , and associated with an increased risk of multiple pregnancies and ovarian hyperstimulation syndrome . We treated 22 patients with clomiphene resistant normogonadotrophic anovulation with naltrexone ( an opioid receptor blocker ) alone or naltrexone in combination with an antioestrogen . In 19 patients ovulation and resumption of a regular menstrual cycle was achieved and in 12 out of 19 a singleton pregnancy was observed . In conclusion , ovulation can be induced successfully using naltrexone alone or naltrexone in combination with an anti-oestrogen in clomiphene citrate resistant anovulatory patients . Compared to gonadotrophin induction of ovulation , this method is safe , simple and inexpensive Secondary amenorrhea is often associated with emotional stress , weight loss , eating disorders or polycystic ovary-like disease . Involvement of the endogenous opioids in the pathophysiology of hypothalamic amenorrhea , by inhibition of hypothalamic GnRH secretion , has been demonstrated in some cases . Chronic blockade of the endogenous opioids with the long-acting opioid antagonist naltrexone could result in increased gonadotropin secretion and ovulation induction in these cases . A single-blind ovulation induction protocol comparing naltrexone , placebo and clomiphene citrate was evaluated in eight patients with secondary amenorrhea . Naltrexone proved not to be more effective than placebo in our study . Only one patient ovulated on naltrexone , one on placebo and four on clomiphene citrate . The latter therapy caused a better endocrine response . In conclusion , although ovulation could be incidentally induced by naltrexone , this drug did not appear to be more successful than placebo and clomiphene citrate for ovulation induction in this population of patients OBJECTIVE To compare the effectiveness of clomiphene citrate used alone and in combination with ethinyl E2 for the induction of ovulation in patients undergoing IUI . DESIGN R and omized , double-blind study . SETTING Four infertility treatment centers . PATIENT(S ) Women aged 25 - 35 years with infertility of at least 2 years ' duration and oligomenorrhea or amenorrhea associated with a positive menstrual response to an IM progesterone challenge . INTERVENTION(S ) A total of 64 patients were r and omized to treatment with CC ( 100 mg daily for 5 days ) or CC ( 100 mg daily for 5 days ) plus ethinyl E2 ( 0.05 mg daily for 5 days ) . MAIN OUTCOME MEASURE(S ) The uterine artery pulsatility index , number of preovulatory follicles , endometrial thickness , and pregnancy rate . RESULT ( S ) Both treatment regimens increased FSH , LH , and 17beta-E2 levels , with no statistically significant differences . There was a statistically significant difference in endometrial thickness between the two treatment groups . No statistically significant differences were noted in pulsatility index values or in the number of preovulatory follicles . CONCLUSION ( S ) Ethinyl E2 can reverse the deleterious effects of CC on endometrial thickness , which may contribute to higher pregnancy rates In a controlled treatment study of 49 anovulatory infertile women , responses to clomiphene citrate ( CC ) and placebo treatments were compared and associations of behavioral and emotional factors with treatment responses were investigated . In the first treatment series , ovulation occurred in 20 of 24 women in the CC group and 8 of 22 women in the placebo group . Pregnancy was achieved by 11 women during CC treatment and 3 women during placebo treatment . Overall , 28 women completed the protocol and 21 withdrew . Those who achieved pregnancy ( n = 14 ) did not differ significantly from the ovulation-only group ( n = 22 ) on pretreatment measures of emotional , behavioral , and personality factors including the Hopkins Symptom Checklist ( HSCL-90 ) , Eysenck Personality Inventory , Langner Screening Scale , Mood Analog Scale , Social Adjustment Scale , Mooney Problem Checklist , and the Minnesota Multiphasic Personality Inventory ( MMPI ) . Conclusions were that a placebo response was observed in both ovulation and pregnancy , but psychologic factors as measured in this sample were not associated with these treatment outcomes OBJECTIVE To evaluate the effects of short-course administration of dexamethasone ( DEX ) combined with clomiphene citrate ( CC ) in CC-resistant patients with polycystic ovary syndrome ( PCOS ) and normal DHEAS levels . DESIGN Prospect i ve , double-blind , placebo-controlled , r and omized study . SETTING Referral university hospitals . PATIENT(S ) Two hundred thirty women with PCOS and normal DHEAS who failed to ovulate after a routine protocol of CC . INTERVENTION(S ) The treatment group received 200 mg of CC from day 5 to day 9 and 2 mg of DEX from day 5 to day 14 of the menstrual cycle . The control group received the same protocol of CC combined with placebo . MAIN OUTCOME MEASURE(S ) Follicular development , hormonal status , ovulation rate , pregnancy rate . RESULT ( S ) Mean follicular diameters were 18.4124 + /- 2.4314 mm and 13.8585 + /- 2.0722 mm for the treatment and control groups , respectively . Eighty-eight percent of the treatment group and 20 % of the control group had evidence of ovulation . The difference in the cumulative pregnancy rate in the treatment and control groups was statistically significant . CONCLUSION ( S ) Hormonal levels , follicular development , and cumulative pregnancy rates improved with the addition of DEX to CC in CC-resistant patients with PCOS and normal DHEAS . This regimen is recommended before any gonadotropin therapy or surgical intervention OBJECTIVE To evaluate the effect on ovulation of a 10-day course of dexamethasone ( DEX ) initiated concurrently with a 5-day course of clomiphene citrate ( CC ) in CC-resistant patients with normal DHEAS levels . DESIGN Retrospective review . SETTING S Patients from the clinical practice of the authors at the Medical College of Georgia , Augusta , Georgia . PATIENTS Thirteen oligomenorrheic women with normal DHEAS levels who failed to ovulate on a graduated regimen of CC up to a dose of 150 mg for 5 days . INTERVENTIONS Ten-day course of DEX initiated concurrently with a 5-day course of CC ; ovulation and pregnancy outcomes recorded . MAIN OUTCOME MEASURE Pregnancy . RESULTS Eleven of 13 women had evidence of ovulation . Five clinical pregnancies were achieved . CONCLUSION These initial data support improvements in follicular development with an overlapping follicular phase regimen of CC and DEX in patients with normal DHEAS levels and a previous poor response The present study was undertaken to verify the efficacy of preparations for inducing follicular maturation and ovulation in patients with polycystic ovary syndrome ( PCOS ) . Successful induction of ovulation in patients with PCOS was observed in treatment cycles with daily injections or pulsatile subcutaneous administration of human menopausal gonadotropin ( hMG ) , the combination of clomiphene citrate and bromocriptine , or the combination of clomiphene citrate and hMG . The incidence of ovarian hyperstimulation syndrome varied with the different clinical conditions in which ovulation was induced , the types of preparations administered , and the doses and schedules administered To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results

None of the trials showed any effect of betahistine on hearing loss . No adverse effects were found with betahistine . REVIEW ER 'S CONCLUSIONS There is insufficient evidence to say whether betahistine has any effect on Menière 's disease

BACKGROUND Menière 's disease is characterised by attacks of hearing loss , tinnitus and disabling vertigo . Betahistine is used by many people to reduce the frequency and severity of these attacks but there is conflicting evidence relating to its effects . OBJECTIVES The objective of this review was to assess the effects of betahistine in people with Menière 's disease .

A double-blind , placebo-controlled , cross-over clinical trial was performed to assess the effect of betahistine hydrochloride ( Serc ) in Ménière 's disease . The diagnosis was based on paroxysmal attacks of rotational vertigo , with tinnitus , and a fluctuating sensori-neural deafness , together with the results of auditory and vestigular tests . Twenty-eight patients were admitted to the trial over 3 years . Twenty-two patients completed the trial . In total , they received betahistine 32 mg daily , for a period of 16 weeks , and placebo also for the same length of time , preceded in every case by a 4-week pre-treatment period . Daily symptom score cards were kept . There was a statistically significant improvement in favour of the drug with regard to vertigo , tinnitus and deafness . Vertigo was the most responsive symptom . No adverse reactions were observed Abstract . The present study compares the efficacy and safety of betahistine dihydrochloride to that of a placebo in recurrent vertigo result ing from Meniere 's disease ( MD ) or in paroxysmal positional vertigo ( PPV ) of probable vascular origin . The design was double-blind , multicentre and parallel-group r and omised . Eleven Italian centres enrolled 144 patients : 75 of the patients were treated with betahistine ( 41 MD/34 PPV ) and 69 with placebos ( 40 MD/29 PPV ) . The betahistine dosage was 16 mg twice per day for 3 months . Compared to the placebo , betahistine had a significant effect on the frequency , intensity and duration of vertigo attacks . Associated symptoms and the quality of life also were significantly improved by betahistine . Both the physician 's judgement and the patient 's opinion on the efficacy and acceptability of the treatment were in agreement as to the superiority of betahistine . The effective and safe profile of betahistine in the treatment of vertigo due to peripheral vestibular disorders was confirmed A double-blind , cross-over , placebo-controlled study of betahistine dihydrochloride ( 12 mg , t.i.d . ) was carried out in patients with vertigo of peripheral vestibular origin . Twenty-four patients completed the study , which consisted of two six-week treatment periods . The patients were diagnosed as suffering from Menière 's disease ( 15 patients ) , vertigo due to other ( specified ) causes ( five patients ) , or vertigo of unknown origin ( four patients ) . Patients were examined by the investigator at the start of the study and were re-assessed at three-weekly intervals . In addition , they recorded the nature , frequency and severity of their symptoms on diary cards . Both the incidence and severity of dizziness ( the predominant presenting complaint ) were found to be significantly reduced during betahistine treatment ( p = 0.004 ) . The occurrence of nausea and vomiting was also significantly reduced during betahistine treatment ( p = 0.014 and 0.036 respectively ) . There were no statistically significant differences in the results of audiometric or vestibulometric tests , or in the severity of tinnitus or deafness , between the two treatment periods . The overall comparisons of the two periods made by both the patients and the investigator were significantly in favour of betahistine ( p less than 0.001 ) . All diagnostic groups responded favourably to betahistine , confirming the efficacy of betahistine in the symptomatic treatment of peripheral vestibular vertigo . No unwanted signs or symptoms were reported The effects of betahistine hydrochloride ( Serc ) on the clinical features of Ménière 's disease were assessed in two double-blind , placebo-controlled , cross-over clinical studies . The diagnosis was based on a peripheral , fluctuating , recruiting , cochlear ( sensorineural ) deafness in one or both ears , tinnitus ( usually of low tone ) and paroxysmal attacks of rotational vertigo . Appropriate auditory and vestibular analyses confirmed the diagnosis . Twenty-four patients were admitted to the studies after careful screening over two- and -a-half years . Twenty-two patients completed the studies , ten of whom received betahistine and placebo for eight weeks each whereas the remaining twelve were given betahistine and placebo for twelve weeks each . the dose of betahistine was the same ( 16 mg . t.i.d . ) in both studies . Daily symptom score cards kept by all patients throughout the studies showed a statistically significant preference for betahistine over placebo with regard to vertigo ( p = 0 - 025 ) , tinnitus ( p = 0 - 010 ) and fullness of the ear ( p = 0 - 036 ) . Symptom scores of deafness and vomiting indicated trends in favour of betahistine but these did not attain statistical significance . Objective measurements of deafness ( mean db . loss ) , however , showed a highly significant improvement in favour of betahistine , when compared with placebo ( p less than 0 - 001 ) . Vestibular testing revealed no important difference between betahistine and placebo . No unwanted effects or adverse reactions attributable to betahistine were observed during the studies WHEN VERTIGO , associated with Meniere 's syndrome , becomes intractable and incapacitating , the patient becomes a c and i date for surgery . This is not a pleasant outlook for the patient , nor for the treating physician . As a consequence , there has been an incessant but yet unrewarding search for a satisfactory medical treatment . Williams 1 recently reported : Neither the definition , the diagnosis nor the dysfunction of Meniere 's disease is much clearer now than when Meniere first described the condition in 1861 .... On the basis of recently acquired information , we may define Meniere 's disease as a disorder of a predisposed stria vascularis , possibly in response to a hypothalamic stimulus , with the local synthesis of toxic amounts of histamine and possibly of norepinephrine , producing in the stria vascularis the picture of the slow stage of shock , increased hydrodynamic pressure in the endolymphatic system , loss of hearing , and , secondarily , attacks of vertigo , nausea and vomiting . In a

The MMSE contributes to a diagnosis of dementia in low prevalence setting s , but should not be used in isolation to confirm or exclude disease .

BACKGROUND The Mini Mental State Examination ( MMSE ) is a cognitive test that is commonly used as part of the evaluation for possible dementia . OBJECTIVES To determine the diagnostic accuracy of the Mini-Mental State Examination ( MMSE ) at various cut points for dementia in people aged 65 years and over in community and primary care setting s who had not undergone prior testing for dementia .

Objective : To determine whether a cognitive test package can predict the onset of dementia up to 11 years later , and the extent to which this prediction is independent of that provided by APOE genotype . Methods : Prospect i ve cohort study based on 54 general practice s in the UK ; 657 survivors of the 1088 participants in the MRC treatment trial of hypertension in older adults were followed for up to 11 years ; 370 participants ( 57 % of survivors ) were traced , screened for dementia , and genotyped for APOE in 1994 . Baseline assessment s included trail making test A , paired associated learning test , Raven ’s progressive matrices , and national adult reading test . At follow up , both mini-mental state examination and CAMCOG were used . Outcome measures were DSM-IIIR dementia and NINCDS-ADRDA possible and probable Alzheimer ’s disease . Results : All the cognitive tests completed in 1983 predicted onset of dementia and Alzheimer ’s disease up to 11 years later , as did APOE genotype . Cognitive test performance was not associated with APOE genotype . Addition of cognitive tests increased the area under the ROC curve for the prediction of Alzheimer ’s disease provided by age , family history , and APOE genotype ( 0.81 v 0.69 , p = 0.048 ) ; addition of APOE genotype did not increase the area under the ROC curve for the prediction provided by age , family history , and cognitive tests ( 0.81 v 0.77 , p = 0.28 ) . Conclusions : Simple tests of cognitive ability provide useful predictive information up to a decade before the onset of dementia . The predictive information provided is independent of , but not enhanced by , the addition of APOE genotype We developed a modified trail-making test using a PC and touch panel and compared it with the mini mental state examination ( MMSE ) . The test consisted of a series of numbers from 1 to 36 , r and omly arranged across the display . The object of the test was for the subject to touch the numbers in order , beginning with 1 and ending with 36 , in as little time as possible . The system consisted of a PC and a liquid crystal display ( LCD ) touch-panel screen . One hundred and thirty-four patients with dementia performed the test . Sixty of the 134 patients ( 15 male , 45 female ; average age , 81.1plusmn7 years ) were diagnosed as having Alzheimer 's disease and the others had cerebrovascular dementia . Sixty-two of 134 patients ( 23 male , 39 female ; average age , 77.6plusmn8 years ; MMSE score , 21.5plusmn5.6 points ) completed the test . The correlation coefficient between test performance time and MMSE score was -0.534 . This test may also be a useful indicator of focal frontal lesions and can be used as an early screening test for Alzheimer 's In the community at large , many older adults with minimal cognitive and functional impairment remain stable or improve over time , unlike patients in clinical research setting s , who typically progress to dementia . Within a prospect i ve population -based study , we identified neuropsychological tests predicting improvement or worsening over 1 year in cognitively driven everyday functioning as measured by Clinical Dementia Rating ( CDR ) . Participants were 1682 adults aged 65 + and dementia-free at baseline . CDR change was modeled as a function of baseline test scores , adjusting for demographics . Among those with baseline CDR = 0.5 , 29.8 % improved to CDR = 0 ; they had significantly better baseline scores on most tests . In a stepwise multiple logistic regression model , tests which remained independently associated with subsequent CDR improvement were Category Fluency , a modified Token Test , and the sum of learning trials on Object Memory Evaluation . In contrast , only 7.1 % with baseline CDR = 0 worsened to CDR = 0.5 . They had significantly lower baseline scores on most tests . In multiple regression analyses , only the Mini-Mental State Examination , delayed memory for visual reproduction , and recall susceptible to proactive interference , were independently associated with CDR worsening . At the population level , changes in both directions are observable in functional status , with different neuropsychological measures predicting the direction of change The project Epidemiology Research on Dementia in Antwerp ( ERDA ) estimated the prevalence of dementia in a r and om , population -based sample , stratified for age and sex . The sample of 1,736 elderly was screened at home with the Mini-Mental State Examination . All elderly under the cutoff of 23 - 24/30 got a diagnostic examination with the Cambridge Mental Disorders of the Elderly Examination and the DSM-IIIR criteria . The prevalence of dementia in the population above 65 years was estimated at 9 % . The following age-specific prevalences of dementia ( included mild dementia ) were found in the age-groups 65 - 69 , 70 - 74 , 75 - 79 , 80 - 84 , 85 + : 0.6 , 5.1 , 7.6 , 16.2 and 33.6 % . The prevalence of at least moderate dementia was 0.3 , 3.9 , 4.0 , 11.2 and 25.0 % , respectively . The prevalence of dementia , vascular dementia and dementia of the Alzheimer type was markedly higher in women than in men Background : Dementia is poorly recognized even by physicians . This study compares three instruments used to assess dementia in a community setting in Sri Lanka . Method : Translated and culturally adapted versions of the Mini Mental State Examination ( MMSE ) , Informant Question naire on Cognitive Decline in the Elderly ( IQCODE ) and Clinical Dementia Rating ( CDR ) were administered to 363 individuals selected by stratified r and om sampling in a periurban community in Sri Lanka . The results on the three instruments were compared with the independent psychiatric evaluation done on a concentrated sample of 37 individuals from the study population . Results : Culturally adapted MMSE , IQCODE and CDR can be used to screen dementia in Sri Lanka . IQCODE is the best among the three instruments with a sensitivity of 71.4 % and a specificity of 82.6 % when 3.5 is the cut-off . In addition , IQCODE is culturally acceptable , easy to administer and can be used in those with a low level of literacy as well as in those with hearing or visual impairment . Conclusion : IQCODE was found to be more effective and culturally acceptable as a screening tool for dementia in Sri Lanka , compared with MMSE and CDR Objective . To design a brief cognitive screener with acceptable sensitivity and specificity for identifying subjects with cognitive impairment Design . Cohort one is assembled from a community-based survey coupled with a second-stage diagnostic evaluation using formal diagnostic criteria for dementia . Cohort two is assembled from referrals to a specialty clinic for dementing disorders that completed the same diagnostic evaluation . Setting . Urban neighborhoods in Indianapolis , Indiana and the Indiana Alzheimer Disease Center . Patients . Cohort one consists of 344 community-dwelling black persons identified from a r and om sample of 2212 black persons aged 65 and older residing in Indianapolis ; cohort two consists of 651 subject referrals to the Alzheimer Disease Center . Measurements . Formal diagnostic clinical assessment s for dementia including scores on the Mini-mental state examination ( MMSE ) , a six-item screener derived from the MMSE , the Blessed Dementia Rating Scale ( BDRS ) , and the Word List Recall . Based on clinical evaluations , subjects were categorized as no cognitive impairment , cognitive impairment-not demented , or demented . Results . The mean age of the community-based sample was 74.4 years , 59.4 % of the sample were women , and the mean years of education was 10.1 . The prevalence of dementia in this sample was 4.3 % and the prevalence of cognitive impairment was 24.6 % . Using a cut-off of three or more errors , the sensitivity and specificity of the six-item screener for a diagnosis of dementia was 88.7 and 88.0 , respectively . In the same sample , the corresponding sensitivity and specificity for the MMSE using a cut-off score of 23 was 95.2 and 86.7 . The performance of the two scales was comparable across the two population s studied and using either cognitive impairment or dementia as the gold st and ard . An increasing number of errors on the six-item screener is highly correlated with poorer scores on longer measures of cognitive impairment . Conclusions . The six-item screener is a brief and reliable instrument for identifying subjects with cognitive impairment and its diagnostic properties are comparable to the full MMSE . It can be administered by telephone or face-to-face interview and is easily scored by a simple summation of errors OBJECTIVE To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer 's Disease ( CERAD ) . PATIENTS A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up . SETTING Twenty-one CERAD clinical sites throughout the United States . RESULTS An average annual decline of 3.4 points in CERAD patients returning for longitudinal re assessment s was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination . There was wide variability in individual rates of decline . Even with 4 years of follow-up , 15.8 % of the patients had no clinical ly meaningful decline in Mini-Mental State Examination score ( defined as a change in initial score > 3 , ie , 1 SD of measurement error ) . Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years . CONCLUSIONS Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function , it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score OBJECTIVES To determine whether the accuracy of the Mini-Mental State Examination ( MMSE ) in predicting future Alzheimer 's disease ( AD ) could be improved by the addition of patient and informant ratings of cognitive difficulties . DESIGN An inception cohort of nondemented patients followed longitudinally for 2 years . SETTING Patients referred to a university teaching hospital research investigation by their family physicians because of concerns about memory impairment . PARTICIPANTS One hundred sixty-five community-residing patients were included who did not have dementia or any identifiable cause for memory impairment . After 2 years , 29 met criteria for AD , and 95 were not demented . MEASUREMENTS Baseline assessment s included MMSE , an Informant Rating Scale , and a Patient Rating Scale of cognitive difficulties . After 2 years , patients were diagnosed following the reference st and ard for probable AD . Diagnosticians were blind to baseline scores . RESULTS Age and education were included in all analyses as covariates . The best logistic regression model included the Informant Rating Scale and the MMSE ( sensitivity = 83 % , specificity = 79 % ) . An empirically reduced six-item model that included two items each from the MMSE , the Patient Rating Scale , and the Informant Rating Scale produced a significantly better model than the one with the full test scores ( sensitivity = 90 % , specificity = 94 % ) . CONCLUSION Results indicate that inclusion of informant ratings with the MMSE significantly improved its accuracy in the prediction of probable AD . Replication in a new prospect i ve cohort of nondemented patients is necessary to confirm these findings Previous studies have suggested that education and race may affect performance on st and ardized mental status tests . In order to more clearly define these relationships , a prospect i ve longitudinal study was devised to answer two questions : ( 1 ) whether race or level of education affects scores on the Mini-Mental State ( MMS ) exam in non-demented people and ( 2 ) what numerical cutpoints maximize the sensitivity and specificity of utilizing the MMS to help diagnose dementia in blacks of varying educational attainment . A total of 100 white and 258 black individuals , recruited from two city hospital primary care geriatric clinics , were evaluated and subsequently followed longitudinally over a 2 1/2 year period in order to assess accurately the presence or absence of dementia . In the non-demented , total MMS scores and performance on each item of the MMS were analyzed , revealing that people with an 8th grade or less education consistently had significantly ( P less than .01 ) worse results than the better educated ( 9th grade or better ) on borough , attention items , recall of table and dog , copying , sentence writing , phrase repeating , and total score . Furthermore , a total of 25 % of the lower education group had an MMS score in the 18 - 23 range , traditionally thought to suggest dementia . There were no consistently significant differences between blacks and whites of equal education . In the better educated groups , using a score of 23 or less to define dementia maximizes the sensitivity and specificity of using the MMS in this diagnosis at 93 % and 100 % , respectively . In the lower education group , using 17 or less to define dementia maximizes sensitivity and specificity at 81 % and 100 % , respectively . ( ABSTRACT TRUNCATED AT 250 WORDS Background and aims : Diagnosis of dementia is often difficult in subjects with low educational level . Our aim was to evaluate the role of functional performance and the possibility of preferring scores of activities of daily living ( ADL ) and instrumental activities of daily living ( IADL ) in screening elderly people for diagnosis of dementia in a rural population of Southern Italy with a very high percentage of non-educated subjects . Methods : a r and om sample of 300 residents , out of 1089 subjects over 60 years of age living in San Marcellino ( Caserta , Campania ) , received door-to-door visit for information about their medical history , with clinical evaluation of general geriatric conditions , including the cumulative illness rating scale ( CIRS ) . Dementia was diagnosed if subjects had a Clinical Dementia Rating score ( CDR ) ≥ 1 and according to the criteria of DSM-IV , but not according to scores on the Mini Mental State Examination ( MMSE ) , ADL and IADL . Two hundred and nineteen normal subjects ( NS ) and 75 patients with dementia ( DP ) were evaluated . Results : in NS , their mean age- and education-corrected MMSE score was 22.15 ( lower than the normal cut-off value of 23.8 ) and 12.60 in DP ( p<0.0001 ) . In NS , the mean ADL score was higher than in DP ( 5.53 vs 2.64 , p<0.0001 ; only age was correlated with ADL scores ( coeff=− 0.44 , t=− 4.557 , p<0.0001 ) . Assuming age as covariate , ADL scores highly differentiated DP from NS ( F(1 , 289)=26.083 , p<0.0001 ) . In both sexes , mean IADL scores were higher in NS than in DP ( 4.46 vs 1.80 in men , p<0.0001 ) ; 6.85 vs 2.31 in women , p<0.0001 . Age and education did not influence IADL scores in men , but age greatly affected performance in women . IADL scores clearly differentiated NS from DP . In NS , a positive correlation was evident between ADL and IADL scores ( r=0.234 , p<0.0005 , but neither scores correlated with the MMSE scores , even when correlation was performed separately for men and women . In DP , a strong correlation was observed between ADL and IADL scores ( r=0.709 , p<0.0001 and significant correlations were also evident between the scores of MMSE and both ADL ( r=0.492,p<0.0001 ) and IADL ( r=0.398 , p<0.0004 ) . Conclusions : in a rural community with a high prevalence of non-educated subjects , cognitive impairment is related to education , whereas independent functioning is limited mainly to age and not to cognition , if the latter remains ( relatively ) unimpaired . These results point to the importance of an “ ecological ” approach to the evaluation of elderly people , particularly those living in small rural communities , where education and the social environment may give rise to difficulties in diagnosis of dementia . The assessment of functional autonomy by ADL and IADL scales may be a better screening tool in diagnosing dementia than the MMSE scores OBJECTIVES To test the Mini-Cog , a brief cognitive screening test , in an epidemiological study of dementia in older Americans . DESIGN A population -based post hoc examination of the sensitivity and specificity of the Mini-Cog for detecting dementia in an existing data set . SETTING The Monongahela Valley in Western Pennsylvania . PARTICIPANTS A r and om sample of 1,119 older adults enrolled in the Monongahela Valley Independent Elders Survey ( MoVIES ) . MEASUREMENTS The effectiveness of the Mini-Cog in detecting independently diagnosed dementia was compared with that of the Mini-Mental State Examination ( MMSE ) and a st and ardized neuropsychological battery . RESULTS The Mini-Cog , scored by an algorithm as " possibly impaired " or " probably normal , " and the MMSE , at a cutpoint of 25 , had similar sensitivity ( 76 % vs 79 % ) and specificity ( 89 % vs 88 % ) for dementia , comparable with that achieved using a conventional neuropsychological battery ( 75 % sensitivity , 90 % specificity ) . CONCLUSION When applied post hoc to an existing population , the Mini-Cog was as effective in detecting dementia as longer screening and assessment instruments . Its brevity is a distinct advantage when the goal is to improve identification of older adults in a population who may be cognitively impaired . Prior evidence of good performance in a multiethnic community-based sample further supports its validity in the ethnolinguistically diverse population s of the United States in which widely used cognitive screens often fail The Mini-Mental State Examination ( MMSE ) is a brief global instrument used to assess cognitive abilities in the elderly , requiring literacy as a prerequisite . Such a precondition is impractical for population s with widespread illiteracy . The present study aim ed to adapt the MMSE for the cultural context of Bangladesh and for use in population s irrespective of literacy skills . In the Bangla Adaptation of Mini-mental State Examination ( BAMSE ) , the MMSE items were changed in such a way that they would be applicable for illiterate individuals , as well as being culturally relevant in Bangladesh . Altogether 672 elderly , 262 literate and 410 illiterate individuals were tested with the BAMSE . To enable comparison between the BAMSE and MMSE , the literate elderly were tested with both instruments . Test-retest reliability of the BAMSE was assessed in 54 r and omly selected individuals . The results showed that , in comparison to the MMSE , the BAMSE demonstrated satisfactory test properties , although reliable differences were found on some of the individual items when the two instruments were compared . The association between the two instruments was good ( r=0.57 ) and the test-retest reliability was satisfactory ( r=0.70 ) . More importantly , the BAMSE was found to be less sensitive to age and education than the MMSE . Finally , our results suggest that in the socio-cultural context of Bangladesh , irrespective of literacy skills , the BAMSE is an instrument that can be used to assess cognitive function of the normal elderly Background To assess and compare the effectiveness and costs of Phototest , Mini Mental State Examination ( MMSE ) , and Memory Impairment Screen ( MIS ) to screen for dementia ( DEM ) and cognitive impairment ( CI ) . Methods A phase III study was conducted over one year in consecutive patients with suspicion of CI or DEM at four Primary Care ( PC ) centers . After undergoing all screening tests at the PC center , participants were extensively evaluated by research ers blinded to screening test results in a Cognitive-Behavioral Neurology Unit ( CBNU ) . The gold st and ard diagnosis was established by consensus of expert neurologists . Effectiveness was assessed by the proportion of correct diagnoses ( diagnostic accuracy [ DA ] ) and by the kappa index of concordance between test results and gold st and ard diagnoses . Costs were based on public prices and hospital accounts . Results The study included 140 subjects ( 48 with DEM , 37 with CI without DEM , and 55 without CI ) . The MIS could not be applied to 23 illiterate subjects ( 16.4 % ) . For DEM , the maximum effectiveness of the MMSE was obtained with different cutoff points as a function of educational level [ k = 0.31 ( 95 % Confidence interval [ 95%CI ] , 0.19 - 0.43 ) , DA = 0.60 ( 95%CI , 0.52 - 0.68 ) ] , and that of the MIS with a cutoff of 3/4 [ k = 0.63 ( 95%CI , 0.48 - 0.78 ) , DA = 0.83 ( 95%CI , 0.80 - 0.92 ) ] . Effectiveness of the Phototest [ k = 0.71 ( 95%CI , 0.59 - 0.83 ) , DA = 0.87 ( 95%CI , 0.80 - 0.92 ) ] was similar to that of the MIS and higher than that of the MMSE . Costs were higher with MMSE ( 275.9 ± 193.3 € [ mean ± sd euros ] ) than with Phototest ( 208.2 ± 196.8 € ) or MIS ( 201.3 ± 193.4 € ) , whose costs did not significantly differ . For CI , the effectiveness did not significantly differ between MIS [ k = 0.59 ( 95%CI , 0.45 - 0.74 ) , DA = 0.79 ( 95%CI , 0.64 - 0.97 ) ] and Phototest [ k = 0.58 ( 95%CI , 0.45 - 0.74 ) , DA = 0.78 ( 95%CI , 0.64 - 0.95 ) ] and was lowest for the MMSE [ k = 0.27 ( 95%CI , 0.09 - 0.45 ) , DA = 0.69 ( 95%CI , 0.56 - 0.84 ) ] . Costs were higher for MMSE ( 393.4 ± 121.8 € ) than for Phototest ( 287.0 ± 197.4 € ) or MIS ( 300.1 ± 165.6 € ) , whose costs did not significantly differ . Conclusion MMSE is not an effective instrument in our setting . For both DEM and CI , the Phototest and MIS are more effective and less costly , with no difference between them . However , MIS could not be applied to the appreciable percentage of our population who were illiterate BACKGROUND Primary care should be the place for the early detection of mild cognitive impairment ( MCI ) and dementia ; however , a considerable proportion of these processes remain undetected at this setting . Family doctors may not have enough time or expertise for cognitive testing . The utility of clinical variables , other than cognitive tests , has hardly been investigated . OBJECTIVES To explore the diagnostic and prognostic value of the variables that are usually collected in the medical history of patients with suspected cognitive impairment . METHODS In this cohort study , people aged ≥ 50 years were prospect ively search ed for cognitive decline of unknown aetiology by seven primary care physicians ( PCP ) during their practice . The baseline assessment included demographic variables , symptom-related variables , medical and psychiatric co-morbidity , family history of dementia and neurological exam . The diagnosis was made by a neurologist at baseline and after 1 year . RESULTS One hundred and seventy-six patients were analysed of whom 81 ( 46.0 % ) had MCI and 18 ( 10.2 % ) had dementia at baseline . After 1 year , 8 ( 9.9 % ) MCI patients had progressed to dementia , but 48 ( 59.3 % ) had reverted to normal cognition . Old age , source of symptoms ( informant or PCP ) , short duration and low education were associated with MCI or dementia at baseline ; low education predicted progression to dementia in MCI patients and less chronic medical conditions and younger age predicted reversion from MCI to normal cognition ( P < 0.05 , adjusted regression models ) . CONCLUSION Clinical data usually collected on medical history by PCP are useful to detect patients with MCI and dementia and also to predict MCI outcome BACKGROUND AND PURPOSE To vali date a Short Form of the Mini-Mental State Examination ( SMMSE ) as a screening test for dementia in older ambulatory individuals followed in a memory clinic for a memory complaint . METHODS A total of 202 cognitively healthy individuals , 100 individuals with a mild cognitive impairment and 304 demented individuals sent for a memory complaint by their primary care physician to a memory clinic were prospect ively included in this cross-sectional study . They were r and omized into derivation ( n = 303 ) and validation ( n = 303 ) groups . The SMMSE score was built from six memory items of MMSE , with a score ranging from 0 to 6 ( i.e. best performance ) . RESULTS The receiver operating characteristic curve showed an area under the curve of 0.98 for the derivation group and 0.97 for the validation group without differences between curves ( P = 0.254 ) . The cut-off between the sensitivity and the specificity of the SMMSE score for clinical ly diagnosed dementia was ≤4 . The performance of the SMMSE for the diagnosis of dementia was high in the derivation and validation groups : sensitivity at 93.1 % and 93.8 % , specificity at 93.8 % and 90.5 % , positive predictive value at 94.3 % and 90.1 % , negative predictive value at 92.5 % and 94.0 % , likelihood ratio of positive test at 14.9 and 9.8 and of negative test at 0.07 and 0.07 , respectively . CONCLUSIONS The Short Form of the Mini-Mental State Examination was a good screening test for dementia in older individuals followed in a memory clinic for a memory complaint . The next step should be the confirmation of its discriminative value in older primary care patients The incidence of dementia and risk factors has not been fully investigated in Japan . Following a prevalence study in 1998 , we investigated the incidence and associated factors in the same population in 2003 and 2005 . R and omly selected 771 residents in Tajiri were targeted . The final participants included 204 ( 65.2 % ) healthy older adults ( Clinical Dementia Rating , CDR 0 ) and 335 ( 73.1 % ) people with question able dementia ( CDR 0.5 ) . We analyzed the incidence of dementia and dementing diseases , and possible risk factors . The risk factors included demographics , lifestyle-related factors , vascular risk factors , cognitive functions , and MRI findings . Overall , 3.9 % of the CDR 0 and 37.0 % of the CDR 0.5 participants developed dementia during the 5-year period , whereas 40.2 % of the CDR 0.5 participants developed dementia during the 7-year period . Older adults had a higher incidence . Higher CDR Box scores had a higher incidence . Of the dementing diseases , 60.8 % of participants developed Alzheimer ' disease ( AD ) , followed by vascular dementia ( VaD ) , 17.9 % . Logistic regression analyses showed that age , MMSE , cognitive functions such as recent memory , and generalized atrophy were significant predictors of progression to AD . Similarly , predictive factors for progression to VaD were age , MMSE , cognitive functions such as frontal function , and white matter lesions and cerebrovascular diseases . A comprehensive system including CDR , cognitive tests , and MRI , is recommended in community-based health policy planning OBJECTIVES To study the yield of three instruments for detection of patients with cognitive impairment in primary care . To investigate whether combining tests is better for detecting impairment than applying them separately . METHODS Seven primary care physicians ( PCP ) systematic ally recruited individuals aged over 49 years with a complaint or suspicion of cognitive impairment . The tests administered were the Mini-Mental State Test ( MMS ) , the Informant Question naire on Cognitive Decline in the Elderly ( IQCODE ) and the Pfeffer Functional Activities Question naire ( FAQ ) . We calculated sensitivity , specificity and the area under the curve ( AUC ) and applied logistic regression analysis to determine the yield of the tests in combination . The gold st and ard was the clinical judgement of a neurologist based on a comprehensive assessment , which included a formal neuropsychological workup . RESULTS Of the 160 study patients , 90 ( 56 % ) had cognitive impairment ( 15 of these had dementia ) . The MMS had a sensitivity of 77 % and a specificity of 70 % in screening for cognitive impairment , with an AUC of 0.82 . Incorporation of the IQCODE increased the AUC to 0.86 ( P = 0.01 ) . As for dementia , the FAQ reached a sensitivity of 87 % and a specificity of 82 % , with an AUC of 0.91 . Incorporation of the MMS increased the AUC to 0.95 ( P = 0.03 ) . CONCLUSIONS Cognitive impairment is probably underdiagnosed in primary care . The combination of the FAQ and the MMS had excellent performance for dementia detection ; however , no satisfactory instrument or instrument combination could be found for cognitive impairment BACKGROUND As population s age , screening instruments for cognitive impairment and dementia will become of increasing importance in clinical practice . Mini-Mental Parkinson ( MMP ) , a derivative of the Mini-Mental State Examination ( MMSE ) , was originally described as a cognitive screening instrument for use in Parkinson 's disease . Its item content addresses some of the acknowledged shortcomings of the MMSE . Pragmatic use of MMP in general cognitive clinics has not previously been examined . AIM To compare the performance of two scales , Mini-Mental Parkinson ( MMP ) and the Mini-Mental State Examination ( MMSE ) , as cognitive screening instruments for dementia in a memory clinic population . METHODS MMP was administered prospect ively to 201 consecutive new patient referrals independent of other tests used to establish dementia diagnosis according to st and ard diagnostic criteria ( DSM-IV ) . Diagnostic utility of MMP for dementia was measured and compared with MMSE . RESULTS MMP proved easy to use and acceptable to patients . Optimal test accuracy ( 0.86 ) was at MMP cutoff of ≤ 17/32 , with sensitivity 0.51 , specificity 0.97 , positive predictive value 0.83 , negative predictive value 0.87 , and area under Receiver Operating Characteristic curve 0.89 . Using a higher cutoff ( ≤ 29/32 ) , MMP sensitivity was 1.00 with specificity 0.70 . MMP scores correlated with MMSE ( r = 0.93 ) and diagnostic agreement was high ( κ = 0.85 ) . CONCLUSIONS MMP is a useful screening instrument in the memory clinic setting , with patients who fall below the design ated cutoff requiring further investigation to ascertain a cause for their cognitive impairment OBJECTIVE To estimate the prevalence of dementia and its subtypes by sex and age group for five regions of Canada . DESIGN Prevalence survey . SETTING Community and institutional setting s in Canada , excluding those in the two territories , Indian reserves and military units . PARTICIPANTS Representative sample of people aged 65 and over interviewed between February 1991 and May 1992 . Those in the community ( 9008 subjects ) were chosen r and omly from medicare lists in nine provinces or from the Enumeration Composite Record in Ontario . People in institutions ( 1255 ) were r and omly selected from residents in stratified r and om sample s of institutions in each region . INTERVENTIONS Screening with the Modified Mini-Mental State ( 3MS ) Examination to identify cognitive impairment . Clinical examination of all those in institutions , those in the community with a 3MS score of less than 78 and a sample of those in the community with a 3MS score of 78 or more to diagnose dementia . Dementia and Alzheimer 's disease were defined according to established criteria . MAIN OUTCOME MEASURES Prevalence of dementia of all types , by region , sex and age group , the estimated number of cases in the population by type of dementia and the age-st and ardized rate per 1000 population . RESULTS The prevalence estimates suggested that 252,600 ( 8.0 % ) of all Canadians aged 65 and over met the criteria for dementia ( 95 % confidence interval [ CI ] 236,800 to 268,400 ) . These were divided roughly equally between the community and institutional sample s ; the female : male ratio was 2:1 . The age-st and ardized rate ranged from 2.4 % , among those aged 65 to 74 years , to 34.5 % , among those aged 85 and over . The corresponding figures for Alzheimer 's disease were 5.1 % overall ( 161,000 cases ; 95 % CI 148,100 to 173,900 ) , ranging from 1.0 % to 26.0 % ; for vascular dementia it was 1.5 % overall , ranging from 0.6 % to 4.8 % . If the prevalence estimates remain constant , the number of Canadians with dementia will rise to 592,000 by 2021 . CONCLUSIONS These Canadian estimates of the prevalence of dementia fall toward the upper end of the ranges in other studies , whereas the estimates for Alzheimer 's disease fall in the middle of the ranges . This may suggest an unusual balance between Alzheimer 's and other forms of dementia in the Canadian population The demographic , health , and mental functioning characteristics of nonresponders to a community-based cross-sectional study of cognitive functioning among the elderly in Amsterdam , the Netherl and s ( Amsterdam Study of the Elderly ( AMSTEL ) , October 1990 to May 1991 ) , were examined and compared with responders . The r and omly selected age-stratified ( 65 - 74 , 75 - 84 years ) sample was drawn from nonresponders listed with a sub sample ( n = 8) of general practitioners whose lists served as the sampling frame for the main study . The general practitioners approached and interviewed the responding nonresponders using the same st and ardized questions that were used in the main study . Nonresponders ( n = 115 ) and responders ( n = 999 ) from the same medical practice s were compared by means of chi-square and odds ratios . Compared with responders , these nonresponders more often reported a history of psychiatric illness , heart attack , stroke , and diabetes , and were more likely to be unmarried , to have a lower education , and to do poorly on the cognitive test ( odds ratio = 1.6 , 95 % confidence interval 1.0 - 2.6 ) . Most significant physical and mental health differences by response status were seen among the persons aged < 75 years and not among those aged > or = 75 years . The odds for poor cognitive test performance associated with age and stroke were relatively more biased than those associated with other risk factors . These results suggest that the characteristics of young-old and old-old elderly nonresponders to cross-sectional studies of cognitive function may differ , and that there may be selective nonresponse that could bias , to a different degree , estimates of risk for poor cognitive functioning . Studies should investigate the possibilities for nonresponse in their own setting As part of the Canadian Study of Health and Aging ( CSHA ) , a battery of neuropsychological measures was administered to 1879 participants . Participants who received neuropsychological evaluations were selected from an age-stratified r and om sample on the basis of scores on a cognitive screening tool , the Modified Mini-Mental State Examination ( 3MS ) . Seventy-five percent of the sample seen for neuropsychological evaluation scored between 50 and 77 on the 3MS and 25 % of the sample scored 78 or over . This paper provides a descriptive summary of the method ological basis of the neuropsychological component of the CSHA . The findings indicated that differences existed between participants administered the battery in English or French in terms of refusal rates and diagnoses of dementia . Cursory examination of the utility of the battery indicated that the battery was tolerated well by both the participants and the psychologists involved with the study and that measures of memory functioning were central to diagnostic decision-making . The relations between neuropsychological , preliminary medical and consensus diagnoses were examined and indicated that neuropsychological information influenced diagnostic decision-making . The neuropsychology component of the CSHA is a rich source of information on persons aged 65 years and older in Canada To investigate the relationship between hypertension and Alzheimer 's disease(AD ) and the change of Alzheimer 's patients ' blood pressure(BP ) before and after the onset of AD , we conducted this epidemiological study . Subjects for this study were individuals who participated in a large scale , r and omized controlled trial of nutritional intervention from 1984 to 1991 . Participants were initially screened for dementia using Chinese Mini-Mental State Examination ( CMMS ) and Activities of Daily Living ( ADL ) . Positive subjects were subsequently administered a detailed neuropsychological and neurobehavioral examination . The diagnosis of AD was made by a consensus conference of psychiatrists using Diagnostic And Statistical Manual Of Mental Disorders-Fourth Edition(DSM-IV ) criteria . 16488 subjects were examined and 301 were diagnosed as AD . We compared the prevalence of AD in different population s that were stratified with 1984 's systolic or diastolic blood pressure(those four stratifications being high blood pressure , borderline blood pressure , normal , low blood pressure ) , and compared the change of blood pressure of 301 AD patients between 1984 and 1999 - 2000 , which is before and after the onset of AD respectively . Multiple Logistic Regression ( 1:1 nested case-control study ) was used to assess if hypertension is an independent risk factor for AD , and Trend test was used to assess the relationship between blood pressure and AD . Here we demonstrate that there was a significant difference in AD prevalence among different population s stratified by systolic or diastolic blood pressure ( P < 0.01 ) . The prevalence is highest in hypertension group , and lowest in hypotension group . Multiple Logistic Regression identified high blood pressure as a risk factor for AD ( OR = 1.97 , 95%CI:1.09 - 3.54 , P = 0.02 ) . Trend test showed that there is a significant dose-response relationship between blood pressure and AD ( P < 0.0002 ) . For hypertensive AD patients , there was no significant difference in systolic blood pressure(SBP ) before and after the onset of AD , but diastolic blood pressure(DBP ) decreased dramatically after the onset of AD ( P < 0.01 ) ; however , the result also showed that DBP decrease occurred in the non-demented group . Based on this , we think the DBP decrease is not related to AD . We further investigated whether BP values differed crossed-sectionally between the AD- patients and non-demented individuals . We found that regardless of SBP or DBP , the BP values of the AD group were all significantly higher than that of non-demented . In summary , these data suggest there is a strong relationship between hypertension and AD ; however , the mechanism remains to be studied This two-stage epidemiologic study was to investigate the prevalence and types of dementia among elderly people in the Saa-Min district of Kaohsiung City in Taiwan . In stage one , the Chinese Mini-Mental Status Examination ( CMMSE ) and Blessed Dementia Rating Scale were employed . In stage two , a comprehensive neurobehavioral examination and neuropsychologic tests were administered by neurologists and neuropsychologists . Dementia was defined by DSM-III-R criteria . The National Institute of Neurological and Communication Disorders and Stroke-Alzheimer 's Disease and Related Disorders Association guidelines for Alzheimer 's disease ( AD ) and the National Institute of Neurological Disorder and Stroke-Association international pour la Recherche et l'Enseignement en Neurosciences criteria for vascular dementia ( VaD ) were applied . A total of 1,016 r and omly selected elderly people participated in phase one : 131 people with CMMSE below cutoff values participated in phase two , of whom 45 were confirmed to have a form of dementia . The prevalence of dementia in this sample was 4.4 % ( 3.2 % in men and 5.8 % in women ) : 2.0 % for those 65 to 74 years old , 8.3 % for those 75 to 84 and 24.4 % for those > or = 85 years old ; 6.0 % for those who were illiterate , 3.3 % for those who attended grade -school ; and 2.8 % for those who finished junior-high-school . AD ( 22 cases , 48.9 % ) was the most common cause of dementia , followed by VaD ( 11 cases , 24.4 % ) and mixed dementia ( MIX : 5 cases , 11.1 % ) . Old age and being female were significant high risk factors for AD . Medical history indicated that stroke and hypertension were significant risk factors for VaD. A relatively high prevalence of dementia was observed in this study , probably because we assessed neurobehavior in great detail . Although AD was the leading cause of dementia in the present population sample . VaD and MIX also comprised an important proportion , reflecting the high prevalence of stroke in Taiwan . Older women had high risk for AD , not for VaD ; and those with a history of stroke and hypertension had high risk for VaD , not for AD To further investigate the relationship between psychiatric disorders and dementia in elderly patients , the authors drew a population -based , age-stratified r and om sample from residents of Rochester , Minnesota , age 65 and older . A trained paramedic completed a 90-minute screening interview , including the Symptom Checklist-90 , Mini-Mental State Exam , and Auditory-Verbal Learning Test . Persons failing the screens were interviewed by a psychiatrist and a neurologist . DSM-III-R diagnoses were assigned for dementia and other psychiatric disorders . Of 201 participants , 37 were evaluated further by both neurologist and psychiatrist . One received a psychiatric diagnosis alone . Dementia alone was present in four people . Concurrent psychiatric diagnoses and dementia were found in 17 subjects . Much of the psychopathology found in older persons occurs in people with cognitive impairment . Current diagnostic nosology may not be able to capture the interrelatedness of psychiatric syndromes and cognitive impairment in elderly patients BACKGROUND Few norms exist for the elderly on the cognitive tests commonly used to screen for dementia ; conventional cutpoints used in clinical setting s may be of limited value in population screening . A particular problem is posed by elderly population s with low educational levels , as performance on most cognitive tests is affected by education . Thus , a healthy but poorly educated population may obtain test scores in the range considered impaired in the clinical setting . METHODS A r and om sample of 1,367 subjects aged 65 + years was screened for dementia in a rural community in Southwestern Pennsylvania . Two sets of cognitive measures were used : a global cognitive scale ( the MMSE ) and a brief battery of tests tapping a variety of cognitive domains . Rather than using a priori cutoff scores , we examined the specificity and sensitivity for dementia of two operationally defined levels of cognitive impairment , at the 5th and 10th percentiles of the study sample on each set of measures . RESULTS Results suggest that the screening of multiple cognitive domains at the 10th percentile had significantly greater sensitivity but not lower specificity for definite dementia than did the use of the single global scale . CONCLUSION Our data support the use of population -based cutpoints over st and ard cutoff scores , in that the global scale at the conventional cutoff was less sensitive than the battery at the same percentile , and because adequate norms do not exist for tests such as those in the battery Background : Although the Mini-Mental State Examination ( MMSE ) is widely used in clinical practice , few norms exist for healthy population s covering a broad range of ages . Objective : To obtain MMSE norms specific for age , gender , and education in healthy adults . Methods : From the population registers of seven communities across Italy , we selected a proportionate r and om sample of residents age 20 to 79 years to evaluate their health status with respect to conditions affecting cognitive performance . This sample yielded 908 persons who were deemed to be without cognitive impairment and who were then given the MMSE . We calculated fifth percentile norms and presented them as step functions . We then vali date d the norms as a screening tool for dementia in persons age 65 to 79 years . The validation was based on unpublished data from a separate study and involved estimates of sensitivity and specificity . Results : The norms declined with advancing age , especially for less educated women . Given any age and sex , the norms were higher for individuals with higher educational levels . In screening for dementia , the norms had a sensitivity of 85 % and a specificity of 89 % . Conclusions : When using MMSE scores , it is important to account for age , gender , and education , especially in population s where the educational level is low . Expressing MMSE norms as step functions provides an easy-to-use tool for neurologists and other clinicians The Helsinki Aging Study is based on a r and om sample of 795 subjects aged 75 years ( N = 274 ) , 80 years ( N = 266 ) and 85 years ( N = 255 ) . Ninety‐three demented patients were found . All were assessed for severity of dementia by Clinical Dementia Rating ( CDR ) scale by a general practitioner and according to the DSM‐III‐R criteria by a neurologist . The Mini‐Mental State Examination ( MMSE ) was carried out by a community nurse and the Index of ADL and the IADL‐scale by a close informant . The correlation of the severity of dementia between the DSM‐III‐R criteria and the CDR scale was moderate . The overall agreement was 64.5 ° and the Kappa index 0.56 . The CDR scale tended to put patients in milder categories than the DSM‐III‐R criteria . The correlation between the clinical scales and categorized MMSE was moderate to fair . The overall agreement between MMSE and DSM‐III‐R criteria was 64 % ( Kappa 0.44 ) and between MMSE and CDR scale 55 % ( Kappa 0.33 % ) . The dispersion of the functional scales ( ADL , IADL ) was much greater indicating that there were also other factors influencing the functional capacity than the degree of dementia . Different methods in staging dementia give different results thus influencing for instance the results of epidemiological studies . Functional scales are needed in clinical practice in addition to the assessment of the severity of dementia . The CDR scale is useful in assessing the need for support services The distribution of total Mini-Mental State Examination ( MMSE ) scores , individual items , and groups of items were studied in French elderly community residents from a r and om sample of 2727 subjects . Serial sevens , recall three objects , and copy pentagons had the lowest percentage of correct responses , while orientation to place , naming two objects , and three objects registration had the highest percentage of correct responses . The structure of correlation of the items was studied using Principal Components Analysis . The projection of the items on the first axis reflects the tendency of the items to vary in the same direction and is compatible with the fact that the MMSE items are all indicators of the same concept : cognitive performance . The second and third axes identify clusters of highly correlated variables and provide support for the internal validity of the MMSE score for a French population . The full MMSE score seems to be a valid instrument for the evaluation of cognitive performance in community-based elderly residents OBJECTIVES To study whether a low , " normal " sumscore ( i.e. , 24 or higher ) on the Mini-Mental Status Examination ( MMSE ) near the cutpoint usually employed for identifying persons with cognitive impairment predicts later development of dementia . DESIGN A prospect i ve study of a r and om sample of nondemented persons aged 75 years and older , according to DSM-III criteria , with follow-ups after 3 and 6 years . PARTICIPANTS The subjects were 215 persons living at home , mean age 81 years , 81 % women . Their mean MMSE sumscore at the start of the study ( T0 ) was 27.9 ( range 24 - 30 ) . MAIN RESULTS A low MMSE sumscore at T0 was identified as a statistically strongly significant predictor of dementia after 3 years ( P < .001 ) , when more than 40 % of those with a sumscore of 24 or 25 at T0 had become demented . A similar , although weaker and statistically nonsignificant , trend was observed for the risk after 6 years in relation to MMSE scoring at baseline . CONCLUSION Persons with a sumscore of 24 or 25 and classified as not suffering from dementia according to the DSM-III criteria are at high risk of developing dementia within 3 years To determine the prevalence and subtypes of dementia in southern Taiwan , a two-phase study consisting of a phase I screening survey using the Mini-Mental Status Examination ( MMSE ) and a phase II diagnostic examination using the CERAD neuropsychological battery and the neurobehavioral examination was conducted . According to the household records , stratified r and om sampling by the degree of urbanization of the community was used , and 2915 inhabitants aged 65 and over participated in this study . The ICD-10NA criteria for dementia , NINCDS-ADRDA guidelines for Alzheimer 's disease ( AD ) , and NINDS-AIREN criteria for vascular dementia ( VaD ) were employed . Three hundred and ninety-eight persons who had MMSE scores below the cutoff values were recruited into the phase II study , of whom 108 had dementia . The prevalence rate ( PR ) of dementia was 3.7 % , increasing from 1.3 % in people 65 - 69 years old to 16.5 % in people 85 years old and older . The age-st and ardized PR ( ASPR ) was 4.0 % . AD ( 58 cases , 53.7 % , PR=2.0 % , ASPR=2.3 % ) was the most common cause of dementia , followed by VaD ( 25 cases , 23.1 % , PR=0.9 % , ASPR=0.9 % ) , and mixed dementia ( eight cases , 7.4 % ) . After adjusting for age , sex and education using logistic regression analysis , aging was a significant risk factor for AD , VaD and total dementia . Female sex and illiteracy were significant risk factors for AD only . We concluded that the prevalence of dementia in Taiwan is lower than in the developed countries , which could be due to a relatively young elderly population and a high mortality from dementia in Taiwan . AD is the leading cause of dementia in Taiwan . Considering the high stroke prevalence , the relatively lower prevalence of VaD in Taiwan deserves further investigation The selective reminding procedure ( SRP ) has been proposed for the assessment of distinct aspects of episodic memory , i.e. storage to and retrieval from short-term and long-term memory , item learning and list learning , and as dementia screening tool . In the present study SRP results were analysed in 256 prob and s from the general elderly population . SRP scores were highly intercorrelated , and principal component analysis yielded only one single factor . The SRP scores were moderately and not differentially correlated with immediate and delayed free recall and recognition and with verbal fluency . All SRP scores discriminated nondemented prob and s with episodic long-term memory impairment from those without . The MMSE performed significantly better than any SRP score in detecting dementia . The theory-based assumption that the SRP allows assessment of different , independent aspects of memory could not be vali date d. It is suggested that the SRP is a mixed measure of semantic memory , episodic long-term and short-term memory , and working memory , and that the different SRP scores do not allow to assess different memory functions . Thus , the SRP may neither be recommended for assessment of different subfunctions of memory nor for dementia screening BACKGROUND The objective of this study was to evaluate the efficacy and safety of metrifonate , a long-acting acetylcholinesterase inhibitor , in patients clinical ly diagnosed with probable Alzheimer 's disease of mild-to-moderate severity . METHOD This was a prospect i ve , multicenter , 26-week , double-blind , parallel group study . The 264 r and omized patients met diagnostic criteria of the National Institute of Neurological and Communicative Diseases and Stroke and the Alzheimer 's Disease and Related Disorders Association for probable Alzheimer 's disease . Patients had Mini-Mental State Examination ( MMSE ) scores of 10 - 26 and ischemic scores ( Rosen modification ) of < 4 . Metrifonate-treated patients received a single 50-mg dose once daily . The efficacy of metrifonate was investigated with respect to 3 symptom domains . Cognitive performance was analyzed using the Alzheimer 's Disease Assessment Scale-Cognitive Subscale ( ADAS-Cog ) and the MMSE . Psychiatric and behavioral disturbances were analyzed using the Neuropsychiatric Inventory ( NPI ) and the ADAS-Noncognitive subscale ( ADAS-Noncog ) . The ability to perform instrumental and basic activities of daily living was evaluated using the Disability Assessment for Dementia ( DAD ) scale . Additionally , global state was assessed using the Clinician Interview-Based Impression of Change with Caregiver Input ( CIBIC-Plus ) scale . RESULTS After 26 weeks of metrifonate therapy , a statistically significant benefit of metrifonate was observed in the cognitive performance of Alzheimer 's disease patients ( ADAS-Cog , t = 2.55 , df = 237 , p = .012 ; MMSE , t = 4.60 , df = 237 , p = .0001 ) . Metrifonate also significantly attenuated the deterioration in activities of daily living of the patients ( DAD total score , t = -2.11 , df = 233 , p = .036 ) and relieved patients ' psychiatric and behavioral disturbances ( NPI total score , t = 2.51 , df = 233 , p = .013 ) . In addition , metrifonate significantly improved the scores for the global state of the patients ( CIBIC-Plus , t = 2.07 , df = 232 , p = .039 ) . Metrifonate was well tolerated ; adverse events were predominantly mild in intensity , and no hepatotoxicity was observed . CONCLUSION In this study , metrifonate was safe and well tolerated . It benefited the cognitive decline , psychiatric and behavioral disturbances , impaired ability to perform instrumental and basic activities of daily living , and global state of patients diagnosed with mild-to-moderate Alzheimer 's disease The population ‐based Helsinki Aging Study was comprised of three age groups : 75‐ , 80‐ and 85‐year‐olds . A r and om sample of 511 subjects completed the Mini Mental State Examination ( MMSE ) and were assessed on the Clinical Dementia Rating ‐ scale ( CDR ) . According to the CDR results 446 subjects were screened as non‐demented . Of these subjects 30 % scored below or at 24 MMSE points . Age , education and social group had a significant effect on the MMSE scores , even after excluding the demented cases . Together they explained 10 % of the total variance within the MMSE . Social group correlated with education . The MMSE scores were corrected according to age and education . Adjustment of the originally used cutpoint of 24 result ed in cutpoints of 25 and 26 among the 75‐year‐olds , in the low and high education groups respectively ; 23 and 26 in the 80‐year‐olds ; 22 and 23 in the 85‐year‐olds OBJECTIVE To establish the criterion validity of the MMSE for dementia in a community-based population . DESIGN Descriptive . SETTING Eight rural general practice s and eight adherent institutions for long-term care near Zwolle , the Netherl and s. METHODS In the first ( screening ) stage , the MMSE was applied , in the second ( diagnostic ) stage the ' Cambridge examination for mental disorders of the elderly ' ( CAMDEX ) was used . After exclusion of subjects with clinical ly relevant impairment of hearing and ( or ) vision , analyses were based on 2151 screened subjects . Based on a non-proportional , stratified r and omized sampling procedure using the MMSE score as the stratification variable , 390 of the screened subjects were examined with the CAMDEX . Seventy-seven cases of DSM-III-R dementia were identified . Based on 390 paired observations the relationship between MMSE score and DSM-III-R dementia was modelled by logistic regression . After extrapolation of this relationship to the total screened population , sensitivity and specificity figures were calculated at several cut-offs of the MMSE , and Receiver Operating Characteristic ( ROC ) curves were constructed for the total population as well as for four sub population s. ( men , women , < 80 , > or = 80 years ) . RESULTS At the cut-off of 23/24 , sensitivity was 0.76 and specificity 0.91 in the total population . However , the criterion validity of the MMSE varied substantially between the four sex-age combinations . Criterion validity was especially poor for women in the younger age range . CONCLUSION The MMSE has only limited value in clinical practice . Use of uniform cut-offs has to be rejected BACKGROUND Provocative international disparities reported in the prevalence rates of dementia and depression require further investigation . This is the first psychiatric study , to the best of our knowledge , about the prevalence of DSM-III-R dementing and depressive disorders and their relationships in a representative , stratified community sample of the elderly in both a Spanish-speaking country and southern Europe . METHODS A two-stage screening was completed in 1080 elderly . Sampling with replacement was done , and the cumulative response rate was 88 % . In phase 1 , lay interviewers administered the Spanish versions of the Mini-Mental State examination and the Geriatric Mental State Schedule-Automated Geriatric Examination for Computer Assisted Taxonomy package . In phase 2 , research psychiatrists administered the same instruments and the History and Aetiology Schedule to all the probable cases and a similar number of r and omly selected , probably normal subjects . RESULTS An estimated 5.5 % of the elderly were considered to have a dementing disorder , the most prevalent types being primary degenerative dementia , Alzheimer 's type ( 4.3 % ) , and multi-infa rct dementia ( 0.6 % ) . Depressive disorders were found in 4.8 % of the elderly . Psychiatric morbidity , specifically depression , was associated with lower educational levels . " Case levels " of depression were documented in 25.4 % of the demented cases and case levels of " organic " disturbance were seen in 18.2 % of cases of major depression . CONCLUSIONS Among the elderly , the prevalence of Alzheimer 's disease and multi-infa rct dementia , as opposed to depression , increases steeply with age . The overlap found between dementia and depression may have nosological implication s. There could be an effect of lower education levels on psychiatric morbidity , particularly on depression OBJECTIVES To estimate and compare the frequency and prevalence of mild cognitive impairment ( MCI ) and related entities using different classification approaches at the population level . DESIGN Cross-sectional epidemiologic study of population -based cohort recruited by age-stratified r and om sampling from electoral rolls . SETTING Small-town communities in western Pennsylvania . PARTICIPANTS Of 2,036 individuals aged 65 years and older , 1,982 participants with normal or mildly impaired cognition ( age-education-corrected Mini-Mental State scores ≥ 21 ) . MEASUREMENTS Demographics , neuropsychological assessment expressed as cognitive domains , functional ability , and subjective reports of cognitive difficulties ; based on these measurements , operational criteria for the Clinical Dementia Rating ( CDR ) scale , the 1999 criteria for amnestic MCI , the 2004 Exp and ed criteria for MCI , and new , purely cognitive criteria for MCI . RESULTS A CDR rating of 0.5 ( uncertain/very mild dementia ) was obtained by 27.6 % of participants , whereas 1.2 % had CDR ≥ 1 ( mild or moderate dementia ) . Among those with CDR < 1 , 2.27 % had amnestic MCI and 17.66 % had exp and ed MCI , whereas 35.17 % had MCI by purely cognitive classification . Isolated executive function impairment was the least common , whereas impairment in multiple domains including executive function was the most common . Prevalence estimates weighted against the U.S. Census are also provided . CONCLUSIONS The manner in which criteria for MCI are operationalized determines the proportion of individuals who are thus classified and the degree of overlap with other criteria . Prospect i ve follow-up is needed to determine progression from MCI to dementia and thus empirically develop improved MCI criteria with good predictive value Background : In the context of suspected cognitive disorders , the validity of memory complaints is subject to considerable debate . This investigation documents the prevalence of memory complaints and assesses the validity of memory complaints for detecting cognitive impairment . Methods : The sample comprises 349 r and omly selected non-institutionalized individuals , aged 75 and over living in the city of Leipzig . Twenty individuals who suffer from moderate and severe dementia according to DSM-III-R were excluded . Memory complaints were measured by means of a single item question . The Mini-Mental State Examination ( MMSE ) and a wider range of cognitive tests which constitute the short neuropsychological battery of the SIDAM ( Structured Interview for the Diagnosis of dementia of Alzheimer type , Multi-infa rct dementia and dementias of other etiology according to ICD-10 and DSM-III-R ) were used to test cognitive performance . Results : One in three individuals aged 75 and over complained about memory deficits . The MMSE is not significantly related to memory complaints , whereas poorer performance on 2 out of 8 tests regarding specific areas of cognitive function ( immediate recall , short-term memory ) were found to be significantly associated with memory complaints . Despite these statistically significant associations , it is shown that memory complaints do not have diagnostic validity in detecting cognitive impairment on the individual level . Conclusion : Memory self- assessment should not be used as a substitute measure of cognitive performance . Initiation of further diagnostic and therapeutic steps should be based on cognitive performance testing . Relaying solely on memory complaints would miss individuals in need and allocate re sources to worried but cognitively healthy persons OBJECTIVE To develop and vali date a simple method for detecting dementia that is valid across cultures , portable and easily administered by primary health care clinicians . DESIGN Culture and Health Advisory Groups were used in Stage 1 to develop culturally fair cognitive items . In Stage 2 , clinical testing of 42 items was conducted in a multicultural sample of consecutive new referrals to the geriatric medicine outpatient clinic at Liverpool Hospital , Sydney , Australia ( n = 166 ) . In Stage 3 , the predictive accuracy of items was assessed in a r and om sample of community-dwelling elderly persons stratified by language background and cognitive diagnosis and matched for sex and age ( n = 90 ) . MEASUREMENTS A research psychologist administered all cognitive items , using interpreters when needed . Each patient was comprehensively assessed by one of three geriatricians , who ordered relevant investigations , and implemented a st and ardized assessment of cognitive domains . The geriatricians also collected demographic information , and administered other functional and cognitive measures . DSM-IV criteria were used to assign cognitive diagnoses . Item validity and weights were assessed using frequency and logistic regression analyses . Receiver-operating characteristic ( ROC ) curve analysis was used to determine overall predictive accuracy of the RUDAS and the best cut-point for detecting cognitive impairment . RESULTS The 6-item RUDAS assesses multiple cognitive domains including memory , praxis , language , judgement , drawing and body orientation . It appears not to be affected by gender , years of education , differential performance factors and preferred language . The area under the ROC curve for the RUDAS was 0.94 ( 95 % CI 0.87 - 0.98 ) . At a cut-point of 23 ( maximum score of 30 ) , sensitivity and specificity were 89 % and 98 % , respectively . Inter-rater ( 0.99 ) and test-retest ( 0.98 ) reliabilities were very high . CONCLUSIONS The 6-item RUDAS is portable and tests multiple cognitive domains . It is easily interpreted to other language s , and appears to be culturally fair . However , further validation is needed in other setting s , and in longitudinal studies to determine its sensitivity to change in cognitive function over time The aim of this study was to determine the diagnostic value and agreement analyses between Clinical Dementia Rating ( CDR ) and dementia diagnostic criteria ( gold st and ard ) , Blessed Dementia Rating scale ( BDRS ) , and Diagnostic and Statistical Manual of Mental Disorders , 3rd Edition , Revised ( DSM III-R ) criteria for severity . In a sample of 343 Southern Brazilian participants , CDR was consecutively assessed in 295 dementia patients ( Alzheimer disease , vascular dementia , and question able ) and 48 healthy elderly . The National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer 's Disease and Related Disorders Association ( NINCDS-ADRDA ) criteria for probable Alzheimer disease and the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences ( NINDS-AIREN ) for probable vascular dementia were the gold st and ard . A battery of cognitive tests and the Mini Mental State Examination ( as a screening test at study entry ) were also applied . Sensitivity and specificity were obtained through contingency tables . Validity and reliability were measured through κ coefficient , Kendall b , and percent agreement . CDR agreement among raters was demonstrated by percent agreement . Agreement to gold st and ard was good ( κ=0.75 ) , as well as to the Blessed scale ( κ=0.73 ) , and excellent to the DSM III-R ( κ=0.78 ) . CDR detection of dementia among healthy elderly or question able dementia was 86 % and 80 % sensitive , respectively , and 100 % specific for both setting s. In conclusion , agreement of CDR global score with the gold st and ard was good , and diagnostic values were high Choosing the measure of cognition in an epidemiologic study investigating cognitive changes over time is a challenging question . A powerful measure must be able to detect small cognitive changes in all the range of cognition observed in the target population . This work aims at comparing the sensitivity to detect cognitive changes in the observed range of cognition of four widely used psychometric tests in an aging- population -based study through a nonlinear latent process model , assuming that the psychometric tests are nonlinear noisy transformations of their common factor . With data from the French prospect i ve cohort study PAQUID ( 1989 - 2001 ) , the authors found that the Mini-Mental State Examination and the Benton Visual Retention Test exhibited a better sensitivity to cognitive changes in low levels of cognition , while the Digit Symbol Substitution Test was more sensitive to changes in high levels of cognition . In contrast , the Isaacs Set Test shortened at 15 seconds appeared to be sensitive to small changes in all the range of cognition and , thus , represents an appropriate measure of cognition in population -based studies including both highly normal and severely impaired subjects OBJECTIVES To investigate the effect of increasing age on cognition in nondemented older people . DESIGN A cross-sectional and longitudinal analysis . PARTICIPANTS A total of 454 control subjects for Alzheimer 's cases from the cohort assembled by the Consortium to Establish a Registry for Alzheimer 's Disease ( CERAD ) . MEASUREMENT The Mini-Mental State Examination ( MMSE ) to assess cognitive function . RESULTS Cross-sectional estimates were derived by generalized linear models and longitudinal estimates by generalized estimating equations . The cross-sectional model indicated a small but significant decline in MMSE of -.4 points per 10 years . The longitudinal model indicated a small but significant increase in MMSE of about + .6 points per 10 years . Evidence of an early learning effect and nonr and om dropout exists . CONCLUSIONS The question of " normal " aging can be approached by considering cross-sectional information and , usually separately , longitudinal information . This study does both using recently developed statistical methods . We conclude that there is a small but significant decline in scores on the MMSE with increasing population age . The effect can be masked in longitudinal cohorts by a learning effect ( especially early in follow-up ) and other factors associated with repeated testing In the context of increasing concern in occidental countries about dementing diseases in the geriatric population , an epidemiological study has been done in the city of Zaragoza , Spain . The sample , r and omly selected from the census , was stratified by age and sex and included 1,134 elderly ( aged 65 plus years ) living in the community . In phase I , lay interviewers administered the Spanish versions of the Geriatric Mental State ( GMS ) and Mini-Mental Status Examination to the elderly . The individuals were considered to be " probable cases " on the basis of GMS " global " scores previously reported to be valid . These " probable cases " were then examined in phase II by st and ardized psychiatrists using both , the GMS and MEC , but also the History and Aetiology Schedule ( HAS ) . A proportion of " probable normals " were also examined by the psychiatrists to assess the validity of the screening procedure in the community . The identified " cases " of dementia and " cases " of depression were then studied by the neurologists in what we call phase III . Specific project criteria for dementia were used but , in fact , all identified " cases " of dementia fulfilled DSM-III criteria . Some data of the application of the AGECAT computer program in both , phase I and phase II are now reported . The different severity levels of cognitive deficits according to AGECAT criteria are compared with clinical criteria . The advantages and disadvantages of the computer program in the detection of minor cognitive difficulties are discussed Normative data were collected in a study population of 150 r and omly selected elderly subjects . Using the SIDAM ( Structured Interview for the Diagnosis of Dementia of the Alzheimer Type , multi-infa rct dementia , and dementias of other etiology according to DSM-III-R and ICD-10 ) , both the dimensional and the categorical aspects of dementia and " mild cognitive impairment " are considered . With the SIDAM score ( SISCO ) [ range 0 (minimum)-55 ( maximum , no cognitive impairment ) ] and the SIDAM Mini-Mental State Examination ( MMSE ) ( range 0 - 30 ) , appropriate cutoffs for the category of DSM-III-R and ICD-10 dementia and " mild cognitive impairment " were defined . MMSE scores of 0 - 22 were found to be indicative of DSM-III-R and ICD-10 dementia . For " mild cognitive impairment , " MMSE scores ranged from 23 - 27 according to a DSM-III-R definition ( ICD-10 : 23 - 28 ) . An MMSE score of 22 or less was found to differentiate between DSM-III-R/ICD-10 dementia and " mild cognitive impairment , " with a specificity of 92 % ( ICD-10 : 95.6 ) and a sensitivity of 96 % ( ICD-10 : 96 % ) . With the SIDAM-based DSM-III-R/ICD-10 diagnoses of dementia as the criterion , the SISCO was 97.3 % specific ( ICD-10 : 99 % ) and 94 % sensitive ( ICD-10 : 94 % ) in detecting dementia . A SISCO of 0 - 33 was highly indicative of DSM-III-R and ICD-10 dementia . For " mild cognitive impairment , " a SISCO between 34 - 47 ( ICD-10 : 34 - 51 ) was found . The SISCO covers a broader range of cognitive functions than the MMSE and is more useful in detecting even very mild cognitive decline . Furthermore , the newly defined category of " mild cognitive impairment " could be vali date d successfully by means of GDS Stages 2 - 3 and CDR Stage 0.5 . These findings confirm the value of the SIDAM as a short diagnostic instrument for measurement and diagnosis of dementia and " mild cognitive impairment . We assessed the validity of two screening tests [ the Mini‐Mental State Examination ( MMSE ) and the Milan Overall Dementia Assessment or ( MODA ) ] in a population study on the prevalence of Alzheimer 's disease , carried out in a small town in the north of Italy . A r and om sample of 1000 subjects aged 60 years or over entered the study . Subjects who scored below the cut‐off points on MODA or on MMSE , or both , were further investigated with neuropsychological , laboratory and instrumental tests to ascertain a final diagnosis , which was considered as the gold st and ard . Our findings show that MODA has a higher sensitivity than MMSE in detecting subjects affected by dementing illnesses , while MMSE shows a higher specificity . MODA seems to be preferable to MMSE as a screening test for studies where a very high sensitivity is required OBJECTIVE The study aim ed to describe the prevalence of Neuropsychiatric symptoms ( NPS ) in Alzheimer 's disease ( AD ) , amnestic mild cognitive impairment ( MCI ) and controls using the 12-item Neuropsychiatric Inventory ( NPI ) and to analyze the relationships between neuropsychiatric symptoms with specific neuropsychological tests . PATIENTS AND METHODS We prospect ively studied 485 patients from the Memory Unit in Cruces Hospital ( Spain ) , 344 met the criteria of NINCDS-ADRDA for probable AD ( 99 were classified as mild and 245 as moderate-severe ) , 91 for MCI and 50 were controls . Mini-mental State Examination ( MMSE ) and CDR ( Clinical Dementia Rating ) were used to evaluate global cognitive function and to classify the severity of cognitive impairment . The neuropsychological test battery included memory test , verbal fluency , visuoespatial skills and daily living scales . The 12-items Neuropsychiatric Inventory ( NPI ) version was used to assess neuropsychiatric symptoms . All patients underwent a neuroimaging study ( CT scan and /or MRI ) . Patients were not treated with antidementia or psychotropic drugs . RESULTS Apathy and depression were more prevalent NPS in moderate-severe AD ( 78.4 % and 44.1 % , respectively ) , mild AD ( 64.6 % and 41.4 % , respectively ) and MCI ( 50.5 % and 33 % , respectively ) patients than in controls ( 6 % and 8 % , respectively ) . The prevalence and the mean scores of all symptoms increased along the severity of the disease , except for sleep and appetite disorders . In patients with mild AD a relationship was found between the presence of NPS and RDRS-2 scale ( p = 0.003 ) ; and between NPS and RDRS-2 ( p = 0.029 ) and SS-IQCODE scales ( p = 0.039 ) in moderate-severe patients . CONCLUSIONS NPS were more prevalent in AD and MCI patients than in controls . In AD and MCI patients apathy and depression were the most prevalent NPS . The prevalence and the mean scores of all symptoms gradually increased along the severity of the disease , except for sleep and appetite disorders . We have no found a relationship between neuropsycological test and the presence of NPS , but in patients with mild and moderate-severe AD there is a relationship with daily living scales OBJECTIVE To study the relationship between social and leisure activities and risk of subsequent dementia in older community residents . SETTING A cohort study of people aged 65 and older were followed-up 1 and 3 years after a baseline screening ( the Paquid study ) . PARTICIPANTS 2040 older subjects living at home in Gironde ( France ) were r and omly selected and followed for at least 3 years . DATA COLLECTION Information about social and leisure activities was collected during the baseline screening with an interview by a psychologist . Incident cases of dementia were detected during the first and third year follow-up screenings according to the DSM-III-R criteria . MAIN RESULTS All but one of the social and leisure activities noted were significantly associated with a lower risk of dementia . Only golden club participation was not significantly associated with this risk . After adjustment for age and cognitive performance measured by the Mini-Mental State Exam , visual memory test , and verbal fluency test , only traveling ( Relative risk ( RR ) = .48,95 % Confidence Interval ( 95 % CI ) = .24-.94 ) , odd jobs or knitting ( RR = .46,95 % CI = .26-.85 ) , and gardening ( RR = .53 , 95 % CI = .28-.99 ) remained significant . CONCLUSIONS Regular participation in social or leisure activities such as traveling , odd jobs , knitting , or gardening were associated with a lower risk of subsequent dementia Background Dementia is considered widely under-detected in primary care , and general practitioners ( GPs ) frequently ask for easy to use tools to assist in its early detection . Aim To determine the degree of correlation between the Mini-Cog Assessment ( Mini-Cog ) as performed by GPs and the Mini-Mental State Examination ( MMSE ) . Design of study This was a prospect i ve study ( 2005 , 2006 ) comparing two cognitive screening instruments . Setting Ten general practice s in Austria , with patients with a hitherto undiagnosed suspicion of dementia seen consecutively . Method Sensitivity , specificity and positive and negative predictive values ( PPVs and NPVs ) of the Mini-Cog ( applying both a colour-coded and the original rating method ) were assessed for degree of correlation with the MMSE . In phase one GPs examined patients suspected of having dementia using the Mini-Cog ; in phase two a neurologist retested them applying the MMSE , a clock-drawing test ( CDT ) and a routine clinical examination . A question naire on the practicability of the Mini-Cog was answered by GPs . Results Of the 107 patients who participated 86 completed the whole study protocol . The Mini-Cog , as performed by the ten GPs , displayed a sensitivity of 0.85 ( 95 % CI : 0.71 , 0.98 ) , a specificity of 0.58 ( 95 % CI : 0.46 , 0.71 ) , a PPV of 0.47 ( 95 % CI : 0.33 , 0.61 ) and an NPV of 0.90 ( 95 % CI : 0.80 , 0.99 ) as against the MMSE carried out by neurologists . The GPs judged the Mini-Cog useful and time saving . Conclusion The Mini-Cog has a high sensitivity and acceptable specificity in the general practice setting and has proved to be a practicable tool for the diagnosis of dementia in primary care BACKGROUND The Clock-in-the-Box is a rapid ( 2-minute ) cognitive screening tool . The purpose of this study was to compare the Clock-in-the-Box with the Mini-Mental State Exam and neuropsychologic tests ; to determine Clock-in-the-Box score normative values by age and education group ; and to determine if the Clock-in-the-Box score is associated with measures of physical function . METHODS Community-dwelling older participants in the Boston area were recruited for a prospect i ve , longitudinal study in which they completed a variety of cognitive and functional assessment s. RESULTS At baseline , participants ( n=798 ; mean age [ ± st and ard deviation]=78.2 [ ±5.5 ] years ; 14 [ ±3 ] mean years of education ) completed in-home assessment s of cognition ( Clock-in-the-Box and Mini-Mental State Exam ) , measures of independent function ( Activities of Daily Living and Instrumental Activities of Daily Living ) , and measures of physical function ( Short Physical Performance Battery ) . The mean Mini-Mental State Exam score was 27.1 ( ±1.6 ; range 0 - 30 [ 0 worst ] ) , and the mean Clock-in-the-Box score was 6.2 ( ±1.6 ; range 0 - 8 [ 0 worst ] ) . Performance on the Clock-in-the-Box was correlated ( Spearman ) with the Mini-Mental State Exam ( r=0.49 , P<.001 ) and neuropsychologic measures ( r=0.37 - 0.50 ; P<.001 ) . Higher Clock-in-the-Box score was significantly associated with no difficulty in Activities of Daily Living ( χ(2 ) = 39.6 , P<.001 ) and Instrumental Activities of Daily Living ( χ(2 ) = 35.5 , P<.001 ) . In addition , higher Clock-in-the-Box scores were associated with higher scores on the Short Physical Performance Battery ( F=5.4 , P<.001 ) . CONCLUSION The Clock-in-the-Box is a brief cognitive screening test that is correlated with the Mini-Mental State Exam , neuropsychologic tests , and measures of independent and physical function in community-dwelling older adults The Mini-Mental State Examination score is often used as a screening test for dementia . We studied its properties for a population of French community residents , using a sample of 2,792 r and omly selected subjects in Gironde , France . When the traditional cutoff point 23 - 24 was used , we observed a sensitivity of 1.0 and a specificity of 0.77 . We sought to increase the specificity of the test , while keeping sensitivity at 1.0 , with the use of logistic regression analysis . We found ( 1 ) a specificity of 0.81 when " recall three objects " and " orientation to time " were added to the Mini-Mental State Examination score ; ( 2 ) a specificity of 0.90 when Benton 's Visual Retention Tests and Isaacs ' Set Test of Verbal Fluency were added to the Mini-Mental State Examination score and subscores ; and ( 3 ) no improvement in specificity when age and educational level were included in the analyses OBJECTIVE Cross validation study of the MoCA for the detection of Alzheimer 's disease ( AD ) and Mild Cognitive Impairment ( MCI ) in a community-based cohort residing in the Southeastern United States . METHODS One hundred and eighteen English-speaking older adults , who underwent diagnostic evaluation as part of an on-going prospect i ve study , were administered the MoCA and MMSE . Twenty were diagnosed with AD , 24 met criteria for amnestic MCI and 74 were considered cognitively normal . Sensitivities and specificities were calculated using the recommended cut-off scores and ROC curve analyses were performed to determine optimal sensitivity and specificity . The influence of age , education and gender on MoCA score was also examined . RESULTS Using a cut-off score of 24 or below , the MMSE was insensitive to cognitive impairment . Using the recommended cut-off score of 26 , the MoCA detected 97 % of those with cognitive impairment but specificity was fair ( 35 % ) . Using a lower cut-off score of 23 , the MoCA exhibited excellent sensitivity ( 96 % ) and specificity ( 95 % ) . CONCLUSION The MoCA appears to have utility as a cognitive screen for early detection of AD and for MCI and warrants further investigation regarding its applicability in primary care setting s , varying ethnic groups , and younger at-risk individuals Although the Blessed Dementia Rating Scale ( BDRS ) , a clinical screening instrument , has been applied extensively , no suitable cut-off values and clinical application have been proposed , particularly in mild cognitive impairment ( MCI ) , the precursor of dementia . The BDRS , Mini Mental State Examination ( MMSE ) , and Clinical Dementia Rating Scale ( CDR ) were administrated in people aged 65 years and above , who were enrolled from southern Taiwan with multistep stratified r and om sampling and followed-up for 2 years . All subjects ( total number = 3,027 ) , with new onset of MCI ( defined as CDR = 0.5 ) in the first year and dementia ( defined as CDR > or = 1 ) in the second and third years were subjected to statistical analysis . In distinguishing normal from MCI , except in the literate group aged 65 - 74 years , MMSE was superior to BDRS , with cut-off values of 1 in both literate groups aged 65 - 74 years and > or = 75 years , and 1.5 and 2 in less educated groups aged 65 - 74 and > or = 75 years , respectively . In distinguishing MCI from dementia , BDRS had cut-off values of 2.5 in both literate groups aged 65 - 74 and > or = 75 years , and 2.5 and 3 in less educated groups aged 65 - 74 and > or = 75 years , respectively . These values were better than those for MMSE in all groups . BDRS might be considered as a better tool than MMSE to screen for MCI and dementia in the increasing proportion of literate elderly aged 65 - 74 years in the aging population Epidemiological research on dementia in Belgium started in 1990 with a prevalence study . In the first phase of the MMSE was used for screening a r and om sample , stratified by age , of 1,800 aged people . In the second phase the diagnostic work was done by a psychiatrist using the CAMDEX . An incidence study will start after 2 years . Potential risk factors will be examined in a case-control study Screening community sample s for dementia often necessitates administering a cognitive test battery by trained personnel . Because diagnostic examinations are expensive , a useful screening battery must be highly specific in addition to having high sensitivity . The Monogahela Valley Independent Elders Survey ( MoVIES ) includes a r and om sample of community-dwelling participants at least 65 years of age who were screened using an extensive test battery of cognitive tests that required over 30 min to administer . Classification and Regression Trees ( CART ) was used to identify a subset of the battery that could be administered quickly and which maintained high levels of sensitivity and specificity for a diagnosis of dementia . The Short and Sweet Screening Instrument ( SASSI ) is a brief battery consisting of three st and ard cognitive tests that can be administered in approximately 10 min . Compared to the full battery , it was more sensitive ( 94 % vs. 90 % ) and had comparable specificity ( 91 % vs. 92 % ) for dementia in this sample A r and om sample of 1,350 persons aged 65 years and older in a rural community underwent cognitive screening as part of a survey to establish a population -based registry of dementing disorders . The screening battery included the neuropsychological tests of the assessment protocol used in the National Institute on Aging multicenter Consortium to Establish a Registry for Alzheimer 's Disease ( CERAD ) . This paper reports a large body of normative neuropsychological data from this sample with members of relatively low socioeconomic status . Age , sex , and educational level were found to have statistically significant effects on test scores . The implication s of these findings for the establishment of screening cutoff scores are discussed In an ongoing prospect i ve community study , a r and om sample of rural elderly persons was screened with cognitive tests ( including the CERAD neuropsychological battery ) at study entry and an average of 2 years later . We examined 1,017 subjects , nondemented at study entry , at both waves , with the Mini-Mental State Exam , Story Recall , Word List Recall and Recognition , Boston Naming Test , Verbal Fluency , Praxis , Clock Drawing , and Trailmaking . Overall , the cognitive performance was stable , with either no mean change or a small mean decline over 2 years ; however , st and ard deviations were relatively large , implying individual variation of question able clinical significance . These data provide a set of population -based longitudinal cognitive norms and have implication s for dementia screening Objective To compare the diagnostic accuracy of the interRAI Acute Care ( AC ) Cognitive Performance Scale ( CPS2 ) and the Mini-Mental State Examination ( MMSE ) , against independent clinical diagnosis for detecting dementia in older hospitalized patients . Design , Setting , and Participants The study was part of a prospect i ve observational cohort study of patients aged ≥70 years admitted to four acute hospitals in Queensl and , Australia , between 2008 and 2010 . Recruitment was consecutive and patients expected to remain in hospital for ≥48 hours were eligible to participate . Data for 462 patients were available for this study . Measurements Trained research nurses completed comprehensive geriatric assessment s and administered the interRAI AC and MMSE to patients . Two physicians independently review ed patients ’ medical records and assessment s to establish the diagnosis of dementia . Indicators of diagnostic accuracy included sensitivity , specificity , predictive values , likelihood ratios and areas under receiver ( AUC ) operating characteristic curves . Results 85 patients ( 18.4 % ) were considered to have dementia according to independent clinical diagnosis . The sensitivity of the CPS2 [ 0.68 ( 95%CI : 0.58–0.77 ) ] was not statistically different to the MMSE [ 0.75 ( 0.64–0.83 ) ] in predicting physician diagnosed dementia . The AUCs for the 2 instruments were also not statistically different : CPS2 AUC = 0.83 ( 95%CI : 0.78–0.89 ) and MMSE AUC = 0.87 ( 95%CI : 0.83–0.91 ) , while the CPS2 demonstrated higher specificity [ 0.92 95%CI : 0.89–0.95 ) ] than the MMSE [ 0.82 ( 0.77–0.85 ) ] . Agreement between the CPS2 and clinical diagnosis was substantial ( 87.4 % ; κ=0.61 ) . Conclusion The CPS2 appears to be a reliable screening tool for assessing cognitive impairment in acutely unwell older hospitalized patients . These findings add to the growing body of evidence supporting the utility of the interRAI AC , within which the CPS2 is embedded . The interRAI AC offers the advantage of being able to accurately screen for both dementia and delirium without the need to use additional assessment s , thus increasing assessment efficiency

Findings demonstrate that sEMG of extra-diaphragmatic muscle activity is a valid and applicable tool to evaluate mechanical loading/unloading of respiratory muscles and respiratory drive or sensation . Although it appears to be a valid and applicable tool , there is a scarcity of literature that directly demonstrates the diagnostic accuracy of sEMG of extra-diaphragmatic muscles in monitoring respiratory mechanics and respiratory drive or sensation during MV assistance across wide population s and conditions

PURPOSE Evidence supporting the utilization of surface EMG ( sEMG ) of extra-diaphragmatic muscles for monitoring of mechanical ventilation ( MV ) assistance is unclear . The purpose of this review was to assess the quality of literature available on using extra-diaphragmatic sEMG as an assessment technique of respiratory responses during MV .

We hypothesized that patients who fail weaning from mechanical ventilation recruit their inspiratory rib cage muscles sooner than they recruit their expiratory muscles , and that rib cage muscle recruitment is accompanied by recruitment of sternomastoid muscles . Accordingly , we measured sternomastoid electrical activity and changes in esophageal ( DeltaPes ) and gastric pressure ( DeltaPga ) in 11 weaning-failure and 8 weaning-success patients . At the start of trial , failure patients exhibited a higher DeltaPga-to-DeltaPes ratio than did success patients ( P = 0.05 ) , whereas expiratory rise in Pga was equivalent in the two groups . Between the start and end of the trial , failure patients developed additional increases in DeltaPga-to-DeltaPes ratio ( P < 0.0014 ) and the expiratory rise in Pga also increased ( P < 0.004 ) . At the start of trial , sternomastoid activity was present in 8 of 11 failure patients contrasted with 1 of 8 success patients . Over the course of the trial , sternomastoid activity increased by 53.0 + /- 9.3 % in the failure patients ( P = 0.0005 ) , whereas it did not change in the success patients . Failure patients recruited their respiratory muscles in a sequential manner . The sequence began with activity of diaphragm and greater-than-normal activity of inspiratory rib cage muscles ; recruitment of sternomastoids and rib cage muscles approached near maximum within 4 min of trial commencement ; expiratory muscles were recruited slowest of all . In conclusion , not only is activity of the inspiratory rib cage muscles increased during a failed weaning trial , but respiratory centers also recruit sternomastoid and expiratory muscles . Extradiaphragmatic muscle recruitment may be a mechanism for off setting the effects of increased load on a weak diaphragm Purpose : Respiratory muscle dysfunction is a key component of weaning failure . Balancing respiratory muscle loading and unloading by applying different ventilation modes along with spontaneous breathing episodes are established weaning strategies . However , the effects of body positioning on the respiratory muscles during weaning remains unclear . Material s and methods : This study aim ed at assessing respiratory drive by surface electromyography ( EMG ) of the diaphragm ( EMGdia ) and parasternal muscles ( EMGpara ) in tracheotomized patients during prolonged weaning in 3 r and omized body positions — supine , 30 ° semirecumbent , and 80 ° sitting — during mechanical ventilation and spontaneous breathing . Results : Nine patients were included for analysis . Cardiorespiratory parameters ( heart rate , blood pressure , arterial oxygen saturation , dyspnea ) did not change under each condition ( all P > .05 ) . EMGpara and EMGdia did not change under mechanical ventilation ( both P > .05 ) . EMGdia changed under spontaneous breathing from supine to sitting ( 0.45 ± 0.26 vs 0.32 ± 0.19 ; P = .012 ) and between semirecumbent to sitting ( 0.41 ± 0.23 vs 0.32 ± 0.19 ; P = .039 ) , whereas EMGpara did not change . Conclusions : This is the first study to show that body positioning influences respiratory drive to the diaphragm in tracheotomized patients with prolonged weaning from mechanical ventilation during unassisted breathing . Sitting position reduces respiratory drive compared with semirecumbent and supine positioning and might therefore be favored during spontaneous breathing trials . HighlightsThis work highlights the effects of simple physical strategies that impose effects on the respiratory drive in difficult to wean patients . Current treatment strategies often include placing a weaning patient in an upright position , to ease unassisted breathing ; however , scientific evidence for doing so was lacking so far . This study assessed the activation of the diaphragm and parasternal muscles in patients with prolonged weaning in 3 body positions — supine , semirecumbent , and sitting — during either mechanical ventilation or unassisted breathing . Interestingly , parasternal and diaphragmatic EMG did not change under mechanical ventilation , but the sitting position leads to a decrease of the neuromuscular drive to the diaphragm . Therefore , the sitting position might be favored during SBTs Context Pressure support ventilation ( PSV ) must be tailored to the load capacity balance of the respiratory system . While " over assistance " generated hyperinflation and ineffective efforts , " under assistance " increased respiratory drive and causes dyspnea . Surface electromyograms ( sEMGs ) of extradiaphragmatic inspiratory muscles were responsive to respiratory loading/unloading . Objectives To determine if sEMGs of extradiaphragmatic inspiratory muscles vary with PSV setting s and relate to the degree of discomfort and the intensity of dyspnea in acutely ill patients . Design Pathophysiological study , prospect i ve inclusion s of 12 intubated adult patients . Interventions Two PSV levels ( high and low ) and two expiratory trigger ( ET ) levels ( high and low ) . Measurements Surface electromyograms of the scalene , parasternal , and Alae Nasi muscles ( peak , EMGmax ; area under the curve , EMGAUC ) ; dyspnea visual analogue scale ( VAS ) ; prevalence of ineffective triggering efforts . Main results For the three recorded muscles , EMGmax and EMGAUC were significantly greater with low PS than high PS . The influence of ET was less important . A strong correlation was found between dyspnea and EMGmax . A significant inverse correlation was found between the prevalence of ineffective efforts and both dyspnea-VAS and EMGmin . Conclusions Surface electromyograms of extradiaphragmatic inspiratory muscles provides a simple , reliable and non-invasive indicator of respiratory muscle loading/unloading in mechanically ventilated patients . Because this EMG activity is strongly correlated to the intensity of dyspnea , it could be used as a surrogate of respiratory sensations in mechanically ventilated patients , and might , therefore , provide a monitoring tool in patients in whom detection and quantification of dyspnea is complex if not impossible Purpose To compare breathing pattern descriptors and diaphragm electromyographic activity (EAdi)-derived indices obtained from a neurally adjusted ventilatory assist catheter during a spontaneous breathing trial ( SBT ) in patients successfully and unsuccessfully separated from the ventilator and to assess their performance as a potential marker to discriminate these two categories of patients . Methods Fifty-seven ready-to-wean patients were included in a prospect i ve observational study . During a 30-min SBT ( pressure support 7 cmH2O , zero end expiratory pressure ) , tidal volume ( VT ) and respiratory rate ( RR ) were obtained from the flow signal at baseline and at 3 , 10 , 20 and 30 min during the SBT . EAdi-derived indices were simultaneously computed : maximum of the EAdi ( EAdimax ) , area under the inspiratory curve of EAdi ( EAdiAUC ) , the difference between EAdimax and EAdimin ( ∆EAdi ) , EAdimax/VT , EAdiAUC/VT and ∆EAdi/VT . Patients , successfully ( success group ; n = 35 ) and unsuccessfully ( failure group ; n = 22 ) separated from the ventilator were compared . Results At baseline , the breathing pattern was similar in the two groups , whereas EAdimax and EAdiAUC were significantly lower in the success group ( p < 0.05 ) . In the failure group , RR and RR/VT increased significantly during the trial , VT decreased , whereas EAdimax and EAdiAUC did not change . At 3 min , the areas under the receiver operating characteristic-curve of RR/VT and the EAdi-derived indices to predict weaning outcome were 0.83 for the rapid shallow breathing index ( RSBI ) , 0.84 for EAdimax/VT , 0.80 for EAdiAUC/VT ( 0.80 ) and 0.82 for ∆EAdi/VT . The coefficient of variation for VT decreased in the failure group while that for EAdimax remained unchanged . Conclusions EAdi-derived indices provide reliable and early predictors of weaning outcome . However , the performance of these indices is not better than the RR/VT Objective To compare the effects of adaptive support ventilation ( ASV ) and synchronized intermittent m and atory ventilation plus pressure support ( SIMV-PS ) on patient-ventilator interactions in patients undergoing partial ventilatory support . Design Prospect i ve , crossover interventional study . Setting Medical intensive care unit , university tertiary care center . Patients Ten patients , intubated and mechanically ventilated for acute respiratory failure of diverse causes , in the early weaning period , ventilated with SIMV-PS and clinical ly detectable sternocleidomastoid activity suggesting increased inspiratory load and patient-ventilator dyssynchrony . Interventions Measurement of respiratory mechanics , P0.1 , sternocleidomastoid electromyographic activity , arterial blood gases , and systemic hemodynamics in three conditions : 1 ) after 45 mins with SIMV-PS ( SIMV-PS 1 ) ; 2 ) after 45 mins with ASV , set to deliver the same minute-ventilation as during SIMV-PS ; 3 ) 45 mins after return to SIMV-PS ( SIMV-PS 2 ) , with setting s identical to those of the first SIMV-PS period . Main Results The same minute ventilation was observed during ASV ( 11.4 ± 3.1 l/min [ mean ± sd ] ) as during SIMV-PS 1 ( 11.6 ± 3.5 L/min ) and SIMV-PS 2 ( 10.8 ± 3.4 L/min ) . No parameter was significantly different between SIMV-PS 1 and 2 , hence subsequent results refer to ASV vs. SIMV-PS 1 . During ASV , tidal volume increased ( 538 ± 91 vs. 671 ± 100 mL , p < .05 ) and total respiratory rate decreased ( 22 ± 7 vs. 17 ± 3 breaths/min , p < .05 ) vs. SIMV-PS . However , spontaneous respiratory rate increased in six patients , decreased in four , and remained unchanged in one . P0.1 decreased during ASV in all patients except three in whom no change was noted ( 1.8 ± 0.9 vs. 1.1 ± 1 cm H2O , p < .05 ) . During ASV , sternocleidomastoid electromyogram activity was markedly reduced ( electromyogram index , where SIMV-PS 1 = 100 , ASV 34 ± 41 , SIMV-PS 2 89 ± 36 , p < .02 ) as was palpable muscle activity . No changes were noted in arterial blood gases , pH , or mean systemic pressure during the trial . Conclusion In patients undergoing partial ventilatory support , with clinical and electromyographic signs of increased respiratory muscle loading , ASV provided levels of minute ventilation comparable to those of SIMV-PS . However , with ASV , central respiratory drive and sternocleidomastoid activity were markedly reduced , suggesting decreased inspiratory load and improved patient-ventilator interactions . These preliminary results warrant further testing of ASV for partial ventilatory support [ Purpose ] This study aim ed to determine the effects of different intensities of inspiratory muscle training on the relative respiratory muscle activity in healthy adults . [ Subjects and Methods ] Thirteen healthy male volunteers were instructed to perform inspiratory muscle training ( 0 % , 40 % , 60 % , and 80 % maximal inspiratory pressure ) on the basis of their individual intensities . The inspiratory muscle training was performed in r and om order of intensities . Surface electromyography data were collected from the right-side diaphragm , external intercostal , and sternocleidomastoid , and pulmonary functions ( forced expiratory volume in 1 s , forced vital capacity , and their ratio ; peak expiratory flow ; and maximal inspiratory pressure ) were measured . [ Results ] Comparison of the relative activity of the diaphragm showed significant differences between the 60 % and 80 % maximal inspiratory pressure intensities and baseline during inspiratory muscle training . Furthermore , significant differences were found in sternocleidomastoid relative activity between the 60 % and 80 % maximal inspiratory pressure intensities and baseline during inspiratory muscle training . [ Conclusion ] During inspiratory muscle training in the clinic , the patients were assisted ( verbally or through feedback ) by therapists to avoid overactivation of their accessory muscles ( sternocleidomastoid ) . This study recommends that inspiratory muscle training be performed at an accurate and appropriate intensity through the practice of proper deep breathing CONTEXT Infection is a major cause of morbidity and mortality in intensive care units ( ICUs ) worldwide . However , relatively little information is available about the global epidemiology of such infections . OBJECTIVE To provide an up-to- date , international picture of the extent and patterns of infection in ICUs . DESIGN , SETTING , AND PATIENTS The Extended Prevalence of Infection in Intensive Care ( EPIC II ) study , a 1-day , prospect i ve , point prevalence study with follow-up conducted on May 8 , 2007 . Demographic , physiological , bacteriological , therapeutic , and outcome data were collected for 14,414 patients in 1265 participating ICUs from 75 countries on the study day . Analyses focused on the data from the 13,796 adult ( > 18 years ) patients . RESULTS On the day of the study , 7087 of 13,796 patients ( 51 % ) were considered infected ; 9084 ( 71 % ) were receiving antibiotics . The infection was of respiratory origin in 4503 ( 64 % ) , and microbiological culture results were positive in 4947 ( 70 % ) of the infected patients ; 62 % of the positive isolates were gram-negative organisms , 47 % were gram-positive , and 19 % were fungi . Patients who had longer ICU stays prior to the study day had higher rates of infection , especially infections due to resistant staphylococci , Acinetobacter , Pseudomonas species , and C and ida species . The ICU mortality rate of infected patients was more than twice that of noninfected patients ( 25 % [ 1688/6659 ] vs 11 % [ 682/6352 ] , respectively ; P < .001 ) , as was the hospital mortality rate ( 33 % [ 2201/6659 ] vs 15 % [ 942/6352 ] , respectively ; P < .001 ) ( adjusted odds ratio for risk of hospital mortality , 1.51 ; 95 % confidence interval , 1.36 - 1.68 ; P < .001 ) . CONCLUSIONS Infections are common in patients in contemporary ICUs , and risk of infection increases with duration of ICU stay . In this large cohort , infection was independently associated with an increased risk of hospital death

Using multivariate models , the most replicated predictors of worse clinical , functional , cognitive , and biological outcomes in EOP were premorbid difficulties and symptom severity ( especially of negative symptoms ) at baseline . Longer duration of untreated psychosis ( DUP ) predicted worse clinical , functional , and cognitive outcomes . Higher risk of attempting suicide was predicted by greater severity of psychotic illness and of depressive symptoms at the first episode of psychosis . Age at onset and sex were not found to be relevant predictors of outcome in most multivariate models , whereas studies using bivariate analyses yielded inconsistent results . Lower intelligence quotient at baseline predicted lower insight at follow-up , worse functional outcomes , and a diagnostic outcome of schizophrenia . Lower levels of antioxidants at baseline predicted greater brain volume changes and worse cognitive functioning at follow-up , whereas neuroimaging markers such as regional cortical thickness and gray matter volume at baseline predicted remission and better insight at follow-up , respectively . EOP patients with poorer premorbid adjustment and prominent negative symptoms at initial presentation are at risk of poor outcome . Early intervention strategies to reduce DUP may also improve outcome in EOP

Given the global burden of psychotic disorders , the identification of patients with early-onset psychosis ( EOP ; that is , onset before the age of 18 ) at higher risk of adverse outcome should be a priority .

OBJECTIVE The relationship between cognition and outcome in people with schizophrenia has been established in studies that , for the most part , examined chronic patients and were cross-sectional in design . The purpose of this study was to analyze the relationships between neurocognitive variables assessed at illness onset and functional outcome in a longitudinal design . An additional area of interest was whether the severity of negative symptoms would predict outcome independently from neurocognitive variables or whether there would be an overlap in their predictive power . METHOD The authors administered a comprehensive cognitive battery and clinical assessment s to 99 subjects who were in their first episode of illness and analyzed the relationship of cognition and symptom severity at intake with community outcome after an average follow-up period of 7 years . RESULTS Verbal memory , processing speed and attention , and the severity of negative symptoms at intake were related to subsequent outcome . Global psychosocial functioning was predicted by negative symptoms and attention . Verbal memory was the significant predictor of the degree of impairment in recreational activities . Impairment in relationships was predicted by negative symptoms and memory , whereas attention and negative symptoms were predictive of work performance . There was an overlap in the variance in outcome explained by cognitive variables and negative symptoms . CONCLUSIONS Verbal memory and processing speed and attention are potential targets for psychosocial interventions to improve outcome . Results from cross-sectional or chronic patient studies do not necessarily correspond to the findings of this prospect i ve first-episode study in which cognition appears to explain less of the variance in outcome CONTEXT Progressive loss of brain gray matter ( GM ) has been reported in childhood-onset schizophrenia ; however , it is uncertain whether these changes are shared by pediatric patients with different psychoses . OBJECTIVE To examine the progression of brain changes in first-episode early-onset psychosis and their relationship to diagnosis and prognosis at 2-year follow-up . DESIGN Prospect i ve , multicenter , naturalistic , 2-year follow-up study . SETTING Six child and adolescent psychiatric units in Spain . PARTICIPANTS A total of 110 patients and 98 healthy controls were recruited between March 1 , 2003 , and November 31 , 2005 . Magnetic resonance imaging of the brain was performed for 61 patients with schizophrenia ( n = 25 ) , bipolar disorder ( n = 16 ) , or other psychoses ( n = 20 ) and 70 controls ( both at baseline and after 2 years of follow-up ) . Mean age at baseline was 15.5 years ( patients ) and 15.3 years ( controls ) . MAIN OUTCOME MEASURES The GM and cerebrospinal fluid ( CSF ) volumes in the total brain and frontal , parietal , and temporal lobes . RESULTS Compared with controls , patients with schizophrenia showed greater GM volume loss in the frontal lobe during the 2-year follow-up ( left : -3.3 vs -0.6 cm(3 ) , P = .004 ; right : -3.7 vs -0.8 cm(3 ) , P = .005 ) and left frontal CSF volume increase ( left : 6.7 vs 2.4 cm(3 ) , P = .006 ) . In addition to frontal volume , changes for total GM ( -37.1 vs -14.5 cm(3 ) , P = .001 ) and left parietal GM ( -4.3 vs -2.2 cm(3 ) , P = .04 ) were significantly different in schizophrenic patients compared with controls . No significant differences emerged for patients with bipolar disease . Greater left frontal GM volume loss was related to more weeks of hospitalization , whereas severity of negative symptoms correlated with CSF increase in patients with schizophrenia . CONCLUSIONS Patients with schizophrenia or other psychoses showed greater loss of GM volume and increase of CSF in the frontal lobe relative to controls . Progressive changes were more evident in patients with schizophrenia than those with bipolar disorder . These changes in specific brain volumes after onset of psychotic symptoms may be related to markers of poorer prognosis Only few prospect i ve longitudinal studies have assessed the course of intelligence deficits in early onset schizophrenia ( EOS ) , and these have used different age appropriate versions of Wechsler Intelligence Scales and age appropriate norms . The post-psychotic development of intelligence in EOS has predominantly been characterized as relatively stable in these studies . However , comparisons of IQs from different test versions based on the different norms may not permit unequivocal interpretations . The objective of the current study was to compare the development of intelligence in EOS patients ( N = 10 ) from their first psychotic episode to 5 years of post onset with that of healthy controls ( N = 35 ) and patients who at baseline had been diagnosed with other non-affective psychoses ( N = 8) . The same version of a Wechsler Intelligence Scale was administered at both baseline and follow-up assessment s , and the same norms were used to derive IQs at baseline and follow-up . Significantly smaller change in mean full scale intelligence quotient ( FSIQ ) was found in diagnostically stable EOS patients compared with healthy controls during the follow-up period . However , no statistically significant difference in mean FSIQ change was observed between patients with EOS and patients with other non-affective psychoses , although this result must be interpreted with caution due to the small sample sizes . The results suggest abnormally slow acquisition of new intellectual information and skills in EOS patients during the first 5 years after full clinical presentation A total of 232 ( 84 % ) first episodes of schizophrenia from our epidemiologically defined ABC sample ( Age , Beginning and Course ) were retrospectively assessed with regard to the onset and early course of the disorder . In a follow-up study a representative subgroup ( n=133 ) was prospect ively examined in five cross sections over 3 years from first admission on . Population -based incidence rates for 5-year age groups comprising a range of < 10-<60 years were calculated on the basis of two definitions of onset : first sign of disorder and first psychotic symptom . In 40 % of adult patients who had been admitted with a first schizophrenic episode after age 20 years the prodromal phase , in 11 % the psychotic prephase , began before that age . This demonstrates that schizophrenia often begins in an age period in which the social and cognitive development and brain maturation are still unfinished . Early-onset schizophrenias ( < -20 years ) were compared with a medium-onset group ( 21<35 years ) and a late-onset group ( 35-<60 years ) with regard to age and type of onset , early symptom-related course , social development and social course . The number of schizophrenia-specific positive and negative syndromes in early-onset schizophrenia is comparable to that of higher age groups . However , neurotic syndromes , emotional disorders and conduct disorders are most frequent in younger patients , especially in young men . Paranoid syndromes seem to prevail in late-onset schizophrenia , whereas less differentiated positive syndromes , such as delusional mood , are more frequent in the youngest age group . An earlier onset of schizophrenia has more severe social consequences than onset in adults , because it interrupts the cognitive and social development at an earlier stage . The worse social course of schizophrenia in men compared with women can not be related to a more severe symtomatology , but to the earlier age at onset and the impairment or stagnation of social ascent at an earlier stage of social and cognitive development . Social disability in the sense of an adaptation to the expectations of the social environment , as well as symtomatology during the further course of schizophrenia , show no major differences between the genders nor between the age groups Premorbid adjustment is an important prognostic factor of schizophrenia . The relationships between sub-components of premorbid adjustment and outcomes on symptoms and cognition in first-episode schizophrenia were under-studied . In the current study , we prospect ively followed up 93 patients aged 18 - 55 years presenting with first-episode schizophrenia-spectrum disorder . Psychopathological and cognitive assessment s were conducted at baseline , clinical stabilization , 12 , 24 and 36 months . Premorbid adjustment was sub-divided into discrete functional domains , developmental stages and premorbid-course types based on ratings of the Premorbid Adjustment Scale ( PAS ) . The study focused on early developmental stages to minimize contamination by prodromal symptoms . Results indicated that gender differences in premorbid functioning were primarily related to early-adolescence adjustment and academic domain . Social domain was more strongly related to negative symptoms , while academic domain was more consistently linked to cognitive outcome ( Wisconsin Card Sorting test and verbal fluency ) . Patients with stable-poor premorbid course had more severe negative symptoms and cognitive impairment . In conclusion , in a Chinese cohort of first-episode schizophrenia-spectrum disorder , sub-components of early premorbid adjustment were shown to be differentially related to clinical and cognitive measures . The results highlighted the importance of applying a more refined delineation of premorbid functioning in study ing illness outcome Background There were few studies on the outcome of schizophrenia in developing countries . Whether the outcome is similar to or different from developed world is still a point for research . The main aim of the current study was to know if patients with early onset non affective psychosis can behave and function properly after few years from start of the illness or not . Other aims included investigation of possible predictors and associated factors with remission and outcome . Method The study prospect ively investigated a group of 56 patients with onset of psychosis during childhood or adolescence . Diagnosis made according to DSM-IV criteria and included ; schizophrenia , psychotic disorder not otherwise specified and acute psychosis . Severity of psychosis was measured by PANSS . Measures of the outcome included ; remission criteria of And reasen et al 2005 , the children 's global assessment scale and educational level . Results Analysis of data was done for only 37 patients . Thirty patients diagnosed as schizophrenia and 7 with Psychotic disorder not otherwise specified . Mean duration of follow up was 38.4 + /- 16.9 months . At the end of the study , 6 patients ( 16.2 % ) had one episode , 23(62.1 % ) had multiple episodes and 8 ( 21.6 % ) continuous course . Nineteen patients ( 51.4 % ) achieved full remission , and only 11(29.7 % ) achieved their average educational level for their age . Twenty seven percent of the sample had good outcome and 24.3 % had poor outcome . Factors associated with non remission and poor outcome included gradual onset , low IQ , poor premorbid adjustment , negative symptoms at onset of the illness and poor adherence to drugs . Moreover , there was tendency of negative symptoms at illness start to predict poor outcome . ConclusionS ome patients with early onset non affective psychosis can behave and function properly after few years from the start of the illness . Although remission is a difficult target in childhood psychosis , it is still achievable BACKGROUND The association between the duration of untreated psychosis ( DUP ) and outcome of schizophrenia may be confounded by other factors such as poor pre-morbid adjustment . The aim of the present study was to examine the independent contributions of DUP and of pre-morbid adjustment to the clinical and social outcomes of schizophrenia . METHOD A longitudinal , prospect i ve , 2-year follow-up study of 423 patients with first-episode schizophrenia-spectrum psychosis was conducted . Patients were comprehensively assessed at entry , 1-year and 2-year follow-up . At entry , DUP was measured by IRAOS ( an instrument for the assessment of onset and early course of schizophrenia ) and pre-morbid adjustment was measured by the Pre-morbid Adjustment Scale ( PAS ) as ' pre-morbid social adaptation ' and ' pre-morbid school adaptation ' . Outcome measures included the Scale for the Assessment of Positive Symptoms ( SAPS ) , the Scale for the Assessment of Negative Symptoms ( SANS ) , the Social Network Schedule and social information . Multiple linear regression models were used for data analysis . RESULTS The median DUP was 48 weeks , which is long compared to other studies . Longer DUP was independently associated with more psychotic symptoms at entry , 1-year and 2-year follow-up . Poorer pre-morbid social adaptation was independently associated with more negative symptoms and smaller social network at entry and 1-year follow-up . Poorer pre-morbid school adaptation was independently associated with poor vocational outcome at 1-year and 2-year follow-up . CONCLUSIONS Longer DUP is associated with poorer 2-year outcome of psychosis in schizophrenia-spectrum disorders , when pre-morbid functioning and other prognostic factors are controlled for . Impaired pre-morbid development is independently associated with more negative symptoms and poorer social outcome Adolescent-onset psychoses often raise diagnostic difficulties because of the mixture of schizophrenic and affective features . This study examined prospect ively which clinical dimensions contribute to difficulty in initial diagnosis and which clinical features have predictive value for outcomes of schizophrenia or affective disorders , and for eventual psychosocial functioning . Thirty-six adolescents consecutively admitted for a psychotic episode were followed up for 1 to 4 years . Symptoms were assessed at admission , at discharge , and once a year . DSM-III-R ( APA 1989 ) diagnoses were assessed at admission and once a year . Comparisons were performed across initial and followup diagnostic groups . Positive symptoms did not differentiate the initial clinical pictures , while negative symptoms , manic symptoms , and disorganization differentiated the manic and depressive episodes in the acute phase . When initial positive symptoms ( mainly delusions ) were severe , they predicted a final diagnosis in the schizophrenia spectrum . Poor outcome was associated with more anhedonia-associality and lower functioning scores at admission . Results suggest ( 1 ) a higher vulnerability to positive symptoms in adolescents who will further develop schizophrenia and ( 2 ) the low specificity of affective symptoms at this age BACKGROUND Most adults with common mental disorders report their first symptoms before 24 years of age . Although adolescent anxiety and depression are frequent , little clarity exists about which syndromes persist into adulthood or resolve before then . In this report , we aim to describe the patterns and predictors of persistence into adulthood . METHODS We recruited a stratified , r and om sample of 1943 adolescents from 44 secondary schools across the state of Victoria , Australia . Between August , 1992 , and January , 2008 , we assessed common mental disorder at five points in adolescence and three in young adulthood , commencing at a mean age of 15.5 years and ending at a mean age of 29.1 years . Adolescent disorders were defined on the Revised Clinical Interview Schedule ( CIS-R ) at five adolescent measurement points , with a primary cutoff score of 12 or higher representing a level at which a family doctor would be concerned . Secondary analyses addressed more severe disorders at a cutoff of 18 or higher . FINDINGS 236 of 821 ( 29 % ; 95 % CI 25 - 32 ) male participants and 498 of 929 ( 54 % ; 51 - 57 ) female participants reported high symptoms on the CIS-R ( ≥12 ) at least once during adolescence . Almost 60 % ( 434/734 ) went on to report a further episode as a young adult . However , for adolescents with one episode of less than 6 months duration , just over half had no further common mental health disorder as a young adult . Longer duration of mental health disorders in adolescence was the strongest predictor of clear-cut young adult disorder ( odds ratio [ OR ] for persistent young adult disorder vs none 3.16 , 95 % CI 1.86 - 5.37 ) . Girls ( 2.12 , 1.29 - 3.48 ) and adolescents with a background of parental separation or divorce ( 1.62 , 1.03 - 2.53 ) also had a greater likelihood of having ongoing disorder into young adulthood than did those without such a background . Rates of adolescent onset disorder dropped sharply by the late 20s ( 0.57 , 0.45 - 0.73 ) , suggesting a further resolution for many patients whose symptoms had persisted into the early 20s . INTERPRETATION Episodes of adolescent mental disorder often precede mental disorders in young adults . However , many such disorders , especially when brief in duration , are limited to the teenage years , with further symptom remission common in the late 20s . The resolution of many adolescent disorders gives reason for optimism that interventions that shorten the duration of episodes could prevent much morbidity later in life . FUNDING Australia 's National Health and Medical Research Council Impaired premorbid functioning prior to the onset of acute psychosis has frequently been noted in schizophrenia . This study examined retrospectively the premorbid status of patients in their first episode of psychosis in order to determine relationships with baseline symptoms , treatment response , and medication side effects . One hundred eleven schizophrenic and schizoaffective patients participating in a large prospect i ve study of first episode schizophrenia were evaluated with the Premorbid Adjustment Scale ( PAS ) . Premorbid functioning in males became progressively worse over time . Deficit state patients exhibited worse premorbid functioning . A third of patients exhibited sustained poor premorbid functioning . At various developmental stages , lower " sociability and withdrawal " scores correlated with increased time to treatment response , more severe negative symptoms , increased drug-induced parkinsonism , and deterioration of premorbid functioning . Various mean PAS scores predicted susceptibility to tardive dyskinesia . Our findings suggest that prior to acute psychosis onset there are certain behavioral precursors reflected in premorbid functioning that may predict subsequent illness manifestations . Measures of premorbid functioning indicate that disease pathogenesis is manifest , albeit more subtly , prior to presentation of first psychotic symptoms OBJECTIVE To compare the long-term outcome in individuals with early-onset ( before age 18 ) and adult-onset schizophrenia spectrum disorder who were initially diagnosed and treated in the same clinical center . METHOD A prospect i ve follow-up study of 723 consecutive first-episode psychosis patients ( age range 14 to 30 years ) on average 7.4 years after initial presentation to an early psychosis service , the Early Psychosis Prevention and Intervention Centre in Melbourne , Australia . The outcome measures included the Brief Psychiatric Rating Scale , the Schedule for the Assessment of Negative Symptoms , the Beck Depression Inventory , the Global Assessment of Functioning Scale , the Social and Occupational Functioning Assessment Scale , and the Quality of Life Scale . RESULTS Follow-up interviews were conducted on 66.9 % ( 484/723 ) individuals , of whom 75.6 % ( 366/484 ) received a schizophrenia spectrum disorder diagnosis at baseline . Early-onset schizophrenia spectrum disorder was observed in 11.2 % ( 41/366 ) . At follow-up , individuals with early-onset reported significantly fewer positive symptoms and were characterised by significantly superior functioning on measures assessing global functioning , social-occupational functioning , and community functioning than individuals with adult-onset . The early-onset group also achieved significantly better vocational outcomes and had a more favourable course of illness with fewer psychotic episodes over the last two years prior to follow-up . Finally , when investigated as a continuous variable , younger age at onset significantly correlated with better symptomatic and functional outcomes . CONCLUSIONS These results question the assumption that early-onset schizophrenia typically has a poor outcome . Early detection and specialised treatment for the first psychotic episode appear to be more effective at improving long-term functional outcomes in people with early-onset schizophrenia as in those with adult-onset schizophrenia . This possibility and the reasons for it need further investigation Outcome according to diagnosis and stability of diagnosis were investigated in a follow-back study of 351 adolescents with various psychiatric disorders hospitalized in a closed psychiatric ward . The duration of follow-back was 15 - 19 years . All diagnoses were based on the ICD-9 . Data were collected from the Health Ministry registry and , in the patients who could be located , by structured telephone interview . Special attention was directed at the diagnosis of transient adolescent psychosis ( TAP ) vs. schizophrenia and prognostic indicators of suicide . The results showed that the most stable diagnosis was anxiety disorder . The stability of the different diagnoses over time was greater between the second and last admission than between the first and last ( for patients with three or more admissions ) . Number of hospitalizations correlated negatively with prognosis . TAP at second admission was an unstable diagnosis ; 66 % of these patients had a final diagnosis of schizophrenia . However , patients with a diagnosis of TAP at first admission had a higher predictive index score and a higher outcome score than schizophrenic patients . TAP appeared to be a valid diagnostic entity , distinguishable from schizophrenia in course , frequency of suicidal behaviour and social-occupational outcome . Suicide victims had a higher cumulative length of stay than age- and sex-matched non-suicidal patients . Fifty per cent of the suicide victims had a final diagnosis of schizophrenia , compared to 30 per cent for the whole sample . In conclusion , these findings indicate that TAP is associated with a relatively good prognosis and should probably be differentiated from schizophrenia . Further retrospective and prospect i ve studies of adolescent psychiatric in patients may help delineate the nature and course of psychosis and other psychopathology in this age group Neurodevelopmental models for the pathology of schizophrenia propose both polygenetic and environmental risks , as well as early ( pre/perinatal ) and late ( usually adolescent ) developmental brain abnormalities . With the use of brain mapping algorithms , we detected striking anatomical profiles of accelerated gray matter loss in very early-onset schizophrenia ; surprisingly , deficits moved in a dynamic pattern , enveloping increasing amounts of cortex throughout adolescence . Early-onset patients were rescanned prospect ively with MRI , at 2-year intervals at three time points , to uncover the dynamics and timing of disease progression during adolescence . The earliest deficits were found in parietal brain regions , supporting visuospatial and associative thinking , where adult deficits are known to be mediated by environmental ( nongenetic ) factors . Over 5 years , these deficits progressed anteriorly into temporal lobes , engulfing sensorimotor and dorsolateral prefrontal cortices , and frontal eye fields . These emerging patterns correlated with psychotic symptom severity and mirrored the neuromotor , auditory , visual search , and frontal executive impairments in the disease . In temporal regions , gray matter loss was completely absent early in the disease but became pervasive later . Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri , deficit regions found consistently in adult studies . These emerging dynamic patterns were ( i ) controlled for medication and IQ effects , ( ii ) replicated in independent groups of males and females , and ( iii ) charted in individuals and groups . The result ing mapping strategy reveals a shifting pattern of tissue loss in schizophrenia . Aspects of the anatomy and dynamics of disease are uncovered , in a changing profile that implicates genetic and nongenetic patterns of deficits BACKGROUND Recent anatomical brain magnetic resonance imaging ( MRI ) studies show a striking postpsychotic progressive loss of cortical gray matter ( GM ) in patients with childhood-onset schizophrenia ( COS ) , which appears greater than that seen for adult patients . However , the diagnostic specificity and the relationship of these changes to drug treatment and cognitive functioning remain unclear . We performed a comparative prospect i ve brain MRI study in patients with COS and pediatric patients with transient psychosis with behavior problems ( psychosis not otherwise specified ) provisionally considered multidimensionally impaired ( MDI ) . We hypothesized that cortical GM loss would occur in patients with COS but not in adolescents with atypical psychoses . METHODS Anatomical brain MRI was performed at baseline and follow-up in 19 patients in the MDI group ( mean [ SD ] age of 13.3 [ 3.1 ] years ) ; in 23 patients with COS matched for age , sex , IQ score , and drug treatment ( mean [ SD ] age of 13.9 [ 2.5 ] years ) ; and 38 healthy control subjects matched for age and sex ( mean [ SD ] age of 13.3 [ 3.1 ] years ) . The mean ( SD ) follow-up was 2.5 ( 0.8 ) years . Volumes of the cerebrum and total and regional GM were obtained by using automated analysis , and percent change in volume across time was calculated . One-way analyses of variance with post hoc Tukey Honestly Significantly Different comparisons were performed to examine group differences in the percent change in GM across follow-up . RESULTS The COS group had significantly greater total , frontal , temporal , and parietal GM loss than did the MDI or healthy control groups ; analysis of variance post hoc P values ranged from.03 to.001 . The MDI and control groups did not differ significantly from each other . CONCLUSIONS The cortical GM volume loss in COS appears diagnostically specific ; it was not seen in children and adolescents with atypical psychosis . Because both patient groups had similar early developmental patterns , cognitive functioning , medications , and hospitalizations , this progressive loss appears to be intrinsic to COS . An ongoing neurodevelopmental process and /or brain response specific to the illness could account for these changes BACKGROUND Only one study has used a prospect i ve method to analyze the diagnostic stability of first psychotic episodes in children and adolescents . The Child and Adolescent First-Episode Psychosis Study ( CAFEPS ) is a 2-year , prospect i ve longitudinal study of early-onset first episodes of psychosis ( EO-FEP ) . AIM To describe diagnostic stability and the variables related to diagnostic changes . METHODS Participants were 83 patients ( aged 9 - 17 years ) with an EO-FEP consecutively attended . They were assessed with a structured interview ( Kiddie-Schedule for Affective Disorders and Schizophrenia , Present and Lifetime version ) and clinical scales at baseline and after 2 years . RESULTS The global consistency for all diagnoses was 63.9 % . The small group of bipolar disorder had high stability ( 92.31 % ) as did the group with schizophrenia spectrum disorders ( 90.00 % ) . Depressive disorder had lower stability ( 37.50 % ) and the lowest values were for psychotic disorder not otherwise specified ( 11.76 % ) and brief psychotic disorder (0%).The most frequent diagnostic shift was to schizophrenia spectrum and bipolar disorders . One group of patients did not meet the criteria for any diagnosis at follow-up . Independent predictors of change to schizophrenia spectrum disorders were lower scores on the Children 's Global Assessment Scale ( CGAS ) and the Hamilton Depression Rating Scale . Predictors of not having a diagnosis at follow-up were the CGAS and the Strauss-Carpenter Outcome Scale . CONCLUSIONS Global diagnostic stability was 63.9 % . Bipolar and schizophrenia spectrum disorders were the most stable diagnoses , while depressive disorder and other psychosis the least stable . Psychosocial functioning at baseline was a good predictor of diagnosis at follow-up . These data show the need for longitudinal follow-up in EO-FEP before a stable diagnosis is reached Objective To examine the diagnostic stability and the functional outcome of patients with early-onset psychosis ( EOP ) over a 2-year follow-up period . Methods A total of 24 patients ( 18 males ( 75 % ) and 6 females ( 25 % ) , mean age ± SD : 15.7 ± 1.6 years ) with a first episode of EOP formed the sample . Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale ( PANSS ) . Social disability was measured with the Global Assessment of Functioning ( GAF ) disability scale . Diagnosis was assessed using the Kiddie-Sads-Present and Lifetime Version ( K-SADS-PL ) , according to DSM-IV criteria . All diagnoses were re-assessed after 1 year and 2 years . Results Schizophrenia had the highest prospect i ve consistency ( 100 % predictive value ) , while diagnostic stability was moderate for bipolar disorder ( 71.4 % ) , and low for schizoaffective disorder ( 50 % ) , schizophreniform and brief psychosis ( 50 % ) , and psychosis not otherwise specified ( NOS ) ( 16.7 % ) . The agreement between the baseline diagnoses and the 1-year follow-up diagnoses was 54.2 % , whereas between the 1-year follow-up and the 2-year follow-up , it rose to 95.7 % . Regardless of diagnosis , baseline negative symptoms were the only significant predictor of level of functioning at the 2-year follow-up ( p = 0.010 ) . Conclusion Our results highlight the primacy of the first-year follow-up diagnosis in predicting diagnostic stability of EOP IMPORTANCE Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis ( FEP ) showed higher relapse rates but no other disadvantages compared with maintenance treatment ; however , long-term effects on recovery have not been studied before . OBJECTIVE To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation ( DR ) vs maintenance treatment ( MT ) trial . DESIGN Seven-year follow-up of a 2-year open r and omized clinical trial comparing MT and DR . SETTING One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million- population catchment area . Of these , 111 patients refused to participate and 18 patients did not experience remission . PARTICIPANTS After 7 years , 103 patients ( 80.5 % ) of 128 patients who were included in the original trial were located and consented to follow-up assessment . INTERVENTION After 6 months of remission , patients were r and omly assigned to DR strategy or MT for 18 months . After the trial , treatment was at the discretion of the clinician . MAIN OUTCOMES AND MEASURES Primary outcome was rate of recovery , defined as meeting the criteria of symptomatic and functional remission . Determinants of recovery were examined using logistic regression analysis ; the treatment strategy ( MT or DR ) was controlled for baseline parameters . RESULTS The DR patients experienced twice the recovery rate of the MT patients ( 40.4 % vs 17.6 % ) . Logistic regression showed an odds ratio of 3.49 ( P = .01 ) . Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates . CONCLUSIONS AND RELEVANCE Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT . To our knowledge , this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP . Additional studies are necessary before these results are incorporated into general practice . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N16228411 Identifying early-onset schizophrenia spectrum disorders ( SSD ) at a very early stage remains challenging . To assess the diagnostic predictive value of multiple types of data at the emergence of early-onset first-episode psychosis ( FEP ) , various support vector machine ( SVM ) classifiers were developed . The data were from a 2-year , prospect i ve , longitudinal study of 81 patients ( age 9–17 years ) with early-onset FEP and a stable diagnosis during follow-up and 42 age- and sex-matched healthy controls ( HC ) . The input was different combinations of baseline clinical , neuropsychological , magnetic resonance imaging brain volumetric and biochemical data , and the output was the diagnosis at follow-up ( SSD vs. non-SSD , SSD vs. HC , and non-SSD vs. HC ) . Enhanced recursive feature elimination was performed for the SSD vs. non-SSD classifier to select and rank the input variables with the highest predictive value for a diagnostic outcome of SSD . After validation with a test set and considering all baseline variables together , the SSD vs. non-SSD , SSD vs. HC and non-SSD vs. HC classifiers achieved an accuracy of 0.81 , 0.99 and 0.99 , respectively . Regarding the SSD vs. non-SSD classifier , a combination of baseline clinical variables ( severity of negative , disorganized symptoms and hallucinations or poor insight ) and neuropsychological variables ( impaired attention , motor coordination , and global cognition ) showed the highest predictive value for a diagnostic outcome of SSD . Neuroimaging and biochemical variables at baseline did not add to the predictive value . Thus , comprehensive clinical /cognitive assessment remains the most reliable approach for differential diagnosis during early-onset FEP . SVMs may constitute promising multivariate tools in the search for predictors of diagnostic outcome in FEP OBJECTIVE To examine the course and outcome of early-onset psychotic disorders . METHOD These are data from a longitudinal , prospect i ve study of youths with psychotic disorders . St and ardized diagnostic and symptom rating measures were used . RESULTS Fifty-five subjects with the following disorders have been recruited : schizophrenia ( n = 18 ) , bipolar disorder ( n = 15 ) , psychosis not otherwise specified ( n = 15 ) , schizoaffective disorder ( n = 6 ) , and organic psychosis ( n = 1 ) . Follow-up assessment s were obtained on 42 subjects at year 1 and 31 subjects at year 2 . Youths with schizophrenia had more chronic global dysfunction , whereas subjects with bipolar disorder overall had better functioning , with a cyclical course of illness . However , according to results of a regression model , premorbid functioning and ratings of negative symptoms , but not diagnosis , significantly predicted the highest level of functioning over years 1 and 2 . CONCLUSIONS Course and level of functioning differentiated bipolar disorder from schizophrenia . However , premorbid functioning and ratings of negative symptoms were the best predictors of functioning over the follow-up period . These findings are consistent with the adult literature , and they further support that psychotic illnesses in young people are continuous with the adult-onset forms IMPORTANCE Adolescent offspring of depressed parents are at high risk for experiencing depressive disorders themselves . OBJECTIVE To determine whether the positive effects of a group cognitive-behavioral prevention ( CBP ) program extended to longer-term ( multiyear ) follow-up . DESIGN A 4-site r and omized clinical trial with 33 months of follow-up was conducted . Recruitment of participants was from August 2003 through February 2006 . SETTING The study setting s included a health maintenance organization , university medical centers , and a community mental health center . PARTICIPANTS Three hundred sixteen adolescent ( aged 13 - 17 years ) offspring of parents with current and /or prior depressive disorders ; adolescents had histories of depression , current elevated depressive symptoms , or both but did not currently meet criteria for a depressive disorder . INTERVENTIONS The CBP program consisted of 8 weekly 90-minute group sessions followed by 6 monthly continuation sessions . Adolescents were r and omly assigned to either the CBP program or usual care ( UC ) . MAIN OUTCOMES AND MEASURES The primary outcome was a probable or definite episode of depression ( Depression Symptom Rating score ≥4 ) for at least 2 weeks through the month 33 follow-up evaluation . RESULTS Over the 33-month follow-up period , youths in the CBP condition had significantly fewer onsets of depressive episodes compared with those in UC . Parental depression at baseline significantly moderated the intervention effect . When parents were not depressed at intake , CBP was superior to UC ( number needed to treat , 6 ) , whereas when parents were actively depressed at baseline , average onset rates between CBP and UC were not significantly different . A 3-way interaction among intervention , baseline parental depression , and site indicated that the impact of parental depression on intervention effectiveness varied across sites . CONCLUSIONS AND RELEVANCE The CBP program showed significant sustained effects compared with UC in preventing the onset of depressive episodes in at-risk youth over a nearly 3-year period . Important next steps will be to strengthen the CBP intervention to further enhance its preventive effects , improve intervention outcomes when parents are currently depressed , and conduct larger implementation trials to test the broader public health impact of the CBP program for preventing depression in youth . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00073671 Objective : To test effectiveness of the Early Detection , Intervention , and Prevention of Psychosis Program in preventing the onset of severe psychosis and improving functioning in a national sample of at-risk youth . Methods : In a risk-based allocation study design , 337 youth ( age 12–25 ) at risk of psychosis were assigned to treatment groups based on severity of positive symptoms . Those at clinical ly higher risk ( CHR ) or having an early first episode of psychosis ( EFEP ) were assigned to receive Family-aided Assertive Community Treatment ( FACT ) ; those at clinical ly lower risk ( CLR ) were assigned to receive community care . Between-groups differences on outcome variables were adjusted statistically according to regression-discontinuity procedures and evaluated using the Global Test Procedure that combined all symptom and functional measures . Results : A total of 337 young people ( mean age : 16.6 ) were assigned to the treatment group ( CHR + EFEP , n = 250 ) or comparison group ( CLR , n = 87 ) . On the primary variable , positive symptoms , after 2 years FACT , were superior to community care ( 2 df , p < .0001 ) for both CHR ( p = .0034 ) and EFEP ( p < .0001 ) subgroups . Rates of conversion ( 6.3 % CHR vs 2.3 % CLR ) and first negative event ( 25 % CHR vs 22 % CLR ) were low but did not differ . FACT was superior in the Global Test ( p = .0007 ; p = .024 for CHR and p = .0002 for EFEP , vs CLR ) and in improvement in participation in work and school ( p = .025 ) . Conclusion : FACT is effective in improving positive , negative , disorganized and general symptoms , Global Assessment of Functioning , work and school participation and global outcome in youth at risk for , or experiencing very early , psychosis Cognitive deficits are a core feature of psychotic disorders . Both in adult and adolescent population s , studies have shown that patients with psychosis have poorer cognitive functioning than controls . The cognitive domains that seem to be affected are mainly attention , working memory , learning and memory , and executive function . However , with regard to the trajectory of cognitive function throughout the illness , there is still a dearth of prospect i ve data in patients who develop psychosis during adolescence . In this article , neuropsychological functioning was assessed in a sample of 24 first episodes of early onset psychosis ( EOP ) and 29 healthy adolescents at baseline and after a two-year follow-up . Patients with EOP showed lower scores than controls in overall cognitive functioning and in all specific domains assessed ( attention , working memory , executive function , and learning and memory ) both at baseline and the two-year follow-up . When changes in cognitive functioning over two years were assessed , patients and controls showed significant improvement in almost all cognitive domains . However , this improvement disappeared in the patient group after controlling for improvement in symptomatology . Our findings support a neurodevelopmental pathological process in this sample of adolescents with psychosis BACKGROUND Antipsychotic drug discontinuation is a key risk factor in psychotic relapses . Clinical relapse is related to poor outcome , especially in the earlier stages of psychotic illness . The attitude toward treatment during the acute phase of a first episode of psychosis has been proposed as one of the main determinants of treatment discontinuation . However , the relationship between attitude toward antipsychotic medication and treatment discontinuation in the adolescent population has not been properly assessed . METHODS Adolescents , aged 12 - 18 years old , consecutively admitted to an adolescent unit with a first lifetime admission for a first episode of psychosis were asked to participate in a r and omized , flexible-dose , 6-month controlled trial of olanzapine vs. quetiapine . Attitude toward antipsychotic medication was assessed using the 10-item Drug Attitude Inventory ( DAI ) . The outcome variable was all-cause treatment discontinuation over the 6-month follow- up . The study sample was composed of 42 patients [ 34 boys ( 82.9 % ) , eight girls ( 17.1 % ) , mean age ± SD : 16.1±1.3 ] . RESULTS Of the 42 patients , only 29 ( 69 % ) continued the medication throughout the entire 6-month follow-up , while 13 ( 31 % ) discontinued the medication . DAI scores were greater than zero at all assessment s , indicating that the general attitude of the patients toward medication was positive . Higher DAI scores at baseline were related to lower all-cause treatment discontinuation [ adjusted hazard ratio ( HR ) = 0.81 ( 95 % CI : 0.68 - 0.96 ) , P=0.016 ] , while DAI scores at 15 days were unrelated to treatment discontinuation [ adjusted HR=1.0 ( 95 % CI : 0.82 - 1.23 ) , P=0.998 ] . CONCLUSIONS A better attitude toward antipsychotic medication at a first lifetime psychiatric admission for a first early-onset psychotic episode was significantly related to lower all-cause antipsychotic treatment discontinuation OBJECTIVE Cognitive impairment is an enduring and functionally relevant feature of early-onset schizophrenia ( EOS ) . Cognitive remediation therapy ( CRT ) improves cognition and functional outcome in adults with schizophrenia , although data in adolescents with EOS remain scarce . The purpose of this study is to examine the efficacy of CRT in improving cognition and functional outcomes in a sample of symptomatically stable but cognitively disabled adolescents with EOS . METHOD We performed a r and omized , controlled trial of individually delivered CRT plus treatment-as-usual compared with treatment-as-usual ( TAU ) . Fifty adolescents with EOS were r and omly assigned to receive CRT ( n = 25 ) or TAU ( n = 25 ) and were included in an intention-to-treat analysis . Clinical symptoms and cognitive and functional performance were assessed before and after treatment in both groups and after 3 months in the CRT group . Cognitive domains were defined according to the Measurement and Treatment Research to Improve Cognition in Schizophrenia ( MATRICS ) consensus battery and averaged in a global cognitive composite score . RESULTS After CRT , significant improvements were found in verbal memory and executive functions , with medium-to-large effect sizes ( ES ) . The derived cognitive composite score showed an improvement after the treatment , with a large ES . This change was reliable in more than two-thirds of the treated patients . Medium-sized ES were found for improvements after CRT in daily living and adaptive functioning , whereas large ES were observed for improvements in family burden . With the exception of functional gains , these changes were maintained after 3 months . CONCLUSION CRT appears to be a useful intervention strategy for adolescents with EOS . Cognitive improvements can be achieved through CRT , although further research is warranted to determine the durability of functional gains . Clinical trial registration information-Cognitive Remediation Therapy ( CRT ) in Adolescents With EOS ; www . clinical trials.gov ; NCT01701609 OBJECTIVE To examine the factor structure of symptom ratings in early-onset psychotic illnesses . METHOD Subjects were drawn from a 2-year prospect i ve study of early onset psychotic disorders . Principal components analysis with orthogonal ( varimax ) rotation was used to create factors from baseline ratings on the Schedule for Positive Symptoms , the Schedule for Negative Symptoms , and the Brief Psychiatric Rating Scale for Children . RESULTS Youths with schizophrenia ( n = 27 ) , bipolar disorder ( n = 22 ) , and psychosis not otherwise specified ( n = 20 ) were included . Four symptom factors were identified : negative symptoms , positive symptoms , behavioral problems , and dysphoria . Negative symptoms were predictive of the diagnosis of schizophrenia and treatment with antipsychotic medications . Neither behavior problems nor dysphoria were predictive of diagnosis . In subjects who completed follow-up assessment s at year 1 ( n = 49 ) and year 2 ( n = 39 ) , negative symptoms and behavioral problems predicted poorer functioning . CONCLUSIONS The four factors are clinical ly relevant , with both treatment planning and prognostic implication s. Negative symptoms best differentiated schizophrenia from the other disorders . Behavior problems and dysphoria were nonspecific problems that occurred in all three disorders , which likely leads to misdiagnosis in community setting OBJECTIVES To assess pre-treatment , baseline , and outcome differences of patients with early- ( onsetor = age 18 ) psychosis in an epidemiological cohort of first-episode patients . METHODS The Early Psychosis Prevention and Intervention Centre ( EPPIC ) in Australia admitted 786 FEP patients from January 1998 to December 2000 . Data were collected from patients ' files using a st and ardized question naire . Seven hundred four files were available , 61 of which were excluded owing to non-psychotic diagnoses or a psychotic disorder due to a general medical condition and 7 owing to missing data on age at onset . 636 patients were analyzed . RESULTS The mean age at onset was 21.3 years ( SD 3.6 ) ; the prevalence of early-onset psychosis was 18.6 % ( onset range 8.2 - 17.9 ) . Patients with early-onset were likely to have a slightly , but significantly worse premorbid functioning and a significantly longer duration of untreated psychosis ( Median 26.3 weeks ) compared to patients with adult-onset ( Median 8.7 weeks ; p<.001 ) . After controlling for relevant confounders , no significant outcome differences including CGI-S , GAF , remission of positive symptoms , or employment status were detected between early- and adult-onset psychoses . CONCLUSIONS Patients with early-onset psychosis may require a different approach to early detection . Outcome differences between early- and adult-onset were minor , but need to be replicated in future ( long-term ) prospect i ve epidemiological studies in other services OBJECTIVE Few studies have examined prediction of schizophrenia outcome in relation to brain magnetic resonance imaging measures . In this study , remission status at the time of discharge was examined in relation to admission cortical thickness for childhood-onset schizophrenia prob and s. We hypothesized that total , frontal , temporal , and parietal gray matter thickness would be greater in patients who subsequently remit . METHOD The relation between admission cortical brain thickness on magnetic resonance imaging and remission status at the time of discharge an average of 3 months later was examined for 56 individuals ( 32 males ) ages 6 to 19 diagnosed with childhood-onset schizophrenia . Cortical thickness was measured across the cerebral hemispheres at admission . Discharge remission criteria were adapted from the 2005 Remission in Schizophrenia Working Group criteria . RESULTS Patients remitted at discharge ( n = 16 [ 29 % ] ) had thicker regional cortex in left orbitofrontal , left superior , and middle temporal gyri and bilateral post central and angular gyri ( p < or = .008 ) . CONCLUSIONS Our results provide neuroanatomic correlates of clinical remission in schizophrenia and evidence that response to treatment may be mediated by these cortical brain regions

The impact on patient participation was varied . The effect of a decision aid and patient navigator interventions on communication with health providers was positive . While the use of a decisions aid successfully facilitated shared decision-making and patients ' perception of treatment adherence , the use of patient navigators was ineffective . A computer support system was found to improve general patient participation ; however little clarification of what this involved was provided . This systematic review identified few rigorous evaluations of interventions to improve treatment participation for CALD people with cancer , highlighting the lack of a robust evidence base to improve this crucial aspect of care .

Disparities in cancer outcomes for people from culturally and linguistically diverse ( CALD ) groups are well known . Improving CALD patients ' active participation in treatment processes holds potential to improve outcomes , but little is known of effective strategies to facilitate this . This systematic review investigated interventions to improve three aspects of participation in cancer care among CALD groups , namely involvement in decision-making , communication with health providers and treatment adherence .

Abstract OBJECTIVE : Assess impact of a computer-based patient support system on quality of life in younger women with breast cancer , with particular emphasis on assisting the underserved . DESIGN : R and omized controlled trial conducted between 1995 and 1998 . SETTING : Five sites : two teaching hospitals ( Madison , Wis , and Chicago , Ill ) , two nonteaching hospitals ( Chicago , Ill ) , and a cancer re source center ( Indianapolis , Ind ) . The latter three sites treat many underserved patients . PARTICIPANTS : Newly diagnosed breast cancer patients ( N=246 ) under age 60 . INTERVENTIONS : Experimental group received Comprehensive Health Enhancement Support System ( CHESS ) , a home-based computer system providing information , decision-making , and emotional support . MEASUREMENTS AND MAIN RESULTS : Pretest and two posttest surveys ( at two- and five-month follow-up ) measured aspects of participation in care , social/information support , and quality of life . At two-month follow-up , the CHESS group was significantly more competent at seeking information , more comfortable participating in care , and had greater confidence in doctor(s ) . At five-month follow-up , the CHESS group had significantly better social support and also greater information competence . In addition , experimental assignment interacted with several indicators of medical underservice ( race , education , and lack of insurance ) , such that CHESS benefits were greater for the disadvantaged than the advantaged group . CONCLUSIONS : Computer-based patient support systems such as CHESS may benefit patients by providing information and social support , and increasing their participation in health care . These benefits may be largest for currently underserved population Background : Low-income African American women face numerous barriers to mammography screening . We tested the efficacy of a combined interactive computer program and lay health advisor intervention to increase mammography screening . Methods : In this r and omized , single blind study , participants were 181 African American female health center patients of ages 41 to 75 years , at ≤250 % of poverty level , with no breast cancer history , and with no screening mammogram in the past 15 months . They were assigned to either ( a ) a low-dose comparison group consisting of a culturally appropriate mammography screening pamphlet or ( b ) interactive , tailored computer instruction at baseline and four monthly lay health advisor counseling sessions . Self-reported screening data were collected at baseline and 6 months and verified by medical record . Results : For intent-to-treat analysis of primary outcome ( medical record – verified mammography screening , available on all but two participants ) , the intervention group had increased screening to 51 % ( 45 of 89 ) compared with 18 % ( 16 of 90 ) for the comparison group at 6 months . When adjusted for employment status , disability , first-degree relatives with breast cancer , health insurance , and previous breast biopsies , the intervention group was three times more likely ( adjusted relative risk , 2.7 ; 95 % confidence interval , 1.8 - 3.7 ; P < 0.0001 ) to get screened than the low-dose comparison group . Similar results were found for self-reported mammography stage of screening adoption . Conclusions : The combined intervention was efficacious in improving mammography screening in low-income African American women , with an unadjusted effect size ( relative risk , 2.84 ) significantly higher ( P < 0.05 ) than that in previous studies of each intervention alone . Cancer Epidemiol Biomarkers Prev ; 19(1 ) ; OBJECTIVES We conducted 1 of the first community-based trials to develop a multicomponent intervention that would increase colorectal cancer screening among an Asian American population . METHODS Filipino Americans ( n = 548 ) nonadherent to colorectal cancer ( CRC ) screening guidelines were r and omized into an intervention group that received an education session on CRC screening and free fecal occult blood test ( FOBT ) kits ; a second intervention group that received an education session but no free FOBT kits ; and a control group that received an education session on the health benefits of physical activity . RESULTS Self-reported CRC screening rates during the 6-month follow-up period were 30 % , 25 % , and 9 % for participants assigned to intervention with FOBT kit , intervention without the kit , and control group , respectively . Participants in either of the 2 intervention groups were significantly more likely to report screening at follow-up than were participants in the control group . CONCLUSIONS A multicomponent intervention that includes an educational group session in a community setting can significantly increase CRC screening among Filipino Americans , even when no free FOBT kits are distributed BACKGROUND North American Chinese women have lower levels of Papanicolaou ( Pap ) testing than other population subgroups . We conducted a r and omized controlled trial to evaluate the effectiveness of two alternative cervical cancer screening interventions for Chinese women living in North America . METHODS Four hundred and eighty-two Pap testing underutilizers were identified from community-based surveys of Chinese women conducted in Seattle , Washington , and Vancouver , British Columbia . These women were r and omly assigned to one of two experimental arms or control status . Several Chinese- language material s were used in both experimental arms : an education-entertainment video , a motivational pamphlet , an educational brochure , and a fact sheet . Women in the first experimental group ( outreach worker intervention ) received the material s , as well as tailored counseling and logistic assistance , during home visits by trilingual , bicultural outreach workers . Those in the second experimental group ( direct mail intervention ) received the material s by mail . The control group received usual care . Follow-up surveys were completed 6 months after r and omization to ascertain participants ' Pap testing behavior . All statistical tests were two-sided . RESULTS A total of 402 women responded to the follow-up survey ( 83 % response rate ) . Of these women , 50 ( 39 % ) of the 129 women in the outreach group , 35 ( 25 % ) of the 139 women in the direct mail group , and 20 ( 15 % ) of the 134 women in the control group reported Pap testing in the interval between r and omization and follow-up data collection ( P<.001 for outreach worker versus control , P = .03 for direct mail versus control , and P = .02 for outreach worker versus direct mail ) . Intervention effects were greater in Vancouver than in Seattle . CONCLUSION Culturally and linguistically appropriate interventions may improve Pap testing levels among Chinese women in North America ABSTRACT This article is the second of a two-part series reporting on a population -based study intended to use an eHealth system to examine the feasibility of reaching underserved women with breast cancer ( Gustafson , McTavish et al. , Reducing the digital divide for low-income women with breast cancer , 2004 ; Madison Center for Health Systems Research and Analysis , University of Wisconsin ; Comprehensive Health Enhancement Support System [ CHESS ] ) and determine how they use the system and what impact it had on them . Participants included women recently diagnosed with breast cancer whose income was at or below 250 % of poverty level and were living in rural Wisconsin ( n = 144 ; all Caucasian ) or Detroit ( n = 85 ; all African American ) . Because this was a population -based study all 229 participants received CHESS . A comparison group of patients ( n = 51 ) with similar demographics was drawn from a separate recently completed r and omized clinical trial . Use rates ( e.g. , frequency and length of use as well as type of use ) as well as impact on several dimensions of quality of life and participation in health care are reported . Low-income subjects in this study logged on and spent more time on CHESS than more affluent women in a previous study . Urban African Americans used information and analysis services more and communication services less than rural Caucasians . When all low-income women from this study are combined and compared with a low-income control group from another study , the CHESS group was superior to that control group in 4 of 8 outcome variables at both statistically and practically significant levels ( social support , negative emotions , participation in health care , and information competence ) . When African Americans and Caucasians are separated the control group 's sample size becomes 30 and 21 thus reducing power . Statistical significance is retained , however , in all four outcomes for Caucasians and in two of four for African Americans . Practical significance is retained for all four outcomes . We conclude that an eHealth system like CHESS will be used extensively and have a positive impact on low-income women with breast cancer Objective . Oncology patients often seek involvement in their medical consultations . Such involvement is endorsed by most health care providers and mirrored in practice guidelines . However , oncologists exhibit great variation in how they provide patients with disease-relevant information , and many remain reluctant to do so at all . The authors examined the impact of a patient-specific decision aid on women ’s decisions about adjuvant therapy for breast cancer . Method . 386 women with breast cancer were r and omized to receive either an informational pamphlet about adjuvant therapy ( usual care ) or a patient-specific , evidence -based decision aid about adjuvant therapy . The authors compared rates of adjuvant therapy between the groups controlling for age , education , marital status , race , tumor severity , and practice type of their physician ( university-based or community-based ) . Results . Among women with low tumor severity , only 58 % ( 35/60 ) of women in the decision aid group chose adjuvant therapy , compared to 87 % ( 33/38 ) of their counterparts in usual care ( P < 0.01 ) . Conclusions . This study illustrates the important impact of medical decision aids on treatment choices , particularly for patients for whom treatment has little benefit . In the case of adjuvant therapy for breast cancer , providing individualized , evidence -based risk information for shared decision making result ed in fewer women with low tumor severity choosing adjuvant treatment Background Minority racial/ethnic groups have low colorectal cancer ( CRC ) screening rates . Objective To evaluate a culturally tailored intervention to increase CRC screening , primarily using colonoscopy , among low income and non-English speaking patients . Design R and omized controlled trial conducted from January to October of 2007 . Setting Single , urban community health center serving a low-income , ethnically diverse population . Patients A total of 1,223 patients 52 - 79 years of age overdue for CRC screening , r and omized to intervention ( n = 409 ) vs. usual care control ( n = 814 ) groups . InterventionIntervention patients received an introductory letter with educational material followed by phone or in-person contact by a language -concordant “ navigator . ” Navigators ( n = 5 ) were community health workers trained to identify and address patient-reported barriers to CRC screening . Individually tailored interventions included patient education , procedure scheduling , translation and explanation of bowel preparation , and help with transportation and insurance coverage . Rates of colorectal cancer screening were assessed for intervention and usual care control patients . Results Over a 9-month period , intervention patients were more likely to undergo CRC screening than control patients ( 27 % vs. 12 % for any CRC screening , p < 0.001 ; 21 % vs. 10 % for colonoscopy completion , p < 0.001 ) . The higher screening rate result ed in the identification of 10.5 polyps per 100 patients in the intervention group vs. 6.8 in the control group ( p = 0.04 ) . Limitations Patients were from one health center . Some patients may have obtained CRC screening outside our system . Conclusions A culturally tailored , language -concordant navigator program design ed to identify and overcome barriers to colorectal cancer screening can significantly improve colonoscopy rates for low income , ethnically and linguistically diverse patients . Clinical Trials.gov registration number : BACKGROUND Latino immigrants face a higher burden of colorectal cancer ( CRC ) and screening rates are low . OBJECTIVE To assess the effectiveness of a multilevel intervention in increasing the rate of CRC screening among Latino immigrants . DESIGN A r and omized controlled trial , with r and omization at the physician level . PARTICIPANTS Pairs of 65 primary care physicians and 65 Latino immigrant patients participated , 31 in the intervention and 34 in the control group . INTERVENTIONCRC educational video in Spanish on a portable personal digital video display device accompanied by a brochure with key information for the patient , and a patient-delivered paper-based reminder for their physician . MEASUREMENTS Completed CRC screening , physician recommendation for CRC screening , and patient adherence to physician recommended CRC screening . RESULTS The overall rate of completed screening for CRC was 55 % for the intervention and 18 % for the control group ( p = 0.002 ) . Physicians recommended CRC screening for 61 % of patients in the intervention group versus 41 % in the control group ( p = 0.08 ) . Of those that received a recommendation , 90 % in the intervention group adhered to it versus 26 % in the control group ( p = 0.007 ) . CONCLUSIONS The intervention was successful in increasing rates of completed CRC screening primarily through increasing adherence after screening was recommended . Additional efforts should focus on developing new strategies to increase physician recommendation for CRC screening , while employing effective patient adherence interventions BACKGROUND We design ed this observational cohort study to assess the association between patient-centered communication in primary care visits and subsequent health and medical care utilization . METHODS We selected 39 family physicians at r and om , and 315 of their patients participated . Office visits were audiotaped and scored for patient-centered communication . In addition , patients were asked for their perceptions of the patient-centeredness of the visit . The outcomes were : ( 1 ) patients ' health , assessed by a visual analogue scale on symptom discomfort and concern ; ( 2 ) self-report of health , using the Medical Outcomes Study Short Form-36 ; and ( 3 ) medical care utilization variables of diagnostic tests , referrals , and visits to the family physician , assessed by chart review . The 2 measures of patient-centeredness were correlated with the outcomes of visits , adjusting for the clustering of patients by physician and controlling for confounding variables . RESULTS Patient-centered communication was correlated with the patients ' perceptions of finding common ground . In addition , positive perceptions ( both the total score and the subscore on finding common ground ) were associated with better recovery from their discomfort and concern , better emotional health 2 months later , and fewer diagnostic tests and referrals . CONCLUSIONS Patient-centered communication influences patients ' health through perceptions that their visit was patient centered , and especially through perceptions that common ground was achieved with the physician . Patient-centered practice improved health status and increased the efficiency of care by reducing diagnostic tests and referrals PURPOSE Previous studies found that African American and Hispanic cancer patients are at risk for undertreatment of pain . We evaluated the efficacy of a pain education intervention for underserved minority patients . PATIENTS AND METHODS Ninety-seven underserved African American and Hispanic out patients with cancer-related pain were enrolled onto a r and omized clinical trial of pain management education . The patients in the education group received a culture-specific video and booklet on pain management . The control group received a video and booklet on nutrition . A research nurse met with each patient to review the material s. We measured changes in pain intensity and pain-related interference 2 to 10 weeks after the intervention , as well as changes in quality of life , perceived pain control , functional status , analgesics , and physician pain assessment s. RESULTS Physicians underestimated baseline pain intensity and provided inadequate analgesics for more than 50 % of the sample . Although the ratings for pain intensity and pain interference decreased over time for both groups , there was no statistically significant difference between groups . Pain education did not affect quality of life , perceived pain control , or functional status . African American patients in the education but not the control group reported a significant decrease in pain worst ratings from baseline to first follow-up ( P < .01 ) , although this decrease was not maintained at subsequent assessment s. CONCLUSION Brief education had limited impact on pain outcomes for underserved minority patients , suggesting that more intensive education for patients and interventions for physicians are needed OBJECTIVE The purpose of this study was to examine the effects of a theory-based decision-making uncertainty management intervention ( DMUMI ) providing newly diagnosed prostate cancer patients with information , communication skills and personally design ed prompts . METHODS A r and omized clinical trial was conducted using a 3x2 design with intervention and control groups including both Caucasian and African-American men . General linear mixed models were used to compare intervention groups over time . RESULTS Significant main effects for the treatment groups were found for uncertainty management ( cancer knowledge , problem-solving , and patient-provider communication ) , medical communication competence , number and helpfulness of re sources for information , and decisional regret . CONCLUSION The intervention was effective in uncertainty management for Caucasian and African-American men , specifically in preparing competent patients with improved knowledge , problem-solving skills , information re sources , and communication skills . Using the Uncertainty in Illness Theory , specific skills were selected with a focus on the antecedents of uncertainty . PRACTICE IMPLICATION S In the treatment decision-making context , patients and supportive others need information about disease , treatment options and side effects but they also need communication skills training prior to the treatment decision consultation

Conclusion Findings from the clinical history and examination are insufficient to " rule in " or " rule out " a diagnosis of LVSD in primary care setting s. BNP and ECG measurement appear to have similar diagnostic utility and are most useful in " ruling out " LVSD with a normal test result when the probability of LVSD is in the intermediate range

Background To assess the accuracy of findings from the clinical history , symptoms , signs and diagnostic tests ( ECG , CXR and natriuretic peptides ) in relation to the diagnosis of left ventricular systolic dysfunction ( LVSD ) in a primary care setting .

Abstract Objective : To investigate the performance of a novel assay for N-terminal pro-brain natriuretic peptide ( NT-proBNP ) in diagnosing heart failure in various r and omly selected general and high risk community population s. Design : Community cohort study ( sub study of the echocardiographic heart of Engl and screening study ) . Setting : Four r and omly selected general practice s in the West Midl and s of Engl and . Participants : 591 r and omly sample d patients over the age of 45 , stratified for age and socioeconomic status and falling into four cohorts ( general population , patients with an existing clinical label of heart failure , patients prescribed diuretics , and patients deemed at high risk of heart failure ) . Main outcome measure : Sensitivity , specificity , positive and negative predictive values , likelihood ratios , and area under receiver operating characteristic curve for NT-proBNP assay in the diagnosis of heart failure . Results : For NT-proBNP in the diagnosis of heart failure in the general population ( population screen ) , a level of > 36 pmol/l had a sensitivity of 100 % , a specificity of 70 % , a positive predictive value of 7 % , a negative predictive value of 100 % , and an area under the receiver operating characteristic curve of 0.92 ( 95 % confidence interval 0.82 to 1.0 ) . Similar negative predictive values were found for patients from the three other population s screened . Conclusions : This NT-proBNP assay seems to have value in the diagnosis of heart failure in the community . High negative predictive values indicate that the assay 's chief use would be to rule out heart failure in patients with suspected heart failure with normal concentrations of NT-proBNP . Positive results may identify patients who need cardiac imaging BACKGROUND Diagnostic echocardiography has poor access for patients with suspected heart failure . Pre-echocardiography screening with electrocardiograms ( ECGs ) is recommended as a means of targeting this scarce re source . There are data to support this policy when ECGs are interpreted by cardiologists but not by GPs . AIM To assess the value of GP-reported ECGs as a pre-echocardiography screening test for left ventricular systolic dysfunction ( LVSD ) . DESIGN OF STUDY Cross-sectional study of GPs ' ECG reporting skills . SETTING General practice , NHS in Scotl and . METHOD A r and omly selected , stratified sample of 123 Scottish GPs review ed 180 ECGs ( 100 abnormal , 50 normal and 30 duplicate ) from 150 patients with suspected heart failure . Forty-one patients had LVSD on echocardiography . GPs were required to categorise ECGs as normal or abnormal . RESULTS Mean sensitivity was 0.94 ( 95 % CI = 0.92 to 0.95 ) . Mean specificity 0.58 ( 95 % CI = 0.56 to 0.60 ) . Mean positive predictive value ( PPV ) was 0.47 ( 95 % CI = 0.46 to 0.48 ) . Mean negative predictive value ( NPV ) was 0.96 ( 95 % CI = 0.95 to 0.97 ) . Mean likelihood ratio was 2.39 ( 95 % CI = 2.28 to 2.50 ) . Seventy of 123 ( 57 % ) GPs achieved sensitivity of 0.9 and specificity of 0.5 for the detection of LVSD . CONCLUSION Most Scottish GPs have the skills to perform pre-echocardiography screening ECGs in patients with suspected LVSD . However , differences in ECG reporting performance between individual GPs will result in widely varying referral rates for echocardiography and differences in the detection rate of LVSD . The implication s of these findings need to be considered when heart failure diagnostic services are being developed BACKGROUND National guidelines suggest the use of natriuretic peptides in suspected heart failure but there have been no studies comparing assays in primary care . AIM To test and compare the diagnostic accuracy and utility of B-type natriuretic peptide ( BNP ) and N-terminal B-type natriuretic peptide ( NT proBNP ) in diagnosing heart failure due to left ventricular systolic dysfunction in patients with suspected heart failure referred by GPs to one-stop diagnostic clinics . DESIGN OF STUDY Community cohort , prospect i ve , diagnostic accuracy study . SETTING One-stop diagnostic clinics in Darlington Memorial and Bishop Auckl and General Hospitals and general practice s in South Durham . SUBJECTS Two hundred and ninety-seven consecutive patients with symptoms and signs suggestive of heart failure referred from general practice . METHOD The study measured sensitivity , specificity , positive and negative predictive values ( PPV , NPV ) , and area under receiver operating characteristic curve for BNP ( near patient assay ) and NT proBNP ( laboratory assay ) in diagnosis of heart failure due to left ventricular systolic dysfunction . The NPV of both assays was determined as a potential method of reducing the number of referrals for echocardiography . RESULTS One hundred and fourteen of the 297 patients had left ventricular systolic dysfunction ( 38 % ) . At the manufacturer 's recommended cut-off of 100 pg/ml BNP gave a NPV of 82 % . BNP performed better at a cut-off of 40 pg/ml with a NPV of 88 % . At a cut-off of 150 pg/ml , NT proBNP gave a NPV of 92 % . Using cut-offs of 40 pg/ml and 150 pg/ml for BNP and NT pro-BNP , respectively , could have prevented 24 % and 25 % of referrals to the clinic , respectively . CONCLUSIONS In this setting , NT pro-BNP performed marginally better than BNP , and would be easier to use practically in primary care . A satisfactory cut-off has been identified , which needs validating in general practice . NT pro-BNP could be used to select referrals to a heart failure clinic or for echocardiography . This process needs testing in real-life general practice BACKGROUND The early identification of patients at risk for the development of clinical heart failure ( HF ) is a new challenge in an effort to improve outcomes . METHODS We prospect ively evaluated whether the combination of brain natriuretic peptide ( BNP ) measurements ( Triage BNP test , Biosite Diagnostics ) and echocardiography would effectively stratify patients with new symptoms in a cost-effective HF program aim ed at early diagnosis of mild HF . A total of 252 patients were referred by 100 general practitioners . RESULTS Among the study population , the median BNP value was 78 ng/L ( range , 5 - 1491 ng/L ) . BNP concentrations were lower among patients without heart disease [ median 15 ng/L ( range , 5 - 167 ng/L ) ; n = 96 ] than among patients with confirmed HF [ median , 165 ng/L ( 22 - 1491 ng/L ) ; n = 157 ; Mann-Whitney U-test , 12.3 ; P < 0.001 ] . Patients were grouped into diastolic dysfunction [ BNP , 195 ( 223 ) ng/L ] , systolic dysfunction [ BNP , 290 ( 394 ) ng/L ] , and both systolic and diastolic dysfunction [ BNP , 776 ( 506 ) ng/L ] . In this model , a cutoff value of 50 ng/L BNP increases the diagnostic accuracy in predicting mild HF , avoiding 41 echocardiograms per 100 patients studied , with a net saving of 14 % of total costs . CONCLUSIONS Blood BNP concentrations , in a cost effective targeted screening , can play an important role in diagnosing mild HF and stratifying patients into risk groups of cardiac dysfunction BACKGROUND Diagnosing suspected left ventricular systolic dysfunction ( LVSD ) in the community is a challenge for GPs . We developed and vali date d a clinical prediction rule ( CPR ) for LVSD based on history , examination and electrocardiogram ( ECG ) . METHODS Prospect i ve cohort studies of 458 symptomatic patients ( derivation cohort ) and 535 patients ( validation cohort ) in 26 general practice s in Tayside and Fife , Scotl and . All patients underwent a structured clinical examination and ECG and the ' reference st and ard ' investigation of echocardiography to establish the presence of LVSD . RESULTS Four elements from the clinical history and examination were all independently associated with LVSD -- male sex [ adjusted odds ratio ( OR ) 2.5 ; 95 % CI 1.1 , 5.0 ] , presence of orthopnoea ( OR 5.4 ; 1.9 , 13.8 ) history of myocardial infa rct ion ( OR 5.6 ; 2.3 , 13.6 ) and elevated jugular venous pulsations ( OR 15.1 ; 4.6 , 49.3 ) . Addition of ECG ( OR 20.6 ; 2.7 , 158.6 ) provides important diagnostic information in terms of probability of LVSD . A CPR based on the presence or absence of these five elements will generate probabilities ranging from 1 % to 97 % for LVSD when applied to an individual patient . In the validation cohort , the model under-predicted the probability of LVSD , particularly at lower levels of expected risk , reflecting differences in the risk-factor profiles of the derivation and validation cohorts . CONCLUSIONS The derived CPR provides quantitative estimates of post-test probability for LVSD . This rule requires further validation in other population s and setting s because of the difficulties encountered in the validation cohort The objective was to prospect ively vali date a method of increasing the sensitivity , specificity and negative predictive value of a normal ECG in the exclusion of left ventricular systolic dysfunction by the addition of clinical history . We performed a prospect i ve three year study of all referrals to our direct access ECHO service for assessment of LV function . The ECG was reported blind of the result of the ECHO , history of MI or not was noted , and result of the ECHO predicted . Over three years 416 patients were assessed for the presence or absence of left ventricular systolic dysfunction and consequent changes in clinical management . A total of 320(77 % ) of patients referred with suspected left ventricular dysfunction were found to have normal left ventricular function . Of the 250(60 % ) patients treated prior to referral for assessment , 183(73 % ) were treated inappropriately . The combination of a normal ECG and a negative history of myocardial infa rct ion had a sensitivity of 98 % and a negative predictive value of 99 % in the assessment of LV function . This was an improvement over a normal ECG alone . Our study shows that diagnosis and treatment of heart failure in the community remains sub-optimal . The combination of a normal ECG and no previous history of myocardial infa rct ion is shown to be a sensitive and accurate predictor of normal left ventricular function . If adopted by general practitioners this would be a valuable method of optimising the use of ECHOCARDIOGRAPHIC in patients with suspected left ventricular dysfunction BACKGROUND The reliability of a clinical diagnosis of heart failure in primary care is poor . Concentrations of natriuretic peptides are high in heart failure . This population -based study examined the predictive value of natriuretic peptides in patients with a new primary -care diagnosis of heart failure . METHODS Concentrations of plasma atrial ( ANP and N-terminal ANP ) and B-type ( BNP ) natriuretic peptides were measured by radioimmunoassay in 122 consecutive patients referred to a rapid-access heart-failure clinic with a new primary -care diagnosis of heart failure . On the basis of clinical assessment , chest radiography , and transthoracic echocardiography , a panel of three cardiologists decided that 35 ( 29 % ) patients met the case definition for new heart failure . ANP and NT-ANP results were available for 117 patients ( 34 with heart failure ) and BNP results for 106 ( 29 with heart failure ) . FINDINGS Geometric mean concentrations of natriuretic peptides were much higher in patients with heart failure than in those with other diagnoses ( 29.2 vs 12.4 pmol/L for ANP ; 63.9 vs 13.9 pmol/L for BNP ; 1187 vs 410.6 pmol/L for NT-ANP ; all p < 0.001 ) . At cut-off values chosen to give negative predictive values for heart failure of 98 % ( ANP > or = 18.1 pmol/L , NT-ANP > or = 537.6 pmol/L , BNP > or = 22.2 pmol/L ) , the sensitivity , specificity , and positive predictive value for ANP were 97 % , 72 % , and 55 % ; for NT-ANP 97 % , 66 % , and 54 % ; and for BNP 97 % , 84 % , and 70 % . Addition of ANP or NT-ANP concentration or both did not improve the predictive power of a logistic regression model containing BNP concentration alone . INTERPRETATION In patients with symptoms suspected by a general practitioner to be due to heart failure , plasma BNP concentration seems to be a useful indicator of which patients are likely to have heart failure and require further clinical assessment BACKGROUND Although echocardiography is the gold st and ard test for suspected left ventricular dysfunction , its cost and availability limits its use as a routine screening tool . The high negative predictive value of B-natriuretic peptide ( BNP ) in dyspneic patients suggests its possible utility in screening patients prior to echocardiography . Determining an appropriate BNP level below which the need for echocardiography is precluded would be valuable . We hypothesized that a fixed plasma BNP level of 20 pg/mL and simple clinical parameters are an effective pre-echocardiographic screening tool for left ventricular dysfunction . METHODS Two hundred and two patients at a Veterans Administration facility with symptoms suggestive of heart disease ( male to female ratio 193:9 , mean age 65 years ) were screened prior to echocardiography . Patients with known cardiac dysfunction were excluded . RESULTS BNP levels of > or = 20 pg/mL were 79 % sensitive and 44 % specific in screening for any abnormality of ventricular function . The negative predictive value was 69 % . When broken down into categories of dysfunction , the cutoff point of 20 pg/mL had a better negative predictive value for those with systolic dysfunction ( 96 % ) or systolic plus diastolic dysfunction ( 100 % ) if patients with diastolic dysfunction were excluded . The majority of patients with falsely low BNP levels ( < 20 pg/mL with positive echocardiographic findings ) had mild diastolic dysfunction , with 3 patients exhibiting mild systolic dysfunction . CONCLUSIONS BNP may be a useful screening tool for left ventricular dysfunction in patients with history suggestive of heart disease and be used to assist in forming a pretest probability , which in turn could greatly assist in appropriateness of patient referral and in optimization of drug therapy Abstract Objectives : To assess the probability of left ventricular systolic dysfunction without echocardiography in patients from general practice . Design : Cross sectional study using multivariate regression models to examine the relation between clinical variables and left ventricular systolic dysfunction as determined by echocardiography . Setting : Three general practice s in Copenhagen . Subjects : 2158 patients aged > 40 years were screened by question naires and case record review s ; 357 patients with past or present signs or symptoms of heart disease were identified , of whom 126 were eligible for and consented to examination . Main outcome measures : Clinical variables that were significantly ( P<0.05 ) related to ejection fraction 0.45 and their predictive value for left ventricular systolic dysfunction . Results : 15 patients ( 12 % ) had left ventricular systolic dysfunction . The prevalence was significantly related to three questions : does the electrocardiogram have Q waves , left bundle branch block , or ST-T segment changes ? ( P=0.012 ) ; is resting supine heart rate greater than the simultaneous diastolic blood pressure ? ( P=0.002 ) ; and is plasma N-terminal atrial natriuretic peptide>0.8 nmol/l ? ( P=0.040 ) ? Only one of 60 patients with a normal electrocardiogram had systolic dysfunction ( 2 % , 95 % confidence interval 0 % to 9 % ) regardless of response to the other two questions . The risk of dysfunction was appreciable in patients with a yes answer to two or three questions ( 50 % , 27 % to 73 % ) . Conclusions : A normal electrocardiogram implies a low risk of left ventricular systolic dysfunction . Patients can be identified for echocardiography on the basis of an abnormal electrocardiogram combined with increased natriuretic peptide concentration or a heart rate greater than diastolic blood pressure , or both . Key messages Early treatment of left ventricular systolic dysfunction reduces morbidity , but diagnosis relies on echocardiography This study examines methods for assessing the risk of left ventricular systolic dysfunction in patients from primary care with past or present signs or symptoms of heart disease Risk can be assessed by three factors : QRS or ST-T changes in the electrocardiogram ; increased plasma concentration of N-terminal atrial natriuretic peptide ; and tachycardia ( supine resting heart rate > diastolic blood pressure ) Risk of systolic dysfunction was very low in patients with normal electrocardiographic results Risk was high in patients who had an abnormal electrocardiogram in combination with at least one other abnormal

Placebo substitution trial methodology represents only one approach to assess ADM maintenance .

BACKGROUND The principle evidence that antidepressant medication ( ADM ) is an effective maintenance treatment for adults with major depressive disorder ( MDD ) is from placebo substitution trials . These trials enter responders from ADM efficacy trials into r and omized , double-blind placebo-controlled ( RDBPC ) effectiveness trials to measure the rate of MDD relapse over time . However , other r and omized maintenance trial method ologies merit consideration and comparison .

CONTEXT Pregnancy has historically been described as a time of emotional well-being , providing " protection " against psychiatric disorder . However , systematic delineation of risk of relapse in women who maintain or discontinue pharmacological treatment during pregnancy is necessary . OBJECTIVE To describe risk of relapse in pregnant women who discontinued antidepressant medication proximate to conception compared with those who maintained treatment with these medications . DESIGN , SETTING , AND PATIENTS A prospect i ve naturalistic investigation using longitudinal psychiatric assessment s on a monthly basis across pregnancy ; a survival analysis was conducted to determine time to relapse of depression during pregnancy . A total of 201 pregnant women were enrolled between March 1999 and April 2003 from 3 centers with specific expertise in the treatment of psychiatric illness during pregnancy . The cohort of women was recruited from ( 1 ) within the hospital clinics , ( 2 ) self-referral via advertisements and community outreach detailing the study , and ( 3 ) direct referrals from the community . Participants were considered eligible if they ( 1 ) had a history of major depression prior to pregnancy , ( 2 ) were less than 16 weeks ' gestation , ( 3 ) were euthymic for at least 3 months prior to their last menstrual period , and ( 4 ) were currently or recently ( < 12 weeks prior to last menstrual period ) receiving antidepressant treatment . Of the 201 participants , 13 miscarried , 5 electively terminated their pregnancy , 12 were lost to follow-up prior to completion of pregnancy , and 8 chose to discontinue participation in the study . MAIN OUTCOME MEASURE Relapse of major depression defined as fulfilling Structured Clinical Interview for DSM-IV [ Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition ] Diagnosis ( SCID ) criteria . RESULTS Among the 201 women in the sample , 86 ( 43 % ) experienced a relapse of major depression during pregnancy . Among the 82 women who maintained their medication throughout their pregnancy , 21 ( 26 % ) relapsed compared with 44 ( 68 % ) of the 65 women who discontinued medication . Women who discontinued medication relapsed significantly more frequently over the course of their pregnancy compared with women who maintained their medication ( hazard ratio , 5.0 ; 95 % confidence interval , 2.8 - 9.1 ; P<.001 ) . CONCLUSIONS Pregnancy is not " protective " with respect to risk of relapse of major depression . Women with histories of depression who are euthymic in the context of ongoing antidepressant therapy should be aware of the association of depressive relapse during pregnancy with antidepressant discontinuation OBJECTIVE Loss of response to a previously effective antidepressant is a common clinical problem . Retrospective analyses have shown that the pattern of response during antidepressant treatment ( late onset and persistent versus other patterns ) can be used to predict relapse during continuation and maintenance treatment and possibly to identify placebo responses to treatment . This study was design ed to test the predictive value of response pattern prospect ively and to examine the data for other predictors of relapse . METHOD Five hundred seventy persons with major depressive disorder were treated with fluoxetine for 12 weeks and their pattern of response was determined . Those who responded ( N=292 ) underwent r and om assignment , under double-blind conditions , to continue taking fluoxetine or to switch to placebo for 52 weeks or until relapse . Survival analysis was used to examine the effect of covariates on relapse . RESULTS Although fluoxetine was significantly more effective than placebo during maintenance treatment , this chronically ill group had a high rate of relapse . Contrary to previous findings , a pattern of acute response was not predictive of relapse . Chronicity , symptom severity , a neurovegetative symptom pattern , and female gender were all associated with a significantly greater risk of relapse , with no difference observed between fluoxetine and placebo . CONCLUSIONS The pattern of response to acute treatment appears to be inconsistently predictive of relapse . There is a high rate of relapse with both active medication and placebo in patients with chronic depression . Illness characteristics predict loss of response both to fluoxetine and to placebo . No variable examined was predictive of differential relapse rates between fluoxetine and placebo OBJECTIVE Duloxetine doses of 80 and 120 mg/day were assessed for efficacy and safety in the treatment of major depressive disorder ( MDD ) . METHODS In this r and omized , double-blind trial , patients age > or = 18 meeting DSM-IV criteria for MDD were r and omized to placebo ( N=99 ) , duloxetine 80 mg/day ( N=93 ) , duloxetine 120 mg/day ( N=103 ) , or paroxetine 20 mg/day ( N=97 ) . The primary outcome measure was mean change from baseline in the 17-item Hamilton rating scale for depression ( HAMD(17 ) ) total score after 8 weeks of treatment ; a number of secondary efficacy measures also were assessed . Safety and tolerability were assessed via collection and analysis of treatment-emergent adverse events ( TEAEs ) , vital signs , and weight . The Arizona sexual experiences scale was used to assess sexual functioning . Patients who had a > or = 30 % reduction from baseline in the HAMD(17 ) total score at the end of the acute phase entered a 6-month continuation phase where they remained on the same treatment as they had taken during the acute phase ; efficacy and safety/tolerability outcomes were assessed during continuation treatment . RESULTS More than 87 % of patients completed the acute phase in each treatment group . Duloxetine-treated patients ( both doses ) showed significantly greater improvement ( P<0.05 ) in the HAMD(17 ) total score at week 8 compared with placebo . Paroxetine was not significantly different from placebo ( P=0.089 ) on mean change on the HAMD(17 ) . Duloxetine 120 mg/day also showed significant improvement on most secondary efficacy measures ( six of nine ) compared with placebo while duloxetine 80 mg/day ( three of nine ) and paroxetine ( three of nine ) were significantly superior to placebo on fewer secondary measures . HAMD(17 ) mean change data from this study and an identical sister study were pooled as defined a priori for the purpose s of performing a non-inferiority test versus paroxetine . Both duloxetine doses met statistical criteria for non-inferiority to paroxetine . TEAE reporting rates were low in all treatment groups and no deaths occurred in the acute or continuation phases . CONCLUSIONS The efficacy of duloxetine at doses of 80 and 120 mg/day in the treatment of MDD was demonstrated . Tolerability , as measured by TEAEs , and safety were similar to paroxetine 20 mg/day and consistent with previous published data on duloxetine in the treatment of MDD BACKGROUND One of the strongest predictors of depression recurrence in those who respond to treatment is the presence of residual depressive symptoms . Our goal was to examine stressful life event exposure as a mechanism of recurrence in previously depressed patients with residual depression symptoms . That is , we predicted that higher levels of residual symptoms will significantly predict exposure to acute life events that will then heighten prospect i ve recurrence risk . METHODS Participants included 68 adult out patients with major depression ( 42 women ; age 18 - 60 ) who completed a 12-month naturalistic follow-up after achieving remission in a 20-week r and omized , open label trial of interpersonal psychotherapy , cognitive-behavioral therapy , or antidepressant medication . Depression recurrence was defined as the reemergence of an episode of major depression as determined by structured interview . Acute life events and chronic stressors were assessed at the end of follow-up using a context ual interview . RESULTS Posttreatment depression scores significantly prospect ively predicted an increased risk for recurrence , and acute life events in the follow-up period . Cox regression survival analyses modeling life events as time-dependent covariates showed that life event exposure mediated the relation of residual symptoms to recurrence even controlling for chronic stress . CONCLUSIONS Our findings implicate residual symptoms in heightening depression recurrence risk through exposure to stressful life events . Depression recurrence adds significantly to the burden of the disorder . Therefore , rigorous follow-up of patients targeting the stressful context has the potential to prevent a lifelong pattern of illness The efficacy and safety of Hypericum extract WS 5570 in preventing relapse during 6 months ' continuation treatment and 12 months ' long-term maintenance treatment after recovery from an episode of recurrent depression were investigated in a double-blind , placebo controlled multicenter trial . Adult out- patients with a recurrent episode of moderate major depression , a 17-item Hamilton Depression Rating Scale ( HAMD ) total score > or = 20 and > or =3 previous episodes in 5 years participated . After 6 weeks of single-blind treatment with 3 x 300 mg/day WS 5570 patients with score < or = 2 on item ' Improvement ' of the Clinical Global Impressions ( CGI ) scale and a HAMD total score decrease > or = 50 % versus baseline were r and omized to 3 x 300 mg/day WS 5570 or placebo for 26 weeks . 426 patients were evaluated for efficacy . Relapse rates during continuation treatment were 51/282 ( 18.1 % ) for WS 5570 and 37/144 ( 25.7 % ) for placebo . Average time to relapse was 177+/-2.8 and 163+/-4.4 days for WS 5570 and placebo , respectively ( time-to-event analysis ; p=0.034 ; alpha=0.025 one-sided ) . Patients treated with WS 5570 showed more favorable HAMD and Beck Depression Inventory time courses and greater over-all improvement ( CGI ) than those r and omized to placebo . In long-term maintenance treatment a pronounced prophylactic effect of WS 5570 was observed in patients with an early onset of depression as well as in those with a high degree of chronicity . Adverse event rates under WS 5570 were comparable to placebo . WS 5570 showed a beneficial effect in preventing relapse after recovery from acute depression . Tolerability in continuation and long-term maintenance treatment was on the placebo level Objective : We compared mindfulness-based cognitive therapy ( MBCT ) with both cognitive psychological education ( CPE ) and treatment as usual ( TAU ) in preventing relapse to major depressive disorder ( MDD ) in people currently in remission following at least 3 previous episodes . Method : A r and omized controlled trial in which 274 participants were allocated in the ratio 2:2:1 to MBCT plus TAU , CPE plus TAU , and TAU alone , and data were analyzed for the 255 ( 93 % ; MBCT = 99 , CPE = 103 , TAU = 53 ) retained to follow-up . MBCT was delivered in accordance with its published manual , modified to address suicidal cognitions ; CPE was modeled on MBCT , but without training in meditation . Both treatments were delivered through 8 weekly classes . Results : Allocated treatment had no significant effect on risk of relapse to MDD over 12 months follow-up , hazard ratio for MBCT vs. CPE = 0.88 , 95 % CI [ 0.58 , 1.35 ] ; for MBCT vs. TAU = 0.69 , 95 % CI [ 0.42 , 1.12 ] . However , severity of childhood trauma affected relapse , hazard ratio for increase of 1 st and ard deviation = 1.26 ( 95 % CI [ 1.05 , 1.50 ] ) , and significantly interacted with allocated treatment . Among participants above median severity , the hazard ratio was 0.61 , 95 % CI [ 0.34 , 1.09 ] , for MBCT vs. CPE , and 0.43 , 95 % CI [ 0.22 , 0.87 ] , for MBCT vs. TAU . For those below median severity , there were no such differences between treatment groups . Conclusion : MBCT provided significant protection against relapse for participants with increased vulnerability due to history of childhood trauma , but showed no significant advantage in comparison to an active control treatment and usual care over the whole group of patients with recurrent depression BACKGROUND Previous studies indicate that depressed patients with partial remission and residual symptoms following antidepressant treatment are common and have high rates of relapse . There is evidence that cognitive therapy may reduce relapse rates in depression . METHODS One hundred fifty-eight patients with recent major depression , partially remitted with antidepressant treatment ( mean daily doses equivalent to 185 mg of amitriptyline or 33 mg of fluoxetine ) but with residual symptoms of 2 to 18 months ' duration , were included in a controlled trial . Subjects were r and omized to receive clinical management alone or clinical management plus cognitive therapy for 16 sessions during 20 weeks , with 2 subsequent booster sessions . Subjects were assessed regularly throughout the 20 weeks ' treatment and for a further year . They received continuation and maintenance antidepressants at the same dose throughout . RESULTS Cognitive therapy reduced relapse rates for acute major depression and persistent severe residual symptoms , in both intention to treat and treated per protocol sample s. The cumulative relapse rate at 68 weeks was reduced significantly , from 47 % in the clinical management control group to 29 % with cognitive therapy ( hazard ratio 0.54 ; 95 % confidence interval , 0.32 - 0.93 ; intention to treat analysis ) . Cognitive therapy also increased full remission rates at 20 weeks but did not significantly improve symptom ratings . CONCLUSION In this difficult-to-treat group of patients with residual depression who showed only partial response despite antidepressant treatment , cognitive therapy produced worthwhile benefit BACKGROUND Psychosocial outcomes from the Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years ( PREVENT ) study were evaluated . METHODS Adult out patients with recurrent major depressive disorder ( MDD ) and response or remission following 6-month continuation treatment with venlafaxine extended release ( ER ) were r and omized to receive venlafaxine ER or placebo for 1 year . Patients without recurrence on venlafaxine ER during year 1 were r and omized to venlafaxine ER or placebo for year 2 . Psychosocial functioning was assessed using the Quality of Life Enjoyment and Satisfaction Question naire-Short Form ( Q-LES-Q ) , Life Enjoyment Scale-Short Version ( LES-S ) , Social Adjustment Scale-Self-Report ( SAS-SR ) total and individual factors , Short Form Health Survey ( SF-36 ) ( vitality , social functioning , and role function-emotional items ) , and Longitudinal Interval Follow-up Evaluation ( LIFE ) . RESULTS At year 1 end , better overall psychosocial functioning was seen among patients r and omly assigned to venlafaxine ER ( n=129 ) vs placebo ( n=129 ) , with significant differences at end point on SF-36 role function-emotional , Q-LES-Q , and SAS-SR total , and work , house work , social/leisure , and extended-family factor scores ( p≤0.05 ) . At year 2 end , significant differences favored venlafaxine ER ( n=43 ) vs placebo ( n=40 ) on SF-36 vitality and role function-emotional , Q-LES-Q , LES-S , LIFE , and SAS-SR total , social/leisure , and extended-family factor scores ( p≤0.05 ) . LIMITATIONS Patients with chronic MDD or treatment resistance were excluded and long-term specialist care was a financial incentive for treatment compliance . Discontinuation-related adverse events may have compromised the integrity of the treatment blind . CONCLUSIONS For patients with recurrent MDD , 2 years ' maintenance therapy with venlafaxine ER may improve psychosocial functioning vs placebo BACKGROUND Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence . Maintenance antidepressants for at least 2 years is the current recommended treatment , but many individuals are interested in alternatives to medication . Mindfulness-based cognitive therapy ( MBCT ) has been shown to reduce risk of relapse or recurrence compared with usual care , but has not yet been compared with maintenance antidepressant treatment in a definitive trial . We aim ed to see whether MBCT with support to taper or discontinue antidepressant treatment ( MBCT-TS ) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months . METHODS In this single-blind , parallel , group r and omised controlled trial ( PREVENT ) , we recruited adult patients with three or more previous major depressive episodes and on a therapeutic dose of maintenance antidepressants , from primary care general practice s in urban and rural setting s in the UK . Participants were r and omly assigned to either MBCT-TS or maintenance antidepressants ( in a 1:1 ratio ) with a computer-generated r and om number sequence with stratification by centre and symptomatic status . Participants were aware of treatment allocation and research assessors were masked to treatment allocation . The primary outcome was time to relapse or recurrence of depression , with patients followed up at five separate intervals during the 24-month study period . The primary analysis was based on the principle of intention to treat . The trial is registered with Current Controlled Trials , IS RCT N26666654 . FINDINGS Between March 23 , 2010 , and Oct 21 , 2011 , we assessed 2188 participants for eligibility and recruited 424 patients from 95 general practice s. 212 patients were r and omly assigned to MBCT-TS and 212 to maintenance antidepressants . The time to relapse or recurrence of depression did not differ between MBCT-TS and maintenance antidepressants over 24 months ( hazard ratio 0·89 , 95 % CI 0·67 - 1·18 ; p=0·43 ) , nor did the number of serious adverse events . Five adverse events were reported , including two deaths , in each of the MBCT-TS and maintenance antidepressants groups . No adverse events were attributable to the interventions or the trial . INTERPRETATION We found no evidence that MBCT-TS is superior to maintenance antidepressant treatment for the prevention of depressive relapse in individuals at risk for depressive relapse or recurrence . Both treatments were associated with enduring positive outcomes in terms of relapse or recurrence , residual depressive symptoms , and quality of life . FUNDING National Institute for Health Research ( NIHR ) Health Technology Assessment ( HTA ) programme , and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula Hypericum perforatum ( St John 's wort : SJW ) has been extensively studied as an antidepressant in short-term trials , however little research has been conducted on longer-term efficacy . Our objective was to analyze the continuation data from a 26-week r and omized , double-blind , controlled study of SJW ( LI-160 ) vs. sertraline and placebo in major depressive disorder . 124 participant " responders " continued treatment after week 8 , until week 26 . They continued r and omly assigned SJW ( 900 - 1 500 mg ) , sertraline ( 50 - 100 mg ) or matching placebo . At week 26 , on the primary outcome , Hamilton depression rating scale ( HAM-D ) completer scores were : SJW ( 6.6±4.5 ) , sertraline ( 7.1±5.4 ) and placebo ( 5.7±5.4 ) with a significant effect for time ( p=0.036 ) . Comparisons between all treatments were however non-significant ( p=0.61 ) . This effect was mirrored on the other outcomes : the BDI , CGI-severity , CGI-improvement , and on intention-to-treat analyses . While the continuation data revealed an equivocal outcome between treatments at week 26 , both SJW and sertraline were still therapeutically effective , with a pronounced " placebo-effect " impeding a significant result at week 26 All maintenance treatment programs are complicated by the issue of patient noncompliance . This report investigates factors contributing to noncompliance during a 2-year study design ed to evaluate the efficacy of long-term antidepressant medication in patients with recurrent unipolar depression . Only 21 of 51 patients ( 49 % ) who entered maintenance treatment successfully completed this phase of the study . Fifteen patients ( 8 completers and 7 dropouts ) were r and omly selected for an interview which focused on their previous psychiatric treatment history and attitudes towards the maintenance treatment program . In addition , these patients also completed a comprehensive personality battery . Results indicate that , while both groups had similar attitudes about the treatment program , they differed significantly along personality and psychiatric treatment history variables . Dropouts scored higher than completers on a measure of hysterical personality style . They were also more likely to have received psychotherapy in previous treatment experiences and to rate it as beneficial , while completers consistently rated prior treatment , which did not include antidepressant medication , as being of no benefit whatsoever . In order to enhance patient compliance , it is important to obtain information early in treatment about patients ' treatment histories and their expectations about effective treatment for depression Recent evidence points to the prophylactic efficacy of maintaining recurrent unipolar patients on the same dose of antidepressant medication that was used to treat the acute episode ( Frank et al. , 1990 ; Kupfer et al. , 1992 ) . Therefore , the question of whether such patients should be tapered to a lower maintenance dose after successful resolution of an acute episode is clearly important . In this report we describe a small r and omized clinical trial in which patients were assigned to either full-dose or half-dose maintenance treatment for a period of 3 years . Survival analysis suggests that superior prophylaxis can be achieved with a full-dose as compared to a half-dose maintenance treatment strategy ( p < 0.07 ) . Mean survival time for the full-dose subjects was 135.17 ( SE 19.75 ) weeks as compared to 74.94 ( SE 19.78 ) weeks ( median of 43.1 weeks ) for the half-dose subjects . We conclude that for patients who have suffered several recurrences , full-dose maintenance treatment is the more effective prophylactic strategy BACKGROUND Major depressive disorder is a recurrent illness that often requires maintenance antidepressant treatment . Escitalopram is a selective serotonin reuptake inhibitor ( SSRI ) that has shown efficacy in both acute and continuation treatment of major depressive disorder . The current trial examined the efficacy of maintenance escitalopram treatment in preventing depression recurrence in patients who responded to acute SSRI therapy . METHOD Patients with recurrent DSM-IV-defined major depressive disorder ( > or= 2 previous episodes ; baseline Montgomery-Asberg Depression Rating Scale [ MADRS ] score > or= 22 ) who had responded ( MADRS score < or= 12 ) to acute open-label treatment ( 8 weeks ) with 1 of 4 SSRIs ( fluoxetine , sertraline , paroxetine , or citalopram ) received open-label , flexible-dose continuation treatment ( 16 weeks ) with escitalopram ( 10 - 20 mg/day ) . At the end of continuation treatment , patients maintaining response criteria were r and omly assigned to 52 weeks of double-blind , fixed-dose maintenance treatment with escitalopram ( 10 or 20 mg/day ) or placebo . Recurrence was defined as a MADRS score > or= 22 or insufficient therapeutic response during the double-blind phase . The study was conducted between October 16 , 2000 , and February 4 , 2003 . RESULTS A total of 234 patients who responded to acute open-label treatment with 1 of 4 SSRIs received at least 1 dose of open-label escitalopram continuation treatment . Of 164 patients who completed escitalopram continuation treatment , 139 were r and omly assigned to double-blind maintenance treatment with escitalopram ( N = 73 ) or placebo ( N = 66 ) . Mean baseline MADRS scores at the start of the maintenance phase were < 5 for both the placebo- and escitalopram-treatment groups . Time to recurrence was significantly longer in patients who received maintenance treatment with escitalopram compared with patients switched to placebo ( hazard ratio = 0.26 , 95 % CI = 0.13 to 0.52 , p < .001 ) . Long-term escitalopram treatment was well tolerated . CONCLUSION Maintenance treatment with escitalopram was well tolerated and significantly reduced the risk for recurrence of depression . Patients with few residual symptoms following continuation treatment with escitalopram experienced a high rate of depression recurrence when switched to placebo , demonstrating the need for maintenance therapy of recurrent major depressive disorder beyond 4 to 6 months of initial symptom resolution even if few residual symptoms are present OBJECTIVE The authors of this study examined multiple recurrences of unipolar major depressive disorder . METHOD A total of 318 subjects with unipolar major depressive disorder were prospect ively followed for 10 years within a multicenter naturalistic study . Survival analytic techniques were used to examine the probability of recurrence after recovery from the index episode . RESULTS The mean number of episodes of major depression per year of follow-up was 0 . 21 , and nearly two-thirds of the subjects suffered at least one recurrence . The number of lifetime episodes of major depression was significantly associated with the probability of recurrence , such that the risk of recurrence increased by 16 % with each successive recurrence . The risk of recurrence progressively decreased as the duration of recovery increased . Within subjects , there was very little consistency in the time to recurrence . CONCLUSIONS Major depressive disorder is a highly recurrent illness . The risk of the recurrence of major depressive disorder progressively increases with each successive episode and decreases as the duration of recovery increases Background Mindfulness-based cognitive therapy ( MBCT ) and maintenance antidepressant medication ( mADM ) both reduce the risk of relapse in recurrent depression , but their combination has not been studied . Aims To investigate whether MBCT with discontinuation of mADM is non-inferior to MBCT+mADM . Method A multicentre r and omised controlled non-inferiority trial ( Clinical Trials.gov : NCT00928980 ) . Adults with recurrent depression in remission , using mADM for 6 months or longer ( n = 249 ) , were r and omly allocated to either discontinue ( n = 128 ) or continue ( n = 121 ) mADM after MBCT . The primary outcome was depressive relapse/recurrence within 15 months . A confidence interval approach with a margin of 25 % was used to test non-inferiority . Key secondary outcomes were time to relapse/recurrence and depression severity . Results The difference in relapse/recurrence rates exceeded the non-inferiority margin and time to relapse/recurrence was significantly shorter after discontinuation of mADM . There were only minor differences in depression severity . Conclusions Our findings suggest an increased risk of relapse/recurrence in patients withdrawing from mADM after MBCT For people at risk of depressive relapse , mindfulness-based cognitive therapy ( MBCT ) has an additive benefit to usual care ( H. F. Coelho , P. H. Canter , & E. Ernst , 2007 ) . This study asked if , among patients with recurrent depression who are treated with antidepressant medication ( ADM ) , MBCT is comparable to treatment with maintenance ADM ( m-ADM ) in ( a ) depressive relapse prevention , ( b ) key secondary outcomes , and ( c ) cost effectiveness . The study design was a parallel 2-group r and omized controlled trial comparing those on m-ADM ( N = 62 ) with those receiving MBCT plus support to taper/discontinue antidepressants ( N = 61 ) . Relapse/recurrence rates over 15-month follow-ups in MBCT were 47 % , compared with 60 % in the m-ADM group ( hazard ratio = 0.63 ; 95 % confidence interval : 0.39 to 1.04 ) . MBCT was more effective than m-ADM in reducing residual depressive symptoms and psychiatric comorbidity and in improving quality of life in the physical and psychological domains . There was no difference in average annual cost between the 2 groups . Rates of ADM usage in the MBCT group was significantly reduced , and 46 patients ( 75 % ) completely discontinued their ADM . For patients treated with ADM , MBCT may provide an alternative approach for relapse prevention Aims Various analytical strategies for addressing missing data in clinical trials are utilised in reporting study results . The most commonly used analytical methods include the last observation carried forward ( LOCF ) , observed case ( OC ) and the mixed model for repeated measures ( MMRM ) . Each method requires certain assumptions regarding the characteristics of the missing data . If the assumptions for any particular method are not valid , results from that method can be biased . Results based on these different analytical methods can , therefore , be inconsistent , thereby making interpretation of clinical study results confusing . In this investigation , we compare results from MMRM , LOCF and OC in order to illustrate the potential biases and problems in interpretation . Methods Data from an 8-month , double-blind , r and omised , placebo-controlled ( placebo ; n= 137 ) , outpatient depression clinical trial comparing a serotonin-noradrenalin reuptake inhibitor ( SNRI ; n= 273 ) with a selective serotonin reuptake inhibitor ( SSRI ; n= 274 ) were used . The study visit schedule included efficacy and safety assessment s weekly to week 4 , bi-weekly to week 8 , and then monthly . Visitwise mean changes for the 17-item Hamilton Depression Rating Scale ( HAMD17 ) Maier subscale ( primary efficacy outcome ) , blood pressure , and body weight were analysed using LOCF , MMRM and OC . Results Last observation carried forward consistently underestimated within-group mean changes in efficacy ( benefit ) and safety ( risk ) for both drugs compared with MMRM , whereas OC tended to overestimate within-group changes . Conclusions Inferences are based on between-group comparisons . Therefore , whether or not underestimating ( overestimating ) within-group changes was conservative or anticonservative depended on the relative magnitude of the bias in each treatment and on whether within-group changes represented improvement or worsening . Preference should be given in analytic plans to methods whose assumptions are more likely to be valid rather than relying on a method based on the hope that its results , if biased , will be conservative In this study , the authors examined prospect ively the 24-month natural course of remission from major depressive disorder ( MDD ) as a function of personality disorder ( PD ) comorbidity . In 302 participants ( 196 women , 106 men ) , psychiatric and PDs were assessed at baseline with diagnostic interviews , and the course of MDD was assessed with the Longitudinal Interval Follow-Up Evaluation at 6- , 12- , and 24-month follow-ups . Survival analyses revealed an overall 24-month remission rate of 73.5 % for MDD that differed little by gender . Participants with MDD who had certain forms of coexisting PD psychopathology ( schizotypal , borderline , or avoidant ) as their primary PD diagnoses had a significantly longer time to remission from MDD than did patients with MDD without any PD . These PDs emerged as robust predictors of slowed remission from MDD even when controlling for other negative prognostic predictors Non-adherence to antidepressant drug treatment is common . In a recent study in depressed primary care patients , we reported a strong relationship between adherence and response after 6 months . With the use of a naturalistic design , the patients in that study were prospect ively followed for 2 years . The purpose of the present study was to investigate the patients ' long-term outcome and , in particular , to examine the impact of patients ' treatment adherence on response , remission and relapse . Of the 1031 patients in the intent-to-treat ( ITT ) sample , 835 completed the study . After 2 years , the overall remission rate defined as a Montgomery – Åsberg Depression Rating Scale score of nine or less was 68 % in the ITT sample analysed with the last observation carried forward ( LOCF ) technique , and 75 % in observed cases . In total , 34 % of the responders experienced at least one relapse . Response rates ( LOCF ) were significantly higher in adherent compared to non-adherent patients at week 24 [ 95 % confidence interval (CI)=21.4–32.1 ] , year 1 ( 95 % CI=12.3–22.2 ) and year 2 ( 95 % CI=9.2–19.0 ) . Remission rates ( LOCF ) were also significantly higher in the group of adherent patients at week 24 ( 95 % CI=9.6–21.5 ) , year 1 ( 95 % CI=10.0–21.5 ) and year 2 ( 95 % CI=11.0–22.0 ) . No relationship between adherence and relapse rate was observed , although the mean time from response to first sign of relapse was significantly longer in the adherent patients ( 95 % CI=9–97 days ) . In conclusion , this 2-year follow-up study showed superior long-term recovery in patients who were adherent to antidepressant medication compared to non-adherent patients The chronic and recurrent nature of major depression is well recognized , and recent data suggest that maintenance therapy with full-dose phar-macotherapy ( i.e. , the dose used to treat the index episode ) is effective in preventing relapse and recurrence . We present results from a 1-year , double-blind trial of paroxetine and imipramine in patients who successfully completed a 6-week acute course of therapy . A total of 717 out patients were included in the 6-week , r and omized , double-blind , placebo-controlled comparative study of paroxetine and imipramine conducted at six centers . At the end of the acute treatment phase , patients showing a therapeutic response were eligible to enter a long-term extension of the study in which they would continue to receive the same drug ( or placebo ) in double-blind fashion for up to 1 year . Of the 219 patients who entered the long-term phase , 94 received paroxetine , 79 received imipramine , and 46 received placebo . During the 1-year maintenance study , both paroxetine and imipramine were more effective than placebo in maintaining euthymia among patients who had responded to short-term treatment . However , approximately twice as many imipramine-treated patients dropped out of the study prematurely because of adverse experiences compared to paroxetine-treated patients , suggesting that paroxetine is more readily tolerated than imipramine during long-term treatment The efficacy of SSRIs in relapse prevention in major depression has been extensively demonstrated . Considering published data , the relapse rate during a psychopharmacological continuation treatment ranges from 10 % to 30 % . Since the reasons of depressive relapses could be heterogeneous , we have tested the effect of clinical , psychosocial and genetic variables in sustained remission from an index depressive episode during continuation treatment with fluvoxamine over a 6-month follow-up period . 101 patients maintained the same full dosage treatment after remission from a depressive episode efficaciously treated with fluvoxamine . During the follow-up period , they were clinical assessed monthly by an experienced psychiatrist and SASS was administered , to assess their psychosocial adjustment . From a genetical point of view , SERTPR and CLOCK polymorphisms were analyzed for each patients , using PCR-based techniques . At the end of follow-up period , the 57.4 % of the patients maintained remission during fluvoxamine continuation treatment ; the 8.9 % relapsed within the first 2 months of continuation ; the 7.9 % switched and the 25.8 % dropped-out for poor compliance . Relapsed subjects presented a significantly longer mean duration of the index depressive episode than non-relapsed subjects and a subjective poor social adjustment than non-relapsed also in the euthymia period . None of the analyzed polymorphisms significantly appear to influence the outcome of the whole sample . The present data confirm that patients with severe depression and a long duration of the episode have a major risk of psychosocial disability . These patients could need a different psychopharmacological strategies and peculiar psychological intervention Patients with major depressive disorder remain at risk for relapse following remission and often continue to experience subthreshold symptoms . This study compared the rate of relapse of major depressive disorder and the prevalence of residual depressive symptoms during the continuation phase for patients treated with fluoxetine dose increase alone or in combination with cognitive therapy . A total of 132 out patients with major depressive disorder who achieved remission with 8 weeks of treatment with fluoxetine 20 mg had the dose increased to 40 mg . They were r and omized to receive cognitive therapy or medication management alone and were followed for up to 28 weeks for depressive relapse and change in depressive symptoms . A total of 47 ( 35.6 % ) out of 132 patients did not complete the 28-week continuation phase . Rates of discontinuation or relapse did not differ significantly between the groups . Change in residual symptoms or wellbeing as measured by Hamilton Depression Scale score or Symptom Question naire self-report also did not differ between groups . In this sample of out patients in continuation phase treatment for major depressive disorder , the combination of cognitive therapy and fluoxetine 40 mg failed to yield any significant benefit in symptoms or relapse rates over fluoxetine 40 mg alone during 28 weeks of follow-up Of 580 patients r and omly assigned to short-term , double-blind treatment with either mirtazapine , amitriptyline or placebo , a total of 217 patients clinical ly judged to be responders subsequently continued on the same medication for up to 2 years in the long-term treatment study ( mirtazapine , n = 74 ; amitriptyline , n = 86 and placebo , n = 57 ) . The efficacy of mirtazapine in relapse prevention was seen in an analysis of the first 20 weeks data . Significantly fewer patients relapsed during treatment with mirtazapine compared with placebo ( p < 0.05 ) , and a significantly longer time to relapse was shown on the survival analysis . There was a significant advantage for amitriptyline compared with placebo in the first 20 weeks , with fewer patients relapsing . There was a significant advantage for mirtazapine compared with amitriptyline at 20 weeks seen on the survival analysis ( p < 0.05 ) . The significant advantage for mirtazapine compared with placebo was also seen in the prophylactic phase of treatment after 20 weeks . At the endpoint there were significantly more patients in the placebo group with a return of symptoms and significantly fewer showing sustained response , Amitriptyline was better than placebo with fewer patients suffering a recurrence of symptoms , but there was no difference from placebo in the proportion of patients with sustained response . Mirtazapine was well tolerated with a side-effect profile similar to that of placebo . The only adverse event reported significantly more frequently on mirtazapine than on placebo was weight gain . Objective ly measured weight gain was more frequent with amitriptyline ( 22 % of patients ) compared with mirtazapine ( 13 % of patients ) . Amitriptyline was associated with significantly more adverse events than either mirtazapine or placebo , in particular sedative and anticholinergic side effects . The efficacy of mirtazapine in reducing the risk of relapse and the recurrence of depression , which on some measures showed an advantage compared with amitriptyline , coupled with its improved side-effect profile , commends this antidepressant for the long-term treatment of depression Since depression impacts all body systems , antidepressant treatments should relieve both the emotional and physical symptoms of depression . Duloxetine demonstrated antidepressant efficacy at a dose of 60 mg qd in two placebo-controlled , r and omized , double-blind studies and significantly improved remission rates compared with placebo . Duloxetine-treated patients had significant reduction in severity of the symptoms of depression as assessed by the HAM-D17 , anxious symptoms as measured by the HAM-A and quality of life measures compared to placebo . Duloxetine also improved somatic symptoms , particularly painful symptoms which may have contributed to significantly improved remission rates compared to placebo . Approximately 10 % of the 1139 patients with major depressive disorder in placebo-controlled trials discontinued treatment due to an adverse event , compared to 4 % of the 777 patients receiving placebo . In addition to nausea ( 1.4 % incidence ) , which was the most common reason for discontinuation , dizziness , somnolence , and fatigue were the most common AEs reported as reasons for discontinuation and all were considered drug-related . Duloxetine treatment lacks effects on ECG , increases heart rate , and has little effect on blood pressure or weight OBJECTIVE There has been concern about a high rate of placebo response and a substantial failure rate in recent clinical trials in major depressive disorder ( MDD ) . This report explores differences in efficacy data from placebo-controlled MDD trials su bmi tted in support of new drug applications ( NDAs ) over a 25-year period . METHOD We compiled efficacy data from 81 r and omized , double-blind clinical trials , with 21,611 evaluable patients , that were su bmi tted to the US Food and Drug Administration as part of NDAs for an antidepressant cl aim between 1983 and 2008 . Trial data were limited to completed , r and omized , multicenter , double-blind , placebo-controlled clinical trials in adult patients diagnosed with MDD according to DSM-III or DSM-IV criteria . The data base was further limited to patients who were involved in clinical trials for drugs widely viewed as effective antidepressants and for doses of these drugs also viewed as effective doses . Trials were rated as successful if they showed statistical superiority vs placebo for the investigational drug on change in Hamilton Depression Rating Scale ( HDRS ) score ( last-observation-carried-forward data ) . ( Trials with multiple investigational drug groups were successful if there was superiority in at least 1 drug group after adjustment for multiplicity . ) In particular , we explored differences in effect size and success rate of these trials , based on when the studies were conducted , geographic location of the study sites ( US vs non-US ) , trial duration , dosing regimen , study size , and baseline disease characteristics . RESULTS Eighty-one percent of MDD patients were enrolled in US sites . Although the observed placebo and drug responses at non-US sites tended to be larger than at US sites , the treatment effect ( drug-placebo difference ) was similar ( mean change from baseline of about -2.5 units in HDRS total score ) in US and non-US trials . In both US and non-US trials , the placebo response showed a modest increase over the observation period ( 1983 - 2008 ) . Treatment effect clearly diminished over this same period , at a similar rate for both US and non-US trials despite a marked increase in the sample size of the trials . Our analysis showed that 53 % of all MDD trials in the last 25 years were successful . US trials had a higher success rate than non-US trials ( 58 % vs 33 % ) . Before 1995 , the overall success rate was 55 % , compared to 50 % for trials in 1995 or later , and , in general , 6-week trials had a higher success rate than 8-week trials ( 55 % vs 42 % ) . It should be noted that the earlier trials were mostly 6 weeks , and the 6-week trials had higher mean baseline HDRS scores than the 8-week trials . Study size did not seem to influence trial success rates . Mean baseline HDRS total scores declined over the 25-year observation period for patients in both US and non-US trials , as did treatment effect in these trials , again , regardless of region . Fixed-dose trials had a numerically slightly greater success rate than flexible-dose trials ( 57 % vs 51 % ) , although on average treatment effect was numerically larger in the flexible-dose trials than in fixed-dose trials ( mean of -2.9 vs -2.0 on HDRS units ) . CONCLUSIONS Treatment effect has declined over time in MDD trials , and there has been a high failure rate for these trials during the entire period , but the reasons for these findings remain elusive . Baseline disease severity seems to be a more important factor in study outcome than study duration , dosing regimen , sample size , time when studies were conducted , and regions where data were generated . Close attention is needed to a variety of factors in the design and conduct of these studies , including patient population , diagnostic considerations , patient assessment , and clinical practice differences . These considerations become increasingly important as globalization of clinical trials continues to increase & NA ; The objective of this analysis was to determine the efficacy of venlafaxine in comparison with that of placebo during long‐term treatment . A pooled analysis of relapse rates in out patients with major depression continuing long‐term treatment ( up to 12 months ) after responding to short‐term treatment ( 6 weeks ) was performed combining the data from four r and omized , doubleblind , placebo‐controlled clinical trials . Relapses were defined as two consecutive Clinical Global Impression ( CGI ) severity scores greater than 3 ( mildly ill ) , as a CGI severity score greater than 3 at withdrawal regardless of the reason for withdrawal , or as withdrawal due to lack of efficacy . Data from 304 patients ( 185 venlafaxine , 119 placebo ) well balanced for baseline characteristics were included in the pooled analysis . Percentages of patients completing the long‐term phase were 38 % venlafaxine and 26 % placebo ( p = 0.034 ) . Cumulative relapse rates by 6 months of long‐term treatment were 11 % venlafaxine and 23 % placebo ( p = 0.019 ) . Cumulative relapse curves for the venlafaxine and placebo groups over the 1‐year long‐term treatment differed significantly ( p = 0.022 ) . The results from this analysis indicate that long‐term treatment with venlafaxine in patients with major depressive disorder is effective in maintaining the initial response compared with placebo and suggest that venlafaxine will be effective in the prevention of relapse BACKGROUND The comparative efficacy of selective serotonin reuptake inhibitors ( SSRIs ) and serotonin-norepinephrine reuptake inhibitors ( SNRIs ) was recently debated . Meta-analyses , based mainly on fluoxetine comparator data , suggest that the SNRI venlafaxine has superior efficacy to SSRIs in treatment of major depression . OBJECTIVE To compare quality of life ( QOL ) , efficacy , safety , and tolerability associated with sertraline and venlafaxine extended release ( XR ) for treatment of DSM-IV major depression . METHOD This was an 8-week , double-blind , r and omized study of sertraline ( 50 - 150 mg/day ) versus venlafaxine XR ( 75 - 225 mg/day ) , followed by a 2-week taper period . Subjects were recruited from 7 sites in Turkey and 6 sites in Australia between October 2002 and July 2003 . The primary outcome measure was the Quality of Life Enjoyment and Satisfaction Question naire . Secondary outcome measures included measures of depression ( including response and remission ) , anxiety , pain , safety ( e.g. , blood pressure ) , and tolerability ( e.g. , discontinuation symptoms ) . RESULTS A total of 163 subjects received study treatment ( women , 69 % ; mean age , 37.0 [ SD = 12.9 ] years ) . No significant differences in QOL or efficacy were noted between treatments on the primary or secondary endpoints for the total study population or the anxious depression and severe depression subgroups . A priori analyses of symptoms associated with treatment discontinuation demonstrated no difference between treatment groups . However , in post hoc analyses , sertraline was associated with less burden of moderate to severe discontinuation symptoms . Venlafaxine XR was associated with a relative increase in mean blood pressure ( supine diastolic blood pressure , -4.4 mm Hg difference at week 8/last observation carried forward ) . CONCLUSION Sertraline and venlafaxine XR demonstrated comparable effects on QOL and efficacy in treatment of major depression , although sertraline may be associated with a lower symptom burden during treatment discontinuation and a reduced risk of blood pressure increase BACKGROUND Chronic forms of depression are associated with significant functional and psychosocial impairments . To date , no study has measured psychosocial functioning in this population during long-term maintenance antidepressant treatment or following the double-blind discontinuation of treatment . METHODS Patients with chronic major or double depression completed 12 weeks of short-term treatment followed by 16 weeks of continuation treatment with sertraline hydrochloride . Responders at the end of the continuation phase were r and omized , double-blind , to 18 months of maintenance therapy with either sertraline ( n = 77 ) or placebo ( n = 84 ) . Multiple domains of psychosocial functioning were assessed during double-blind therapy . RESULTS Substantial worsening in psychosocial function measures occurred in patients taking placebo compared with sertraline during maintenance . Patients with reemergence of depression lost psychosocial gains regardless of treatment . In the sub sample of patients who remained in remission throughout maintenance , most of the observed improvement in psychosocial functioning occurred during short-term treatment . By maintenance end point , normalization of functioning was achieved by 58 % to 84 % of remitters , depending on the outcome measure used . CONCLUSIONS These results indicate that long-term treatment of chronic forms of depression can result in sustained psychosocial benefits . Discontinuation of treatment results in frequent reemergence of symptoms and loss of psychosocial gains . Long-term treatment result ed in only modest further improvement of psychosocial measures over that achieved in the short-term phase Purpose To examine the natural course and outcome of major depressive disorder ( MDD ) in primary care over 39 months . Methods Prospect i ve cohort study of 1,338 consecutive attendees with follow-up after 6 , 12 , and 39 months with DSM-IV MDD using the Composite International Diagnostic Interview ( CIDI ) . We measured severity of depressive symptoms ( Patient Health Question naire 9 ) , somatic symptoms ( Patient Health Question naire 15 ) , and mental and physical function ( Short Form 12 , mental and physical component summary ) . Analysis of variance and r and om coefficient models were performed . Results At baseline , 174 people ( 13 % ) had MDD of which 17 % had a chronic and 40 % had a fluctuating course , while 43 % remitted . Patients with chronic courses had more severe depressive symptoms ( mean difference 6.54 ; 95 % CI 4.38–8.70 ) , somatic symptoms ( mean difference 3.31 ; 95 % CI 1.61–5.02 ) , and greater mental dysfunction ( mean difference −10.49 ; 95 % CI −14.42 to −6.57 ) at baseline than those who remitted from baseline , independent of age , sex , level of education , presence of a chronic disease , and a lifetime history of depression . Conclusions Although 43 % of patients with MDD attending primary care recover , this leaves a majority of patients ( 57 % ) who have a chronic or intermittent course . Chronic courses are associated with higher levels of depressive symptoms and somatic symptoms and greater mental dysfunction at baseline Recovered recurrently depressed patients were r and omized to treatment as usual ( TAU ) or TAU plus mindfulness-based cognitive therapy ( MBCT ) . Replicating previous findings , MBCT reduced relapse from 78 % to 36 % in 55 patients with 3 or more previous episodes ; but in 18 patients with only 2 ( recent ) episodes corresponding figures were 20 % and 50 % . MBCT was most effective in preventing relapses not preceded by life events . Relapses were more often associated with significant life events in the 2-episode group . This group also reported less childhood adversity and later first depression onset than the 3-or-more-episode group , suggesting that these groups represented distinct population s. MBCT is an effective and efficient way to prevent relapse/recurrence in recovered depressed patients with 3 or more previous episodes Many studies have demonstrated that venlafaxine is an efficacious and safe treatment for major depressive disorder ( MDD ) . This double-blind , placebo-controlled study was performed to evaluate the efficacy of venlafaxine extended-release ( XR ) ( 75 - 225 mg/day ) in the prevention of relapse of depression . Patients with MDD who responded to an 8-week course of venlafaxine XR treatment , i.e. , had a score < or = 3 on the Clinical Global Impressions scale-Severity of Illness item ( CGI-S ) and a 21-item Hamilton Rating Scale for Depression ( HAM-D(21 ) ) score < or = 10 , were r and omly assigned to receive continuation treatment ( up to 6 months ) with venlafaxine XR ( n=161 ) or placebo ( n=157 ) . The main efficacy outcome measure was the number of patients who experienced a relapse of depression . Relapse was defined by either a combination of a patient meeting Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria for MDD and a CGI-S score > or = 4 , two consecutive CGI-S scores > or = 4 , or a final CGI-S score > or = 4 for a patient who withdrew from the study . The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis . During the 6-month evaluation period , significantly more patients in the placebo group had a relapse of MDD than did patients who continued treatment with venlafaxine XR . Cumulative relapse rates at 3 and 6 months were 19 and 28 % , respectively , for venlafaxine XR , and 44 and 52 % , respectively , for placebo . This study demonstrates that venlafaxine XR is an effective and safe continuation therapy CONTEXT Elderly patients with major depression are at high risk for recurrence , increased mortality , and chronic disability . OBJECTIVE To determine the efficacy of maintenance nortriptyline hydrochloride and interpersonal psychotherapy ( IPT ) in preventing recurrence of major depressive episodes in patients older than 59 years . DESIGN A 2 x 2 r and omized , double-blind , placebo-controlled clinical trial , stratified by therapist . SETTING University-based psychiatric research clinic . PATIENTS Of a total of 187 patients with recurrent nonpsychotic unipolar major depression ( average age , 67 years ; one third aged > or = 70 years ) recruited through clinical referral and media announcements , 107 were fully recovered after open acute and treatment continuation with nortriptyline and IPT . These patients were r and omly assigned to 1 of 4 maintenance therapy conditions . INTERVENTIONS Monthly medication clinic with nortriptyline hydrochloride ( 80 - 120 ng/mL steady-state levels ) ( n = 24 ) ; medication clinic with placebo ( n = 29 ) ; monthly maintenance IPT with placebo ( n = 21 ) ; and monthly maintenance IPT with nortriptyline ( n = 22 ) . MAIN OUTCOME MEASURE Recurrence of major depressive episode . RESULTS The time to recurrence of a major depressive episode for all 3 active treatments was significantly better than for placebo . Recurrence rates over 3 years were as follows : nortriptyline and IPT , 20 % ( 95 % confidence interval [ CI ] , 4%-36 % ) ; nortriptyline and medication clinic visits , 43 % ( 95 % CI , 25%-61 % ) ; IPT and placebo , 64 % ( 95 % CI , 45%-83 % ) ; and placebo and medication clinic visits , 90 % ( 95 % CI , 79%-100 % ) . Combined treatment with nortriptyline and IPT was superior to IPT and placebo and showed a trend to superior efficacy over nortriptyline monotherapy ( Wald chi2 = 3.56 ; P = .06 ) . Subjects aged 70 years and older had a higher and more rapid rate of recurrence than those aged 60 to 69 years . CONCLUSION In geriatric patients with recurrent major depression , maintenance treatment with nortriptyline or IPT is superior to placebo in preventing or delaying recurrence . Combined treatment using both appears to be the optimal clinical strategy in preserving recovery Relapse of major depressive disorder ( MDD ) is a common clinical problem . Identifying relapse predictors could lead to strategies that reduce relapse risk . This study is design ed to determine whether residual symptoms predict relapse risk during the continuation/maintenance treatment of MDD . 570 MDD patients received open-label fluoxetine for 12 weeks . Under double blind conditions , 262 patients who responded by week 12 were r and omly assigned to continue fluoxetine or switch to placebo for 52 weeks or until relapse . Residual symptoms were measured using the Symptom Checklist-90 and the Symptom Question naire . The relationship between residual symptom severity and relapse risk was assessed . Without adjusting for overall residual symptom severity , a greater severity of residual obsessive-compulsive and phobic anxiety symptoms predicted greater relapse risk . After adjusting for overall residual symptom severity , only severity of phobic anxiety symptoms predicted relapse risk . The predictive value of phobic anxiety symptoms with respect to relapse risk was independent of treatment assignment . The results indicated that there may be a specific pattern of residual symptoms associated with depressive relapse during antidepressant continuation/maintenance , which is unrelated to treatment assignment . Future studies are needed to further explore the relationship between residual symptoms and relapse risk in MDD . Clinical implication s : ( 1 ) It is important to treat residual symptoms among antidepressant responders/remitters in order to decrease relapse risk . ( 2 ) Clinicians should target residual phobic anxiety symptoms in order to decrease relapse risk . ( 3 ) Clinicians should target residual obsessive-compulsive symptoms in order to decrease relapse risk . Limitations : ( 1 ) limited generalizability due to inclusion /exclusion criteria ; ( 2 ) lack of active comparator treatment group ; ( 3 ) post hoc analysis BACKGROUND In chronic diseases adherence is a problem . Little is known about adherence to antidepressants after the acute phase in recurrent depression . This study evaluates adherence to antidepressants in the continuation and maintenance phase in remitted recurrently depressed patients . METHODS We prospect ively assessed adherence to continuation and maintenance antidepressant use , the longest phase in antidepressant treatment , over 2 years and the association of adherence with future recurrence in 131 recurrently depressed patients remitted on antidepressants . LIMITATIONS Self reported non-adherence . RESULTS Non-adherence ranged from 39.7 % to 52.7 % ; 20.9 % were always non-adherent , 48.4 % were intermittently non-adherent and 30.8 % were always adherent . Adherence rates did not significantly differ between intermittent and continuous antidepressant users ( 37.2 % vs. 25 % ) . Non-adherence predicted time to recurrence . CONCLUSION Non-adherence to continuation and maintenance antidepressant treatment in recurrent depression is frequent , like in other chronic diseases , and a potential risk of recurrence . Doctors continuously have to be aware of this problem and should keep on discussing it with their patients . Finally , as many patients do n't seem to be able or willing to take AD as prescribed , alternatives to prevent relapse deserve more attention BACKGROUND Recent reports describe discontinuation-emergent adverse events upon cessation of selective serotonin reuptake inhibitors including dizziness , insomnia , nervousness , nausea , and agitation . We hypothesized that interruption of fluoxetine treatment would be associated with fewer discontinuation-emergent adverse events than interruption of sertraline or paroxetine treatment , based on fluoxetine 's longer half-life . METHODS In this 4-week study , 242 patients with remitted depression receiving maintenance therapy with open-label fluoxetine , sertraline , or paroxetine for 4 - 24 months had their maintenance therapy interrupted with double-blind placebo substitution for 5 - 8 days . The Symptom Question naire ( SQ ) , the Discontinuation-Emergent Signs and Symptoms checklist , the 28-item Hamilton Depression Rating Scale , and the Montgomery-Asberg Depression Rating Scale were used to assess somatic distress and stability of antidepressant response . RESULTS Two hundred twenty patients ( 91 % ) completed the study . Following interruption of therapy , fluoxetine-treated patients experienced fewer discontinuation-emergent events than either sertraline-treated or paroxetine-treated patients ( p < .001 ) . The mean SQ somatic symptom scale score in fluoxetine-treated patients was significantly lower than that in sertraline-treated and paroxetine-treated patients ( p < .001 ) . Fluoxetine-treated patients also experienced less reemergence of depressive symptoms than sertraline-treated or paroxetine-treated patients ( p < .001 ) . CONCLUSIONS Abrupt interruption of antidepressant therapy for 5 - 8 days was associated with the emergence of new somatic and psychological symptoms in patients treated with paroxetine and to a lesser degree sertraline , with few symptoms seen with fluoxetine This study evaluated mindfulness-based cognitive therapy ( MBCT ) , a group intervention design ed to train recovered recurrently depressed patients to disengage from dysphoria-activated depressogenic thinking that may mediate relapse/recurrence . Recovered recurrently depressed patients ( n = 145 ) were r and omized to continue with treatment as usual or , in addition , to receive MBCT . Relapse/recurrence to major depression was assessed over a 60-week study period . For patients with 3 or more previous episodes of depression ( 77 % of the sample ) , MBCT significantly reduced risk of relapse/recurrence . For patients with only 2 previous episodes , MBCT did not reduce relapse/recurrence . MBCT offers a promising cost-efficient psychological approach to preventing relapse/recurrence in recovered recurrently depressed patients Elderly depressed patients are vulnerable to recurrence of depression and benefit from long-term antidepressant therapy . Physicians increasingly use selective serotonin re-uptake inhibitors ( SSRIs ) as maintenance therapy , although in the absence of data showing that SSRIs are as efficacious as tricyclic antidepressants ( TCAs ) in the prevention of depression relapse and recurrence . Our objective was to evaluate , in an open trial , the efficacy of paroxetine versus nortriptyline for preventing recurrence of depression in the elderly . Elderly patients with major depression were r and omly assigned in a double-blinded fashion to receive either paroxetine or nortriptyline for the acute treatment of depression . Patients who did not respond or tolerate their assigned medications were crossed over openly to the comparator agent . Patients whose depression remitted continued antidepressant medication ( paroxetine n = 38 ; nortriptyline n = 21 ) during an open 18-month follow-up study . We examined the rates of and times to relapse and to termination of treatment for any reason . Paroxetine ( PX ) and nortriptyline ( NT ) patients had similar rates of relapse ( 16 % vs. 10 % , respectively ) and time to relapse ( 60.3 weeks vs. 58.8 weeks , respectively ) over 18 months . A lower burden of residual depressive symptoms and side effects during continuation and maintenance treatment was evident in nortriptyline-treated patients . Paroxetine and nortriptyline demonstrated similar efficacy in relapse and recurrence prevention in elderly depressed patients over an 18-month period Optimal outcomes from depression treatment are long-term recovery and , in the case of recurrent depression , prevention of new episodes . However , few data are available concerning the long-term efficacy of antidepressants in prophylactic treatment to prevent recurrences of depression . The efficacy and safety of fluoxetine 20 mg/day was evaluated in reducing the number of depressive episodes and in extending the time free of symptoms in patients with recurrent unipolar major depression . Patients with recurrent unipolar major depression according to DSM-III-R criteria and who responded to 32 weeks of open-label fluoxetine were r and omly assigned to receive fluoxetine 20 mg/day ( N = 70 ) or placebo ( N = 70 ) for 48 weeks of double-blind maintenance treatment . Outcome measures were the percentage of recurrences and time to recurrence . Safety assessment s included treatment-emergent adverse events , reasons for discontinuation , vital signs , and laboratory measures . Fluoxetine was associated with a statistically significantly smaller percentage of patients who had a recurrence compared with placebo ( 20 % vs. 40 % ; χ 2 analysis , p = 0.010 ) . The symptom-free period was significantly longer for patients treated with fluoxetine versus placebo ( 295 vs. 192 days ; Kaplan-Meier estimates , log-rank test , p = 0.002 ) . Treatments were well tolerated during maintenance treatment . The only statistically significant difference in adverse events between treatment groups was anxiety , which was more frequent in the placebo group ( fluoxetine , 12.9 % vs. placebo , 30 % ; χ 2 analysis , p = 0.013 ) . Two placebo-treated patients and no fluoxetine-treated patients were withdrawn because of adverse events . In conclusion , fluoxetine at 20 mg/ day was effective and well tolerated for the prophylactic treatment of recurrent unipolar major depression In the early 1980s , the National Institute of Mental Health supported a multicenter , r and omized , controlled , clinical trial on unipolar and bipolar disorder to evaluate the comparative efficacies of lithium carbonate , imipramine hydrochloride , a lithium-imipramine combination , and placebo in preventing the recurrence of affective disorders . The objective of this report is to present a re analysis of the relative efficacies of these treatments in patients with unipolar disorder to focus attention on general issues related to the design and conduct of maintenance therapy trials . We show that the earlier conclusions of that study that imipramine and the combination therapy are more effective than lithium and placebo in preventing the recurrence of depression in unipolar patients can be accounted for by alternative explanations that are a consequence of the design of the study . Our findings have important implication s for the design , conduct , and interpretation of results of maintenance therapy clinical trials in general OBJECTIVE To assess the consequences to mother and baby of abruptly discontinuing antidepressant or benzodiazepine medication during pregnancy and to assess the impact of our counselling . PARTICIPANTS All women who consulted the Motherisk Program between November 1996 and December 1997 and who stopped taking antidepressant or benzodiazepine medication when pregnancy was confirmed agreed to participate in the study . DESIGN AND INTERVENTIONS Subjects were interviewed , received counselling , and completed a question naire 1 month after their initial call and after the birth of their baby . RESULTS Of 36 women who completed the study , 34 discontinued their medication abruptly for fear of harming the fetus , 28 on the advice of their physician ; 26 ( 70.3 % ) women reported physical and psychological adverse effects , 11 reported psychological effects only , and 11 reported suicidal ideation ( 4 were admitted to hospital ) . After counselling , 22 of 36 ( 61.1 % ) women resumed taking their medication , and 4 found that they no longer required it . One woman had a therapeutic abortion and 2 experienced spontaneous abortions ; there were therefore 35 healthy babies ( including 2 sets of twins ) born to 33 women ; 14 of 21 mothers breast-fed their babies while taking their psychotropic medication , with no adverse effects reported . CONCLUSIONS When assessing the risks and benefits of taking psychotropic medication during pregnancy , women and their physicians should be aware that the abrupt discontinuation of psychotropic drugs can lead to serious adverse effects . Counselling is effective in reassuring women to adhere to therapy IMPORTANCE Antidepressant medication ( ADM ) is efficacious in the treatment of depression , but not all patients achieve remission and fewer still achieve recovery with ADM alone . OBJECTIVE To determine the effects of combining cognitive therapy ( CT ) with ADM vs ADM alone on remission and recovery in major depressive disorder ( MDD ) . DESIGN , SETTING , AND PARTICIPANTS A total of 452 adult out patients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States . The patients were r and omly assigned to ADM treatment alone or CT combined with ADM treatment . Treatment was continued for up to 42 months until recovery was achieved . INTERVENTIONS Antidepressant medication with or without CT . MAIN OUTCOMES AND MEASURES Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation . RESULTS Combined treatment enhanced the rate of recovery vs treatment with ADM alone ( 72.6 % vs 62.5 % ; t451 = 2.45 ; P = .01 ; hazard ratio [ HR ] , 1.33 ; 95 % CI , 1.06 - 1.68 ; number needed to treat [ NNT ] , 10 ; 95 % CI , 5 - 72 ) . This effect was conditioned on interactions with severity ( t451 = 1.97 ; P = .05 ; NNT , 5 ) and chronicity ( χ2 = 7.46 ; P = .02 ; NNT , 6 ) such that the advantage for combined treatment was limited to patients with severe , nonchronic MDD ( 81.3 % vs 51.7 % ; n = 146 ; t145 = 3.96 ; P = .001 ; HR , 2.34 ; 95 % CI , 1.54 - 3.57 ; NNT , 3 ; 95 % CI , 2 - 5 ) . Fewer patients dropped out of combined treatment vs ADM treatment alone ( 18.9 % vs 26.8 % ; t451 = -2.04 ; P = .04 ; HR , 0.66 ; 95 % CI , 0.45 - 0.98 ) . Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity . Patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders regardless of the condition ( P = .01 ) . Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone ( 49 vs 71 ; P = .02 ) , largely because they experienced less time in an MDD episode . CONCLUSIONS AND RELEVANCE Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone , with the effect limited to patients with severe , nonchronic depression . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00057577 Background : Maintenance antidepressant ( AD ) medication is the most commonly used preventive strategy in a highly recurrent disease , i.e. depression . Little is known about the discontinuation of maintenance AD use and the association with recurrence in daily clinical practice . The purpose was to examine the discontinuation rate of maintenance AD in daily clinical practice in recurrently depressed patients and the associated risk of recurrence . Methods : Prospect ively AD maintenance medication and recurrence were examined in 172 euthymic patients with recurrent depression . AD user profiles before recurrence ( nonusers , intermittent users , continuous users ) were examined and related to recurrence over a 2-year follow-up period . Results : Less than half of the patients ( 42 % ) used AD continuously . Taking into account the minimal required adequate used dosage ( ≧20 mg fluoxetine equivalent ) , only 26 % of the patients used AD as recommended by international guidelines . Despite continuous use of AD , 60.4 % relapsed in 2 years . This relapse rate was comparable to the rate of the intermittent users ( 63.6 % ) . In patients who stopped taking AD after remission and who received additional preventive CT , the recurrence rates were significantly lower than in non-AD-using patients treated with usual care ( 8 vs. 46 % ) . Conclusions : The majority of recurrently depressed patients treated with AD discontinue maintenance AD therapy in daily primary and secondary clinical practice . AD seems to offer poor protection against relapse in this patient group . Patients who stopped using AD experienced less relapse , especially if they were treated with preventive CT . Alternative maintenance treatments ( including preventive cognitive therapy after discontinuation of AD ) should be studied in recurrently depressed patients with intermittent good remission , not only in secondary but also in primary care BACKGROUND Elderly patients with major depression , including those having a first episode , are at high risk for recurrence of depression , disability , and death . METHODS We tested the efficacy of maintenance paroxetine and monthly interpersonal psychotherapy in patients 70 years of age or older who had depression ( 55 percent of whom were having a first episode ) in a 2-by-2 , r and omized , double-blind , placebo-controlled trial . Among patients with a response to treatment with paroxetine and psychotherapy , 116 were r and omly assigned to one of four maintenance-treatment programs ( either paroxetine or placebo combined with either monthly psychotherapy or clinical -management sessions ) for two years or until the recurrence of major depression . Clinical -management sessions , conducted by the same nurses , social workers , and psychologists who provided psychotherapy , involved discussion of symptoms . RESULTS Major depression recurred within two years in 35 percent of the patients receiving paroxetine and psychotherapy , 37 percent of those receiving paroxetine and clinical -management sessions , 68 percent of those receiving placebo and psychotherapy , and 58 percent of those receiving placebo and clinical -management sessions ( P=0.02 ) . After adjustment for the effect of psychotherapy , the relative risk of recurrence among those receiving placebo was 2.4 times ( 95 percent confidence interval , 1.4 to 4.2 ) that among those receiving paroxetine . The number of patients needed to be treated with paroxetine to prevent one recurrence was 4 ( 95 percent confidence interval , 2.3 to 10.9 ) . Patients with fewer and less severe coexisting medical conditions ( such as hypertension or cardiac disease ) received greater benefit from paroxetine ( P=0.03 for the interaction between treatment with paroxetine and baseline severity of medical illness ) . CONCLUSIONS Patients 70 years of age or older with major depression who had a response to initial treatment with paroxetine and psychotherapy were less likely to have recurrent depression if they received two years of maintenance therapy with paroxetine . Monthly maintenance psychotherapy did not prevent recurrent depression . ( Clinical Trials.gov number , NCT00178100 . ) The objective was to present naturalistic 1‐year follow‐up information of 96 child and adolescent out patients with major depressive disorder who had been r and omized in an 8‐week double‐blind , placebo‐controlled trial of fluoxetine Introduction : Patients in clinical r and omized controlled trials ( RCTs ) of antidepressants are different from those typically treated in clinical practice , which may affect the generalizability of data from RCTs . We attempted to replicate the work of Zimmerman and colleagues ( Zimmerman M , Mattia JI , Posternak MA . Are subjects in phamacological treatment trials of depression representative of patients in routine clinical practice ? Am J Psychiatry . 2002;159:469 - 473 ) , demonstrating that most patients seeking clinical treatment of depression would not qualify for an RCT based on common exclusion criteria . Methods : Eight hundred seventeen patients presenting to an outpatient private practice were evaluated by retrospective chart review . The 11 exclusion criteria outlined in the previous study were applied to a sample of 348 depressed adults to determine the percentage that would have qualified for an RCT . Results : We have closely replicated the study of Zimmerman et al , finding that 91 % of our sample would not qualify for an RCT based on presence of any of the 11 exclusion criteria . Prevalence of 7 criteria applied were found significantly different in our population when compared with the study of Zimmerman et al , yet exclusion rates came within 0.2 % . When only the 5 most common criteria were applied , exclusion rates remained high . Conclusions : Some exclusion criteria are essential for ethical or diagnostic purpose s or to reduce heterogeneity ; others are somewhat arbitrary , widening the gap between research and clinical practice . Ninety-one percent of patients presenting for treatment of depression would not qualify for RCTs if the 11 exclusion criteria identified were applied ; if a st and ard severity cutoff score and 4 criteria considered relevant to safety or diagnostic validity were used , nearly 75 % would not qualify . Use of antidepressants in a typical clinical population is an extrapolation from research data reuptake inhibitors ( SSRIs ) during continuation therapy . This investigation reports the differential effect of 6 months of treatment with sertraline versus paroxetine for symptoms of depression , quality of life , and personality outcomes . Out patients with unipolar major depression ( DSM-III-R ) were r and omly assigned to receive 24 weeks of double-blind treatment with flexible doses of paroxetine ( 20 - 40 mg ) or sertraline ( 50 - 150 mg ) . Assessment s included the Montgomery-Asberg Depression Rating Scale ( MADRS ) , the Clinical Global Impression Scale , the Battelle Quality of Life Question naire , and the Structured Clinical Interview for DSM-III-R Personality Disorders screen question naire . One hundred seventy-six patients ( mean age , 43 years ; 64 % female ; baseline MADRS , 30.3 ) were treated with sertraline and 177 patients ( mean age , 42 years ; 71 % female ; MADRS , 30.7 ) with paroxetine . Antidepressant efficacy during continuation therapy was sustained , with only 2 % of patients receiving sertraline and 9 % of patients receiving paroxetine suffering a relapse . Continuation therapy result ed in a substantial conversion of responders during short-term treatment to full remission : remitter rates increased from 52 % to 80 % for sertraline and from 57 % to 74 % for paroxetine . The improvements in quality of life were related to a reduced depression score . SSRI treatment had significant beneficial effects on both categorical and dimensional measures of personality . A logistic regression analysis identified early response ( 25 % reduction in MADRS scores at week 2 ) as the most important predictor of treatment response , whereas high severity , chronicity , and poor baseline quality of life had no effect . Both treatments were well-tolerated , with sertraline having a somewhat lower side effect profile . Sertraline and paroxetine demonstrated comparable efficacy during short-term and continuation therapy . Treatment was associated with significant improvement in quality of life and with reductions in axis II personality psychopathology Abrupt interruption or cessation of selective serotonin reuptake inhibitor ( SSRI ) treatment may result in discontinuation or treatment interruption symptoms . Recent reports suggested these symptoms occur more frequently with shorter half-life SSRIs . Previous studies indicated a 5–8-day treatment interruption result ed in fewer discontinuation-emergent adverse events in fluoxetine-treated patients than in paroxetine-treated patients . This study examines the effects of shorter treatment interruption ( 3–5 days ) , as would occur if patients miss just a few doses of medication . Patients successfully treated for depression with fluoxetine or paroxetine underwent treatment interruption in a double-blind fashion . Treatment interruption-emergent symptoms were assessed using the Discontinuation-Emergent Signs and Symptoms checklist . Other assessment s included the Montgomery – Åsberg Depression Rating Scale , Clinical Global Impressions-Severity scale and a social functioning question naire . Of 150 patients enrolled , 141 completed the study . Following treatment interruption , fluoxetine-treated patients experienced fewer treatment interruption-emergent events than did paroxetine-treated patients . The paroxetine treatment group also experienced significant increases in depressive symptoms , clinical global severity scores and difficulty in social functioning ; the fluoxetine treatment group did not . These results are consistent with reports suggesting abrupt interruption of treatment with paroxetine is more often associated with somatic and psychological symptoms than is abrupt interruption of fluoxetine . Patients treated with fluoxetine appeared to be protected by its longer half-life BACKGROUND We evaluated and compared the efficacy and safety of sertraline and fluvoxamine in a r and omized , double-blind , parallel-group study during a follow-up of 24 months . METHOD Sixty-four patients with recurrent , unipolar depression ( DSM-IV criteria ) who had at least one depressive episode during the 18 months preceding the index episode were accepted into the trial . Patients were r and omly assigned to one of the two long-term treatment groups and evaluated monthly by trained psychiatrists , blinded to treatment option , on the basis of the Hamilton Rating Scale for Depression . RESULTS All patients completed the 24-month follow-up period . Sertraline and fluvoxamine showed an equal efficacy in preventing new recurrences . In fact , there was no significant difference in survival rates between the two medication groups : 7 sertraline-treated patients ( 21.9 % ) and 6 fluvoxamine-treated patients ( 18.7 % ) had a single new recurrence ( z = 0.14 ; p = .88 ) . Moreover , recurrence observed during maintenance therapies was less severe and /or of shorter duration than index episodes . CONCLUSION Long-term treatment with sertraline or fluvoxamine has been shown to be effective for prevention of highly recurrent unipolar depression . The high tolerability of these compounds , together with their prophylactic effectiveness , has an important role in improving the quality of life of these patients OBJECTIVE Later age at onset of depression appears to be a risk factor for early recurrence . Therefore , the authors examined the 2-year outcomes of elderly patients with first-episode major depression following discontinuation of their maintenance antidepressant medication . METHOD The study group consisted of 21 elderly patients who had recovered from a first lifetime episode of major depression . They had taken maintenance antidepressant medication for 2 years and had not had a relapse or recurrence during that time . The antidepressant was then withdrawn , and patients were followed for another 2 years or until recurrence , whichever occurred first . RESULTS The cumulative probability of suffering a recurrence of major depression was 61 % . Eleven of the 12 patients who suffered a recurrence restarted the antidepressant , and 10 responded . CONCLUSIONS Elderly patients with first-episode major depression were at high risk of recurrence following discontinuation of maintenance antidepressant medication . However , the vast majority of patients who experienced a recurrence responded to reinstated treatment Twenty-eight psychiatric patients older than 65 years with major depression with high probability of recurrence were enrolled in a 24-month open label clinical trial aim ed at evaluating the long-term efficacy and safety of venlafaxine . All patients completed the acute phase of the study ; 21 were responders and entered the follow-up period . During the continuation phase no relapse was observed . During the maintenance period , 20 % of the patients had a single new recurrence . No significant side effects were observed . The results demonstrate that venlafaxine is both effective and safe in the long-term treatment of major depression in geropsychiatric patients OBJECTIVE Cognitive behavioral treatment has been used extensively in the acute phase of depression . The purpose of this study was to determine the applicability and effectiveness of this treatment modality in addressing the residual symptoms of primary major depressive illness . METHOD The subjects were 40 patients with major depressive disorder who were successfully treated with antidepressant drugs . They were then r and omly assigned to either cognitive behavioral treatment or clinical management of residual symptoms . In both subgroups , antidepressant drugs were tapered and discontinued . RESULTS The group that received cognitive behavioral treatment had a significantly lower level of residual symptoms after drug discontinuation in comparison with the clinical management group . Cognitive behavioral treatment also result ed in a lower rate of relapse ( 15 % ) at a 2-year follow-up than did clinical management ( 35 % ) , although this difference did not reach statistical significance . Most of the residual symptoms were found to have occurred also in the prodromal phase of illness . CONCLUSIONS This preliminary study points to the potential clinical advantages of cognitive behavioral treatment targeted to the residual symptoms of depression The aim of the present study was to determine whether , in patients with depression who had responded favourably to the selective serotonin reuptake inhibitor citalopram , there was a therapeutic benefit in continuation treatment . Three hundred and ninety-one depressive patients were included in an open short-term citalopram treatment period . Only patients who responded to treatment at 8 weeks ( total score of 12 or less on the MADRS scale ) were r and omized to the 24 week double-blind phase . Seventy-four patients were treated with placebo and 152 with citalopram at the same constant dose to which the patient had responded in the first phase . Relapse was defined as a total score of 25 or more on the MADRS scale . Twenty-one patients ( 13.8 % ) continuing to receive citalopram relapsed compared with 18 patients ( 24.3 % ) receiving placebo . The log rank test for survival data used to test the e quality of relapse hazards between the placebo group and the citalopram group showed that patients treated with citalopram had a significantly lower relapse rate { p = 0.04 ) . The results of this study are in general agreement with those of other studies on antidepressants , and support the hypothesis that full dose continuation treatment is more effective than placebo in preventing relapse of depression BACKGROUND The efficacy of citalopram , 20 to 60 mg/day , in relapse prevention in major depression was demonstrated in 6-month placebo-controlled studies . The authors tested the efficacy of citalopram , 40 mg/day , in relapse prevention over a 4-month period and citalopram , 20 mg/day , in recurrence prevention over a 24-month period . METHOD Fifty in patients with recurrent major depressive disorder ( DSM-IV criteria ) who had had at least one depressive episode during the 18 months preceding the index episode were openly treated with citalopram , 40 mg/day . Thirty-six subjects had a stable response to citalopram and remained in the continuation treatment with citalopram , 40 mg/day , for 4 months as out patients . At the time of recovery , 32 patients gave their written informed consent before entering the 24-month maintenance period with citalopram , 20 mg/day . They were evaluated monthly by trained psychiatrists on the basis of the 21-item Hamilton Rating Scale for Depression . Every 3 months , patients were given the Sheehan Disability Scale , a self-rating instrument , to assess their psychosocial adjustment . RESULTS No relapse was observed in the 4-month continuation period . Sixteen ( 50 % ) of 32 patients who entered the 24-month maintenance period had a new recurrence . Patients with recurrence showed a persistent moderate disability on Sheehan Disability Scale score , while no further differences were highlighted in clinical and demographic characteristics between patients with and without recurrence . CONCLUSION In agreement with previous findings , these data suggest that a full dose of antidepressant is strongly recommended in prophylactic therapy of patients with recurrent major depression . Moreover , it appears that psychosocial impairment may increase the risk of recurrence , thus conditioning a poor outcome BACKGROUND Mindfulness-based cognitive therapy ( MBCT ) and maintenance antidepressant medication ( mADM ) both reduce the risk of relapse in recurrent depression , but their combination has not been studied . Our aim was to investigate whether the addition of MBCT to mADM is a more effective prevention strategy than mADM alone . METHODS This study is one of two multicenter r and omised trials comparing the combination of MBCT and mADM to either intervention on its own . In the current trial , recurrently depressed patients in remission who had been using mADM for 6 months or longer ( n=68 ) , were r and omly allocated to either MBCT+mADM ( n=33 ) or mADM alone ( n=35 ) . Primary outcome was depressive relapse/recurrence within 15 months . Key secondary outcomes were time to relapse/recurrence and depression severity . Analyses were based on intention-to-treat . RESULTS There were no significant differences between the groups on any of the outcome measures . LIMITATIONS The current study included patients who had recovered from depression with mADM and who preferred the certainty of continuing medication to the possibility of participating in MBCT . Lower expectations of mindfulness in the current trial , compared with the parallel trial , may have caused selection bias . In addition , recruitment was hampered by the increasing availability of MBCT in the Netherl and s , and even about a quarter of participants included in the trial who were allocated to the control group chose to get MBCT elsewhere . CONCLUSIONS For this selection of recurrently depressed patients in remission and using mADM for 6 months or longer , MBCT did not further reduce their risk for relapse/recurrence or their ( residual ) depressive symptoms The r and omized discontinuation trial ( RDT ) is a two-phase trial . In phase I all patients are openly treated with the medication being evaluated . In phase II , those who have responded are r and omly assigned to continue the same treatment or switch to placebo . Usually , non-compliers and " adverse reactors " identified in phase I are excluded from phase II . To investigate the value of this design , we review ed the advantages and limitations of discontinuation studies , and compared the RDT design to the classic r and omized clinical trial design in terms of clinical utility and efficiency ( sample size ) . A computer model was used to study the efficiency of the two design s under a broad range of assumptions . The RDT design is particularly useful in study ing the effect of long-term , non-curative therapies , especially when the clinical ly important effect is relatively small , and the use of placebo should be minimized for ethical or feasibility reasons . However , its use is limited if the objective of an investigation is to estimate the magnitude of absolute treatment effects and toxic effects in the source population , or to evaluate a potentially curative treatment . Our results indicate that selecting responders prior to r and omization has a very strong effect on the relative efficiency of the trial . Further improvement may be achieved by excluding non-compliers and adverse reactors . Under the assumptions tested in our model , the sample size required in phase II of an RDT was only 20 - 50 % of that in a classic trial A group of 480 patients , aged 19 - 78 with an HRSD score of at least 17 and who met DSM-III criteria for major depressive disorder were studied . Patients were given placebo for a one-week single-blind run-in period , after which sertraline was administered for eight weeks . This was followed by 44 weeks in which patients received sertraline or placebo on a double-blind , r and omised basis . Patients were assessed periodically using the 17-item HRSD and the Clinical Global Impression scales . During the entire double-blind period 24 ( 13.0 % ) sertraline patients relapsed compared with 48 ( 45.7 % ) placebo patients ( P less than 0.001 ) . The protective effect of sertraline was maintained throughout the 44 weeks . The study provides evidence that sertraline prevents relapse of the index episode of depression as well as recurrence of further episodes and has few side-effects BACKGROUND Attrition , or dropping out of treatment , remains a major issue in the care of depressed out patients . Whether different factors are associated with attrition for different socioeconomic groups is not known . This report assessed whether attrition rates and predictors of attrition differed among depressed out patients with different income levels . METHODS Out patients with nonpsychotic major depressive disorder treated for up to 14 weeks with citalopram in the first step of the Sequenced Treatment Alternatives to Relieve Depression ( STAR*D ) study were divided by household incomes of < $ 20,000 , $ 20,000-<$40,000 , and > or=$40,000 . Attrition rates and sociodemographic and clinical correlates of attrition were identified for each group . RESULTS Regardless of income level , remission rates were lower for participants who dropped out of treatment . Attrition rates increased as income decreased . For all income levels , younger age was independently associated with attrition . For the lowest income level , less education , better mental health functioning , being on public insurance , and having more concurrent Axis I conditions were associated with a greater likelihood of attrition . For the middle income group , less education , better mental health functioning , being Black or of another non-White race , and treatment in a psychiatric versus primary -care setting predicted greater attrition . For the highest income group , being Hispanic , having a family history of drug abuse , and melancholic features predicted attrition . Atypical symptom features ( middle income group ) and recurrent depression ( highest income group ) were associated with retention . CONCLUSIONS Efforts to retain patients in antidepressant treatment should focus especially on less educated patients with lower household incomes and younger patients The acute efficacy of selective serotonin reuptake inhibitors ( SSRIs ) in the treatment of major depressive disorder ( MDD ) is well established ; however their role in longer-term prevention of recurrence remains unconfirmed . This study aims at examining : the prophylactic efficacy of four commonly used SSRIs in MDD in a naturalistic setting with long-term follow-up , the effect of concomitant cognitive behavioral therapy ( CBT ) , and the predictors of outcome . In a prospect i ve cohort study , 387 patients who either remitted or responded following treatment with four different SSRIs-fluoxetine , escitalopram , sertraline and paroxetine-were followed up over several years . During an average follow-up period of 34.5 months , 76.5 % of patients experienced MDD recurrence . Escitalopram and fluoxetine showed a numerically higher prophylactic efficacy than paroxetine and sertraline but the difference was statistically insignificant . The prophylactic efficacy for SSRI-only treatment was limited , with a recurrence rate of 82.0 % , compared to 59.0 % of patient recurrence rate in concomitant Cognitive Behavioral Therapy ( CBT ) . The relatively small size of the CBT group and the lack of r and omization may undermine the extrapolation of its findings to clinical practice . Nevertheless , the study preliminary data may help in defining the clinical utility of antidepressants and CBT in the prophylaxis from MDD recurrence BACKGROUND We report a r and omised controlled trial , in both the acute and maintenance stage of treatment , in 75 out- patients with recurrent major depression . METHOD Patients were allocated to three groups : 16 weeks of acute treatment and two years ' maintenance treatment in the following way : antidepressants and maintenance antidepressants ; cognitive therapy and maintenance cognitive therapy ; antidepressants and maintenance cognitive therapy . Both completers ' and end-point data were analysed . RESULTS In the acute phase of treatment , all patients improved significantly and there was no significant difference among treatments , or in the pattern of improvement over time . In the maintenance stage of treatment , patients kept improving over time in all three groups and there was no significant difference among treatments . Cognitive therapy was consistently superior to medication . CONCLUSIONS The results indicate that maintenance cognitive therapy has a similar prophylactic effect to maintenance medication and is a viable option for maintenance after acute treatment with medication in recurrent depression Patients successfully treated during a 3-month period with either imipramine hydrochloride pharmacotherapy , cognitive therapy , or combined cognitive-pharmacotherapy were monitored during a 2-year posttreatment follow-up period . Half of the patients treated with pharmacotherapy alone continued to receive study medications for the first year of the follow-up . All other patients discontinued treatment at the end of the acute treatment phase . Patients treated with cognitive therapy ( either alone or in combination with medication ) evidence d less than half the rate of relapse shown by patients in the medication -- no continuation condition , and their rate did not differ from that of patients provided with continuation medication . It appears that providing cognitive therapy during acute treatment prevents relapse . Whether this preventive effect extends to recurrence remains to be determined The efficacy of nefazodone in prevention of relapse of depression was evaluated in a 36-week double-blind , placebo-substitution , continuation treatment trial . After 16 weeks of acute , single-blind treatment with nefazodone , 131 patients responding to treatment and in stable remission were r and omized in a 36-week double-blind trial to either nefazodone ( n = 65 ) or placebo ( n = 66 ) . Patients were defined as having relapsed if they had a total score > or = 18 on the 17-item Hamilton Depression Scale on two consecutive visits or if they discontinued treatment for lack of efficacy . Relapse rates were significantly lower for patients r and omized to continued nefazodone treatment than for patients switched to placebo . Kaplan-Meier estimates of relapse rates 9 months ( 36 weeks ) after the end of acute treatment were 1.8 % for nefazodone versus 18.3 % for placebo ( P = 0.009 ) by the Hamilton Depression Scale and 17.3 % versus 32.8 % ( P = 0.028 ) by discontinuation for lack of efficacy . The mean modal dose of nefazodone was 412 mg/day at study endpoint . These results demonstrate the clinical effectiveness of up to 1 year 's treatment ( 16 weeks acute and 36 weeks continuation ) with nefazodone in depressed patients . Long-term efficacy of nefazodone was accompanied by a good safety profile without any weight gain and with minimal symptoms of withdrawal upon abrupt discontinuation of treatment OBJECTIVE The purpose of this study was to determine prospect ively the optimal length of therapy in a long-term , placebo-controlled continuation study of patients who responded to acute fluoxetine treatment for major depression ( defined by DSM-III-R ) . METHOD The study was conducted at five outpatient psychiatric clinics in the United States . Patients who met criteria for remission after 12 or 14 weeks of open-label acute fluoxetine therapy , 20 mg/day ( N=395 of 839 patients ) , were r and omly assigned to one of four arms of a double-blind treatment study ( 50 weeks of placebo , 14 weeks of fluoxetine and then 36 weeks of placebo , 38 weeks of fluoxetine and then 12 weeks of placebo , or 50 weeks of fluoxetine ) . Relapse rate was the primary outcome measure . Both Kaplan-Meier estimates and observed relapse rates were assessed in three fixed 12-week intervals after double-blind transfers from fluoxetine to placebo at the start of the double-blind period and after 14 and 38 weeks of continued fluoxetine treatment . RESULTS Relapse rates ( Kaplan-Meier estimates ) were lower among the patients who continued to take fluoxetine compared with those transferred to placebo in both the first interval , after 24 total weeks of treatment ( fluoxetine , 26.4 % ; placebo , 48.6 % ) , and the second interval , after 38 total weeks of treatment ( fluoxetine , 9.0 % ; placebo , 23.2 % ) . In the third interval , after 62 total weeks of treatment , rates were not significantly different between the groups ( fluoxetine , 10.7 % ; placebo , 16.2 % ) . CONCLUSIONS Patients treated with fluoxetine for 12 weeks whose depressive symptoms remit should continue treatment with fluoxetine for at least an additional 26 weeks to minimize the risk of relapse OBJECTIVE Few data exist to help clinicians predict likelihood of treatment response in individual patients with major depressive disorder ( MDD ) . Our aim was to identify subgroups of MDD patients with differential treatment outcomes based on presenting clinical characteristics . We also sought to quantify the likelihood of treatment success based on the degree of improvement and side effects after 2 and 4 weeks of selective serotonin reuptake inhibitor ( SSRI ) pharmacotherapy . METHOD We analyzed data from the first treatment phase of the Sequenced Treatment Alternatives to Relieve Depression ( STAR*D ) trial , in which subjects with a DSM-IV diagnosis of MDD were treated for 8 - 14 weeks with open-label citalopram . A receiver operating characteristic ( ROC ) analysis was conducted to determine homogenous subgroups with different rates of response and remission in depressive symptoms . Included predictor variables were initial clinical characteristics , initial improvement , and side effects after 2 and 4 weeks of SSRI treatment . The primary outcome measures were treatment response ( defined as a greater than 50 % reduction in 17-item Hamilton Depression Rating Scale [ HDRS-17 ] score from baseline ) and remission ( defined as an HDRS-17 score ≤ 17 ) . RESULTS Baseline clinical characteristics were able to identify subgroups from a low likelihood of response of 18 % ( income < $ 10,000 , comorbid generalized anxiety disorder , < 16 years of education ; P < .01 ) to a high likelihood of response of 68 % ( income ≥ $ 40,000 , no comorbid posttraumatic stress disorder ; P < .01 ) . Among baseline clinical characteristics , employment status ( N = 2,477 ; χ²₁ = 78.1 ; P < .001 ) and income level ( N = 2,512 ; χ²₁ = 77.7 ; P < .001 ) were the most informative in predicting treatment outcome . For the models at weeks 2 and 4 , treatment success was best predicted by early symptom improvement . CONCLUSIONS Socioeconomic data such as low income , education , and unemployment were most discriminative in predicting a poor response to citalopram , even with disparities in access to care accounted for . This finding implies that socioeconomic factors may be more useful predictors of medication response than traditional psychiatric diagnoses or past treatment history . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00021528 We conducted a r and omized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy . A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence . A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a " maintenance " dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed . Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy . We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication OBJECTIVE In a placebo-controlled , double-blind study , the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder . METHOD Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder ( Young Mania Rating Scale [ YMRS ] total score < or = 12 and 21-item Hamilton Depression Rating Scale [ HAM-D ] score < or = 8) at two consecutive weekly visits following 6 - 12 weeks of open-label acute treatment with 5 - 20 mg/day of olanzapine were r and omly assigned to double-blind maintenance treatment with olanzapine ( N=225 ) or placebo ( N=136 ) for up to 48 weeks . The primary measure of efficacy was time to symptomatic relapse into any mood episode ( YMRS score > or = 15 , HAM-D score > or = 15 , or hospitalization ) . RESULTS Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine ( a median of 174 days , compared with a median of 22 days in patients receiving placebo ) . Times to symptomatic relapse into manic , depressive , and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo . The relapse rate was significantly lower in the olanzapine group ( 46.7 % ) than in the placebo group ( 80.1 % ) . During olanzapine treatment , the most common emergent event was weight gain ; during the open-label phase , patients who received olanzapine gained a mean of 3.1 kg ( SD=3.4 ) . In double-blind treatment , placebo patients lost a mean of 2.0 kg ( SD=4.4 ) and patients who continued to take olanzapine gained an additional 1.0 kg ( SD=5.2 ) . CONCLUSIONS Compared to placebo , olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode A major problem for the practitioner is the lack of satisfactory guidelines as to how long continuation drug treatment of depressive episodes must be maintained to ensure that the episode is over . This often leads to either premature withdrawal of the drug and subsequent relapse or unnecessarily prolonged treatment . Results from a collaborative project of the National Institute of Mental Health provide the first study -derived guidelines on the length of continuation therapy . Findings indicate that withdrawal of such therapy is safe only after the patient has been free of significant symptoms for 16 to 20 weeks and that focusing on mild as well as severe symptoms is critical in this decision OBJECTIVE Previous antidepressant maintenance trials have used the same medication from acute through maintenance phases , confounding the interpretation of prophylactic effects . The purpose of this study was to determine whether sertraline prevents the recurrence of major depressive disorder among patients with recurrent depression who had been treated to remission with medications other than sertraline . METHOD Patients who had experienced at least three documented episodes of major depressive disorder within the last 4 years and who were currently in full remission were eligible . The last episode must have been treated for at least 4 months with any antidepressant except sertraline . For the initial single-blind placebo lead-in phase , 371 patients were included ; 288 were included in the analyses for the 18-month double-blind phase in which patients were r and omly assigned to sertraline ( 50 or 100 mg ) or placebo ( two capsules per day ) . Recurrence was defined as a depressive episode that fulfilled DSM-IV criteria or the appearance of symptoms that required the administration of another antidepressant treatment . RESULTS Sixty-one patients discontinued before the double-blind phase , including 33 who experienced a relapse . Out of the 288 who entered the double-blind prophylactic phase , 123 discontinued , including 65 for recurrences . Recurrences were significantly lower in the sertraline groups compared with placebo ( sertraline , 50 mg : 16 [ 16.8 % ] of 95 ; sertraline , 100 mg : 16 [ 17.0 % ] of 94 ; placebo : 33 [ 33.3 % ] of 99 ) . Patients treated with sertraline also had a significantly longer time until recurrence compared with placebo-treated patients . CONCLUSIONS Among remitted patients with a history of multiple depressive episodes , sertraline at a dose of either 50 or 100 mg/day prevented recurrences significantly more than did placebo A double-blind , placebo-controlled trial was undertaken to compare the safety and efficacy of venlafaxine and trazodone in patients with major depression . Two hundred twenty-five patients entered an initial 6-week treatment phase , and 149 completed it . Ninety-six patients who were responders continued in a 1-year , double-blind , long-term phase during which they received the same medication and doses they had during the short-term phase . Both active treatments were significantly more effective than placebo on some measures during the short-term study , but venlafaxine produced more improvement in the cognitive disturbance and retardation factors on the Hamilton Rating Scale for Depression . Trazodone was more effective against the sleep disturbance factor . Patients on venlafaxine were most likely to enter the long-term phase and to remain in the trial longest . The side effect profiles of the three treatment groups were compared . Venlafaxine was most likely to cause nausea , whereas trazodone was associated with the most dizziness and somnolence OBJECTIVE The authors tested the hypothesis that nortriptyline and interpersonal psychotherapy , alone and in combination , are superior to placebo in achieving remission of bereavement-related major depressive episodes . METHOD Eighty subjects , aged 50 years and older , with major depressive episodes that began within 6 months before or 12 months after the loss of a spouse or significant other were r and omly assigned to a 16-week doubleblind trial of one of four treatment conditions : nortriptyline plus interpersonal psychotherapy ( N = 16 ) , nortriptyline alone in a medication clinic ( N = 25 ) , placebo plus interpersonal psychotherapy ( N = 17 ) , or placebo alone in a medication clinic ( N = 22 ) . The protocol required that the acute-phase double-blind treatment be ended after 8 weeks if Hamilton depression scale ratings had not improved by 50 % . Remission was defined as a 17-item Hamilton scale score of 7 or lower for 3 consecutive weeks . RESULTS The rate of remission for nortriptyline plus interpersonal psychotherapy was 69 % ( N = 11 ) ; for medication clinic , nortriptyline , 56 % ( N = 14 ) ; for placebo plus interpersonal psychotherapy , 29 % ( N = 5 ) ; and for medication clinic , placebo , 45 % ( N = 10 ) . In a generalized logit model , there was a significant effect of nortriptyline over placebo but no interpersonal psychotherapy effect and no nortriptyline-by-interpersonal psychotherapy interaction . Rates of all-cause attrition were lowest in the nortriptyline plus interpersonal psychotherapy group . CONCLUSIONS Nortriptyline was superior to placebo in achieving remission of bereavement-related major depressive episodes . The combination of medication and psychotherapy was associated with the highest rate of treatment completion . These results support the use of pharmacologic treatment of major depressive episodes in the wake of a serious life stressor such as bereavement BACKGROUND The authors evaluated and compared the efficacy of 20 mg versus 40 mg of paroxetine in a r and omized , double-blind , parallel-group study during a maintenance period of 28 months . METHOD Ninety-nine in patients with recurrent , unipolar depression ( DSM-IV criteria ) who had at least 1 depressive episode during the 18 months preceding the index episode were openly treated with paroxetine 40 mg/day . Seventy-two subjects had a stable response ( Hamilton Rating Scale for Depression score < 8) to paroxetine treatment and remained in the continuation treatment as out patients for 4 months . At the time of recovery , 68 patients were r and omly assigned to 1 of the 2 maintenance treatment groups : paroxetine 20 mg or paroxetine 40 mg daily . RESULTS Sixty-seven patients completed the 28-month follow-up period . Seventeen ( 51.5 % ) of 33 patients in the 20-mg paroxetine regimen had a single recurrence compared with 8 ( 23.5 % ) of 34 subjects in the 40-mg dose regimen ( chi2 = 5.56 , p = .018 ) . CONCLUSION These data suggest that a full dose of paroxetine is recommended in unipolar patients who are at high risk for recurrent depressive episodes BACKGROUND The clinical ly relevant outcomes in treating depression are persistent recovery , relapse , and treatment resistance . METHOD 175 out patients treated with antidepressants for 6 months were assessed for major depression . Those who had recovered were prospect ively monitored for one year to study rates of relapse ( at least two weeks of major depression ) . Those who were depressed at 6 months were monitored for rates of recovery ( at least 8 weeks of no major depression ) . RESULTS 94 % of the sample was monitored for one year . Of the 123 patients who were not depressed at 6 months 57 ( 46 % ) relapsed . Patients who relapsed were more likely to have a history of recurrent depression , to have residual depressive symptoms , to have a less sustained response to initial treatment , to have avoidant personality disorder symptoms , schizotypal personality disorder symptoms , higher harm avoidance ( HA ) scores and lower self directedness ( SD ) scores . Of the 38 patients who were depressed at 6 months 13 ( 34 % ) recovered . There were no patient characteristics associated with recovery . LIMITATIONS The findings apply to moderately depressed out patients . There was no placebo control . CONCLUSION Most patients with depression will recover but many become unwell again within a year . Clinical ly long term monitoring and sustained efforts to treat patients with major depression seem warranted BACKGROUND We compared citalopram and clomipramine against placebo with respect to recurrence prevention as opposed to relapse prevention in patients with recurrent depression , independently of any acute response to the test drug(s ) . METHODS Patients with recurrent depressive disorder with a current depressive episode of moderate to severe degree were recruited over a period of 6.5 years . After 6 - 15 months of routine open acute and continuation therapy , and a discontinuation/drug-free period of one month following sustained response ( at least 3 consecutive monthly ratings with a HAM-D-17-score below 13 ) , patients were r and omised under double-blind conditions , with a follow-up period of 2 years . The major endpoint was recurrence ( HAM-D-17-score of 16 or above ) . RESULTS A total of 307 patients were included in the open phase and 174 patients completed at least 6 months of treatment and achieved sustained response . Out of these , only 59 patients ( 34 % ) could be r and omised to placebo ( n=22 ) , citalopram ( n=19 ) or clomipramine ( n=22 ) , with protocol violation and /or non-consent being the major reasons for non-r and omisation . There were no between-group differences in outcome ; almost half of the r and omised patients met the criterion for recurrence . LIMITATIONS The size of the r and omised sample was considerably smaller than the planned size . CONCLUSIONS The high risk of drop out prior to r and omisation among the eligible patients was presumably caused by an interaction between the study design and the study population . The findings suggest that long-term trial design s interposing a drug-free period prior to r and omisation are not feasible and recommendable in severely ill patients OBJECTIVES To st and ardise the delivery of a brief group cognitive behaviour therapy intervention ( CBT-G ) . To apply the intervention in a research setting and to estimate its effect on recurrence rates in recently depressed older adults , in preparation for a definitive study . METHOD A CBT-G therapy manual was produced and the Cognitive Therapy Rating Scale ( CTS-R ) modified to assess therapy delivery . Forty-five adults aged 60 and over who had met ICD-10 criteria for major depression in the previous year and were still taking antidepressant medication were r and omly allocated to CBT-G/antidepressant combination or antidepressant alone . Depression severity was measured at baseline , r and omisation and 6 and 12 months after start of CBT-G using the Montgomery Asberg Rating Scale for Depression ( MADRS ) . RESULTS AND CONCLUSION One-year recurrence rates on the MADRS were encouragingly lower in participants receiving CBT-G [ 5/18 ( 27.8 % ) ] compared with controls [ 8/18 ( 44.4 % ) ] although this did not achieve statistical significance ( adjusted RR 0.70 [ 95 % CI 0.26 - 1.94 ] ) . In contrast , overall scores on the secondary outcome measure , the Beck Depression Inventory , increased in participants receiving CBT-G. The CBT-G manual was successfully implemented and therapy delivery achieved an overall satisfactory level of competence . We believe that evaluation of this promising intervention in a full-scale trial is warranted Antidepressants effectiveness in major depressive disorder ( MDD ) is still question ed because the extrapolation of r and omized controlled trial ( RCT ) results to " real life " setting s is problematic . The application of the RCT paradigm in a disorder of this type , where global care plays a central role , raises questions regarding the internal and external validity of this type of study . Outcome measurement , attrition rates , the ability of the double-blind design to control for expectations , placebo response , the representativeness of trial participants and publication bias are major method ological pitfalls . This review discusses these issues . It is illustrated using original data and proposes some alternatives for assessing antidepressant effectiveness via different approaches . Some are easy to implement , such as ecological measures , qualitative approaches , improvement of analytical strategy and improvement of blinding procedures . Some are sophisticated , involving temporary deception to deal with the confounding effect of expectations , and they raise ethical issues . Others resort to external validity , this being the case in observational studies . But all are necessary to explore antidepressant effectiveness

Pooled results of clinical trials reveal a very weak clinical response rate of < 1 % for active specific immunization procedures currently available for advanced colorectal cancer .

Colorectal cancer is a common malignant disease , which , despite some progress , still requires improved therapeutic options . Several clinical studies have used active specific immunotherapy ( i.e. , vaccination ) in colorectal cancer . However , the literature still lacks a comprehensive meta- analysis of this approach in advanced colorectal cancer . We did a systematic review with a meta- analysis of clinical studies to evaluate the objective clinical and immunologic response to active specific immunotherapy in patients with colorectal cancer .

The MAGE gene is selectively expressed in cancer tissues such as melanoma or gastrointestinal carcinomas , whereas no expression is observed in normal tissues except testis . There are several reports of successful induction of HLA class I-restricted antitumor CTLs using MAGE peptides , and some clinical trials with these immunogenic peptides were reported as effective for some patients with malignant melanoma . However , there are no similar studies in gastrointestinal carcinomas , which are important neoplasms . Autologous dendritic cells ( DCs ) were generated ex vivo and were pulsed with MAGE-3 peptide , depending on the patient 's HLA haplotype ( HLA-A2 or A24 ) . Patients were immunized with DC pulsed with MAGE-3 peptide every 3 weeks at four times . Twelve patients with advanced gastrointestinal carcinoma ( six stomach , three esophagus , and three colon ) were treated , and no toxic side effects were observed . Peptide-specific CTL responses after vaccination were observed in four of eight patients . Improvement in performance status was recognized in four patients . Tumor markers decreased in seven patients . In addition , minor tumor regressions evidence d by imaging studies were seen in three patients . These results suggested that DC vaccination with MAGE-3 peptide is a safe and promising approach in the treatment of gastrointestinal carcinomas Carcinoembryonic antigen ( CEA ) is expressed in a wide variety of adenocarcinomas , and it is well recognized that cancer patients are immunologically " tolerant " to CEA . The purpose of this study was to determine whether we could break immune tolerance to CEA by vaccinating patients with a monoclonal anti-idiotype antibody that is the internal image of CEA and to determine what impact this might have on patient survival . Twenty-four patients with advanced CEA-positive colorectal cancer who failed st and ard therapies except for two were entered into this Phase Ib trial . One patient was considered not assessable , because on the day of entering into the study , she was diagnosed with acute myelogenous leukemia . Patients were treated with 1 , 2 , or 4 mg of aluminum hydroxide-precipitated 3H1 anti-idiotype antibody every other week for four injections and then monthly until tumor progression was observed . Immunological monitoring included humoral and cellular idiotypic and CEA responses , and all patients were evaluated for toxicity , response , and survival . Hyperimmune sera from 17 of 23 patients demonstrated an anti-anti-idiotypic Ab3 response , and 13 of these responses were demonstrated to be true anti-CEA responses ( Ab1 ' ) . The antibody response was polyclonal , and 11 mediated antibody-dependent cellular cytotoxicity . Ten patients had idiotypic T-cell responses , and five had specific T-cell responses to CEA . None of the patients had objective clinical responses , but overall median survival for the 23 evaluable patients was 11.3 months , with 44 % 1-year survival ( 95 % confidence interval , 23 - 64 % ) . Toxicity was limited to local swelling and minimal pain . Anti-idiotype monoclonal antibody 3H1 that mimics CEA was able to break immune tolerance in the majority of treated patients . Overall survival of 11.3 months was comparable to other phase II data with advanced colorectal cancer patients treated with a variety of chemotherapy agents , including irinotecan , with considerably less toxicity . Although it is not clear that the vaccine itself had an impact on survival , this should be determined in a Phase III r and omized trial Most tumor-associated antigens represent self-proteins and as a result are poorly immunogenic due to immune tolerance . Here we show that tolerance to carcinoembryonic antigen ( CEA ) , which is overexpressed by the majority of lethal malignancies , can be reversed by immunization with a CEA-derived peptide . This peptide was altered to make it a more potent T cell antigen and loaded onto dendritic cells ( DCs ) for delivery as a cellular vaccine . Although DCs are rare in the blood , we found that treatment of advanced cancer patients with Flt3 lig and , a hematopoietic growth factor , exp and ed DCs 20-fold in vivo . Immunization with these antigen-loaded DCs induced CD8 cytotoxic T lymphocytes that recognized tumor cells expressing endogenous CEA . Staining with peptide-MHC tetramers demonstrated the expansion of CD8 T cells that recognize both the native and altered epitopes and possess an effector cytotoxic T lymphocyte phenotype ( CD45RA+CD27−CCR7− ) . After vaccination , two of 12 patients experienced dramatic tumor regression , one patient had a mixed response , and two had stable disease . Clinical response correlated with the expansion of CD8 tetramer+ T cells , confirming the role of CD8 T cells in this treatment strategy Despite an abundance of pre clinical data , relatively little is known regarding the efficacy of DNA vaccination in humans . Here , we present results from a dose-escalation clinical trial of a dual expression plasmid encoding carcinoembryonic antigen ( CEA ) and hepatitis B surface antigen ( HBsAg ) in 17 patients with metastatic colorectal carcinoma . CEA was selected as a prototypic tumor-associated self-antigen , and the HBsAg cDNA was included as a positive control for immune response to the DNA vaccine without relying upon breaking tolerance to a self-antigen . Groups of 3 patients received escalating single i.m . doses of the DNA vaccine at 0.1 , 0.3 , and 1.0 mg . Subsequent groups of 3 patients received three repetitive 0.3- or 1.0-mg doses at 3-week intervals . A final group of 2 patients received three repetitive 2.0 mg doses at 3-week intervals . Toxicity was limited to transient grade 1 injection site tenderness , fatigue , and creatine kinase elevations , each affecting a minority of patients in a non-dose-related manner . Repetitive dosing of the DNA vaccine induced HBsAg antibodies in 6 of 8 patients , with protective antibody levels achieved in four of these patients . CEA-specific antibody responses were not observed , but 4 of 17 patients developed lymphoproliferative responses to CEA after vaccination . No objective clinical responses to the DNA vaccine were observed among this population of patients with widely metastatic colorectal carcinoma . Nevertheless , this pilot trial has provided encouraging human immune response data in support of this vaccine technology We report here the adoptive transfer , to patients with metastatic melanoma , of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen . This approach result ed in the persistent clonal re population of T cells in those cancer patients , with the transferred cells proliferating in vivo , displaying functional activity , and trafficking to tumor sites . This led to regression of the patients ' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction . This approach presents new possibilities for the treatment of patients with cancer as well as patients with human immunodeficiency virus – related acquired immunodeficiency syndrome and other infectious diseases BACKGROUND Colon cancer is curable by surgery , but cure rate depends on the extent of disease . We investigated whether adjuvant active specific immunotherapy ( ASI ) with an autologous tumour cell-BCG vaccine with surgical resection was more beneficial than resection alone in stage II and III colon cancer . METHODS In a prospect i ve r and omised trial , 254 patients with colon cancer were r and omly assigned postoperative ASI or no adjuvant treatment . ASI was three weekly vaccinations starting 4 weeks after surgery , with a booster vaccination at 6 months with 10(7 ) irradiated autologous tumour cells . The first vaccinations contained 10(7 ) BCG organisms . We followed up patients for time to recurrence , and recurrence-free and overall survival . Analysis was by intention to treat . FINDINGS The 5.3 year median follow-up ( range 8 months to 8 years 11 months ) showed 44 % ( 95 % CI 7 - 66 ) risk reduction for recurrence in the recurrence-free period in all patients receiving ASI ( p=0.023 ) . Overall , there were 40 recurrences in the control group and 25 in the ASI group . Analysis by stage showed no significant benefit of ASI in stage III disease . The major impact of ASI was seen in patients with stage II disease , with a significantly longer recurrence-free period ( p=0.011 ) and 61 % ( 18 - 81 ) risk reduction for recurrences . Recurrence-free survival was significantly longer with ASI ( 42 % risk reduction for recurrence or death [ 0 - 68 ] , p=0.032 ) and there was a trend towards improved overall survival . INTERPRETATION ASI gave significant clinical benefit in surgically resected patients with stage II colon cancer . ASI has minimal adverse reactions and should be considered in the management of stage II colon cancer The purpose of this study was to determine the safety , toxicity , and antitumor immune response following S.C. immunizations with a mixture of irradiated , autologous tumor cells and autologous fibroblasts that were genetically modified to express the gene for interleukin 2 ( IL-2 ) in patients with colorectal carcinoma . Ten patients were treated with a fixed dose of tumor cells ( 10(7 ) ) and escalating doses of fibroblasts secreting IL-2 ( per 24 h ) : 100 units ( three patients ) , 200 units ( three patients ) , 400 units ( three patients ) , and 800 units ( one patient ) . Pre- and posttreatment peripheral blood mononuclear cells were evaluated for evidence of antitumor immune responses . Fatigue and /or flu-like symptoms were experienced by seven patients and delayed-type hypersensitivity-like skin reactions were observed at the sites of the second or subsequent vaccinations in five patients . Low frequencies of tumor cytotoxic T-cell precursors ( range , 1/190,000 - 1/1,320,000 peripheral blood mononuclear cells ) were detected prior to therapy in four of seven patients . There was a 5-fold increase following treatment in the frequency of tumor cytotoxic T-cell precursors in two of six evaluable patients . Some patients with colorectal cancer have low frequencies of tumor cytotoxic T-cell precursors that may be increased by this well-tolerated form of IL-2 gene therapy , which warrants continued clinical evaluation Purpose : We intranodally immunized metastatic colorectal carcinoma patients , who had failed st and ard chemotherapy , with dendritic cells ( DCs ) pulsed with HLA-A*0201- or HLA-A*2402-restricted carcinoembryonic antigen ( CEA ) peptides to evaluate the safety of this treatment and the immune response against CEA peptides before and after the treatment . Experimental Design : Six patients with the HLA-A*2402 genotype and 4 patients with the HLA-A*0201 genotype were enrolled . A single CEA peptide ( YLSGANLNL ) or two CEA peptides ( QYSWFVNGTF and TYACFVSNL ) were used for patients with the HLA-A*0201 or HLA-A*2402 genotype , respectively . Autologous DCs were generated by culturing adherent mononuclear cells with interleukin 4 and granulocyte macrophage colony-stimulating factor for 6 days . Maturation of DCs was then induced with tumor necrosis factor α for 40 h. Mature DCs were pulsed with appropriate CEA peptides for 2 h. After washing , 1 million peptide-pulsed DCs were injected into one inguinal lymph node under sonographic guidance . Each patient received four injections . Results : No grade II/III toxicity or autoimmunity was observed . An increase in the number of CEA-specific T cells after DC vaccination could be detected in 7 of 10 ( 70 % ) patients . Two ( 20 % ) patients had stable disease for at least 12 weeks . One of these 2 patients experienced a transient decrease in CEA levels during the treatment period and also had the most significant T-cell response against the immunizing CEA peptides . Conclusions : These results suggest that our vaccination procedure can generate or boost specific T-cell responses and may provide clinical benefit in certain cancer patients In most protocol s of peptide-based vaccination , no consideration has been paid to whether or not peptide-specific cytotoxic T-lymphocyte ( CTL ) precursors are pre-existent in cancer patients . Initiation of immune boosting through vaccination is better than that of immune priming to induce prompt and strong immunity . In this study , 10 human histocompatibility leukocyte antigen-A24 + patients with advanced colorectal carcinomas were treated with up to four peptides that had been positive for pre-vaccination measurement of peptide-specific CTL precursors in the circulation ( CTL precursor-oriented peptide vaccine ) . No severe adverse effect was observed , although local pain and fever of grade I or II were observed . Post-vaccination peripheral blood mononuclear cells ( P BMC s ) from five patients demonstrated an increased peptide-specific immune response to the peptides . Increased CTL response to cancer cells was detected in post-vaccination P BMC s of five patients . Antipeptide immunoglobulin G became detectable in post-vaccination sera of seven patients . Three patients developed a positive delayed-type hypersensitivity response to at least one of the peptides administrated . One patient was found to have a partial response ; another had a stable disease , sustained through 6 months . These results encourage further development of CTL precursor-oriented vaccine for colorectal cancer patients Abstract Background : The inadequacy of systemic treatments of advanced colorectal cancer has aroused interest in biologic therapy . Recent animal models have demonstrated the efficacy and safety of a recombinant vaccine that contains vaccinia and the gene for carcinoembryonic antigen ( rV-CEA ) . Methods : A phase I clinical trial of rV-CEA was conducted to assess vaccine toxicities , the maximum tolerated dosage , result ing immune activities , and tumor responses . A dose-escalation protocol was devised for three concentrations . Six patients per dosage were each to receive three vaccinations . Results : Seventeen patients with advanced colorectal cancer received a total of 44 vaccinations . Mild local and systemic reactions — comparable to those seen with vaccinia alone — were observed and were typically associated with the first vaccination . No significant complications or deaths were caused by the rV-CEA . In particular , no autoimmune colitis developed , nor did leukopenia occur , despite some homology between CEA and leukocyte antigens . All three vaccine concentrations were equally well tolerated . Most patients demonstrated tumor progression by clinical and radiographic parameters and by CEA levels . Immune assays are pending . Conclusions : This phase I trial demonstrated the safety of rV-CEA in patients with advanced colorectal cancer . Future clinical studies are warranted and will likely be influenced by investigations of the immune responses to the vaccine We evaluated the method of active specific intralymphatic immunization to treat cancer in 32 patients with various tumor types as part of a broad-based phase I-II evaluation and describe the results of 3 sequential series . In series 1 , the patients ( n = 13 ) received 2 or more injections of autologous , cryopreserved , irradiated tumor cells directly into the lymphatic system through the cannulation of a dorsal pedal lymphatic channel . In series 2 , the patients ( n = 7 ) received low-dose cyclophosphamide , 300 mg per m2 , 3 days before the autologous cell vaccine was administered . Series 3 ( 12 patients ) was similar to series 2 except that the tumor cells were treated with cholesteryl hemisuccinate immediately before irradiation . Patients received from 2 to 6 injections of cells , depending on availability , at 2-week intervals . In all , 91 treatments are evaluated in this study . Clinical responses occurred in 7 of the 32 patients and were seen in all 3 series with about the same frequency . These responses occurred in cases of melanoma , lung cancer , colon cancer , and sarcoma . Regressions occurred in both visceral and subcutaneous sites . There was little toxicity , the chief side effect being local discomfort or inflammation . This experience indicates that active specific intralymphatic immunotherapy is safe , produces antitumor effects , and requires more investigation to increase the frequency and duration of observable tumor regression PURPOSE This trial sought to determine , for the first time , the validity in human vaccinations of using two different recombinant vaccines in diversified prime- and -boost regimens to enhance T-cell responses to a tumor antigen . PATIENTS AND METHODS Eighteen patients with advanced tumors expressing carcinoembryonic antigen ( CEA ) were r and omized to receive either recombinant vaccinia (rV)-CEA followed by three avipox-CEA vaccinations , or avipox-CEA ( three times ) followed by one rV-CEA vaccination . Subsequent vaccinations in both cohorts were with avipox-CEA . Immunologic monitoring was performed using a CEA peptide and the enzyme-linked immunospot assay for interferon gamma production . RESULTS rV-CEA followed by avipox-CEA was superior to the reverse order in the generation of CEA-specific T-cell responses . Further increases in CEA-specific T-cell precursors were seen when local granulocyte-macrophage colony-stimulating factor ( GM-CSF ) and low-dose interleukin (IL)-2 were given with subsequent vaccinations . The treatment was extremely well tolerated . Limited clinical activity was seen using vaccines alone in this patient population . Antibody production against CEA was also observed in some of the treated patients . CONCLUSION rV-CEA was more effective in its role as a primer of the immune system ; avipox-CEA could be given up to eight times with continued increases in CEA T-cell precursors . Future trials should use rV-CEA first followed by avipox-CEA . Vaccines specific to CEA are able to generate CEA-specific T-cell responses in patients without significant toxicity . T-cell responses using vaccines alone may be inadequate to generate significant anticancer objective responses in patients with advanced disease . Cytokines such as GM-CSF and IL-2 may play a key role in generating such responses A human monoclonal anti-idiotypic antibody ( 105AD7 ) has been developed which mimics a colorectal-tumour-associated antigen and induces cellular anti-colorectal tumour immune responses in animals . Thirteen patients with advanced colorectal cancer were immunized with 105AD7 and their survival was compared with that of a contemporary group of unimmunized patients with similar disease status . No toxicity related to anti-idiotype immunization was seen . Cellular responses to anti-idiotypic immunization were indicated by lymphocyte proliferation to gp72-positive tumour cells , and production of interleukin-2 ; anti-tumour antibodies were not detected . Median survival following diagnosis of advanced disease of immunized patients was 12 months , compared with 4 months in unimmunized patients . The improved survival of immunized patients in this study without associated toxicity suggests that 105AD7 immunization may have considerable potential for immunotherapy of colorectal cancer PURPOSE A r and omized phase III clinical trial of adjuvant active specific immunotherapy ( ASI ) with an autologous tumor cell-bacillus Calmette-Guérin ( BCG ) vaccine was conducted to determine whether surgical resection plus ASI was more beneficial than resection alone in stage II and III colon cancer patients . PATIENTS AND METHODS Patients ( n = 412 ) with colon cancer ( 297 with stage II disease , 115 with stage III disease ) were r and omly allocated to an observation arm or to a treatment arm in which they received three weekly intradermal vaccine injections of 10(7 ) irradiated autologous tumor cells beginning approximately 4 weeks after surgery . The first two weekly injections also contained 10(7 ) BCG organisms . Patients were observed for determination of time to recurrence and disease-free and overall survival . RESULTS This was a negative study in that after a 7.6-year median follow-up period , there were no statistically significant differences in clinical outcomes between the treatment arms . However , there were disease-free survival ( P = .078 ) and overall survival ( P = .12 ) trends in favor of ASI when treatment compliance was evaluated , ie , patients who received the intended treatment had a delayed cutaneous hypersensitivity ( DCH ) response to the third vaccination ( in duration > /=5 mm ) . Also , the magnitude of the DCH response correlated with improved prognosis . The 5-year survival proportion was 84.6 % for those with in duration s greater than 10 mm , compared with 45.0 % for those with in duration s less than 5 mm . CONCLUSIONS When all r and omized patients were evaluated , no significant clinical benefit was seen with ASI in surgically resected colon cancer patients with stage II or III colon cancer . However , there was an indication that treatment compliance with effective immunization results in disease-free and overall survival benefits To improve patient immune recognition of autologous tumor cells , we have developed a tumor B-cell lymphocyte hybridoma ( TBH ) autovaccination protocol . This approach is based on immunization of a cancer patient with a hybridoma cell suspension derived from the fusion of autologous activated B-cells and autologous cancer cells . This hybrid allows the host immune system to recognize and destroy oncocytes with low toxicity and high specificity . Of 21 treated patients with very advanced diseases , six complete responses and four partial responses were achieved . Overall , survival was prolonged . Side-effects and combination therapies with IL2 , IL6 and gamma I/FN are discussed in this paper . Breast and colon cancer seem to be sensitive to this therapy PURPOSE Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen ( CEA ) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival . Pre clinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules ( B7 - 1 , ICAM-1 , LFA-3 , design ated TRICOM ) results in a significant improvement in antigen-specific T-cell responses and antitumor activity . We describe here the first trial in humans of the CEA-TRICOM vaccines ( also including an enhancer agonist epitope within the CEA gene ) . PATIENTS AND METHODS Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following : replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM ; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations ; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM , plus granulocyte-macrophage colony-stimulating factor ( GM-CSF ) with vaccines , or with divided doses of vaccine with GM-CSF . Vaccines were administered every 28 days for six doses and then once every 3 months . Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule . RESULTS In this phase I study , no significant toxicity was observed . Twenty-three patients ( 40 % ) had stable disease for at least 4 months , with 14 of these patients having prolonged stable disease ( > 6 months ) . Eleven patients had decreasing or stable serum CEA , and one patient had a pathologic complete response . Enhanced CEA-specific T-cell responses were observed in the majority of patients tested . CONCLUSION We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses , and they seem to have clinical benefit in some patients with advanced cancer Coordinated presentation of antigen and costimulatory molecules has been shown to result in the induction of an antigen-specific T-cell response rather than the development of anergy . This study evaluated the vaccine ALVAC-CEA B7.1 , a canary pox virus that has been engineered to encode the gene for the tumor-associated antigen carcinoembryonic antigen ( CEA ) and B7.1 , a T-cell costimulatory molecule . Patients with CEA-expressing tumors were immunized with 2.5 x 10(7 ) ( n = 3 ) , 1.0 x 10(8 ) ( n = 6 ) , and 4.5 x 10(8 ) ( n = 30 ) plaque-forming units intradermally every other week for 8 weeks . Patients with stable or responding disease received monthly boost injections . Biopsies of vaccine sites were obtained 48 h after vaccination to evaluate leukocytic infiltration and CEA expression . Induction of CEA-specific T-cell precursors was assessed by an ELISPOT assay looking for the production of IFN-gamma . Therapy was well tolerated , without significant toxicity attributable to vaccine . All patients had evidence of leukocytic infiltration and CEA expression in vaccine biopsy sites . Six patients with elevated serum CEA values at baseline had declines in their levels lasting 4 - 12 weeks . These patients all had stable disease after four vaccinations . After four vaccinations , patients who were HLA-A-2-positive demonstrated increases in their CEA-specific T-cell precursor frequencies to a CEA-A2-binding peptide from baseline . The number of prior chemotherapy regimens was inversely correlated with the ability to generate a T-cell response . ALVAC-CEA B7.1 is safe in patients with advanced , recurrent adenocarcinomas that express CEA , and it is associated with the induction of a CEA-specific T-cell response Immunizations with dendritic cells ( DC ) transfected with RNA encoding tumor antigens induce potent tumor antigen-specific immune responses in vitro and in murine models . We performed a phase I study of patients with advanced carcinoembryonic antigen (CEA)-expressing malignancies followed by a phase II study of patients with resected hepatic metastases of colon cancer to assess safety and feasibility of administering autologous DC loaded with CEA mRNA . The immunizations were well tolerated . Of the 24 evaluable patients in the dose-escalation phase , there was 1 complete response ( by tumor marker ) , 2 minor responses , 3 with stable disease , and 18 with progressive disease . In the phase II study , 9 of 13 patients have relapsed at a median of 122 days . Evidence of an immunologic response was demonstrated in biopsies of DC injection sites and peripheral blood of selected patients . We conclude that it is feasible and safe to administer mRNA-loaded DC to patients with advanced malignancies Purpose : To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen . Experimental Design : In this phase I study , we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen ( CEA ) and a triad of costimulatory molecules [ rF-CEA(6D)-TRICOM ] . Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2–restricted peptide derived from cytomegalovirus pp65 protein . Results : Fourteen patients ( 11 with colorectal cancer and 3 with non – small cell lung cancer ) were enrolled and 12 completed at least one cycle of immunization . There were no grade 3/4 toxicities directly referable to the immunizations . One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations . Five other patients were stable through at least one cycle of immunization ( 3 months ) . Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients ( range , 10 - 541 CEA-specific cells/105 peripheral blood mononuclear cells ) . There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy . A second cycle was not associated with higher T-cell frequencies . Cytokine flow cytometry showed CEA-specific immune response among both CD4 + and CD8 + T cells in all immune responders . Conclusion : This immunization strategy is safe and activates potent CEA-specific immune responses We tested a 105 amino acid synthetic mucin MUC-1 peptide that has 5 repeated immunodominant epitopes to evaluate toxicity and detect mucin-specific immune responses in patients with adenocarcinoma . We also studied the enhancement of these responses by vaccinating patients with the synthetic mucin peptide admixed with BCG . Mucins are glycoproteins present on the luminal surface of ductal epithelial cells and on tumors derived from them . The MUC-1 mucin is hypoglycosylated and nonpolarized on tumors and this exposes epitopes that can stimulate cytotoxic T-Cells ( CTL ) . We vaccinated 63 patients with 100 micrograms of the 105aa mucin peptide mixed with BCG . Two additional vaccinations were given at 3-week intervals . All patients were able to tolerate vaccination , with most experiencing local ulceration at the vaccination site . All patients underwent hypersensitivity ( DTH ) testing with the 105aa and shorter mucin peptides , prior to vaccination . DTH responses were evaluated at 48 hr and the sites of highest peptide concentration were biopsied . Only 3 patients had a strong skin response to the long peptide . Examination of 55 biopsies showed intense T-Cell infiltration in 37 patients and lesser infiltration in 7 . Seven of 22 patients tested had a 2- to 4-fold increase in mucin-specific CTLp . Serum levels of IL-6 were measured sequentially using the B9 hybridoma bioassay . Increasing serum levels of IL-6 correlated with constitutional symptoms ( significance 0.001 ) and hypoalbuminemia ( significance 0.007 ) but not with the extent of skin breakdown at vaccination sites . We conclude that mucin vaccination is safe and might serve to enhance specific responses to tumor antigens . IL-6 may be responsible for the constitution symptoms and hypoalbuminemia in these patients KSA ( Ep-CAM ) is highly expressed by colorectal cancers . The safety and immunologic effects of a vaccine consisting of recombinant baculovirus-derived KSA formulated with monophosphoryl lipid A ( MPL ) in liposomes and emulsified in mineral oil were evaluated , with and without co-administration of granulocyte-macrophage colony-stimulating factor ( GM-CSF ) . Eleven patients with metastatic colorectal cancer received three subcutaneous ( s.c . ) injections of the vaccine at 4-week intervals . Six patients were r and omized to also receive human recombinant GM-CSF ( rGM-CSF ) by subcutaneous injection daily for 4 days with each vaccination . Immunizations with and without rGM-CSF were well tolerated . Seven of the 11 patients developed significant KSA-specific cellular immune responses as assessed by lymphoproliferation and interferon-gamma ( IFN-gamma ) ELISPOT assays . All nine tested patients developed positive delayed type hypersensitivity reactions . Eight of the 11 patients developed KSA-specific antibody responses . The highest levels of cellular immune responses were observed in patients who received GM-CSF . Immunization with baculovirus-derived KSA formulated with monophosphoryl lipid A in liposomal emulsion is safe and can elicit KSA-specific immune responses . Co-administration of GM-CSF with this formulation is an effective method of generating KSA-specific T-helper ( Th ) 1-associated cellular immune responses

Studies that used both tailored and educational interventions showed significant relationship between adherence and clinical outcomes ; however , the study that used dosage simplification did not . Interventions to improve adherence with oral chemotherapies in hematological malignancies remain limited . Though they were heterogeneous in nature , interventions tested in the retained studies suggested a positive impact on the adherence outcome ; some established a significant relationship between adherence and clinical outcomes .

BACKGROUND Poor adherence to treatment for chronic diseases including some hematological malignancies impedes health outcomes and increases costs . Oral chemotherapy is an emerging trend that raises concern about nonadherence problems in these targeted patients . OBJECTIVES This systematic literature review explores evidence and gaps in the literature regarding interventions to enhance adherence with prescribed oral chemotherapy in patients with hematological malignancies .

The aim of this study was to characterise the pharmacokinetics of the anticancer agent topotecan , and explore the influence of patient covariates and interoccasion variability on drug disposition . Data were obtained from 190 patients who received the drug as a 30-min infusion ( N=72 ) or orally ( N=118 ) . The population model was built with the use of NONMEM to identify c and i date covariates , and obtain models for clearance ( CL ) and volume of distribution . The final models were based on first-order absorption with lag-time ( oral data ) , and a two-compartment model with linear elimination from the central compartment . The Cockcroft – Gault creatinine clearance ( CrCl ) and WHO performance status ( PS ) were the only significant covariates : CL=(12.8 + 2.1 × CrCl ) × ( 1−0.12 × PS ) . For the volume of distribution , a correlation was found between body weight and the central volume (V1)=0.58 × body weight . Based on the structural models , a limited-sampling strategy was developed with minor bias and good precision that can be applied a posteriori using timed sample s obtained at 1.5 , and 6 h after the administration of topotecan . In conclusion , a population pharmacokinetic model for topotecan has been developed that incorporates measures of renal function and PS to predict CL . In combination with drug monitoring , the limited sampling strategy allows individualised treatment for patients receiving oral topotecan Imatinib mesylate ( imatinib ) has been shown to be highly efficacious in the treatment of chronic myeloid leukemia ( CML ) . Continuous and adequate dosing is essential for optimal outcomes and with imatinib treatment possibly being lifelong , patient adherence is critical . The ADAGIO ( Adherence Assessment with Glivec : Indicators and Outcomes ) study aim ed to assess prospect ively over a 90-day period the prevalence of imatinib nonadherence in patients with CML ; to develop a multivariate canonical correlation model of how various determinants may be associated with various measures of nonadherence ; and to examine whether treatment response is associated with adherence levels . A total of 202 patients were recruited from 34 centers in Belgium , of whom 169 were evaluable . One-third of patients were considered to be nonadherent . Only 14.2 % of patients were perfectly adherent with 100 % of prescribed imatinib taken . On average , patients with suboptimal response had significantly higher mean percentages of imatinib not taken ( 23.2 % , st and ard deviation [ SD ] = 23.8 ) than did those with optimal response ( 7.3 % , SD = 19.3 , P = .005 ; percentages calculated as proportions x 100 ) . Nonadherence is more prevalent than patients , physicians , and family members believe it is , and therefore should be assessed routinely . It is associated with poorer response to imatinib . Several determinants may serve as alert signals , many of which are clinical ly modifiable Purpose In this prospect i ve multi-centre observational cohort study , we investigated the effect of an intensified multidisciplinary pharmaceutical care programme on the adherence of cancer patients treated with capecitabine , a prodrug of fluorouracil . Patients and methods Twenty-four colorectal and 24 breast cancer patients participated in this study . Patients of the control group ( n = 24 ) received st and ard care , patients of the intervention group ( n = 24 ) received intensified pharmaceutical care consisting of written and spoken information . Adherence to capecitabine chemotherapy was measured using an electronic medication event monitoring system ( MEMS ™ ) . Results Patients in the intervention group exhibited an enhanced but not significantly different mean overall adherence compared to the control group ( 97.9 % vs 90.5 % , p = 0.069 ) . Mean daily adherence was significantly higher in the intervention group ( 96.8 % vs 87.2 % , p = 0.029 ) . Variability of both adherence parameters was considerably reduced when pharmaceutical care was provided . At the end of the observation period of 126 days , the probability of still being treated with capecitabine was found to be 48 % in the control group and 83 % in the intervention group ( p = 0.019 , log-rank test ) . The relative risk for a deviating drug intake interval , i.e. < 10 or > 14 instead of 12 h , in the intervention group was found to be 0.51 ( 95 % CI , 0.46–0.56 ) compared with the control group ( p < 0.05 , Chi-square test ) . Conclusions The provision of intensified pharmaceutical care can enhance adherence to and prolong treatment with capecitabine . The results underline the importance of multidisciplinary care to assure the effectiveness of oral chemotherapy BACKGROUND The cause of chronic myeloid leukemia ( CML ) is a constitutively active BCR-ABL tyrosine kinase . Imatinib inhibits this kinase , and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase . For 5 years , we followed patients with CML who received imatinib as initial therapy . METHODS We r and omly assigned 553 patients to receive imatinib and 553 to receive interferon alfa plus cytarabine and then evaluated them for overall and event-free survival ; progression to accelerated-phase CML or blast crisis ; hematologic , cytogenetic , and molecular responses ; and adverse events . RESULTS The median follow-up was 60 months . Kaplan-Meier estimates of cumulative best rates of complete cytogenetic response among patients receiving imatinib were 69 % by 12 months and 87 % by 60 months . An estimated 7 % of patients progressed to accelerated-phase CML or blast crisis , and the estimated overall survival of patients who received imatinib as initial therapy was 89 % at 60 months . Patients who had a complete cytogenetic response or in whom levels of BCR-ABL transcripts had fallen by at least 3 log had a significantly lower risk of disease progression than did patients without a complete cytogenetic response ( P<0.001 ) . Grade 3 or 4 adverse events diminished over time , and there was no clinical ly significant change in the profile of adverse events . CONCLUSIONS After 5 years of follow-up , continuous treatment of chronic-phase CML with imatinib as initial therapy was found to induce durable responses in a high proportion of patients . ( Clinical Trials.gov number , NCT00006343 [ Clinical Trials.gov ] . Abstract . Background : The aim of this study was to explore the characteristics and efficacy of psychoeducational family intervention for persons with schizophrenia in rural China . Methods : A cluster r and omised controlled trial of psychoeducational family intervention for families experiencing schizophrenia ( three groups , 326 cases ) was conducted in Xinjin County , Chengdu . Treatment groups consisted of family intervention and medication , medication alone , and a control . Results : The results showed a gain in knowledge , a change in the relatives ' caring attitudes towards the patients , and an increase in treatment compliance in the psychoeducational family intervention group ( p < 0.05 , 0.001 ) . Most importantly , the relapse rate over 9 months in this group ( 16.3 % ) was half that of the drug-only group ( 37.8 % ) , and just over one-quarter of that of the control group ( 61.5 % ) ( p < 0.05 ) . Antipsychotic drug treatment and families ' attitudes towards patients after the 9-month follow-up were significantly associated with clinical outcome ( p < 0.05 ) . Conclusions : In rural China , family intervention should focus on improving the relatives ' recognition of illness , the caring attitude towards the patients , treatment compliance , relapse prevention , and the training of the patients ' social functioning . This trial , one of the largest in the literature , has shown that psychoeducational family intervention is effective and suitable for psychiatric rehabilitation in Chinese rural communities

AND RELEVANCE In critically ill patients requiring acute volume resuscitation , use of hydroxyethyl starch compared with other resuscitation solutions was not associated with a decrease in mortality . Moreover , after exclusion of 7 trials performed by an investigator whose research has been retracted because of scientific misconduct , hydroxyethyl starch was associated with a significant increased risk of mortality and acute kidney injury .

IMPORTANCE Hydroxyethyl starch is commonly used for volume resuscitation yet has been associated with serious adverse events , including acute kidney injury and death . Clinical trials of hydroxyethyl starch are conflicting . Moreover , multiple trials from one investigator have been retracted because of scientific misconduct . OBJECTIVES To evaluate the association of hydroxyethyl starch use with mortality and acute kidney injury .

Introduction Inadequate initial treatment and delayed hemodynamic stabilization ( HDS ) may be associated with increased risk of death in severe sepsis patients . Methods In order to compare the hemodynamic efficacy and safety of 6 % HES 130/0.4 and NaCl 0.9 % for HDS in patients with severe sepsis , we design ed a prospect i ve , multicenter , active-controlled , double-blind , r and omized study in intensive care units . Results 174 out of 196 patients reached HDS ( 88 and 86 patients for HES and NaCl , respectively ) . Significantly less HES was used to reach HDS vs. NaCl ( 1,379 ±886 ml in the HES group and 1,709 ±1,164 ml in the NaCl group ( mean difference = -331± 1,033 , 95 % CI -640 to -21 , P = 0.0185 ) . Time to reach HDS was 11.8 10.1 hours vs. 14.3 ±11.1 hours for HES and NaCl , respectively . Total quantity of study drug infused over four consecutive days , ICU and hospital LOS , and area under the curve of SOFA score were comparable . Acute renal failure occurred in 24 ( 24.5 % ) and 19 ( 20 % ) patients for HES and NaCl , respectively ( P = 0.454 ) . There was no difference between AKIN and RIFLE criteria among groups and no difference in mortality , coagulation , or pruritus up to 90 days after treatment initiation . Conclusion Significantly less volume was required to achieve HDS for HES vs. NaCl in the initial phase of fluid resuscitation in severe sepsis patients without any difference for adverse events in both groups . Clinical Trials.gov Objective Both albumin and synthetic colloids such as hydroxyethyl starch ( HES ) solution are used to optimize hemodynamics in the critically ill . The influence of different long-term infusion regimes on platelet function was studied . Design Prospect i ve , r and omized study . Setting Clinical investigation on a university hospital surgical intensive care unit . Patients Twenty-eight consecutive trauma patients ( injury severity score>15 points ) and 28 consecutive nontraumatized surgical patients with sepsis . Interventions The patients received either 20 % human albumin ( HA trauma , n=14 ; HA sepsis , n=14 ) or 10 % low-molecular-weight HES solution HES 200/0.5 ( HES trauma , n=14 ; HES sepsis;n=14 ) for 5 days to maintain central venous pressure and /or pulmonary capillary wedge pressure between 12 and 16 mmHg . Measurements and results Platelet function was assessed by aggregometry ( = turbidimetric technique ) using adenosine diphosphate 2.0 μmol/l , collagen 4 μl/ml , and epinephrine 25 μmol/l as inductors . Arterial blood was sample d on the day of admission or the day of diagnosis of sepsis ( = baseline value ) and over the next 5 days . St and ard coagulation parameters ( antithrombin III , fibrinogen , partial thromboplastin time ) were also measured . Total use of HES by the 5th day totalled 4870±990 ml in the trauma and 3260±790 ml in the sepsis patients ( HA trauma : 1850±380 ml ; HA sepsis : 1790±400 ml ) . Maximum platelet aggregation decreased significantly during the first 2–3 days after baseline in all groups . At the end of the investigation period , platelet aggregation variables had recovered and reached ( or even exceeded ) baseline values . Within the entire investigation period , the course of platelet aggregation variables did not differ significantly between HA and HES-treated patients irrespective of whether they were trauma or sepsis patients . Conclusions Alterations in hemostasis may occur for several reasons in the critically ill . Human albumin is the preferred first-line volume therapy in patients at risk for coagulation disorders . With respect to platelet function , volume replacement with ( lower-priced ) low-molecular-weight HES solutions can be recommended in this situation without any risk PURPOSE The aim of this study was to show that 6 % hydroxyethyl starch ( HES ) 130/0.4 achieves a better resuscitation of the microcirculation than normal saline solution ( SS ) , during early goal -directed therapy ( EGDT ) in septic patients . MATERIAL S AND METHODS Patients with severe sepsis were r and omized for EGDT with 6 % HES 130/0.4 ( n = 9 ) or SS ( n = 11 ) . Sublingual microcirculation was evaluated by sidestream dark field imaging 24 hours after the beginning of EGDT . RESULTS On admission , there were no differences in Sequential Organ Failure Assessment score , mean arterial pressure , lactate , or central venous oxygen saturation . After 24 hours , no difference arose in those parameters . Sublingual capillary density was similar in both groups ( 21 ± 8 versus 20 ± 3 vessels/mm(2 ) ) ; but capillary microvascular flow index , percent of perfused capillaries , and perfused capillary density were higher in 6 % HES 130/0.4 ( 2.5 ± 0.5 versus 1.6 ± 0.7 , 84 ± 15 versus 53 ± 26 % , and 19 ± 6 versus 11 ± 5 vessels/mm(2 ) , respectively , P < .005 ) . CONCLUSIONS Fluid resuscitation with 6 % HES 130/0.4 may have advantages over SS to improve sublingual microcirculation . A greater number of patients would be necessary to confirm these findings BACKGROUND The safety and efficacy of hydroxyethyl starch ( HES ) for fluid resuscitation have not been fully evaluated , and adverse effects of HES on survival and renal function have been reported . METHODS We r and omly assigned 7000 patients who had been admitted to an intensive care unit ( ICU ) in a 1:1 ratio to receive either 6 % HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 ( 130/0.4 , Voluven ) in 0.9 % sodium chloride or 0.9 % sodium chloride ( saline ) for all fluid resuscitation until ICU discharge , death , or 90 days after r and omization . The primary outcome was death within 90 days . Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy . RESULTS A total of 597 of 3315 patients ( 18.0 % ) in the HES group and 566 of 3336 ( 17.0 % ) in the saline group died ( relative risk in the HES group , 1.06 ; 95 % confidence interval [ CI ] , 0.96 to 1.18 ; P=0.26 ) . There was no significant difference in mortality in six predefined subgroups . Renal-replacement therapy was used in 235 of 3352 patients ( 7.0 % ) in the HES group and 196 of 3375 ( 5.8 % ) in the saline group ( relative risk , 1.21 ; 95 % CI , 1.00 to 1.45 ; P=0.04 ) . In the HES and saline groups , renal injury occurred in 34.6 % and 38.0 % of patients , respectively ( P=0.005 ) , and renal failure occurred in 10.4 % and 9.2 % of patients , respectively ( P=0.12 ) . HES was associated with significantly more adverse events ( 5.3 % vs. 2.8 % , P<0.001 ) . CONCLUSIONS In patients in the ICU , there was no significant difference in 90-day mortality between patients resuscitated with 6 % HES ( 130/0.4 ) or saline . However , more patients who received resuscitation with HES were treated with renal-replacement therapy . ( Funded by the National Health and Medical Research Council of Australia and others ; CHEST Clinical Trials.gov number , NCT00935168 . ) Background : It is unknown whether fluid resuscitation with colloid or crystalloid in patients with severe sepsis or septic shock is associated with an improvement in clinical outcome . This r and omized controlled trial determined the feasibility of conducting a large trial testing resuscitation with pentastarchvs normal saline in early septic shock , powered for a difference in mortality . Methods : At three Canadian and one New Zeal and academic centre , 40 patients with early septic shock defined by at least two systemic inflammatory response syndrome criteria , infectious source , and persistent hypotension after ≥ 1 L of crystalloid fluid were recruited . Feasibility measures were patient recruitment , blinding of the study fluids , and acceptability of the goal directed algorithms . Boluses of blinded normal saline or pentastarch ( 500 mL − maximum 3 L or 28 mL·kg−1 ) were administered within goal directed care for the first 12 hr . Results : Of 161 patients screened , 121 were excluded and 40 patients were enrolled , for a recruitment rate of 0.75 patients / site/month . Only 57 % of physicians and 54 % of nurses correctly guessed the study fluid ( P = 0.46 and P = 0.67 , respectively ) . The goal directed algorithms were acceptable to 97 % of physicians . Conclusion : The ability to recruit patients in this pilot r and omized controlled trial was below expectations . Blinding of study fluids was adequate , and resuscitation algorithms were acceptable to most physicians . Methods to improve recruitment are required to enhance the feasibility of conducting a multicentre fluid resuscitation trial in early septic shock . Résumé Context e : Nous ne savons pas si la réanimation liquidienne avec des colloïdes ou des cristalloïdes chez les patients présentant un sepsis grave ou un choc septique est associée à un devenir clinique meilleur . Cette étude r and omisée contrôlée a déterminé la faisabilité d’une étude d’envergure testant la réanimation avec le pentastarch par rapport au sérum physiologique en début de choc septique , avec pour objectif primaire de détecter une différence dans les taux de mortalité . Method e : Quarante patients en début de choc septique , défini comme au moins deux critères du syndrome de réaction inflammatoire , une source d’infection et une hypotension persistante après ≥ 1 L de cristalloïde ont été recrutés dans trois centres universitaires canadiens et un centre néo-zél and ais . Les mesures de faisabilite étaient : le recrutement des patients , le masquage des liquides à l’étude , et I’acceptabilité des algorithmes dirigés vers des objectifs . Des bolus de normal sal in ou de pentastarch ( 500 mL — maximum 3 L ou 28 mL·kg−1 ) ont été administrés en aveugle dans le cadre de soins guidés dirigés vers des objectifs durant les 12 premieres heures . Result ats : Sur 161 patients dépistés , 121 ont été exclus et 40 patients recrutés dans le cadre de I’étude , avec un taux de recrutement de 0,75 patient/site/mois . Seulement 57 % des médecins et 54 % des infirmières ont réussi à deviner correctement le type de liquide à I’étude ( P = 0,46 etP = 0,67 , respectivement ) . Les algorithmes ont été jugés acceptables par 97 % des médecins . Conclusion : La capacité à recruter des patients pour cette étude pilote r and omisée contrôlée était moins importante qu’attendue . Le masquage des liquides était satisfaisant , et les algorithmes de réanimation ont été jugés acceptables par la majorité des médecins . Des méthodes dans le but d’améliorer le recrutement sont nécessaire pour accroître la faisabilité d’une étude multicentrique sur la réanimation liquidienne en début de choc septique OBJECTIVE To evaluate the effect of 7.5 % hypertonic saline ( HS ) and 6 % hydroxyethyl starch ( HES ) 130/0.4 on early fluid resuscitation for severe sepsis . METHODS Prospect i ve r and omized control trial was carried out in intensive care unit ( ICU ) of the Affiliated Hospital of Jianghan University . One hundred and thirty five patients with severe sepsis were r and omly divided into three groups , each group consisted of 45 patients . Patients in HS+HES group received lactated Ringer solution following 4 ml/kg of 7.5 % HS and 6 % HES 130/0.4 500 ml , those in HES group received lactated Ringer solution following 6 % HES 130/0.4 500 ml , and those in the lactated Ringer group ( RL group ) received lactated Ringer solution only . Mean arterial pressure ( MAP ) , oxygenation index (PaO₂/FiO₂),arterial lactate (Lac),lactate clearance rate , acute physiology and chronic health evaluation II(APACHEII ) score , fluid infusion volume , urine output as well as incidence of multiple organ dysfunction syndrome ( MODS ) , and mortality were compared among three groups at 6 hours and 24 hours after ICU admission . RESULTS At 6 hours after ICU admission , MAP[mm Hg ( 1 mm Hg=0.133 kPa ) : 68.7 ± 3.0 ] , PaO₂/FiO₂(mm Hg : 262.2 ± 17.4 ) , lactate clearance rate [ ( 21 ± 4)% ] in HS+HES group were significantly higher than those in HES group [ MAP : 63.8 ± 3.5,PaO(2)/FiO(2 ) : 252.0 ± 21.2 , lactate clearance rate : ( 11 ± 2)% ] and RL group [ MAP : 62.6 ± 3.6 , PaO₂/FiO₂:248.4 ± 17.0,lactate clearance rate : ( 9 ± 1)% , all P < 0.01 ] . Arterial Lac in HS+HES group ( mmol/L : 3.5 ± 0.7 ) was significantly lower than that in HES group ( 4.1 ± 0.7 ) and RL group ( 4.0 ± 0.7 , both P < 0.01 ) . There was no significant difference in APACHE II score between HS+HES group ( 13.2 ± 1.9 ) and HES group ( 14.0 ± 1.6 ) , and the APACHEII score in HS+HES group was significantly lower than that in RL group ( 15.2 ± 1.7 , P < 0.01 ) . At 24 hours after ICU admission , PaO₂/FiO₂ ( mm Hg : 303.3 ± 17.3 ) was significantly higher in HS+HES group than that in HES group ( 282.9 ± 21.1 ) and RL group ( 268.9 ± 15.2 , both P < 0.01 ) . There was no significant difference in MAP , arterial Lac , lactate clearance rate and APACHEII score among three groups . At 6 hours and 24 hours after ICU admission , fluid infusion volume in HS+HES group ( ml , 6 hours : 1 877.8 ± 215.2 , 24 hours : 5 475.6 ± 208.8 ) was markedly less than that in HES group ( 6 hours : 2 505.6 ± 276.2 , 24 hours : 6 383.3 ± 287.4 ) and RL group ( 6 hours : 3 496.7 ± 325.5,24 hours : 7 439.6 ± 229.6 ) , yet urine output in HS+HES group ( ml , 6 hours : 294.2 ± 36.9 , 24 hours : 2 793.8 ± 37.1 ) was significantly higher than that in HES group ( 6 hours : 248.9 ± 25.3 , 24 hours : 2 248.9 ± 25.3 ) and RL group ( 6 hours : 178.9 ± 14.8 , 24 hours : 2 000.4 ± 147.0 , all P < 0.01 ) . The incidence of MODS in HS+HES group ( 6.7 % ) was statistically lower than that in RL group ( 28.9 % , P < 0.05 ) , while no obvious difference was found between HS+HES group and HES group ( 17.8 % , P > 0.05 ) . There was no significant difference in mortality among three groups ( HS+HES group : 2.2 % , HES group : 4.4 % , RL group : 8.9 % , all P > 0.05 ) . CONCLUSION 7.5%HS and 6%HES 130/0.4 could improve the effect of early fluid resuscitation on severe sepsis , and it could lower the incidence of MODS BACKGROUND The role of intensive insulin therapy in patients with severe sepsis is uncertain . Fluid resuscitation improves survival among patients with septic shock , but evidence is lacking to support the choice of either crystalloids or colloids . METHODS In a multicenter , two-by-two factorial trial , we r and omly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10 % pentastarch , a low-molecular-weight hydroxyethyl starch ( HES 200/0.5 ) , or modified Ringer 's lactate for fluid resuscitation . The rate of death at 28 days and the mean score for organ failure were co primary end points . RESULTS The trial was stopped early for safety reasons . Among 537 patients who could be evaluated , the mean morning blood glucose level was lower in the intensive-therapy group ( 112 mg per deciliter [ 6.2 mmol per liter ] ) than in the conventional-therapy group ( 151 mg per deciliter [ 8.4 mmol per liter ] , P<0.001 ) . However , at 28 days , there was no significant difference between the two groups in the rate of death or the mean score for organ failure . The rate of severe hypoglycemia ( glucose level , < or = 40 mg per deciliter [ 2.2 mmol per liter ] ) was higher in the intensive-therapy group than in the conventional-therapy group ( 17.0 % vs. 4.1 % , P<0.001 ) , as was the rate of serious adverse events ( 10.9 % vs. 5.2 % , P=0.01 ) . HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer 's lactate . CONCLUSIONS The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia . As used in this study , HES was harmful , and its toxicity increased with accumulating doses . ( Clinical Trials.gov number , NCT00135473 . OBJECTIVE To investigate the influence of lactate Ringer solution ( RL ) versus hydroxyethyl starch 130/0.4 ( HES130/0.4 ) solution on coagulation and fibrinolytic system in the patients with septic shock . METHODS Forty-two consecutive patients with septic shock diagnosed between September 2009 and June 2011 were r and omized to two study groups : RL resuscitation group ( RL group ) with 20 patients , and HES130/0.4 resuscitation group ( HES group ) with 22 patients . In all of them peripheral blood was collected at four points of time : before resuscitation , 6 , 12 , 24 hours after resuscitation , and then prothrombin time ( PT ) , activated partial thromboplastin time ( APTT ) and levels of plasma tissue plasminogen activator ( t-PA ) , and plasminogen activator inhibitor ( PAI ) were determined . Meanwhile , the patients ' outcome and the length of intensive care unit stay ( ICU-LOS ) were recorded . RESULTS ICU-LOS ( days ) in HES group was significantly shorter than the RL group ( 12.5 ± 8.8 vs. 17.1 ± 16.6 , P < 0.01 ) . Meanwhile , the volume of fluid ( L : 2.77 ± 0.59 ) as well as vasoactive drugs [ μg × kg(-1) × min(-1 ) : 0.56 ± 0.15 ] used in the HES group were significantly lower than RL group ( 3.46 ± 0.73 , 0.81 ± 0.41 , both P < 0.01 ) . In RL group , 12 patients died and 8 patients survived , while in HES group , 7 patients died and 15 patients survived , showing no difference between two groups . PT , APTT and the levels of t-PA showed no significant differences between two groups at different time points , but the levels of plasma PAI ( μg/L ) of the HES group decreased gradually , and was significantly lower than that before resuscitation and RL group at 24 hours after resuscitation ( 41.76 ± 25.95 vs. 89.11 ± 14.27 , 55.08 ± 35.43 , both P < 0.05 ) . CONCLUSIONS Both RL and HES130/0.4 fluid resuscitation did not affect the outcome of the patients with septic shock , but the resuscitation efficiency of HES130/0.4 is much better than RL . Both type of fluids did not show the effect on coagulability of the septic patients , but colloid fluid resuscitation may protect the vascular endothelial cell , reduce the inhibition of fibrinolytic system , and alleviate hypercoagulability state of patients in early stage Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background and objective To examine the kinetics of volume loading with crystalloid and colloid infusions in critically ill patients after major surgery , using the pulse contour cardiac output ( PiCCO ) monitoring technique . Methods This prospect i ve , r and omized , multicentre study of 11 ICUs involved 200 mixed postoperative hypovolaemic patients ( 50 patients per group ) in Hungary . Patients received 10 ml kg−1 of lactated Ringer 's solution , succinylated gelatin 4 % w/v , 130/0.4 hydroxyethyl starch 6 % w/v ( HES ) or human albumin 5 % w/v over 30 min . A complete haemodynamic profile was obtained at 30 , 45 , 60 , 90 and 120 min after baseline . The peak haemodynamic effects , the 120 min changes compared with baseline , the area under the curve ( AUC ) for the haemodynamic parameters over 120 min and the haemodilution effect of the solutions were analysed . The primary outcome was to compare the AUCs and the secondary outcome was to evaluate the haemodynamic changes at 120 min . Results There were significant differences in the AUCs of the haemodynamic parameters between colloids and lactated Ringer 's solution in the cardiac index and global end-diastolic volume index ( GEDVI ) ; human albumin vs. lactated Ringer 's solution in stroke volume variation ( SVV ) ; and succinylated gelatin , HES vs. lactated Ringer 's solution in the oxygen delivery index ( DO2I ) . Colloid infusions ( mainly HES and human albumin ) at 120 min caused significant changes in central venous pressure , cardiac index , GEDVI , SVV , DO2I and central venous oxygen saturation compared with baseline . The haemodilution effect was significantly greater in colloids vs. lactated Ringer 's solution . Conclusion In postoperative hypovolaemic patients , lactated Ringer 's solution can significantly improve haemodynamics at the end of volume loading , but this effect completely disappears at 120 min . Ten millilitres per kilogram of colloid bolus ( especially HES ) improved the haemodynamics at 120 min ; however , this was by only 5–25 % compared with baseline . The colloids caused significantly larger AUCs than lactated Ringer 's solution , but only in the cardiac index , GEDVI and DO2I , plus human albumin in the SVV BACKGROUND / AIMS Recent studies demonstrated that extravascular lung water ( EVLW ) is a reliable and independent marker for outcome . The primary therapeutically goal in critically ill patients is to resuscitate and retain adequate organ perfusion by fluid administration , where is necessary to achieve adequate intravascular filling , but avoid initiation of pulmonary edema . METHODOLOGY Patients with severe sepsis were r and omly allocated to a group treated with 20 % Albumin 100 ml every 12 hours ( ALB ; n = 30 ) or with 6 % hydroxyethylstarch 130/0 , 4 250 ml every 6 hours ( HES ; n = 26 ) . Both treatments were completed by crystalloids or norephinephrin as necessary . We analyzed amount of developed EVLW , and relation with mortality , PaO2/FiO2 and alveolo-arterial oxygen difference . RESULTS We observed significantly greater decrease of EVLW when compared with baseline during whole monitored period of 72 hours in ALB group in contrast to HES patients ( p < 0.05 ) . Despite no significant changes of EVLW in HES group , we noted improve of PaO2/FiO2 and AaDO2 in both groups . We did not observed significant difference in mortality . CONCLUSION The present study results show can summarize that albumin reduces in a higher amount and earlier the extravascular lung water than HES , but this reduction was not associated with improvement of oxygenation functions , which was better in HES group Background Fluids are often given liberally after the return of spontaneous circulation . However , the optimal fluid regimen in survivors of cardiac arrest is unknown . Recent studies indicate an increased fluid requirement in post-cardiac arrest patients . During hypothermia , animal studies report extravasation in several organs , including the brain . We investigated two fluid strategies to determine whether the choice of fluid would influence fluid requirements , capillary leakage and oedema formation . Methods 19 survivors with witnessed cardiac arrest of primary cardiac origin were allocated to either 7.2 % hypertonic saline with 6 % poly ( O-2-hydroxyethyl ) starch solution ( HH ) or st and ard fluid therapy ( Ringer 's Acetate and saline 9 mg/ml ) ( control ) . The patients were treated with the r and omised fluid immediately after admission and continued for 24 hours of therapeutic hypothermia . Results During the first 24 hours , the HH patients required significantly less i.v . fluid than the control patients ( 4750 ml versus 8010 ml , p = 0.019 ) with comparable use of vasopressors . Systemic vascular resistance was significantly reduced from 0 to 24 hours ( p = 0.014 ) , with no difference between the groups . Colloid osmotic pressure ( COP ) in serum and interstitial fluid ( p < 0.001 and p = 0.014 respectively ) decreased as a function of time in both groups , with a more pronounced reduction in interstitial COP in the crystalloid group . Magnetic resonance imaging of the brain did not reveal vasogenic oedema . Conclusions Post-cardiac arrest patients have high fluid requirements during therapeutic hypothermia , probably due to increased extravasation . The use of HH reduced the fluid requirement significantly . However , the lack of brain oedema in both groups suggests no superior fluid regimen . Cardiac index was significantly improved in the group treated with crystalloids . Although we do not associate HH with the renal failures that developed , caution should be taken when using hypertonic starch solutions in these patients .Trial registration NCT00347477 Various vasoactive substances are involved in the regulation of the macro- and microcirculation . We have investigated if these regulators change during long-term volume therapy with human albumin ( HA ) or hydroxyethylstarch solution ( HES ) in trauma and sepsis patients . To maintain pulmonary capillary wedge pressure ( PCWP ) at 10 - 15 mm Hg , either 20 % HA ( HA-trauma , n = 14 ; HA-sepsis , n = 14 ) or 10 % low-molecular weight HES solution ( HES-trauma , n = 14 ; HES-sepsis , n = 14 ) were infused for 5 days , otherwise patient management did not differ between the two groups ( trauma/sepsis ) . Mean arterial pressure ( MAP ) , heart rate ( HR ) , PCWP and cardiac index ( CI ) were monitored in all patients . Liver function was assessed using the monoethylglycinexylidide ( MEGX ) test , and gastric intramucosal pH ( pHi ) was monitored by tonometry to assess splanchnic perfusion . Plasma concentrations of vasopressin , endothelin-1 , adrenaline , noradrenaline , atrial natriuretic peptide and 6-keto-prostagl and in F1 alpha were measured from arterial blood sample s. All measurements were carried out on the day of admission to the intensive care unit ( trauma patients ) or on diagnosis of sepsis , and daily over the next 5 days at 12:00 . MAP , HR and PCWP did not differ between the corresponding subgroups ( trauma/sepsis ) . Cl increased significantly more in the HES than in the HA groups . pHi and MEGX plasma concentrations did not differ in the trauma patients throughout the study . Both were lower than normal in the sepsis groups and increased more markedly in the HES than in the albumin-treated patients ( P < 0.05 ) . In the trauma patients , concentrations of all vasoactive regulators were very similar in both groups . In both sepsis groups , vasopressors ( vasopressin , endothelin-1 , noradrenaline and adrenaline ) were significantly increased above normal at baseline and decreased more markedly in HES than in HA patients . Concentrations of atrial natriuretic peptide increased only in the HA patients ( from 159 ( SD 31 ) to 215 ( 38 ) pg ml-1 on day 2 ) . Plasma concentrations of 6-keto-prostagl and in F1 alpha decreased significantly only in the HES sepsis patients ( from 112 ( 25 ) to 47 ( 15 ) pg ml-1 ) BACKGROUND The role of fluids in trauma resuscitation is controversial . We compared resuscitation with 0.9 % saline vs hydroxyethyl starch , HES 130/0.4 , in severe trauma with respect to resuscitation , fluid volume , gastrointestinal recovery , renal function , and blood product requirements . METHODS R and omized , controlled , double-blind study of severely injured patients requiring > 3 litres of fluid resuscitation . Blunt and penetrating trauma were r and omized separately . Patients were followed up for 30 days . RESULTS A total of 115 patients were r and omized ; of which , 109 were studied . For patients with penetrating trauma ( n=67 ) , the mean ( sd ) fluid requirements were 5.1 ( 2.7 ) litres in the HES group and 7.4 ( 4.3 ) litres in the saline group ( P<0.001 ) . In blunt trauma ( n=42 ) , there was no difference in study fluid requirements , but the HES group required significantly more blood products [ packed red blood cell volumes 2943 ( 1628 ) vs 1473 ( 1071 ) ml , P=0.005 ] and was more severely injured than the saline group ( median injury severity score 29.5 vs 18 ; P=0.01 ) . Haemodynamic data were similar , but , in the penetrating group , plasma lactate concentrations were lower over the first 4 h ( P=0.029 ) and on day 1 with HES than with saline [ 2.1 ( 1.4 ) vs 3.2 ( 2.2 ) mmol litre⁻¹ ; P=0.017 ] . There was no difference between any groups in time to recovery of bowel function or mortality . In penetrating trauma , renal injury occurred more frequently in the saline group than the HES group ( 16 % vs 0 % ; P=0.018 ) . In penetrating trauma , maximum sequential organ function scores were lower with HES than with saline ( median 2.4 vs 4.5 , P=0.012 ) . No differences were seen in safety measures in the blunt trauma patients . CONCLUSIONS In penetrating trauma , HES provided significantly better lactate clearance and less renal injury than saline . No firm conclusions could be drawn for blunt trauma . STUDY REGISTRATION IS RCT N 42061860 Abstract Objective : To investigate the effect of 4 % succinylated modified fluid gelatin ( MFG ) versus mean weight , highly substituted 6 % hydroxyethyl starch ( HES ) on hemodynamic and gastric mucosal acidosis variables , in septic hypovolemic patients . Design : Prospect i ve , r and omized , clinical investigation . Setting : University hospital intensive care unit . Patients : Thirty-four septic hypovolemic ventilated and hemodynamically controlled patients . Interventions : Invasive hemodynamic and gastric tonometric measurements . Measurements and results : Hemodynamic and tonometric parameters were recorded at baseline and 60 min after infusion of 500 ml of each colloid . In all patients central venous pressure , pulmonary artery occlusion pressure , cardiac index and mean arterial pressure increased significantly with both colloids , and hemoglobin concentration decreased by the same amount while oxygen delivery remained stable . Gastric intramucosal pH increased from 7.27±0.08 to 7.31±0.07 ( p<0.001 ) with MFG and decreased non-significantly from 7.26±0.11 to 7.22±0.08 ( ns ) with HES . Carbon dioxide gastric mucosal arterial gradient decreased from 18±9 to 13±9 mmHg ( p<0.0005 ) in the MFG group and rose non-significantly from 18±11 to 21±11 mmHg with HES . Conclusions : Although MFG and 6 % HES have the same hemodynamic effects , their physicochemical properties induce different responses on gastric mucosal acidosis in septic , hypovolemic and ventilated patients . These effects of MFG and HES on gastric mucosa need to be considered in patient management Summary Objective To determine whether intravenous infusion of either human albumin or hydroxyethylstarch ( HES ) in hypo-albuminemic critically ill may lead to an increase in colloid osmotic pressure and to a better clinical outcome , i.e. lower mortality and fewer complications , compared to fluid replacement with normal saline Design Prospect i ve , r and omized controlled clinical trial during 72 hours in 61 consecutively admitted severely ill patients . R and omisation took place by sealed envelope , kept outside of the hospital . Setting Intensive care unit of the Twenteborg Hospital , Almelo , The Netherl and s . SubjectsSixty-three severely ill , hypo-albuminemic patients were selected ; 27 patients had severe sepsis and 36 were post-surgical patients with SIRS . Two patients died shortly after r and omization , 15 patients received human albumin , 15 HES 500 and 15 HES 1000 ml , and 16 saline . Interventions The patients were r and omized to receive 300 ml human albumin ( 20 % ) per day , or 1000 ml normal saline per day , or 500 ml or 1000 ml HES per day , all for 72 hours . Main outcome measures The primary outcome was plasma colloid osmotic pressure ( COP ) . Secondary end-points were fluid balance and the development of pulmonary edema . Results Administration of human albumin was effective in raising COP ( P<0.001 on day 2 and day 3 , compared to saline and HES ) . Neither fluid balances nor the development of peripheral or pulmonary edema were different between the groups . Mortality as well as length of stay at ICU were slightly higher in the group receiving human albumin although not statistically significant . Conclusion Raising colloid osmotic pressure with human albumin in hypoalbuminemic patients is not associated with improvement of the clinical BACKGROUND Hypovolemia is a common clinical entity in critical patients , and adequate volume replacement therapy seems to be essential for maintaining tissue perfusion . However , it is still uncertain which solution is most appropriate for fluid resuscitation . OBJECTIVE The aim of this study was to investigate the effects of fluid resuscitation with 3.5 % polygeline versus 6 % hydroxyethyl starch solutions on hemodynamic functions and liver functions assessed with a noninvasive liver function monitoring system ( LIMON ) in hypovolemic patients . DESIGN This study is a prospect i ve r and omized clinical trial . MEASUREMENTS AND RESULTS Thirty hypovolemic patients ( intrathoracic blood volume index , < 850 mL/m(2 ) ) were r and omized into hydroxyethyl starch ( mean molecular weight , 130,000 Da ) and polygeline ( mean molecular weight , 30,000 Da ) groups ( 15 patients each ) . Indocyanine green plasma disappearance elimination ( ICG-PDR ) were conducted concurrently using LIMON . A dose of 0.3 mg/kg ICG was given through a cubital fossa vein as a bolus . For fluid resuscitation , 500 mL of colloid was given to the patients . Repeated hemodynamic and ICG-PDR measurements were done at baseline , after infusion , and then at 30 minutes after infusion . RESULTS Intrathoracic blood volume index and systolic , diastolic , and mean blood pressures increased significantly after infusion and remained elevated for 30 minutes after infusion , but there was no significant difference between the 2 groups . Indocyanine green plasma disappearance elimination values were similar in both groups with no significant difference between the two . CONCLUSION Increasing intrathoracic blood volume index and hemodynamic variables by fluid loading is not associated with a significant change in ICG-PDR BACKGROUND Hydroxyethylstarch used as a plasma-volume exp and er in brain-dead kidney donors has been suggested to induce osmotic-nephrosis-like lesions . We have studied its effect on kidney-transplant function . METHODS 52 patients who had received hydroxyethylstarch of iodinated contrast-media before brain death were excluded . 69 other brain-dead patients were prospect ively included over 18 months and r and omised into two groups . In the hydroxyethylstarch-gelatin group , patients received hydroxyethylstarch up to 33 mL/kg for colloid plasma-volume expansion , and afterwards received modified fluid gelatin . In the gelatin-only group , patients received only modified fluid gelatin as colloid plasma-volume exp and er . Multiple organs were procured in 29 cases , which included the kidneys in 27 cases ( hydroxyethylstarch-gelatin 15 , gelatin-only 12 ) . FINDINGS There were no significant differences in the characteristics of patients between the two groups of kidney donors or of recipients ( except for a small imbalance in sex in the recipients ) . During the first 8 days after transplantation , nine of 27 ( 33 % ) patients required extrarenal haemodialysis or haemodiafiltration in the hydroxyethylstarch-gelatin group compared with one of 20 ( 5 % ) in the gelatin-only group ( p = 0.029 ) . Serum creatinine concentrations were significantly lower in the gelatin-only group than in the other group ( p = 0.009 ) . 10 days after transplantation , mean ( SD ) serum creatinine was , respectively , 145 ( 70 ) and 312 ( 259 ) mumol/L. INTERPRETATION These data suggest that hydroxyethylstarch used as a plasma-volume exp and er in brain-dead donors impairs immediate renal function in kidney-transplant recipients BACKGROUND Hydroxyethylstarch used for volume restoration in brain-dead kidney donors has been associated with impaired kidney function in the transplant recipients . We undertook a multicentre r and omised study to assess the frequency of acute renal failure ( ARF ) in patients with severe sepsis or septic shock treated with hydroxyethylstarch or gelatin . METHODS Adults with severe sepsis or septic shock were enrolled prospect ively in three intensive-care units in France . They were r and omly assigned 6 % hydroxyethylstarch ( 200 kDa , 0.60 - 0.66 substitution ) or 3 % fluid-modified gelatin . The primary endpoint was ARF ( a two-fold increase in serum creatinine from baseline or need for renal replacement therapy ) . Analyses were by intention to treat . FINDINGS 129 patients were enrolled over 18 months . Severity of illness and serum creatinine ( median 143 [ IQR 88 - 203 ] vs 114 [ 91 - 175 ] micromol/L ) were similar at baseline in the hydroxyethylstarch and gelatin groups . The frequencies of ARF ( 27/65 [ 42 % ] vs 15/64 [ 23 % ] , p=0.028 ) and oliguria ( 35/62 [ 56 % ] vs 23/63 [ 37 % ] , p=0.025 ) and the peak serum creatinine concentration ( 225 [ 130 - 339 ] vs 169 [ 106 - 273 ] micromol/L , p=0.04 ) were significantly higher in the hydroxyethylstarch group than in the gelatin group . In a multivariate analysis , risk factors for acute renal failure included mechanical ventilation ( odds ratio 4.02 [ 95 % CI 1.37 - 11.8 ] , p=0.013 ) and use of hydroxyethylstarch ( 2.57 [ 1.13 - 5.83 ] , p=0.026 ) . INTERPRETATIONS The use of this preparation of hydroxyethylstarch as a plasma-volume exp and er is an independent risk factor for ARF in patients with severe sepsis or septic shock Brain‐dead organ donors are often dehydrated and have serum electrolyte disorders . This study was design ed to analyse the haemodynamic condition and serum electrolyte balance of liver donors . Two different fluid management plans for the harvesting operation were studied . Sixteen consecutive organ donors were included . They were r and omly infused either with a combination of colloid ( hydroxy ethyl starch ) and electrolyte solution ( group COL ) or with crystalloid fluid alone ( group CR ) . Arterial pressures , heart rate , central venous pressure and oesophageal temperature were monitored and serum electrolytes were analysed before the beginning of the operation and during harvesting . The amount of fluid needed in the COL group was signific and y less ( P<0.01 ) than in the CR group . There were no statistical differences between the groups in the haemodynamic parameters during the study period . The oesophageal temperature was maintained in both groups . All donors were initially hypernatraemic , but the serum sodium values returned towards normal during surgery in both groups . Immediate function was seen in all livers . In conclusion , the haemodynamic stability is maintained with a smaller infused volume if hydroxyethyl starch is combined with crystalloid fluids . The formation of interstitial oedema will be less when colloids are used , but its significance in organ donation needs further evaluation OBJECTIVE To evaluate the effectiveness and safety of hydroxyethyl starch ( HES 130/ 0.4 , 60 g/L ) in resuscitation during shock stage of burns . METHODS Sixty-six burn patients who were admitted to hospital within 2 hours after burn injury requiring fluid resuscitation were enrolled into this study , and they were r and omized into HES ( n = 33 , with HES as a component of fluid resuscitation ) and plasma ( P , n = 33 , with plasma as a component of fluid resuscitation ) groups . HES or plasma was given as colloid within 48 postburn hours ( PBH ) , and only albumin [ ( 111 + /- 4 ) , ( 105 + /- 5 ) g for each group ] were given to the patients during 3 to 7 postburn days ( PBD ) . Heart rate , blood pressure , central venous pressure ( CVP ) , urine output per hour were measured , gain/loss of body fluid during the first and second 24 PBH were recorded , serum total protein , albumin , hemoglobin ( Hb ) , prothrombin time ( PT ) , fibrinogen ; platelet ( PLT ) , as well as liver and renal function , allergy and bleeding tendency were determined and observed at corresponding time-points . RESULTS There were no obvious differences in heart rate , blood pressure , CVP and urine output per hour within 24 PBH between the two groups ( P > 0.05 ) . Also there was no difference in gain/loss of body fluid during the first and second 24 PBH . The content of hemoglobin on 1 , 3 , 7,14 PBD , and the PT , the content of fibrinogen , the number of PLT on 1,3,14 PBD also exhibited no difference between the two groups ( P > 0.05 ) . The serum contents of total protein and albumin in HES group were [ ( 31 + /- 3 ) g/L , ( 30 + /- 3)g/L ] on 1 PBD , and [ ( 20.4 + /- 3.6 ) g/L , ( 18.4 + /-2.3 ) g/L ] on 3 PBD , which were obviously lower than those in P group [ ( 45 + /- 4 ) g/L , ( 39 + /- 3 ) g/L on 1 PBD , and 1 ( 24.5 + /- 4.3 ) g/L , ( 21.3 + /- 3.9 ) g/L ) on 3 PBD , ( P < 0 . 01 ) . Though the serum content of albumin on 7 PBD was similar in the two groups ( P > 0.05 ) , the serum total protein in HES group ( 40 + /- 4 ) g/L was markedly lower than that in P group [ ( 45 + /- 4 ) g/L , P < 0.01 ] . Within 7 PBD , no abnormal bleeding was found in the two groups , and the liver function and renal function were similar . There were 4 cases showing allergic reaction in plasma group while none in HES group . CONCLUSION New type of HES can partially substitute plasma and be used in fluid resuscitation for burn patients . However , plasma protein replenishment should still be emphasized Sufficient intravascular fluid therapy is of major importance in the treatment of the critically ill patient . The present study assessed whether the cardiorespiratory response of long-term volume replacement with low-molecular weight ( LMW ) hydroxyethyl starch solution ( HES ) differs from that of human albumin ( HA ) . According to a r and omized sequence , 30 trauma patients ( injury severity score [ ISS ] between 15 and 30 ) and 30 sepsis patients ( secondary to major general surgery ) received either 10 % HES ( mean molecular weight 200,000 daltons ; HES trauma [ n = 15 ] , HES sepsis [ n = 15 ] ) or human albumin 20 % ( HA trauma [ n = 15 ] , HA sepsis [ n = 15 ] ) over 5 days to keep pulmonary capillary wedge pressure ( PCWP ) between 12 and 18 mm Hg . Cardiorespiratory variables were measured by a pulmonary artery catheter on the day of inclusion into the study and daily during the next 5 days . Gastric intramucosal pH ( pHi ) was measured by tonometry . Central venous pressure and PCWP were comparable within the subgroups ( trauma/sepsis ) throughout the entire study period . In the trauma patients , cardiac index ( CI ) , oxygen consumption index ( VO2 I ) , and oxygen delivery index ( DO ( 2 ) I ) , significantly increased only in the HES-treated patients . In the sepsis patients , CI , VO2 I , and DO2 I increased and remained higher than baseline only in the HES group ( P < 0.01 ) . Right ventricular ejection fraction ( RVEF ) was reduced ( < 40 % ) in the HA patients and increased only in the HES patients ( from 34 % + /- 4 % to 42 % + /- 3 % ; P < 0.05 ) . pHi remained normal ( > 7.35 ) in both trauma groups and in the HES-treated sepsis patients . In the HA sepsis group , pHi decreased ( < 7.20 ) within the study period ( 7.15 + /- 0.12 on Day 4 ) , indicating deteriorated splanchnic perfusion . We conclude that long-term intravascular fluid therapy with HA in traumatized and sepsis patients has no advantages in comparison to LMW-HES . In both groups , volume replacement with HES even result ed in improved systemic hemodynamics . Decrease in pHi in the sepsis patients was blunted by HES infusion indicating improved splanchnic perfusion by this regimen of volume therapy . ( Anesth Analg 1996;83:254 - 61 Pentastarch is a colloid that is chemically similar to Hetastarch . It has a shorter half-life ( 12 hr ) , and produces volume expansion at least 1.5 times the administered volume . We compared Pentastarch to Ringer 's lactate in 41 patients ( 21 Pentastarch , 20 Ringer 's lactate ) presenting with hemorrhagic shock . The groups were similar in age , sex , race , and type of injury . Significantly less volume of Pentastarch was required initially to resuscitate to a normal blood pressure and urine output than Ringer 's lactate ( P < 0.005 ) . Coagulation parameters ( prothrombin time , partial thromboplastin time , fibrinogen , and factor VIII ) were measured for 48 hr post-resuscitation , and no abnormalities were noted in the Pentastarch group . Serum albumin was the same in both groups throughout the study period ; however , serum colloid oncotic pressure was elevated at 1 hr post-resuscitation in the Pentastarch group ( P < 0.005 ) . There was no difference in ventilatory parameters , blood gases , pulmonary function tests , ventilator days , or hospital days between the two groups . We conclude that Pentastarch is safe and effective for the initial resuscitation from hemorrhagic shock The effect of 6 % hydroxyethyl starch ( hetastarch ) and 5 % human serum albumin ( albumin ) infusion on coagulation in 12 patients with septic shock was evaluated . Patients were r and omly assigned to receive either albumin ( N = 6 ) or hetastarch ( N = 6 ) infusion over a 24-hour study interval . The prothrombin time ( PT ) , partial thromboplastin time ( PTT ) , and quantitative platelet count ( PC ) were obtained prior to and following 24 hours of fluid infusion . Hetastarch patients received 4934 + /- 1354 mL and albumin patients received 3067 + /- 256 mL over the study interval . After hetastarch infusion , the PT increased 2.2 + /- 0.7 seconds , PTT increased 20.0 + /- 4.1 seconds ( P less than .01 ) , and PC decreased 158 + /- 36 X 10(3)/mm3 ( P less than .02 ) . After albumin administration , the PT decreased 1.2 + /- 1.7 seconds , PTT increased 20.5 + /- 10.6 seconds and PC decreased 100 + /- 34 X 10(3)/mm3 . There were no significant differences in the changes in PT , PTT , or PC between the groups . The authors conclude that hetastarch infusion does not result in increased bleeding in patients with septic shock compared with albumin infusion , despite moderate effects on the hemostatic coagulation profile Abstract . This study evaluates the hemodynamic effects of the administration of 10 % pentastarch solution ( PS ) during the initial treatment of hypovolemia in trauma patients . This prospect i ve r and omized phase II study included trauma patients admitted to the emergency room with hemorrhagic hypovolemia : systolic blood pressure ( SBP ) < 90 mmHg . Upon admission , the patients were r and omized to receive 10 % PS ( n= 12 ) or isotonic 0.9 % NaCl solution ( IS ) ( n= 11 ) , infused intravenously in 250-ml boluses , repeated until SBP > 100 mmHg . Blood pressure , infused volumes necessary to maintain SBP , and overall survival rates were determined and compared between groups . SBP increased significantly following either IS ( from 64.4 ± 9.2 mmHg to 111.1 ± 6.3 mmHg ) , or PS ( from 63.7 ± 10.6 mmHg to 108.1 ± 9.8 mmHg ) when compared to admission values ( p < 0.05 ) . Endovenous volumes infused were greater ( p= 0.001 ) in IS patients ( 1420 ± 298 ml ) than in PS patients ( 356 ± 64 ml ) . No blood was transfused into PS patients , compared to 370 ± 140 ml of red blood cells transfused into IS patients ( p= 0.015 ) . Mortality rates were similar in the two groups ( p= 0.725 ) . We concluded that PS is a safe , efficient method for inducing hemodynamic recovery of hypovolemic trauma patients , with a clear reduction in the intravenous volumes required for acute resuscitation INTRODUCTION Hydroxyethylstarches ( HES ) are thought to be beneficial in trauma and major surgery management , due to their volume expansion and anti-inflammatory properties . This study examined the use of 6 % ( HES ) in burn resuscitation . METHODS 26 adult patients with burns exceeding 15 % total body surface area ( TBSA ) were r and omised to either crystalloid ( Hartmann 's solution ) or a colloid-supplemented resuscitation regime , where 1/3 of the crystalloid-predicted requirement was replaced by 6 % HES . RESULTS There was no difference in age , gender or TBSA between the two groups . The median ( 95 % CI ) fluid volume/%TBSA received in the first 24 h was 307 ml and 263 ml for the crystalloid only and HES-supplemented group respectively ( p=0.0234 , Mann-Whitney ) . Body weight gain within the first 24 h after injury was significantly lower in the HES-supplemented group 2.5 kg versus 1.4 kg respectively ( p=0.0039 ) . The median ( 95 % CI ) serum C-reactive protein at 48 h after injury was 210 ( 167 - 257 ) and 128 ( 74 - 145 ) mg/L for the crystalloid only and HES-supplemented group respectively ( p=0.0001 ) . Albumin-creatinine ratio per % burn ( ACR , a marker of capillary leak ) was lower in the HES-supplemented group at 12h after burn ( p=0.0310 ) . CONCLUSIONS Patients treated with HES-supplemented resuscitation required less fluid , showed less interstitial oedema and a dampened inflammatory response compared to patients receiving isotonic crystalloid alone OBJECTIVE To study the effects of different fluids on blood pressure ( BP ) , blood lactate clearance and mortality in patients with septic shock after early fluid resuscitation . METHODS Sixty patients were enrolled and r and omly divided into four groups according to the fluids used in resuscitation : normal saline ( NS ) group ( 15 cases ) , hydroxyethyl starch ( HES ) group ( 15 cases ) , 4 % hypertonic saline solution ( 4%NaCl ) group ( 15 cases ) , hypertonic sodium chloride hydroxyethyl starch 40 solution ( HSH40 ) group , ( 15 cases ) . Patients of different groups received fluid resuscitation via central vein , at the same time , received the anti-shock treatment . Hemodynamic parameters , blood lactate clearance and mortality in patients were monitored after resuscitation . RESULTS The study fluid volume and the total fluid volume in the 4%NaCl group and HSH40 group was lower than that in NS group and HES group significantly ( all P<0.01 ) . The mean arterial pressure ( MAP ) in HSH40 group was significantly higher than in the other three groups 1 hour after the fluid resuscitation ( all P<0.01 ) . The 24-hour blood lactate clearance in HSH40 group was also higher than in the other three groups ( all P<0.01 ) . The scores of sepsis-related organ failure assessment ( SOFA ) scores , acute physiology and chronic health evaluation II ( APACHE II ) scores , and 28-day mortality showed no significant differences among these groups ( all P>0.05 ) , but a lowering trend on 28-day mortality could be observed in HSH40 group . CONCLUSION The rapid elevation of BP can improve blood lactate clearance in patients with septic shock receiving early fluid resuscitation . Compared with other fluids , HSH40 raises BP more quickly and needs lower total resuscitation volume to achieve the same goal Objective To compare the hemodynamic and oxygen transport responses to a rapid ( < 10-min ) infusion of 500 mL of modified fluid gelatin ( group A ) or hydroxyethyl starch ( group B ) in patients suffering from acute hypovolemia . Design Prospect i ve , r and omized , noncrossover study . Setting University hospital , general intensive care unit . Patients Twenty-eight patients with hypovolemia mechanically ventilated for concurrent acute respiratory failure . Interventions Patients were mechanically ventilated . Pulmonary and femoral artery catheters were used for hemodynamic monitoring . Measurements and Main Results Hemodynamic and oxygen transport variables were determined at baseline , 15 mins , and 30 mins after the infusion of each fluid . In both groups pulmonary artery occlusion pressure , stroke volume , and cardiac index significantly increased . In neither group did heart rate decrease . Oxygen delivery increased significantly in group A patients but not in group B patients . This result was due to greater hemodilution in group B patients . Conclusions There are no significant differences in the hemodynamic responses to hydroxyethyl starch or modified fluid gelatin . The hemodynamic and oxygen transport effects of artificial colloid solutions may not be entirely predictable and should be monitored in critically ill patients . ( Crit Care Med 1994 ; 22:600–605 The endothelium plays an important role in the regulation of haemostasis by producing substances such as thrombomodulin ( TM ) . The influence of long-term volume replacement with different types of fluid on the TM-protein C-protein S system was investigated in a prospect i ve , r and omized study . Thirty trauma patients and 30 patients suffering from sepsis after major surgery received either 10 % low-molecular weight ( LMW ) hydroxyethylstarch solution ( HES-trauma , n = 15 ; HES-sepsis , n = 15 ) or 20 % human albumin ( HA-trauma , n = 15 ; HA-sepsis , n = 15 ) for 5 days to maintain central venous pressure ( CVP ) between 12 and 16 mm Hg . Plasma concentrations of TM , protein C , ( free ) protein S and thrombin-antithrombin ( TAT ) were measured in arterial blood sample s obtained on the day of admission to the intensive care unit or on the day of diagnosis of sepsis and over the next 5 days . There were no differences between HA- and HES-treated trauma patients . Protein C and protein S also did not differ between HA- and HES-treatments . At baseline , TM plasma concentrations were increased to > 40 micrograms litre-1 in both sepsis groups only . In the HA-sepsis group , TM increased significantly ( from 48.1 ( SD 13.9 ) to 68.4 ( 13.0 ) micrograms litre-1 ) , whereas it remained almost unchanged in the HES-sepsis group . In HES-sepsis patients , protein C ( from 51.0 ( 10.1 ) to 71.9 (8.9)% ) and protein S ( from 19.0 ( 6.0 ) to 40.8 (11.4)% ) increased significantly during the study , whereas both remained reduced in HA- patients . TAT ( indicating intravascular coagulation ) did not differ between the two fluid groups . We conclude that in trauma patients , the type of volume therapy had no influence on the TM-protein C-protein S system . In sepsis patients , volume therapy with HES was beneficial , whereas infusion of HA had no substantial positive effect on endothelial-associated coagulation Objective : There are still several concerns about the extensive and prolonged use of hydroxyethylstarch solution ( HES ) in critically ill patients . The effects of volume replacement with HES over 5 days on hemodynamics , laboratory data , and organ function were compared with volume therapy using human albumin ( HA ) . Design : Prospect i ve , r and omized study . Setting : Clinical investigations on a surgical intensive care unit ( ICU ) of a university hospital . Patients : 150 traumatized patients ( injury severity score > 15 ) and 150 postoperative patients with sepsis were analyzed . Interventions : Either 10 % low-molecular weight HES ( HES-trauma , n = 75 ; HES-sepsis , n = 75 ) or 20 % HA ( HA-trauma , n = 75 ; HA-sepsis , n = 75 ) was given for 5 days to maintain the pulmonary capillary wedge pressure ( PCWP ) between 12 and 15 torr . The entire management of therapy of the patients was performed by physicians who were not involved in the study and blinded to the infusion regimen . Measurements and results : In addition to extensive cardiorespiratory monitoring , several routine laboratory parameters for assessing pulmonary , renal , hepatic , and coagulation function were analyzed from arterial blood sample s on the day of admission to the ICU and on the day of sepsis diagnosis , respectively ( “ baseline ” value ) and daily over the following 5 days . Mortality during and after the study did not differ significantly between the infusion groups . There were also no differences between the incidence of pulmonary , renal , or hepatic failure in the two subgroups . Mean arterial pressure , heart rate , and PCWP were similar in both subgroups , whereas cardiac index , oxygen delivery index , oxygen consumption index , and the ratio between the partial pressure of oxygen in arterial blood and fractional inspired oxygen were higher in the HES- than in the HA-treated groups . St and ard coagulation parameters did not differ , albumin concentration increased significantly in both HA groups , and lactate concentrations decreased only in the HES-sepsis patients ( from 2.8 ± 0.5 to 1.5 ± 0.4 mg/dl ) . Volume replacement using albumin was significantly ( p < 0.001 ) more costly than therapy with HES . Conclusions : Volume therapy with 10 % HES for 5 days in the ICU patient showed no disadvantages compared with an infusion regimen using 20 % albumin . Volume replacement using HES may even be associated with improved hemodynamics . HES appears to be a valuable and significantly cheaper alternative to albumin – even for prolonged volume therapy in the critically ill patient Objective : To compare crystalloid and colloid fluids in their effect on pulmonary edema in hypovolemic septic and nonseptic patients with or at risk for acute lung injury/acute respiratory distress syndrome . We hypothesized that 1 ) crystalloid loading results in more edema formation than colloid loading and 2 ) the differences among the types of fluid decreases at high permeability . Design , Setting , and Patients : Prospect i ve r and omized clinical trial on the effect of fluids in 24 septic and 24 nonseptic mechanically ventilated patients with clinical hypovolemia . Interventions : Patients were assigned to NaCl 0.9 % , gelatin 4 % , hydroxyethyl starch 6 % , or albumin 5 % loading for 90 minutes according to changes in filling pressures . Measurements and Main Results : Twenty-three septic and 10 nonseptic patients had acute lung injury/acute respiratory distress syndrome ( p < 0.001 ) . Septic patients had greater pulmonary capillary permeability , edema , and severity of lung injury than nonseptic patients ( p < 0.01 ) , as measured by the pulmonary leak index ( PLI ) for 67Gallium-labeled transferrin , extravascular lung water ( EVLW ) , and lung injury score ( LIS ) , respectively . Colloids increased plasma volume , cardiac index , and central venous pressure ( CVP ) more than crystalloids ( p < 0.05 ) , although more crystalloids were infused ( p < 0.05 ) . Colloid osmotic pressure ( COP ) increased in colloid and decreased in crystalloid groups ( p < 0.001 ) . Irrespective of fluid type or underlying disease , the pulmonary leak index increased by median 5 % ( p < 0.05 ) . Regardless of fluid type or underlying disease , EVLW and LIS did not change during fluid loading and EVLW related to COP-CVP ( rs = −.40 , p < 0.01 ) . Conclusions : Pulmonary edema and LIS are not affected by the type of fluid loading in the steep part of the cardiac function curve in both septic and nonseptic patients . Then , pulmonary capillary permeability may be a smaller determinant of pulmonary edema than COP and CVP . Safety factors may have prevented edema during a small filtration pressure-induced rise in pulmonary protein and thus fluid transport Objectives : This study aim ed to address whether hydroxyethyl starch ( HES ) is beneficial for intra-abdominal pressure ( IAP ) in severe acute pancreatitis ( SAP ) in early stages . Methods : Forty-one patients with SAP were r and omized to HES group ( n = 20 ) and the Ringer 's lactate ( RL ) group ( n = 21 ) . The groups received 6 % HES 130/0.4 for 8 days and RL solution without colloid , respectively . The primary end point was the IAP . The secondary end points were fluid balance , major organ complications , the Acute Physiology and Chronic Heath Evaluation II score , and the serum levels of C-reactive protein , interleukin-6 , and interleukin-8 . Results : The characteristics of baseline data were similar in the 2 groups . In the HES group , the IAP was significantly lower in 2 to 7 days , and fewer patients received mechanical ventilation ( 15.0 % vs 47.6 % ) . A negative fluid balance was observed earlier in the HES group than in the RL group ( 2.5 ± 2.2 vs 4.0 ± 2.5 days ) . Conclusions : Fluid resuscitation with HES in the early stages of SAP can decrease the risk of intra-abdominal hypertension and reduce the use of mechanical ventilation

Self-weighing is likely to improve weight outcomes , particularly when performed daily or weekly , without causing untoward adverse effects .

BACKGROUND Self-weighing increases a person 's self-awareness of current weight and weight patterns . Increased self-weighing frequency can help an individual prevent weight gain . Literature , however , is limited in describing variability in self-weighing strategies and how the variability is associated with weight management outcomes . AIM This review analyzed self-weighing in weight management interventions and the effects of self-weighing on weight and other outcomes .

OBJECTIVE To determine whether daily self-weighing ( DSW ) is associated with disordered eating ( DE ) symptoms within an adult lifestyle intervention ( LI ) , and to examine changes in DE symptoms during the 18-month trial . METHOD One-hundred and seventy-eight adults ( 53 % female , 90 % White , 52.0 ± 8.6 years , BMI = 35.0 ± 4.4 kg/m2 ) were enrolled in a r and omized trial testing 2 dietary prescriptions within a LI ( st and ard vs. limited dietary variety ) . Both arms were taught DSW and had the same contact schedule and calorie and activity goals . Frequency of weighing and DE were assessed at 0 , 6 , 12 , and 18 months . Analyses controlled for treatment arm . RESULTS At baseline , 16.3 % of participants reported weighing ≥ daily compared with 83.7 % , 72.3 % , and 68.2 % at 6 , 12 , and 18 months , respectively . There was no relationship between change in frequency of self-weighing and change in DE symptoms at any time point . Further , there were no significant differences between those who weighed ≥ daily versus < daily on DE composite scores at baseline or 6 months ; at 12 and 18 months participants who weighed ≥ daily reported lower DE scores compared with those who weighed < daily ( p = .008 and .043 at 12 and 18 months , respectively ) . Participants who weighed ≥ daily achieved better weight losses than those weighing < daily at 12 and 18 months ( p = .003 and < .001 ) . There was a significant reduction over time in DE symptoms ( p < .0001 ) and a reduction in odds of meeting criteria for Binge Eating Disorder ( BED ; ps < .001 ) . CONCLUSIONS Daily self-weighing did not appear to be related to increased disordered eating behavior and was associated with better weight loss outcomes Background : Although the optimization of behavioral interventions offers the potential of both public health and research benefits , currently there is no widely agreed-upon principled procedure for accomplishing this . Purpose : This article suggests a multiphase optimization strategy ( MOST ) for achieving the dual goals of program optimization and program evaluation in the behavioral intervention field . Methods : MOST consists of the following three phases : ( a ) screening , in which r and omized experimentation closely guided by theory is used to assess an array of program and /or delivery components and select the components that merit further investigation ; ( b ) refining , in which interactions among the identified set of components and their interrelationships with covariates are investigated in detail , again via r and omized experiments , and optimal dosage levels and combinations of components are identified ; and ( c ) confirming , in which the result ing optimized intervention is evaluated by means of a st and ard r and omized intervention trial . To make the best use of available re sources , MOST relies on design and analysis tools that help maximize efficiency , such as fractional factorials . Results : A slightly modified version of an actual application of MOST to develop a smoking cessation intervention is used to develop and present the ideas . Conclusions : MOST has the potential to husb and program development re sources while increasing our underst and ing of the individual program and delivery components that make up interventions . Considerations , challenges , open questions , and other potential benefits are discussed BACKGROUND Since many successful dieters regain the weight they lose , programs that teach maintenance skills are needed . We developed a maintenance program based on self-regulation theory and tested the efficacy of delivering the program face to face or over the Internet . METHODS We r and omly assigned 314 participants who had lost a mean of 19.3 kg of body weight in the previous 2 years to one of three groups : a control group , which received quarterly newsletters ( 105 participants ) , a group that received face-to-face intervention ( 105 ) , and a group that received Internet-based intervention ( 104 ) . The content of the programs in the two intervention groups was the same , emphasizing daily self-weighing and self-regulation , as was the frequency of contact with the groups . The primary outcome was weight gain over a period of 18 months . RESULTS The mean ( + /-SD ) weight gain was 2.5+/-6.7 kg in the face-to-face group , 4.7+/-8.6 kg in the Internet group , and 4.9+/-6.5 kg in the control group , with a significant difference between the face-to-face group and the control group ( 2.4 kg ; 95 % confidence interval [ CI ] , 0.002 to 10.8 ; P=0.05 ) . The proportion of participants who regained 2.3 kg or more over the 18-month period was significantly higher in the control group ( 72.4 % ) than in the face-to-face group ( 45.7 % ; absolute difference , 27 % ; 95 % CI , 14 to 39 ; P<0.001 ) or the Internet group ( 54.8 % ; absolute difference , 18 % ; 95 % CI , 5 to 30 ; P=0.008 ) . Daily self-weighing increased in both intervention groups and was associated with a decreased risk of regaining 2.3 kg or more ( P<0.001 ) . CONCLUSIONS As compared with receiving quarterly newsletters , a self-regulation program based on daily weighing improved maintenance of weight loss , particularly when delivered face to face . ( Clinical Trials.gov number , NCT00067145 [ Clinical Trials.gov ] . OBJECTIVE To examine the effect of self-weighing frequency on weight change and body satisfaction . DESIGN Observational study based on findings from a 6-month r and omized controlled telephone-based weight loss trial . Data collected at baseline and 6 months . SETTING Metropolitan community-based sample . PARTICIPANTS Sixty-three obese adults . Mean age 49.5 years , 82 % percent white , and 79 % female . Mean body mass index at baseline was 34.2 kg/m(2 ) . MAIN OUTCOME MEASURES Change in weight and body satisfaction . ANALYSIS General linear model regression was used to assess the effect of self-weighing on outcomes of interest . Statistical significance was set at alpha level .05 . Treatment group and baseline values of dependent variables included as covariates in all analyses . RESULTS Participants who increased their frequency of self-weighing over the 6-month period demonstrated significantly better weight loss outcomes than those who maintained or decreased their frequency of self-weighing ( -6.8 kg vs -3.1 kg , F = 8.59 , P = .006 ) . There were no significant associations between self-weighing frequency and body satisfaction at 6 months ( F = 0.55 , P = .58 ) . CONCLUSIONS AND IMPLICATION S These findings support frequent self-weighing for weight control . There appears to be little or no effect of self-weighing on body satisfaction . Future research should replicate these findings across a larger , more diverse population of overweight adults Few studies have examined predictors of weight regain after significant weight losses . This prospect i ve study examined behavioral and psychological predictors of weight regain in 261 successful weight losers who completed an 18-month trial of weight regain prevention that compared a control condition with self-regulation interventions delivered face-to-face or via the Internet . Linear mixed effect models were used to examine behavioral and psychological predictors of weight regain , both as main effects and as interactions with treatment group . Decreases in physical activity were related to weight regain across all 3 groups , and increased frequency of self-weighing was equally protective in the 2 intervention groups but not in the control group . Increases in depressive symptoms , disinhibition , and hunger were also related to weight regain in all groups . Although the impact of changes in restraint was greatest in the Internet group and weakest in the face-to-face group , the latter was the only group with increases in restraint over time and consequent decreases in magnitude of weight regain . Future programs should focus on maintaining physical activity , dietary restraints , and frequent self-weighing and should include stronger components to modify psychological parameters PURPOSE : The present study evaluated the cross-section and prospect i ve associations between the Eating Inventory 's ( EI ) total , flexible and rigid dietary restraint scales and changes in weight and behaviors in a community sample of adults enrolled in a 3 y weight gain prevention study . METHODS : Subjects were participants in the Pound of Prevention ( POP ) study , a community-based weight gain prevention trial . RESULTS : Higher levels of baseline total , flexible and rigid dietary restraint were related to lower weight and more weight-controlling behaviors at the baseline assessment . Baseline restraint measures positively predicted increases in weighing frequency over the 3 y follow-up . Increases in restraint over the follow-up period were related to decreases in weight , energy intake and television watching , and increases in self-weighing and physical activity . CONCLUSION : The EI 's total , flexible and rigid restraint scales were not differently associated with weight and behaviors in this heterogeneous sample of adults who were attempting to lose weight . Developing methods to increase behavioral and cognitive strategies to control weight may help to prevent weight gain in clinical and community sample s . International Journal of Obesity ( 2001 ) 25 , Several recent studies suggest that daily weighing is important for long-term weight control , but concerns have been raised about possible adverse psychological effects . The " STOP Regain " clinical trial provides a unique opportunity to examine this issue both cross-sectionally and prospect ively . Successful weight losers ( N = 314 ) were r and omly assigned to a control or to a face-to-face or Internet intervention design ed to help them maintain their weight loss and were then followed for 18 months . The intervention groups reported increases in daily self-weighing , which were associated with successful weight loss maintenance . We found no evidence that increases in frequency of weighing or daily weighing per se had any adverse effects in this study population . Rather , increases in self-weighing were associated with increases in dietary restraint ( p < .001 ) , decreases in disinhibition ( p < .003 ) , and decreases in depressive symptoms ( p < .002 ) . Moreover , those who weighed daily at 18 months were less likely to report having > or=4 binge episodes per month ( p = .03 ) . Daily weighing appears to be an important aspect of weight loss maintenance and was not associated with adverse psychological effects BACKGROUND Frequent self-weighing has been proposed as an adjuvant strategy to promote weight loss . Not all experts agree on its utility , and the literature supporting its effectiveness is somewhat limited by method ologic shortcomings related to the subjective assessment of self-weighing frequency . DESIGN A prospect i ve cohort design was utilized to examine 100 participants enrolled in a weight-loss trial that encouraged frequent , objective ly measured self-weighing at home . Measurements were made at pretreatment and at follow-up visits at 6 and 12 months . SETTING / PARTICIPANTS Participants were employed , obese adults enrolled in the Weigh By Day trial . Study data were collected between October 2005 and May 2007 . INTERVENTION The intervention consisted of a 6-month behavioral weight-loss program that employed telephone counseling , a written manual , and a home telemonitoring scale . MAIN OUTCOME MEASURES The primary outcomes of interest were body weight and clinical ly meaningful weight loss ( i.e. , > or = 5 % ) . Analyses were performed in March 2008 . RESULTS Self-weighing was a significant predictor of body weight over time . Participants lost about 1 extra pound for every 11 days they self-weighed during treatment . In addition , participants who self-weighed at least weekly were 11 times more likely to lose at least 5 % of their pretreatment weight after 6 months . Improvements attenuated after 12 months . CONCLUSIONS Self-weighing may be a strategy to enhance behavioral weight-loss programs . Weekly self-weighing seems to be a reasonable , evidence -supported recommendation for successful weight loss , but more research is warranted to determine the independent contribution of self-weighing to successful weight loss , as well as its potential risk of negative psychological impact OBJECTIVE To investigate the effectiveness of self-weighing twice a day with a supportive program installed on a body composition monitor in overweight adults . SUBJECTS Sixty adults with BMI > 24 kg/m(2 ) were r and omly assigned to either a group that weighed themselves once per day ( group 1 , n = 30 ) or a group that weighed themselves twice per day ( group 2 , n = 30 ) . INTERVENTION Group 1 was instructed to self-weigh at the same time once per day and group 2 was instructed to self-weigh immediately after waking up in the morning and immediately before going to bed every day for twelve weeks . In addition , participants in group 2 was received the daily target setting during morning weighing and the difference between the measured weight and the target weight during bedtime weighing . RESULTS Average weight reduction in group 1 was significantly lower than that in group 2 ( 1.0 ± 1.4 kg vs. 2.7 ± 2.1 kg , p < 0.05 ) . The proportion of participants who lost ≥ 5 % of their pre-program weight in group 2 was significantly higher than that in group 1 ( 28.6 % vs. 3.6 % , p < 0.05 ) . CONCLUSION A self-weighing twice per day plus daily target setting and feedback is more effective in promoting weight loss than once-daily self-measurement Background : Improved self-care behaviour is a goal in educational programmes for patients with heart failure , especially in regard to daily self-weighing and salt and fluid restriction . Aims : The objectives of the present study were to : ( 1 ) describe self-care with special regard to daily self-weighing and salt and fluid restriction in patients with heart failure in primary health care , during one year of monthly telephone follow-up after a single session education , ( 2 ) to describe gender differences in regard to self-care and ( 3 ) to investigate if self-care was associated with health-related quality of life . Methods : The present analysis is a subgroup analysis of a larger r and omised trial . After one intensive educational session , a primary health care nurse evaluated 60 patients ( mean age 79 years , 52 % males , 60 % in New York Heart Association class III – IV ) by monthly telephone follow-up during 12 months . Results : The intervention had no effect on quality of life measured by EuroQol 5D and no significant associations were found between quality of life and self-care behaviour . Self-care behaviour measured by The European Self-care Behaviour Scale remained unchanged throughout the study period . No significant gender differences were shown but women had a tendency to improve adherence to daily weight control between 3- and 12 months . Conclusion : The self-care behaviour and quality of life in patients with heart failure did not change during one year of monthly telephone follow-up after a single session education and this indicates a need for more extensive interventions to obtain improved self-care behaviour in these patients Objective To develop and evaluate the effectiveness of a community behavioural intervention to prevent weight gain and improve health related behaviours in women with young children . Design Cluster r and omised controlled trial . Setting A community setting in urban Australia . Participants 250 adult women with a mean age of 40.39 years ( SD 4.77 , range 25 - 51 ) and a mean body mass index of 27.82 kg/m2 ( SD 5.42 , range 18 - 47 ) were recruited as clusters through 12 primary ( elementary ) schools . Intervention Schools were r and omly assigned to the intervention or the control . Mothers whose schools fell in the intervention group ( n=127 ) attended four interactive group sessions that involved simple health messages , behaviour change strategies , and group discussion , and received monthly support using mobile telephone text messages for 12 months . The control group ( n=123 ) attended one non-interactive information session based on population dietary and physical activity guidelines . Main outcome measures The main outcome measures were weight change and difference in weight change between the intervention group and the control group at 12 months . Secondary outcomes were changes in serum concentrations of fasting lipids and glucose , and changes in dietary behaviours , physical activity , and self management behaviours . Results All analyses were adjusted for baseline values and the possible clustering effect . Women in the control group gained weight over the 12 month study period ( 0.83 kg , 95 % confidence interval ( CI ) 0.12 to 1.54 ) , whereas those in the intervention group lost weight ( −0.20 kg , −0.90 to 0.49 ) . The difference in weight change between the intervention group and the control group at 12 months was −1.13 kg ( −2.03 to −0.24 kg ; P<0.05 ) on the basis of observed values and −1.11 kg ( −2.17 to −0.04 ) after multiple imputation to account for possible bias created by missing values . Secondary analyses after multiple imputation showed a difference in the intervention group compared with the control group for total cholesterol concentration ( −0.35 mmol/l , −0.70 to −0.001 ) , self management behaviours ( diet score 0.18 , 0.13 to 0.33 ; physical activity score 0.24 , 0.05 to 0.43 ) , and confidence to control weight ( 0.40 , 0.11 to 0.69 ) . Regular self weighing was associated with weight loss in the intervention group only ( −1.98 kg , −3.75 to −0.23 ) . Conclusions Weight gain in women with young children could be prevented using a low intensity self management intervention delivered in a community setting . Self management of health behaviours improved with the intervention . The response rate of 12 % , although comparable with that in other community studies , might limit the ability to generalise to other population s. Trial registration Australian New Zeal and Clinical Trials Registry number ACTRN12608000110381 CONTEXT Weight gain in young adults is an important public health problem and few interventions have been successful . BACKGROUND This pilot study evaluated the preliminary efficacy of two self-regulation approaches to weight-gain prevention : Small Changes ( changes in energy balance of roughly 200 kcal/day ) and Large Changes ( initial weight loss of 5 - 10 lbs to buffer against future weight gains ) . INTERVENTION Participants were enrolled in 8-week programs teaching Small or Large Changes ( SC ; LC ) . Both approaches were presented in a self-regulation framework , emphasizing daily self-weighing . DESIGN R and omized controlled pilot study . SETTING / PARTICIPANTS Young adults ( N=52 ) aged 18 - 35 years ( 25.6+/-4.7 years , BMI of 26.7+/-2.4 kg/m(2 ) ) were recruited in Providence RI and Chapel Hill NC . MAIN OUTCOME MEASURES Adherence to intervention , weight change , and satisfaction/confidence in approach assessed at 0 , 8 , and 16 weeks . Data were collected in 2008 and analyzed in 2008 - 2009 . RESULTS Participants attended 84 % of sessions , and 86.5 % and 84.5 % of participants completed post-treatment and follow-up assessment s , respectively . Participants adhered to their prescriptions . Daily weighing increased markedly in both groups , whereas the eating and exercise changes observed in the SC and LC reflected the specific approach taught . Weight changes were significantly different between groups at 8 weeks ( SC= -0.68+/-1.5 kg , LC= -3.2+/-2.5 kg , p<0.001 ) and 16 weeks ( SC= -1.5+/-1.8 kg , LC= -3.5+/-3.1 kg , p=0.006 ) . Participants in both groups reported high levels of satisfaction and confidence in the efficacy of the approach they were taught . CONCLUSIONS Both Small and Large Change approaches hold promise for weight-gain prevention in young adults ; a fully powered trial comparing the long-term efficacy of these approaches is warranted BACKGROUND Despite evidence that daily self-weighing is an effective strategy for weight control , concerns remain regarding the potential for negative psychological consequences . PURPOSE The goal of the study was to examine the impact of a daily self-weighing weight-loss intervention on relevant psychological constructs . DESIGN A 6-month RCT . SETTING / PARTICIPANTS The study sample ( N=91 ) included overweight men and women in the Chapel Hill NC area . INTERVENTION Between February and August 2011 , participants were r and omly assigned to a daily self-weighing intervention or delayed-intervention control group . The 6-month intervention included daily self-weighing for self-regulation of diet and exercise behaviors using an e-scale that transmitted weights to a study website . Weekly e-mailed lessons and tailored feedback on daily self-weighing adherence and weight-loss progress were provided . MAIN OUTCOME MEASURES Self-weighing frequency was measured throughout the study using e-scales . Weight was measured in-clinic at baseline , 3 months , and 6 months . Psychological outcomes were assessed via self-report at the same time points . RESULTS In 2012 , using linear mixed models and generalized estimating equation models , there were no significant differences between groups in depressive symptoms , anorectic cognitions , disinhibition , susceptibility to hunger , and binge eating . At 6 months , there was a significant group X time interaction for body dissatisfaction ( p=0.007 ) and dietary restraint ( p<0.001 ) , with the intervention group reporting lower body dissatisfaction and greater dietary restraint compared to controls . CONCLUSIONS Results indicate that a weight-loss intervention that focuses on daily self-weighing does not cause adverse psychological outcomes . This suggests that daily self-weighing is an effective and safe weight-control strategy among overweight adults attempting to lose weight . TRIAL REGISTRATION This study is registered at clinical trials.gov NCT01369004 Background Little is known about the association between self-weighing frequency and weight gain prevention , particularly in worksite population s. Purpose The degree to which self-weighing frequency predicted 2-year body weight change in working adults was examined . Method The association between self-weighing frequency ( monthly or less , weekly , daily , or more ) and 24-month weight change was analyzed in a prospect i ve cohort analysis ( n = 1,222 ) as part of the larger HealthWorks trial . Results There was a significant interaction between follow-up self-weighing frequency and baseline body mass index . The difference in weight change ranged from −4.4 ± 0.8 kg weight loss among obese daily self-weighers to 2.1 ± 0.4 kg weight gain for participants at a healthy weight who reported monthly self-weighing . Conclusion More frequent self-weighing seemed to be most beneficial for obese individuals . These findings may aid in the refinement of self-weighing frequency recommendations used in the context of weight management interventions Clinical obesity treatments are of limited reach . Self-directed weight control attempts are common , but little attention has been given to providing guidance for such efforts in the population . The present research tests a brief intervention approach to weight control . Pilot data were collected from 66 University of Minnesota employees ( 72.7 % women , 81.8 % white ) r and omized to an assessment -only control condition or a single intervention session to teach empirically valid self-directed weight-control methods . Mean baseline weight was 87.1 kilograms ( range 64.0–120.3 kilograms ) . Though statistically nonsignificant , intervention participants averaged greater weight loss by 6 months than controls ( –.80 kilograms vs. –.19 kilograms ) , F(1 , 44 ) = .47 , p = .50 , Cohen 's d = .21 . There was a significant group × time interaction for self-weighing frequency , F(2 , 41 ) = 10.84 , p < .001 . With some enhancement and more attention to dissemination , a brief self-directed program has potential as a useful approach to population weight-gain prevention BACKGROUND Many overweight people take action to lose weight but most regain this weight . PURPOSE To examine the effectiveness of a weight maintenance intervention focused on regular self-weighing after receiving a 12-week weight loss programme . METHODS Quasi-r and omized controlled trial of 3768 obese or overweight men and women . The intervention group ( n = 3290 ) received two telephone calls , the offer of free weighing scales , encouragement to weigh themselves weekly and record this on a card . The main outcome was change in weight between 3 and 12 months . RESULTS Using intention to treat analysis both groups regained weight ; however , the intervention group on average regained 1.23 kg , whereas the control group regained 1.83 kg . Adjusting for covariates result ed in a mean difference of 0.68 kg ( 95 % CI 0.12 , 1.24 ) at 12-month follow-up . CONCLUSIONS Encouraging people who have recently lost weight to weigh themselves regularly prevents some weight regain

The 5-HT3 receptor antagonists are considered to be effective antiemetics with an acceptable side effects profile . Ondansetron was the most commonly studied member of this group . Another effective antiemetic is droperidol . A single dose of dexamethasone has been reported to be effective for PONV prophylaxis without evidence of significant side effects . It has also been suggested that dexamethasone might be especially effective against late PONV .

Although a number of therapies are available for the management of postoperative nausea and vomiting ( PONV ) , none is entirely effective . Currently , the overall incidence of PONV for all surgeries and patient population s is estimated to be 25 % to 30 % . In certain high-risk patients , this incidence is as high as 60 % to 70 % . Furthermore , it is estimated that approximately 0.18 % of all patients may experience intractable PONV , leading to a delay in hospital discharge and unanticipated hospital admissions . The number needed to treat ( NNT ) is a useful way of looking at the efficacy of different antiemetics . A NNT of 4 or less represents a clinical ly relevant effect .

Because no completely effective antiemetic exists for the prevention of postoperative nausea and vomiting ( PONV ) , we hypothesize that a multimodal approach to management of PONV may reduce both vomiting and the need for rescue antiemetics in high-risk patients . After IRB approval , women undergoing outpatient laparoscopy were r and omized to one of three groups . Group I ( n = 60 ) was managed by using a predefined multimodal clinical care algorithm . Patients undergoing the same surgical procedure who received a st and ard balanced outpatient anesthetic with ondansetron 4 mg ( Group II , n = 42 ) or placebo ( Group III , n = 37 ) prophylaxis were chosen to establish baseline incidence of nausea and vomiting . None of the Group I patients vomited before discharge , compared with 7 % in Group II ( P = 0.07 ) and 22 % in Group III ( P = 0.0003 ) . However , one patient ( 2 % ) in Group I required treatment for symptoms in the postanesthesia care unit , compared with 24 % in Group II ( P < 0.0001 ) and 41 % in Group III ( P < 0.0001 ) . Time to discharge-ready was significantly shorter in Group I ( 128 , 118–139 min ; mean , 95 % confidence interval ) versus Group II ( 162 , 145–181 min;P = 0.0015 ) and Group III ( 192 , 166–222 min;P = 0.0001 ) . Patient satisfaction with control of PONV was not different between Group I and Group II . Return to normal daily activity and overall satisfaction were not different among groups . Multimodal management result ed in a 98 % complete response rate and a 0 % incidence of vomiting before discharge ; however , this improvement did not result in an increased level of patient satisfaction when compared with routine monotherapy prophylaxis . We conclude that both multimodal management and routine monotherapy antiemetic prophylaxis result ed in an increased level of patient satisfaction than symptomatic treatment in this high-risk population . Implication s Use of a multimodal clinical care algorithm eliminates predischarge vomiting and improves satisfaction in patients undergoing outpatient laparoscopy Two hundred adults undergoing laparoscopic cholecystectomy were enrolled in a prospect ively r and omized , double-blind investigation comparing ondansetron , 4 mg ( Group O ) with the combination of droperidol , 0.625 mg , and metoclopramide , 10 mg ( Group DM ) . Antiemetic drugs were administered intravenously ( IV ) after induction of general anesthesia ( propofol , desflurane ) . Moderate or severe nausea in the postanesthesia care unit was treated with the crossover drug , i.e. , ondansetron for patients in Group DM or droperidol plus metoclopramide for patients in Group O. Data were analyzed using t-tests and chi squared analyses , with P < 0.05 considered statistically significant . The groups were similar with respect to gender , age , weight , duration of surgery , number receiving intraoperative atropine or ephedrine , number admitted overnight , and time to discharge home . Of 102 patients in Group O , 44 required antiemetics in the postanesthesia care unit , compared with 24 of 98 patients in Group DM ( P < 0.01 ) . One patient ( in Group DM ) was admitted for persistent nausea . In conclusion , droperidol 0.625 mg IV in combination with metoclopramide 10 mg IV was more effective in preventing postoperative nausea than was ondansetron 4 mg IV in patients undergoing laparoscopic cholecystectomy , with no difference in the time to discharge . ( Anesth Analg 1996;83:1081 - 3 STUDY OBJECTIVE To evaluate the efficacy of a two-dose combination of droperidol and ondansetron as compared with single-dose droperidol alone , single-dose combined droperidol and ondansetron , and two-dose droperidol alone , for management of postoperative nausea and vomiting ( PONV ) among gynecologic laparoscopy out patients . DESIGN R and omized , double-blind comparison trial . SETTING Tertiary outpatient gynecologic unit . PATIENTS A total of 120 female patients scheduled for gynecologic laparoscopy were enrolled . Patients who had experienced nausea or vomiting , or who had taken drugs with antiemetic action in the 24-hour period prior to the study , as well as breast-feeding mothers , were excluded from participation . INTERVENTIONS Patients were assigned to four treatment groups : i ) single dose of droperidol 1.25 mg , ii ) two doses of droperidol 1.25 mg , iii ) single dose of droperidol 1.25 mg and ondansetron 4 mg in combination , and iv ) two doses of droperidol 1.25 mg and ondansetron 4 mg in combination . The first dose of antiemetic was administered prior to induction and the second dose was given by infusion 4 hours later , prior to discharge . MEASUREMENTS AND MAIN RESULTS A visual analogue scale ( VAS , 10 cm ) was used to obtain patients ' experience of nausea , vomiting , and pain at 0.5 , 1.5 , 2.5 , and 3.5 hours after arrival at the postanesthetic care unit ( PACU ) . Following discharge , approximately 24 hours after arrival at the PACU , the same measures were obtained by a follow-up interview using a verbal 10-point scale . No significant differences in incidence of PONV were noted among the four treatment groups ( p = 0.419 ) . However , both single- and two-dose droperidol and ondansetron combination therapy demonstrated attenuation of PONV severity in the 3.5- to 24-hour postinduction period ( p < 0.05 ) . CONCLUSIONS The findings of this study suggest that prophylactic two-dose combined ondansetron and droperidol offers no added benefit over single-dose therapy for routine use in the gynecologic outpatient population STUDY OBJECTIVES To investigate the hypothesis that the combination of ondansetron and droperidol would be more effective than droperidol alone in reducing nausea and vomiting . DESIGN R and omized , doubleblind study . SETTING Magee-Womens Hospital , Pittsburgh , Pennsylvania . PATIENTS 160 healthy , ASA physical status I and II , female patients scheduled for total abdominal hysterectomy . INTERVENTIONS After induction of anesthesia with propofol , Group 1 received intravenous ( i.v . ) droperidol 1.25 mg plus i.v . ondansetron 4 mg . Group 2 received i.v . droperidol plus i.v . saline . MEASUREMENTS AND MAIN RESULTS The complete response ( no emesis , no rescue ) for Group 1 was 36 of 80 patients ( 45 % ) versus 30 of 80 patients ( 38 % ) in Group 2 ( p = 0.21 ) . In Group 1 , 42 of 80 patients ( 53 % ) required rescue antiemetic as compared with 44 of 80 patients ( 55 % ) in Group 2 ( p = 0.43 ) . There were 72 total rescues in Group 1 versus 73 in Group 2 , ( p = 0.24 ) . Mean time until first rescue was 578 + /- 429 minutes in Group 1 and 418 + /- 354 minutes in Group 2 , ( p = 0.03 ) . In Group 1 , 81 % ( 34/42 ) were rescued for nausea only versus 90 % ( 39/44 ) of Group 2 ( p = 0.16 ) . In Group 1 , 21 % of patients ( 17/80 ) had at least one emetic episode versus 34 % ( 27/80 ) of Group 2 patients ( p = 0.05 ) . There were 31 emetic episodes in Group 1 versus 72 episodes in Group 2 . ( p = 0.02 ) . Mean time to the first emetic episode was 699 + /- 403 minutes in Group 1 and 616 + /- 376 minutes in Group 2 , ( p = 0.23 ) . CONCLUSION For patients undergoing total abdominal hysterectomies , the addition of ondansetron to droperidol increases the time until first rescue and reduces the number of emetic episodes , as well as the percentage of patients , having at least one emetic episode PURPOSE A relatively high incidence of postoperative nausea and vomiting ( PONV ) occurs in patients undergoing laparoscopic cholecystectomy . This study was undertaken to compare the efficacy of granisetron-droperidol combination with each drug alone for the prevention of PONV after laparoscopic cholecystectomy . METHODS In a r and omized , double-blind manner , 150 female in patients received 3 mg granisetron ( Group G ) , 1.25 mg droperidol ( Group D ) or 3 mg granisetron plus 1.25 mg droperidol ( Group GD)(n = 50 for each ) i.v . immediately before the induction of anaesthesia . The same st and ard general anaesthetic technique , which consisted of isoflurane and nitrous oxide in oxygen , was used . Nausea , vomiting and safety assessment s were performed continuously during the first 24 hr after anaesthesia . RESULTS Complete response , defined as no PONV and no administration of rescue antiemetic medication , was 86 % in Group G , 64 % in Group D and 98 % in Group GD ( P = 0.03 vs Group G , P = 0.001 vs Group D ) . No clinical ly adverse events were observed in any group . CONCLUSION Granisetron-droperidol combination is more effective than each antiemetic alone in the prevention of PONV after laparoscopic cholecystectomy Drugs with anti-emetic properties can exert their actions at more than one receptor site , histamine H1 , muscarinic cholinergic or dopaminergic D2 receptors . This study was design ed to test the hypothesis that a combination of drugs acting at different receptor sites in lower than st and ard doses would be at least as effective as a st and ard therapeutic dose of a single anti-emetic agent . A combination of droperidol , hyoscine and metoclopramide in subtherapeutic doses has been shown to be at least as effective as droperidol ( 1.25 mg ) alone . In both groups there was a low incidence of emetic sequelae in the first 3 hours postoperatively Purpose This study tested the hypothesis that the antiemetic effects of a combination of ondansetron and propofol were superior to propofol alone in children undergoing tonsillectomy surgery . Methods A prospect i ve , r and omized , double-blind , placebo-controlled study design was employed . Young children underwent mask induction with halothane , nitrous oxide and oxygen and then hadiv access established : older children hadiv induction with propofol . All patients received 0.3 mg·kg−1 mivacurium and 2–4 μg·kg−1 fentanyliv and 30 mg·kg−1 acetaminophenpr to a maximum dose of 650 mg . Following induction , patients received either 100 μg·kg−1 ondansetron or placebo . Anaesthesia was maintained with 120 – 140 μg·kg−1·min−1 propofol , nitrous oxide and oxygen to maintain vital signs within 20 % of baseline . After surgery , in all patients the tracheas were extubated in the operating room without use of neuromuscular reversing agents . Episodes of emesis were recorded by PACU nurses for four to six hours . A telephone interview on the following day was also used for data recovery . Groups were compared in relation to age using the Mann-Whitney test , and with respect to sex and number of episodes of vomiting using the Fisher Exact Test . Results Three of the 45 patients who received ondansetron vomited ( 6.7 % ) , whereas 10 of the 45 patients who received placebo vomited ( 22.2 % ) . ( P = 0.035 ) Conclusion Ondansetron in a dose of 100 μg·kg−1 , when combined with propofol for children undergoing ton-sillectomy reduced the incidence of postoperative vomiting to very low levels . RésuméObjectifVérifier l’hypothèse voulant que les effets antiémétiques d’une combinaison d’ondansétron et de propofol soit supérieure à ceux du propofol seul chez des enfants qui subissent une amygdalectomie . MéthodeOn a utilisé une étude prospect i ve , r and omisée et en double aveugle contre placebo . Chez les jeunes enfants , l’induction au masque s’est faite avec de l’halothane et un mélange de protoxyde d’azote et d’oxygène , et on a établi ensuite l’accèsiv ; chez les enfants plus âgés , c’était une inductioniv avec du propofol . Tous les patients ont reçu 0,3 mg·kg−1 de mivacurium et 2 — 4 μg·kg−1 de fentanyliv et 30 mg·kg−1 d’acétaminophènepr jusqu’à une dose maximale de 650 mg . Après l’induction , les patients ont reçu soit 100 μg·kg−1 d’ondansétron ou un placebo . L’anesthésie a été maintenue avec 120 – l40 μg·kg−1·min−1 de propofol et d’un mélange de protoxyde d’azote et d’oxygène pour conserver les signes vitaux à ± 20 % des mesures de base . Après la chirurgie , on a extubé tous les patients dans la salle d’opération sans utiliser de décurarisant . Les épisodes de vomissements ont été notés pour une période de 4 – 6 h par les infirmières de la salle de réveil . Le jour suivant , une interview téléphonique a aussi fourni des données sur la récupération . On a comparé les groupes selon l’âge par le test de Mann-Whitney et selon le sexe et le nombre d’épisodes de vomissements par le test exact de Fisher . RésultatsTrois patients sur 45 qui ont reçu de l’ondansétron ont eu des vomissements ( 6,7 % ) , mais 10 patients sur 45 qui avaient reçu le placebo ( 22,2 % ) . ( P = 0,035 ) Conclusion Une dose de 100 μg·kg−1 d’ondansétron combinée à du propofol et administrée à des enfants lors d’une amygdalectomie a réduit l’incidence postopératoire de vomissements à de très bas niveaux Background The safety and antiemetic efficacy of CP-122,721 , a novel neurokinin-1 antagonist , was evaluated when administered alone or in combination with ondansetron . Methods Using a r and omized , double-blind , placebo-controlled study design , CP-122,721 was initially compared with placebo and subsequently to ondansetron alone and in combination for prophylaxis against postoperative nausea and vomiting in 243 women undergoing abdominal hysterectomy . In the dose-ranging studies ( n = 86 ) , patients received either CP-122,721 100 mg ( vs. placebo ) or 200 mg ( vs. placebo ) orally 60–90 min before induction of anesthesia . In the interaction study ( n = 157 ) , patients received CP-122,721 200 mg or placebo 60–90 min before induction of anesthesia , and ondansetron 4 mg or saline 2 ml intravenously 15–30 min before the end of surgery . Patients assessed their level of nausea and pain on arrival in the postanesthesia care unit and at 0.5- , 1- , 1.5- , 2- , 4- , 8- , 12- , and 24-h intervals postoperatively . Emetic episodes , need for rescue antiemetic – antinausea medication , postoperative complications , and patient satisfaction were recorded . Results In the initial dose-ranging study , only 10 % of the patients experienced emesis within the first 8 h after surgery with CP-122,721 200 mg compared with 50 % in the placebo group . CP-122,721 200 mg also decreased the need for rescue medication ( 25%vs . 48 % ) . CP-122,721 100 mg was less effective than 200 mg in decreasing the incidence of repeated episodes of emesis . In the interaction study , 6 % of the patients receiving CP-122,721 200 mg orally experienced emesis less than 2 h after surgery compared with 17 % with ondansetron alone . With combined therapy , only 2 % experienced emesis . In addition , the median times for 75 % of patients to remain free from postoperative nausea and vomiting were 82 , 75 , and 362 min in the ondansetron , CP-122,721 , and combination groups , respectively . Conclusions Oral CP-122,721 200 mg decreased emetic episodes compared with ondansetron ( 4 mg intravenously ) during the first 24 h after gynecologic surgery ; however , there was no difference in patient satisfaction Background : In an era of growing economic constraints on healthcare delivery , anesthesiologists are increasingly expected to underst and cost analysis and evaluate clinical practice s. Postoperative nausea and vomiting ( PONV ) are distressing for patients and may increase costs in an ambulatory surgical unit . The authors compared the cost-effectiveness of four prophylactic intravenous regimens for PONV:—4 mg ondansetron , 0.625 mg droperidol , 1.25 mg droperidol , and placebo . Methods : Adult surgical out patients at high risk for PONV were studied . Study drugs were administered intravenously within 20 min of induction of nitrous oxide – isoflurane or enflurane anesthesia . A decision-tree analysis was used to group patients into 12 mutually exclusive subgroups based on treatment and outcome . Costs were calculated for the prevention and treatment of PONV . Cost-effectiveness analysis was performed for each group . Results : Two thous and sixty-one patients were enrolled . Efficacy data for study drugs have been previously reported , and the data base from that study was used for pharmacoeconomic analysis . The mean – median total cost per patient who received prophylactic treatment with 4 mg ondansetron , 0.625 mg droperidol , 1.25 mg droperidol , and placebo were $ 112 or $ 16.44 , $ 109 or $ 0.63 , $ 104 or $ 0.51 , and $ 164 or $ 51.20 , respectively ( P = 0.001 , active treatment groups vs. placebo ) . The use of a prophylactic antiemetic agent significantly increased patient satisfaction ( P < 0.05 ) . Personnel costs in managing PONV and unexpected hospital admission constitute major cost components in our analysis . Exclusion of nursing labor costs from the calculation did not alter the overall conclusions regarding the relative costs of antiemetic therapy . Conclusion : The use of prophylactic antiemetic therapy in high-risk ambulatory surgical patients was more effective in preventing PONV and achieved greater patient satisfaction at a lower cost compared with placebo . The use of 1.25 mg droperidol intravenously was associated with greater effectiveness , lower costs , and similar patient satisfaction compared with 0.625 mg droperidol intravenously and 4 mg ondansetron intravenously Background : Pediatric strabismus surgery is associated with a very high incidence of postoperative nausea and vomiting [ ( PONV ) 44–88 % ] . Droperidol ( 10–75 μg kg−1 ) and ondansetron ( 50–150 μg kg−1 ) have shown variable success in reducing the incidence and severity of PONV . Combination of these two drugs has shown promising results . This r and omized , double‐blind , placebo‐controlled clinical trial was conducted to evaluate the efficacy and safety of the combination of these two drugs in reducing the incidence and severity of PONV in pediatric strabismus surgery We have compared the efficacy and safety of combined granisetron and droperidol with each anti-emetic alone for preventing post-operative nausea and vomiting after thyroidectomy . In a prospect i ve , r and omized , double-blind study , 180 women received granisetron 40 micrograms kg-1 , droperidol 20 micrograms kg-1 , or granisetron 40 micrograms kg-1 plus droperidol 20 micrograms kg-1 ( n = 60 of each ) intravenously immediately before induction of anaesthesia . A st and ard general anaesthetic technique and post-operative analgesia were used . A complete response , defined as no post-operative nausea and vomiting and no need for another rescue anti-emetic , during the first 24 h after anaesthesia occurred in 88 % , 60 % and 98 % of patients who had received granisetron , droperidol and granisetron plus droperidol ( P < 0.05 ; overall Fisher 's exact probability test ) . No clinical ly important adverse events due to the drugs were observed in any of the groups . In summary , prophylactic use of combined granisetron and droperidol is more effective than each drug alone for the prevention of post-operative nausea and vomiting in female patients undergoing thyroidectomy We conducted a prospect i ve , r and omized , double-blind clinical trial comparing droperidol 1.25 mg intravenously ( i.v . ) ( group 1 , n = 30 ) , ondansetron 4 mg i.v . ( group 2 , n = 30 ) , or both ( group 3 , n = 30 ) in the prevention of postoperative nausea and vomiting ( PONV ) in the first 24 h following major gynaecological procedures under combined general and epidural anaesthesia . PONV was analysed by a linear nausea/vomiting score , incidence of nausea and vomiting , and the need for antiemetic rescue . Our results showed a similar incidence of nausea and vomiting in all groups ( G1 33 % , G2 40 % , G3 43 % ) . However , when comparisons were made according to the time of assessment , combination therapy result ed in significantly lower PONV than droperidol in the first hour ( 0 % vs. 13 % , P < 0.05 ) and second hour ( 0 % vs. 13 % , P < 0.05 ) , and than ondansetron on the first hour ( 0 % vs. 13 % , P < 0.05 ) . A trend persisted up to the fourth hour but was not statistically significant in either group . In conclusion , droperidol and ondansetron are effective agents in the prevention of PONV , and their combination seems to provide slightly better results than either drug alone We have performed a prospect i ve , r and omized , double-blind clinical study to assess the efficacy of ondansetron , droperidol , or both , in preventing postoperative emesis . We studied 242 patients undergoing biliary or gynaecological surgery under general anaesthesia . Shortly before induction of anaesthesia , patients received : saline i.v . ( group I , n = 62 ) ; droperidol 2.5 mg i.v . ( group 2 , n = 60 ) ; ondansetron 4 mg i.v . ( group 3 , n = 57 ) ; or droperidol 2.5 mg with ondansetron 4 mg i.v . ( group 4 , n = 63 ) . Nausea occurred in 45 % , 37 % , 32 % and 29 % ( P = 0.234 ) and vomiting in 23 % , 17 % , 9 % and 5 % ( P = 0.016 ) of patients in groups 1 , 2 , 3 and 4 , respectively , during the first 24 h. Groups 2 and 4 had greater sedation scores than group 1 during the first 3 h ( P < 0.01 ) . We conclude that both droperidol and ondansetron showed a significant antiemetic effect , ondansetron was not significantly better than droperidol , and the combination of droperidol and ondansetron was better than droperidol but no better than ondansetron alone We have compared the efficacy of granisetron in combination with dexamethasone with each drug alone in the prevention of postoperative nausea and vomiting ( PONV ) after middle ear surgery . In a r and omized , double-blind study , 120 patients ( 85 females ) received granisetron 3 mg , dexamethasone 8 mg or granisetron 3 mg with dexamethasone 8 mg i.v . ( n = 40 in each group ) , immediately before induction of anaesthesia . A st and ardized general anaesthetic technique was used . A complete response , defined as no PONV and no need for another rescue antiemetic during the first 3 h after anaesthesia , was recorded in 83 % , 50 % and 98 % of patients who had received granisetron , dexamethasone and granisetron-dexamethasone , respectively . The corresponding incidences during the next 21 h after anaesthesia were 80 % , 55 % and 98 % ( P < 0.05 ; overall Fisher 's exact probability test ) . In summary , prophylactic use of combined granisetron and dexamethasone was more effective than each antiemetic alone for the prevention of PONV after middle ear surgery Background : Dexamethasone decreases chemotherapy‐induced emesis when added to an antiemetic regimen . This study was undertaken to evaluate the efficacy of granisetron‐dexamethasone combination for the prevention of postoperative nausea and vomiting ( PONV ) in female patients undergoing general anaesthesia for breast surgery We have studied the effect of combination antiemetic therapy ( ondansetron and droperidol ) with morphine delivered by patient‐controlled analgesia following major gynaecological surgery . Sixty patients were r and omly allocated to one of three treatment regimens ; ondansetron alone ( 4 mg bolus and 0.13 mg.ml‐1 in the morphine solution ) , droperidol alone ( 1.25 mg bolus and 0.05 mg.ml‐1 in the morphine solution ) , or both drugs in combination . For the first 12 postoperative hours , patients receiving combination therapy experienced significantly less nausea than those receiving single antiemetic therapy ( p < 0.001 ) . There was no difference between the regimens from 12 to 18 h. We conclude that a combination of ondansetron and droperidol added to morphine in a patient‐controlled analgesia system reduces postoperative nausea to a greater extent than treatment with either drug alone following major gynaecological surgery We have compared the efficacy and safety of the combination granisetron-droperidol with each antiemetic alone in preventing postoperative nausea and vomiting ( PONV ) after breast surgery . In a r and omized , double-blind study , 150 female patients received granisetron 3 mg , droperidol 1.25 mg or granisetron 3 mg with droperidol 1.25 mg ( n = 50 each ) i.v . , immediately before induction of anaesthesia . A st and ard general anaesthetic technique was used . The incidence of PONV during the first 24 h after anaesthesia was 18 % with granisetron , 38 % with droperidol and 4 % with the granisetron-droperidol combination ( P < 0.05 ; overall Fisher 's exact probability test ) . We conclude that the granisetron-droperidol combination was more effective than each antiemetic alone in the prevention of PONV in female patients undergoing breast surgery Background Ondansetron and dexamethasone have been observed to decrease the incidence of vomiting by children after general anesthesia . This study compared the effect of high‐dose ( 150 micro gram/kg ) ondansetron with low‐dose ( 50 micro gram/kg ) ondansetron plus 150 micro gram/kg dexamethasone on the incidence of vomiting after strabismus in children . Methods This study had a double‐blind , blocked , stratified , r and omized design . With parental consent and Hospital Ethics Committee approval , healthy children aged 2–14 yr who were undergoing elective strabismus surgery were studied . Anesthesia was induced intravenously with propofol or by inhalation with halothane and nitrous oxide . Patients in the high‐dose group were given placebo plus 150 micro gram/kg ( maximum dose , 8 mg ) of ondansetron intravenously , whereas patients in the low‐dose group were given 150 micro gram/kg dexamethasone ( maximum dose , 8 mg ) and 50 micro gram/kg ondansetron intravenously in a double‐blind manner . Anesthesia was maintained with halothane and nitrous oxide . All incidences of vomiting occurring as long as 24 h after anesthesia were recorded . Results Three of the 200 patients enrolled in the study were excluded from data analysis . The groups were similar with respect to demographic data and potential confounding variables . Patients vomited from 0–12 times . The low‐dose ondansetron plus dexamethasone group had a lower incidence of vomiting , 9 % ( 95 % CI = 4–17 % ) versus 28 % ( 95 % CI = 20–38 % ; P < 0.001 ) . Only 1 % of the patients in the low‐dose ondansetron plus dexamethasone group vomited while in the hospital . Conclusions Low‐dose ondansetron plus dexamethasone is an effective prophylactic antiemetic combination for children undergoing strabismus surgery Purpose : Dimenhydrinate and metoclopramide are inexpensive antiemetic drugs . Metoclopramide , especially , has been stueied extensively in the past , but there are no studies on the combination of both drugs for prevention of postoperative nausea and vomiting ( PONV ) . Methods : One hundred and sixty male in patients undergoing endonasal surgery were r and omized to receive one of four antiementic regimens in a double-blind manner : placebo , 1 mg·kg−1 dimenhydrinate , 0.3 mg·kg−1 metoclopramide , or the combination of both drugs was administered after induction of anesthesia . Patients received a second dose of these drugs six hours after the first administration to mitigate their short half-life . St and ardized general anesthesia included benzodiazepine premedication , propofol , desflurane in N2O/O2 vecuronium , and a continuous infusion of remifentanil . Postoperative analgesia and antiemetic rescue medication were st and ardized . Episodes of vomiting , retching , nausea , and the need for additional antiedmetics were recorded for 24 hr . The incidences of PONV were analyzed witth Fisher ’s Exact test and the severity of PONV ( rated by a st and ardized scoring algorithm ) with the Jonckheere- Terpestra-test . Results : The incidence of patients free from PONV was 62.5 % in the placebo-group and increased to 72.5 % in the metoclopramide-group ( P=0.54 ) , 75.0 % in the dimenhydrinate-group ( P=0.34 ) , and 85.0 % in the combination- group ( P=0.025 ) . In the latter group , the severity of PONV was reduced compared with placebo treatment ( P=0.017 ; Jonckheere-Terpestra-test ) . Conclusion : Dimenhydrinate and metoclopramide were ineffective in reducing the incidence and the severity of PONV . Their combination reduced the incidence of PONV compared with placebo . RésuméObjectif : Le dimenhydrinate et le métoclopramide sont des antiémétiques pas chers . Beaucoup d’études ont déjà été faites , avec le métoclopramide surtout , mais aucune avec la combinaison des deux comme moyen de prévention des nausées et des vomissements postopératoires (NVPO).Méthode : Cent soixante patients masculins qui devaient subir une intervention endonasale ont consenti à participer à une étude prospect i ve , r and omisée et en double aveugle , et à recevoir un des quatre traitements antiémétiques suivants : un placebo ; 1 mg·kg−1 de dimenhydrinate ; 0,3 mg·kg−1 de métoclopramide ou une combinaison des deux médicaments après l’induction de l’anesthésie . Ceux qui ont reçu du dimenhydrinate ou les deux médicaments ont eu une seconde dose de dimenhydrinate six heures après la première étant donné la courte demi-vie de ce médicament . L’anesthésie générale st and ardisée comprenait une prémédication de benzodiazépine , du propofol , du desflurane dans un mélange de N2O/O2 , du vécuronium et une perfusion continue de rémifentanil . L’analgésie postopératoire et les antiémétiques de rattrapage ont été st and ardisés . Les nausées , les vomissements , les efforts pour vomir et les dem and ses d’antkémétiques additionnels ont été enregistrés pendant 24 h. Les incidences de NVPO ont été analysées selon le test Exact de Fisher et la sévérité des NVPO ( estimée avec un algorithme de cotation st and ardisé ) , avec le test de Jonckheere-Terpestra . Résultats : L’absence de NVPO a été de 62,5 % dans le groupe placebo et a augmenté à 72,5 % parmi les patients qui ont reçu du métoclopramide ( P=0,54 ) ; à 75,0 % chez ceux qui ont reçu du dimenhydrinate ( P= 0,34 ) et à 85,0 % chez ceux qui ont reçu les deux médicaments ( P= 0,025 ) . La sévérité des NVPO a été réduite chez les patients recevant la combinaison de médicaments , comparés à ceux qui ont reçu le placebo ( P=0,017 ; test de Jonckheere-Terpestra ) . Conclusion : Le dimenhydrinate et le métoclopramide n’ont pas réduit l’incidence et la sévérité des NVPO . Leur combinaison , comparée placebo , a diminué l’incidence de NVPO This study was undertaken to compare the efficacy and safety of granisetron , a 5-hydroxytryptamine type 3 receptor antagonist , and dexamethasone and each drug alone for the prevention of post-operative vomiting by children , with no history of motion sickness and /or previous post-operative vomiting , undergoing general inhalational anaesthesia for surgery ( inguinal hernia and phimosis ) . In a r and omized , double-blind manner , 150 children , ASA physical status 1 , aged 4 - 10 years , were assigned to receive granisetron 40 mg kg-1 , dexamethasone 150 mg kg-1 , or granisetron 40 mg kg-1 plus dexamethasone 150 mg kg-1 intravenously immediately after inhalation induction of anaesthesia ( n = 50 of each ) . A complete response , defined as no emesis and no need for another rescue anti-emetic during the first 24 h after anaesthesia , was 86 % with granisetron , 68 % with dexamethasone and 98 % with granisetron plus dexamethasone , respectively ( P < 0.05 ; overall Fisher 's exact probability test ) . No clinical ly serious adverse events were observed in any of the groups . In conclusion , prophylactic therapy with combined granisetron and dexamethasone was more effective than was each anti-emetic alone for the prevention of vomiting after paediatric surgery The aim of this study was to compare the efficacy and safety of ondansetron plus droperidol with each drug alone or placebo in the prevention of postoperative nausea and vomiting (PONV).One hundred females , aged 18 - 65 yr , ASA physical status I-II , undergoing general anesthesia for elective abdominal surgery were included in a prospect i ve , double-blind , placebo-controlled , r and omized study . A st and ardized anesthetic technique and postoperative analgesia ( ketorolac plus patient-controlled analgesia [ PCA ] with morphine ) were used in all patients . Patients were r and omly assigned to receive placebo ( Group 1 , n = 25 ) , droperidol 2.5 mg with induction of anesthesia and 1.25 mg 12 h later ( Group 2 , n = 25 ) , ondansetron 4 mg with induction ( Group 3 , n = 25 ) , and ondansetron plus droperidol at the same doses as Groups 3 and 2 , respectively ( Group 4 , n = 25 ) . A complete response , defined as no PONV in 48 h , occurred in 28 % of patients in Group 1 , 60 % in Group 2 ( P < 0.05 vs Group 1 ) , 56 % in Group 3 ( P < 0.05 vs Group 1 ) , and 92 % in Group 4 ( P < 0.01 vs Groups 1 , 2 , and 3 ) . Sedation was significantly greater with droperidol ( Groups 2 and 4 ) for 12 h postoperatively . In conclusion , the combination of ondansetron plus droperidol was more effective than each antiemetic alone or placebo in the prevention of PONV in women undergoing elective abdominal surgery . ( Anesth Analg 1996;83:117 - 22 The anti-emetic efficacy of prophylactic ondansetron and tropisetron in combination with a low dose of droperidol in patients with high probability for post-operative nausea and vomiting undergoing gynaecological laparoscopy was compared . Patients were r and omly allocated in a double-blind manner to receive either ondansetron 8 mg ( n = 45 ) or tropisetron 5 mg ( n = 43 ) at the end of surgery . A st and ardized general anaesthetic technique was used , including droperidol 0.75 mg . The incidence of nausea was 36 % and 49 % ( P = 0.28 ) , and vomiting occurred in 13 % and 14 % of the patients in the ondansetron and tropisetron groups , respectively . The onset time for rescue medication was significantly sooner after tropisetron than ondansetron ( 3 h 18 min vs. 6 h 25 min ; P = 0.007 ) . There were no statistically significant differences in efficacy between prophylactic ondansetron and tropisetron combined with droperidol in a high-risk population . However , ondansetron appeared to be more effective in preventing post-operative nausea and vomiting in the early hours after surgery compared with tropisetron We observed 50 patients receiving high‐dose cisplatin‐based chemotherapy in a prospect i ve , r and omized double‐blind trial . One group received metoclopramide ( MCP ) alone ( total dose , 6 mg/kg ) , whereas the other group was given dexamethasone ( DMS ) ( total dose , 60 mg ) in addition to MCP . The patient characteristics of the two groups were comparable , confirming satisfactory r and omization . Multivariate regression analysis failed to show any statistical significance in the antiemetic response between the two treatment groups . However , female patients receiving Adriamycin ( Adria Laboratories , Columbus , OH ) concurrently and obese persons exhibited more vomiting . The overall antiemetic response rate was 66 % . Because the side effects were minimal , a higher dose of MCP is expected to improve emetic control without increasing toxicity . The use of a 36‐hour assessment period in our study gave more meaningful data . An exponential increase in the dose of MCP is probably required , with respect to weight , to obtain the same antiemetic efficacy STUDY OBJECTIVES To determine the incidence of postoperative nausea and vomiting when a combination of ondansetron and promethazine is given prophylactically , and to ascertain the effect of postoperative nausea and vomiting on recovery room duration and patient satisfaction . DESIGN Prospect i ve , r and omized , placebo-controlled , double-blind study . SETTING University-affiliated tertiary-care hospital . PATIENTS 87 ASA physical status I and II adult patients scheduled for middle ear surgery . INTERVENTIONS Patients were r and omly assigned to receive one of the following interventions intravenously : ondansetron 4 mg ( Group 1 ) , promethazine 25 mg ( Group 2 ) , ondansetron 2 mg plus promethazine 12.5 mg ( Group 3 , combination ) , or placebo ( Group 4 ) . MEASUREMENTS AND MAIN RESULTS Independent , study blinded observers recorded complaints of nausea and number of episodes of vomiting for 24 hours following the patient 's first response to comm and s. All patients were contacted the day after discharge to inquire about nausea and vomiting . The awakening time , postanesthesia care unit and day surgery unit duration s , opioid use , and side effects were recorded . At the end of the 24-hour period , the study blinded observers asked patients for an overall assessment of their global anesthesia experience using an 11-point scale . During the 24-hour period , the incidence of postoperative nausea and vomiting was reduced from 74 % ( placebo ) to 39 % ( promethazine ; p = 0.03 ) and 29 % ( combination ; p = 0.003 ) . Compared with placebo , the severity of vomiting was significantly less in the combination group ( p = 0.04 ) . The number of very satisfied patients correlated negatively with the incidence of postoperative nausea and vomiting ( p < 0.0001 ) and with the severity of vomiting ( p = 0.003 ) . CONCLUSION The prophylactic use of an antiemetic with middle ear surgery may reduce postoperative nausea and vomiting over 24 hours , and the ondansetron/promethazine combination or promethazine alone are cost-effective choices . Finally , the combination reduced significantly the severity of vomiting We studied 100 ASA I-II females undergoing general anaesthesia for major gynaecological surgery , in a prospect i ve , double-blind , placebo-controlled , r and omized study . Patients received one of four regimens for the prevention of postoperative nausea and vomiting ( PONV ) : ondansetron 4 mg ( n = 25 ) , dexamethasone 8 mg ( n = 25 ) , ondansetron with dexamethasone ( 4 mg and 8 mg , respectively , n = 25 ) or placebo ( saline , n = 25 ) There were no differences in background factors or factors related to operation and anaesthesia , morphine consumption , pain or side effects between groups . The incidence of nausea and emetic episodes in the ondansetron with dexamethasone group was lower than in the placebo ( P < 0.01 ) , ondansetron ( P < 0.05 ) and dexamethasone ( P = 0.057 ) groups . There were no differences between ondansetron and dexamethasone , and both were more effective than placebo ( P < 0.05 and P < 0.01 , respectively ) . Dexamethasone appeared to be preferable in preventing nausea than emetic episodes . Fewer patients in the ondansetron with dexamethasone group needed antimetic rescue ( P < 0.01 vs placebo and P < 0.05 vs ondansetron ) . We conclude that prophylactic administration of combined ondansetron and dexamethasone is effective in preventing PONV This study was undertaken to compare the efficacy of granisetron plus droperidol with each antiemetic alone for the prevention of vomiting after paediatric strabismus surgery . In a prospect i ve , r and omized , double-blinded trial , 120 ASA physical status I children , aged 4 - 10 years , received granisetron 40 microg.kg- 1 , droperidol 50 microg.kg- 1 , granisetron 40 microg.kg- 1 plus droperidol 50 microg.kg- 1 ( n=40 of each ) intravenously after an inhalation induction of anaesthesia . A complete response , defined as no vomiting , no retching and no need for another rescue antiemetic medication , during 0 - 3 h after anaesthesia was 80 % with granisetron , 45 % with droperidol and 98 % with granisetron plus droperidol , respectively ; the corresponding incidence during 3 - 24 h after anaesthesia was 78 % , 38 % and 98 % ( P < 0.05 ; overall chi-squared test with Yates continuity correction ) . No clinical ly important adverse events were observed in any of the groups . In conclusion , a combination of granisetron and droperidol was more effective than granisetron or droperidol as a sole antiemetic for the prevention of postoperative vomiting in children undergoing strabismus repair Droperidol and dimenhydrinate are inexpensive antiemetic drugs . Droperidol , especially , has been studied extensively , but there are no studies on the combination of both drugs for prevention of post-operative nausea and vomiting . One hundred and forty male hospitalized patients undergoing nasal surgery were r and omized to receive one of four anti-emetic regimes : placebo , dimenhydrinate ( 1 mg kg-1 ) , droperidol ( 15 micrograms kg-1 ) , or the combination of both drugs ( droperidol 15 micrograms kg-1 + dimenhydrinate 1 mg kg-1 ) administered after induction of anaesthesia . Patients in the dimenhydrinate-group and the combination-group received a second dose of dimenhydrinate 6 h after the first administration to mitigate the short half-life of the drug . For general anaesthesia a st and ardized technique , including benzodiazepine premedication , propofol , desflurane in N2O/O2 , vecuronium , and a continuous infusion of remifentanil , was used . Post-operative analgesia and anti-emetic rescue medication were st and ardized . Episodes of vomiting , retching , nausea , and the need for additional anti-emetics were recorded for 24 h. The main endpoint of this study was the number of patients who were completely free of post-operative nausea and vomiting ( Fisher 's Exact Test ) . Furthermore , the severity of post-operative nausea and vomiting was analysed using a st and ardized scoring algorithm . The incidence of patients completely free of post-operative nausea and vomiting was 62.9 % in the placebo-group , 77.1 % in the dimenhydrinate-group ( P = 0.21 ) , and 82.9 % in the droperidol-group ( P = 0.07 ) . This increased to 94.3 % in the combination-group ( P = 0.0015 ) . In all three treatment groups the severity of post-operative nausea and vomiting was reduced significantly compared with placebo treatment ( P = 0.0003 ) . The incidence of side effects was similar in the four groups . Dimenhydrinate was ineffective in reducing the incidence of post-operative nausea and vomiting and droperidol only reduced the severity of post-operative nausea and vomiting . However , the combination of both drugs significantly reduces the incidence of post-operative nausea and vomiting when compared with placebo treatment A multicentre , r and omised , double-blind , cross-over trial was done to compare the efficacy and safety of a serotonin receptor antagonist -- ondansetron-- and dexamethasone in the prophylaxis of acute and delayed emesis and nausea induced by moderately emetogenic non-platinum-containing chemotherapy regimens . Patients were treated as out patients and received intravenous ondansetron 4 mg or dexamethasone 8 mg before chemotherapy and oral maintenance ( ondansetron 4 mg every 6 h and dexamethasone reducing from 4 mg to 1 mg 6-hourly between days 1 and 5 ) for 5 days . 112 patients were treated ( 38 men , 73 women , 1 with no gender recorded ; age range 30 - 73 years ) and 100 were evaluable for cross-over analysis . Patients taking ondansetron or dexamethasone reported no significant difference in complete and major control of acute ( 83 % vs 79 % , p = 0.46 ) or delayed ( 82 % vs 88 % , p = 0.214 ) emesis ( vomiting plus retches ) . Significantly more patients on dexamethasone ( 87 % ) than on ondansetron ( 72 % ) reported control of delayed nausea ( days 2 - 5 ) ( p = 0.003 ) . Both drugs were well tolerated with no significant difference in the number of adverse events , and this is reflected by similar patient preference for ondansetron ( 40 % ) and dexamethasone ( 30 % ) ( p = 0.244 ) . Both drugs offer adequate out-patient control of chemotherapy-induced emesis ; however , dexamethasone has an advantage in the control of delayed nausea , and also in terms of cost and re source allocation Background Breast surgery is associated with a high incidence of postoperative nausea and vomiting . Propofol and prophylactic administration of ondansetron are associated with a lower incidence of postoperative nausea and vomiting . To date no comparison of these two drugs has been reported . A r and omized study was done to compare the efficacy of ondansetron and intraoperative propofol given in various regimens . Methods Study participants included 89 women classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled for major breast surgery . Patients were r and omly assigned to one of four groups . Group O received 4 mg ondansetron in 10 ml 0.9 % saline and groups PI , PIP , and PP received 10 ml 0.9 % saline before anesthesia induction . Group O received thiopental , isoflurane , nitrous oxide-oxygen , and fentanyl for anesthesia . Group PI received propofol , isoflurane , nitrous oxide-oxygen , and fentanyl . Group PIP received propofol , isoflurane , nitrous oxide-oxygen , and fentanyl . Thirty minutes before expected skin closure , isoflurane was discontinued and 50 to 150 micro gram [ centered dot ] kg sup -1 [ centered dot ] min sup -1 propofol was given intravenously to maintain anesthesia . Group PP received propofol for induction and maintenance of anesthesia , nitrous oxide-oxygen , and fentanyl . Postoperative pain relief was provided with morphine administered by a patient-controlled analgesia pump . The incidence of nausea and vomiting , requests for rescue antiemetic and sedation , pain scores , and hemodynamic data were recorded for 24 h. Results Within 6 h of surgery , groups O and PP had a lower incidence of nausea compared with groups PI and PIP ( P < 0.05 ) . Fewer patients in group PP ( 19 % ) vomited during the 24-h period compared with groups O ( 48 % ) , PI ( 64 % ) , and PIP ( 52 % ) ( P < 0.05 ) . The incidence of antiemetic use was also less in group PP ( P < 0.05 ) . Patients in group PP had lower sedation scores at 30 min and at 1 h ( P < 0.05 ) . There were no differences among the groups in pain scores , blood pressure , heart rate , respiratory rate , and incidence of pruritus . Conclusions Propofol administered to induce and maintain anesthesia is more effective than ondansetron ( with thiopental-isoflurane anesthesia ) in preventing postoperative vomiting and is associated with fewer requests for rescue antiemetic and sedation in the early phase of recovery . It is equally effective in preventing postoperative nausea as ondansetron in the first 6 h after operation . Propofol used only as an induction agent or for induction and at the end of surgery were not as protective against postoperative nausea and vomiting Purpose : To determine the efficacy of ondansetron and droperidol , alone and in combination , administered for prophylaxis of postoperative nausea and vomiting ( PONV ) in women undergoing general anesthesia for out-patient gynecological laparoscopy . Methods : Following Institutional Ethics Board approval and patient consent , 160 female out- patients scheduled for laparoscopy were r and omly allotted in a double-blind fashion to receive : i ) saline ( placebo ) , ii ) 4 mg ondansetron , iii ) 1.25 mg droperidol , or iv ) 4 mg ondansetron and 1.25 mg droperidol combination intravenously on induction . Following a st and ardized general anesthesia , patients were interviewed and assessed for PONV at various times . Results : During the first 24 hr after surgery , the incidence of PONV in the placebo group was 71 % . This was reduced to 61 % with droperidol alone ( P=0.334 ) , to 46 % with ondansetron alone ( P=0.027 ) , and to 23 % with the combination group ( P<0.001 ) . A statistically significant difference was observed between combination and droperidol ( P<0.001 ) and between combination and ondansetron ( P=0.036 ) . There were fewer requests for rescue medication from the combination group ( 7.7 % ) than from the ondansetron and placebo groups . Conclusion : The results of this study suggest that the combination of 4 mg ondansetron and 1.25 mg droperidol is more efficacious as a prophylactic anti-emetic than either agent alone during the 24 hr post-surgery . This additive effect may be due to the different mechanisms of action of ondansetron and droperidol . RésuméObjectif : Déterminer l’efficacité de l’ondansétron et du dropéridol , seuls ou combinés , administrés comme prophylaxie des nausées et vomissements postopératoires ( NVPO ) chez des patientes sous anesthésie générale lors d’une laparoscopie gynécologique en clinique externe . Méthode : Après avoir obtenu l’autorisation du Comité d’éthique médicale et le consentement des patientes , on a procédé à l’étude de 160 femmes , réparties au hasard en double aveugle , qui ont reçu avant la laparoscopie ambulatoire prévue : i ) une solution salée ( placebo ) , ii ) 4 mg d’ondansétron , iii ) 1,25 mg de dropéridol , ou iv ) une combinaison intraveineuse de 4 mg d’ondansétron et de 1,25 mg de dropéridol à l’induction de l’anesthésie . Après l’anesthésie générale st and ard , les patientes ont été interrogées sur les NVPO à différents temps . Résultats : Pendant les 24 premières heures postopératoires , l’incidence des NVPO ont été de 71 % dans le groupe placebo . Cette incidence a été réduite à 61 % avec de dropéridol employé seul ( P=0,334 ) , à 46 % avec l’ondansétron seul ( P=0,027 ) et à 23 % avec la combinaison des deux médicaments ( P<0,001 ) . Une différence statistiquement différente a été observée entre la combinaison et le dropéridol ( P<0,001 ) et entre la combinaison et l’ondansétron ( P=0,036 ) . On enregistre moins de dem and es de médication de rattrapage provenant des patientes qui ont reçu la combinaison de médicaments ( 7,7 % ) que de celles qui ont reçu l’ondansétron ou le placebo . Conclusion : Les résultats de l’étude suggèrent que la combinaison de 4 mg d’ondansétron et de 1,25 mg de dropéridol est plus efficace comme prophylaxie antiémétique que chacun des médicaments utilisés seuls pendant les 24 premières heures postopératoires . Cet effet additionnel pourrait être attribué aux différents mécanismes d’action de l’ondansétron et du dropéridol STUDY OBJECTIVES To test the hypothesis that for major gynecologic surgery the combination of propofol for induction , ondansetron , and dexamethasone would be a more effective antiemetic combination than propofol for induction , ondansetron , and saline ; and to determine if a propofol induction of anesthesia improved our previously reported results when thiamylal was the induction drug . DESIGN Double-blind , r and omized study . SETTING Magee-Womens Hospital , Pittsburgh , Pennsylvania . PATIENTS 80 healthy ASA physical status I , II , and III female in patients scheduled for major gynecologic surgery . INTERVENTIONS After induction of anesthesia with propofol , Group 1 received intravenous ( IV ) ondansetron 4 mg and saline , and Group 2 received IV ondansetron 4 mg followed by IV dexamethasone 20 mg . MEASUREMENTS AND MAIN RESULTS For Group 1 and Group 2 , respectively , no emesis and no rescue occurred in 15 ( 37.5 % ) and 21 ( 52.5 % ) patients ( p = 0.13 ) ; emesis occurred in 7 ( 17.5 % ) Group 1 patients and 5 ( 12.5 % ) Group 2 patients , rescue antiemetic 23 ( 57.5 % ) Group 1 patients and 19 ( 47.5 % ) Group 2 patients . Nausea was reported by 31 ( 77.5 % ) Group 1 patients and 30 ( 75 % ) Group 2 patients . CONCLUSIONS The hypothesis that the addition of dexamethasone to the propofolondansetron combination would significantly reduce postoperative nausea and vomiting ( PONV ) was not confirmed . A propofol induction of anesthesia result ed in a comparable incidence of PONV when compared with our previously reported results using thiamylal for induction of anesthesia for women having major gynecologic operations STUDY OBJECTIVE To compare the prophylactic administration of ondansetron plus droperidol , droperidol plus metoclopramide , and perphenazine to determine effects on postoperative nausea , vomiting , and sedation after laparoscopic cholecystectomy . DESIGN Prospect i ve , r and omized , double-blind study . SETTING University medical center . PATIENTS 212 ASA physical status I and II adults presenting for laparoscopic cholecystectomy . INTERVENTIONS Patients were r and omly assigned to receive one of three prophylactic antiemetic drug combinations : ondansetron 4 mg plus droperidol 0.625 mg ( Group OD ) , droperidol 0.625 mg plus metoclopramide 10 mg ( Group DM ) , or perphenazine 5 mg ( Group P ) . Study drugs were administered intravenously after induction of general anesthesia . MEASUREMENTS AND MAIN RESULTS The groups were similar with respect to gender , age , weight , duration of surgery , numbers of patients receiving intraoperative atropine or ephedrine , number admitted overnight , and time to discharge home . Patients in Group P used lower total doses of opioids than did patients in Group OD . There were no significant differences in postoperative nausea , pain , or sedation scores , in numbers of patients requiring antiemetics ( Group OD , 13 of 66 ; Group DM , 15 of 66 ; Group P , 14 of 68 ) , or in numbers of patients vomiting , either in hospital or during the first postoperative day . CONCLUSIONS These three drug regimens are equivalent for antiemetic prophylaxis before laparoscopic cholecystectomy This study was performed to compare the efficacy of a granisetron-droperidol combination with each antiemetic alone to prevent postoperative vomiting after tonsillectomy with or without adenoidectomy in children . One hundred eighty pediatric patients , ASA physical status I , aged 4 - 10 yr , were enrolled in a prospect i ve , r and omized , double-blind investigation and assigned to one of three treatment regimens : granisetron 40 [ micro sign]g/kg ( Group G ) , droperidol 50 [ micro sign]g/kg ( Group D ) , or granisetron 40 [ micro sign]g/kg plus droperidol 50 [ micro sign]g/kg ( Group GD ) ( n = 60 in each group ) . These drugs were administered IV after an inhaled induction . The same st and ard general anesthetic technique and postoperative analgesia were used throughout . The rate of complete response , defined as no emesis and no need for rescue antiemetic , 0 - 3 h after anesthesia was 83 % in Group G , 60 % in Group D , and 97 % in Group GD ( P = 0.029 versus Group G , P = 0.001 versus Group D ) . The corresponding rates 3 - 24 h after anesthesia were 83 % , 55 % , and 97 % ( P = 0.029 versus Group G , P = 0.001 versus Group D ) . No clinical ly important adverse events were observed in any of the groups . In conclusion , a granisetron-droperidol combination is superior to each antiemetic alone in complete response in children undergoing general anesthesia for tonsillectomy . Implication s : We compared the efficacy of granisetron plus droperidol with each antiemetic alone for the prevention of postoperative vomiting in children . The granisetron-droperidol combination was highly effective against postoperative emesis . ( Anesth Analg 1998;87:761 - 5 The antiemetic activity of droperidol is attributed to antagonizing the dopaminergic neurons of the chemoreceptor trigger zone . Ondansetron is a serotonin ( 5HT ) receptor antagonist at both peripheral and central 5-HT3 receptor sites with no known action on dopamine-mediated activity . We hypothesized that the combination of these two antiemetics would be more effective than droperidol alone . Women with ASA classified physical status I or II , scheduled for laparoscopic tubal b and ing , participated in a r and omized double-blind clinical trial using a st and ardized anesthesia regimen . Within 15 min after induction of anesthesia , Group 1 ( n = 60 ) received IV droperidol 1.25 mg and ondansetron 4 mg and Group 2 ( n = 60 ) received IV droperidol 1.25 mg and saline . Before surgery and during recovery at 1 , 2 , and 24 h , emetic episodes , nausea , pain , drowsiness , medications taken , and adverse events were recorded . The complete response ( no emesis , no rescue ) for Group 1 was 55 of 60 ( 91.6 % ) versus 47 of 60 ( 78.3 % ) in Group 2 ( P = 0.04 ) . No patient needed rescue antiemetic medication in Group 1 , whereas 5 of 60 ( 8.3 % ) patients were rescued in Group 2 ( P = 0.03 ) . There were seven emetic episodes in five patients in Group 1 and 30 emetic episodes in 12 patients in Group 2 over the 24-h study period ( P = 0.03 ) . The time to the first emetic episode was more than twice as long for Group 1 than Group 2 ( P = 0.03 ) and total nausea scores were lower in Group 1 than Group 2 ( P = 0.01 ) . The droperidol/ondansetron combination was significantly superior to droperidol in complete response , time to and number of emetic episodes , and the incidence and severity of nausea in women having tubal b and ing . ( Anesth Analg 1996;83:1218 - 22 During the past decade the dem and for outpatient surgery has grown rapidly . To keep pace with the changing surgical environment , anesthesiologists have been modifying their anesthetic techniques to ensure a more rapid and a smoother recovery . However , postoperative nausea and vomiting remain the most common anesthesia-related side effects in outpatient surgical facilities ( 1,2 ) . The incidence of postoperative nausea and vomiting in female out patients undergoing laparoscopy has been reported to be as high as 50 - 60 % ( 3 ) . The incidences after strabismus surgery ( 4 ) and after therapeutic abortions ( 5 ) are also high . A prophylactic antiemetic would be of great value in outpatient surgery and anesthesia . A large number of papers have been published suggesting the use of droperidol , a butyrophenone derivative , as a prophylactic antiemetic agent . Although the majority of the authors found droperidol to be an effective antiemetic , the recommended doses vary widely ( 4,643 ) . However , side effects , especially somnolence , have been reported with larger doses ( 4,9 ) . Metoclopramide , a dopaminergic receptor blocker devoid of sedative effects , has also been advocated as an antiemetic , but conflicting results have been reported regarding its efficacy ( 5,lO-14 ) . A recent paper by Rao , et al. ( 15 ) reported no nausea This r and omized , double-blind study compared the effects of dexamethasone plus either droperidol , metoclopramide , or granisetron with each antiemetic alone for preventing postoperative nausea and vomiting ( PONV ) in 270 female patients undergoing general anesthesia for major gynecological surgery . Patients were r and omly assigned to receive either droperidol 1.25 mg ( Group D1 , n = 45 ) , droperidol 1.25 mg plus dexamethasone 8 mg ( Group D2 , n = 45 ) , metoclopramide 10 mg ( Group M1 , n = 45 ) , metoclopramide 10 mg plus dexamethasone 8 mg ( Group M2 , n = 45 ) , granisetron 40 micro g/kg ( Group G1 , n = 45 ) , or granisetron 40 micro g/kg plus dexamethasone 8 mg ( Group G2 , n = 45 ) immediately before the induction of anesthesia . A st and ard general anesthetic technique and postoperative analgesia were used throughout the study . Complete response , defined as no PONV and no administration of rescue antiemetic medication during the first 24 h after anesthesia , was 49 % in Group D1 , 60 % in Group D2 ( P = 0.199 versus Group D1 ) , 51 % in Group M1 , 62 % in Group M2 ( P = 0.198 versus Group M1 ) , 80 % in Group G1 , and 96 % in Group G2 ( P = 0.025 versus Group G1 ) . Our results suggest that dexamethasone enhances the antiemetic efficacy of granisetron but does not potentiate the other antiemetics-droperidol and metoclopramide-in female patients undergoing major gynecological surgery . Implication s : We compared the efficacy of dexamethasone plus three different antiemetics-droperidol , metoclopramide , and granisetron-for the prevention of nausea and vomiting after gynecologic surgery . The granisetron-dexamethasone combination was the most effective for preventing postoperative emetic symptoms . ( Anesth Analg 1997;85:913 - 7 OBJECTIVE PONV is a frequent postoperative complication . The aim of this study was to assess the efficacy of oral dolasetron in comparison to intravenous droperidol ( DHB ) and to a combination of both drugs for prophylaxis of PONV . METHODS 80 patients ( ASA I-III ) were r and omly allocated to one of four groups and received the following medication : group A : 50 mg dolasetron was given orally 45 - 60 minutes before anaesthesia was induced , group B : 2.5 mg i.v . DHB + placebo p.o . was administered while inducing anaesthesia ( positive control group ) , group C : 50 mg dolasetron was given 45 - 60 minutes before anaesthesia was induced and 2.5 mg i.v . DHB was given while inducing anaesthesia , group D : placebo tablet was administered 45 - 60 minutes before anaesthesia was induced ( negative control group ) . PONV was assessed using a 5-point score : 0 = no symptoms , 1 = nausea , 2 = retching , 3 = vomiting , 4 = multiple vomiting . Metoclopramid was given as antiemetic if a patient reached two or more score points . RESULTS PONV scores were significantly lower in group A and C ( p < 0.001 ) compared to the control group . Patients treated with DHB showed a significantly lower PONV score in comparison to the placebo treated patients ( p < 0.05 ) . Between the groups A , B and C we found no significantly different PONV scores . Postoperative consumption of metoclopramid was significantly lower in the groups A ( 2.4 + /- 5.2 mg ) and C ( 1.0 + /- 3.1 mg ) than in the placebo group ( 6.0 + /- 6.8 mg ) , whereas between group B ( 3.0 + /- 5.7 mg ) and D we found no significant differences . CONCLUSIONS Single dose of oral dolasetron and single dose of intravenous DHB reduced PONV effectively , in patients undergoing gynaecologic surgery . A combination of dolasetron and DHB has no better effect than a single dose of oral dolasetron . Contrary to DHB the application of dolasetron decreased the postoperative antiemetic requirement significantly Background Postoperative nausea and emesis , especially in ambulatory surgical patients , remains a troublesome problem . This study was performed to compare the incidence of nausea and emesis during the 24-h postoperative period in ondan-setron-treated patients versus placebo-treated patients . Methods Using a r and omized prospect i ve double-blind study design , women between the ages of 18 and 70 yr undergoing gynecologic surgical procedures with general opioid anesthesia on an outpatient basis were enrolled . Ondansetron or placebo was administered prior to induction of anesthesia . Patients were stratified according to history of nausea and emesis during previous exposure to general anesthesia and r and omized to dose received . Results Data from the 544 women showed that all doses of intravenous ondansetron tested ( 1 , 4 , and 8 mg ) were significantly more effective ( 62 % , 76 % , and 77 % , respectively ) than placebo ( 46 % ) in reducing the incidence of emesis following surgery until 24 h after recovery room entry . All these doses were more effective than placebo in patients with no prior history of emesis following surgery and the 4− and 8-mg doses were more effective than placebo in patients with a prior history of emesis following surgery . All doses of ondansetron tested were generally well tolerated with adverse events , clinical laboratory tests , and recovery room vital signs similar to those of placebo . Serum aspartate transaminase ( AST ) was increased in five patients ( 1 mg , 2 patients ; 4 mg , 1 patient ; 8 mg , 2 patients ) . In the three patients in whom subsequent analysis were performed , the serum AST had decreased to preoperative levels . Conclusions Ondansetron given intravenously to prevent postoperative nausea and emesis was highly effective in the 4− and 8-mg doses in women having ambulatory gynecologic surgery BACKGROUND Serotonin-receptor antagonists seem to be as effective as corticosteroids in preventing emesis induced by moderately emetogenic antineoplastic agents . We compared the antiemetic effect of a combination of granisetron and dexamethasone with that of granisetron or dexamethasone administered alone . METHODS From December 1992 to January 1994 , 482 consecutive patients who were to receive moderately emetogenic chemotherapy for the first time ( 600 to 1000 mg of cyclophosphamide per square meter of body-surface area , > or = 50 mg of doxorubicin per square meter , > or = 75 mg of epirubicin per square meter , or > or = 300 mg of carboplatin per square meter , alone or in some combination ) were enrolled in a double-blind , r and omized , multi-center study evaluating the efficacy and toxicity of three antiemetic regimens . The following antiemetic regimens were used : 8 mg of dexamethasone given intravenously before chemotherapy plus 4 mg given orally immediately before chemotherapy and then every six hours for a total of four doses , 3 mg of granisetron given intravenously before chemotherapy , or a combination of granisetron and dexamethasone given in the doses used for the single-drug regimens . RESULTS We evaluated 408 patients ( 136 receiving dexamethasone , 137 receiving granisetron , and 135 receiving both drugs ) . In the first 24 hours after chemotherapy , complete protection from vomiting and complete protection from nausea were achieved in 70.6 and 55.1 percent , respectively , of the patients receiving dexamethasone , in 72.3 and 48.2 percent of those receiving granisetron , and in 92.6 and 71.9 percent of those receiving granisetron combined with dexamethasone ( P < 0.001 for all comparisons ) . Patients who received granisetron alone had less protection from delayed vomiting and nausea than those who received dexamethasone alone or the two drugs combined . All the regimens were equally well tolerated . CONCLUSION Granisetron combined with dexamethasone was the most effective regimen for the prevention of emesis induced by moderately emetogenic chemotherapy Ondansetron , a serotonin antagonist , is effective in controlling the emesis associated with cancer chemotherapy ; however , emesis in patients receiving high-dose cisplatin is poorly controlled by ondansetron alone . Dexamethasone is an effective antiemetic with no known interaction with serotonin receptors and was thus chosen for study in combination with ondansetron . 31 patients ( 30 male , 1 female ; median age 28.5 years , range 18 - 49 ) receiving a 4-day course of a chemotherapy regimen containing cisplatin ( 100 - 120 mg/m2 ) for metastatic germ-cell tumours were entered in a r and omised , double-blind , cross-over trial comparing oral ondansetron plus placebo with oral ondansetron plus dexamethasone as antiemetic prophylaxis . Ondansetron ( 8 mg every 8 h ) was given to all patients for 8 days from the start of chemotherapy . Patients were given 8 mg of dexamethasone or placebo every 8 h starting 2 h before cisplatin ( on day 4 ) and continuing for six doses ( ie , for 2 days only ) . A second course of chemotherapy began 14 days after the start of the first , during which patients crossed over to the alternative antiemetic regimen . Results were available from 27 patients . In the 24 - 48 h after cisplatin 78 % of patients taking ondansetron plus dexamethasone reported complete or major control of emesis compared with 30 % of those taking ondansetron plus placebo ( p = 0.001 ) . Cross-over analysis showed a significant advantage for ondansetron plus dexamethasone in the control of nausea ( p = 0.013 ) and emesis ( p less than 0.001 ) over the 8-day study . 24 of 26 patients expressed a preference for the combination therapy ( p less than 0.001 ) . Ondansetron plus dexamethasone is effective antiemetic prophylaxis for high-dose cisplatin chemotherapy , has few side effects , and is active when given orally In this double‐blind study the clinical efficacy of a single pre‐operative intravenous dose of droperidol 1.25 mg ( 137 patients ) , granisetron 1 mg ( 130 patients ) and granisetron 1 mg plus dexamethasone 5 mg ( 130 patients ) was investigated for the prevention of postoperative nausea and vomiting after gynaecological surgery , breast surgery , abdominal surgery and ear , nose and throat surgery . The incidence of nausea in the first 24 h postoperatively was 52 % in the droperidol group , 48 % in the granisetron group and 34 % with the combination , respectively . Both granisetron and granisetron/dexamethasone performed better than droperidol in their effects on vomiting or combined nausea and vomiting ( incidence in the first 24 h 22 % , 18 % and 42 % , respectively ) . The number of emetic episodes during the 5‐day study period was significantly higher in the droperidol group ( 198 ) than in the granisetron ( 73 ) or combination group ( 78 ) The purpose of this double-blind , r and omized study was to compare the effectiveness of ondansetron plus saline versus ondansetron plus dexamethasone in the prevention of postoperative nausea and vomiting . Of 180 women having general anesthesia for major gynecologic surgery , 89 received intravenous ondansetron , 4 mg , plus saline ( Group 1 ) and 91 received intravenous ondansetron , 4 mg , plus dexamethasone 8 mg ( Group 2 ) during their operation . A complete response , defined as no emesis and no need for rescue antiemetic during the 24-h postoperative period , occurred in 38 % of patients in Group 1 and in 52 % in Group 2 ( P = 0.048 ) . Emesis occurred in 34 % of patients in Group 1 and in 15 % in Group 2 ( P = 0.003 ) . Nausea scores were significantly lower for patients in Group 2 at 2 h ( P = 0.023 ) and at 24 h ( P = 0.001 ) . In the ondansetron plus dexamethasone group , 9 out of 10 patients who received propofol for induction of anesthesia had no emesis . The only failure occurred in a patient who had a single emetic episode during the 24th postoperative hour . The combination of ondansetron and dexamethasone was more effective than ondansetron and saline in the prevention of postoperative nausea and vomiting for women having major gynecologic surgery The 5-HT3 antagonists are effective in reducing postoperative nausea and vomiting ( PONV ) associated with paediatric tonsillectomy . Although prophylactic tropisetron can reduce the incidence of PONV by half , the result ing level of over 40 % is still unacceptably high . The aim of this study was to evaluate the effect of adding dexamethasone to tropisetron . In a blinded study , 59 children ( mean age 6.1 years ) were administered 0.1 mg.kg-1 up to 2 mg of tropisetron and 66 children ( mean age 5.7 years ) received the same dose of tropisetron plus 0.5 mg.kg-1 up to 8 mg of dexamethasone . Both drugs were given intravenously during induction of anaesthesia for tonsillectomy . During the inpatient stay of 24 h , the incidence of postoperative vomiting in the tropisetron alone group was 53 % compared with 26 % in the combination group ( P=0.002 , chi-squared ) . A significant reduction in nausea from 53 % to 30 % was also observed ( P=0.02 ) . Parents completed a daily diary for 5 days following discharge . Delayed vomiting occurred in 27 % and 11 % of the tropisetron and combination therapy groups , respectively ( P=0.025 ) Sixteen percent and 9 % , respectively , required medical attention ( P=0.27 ) . Tropisetron plus dexamethasone is more effective than tropisetron alone in reducing the incidence of PONV following paediatric tonsillectomy In a r and omized , double-blind trial , we compared i.v . ondansetron 4 mg ( control ) , i.v . ondansetron 4 mg and cyclizine 50 mg ( combination ) and i.v . saline 0.9 % ( placebo ) , given after induction of st and ardized anaesthesia , for the prevention of nausea and vomiting ( PONV ) after day-case gynaecological laparoscopic surgery . Compared with placebo , fewer patients in the control group vomited ( 9/20 versus 11/59 , P = 0.02 ) or needed rescue antiemetic ( 7/20 versus 9/59 , P = 0.06 ) before discharge . Compared with the control , fewer patients in the combination group ( n = 60 ) vomited ( 11/59 versus 2/60 , P = 0.01 ) or needed rescue antiemetic ( 29/59 versus 2/60 , P = 0.03 ) before discharge . The incidence of vomiting in the combination group was less than 5 % overall . Compared with the control , the combination group had a significantly lower incidence ( P = 0.001 ) and severity ( P < 0.001 ) of nausea after discharge and more patients with no PONV at any time during the study ( 15/59 versus 27/60 , P = 0.03 ) . Unlike the placebo and control groups , no patient receiving combination prophylaxis was admitted overnight for PONV management STUDY OBJECTIVE To compare the efficacy of oral droperidol versus oral metoclopramide , or both oral droperidol and metoclopramide , on postoperative vomiting when used as a premedicant for strabismus surgery . DESIGN Double-blind , r and omized , prospect i ve study . SETTING Academic children 's hospital . PATIENTS 154 ASA physical status I and II ambulatory patients , ages 1 to 15 years , scheduled for strabismus surgery . INTERVENTIONS Patients were r and omly assigned to receive colored sugar water containing either droperidol 300 mcg/kg orally , metoclopramide 0.15 mg/kg orally , both droperidol 300 mcg/kg and metoclopramide 0.15 mg/kg orally , or no active ingredient ( placebo group ) as a premedicant . The premedications were given orally 1 to 1.5 hours prior to the operation . MEASUREMENTS AND MAIN RESULTS Patients were analyzed for the number of episodes of vomiting from the time of their emergence from anesthesia through the first 24 hours postoperatively , including the convalescent period at home . Patients were also analyzed for length of hospital stay . There were no statistically significant differences between groups regarding age , premedication time , surgery time , or discharge time . Droperidol and droperidol-metoclopramide were significantly more effective ( p < 0.012 ) than either the metoclopramide group or the placebo group in preventing postoperative nausea and vomiting following strabismus surgery . CONCLUSIONS Our data suggest that oral droperidol 300 mcg/kg and the combination of oral droperidol 300 mcg/kg and metoclopramide 0.15 mg/kg are effective in reducing the frequency of vomiting within the first 24 hours after strabismus surgery . The combination of oral droperidol and oral metoclopramide is highly effective in reducing the frequency of vomiting postoperatively in strabismus ambulatory surgery patients ( p = 0.017 ) . This combination seems to represent an inexpensive alternative to the more costly ondansetron In this double-blind , r and omized , placebo-controlled study , we have evaluated the effect of preoperative administration of dexamethasone on postoperative vomiting and pain in 60 women undergoing general anaesthesia for major gynaecological surgery . Dexamethasone 10 mg ( group D ) or saline ( group S ) was administered i.v . in a double-blind manner during induction of anaesthesia . Postoperative pain relief was controlled with bolus doses of morphine using an i.v . patient-controlled analgesia device , and patients were assessed for incidence of vomiting , sedation score , verbal pain rating score , time to first morphine dem and and morphine consumption at 4 , 8 , 12 and 24 h after surgery . Six patients in group D and 19 in group S experienced vomiting at least once within the 24-h postoperative period ; dexamethasone was effective in reducing the overall incidence of vomiting from 63.3 % to 20.0 % ( P < 0.01 ) . Other variables were similar between the groups , and the influence of dexamethasone on postoperative pain was minimal UNLABELLED We compared the efficacy of granisetron plus dexamethasone with that of granisetron alone for preventing nausea and vomiting in parturients undergoing cesarean section under spinal anesthesia . In a r and omized , double-blinded manner , 120 patients received either granisetron 3 mg ( Group I , n = 60 ) or granisetron 3 mg plus dexamethasone 8 mg ( Group II , n = 60 ) IV immediately after clamping of the fetal umbilical cord . A complete response , defined as no emetic symptoms and no need for another rescue antiemetic medication in the intraoperative , postdelivery period was 83 % in Group I and 98 % in Group II ( P = 0.008 ) ; the corresponding rates during the first 24 h after surgery was 85 % and 98 % ( P = 0.016 ) . No clinical ly serious adverse events were observed in any of the groups . In conclusion , the prophylactic use of a granisetron/dexamethasone combination is more effective than granisetron alone for reducing nausea and vomiting in patients during and after spinal anesthesia for cesarean section . IMPLICATION S Intraoperative , postdelivery , and postoperative nausea and vomiting are distressing to patients undergoing cesarean section under spinal anesthesia . The combination of granisetron plus dexamethasone was evaluated and found to be effective for preventing these emetic symptoms BACKGROUND Both , droperidol and the new 5-HT3-antagonist ( e.g. dolasetron ) are effective drugs in the prevention of postoperative nausea and vomiting ( PONV ) . It was the aim of this prospect i ve double blind placebo controlled study to determine the efficacy of low-dose droperidol , dolasetron , and a combination of both drugs in the prevention of PONV after extracapsular cataract extraction . METHODS 148 in patients undergoing cataract surgery were stratified according to gender and then r and omised to receive one of four antiemetic regimens : placebo , droperiodol ( 10 micrograms x kg-1 ) , dolasetron ( 12.5 mg ) , or the combination of both drugs ( 10 micrograms x kg-1 + 12.5 mg ) . The drugs were administered intravenously 5 - 10 minutes before the end of anaesthesia . General anaesthesia and the perioperative management of the patients were st and ardised : benzodiazepine premedication , induction with etomi date , alfentanil and mivacurium . Maintenance using desflurane in N2O/O2 , and a continuous infusion of mivacurium was used . Postoperative analgesia ( diclofenac or paracetamol ) and antiemetic rescue medication ( dimenhydrinate and metoclopramide ) was st and ardised . Nausea , episodes of vomiting , retching and the need for additional antiemetics were recorded for 24-hours . The severity of PONV was categorised using a st and ardised scoring algorithm . The main aim of the study was the number of patients who stayed completely free from PONV . RESULTS There were no differences between the two groups with regard to biometric data , type of surgery , and distribution of risk factors for developing PONV . In all three treatment groups significantly less patients suffered from PONV ( placebo : 66 % ; droperidol : 89 % , dolasetron : 92 % , combination : 89 % ; p = 0.011 ) . Furthermore , the severity of PONV was reduced ( p = 0.012 ) . CONCLUSION Low-dose droperidol and dolasetron are equally effective to reduce the incidence of PONV after cataract surgery under general anaesthesia . The combination of both drugs revealed no additional effect This prospect i ve , r and omized and double-blinded study was design ed to evaluate the anti-emetic efficacy of a combination of ondansetron and metoclopramide in 100 ASA physical status I and II children of either sex and 1 - 15 years of age undergoing elective surgery for strabismus . A st and ardized anaesthetic technique and post-operative analgesia were used for all the children . Children were divided into four groups . They received saline , metoclopromide 250 micrograms kg-1 , ondansetron 150 micrograms kg-1 or a combination of metoclopramide 150 micrograms kg-1 and ondansetron 100 micrograms kg-1 intravenously immediately after the insertion of an intravenous cannulae . There were no differences between the groups in their age , gender , weight , duration of surgery , number of muscles subjected to surgery or intravenous fluids received . In the first 24 post-operative hours , 18 ( 72 % ) patients in the placebo group , 15 ( 60 % ) patients in the metoclopramide group , 10 ( 40 % ) patients in the ondansetron group and 11 ( 44 % ) patients in the combination group had nausea or vomiting . The overall incidence of post-operative nausea and vomiting was significantly ( P < 0.05 ) lower in the combination group and in the ondansetron group compared with the placebo group . Nine ( 36 % ) patients in both the placebo and the metoclopramide groups and one ( 4 % ) patient in the ondansetron group required rescue anti-emetic treatment . None of the patients in the combination group required rescue anti-emetic and this was significantly less ( P < 0.01 ) when compared with the placebo and the metoclopramide groups . Recovery and sedation scores were comparable in all the four groups . A combination of metoclopramide 150 micrograms kg-1 and ondansetron 100 micrograms kg-1 administered prior to surgery was not found to be more effective than ondansetron 150 micrograms kg-1 alone for the prophylaxis of nausea and vomiting following surgical repair of strabismus in paediatric patients STUDY OBJECTIVES To evaluate the efficacy and safety of granisetron-droperidol combination for the prevention of postoperative nausea and vomiting ( PONV ) after middle ear surgery . DESIGN Prospect i ve , r and omized , double-blind study . SETTING University hospital . PATIENTS 150 ASA physical status I patients ( 108 females , 42 males ) scheduled for elective middle ear surgery . INTERVENTIONS Patients received granisetron 40 micrograms/kg ( n = 50 ) , droperidol 20 micrograms/kg ( n = 50 ) , or granisetron 40 micrograms/kg plus droperidol 20 micrograms/kg ( n = 50 ) intravenously immediately before induction of anesthesia . MEASUREMENTS AND MAIN RESULTS A st and ard general anesthetic technique and postoperative analgesia were used throughout the study . A complete response , defined as no PONV and no need for another rescue antiemetic , from 0 to 3 hours after anesthesia occurred in 78 % , 56 % , and 94 % of patients who had received granisetron , droperidol , and granisetron plus droperidol , respectively . The corresponding incidence between 3 and 24 hours after anesthesia was 80 % , 52 % and 94 % . Thus , a complete response within the first 24-hour postanesthetic period was greater in patients receiving granisetron-droperidol combination than in those receiving granisetron alone or droperidol alone ( p < 0.05 ) . No clinical ly adverse events were observed in any of the groups . CONCLUSIONS A combination of granisetron and droperidol is more effective than droperidol or granisetron alone for the prevention of PONV after middle ear surgery Background Postoperative nausea and vomiting after laparoscopic cholecystectomy remains a common problem despite routine antiemetic prophylaxis . Therefore , the authors investigated the effect of administering 4 mg intravenous dexamethasone as an adjunct to a 5-HT3 antagonist ( 12.5 mg intravenous dolasetron ) with respect to patient outcome . Methods Out patients ( N = 140 ) were enrolled in this prospect i ve , r and omized , placebo-controlled , double-blind , institutional review board – approved protocol involving two antiemetic treatment groups . After induction of anesthesia , the control group received 1 ml intravenous saline , whereas the dexamethasone group received 4 mg intravenous dexamethasone . Both groups received 12.5 mg intravenous dolasetron at the time of gallbladder removal . A blinded observer recorded the recovery times , emetic episodes , rescue antiemetics , maximum nausea score , and time to achieve discharge criteria . Postdischarge side effects , as well as patient satisfaction and quality of recovery scores were assessed at 24 h after surgery . Results Although there was no difference in the incidence of postoperative nausea and vomiting in the early recovery period , the dexamethasone group had a shorter stay in the day-surgery unit ( 136 ± 57 vs. 179 ± 62 min ) and more rapidly achieved discharge criteria ( 161 ± 32 vs. 209 ± 39 min ) . In addition , fewer patients in the dexamethasone group experienced nausea at home within 24 h after discharge ( 13 vs. 28 % , P < 0.05 ) . Finally , the dexamethasone group reported higher quality of recovery and patient satisfaction scores ( P < 0.05 ) . Conclusions The authors conclude that the adjunctive use of 4 mg intravenous dexamethasone shortened the time to achieve discharge criteria and improved the quality of recovery and patient satisfaction scores after laparoscopic cholecystectomy procedures in out patients receiving prophylaxis with 12.5 mg intravenous dolasetron In children , strabismus surgery is frequently followed by vomiting . The present study compares the antiemetic effects of droperidol ( 10 micrograms/kg ) and /or metoclopramide ( 0.1 mg/kg ) in 104 children undergoing strabismus surgery . The patients were r and omly divided into four groups . Group I ( n = 28 ) received placebo ( saline ) , Group II ( n = 26 ) droperidol 10 micrograms/kg , Group III ( n = 25 ) metoclopramide 0.1 mg/kg and Group IV ( n = 25 ) droperidol 10 micrograms/kg and metoclopramide 0.1 mg/kg . Droperidol was given just after induction and metoclopramide at the end of surgery , just before recovery . The technique of anesthesia involved an anticholinergic premedication , IV fentanyl ( 2 micrograms/kg ) , controlled ventilation using isoflurance and N2O in oxygen and systematic gastric emptying before extubation . Vomiting , retching and nausea were noted at 5 different moments : in the Post Anesthetic Care Unit , when arriving on the ward (= after carriage by lift ) , during the first hour following the return in the ward , from the 6th to the 12th postoperative hour and on the morning of day 1 . There was no statistically significant difference in the incidence of vomiting among these four groups . Moreover , the incidence of vomiting in the placebo group was much lower ( 17.9 % in the recovery room , 3.6 % at return in the ward , 25 % during the first hour , 7.1 % from 6 to 12 hours and 3.6 % the next day ) than that reported in previous studies . We think that this could result from the additive effects of some aspects of the technique of anesthesia described and discussed in this paper OBJECTIVES Dimenhydrinate and metoclopramide are inexpensive antiemetic drugs . Metoclopramide , especially , has been studied extensively in the past , but there are no studies that used the combination of both drugs for prevention of postoperative nausea and vomiting ( PONV ) . METHODS 120 female in patients undergoing endonasal surgery were r and omised to receive one of four antiemetic regimes : placebo , dimenhydrinate ( 1 mg x kg-1 ) , metoclopramide ( 0.3 mg x kg-1 ) , or the combination of both drugs ( 1 mg x kg-1 + 0.3 mg x kg-1 ) were administered intravenously after induction of anaesthesia and repeated 6 hours after the first administration . For general anaesthesia a st and ardised technique including benzodiazepine premedication , propofol , desflurane in N2O/O2 vecuronium and a continuous infusion of remifentanil was used . Postoperative analgesia ( diclofenac or metamizole supplemented with piritramide ) and antiemetic rescue medication ( dolasetron and droperidol ) were st and ardised . Episodes of vomiting , retching , nausea , and the need for additional antiemetics were recorded in the recovery room and 2 , 5 , 8 , and 24 hours after surgery . The main goal of the study was to increase the number of females staying completely free from PONV ( Chi 2-test ) . Furthermore , the severity of PONV was analysed , using a st and ardised scoring algorithm . RESULTS There were no differences between the two groups with regard to biometric data and distribution of risk factors for developing PONV . In all four groups nearly the similar number of patients stayed completely free from PONV : Placebo : 60.7 % , metoclopramide : 66.7 % , dimenhydrinate : 64.3 % , combination : 64.4 % ( differences not significant ) . There was also no difference in the severity of nausea and emetic sequel . DISCUSSION In females undergoing endonasal surgery under propofol-desflurane-remifentanil anaesthesia the incidence of PONV is about 40 % . In this setting , both metoclopramide and dimenhydrinate were ineffective to reduce the incidence and the severity of PONV . The combination of both drugs revealed no additional synergistic effect In this study the antiemetic effects of droperidol , ondansetron and their combination were evaluated in 160 ASA Grade I and II children undergoing surgery for strabismus , who were r and omly assigned to one of four groups : Group D received droperidol 75 micrograms kg-1 , group O ondansetron 0.1 mg kg-1 , group D+O received both droperidol 75 micrograms kg-1 and ondansetron 0.1 mg kg-1 , and group N NaCl as placebo . Emesis within the first 24 h occurred in 95.0 % of the children with placebo medication , compared with 32.5 % ( D ) , 40.0 % ( O ) and 45.0 % ( D+O ) in the groups with antiemetic prophylaxis . The differences between group N and all other groups were significant ( P < 0.001 ) . However , there were no statistically significant differences between the groups D , O and D+O. It is concluded that droperidol ( 75 micrograms kg-1 ) and ondansetron ( 0.1 mg kg-1 ) both significantly reduce PONV in children undergoing surgery for strabismus . Neither ondansetron , nor the combination D+O were superior to droperidol alone Background : The purpose of this study was to compare the effects of a low‐dose propofol infusion with a four‐drug multimodal regimen for prophylaxis of postoperative nausea and vomiting ( PONV ) In this r and omized , double-blind study , we compared the efficacy and safety of granisetron plus droperidol with each antiemetic alone for preventing postoperative nausea and vomiting ( PONV ) in 150 female patients scheduled for elective major gynecological surgery . Patients were r and omly assigned to receive IV either granisetron 2.5 mg ( Group G ) , droperidol 1.25 mg ( Group D ) , or granisetron 2.5 mg plus droperidol 1.25 mg ( Group GD ) immediately before the induction of anesthesia ( n = 50 in each group ) . A st and ard anesthetic technique and postoperative analgesia were used . Complete response , defined as no PONV and no administration of rescue antiemetic medication during the first 24 h after anesthesia , was 84 % in Group G , 54 % in Group D , and 96 % in Group GD ( P = 0.046 versus Group G , P = 0.001 versus Group D ) . No clinical ly important adverse effects were observed in any group . In conclusion , the combination of granisetron and droperidol is more effective than each antiemetic alone for complete response in patients undergoing general anesthesia for major gynecological surgery . Implication s : We compared the efficacy of granisetron plus droperidol with each antiemetic alone for the prevention of nausea and vomiting after gynecological surgery . The granisetron/droperidol combination was the most effective against these emetic symptoms . ( Anesth Analg 1998;86:613 - 6 Purpose To compare the efficacy of ondansetron-dexamethasone combination with ondansetron alone for prevention of postoperative nausea and vomiting ( PONV ) . Methods This double blind , r and omized study was carried out in 51 female patients , aged 20–40 yr , ASA-1 physical status undergoing gynecological diagnostic laparoscopy . Group 1 ( n = 26 ) received 4 mg ondansetroniv and group 2 ( n = 25 ) received a combination of 4 mg ondansetron and 8 mg dexamethasoneiv soon after induction of anesthesia . Postoperatively patients were assessed hourly for four hours and then at 24 hr for nausea , vomiting , pain and post anesthetic discharge score . Vomiting occurring up to two hours was considered early vomiting and from 2–24 hr as delayed vomiting . Results The postoperative nausea score was lower in patients receiving a combination of ondansetron and dexamethasone ( 3.76 ) than ondansetron alone ( 4.38 ) at 0 hr ( P < 0.01 ) , 2 hr ( P < 0.05 ) and 24 hr ( P < 0.01 ) . In group 1 , 38.5 % of patients had a nausea score of ≥ 5 ( major nausea ) compared with only 12 % of patients in group 2 ( P < 0.025 ) . The overall incidence of vomiting was greater in group 1 ( 35 % ) than in group 2 ( 8 % ) ( P < 0.05 ) . The combination group showed better control of delayed vomiting compared with the ondansetron group ( 4%vs 35%)(P < 0.0l ) . Conclusion The combination of ondansetron and dexamethasone provides adequate control of PONV with delayed PONV being better controlled than early PONVRésuméObjectifComparer l’efficacité d’une combinaison d’ondansétron et de dexaméthasone avec l’ondansétron employé seul pour la prévention de nausées et de vomissements postopératoires (NVPO).MéthodeLa présente étude , r and omisée et en double aveugle , a été réalisée auprès de 51 patientes , âgées de 20 à 40 ans , d’état physique ASA I qui devaient subir une laparoscopie gynécologique . Le groupe I ( n = 26 ) a reçu 4 mg d’ondansétroniv et le groupe 2 ( n = 25 ) , une combinaison de 4 mg d’ondansétron et de 8 mg de dexaméthasoneiv peu après l’induction de l’anesthésie . À la suite de l’intervention , on a évalué les nausées , les vomissements , l’échelle de douleur et de congé à chaque heure , pendant quatre heures , et à 24 h. Les vomissements se produisant jusqu’à deux heures après l’intervention étaient considérés comme des vomissements précoces et ceux qui survenaient entre 2 et 24 h , comme des vomissements tardifs . RésultatsLe score des nausées postopératoires était plus bas chez les patientes qui avaient reçu une combinaison d’ondansétron et de dexaméthasone ( 3,76 ) plutôt que de l’ondansétron seulement ( 4,38 ) à 0 h ( P < 0,01 ) , à 2 h ( P < 0,05 ) et à 24 h ( P < 0,01 ) . Dans le groupe 1 , 38,5 % des patientes ont présenté un score de nausées 5 ( nausées importantes ) comparativement à 12 % seulement des patientes dans le groupe 2 ( P < 0,025 ) . Lincidence totale de vomissements était plus gr and e dans le groupe 1 ( 35 % ) que dans le groupe 2 ( 8 % ) ( P < 0,05 ) . Le groupe ayant reçu une combinaison de médicaments , comparé au groupe qui a reçu de l’ondansétron , a présenté un meilleur contrôle des vomissements tardifs ( 4 % vs 35 % ) ( P < 0,01 ) . Conclusion La combinaison d’ondansétron et de dexaméthasone fournit un bon contrôle des NVPO , meilleur pour les NVPO précoces que pour les NVPO tardifs Dexamethasone decreases chemotherapy-induced emesis when added to an antiemetic regimen . This study was undertaken to evaluate the efficacy of granisetron/dexamethasone combination for preventing postoperative nausea and vomiting ( PONV ) after lapIaroscopic cholecystectomy ( LC ) . In a prospect i ve , r and omized , double-blind manner , 120 patients ( 83 females ) , aged 25 - 65 years , were assigned to receive granisetron 40 microg kg-1 alone or granisetron 40 microg kg-1 plus dexamethasone 8 mg ( n=60 of each ) intravenously immediately before the induction of anaesthesia . A st and ardized general anaesthetic procedure and postoperative analgesia were used . A complete response , defined as no PONV and no need for another rescue antiemetic , during 0 - 3 h after anaesthesia was 83 % with granisetron and 98 % with granisetron plus dexamethasone , respectively ( P=0.008 ) ; the corresponding incidence during 3 - 24 h after anaesthesia was 83 % and 98 % ( P=0.008 ) . No clinical ly important adverse events were observed in any of the group . In conclusion , prophylactic therapy with granisetron/dexamethasone combination is more effective than granisetron alone for the prevention of PONV after LC Nausea and vomiting remain common and debilitating side effects of therapy with many anticancer drugs . Recent reports have shown that both metoclopramide and dexamethasone are effective drugs for the treatment of severe nausea and vomiting caused by cis-platinum . A double-blind crossover study comparing the antiemetic properties of high-dose oral and intravenous regimens of metoclopramide and dexamethasone in out patients was carried out . St and ardized patient question naires and interviews were used to evaluate response . Dexamethasone and metoclopramide protected against more than five episodes of emesis in 48 % and 40 % of patients , respectively . Nausea persisted for less than six hours in 45 % of patients on dexamethasone and in 37 % on metoclopramide . The antiemetic efficacy of both regimens was retained through repeated courses of chemotherapy . Side effects were minimal with dexamethasone ; however , 33 % of patients experienced unacceptable extrapyramidal side effects to metoclopramide . Patient preference was significantly in favor of dexamethasone : 70 % of patients chose to continue dexamethasone compared to 22 % who preferred metoclopramide and 8 % who chose other antiemetics . Dexamethasone was the preferred antiemetic in this patient population due to minimal side effects This study was undertaken to evaluate the efficacy of granisetron plus dexamethasone for preventing postoperative nausea and vomiting ( PONV ) after thyroidectomy . In a prospect i ve , r and omized , double-blind study , 130 female patients received either granisetron 40 micrograms/kg or granisetron 40 micrograms/kg plus dexamethasone 8 mg intravenously immediately before the induction of anaesthesia ( n = 65 in each group ) . A st and ard general anaesthetic technique was used . A complete response ( no PONV , no rescue ) during the first three hours after anaesthesia occurred in 85 % of patients with granisetron alone and 98 % with granisetron plus dexamethasone ; the corresponding incidence for the period 3 to 24 hours after anaesthesia was 86 % and 98 % ( P < 0.05 ; Fisher 's exact probability test ) . No clinical ly serious adverse events were observed in any of the groups . In conclusion , prophylactic use of granisetron/dexamethasone combination is more effective than granisetron alone for preventing PONV in women undergoing thyroidectomy

Two r and omized controlled trials and 3 quasiexperimental studies reported lateral wedge insoles may have at least some pain-relieving effects and improved functional mobility in older adults at 4 weeks to 2 years ' follow-up , particularly when used with subtalar and ankle strapping . Discussion and Conclusion : Because of the limited number of r and omized control trials , it is not possible to make a definitive conclusion about the long-term effects of footwear on lower extremity joint pain caused by OA . There is mounting evidence that shock-absorbing insoles , subtalar strapping , and avoidance of high heels and s and als early in life may prevent lower extremity joint pain in older adults , but no conclusive evidence exists to show that lateral wedge insoles will provide long-term relief from knee joint pain and improved mobility in older adults with OA .

Background and Purpose : Lower extremity osteoarthritis ( OA ) is a common condition among older adults ; given the risks of surgical and pharmaceutical interventions , conservative , lower-cost management options such as footwear warrant further investigation . This systematic review investigated the effects of footwear , including shoe inserts , in reducing lower extremity joint pain and improving gait , mobility , and quality of life in older adults with OA .

OBJECTIVE To assess the optimal duration of daily wear for a laterally wedged insole with subtalar strapping in subjects with medial compartment osteoarthritis of the knee ( knee OA ) . DESIGN The setting was an outpatient clinic . Eighty-one patients with knee OA were prospect ively r and omized according to birth date and to either 2 weeks of treatment with a lateral wedge with subtalar strapping for less than 5 h ( the short group ) , 5 - 10 h ( the medium group ) or greater than 10 h ( the long group ) each day , or to treatment with a subtalar strapping b and without lateral wedge ( the placebo group ) . St and ing radiographs were used to analyze the femorotibial angle for each subject , both with and without their respective orthotic device . The remission scores of Lequesne index were compared among the four groups at the conclusion . RESULTS The short ( n=21 ) , medium ( n=20 ) and long ( n=18 ) groups demonstrated a significant greater valgus correction of the femorotibial angle than the placebo group ( n=22 ) ( P<0.0001 ) . The remission score was significantly improved in the medium group compared to the placebo ( P=0.001 ) and long ( P=0.001 ) groups . CONCLUSIONS An optimal duration of insole with subtalar strapping wear for patients with varus deformity knee OA may be between 5 and 10 h each day Objective To assess the effect of lateral wedge insoles compared with flat control insoles on improving symptoms and slowing structural disease progression in medial knee osteoarthritis . Design R and omised controlled trial . Setting Community in Melbourne , Australia . Participants 200 people aged 50 or more with clinical and radiographic diagnosis of mild to moderately severe medial knee osteoarthritis . Interventions Full length 5 degree lateral wedged insoles or flat control insoles worn inside the shoes daily for 12 months . Main outcome measures Primary symptomatic outcome was change in overall knee pain ( past week ) measured on an 11 point numerical rating scale . Primary structural outcome was change in volume of medial tibial cartilage from magnetic resonance imaging scans . Secondary clinical outcomes included changes in measures of pain , function , stiffness , and health related quality of life . Secondary structural outcomes included progression of medial cartilage defects and bone marrow lesions . Results Between group differences did not differ significantly for the primary outcomes of change in overall pain ( −0.3 points , 95 % confidence intervals −1.0 to 0.3 ) and change in medial tibial cartilage volume ( −0.4 mm3 , 95 % confidence interval −15.4 to 14.6 ) , and confidence intervals did not include minimal clinical ly important differences . None of the changes in secondary outcomes showed differences between groups . Conclusion Lateral wedge insoles worn for 12 months provided no symptomatic or structural benefits compared with flat control insoles . Trial registration Australian New Zeal and Clinical Trials Registry ACTR12605000503628 and Clinical Trials.gov NCT00415259 BACKGROUND AND PURPOSE Footwear is not consistently st and ardized in the administration of the Functional Reach Test ( FRT ) , Timed Up & Go Test ( TUG ) , and 10-Meter Walk Test ( TMW ) . This study was conducted to determine whether footwear affected performance on these tests in older women . SUBJECTS Thirty-five women , aged 65 to 93 years , were recruited from assisted living facilities and retirement communities . METHODS Each subject performed the FRT , TUG , and TMW wearing walking shoes , wearing dress shoes , and barefooted . Because of space constraints at the facilities where the testing was performed , 22 subjects performed the FRT and TUG on a linoleum floor and 13 subjects performed the tests on a firm , low-pile , carpeted floor . All 35 subjects completed the TMW on a firm , low-pile , carpeted floor . One-way repeated- measures analyses of variance ( ANOVAs ) and a Tukey Honestly Significant Difference test were used to compare the outcomes for the 3 footwear conditions , with separate ANOVAs conducted for the different floor surfaces for the FRT and TUG . RESULTS Subjects performed better on the FRT when barefooted or wearing walking shoes compared with when they wore dress shoes , regardless of floor surface . Differences were found among all footwear conditions for the TUG performed on the linoleum floor and for the TMW . For these tests , the women moved fastest in walking shoes , slower barefooted , and slowest wearing dress shoes . CONCLUSION AND DISCUSSION Footwear should be documented and should remain constant from one test occasion to another when the FRT , TUG , and TMW are used in the clinic and in research . Footwear intervention may improve performance of balance and gait tasks in older women OBJECTIVE To determine the minimal perceptible clinical improvement ( MPCI ) in patients with osteoarthritis ( OA ) with the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) question naire , and patient and investigator global assessment of disease status in r and omized clinical trials for treatment of OA . METHODS Subjects with OA of the knee or hip were r and omized to receive either rofecoxib 12.5 or 25 mg once daily , ibuprofen 800 mg 3 times daily , or placebo for 6 weeks . The WOMAC and global assessment s were completed at baseline and Weeks 2 , 4 , and 6 . A patient global assessment of response to therapy ( 0 to 4 scale ) was used to " anchor " the WOMAC scores . MPCI was defined as the difference in mean change from baseline in WOMAC ( 100 mm normalized visual analog scale , VAS ) between patients with 0 = " None " global response to therapy and patients with 1 = " Poor " global response to therapy . RESULTS MPCI was determined to be 9.7 , 9.3 , and 10.0 mm for the WOMAC pain , physical function and stiffness subscales , respectively , and 11.1 mm for WOMAC question 1 : Pain walking on a flat surface . The MPCI for the investigator was 0.4 with investigator assessment of disease status reported on a 0 to 4 Likert scale . Of note , the estimated MPCI for the WOMAC and investigator globals were similar irrespective of treatment , sex , age , or geographic region . CONCLUSION In this analysis , mean changes of roughly 9 to 12 mm ( 100 mm normalized VAS ) on WOMAC scales were perceptible changes to patients with hip and knee OA . A mean decrease of 0.4 in global disease status ( 0 to 4 Likert scale ) as assessed by the investigator corresponded to the patients ' MPCI . Underst and ing the minimal perceptible differences may permit a better assessment of the clinical relevance of therapeutic interventions in OA OBJECTIVE To compare the clinical effects of laterally wedged insoles and neutrally wedged insoles ( used as control ) in patients with medial femoro-tibial knee osteoarthritis . METHODS STUDY DESIGN 24-month prospect i ve r and omized controlled study . PATIENTS Out patients with painful medial femoro-tibial knee osteoarthritis . OUTCOME MEASURES Patient 's overall assessment of disease activity ( 5 grade scale ) , WOMAC index subscales and concomitant treatments . STATISTICAL ANALYSIS Performed as an intention-to-treat analysis , with the last observation carried forward ( LOCF ) . Main symptomatic criterion : Improvement in the patient 's assessment of activity ( defined as a reduction of one grade or more at the end of the study as compared to baseline , and no intra-articular injection or lavage during the 6 months previous to the last visit ) . Secondary criteria for assessment : ( a ) Changes in the WOMAC subscales at month 24 , and ( b ) concomitant therapies ( analgesics , NSAIDs and intra-articular injections or lavages ) . Structural criterion : Joint space width ( JSW ) at the narrowest point . Non-compliance was defined as intermittent or lack of insole fitting at two consecutive visits . Compliance within groups was compared by using a life table analysis technique ( Log-Rank ) . RESULTS The baseline characteristics of the 156 recruited patients ( 41 males , 115 females , mean age 64.8 years ) were not different in the 2 treatment groups . At year 2 , there was no statistically significant difference between the 2 groups concerning the percentages of patients with improvement in both global assessment of disease activity and in WOMAC subscales ( pain , stiffness , function ) . The number of days with NSAIDs intake was lower in the group with laterally wedged insoles than in the neutrally wedged group ( 71+/-173 days vs. 127+/-193 days , P=0.003 , Mann-Whitney test ) . The mean joint space narrowing rate did not differ between the two groups : 0.21+/-0.59 mm/year in the laterally wedged group vs 0.12+/-0.32 mm/year in the neutrally wedged group . Compliance and tolerance were satisfactory . Compliance was different between the 2 groups at month 24 , with a greater frequency of patients who wore insoles permanently in the laterally wedged insole group than in the other group ( 85.8 % vs 71.9 % , P=0.023 ) . CONCLUSION This study failed to demonstrate a relevant symptomatic and /or structural effect of laterally-wedged insoles in medial femoro-tibial OA . However , the reduced NSAIDs intake and the better compliance in the treatment group are in favor of a beneficial effect of laterally-wedged insoles in medial femoro-tibial OA An articular index was devised for the sequential assessment of patients with osteoarthritis ( OA ) . Forty-eight joint units , chosen to reflect the characteristic pattern of the disease , were scored for tenderness on pressure or movement on a 4-point scale . Four observers examined patients to assess inter- and intraobserver error . The index was highly reproducible both within and between observers ; intraobserver error was , however , significantly smaller . In a double-blind , cross-over trial the index was sufficiently sensitive to detect a statistically significant difference between the responses of patients with OA to an anti-inflammatory agent and to a simple analgesic . It is likely to be a useful addition to current methods of measurement in osteoarthritis A Physical Activity Scale for the Elderly ( PASE ) was evaluated in a sample of community-dwelling , older adults . Respondents were r and omly assigned to complete the PASE by mail or telephone before or after a home visit assessment . Item weights for the PASE were derived by regressing a physical activity principal component score on responses to the PASE . The component score was based on 3-day motion sensor counts , a 3-day physical activity dairy and a global activity self- assessment . Test-retest reliability , assessed over a 3 - 7 week interval , was 0.75 ( 95 % CI = 0.69 - 0.80 ) . Reliability for mail administration ( r = 0.84 ) was higher than for telephone administration ( r = 0.68 ) . Construct validity was established by correlating PASE scores with health status and physiologic measures . As hypothesized , PASE scores were positively associated with grip strength ( r = 0.37 ) , static balance ( r = + 0.33 ) , leg strength ( r = 0.25 ) and negatively correlated with resting heart rate ( r = -0.13 ) , age ( r = -0.34 ) and perceived health status ( r = -0.34 ) ; and overall Sickness Impact Profile score ( r = -0.42 ) . The PASE is a brief , easily scored , reliable and valid instrument for the assessment of physical activity in epidemiologic studies of older people We assessed the validity of the Physical Activity Scale for the Elderly ( PASE ) in a sample of sedentary adults ( 56 men , 134 women , mean age + /- [ SD ] 66.5+/-5.3 years ) who volunteered to participate in a r and omized controlled trial on the effect of aerobic conditioning on psychological function . Construct validity was established by correlating PASE scores with physiologic and performance characteristics : peak oxygen uptake , resting heart rate and blood pressure , percent body fat , and balance . The mean PASE scores were higher in men than in women ( men = 145.8+/-78.0 ; women = 123.9+/-66.3 , P<0.05 ) , and in those age 55 - 64 years compared with those age 65 years and over ( 55 - 64 = 144.2+/-75.8 ; 65 and over = 118.9+/-63.9 , P<0.05 ) . PASE scores were also significantly higher in those who did not report a chronic health condition ( cardiovascular disease , hypertension , cancer , or recent surgery ) . PASE scores were significantly associated ( P<0.05 ) with peak oxygen uptake ( r = 0.20 ) , systolic blood pressure ( r = -0.18 ) and balance score ( r = 0.20 ) . No significant associations of PASE score and diastolic blood pressure , resting heart rate , or percent body fat were noted . These results provide additional evidence for the validity of the PASE as a measure of physical activity suitable for use in epidemiology studies on the association of physical activity , health , and physical function in older individuals OBJECTIVE To compare the influence of concomitant heeled footwear when wearing a lateral wedged insole for medial compartment of osteoarthritis ( OA ) of the knee , between everyday walking shoes for outdoor use and socks or flat footwear without a heel for indoor use . DESIGN A total of 227 out patients were prospect ively r and omized and treated with a neutral wedged insole inserted into shoes ( placebo with shoes ; n=45 ) , a wedged insole inserted into shoes ( inserted insole with shoes ; n=45 ) , a sock-type ankle supporter with a wedged insole when wearing socks or flat footwear ( inserted insole without shoes ; n=46 ) , a subtalar strapped insole when wearing shoes ( strapped insole with shoes ; n=45 ) , and the strapped insole with socks or flat footwear ( strapped insole without shoes ; n=46 ) . The Lequesne index of knee OA at week 12 was compared with the baseline in each treatment group . RESULTS Twenty patients withdrew from the study , and the 207 patients who completed the 12-week study were evaluated . At the final assessment , participants wearing the inserted insole without shoes ( P=0.003 ) , the strapped insole with shoes ( P<0.0001 ) , and the strapped insole without shoes ( P<0.0001 ) demonstrated significantly improved Lequesne index scores in comparison with their baseline assessment s. No significant differences were found in the placebo ( P=0.16 ) or the inserted insole with shoes ( P=0.2 ) groups . CONCLUSION Concomitant heeled footwear may decrease the efficacy of an inserted lateral wedged insole . The optimal usage of a lateral wedged insole for knee OA would be the combination with socks or flat footwear without heels OBJECTIVE To determine the effects of lateral wedged insoles on knee kinetics and kinematics during walking , according to radiographic severity of medial compartment knee osteoarthritis ( OA ) . DESIGN A prospect i ve case control study of patients with medial compartment OA of the knee . SETTING Gait analysis laboratory in a university hospital . PARTICIPANTS Forty-six medial compartment knees with OA of 23 patients with bilateral disease and 38 knees of 19 age-matched healthy subjects as controls . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES We measured the peak external adduction moment at the knee during the stance phase of gait and the first acceleration peak after heel strike at the lateral side of the femoral condyles . Kellgren and Lawrence grading system was used for radiographic assessment of OA severity . RESULTS The mean value of peak external adduction moment of the knee was higher in OA knees than the control . Application of lateral wedged insoles significantly reduced the peak external adduction moment in Kellgren-Lawrence grade s I and II knee OA patients . The first acceleration peak value after heel strike in these patients was relatively high compared with the control . Application of lateral wedged insoles significantly reduced the first acceleration peak in Kellgren-Lawrence grade s I and II knee OA patients . CONCLUSIONS The kinetic and kinematic effects of wearing of lateral wedged insoles were significant in Kellgren-Lawrence grade s I and II knee OA . The results support the recommendation of use of lateral wedged insoles for patients with early and mild knee OA Within the context of a double blind r and omized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs , we vali date d WOMAC , a new multidimensional , self-administered health status instrument for patients with osteoarthritis of the hip or knee . The pain , stiffness and physical function subscales fulfil conventional criteria for face , content and construct validity , reliability , responsiveness and relative efficiency . WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials The objective of this study was to examine mechanisms underpinning the reduction in knee adduction moment ( KAM ) and changes in frontal plane knee-ground reaction force ( GRF ) lever arm with a modified shoe that incorporates both a variable-stiffness sole and lateral wedging . Thirty individuals with symptomatic knee osteoarthritis ( OA ) and 30 overweight asymptomatic individuals underwent gait analyses wearing modified and st and ard shoes . In both groups , there was a decrease in the lever arm ( p<0.001 ) , and a lateral shift in the center of pressure ( COP ) offset ( p ≤ 0.001 ) . There was no change in frontal plane or medial-lateral GRF magnitudes , lateral trunk lean or stance duration in either group . There was no significant change in the frontal plane hip-knee-ankle angle in the OA group but a significant decrease in the overweight group ( p=0.003 ) . In both groups , changes in lever arm and frontal plane GRF magnitude predicted change in peak KAM ( p<0.01 ) , but only change in lever arm predicted change in KAM impulse ( p<0.001 ) . In the OA group , changes in COP offset and medial-lateral GRF magnitude predicted change in lever arm ( p<0.05 ) , whereas changes in trunk lean and hip-knee-ankle angle predicted change in lever arm in the overweight group ( p=0.01 ) . In conclusion , the change in lever arm contributed the most to explaining change in KAM parameters with modified shoes . The change in the lever arm was driven by changes evident at the foot in the OA participants ( COP and medial-lateral GRF ) , and by more proximal changes ( hip-knee-ankle angle and trunk lean ) in the overweight group OBJECTIVE In uncontrolled studies , a lateral-wedge insole has reduced knee pain in patients with medial knee osteoarthritis ( OA ) . The aim of this study was to test the efficacy of this simple , low-cost intervention for pain in patients with medial knee OA . METHODS We conducted a double-blind , r and omized , crossover trial design ed to detect a small effect of treatment . Participants were at least 50 years of age and had medial joint space narrowing on posteroanterior semiflexed radiographs and scores indicating moderate pain for 2 of the 5 items on the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) pain scale . Participants were r and omized to receive a 5 degrees lateral-wedge insole or a neutral insole for 6 weeks . Following a 4-week washout period , participants crossed over to the other treatment for 6 weeks . Knee pain , the primary outcome , was assessed by the WOMAC pain scale ( visual analog scale version ) . Secondary outcomes included the WOMAC disability subscale , overall knee pain , 50-feet walk time , chair-st and time , and use of medications for knee pain . RESULTS Ninety patients were r and omized . The mean difference in pain between the 2 treatments was 13.8 points on the WOMAC pain scale ( 95 % confidence interval -3.9 , 31.4 [ P=0.13 ] ) . We observed similar small effects for the secondary outcomes . CONCLUSION The effect of treatment with a lateral-wedge insole for knee OA was neither statistically significant nor clinical ly important This paper describes constructing the Assessment of Quality of Life ( AQoL ) instrument ; design ed to measure health-related quality of life ( HRQoL ) , and to be the descriptive system for a multi-attribute utility instrument . Unlike previous utility instruments ' descriptive systems , the AQoL 's has been developed using state-of-the-art psychometric procedures . The result is a descriptive system which emphasizes five different facets of HRQoL and which can cl aim to have construct validity . Based on the WHO 's definition of health a model of HRQoL was developed . Items were written by focus groups of doctors and the research ers . These were administered to a construction sample , comprising hospital patients , and community members chosen at r and om . Final construction was through an iterative process of factor and reliability analyses . The AQoL measures 5 dimensions : illness , independent living , social relationships , physical senses and psychological wellbeing . Each has three items . Exploratory factor analysis showed the dimensions were orthogonal , and each was unidimensional . Internal consistency was α = 0.81 . Structural equation modeling explored its internal structure ; the comparative fit index was 0.90 . These preliminary results indicate the AQoL has the prerequisite qualities for a psychometric HRQoL instrument for evaluation ; replication with a larger sample is needed to verify these findings . Scaling it for economic evaluation using utilities is being undertaken . Respondents have indicated the AQoL is easy to underst and and is quickly completed . Its initial properties suggest it may be widely applicable BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However , the reliability of data obtained with most quality assessment scales has not been established . This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions . METHOD In the first study , 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base . In the second study , 2 raters rated 120 RCTs r and omly selected from the PEDro data base , and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings . The process was repeated by independent raters to create a second set of individual and consensus ratings . Reliability of ratings of PEDro scale items was calculated using multirater kappas , and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ) . RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters . The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals , and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ) . DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from " fair " to " substantial , " and the reliability of the total PEDro score was " fair " to " good . The assessment of a measure of chronic pain , should be reliable , valid and sensitive to change . Our study evaluated the reliability of 3 pain scales , visual analogue scale ( VAS ) , numerical rating scale ( NRS ) and verbal rating scale ( VRS ) in literate and illiterate patients with rheumatoid arthritis ( RA ) . Patients with RA attending an outpatient rheumatology clinic were interviewed and asked to score their pain levels on the 3 pain scales . The scales were presented in r and om order , twice , before and just after a regular medical consultation . Ninety-one patients were studied ( 25 illiterate and 66 literate ) . The Pearson product moment correlation between first and second assessment was 0.937 for VAS , 0.963 for NRS and 0.901 for VRS in the literate patient group and 0.712 for VAS , 0.947 for NRS and 0.820 for VRS in the illiterate patient group . These results indicate that the NRS has the higher reliability in both groups of patients OBJECTIVE To estimate minimal clinical ly important differences ( MCID ) of effects measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) in patients with osteoarthritis ( OA ) of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention . METHODS A prospect i ve cohort study assessed patients ' health by the WOMAC at baseline ( entry into the clinic ) and at the 3 month followup , and by a transition question naire asking about the change of " health in general related to the OA joint " during that time period . The WOMAC section score differences between the " equal " group and the " slightly better " and " slightly worse " groups result ed in the MCID for improvement and for worsening . RESULTS In total 192 patients were followed up . The MCID for improvement ranged from 0.80 to 1.01 points on the continuous WOMAC numerical rating scale from 0 to 10 , reflecting changes of 17 to 22 % of baseline scores . The MCID for worsening conditions ranged from 0.29 ( 6 % ) to 1.03 points ( 22 % ) . In the transition reply subjectively unchanged patients reported a " pessimistic bias " of 0.35 to 0.51 points , except for the stiffness section . Both MCID and pessimistic bias showed regression to the mean and baseline dependency . CONCLUSION The assessment of MCID using the transition method is a heuristic and valid strategy to detect particular rehabilitation effects in patients with OA of the lower extremities with the use of the WOMAC , and it is worth implementing . The size of the MCID and of the systematic bias is comparable to that assessed by other methods and in other therapeutic setting OBJECTIVE To determine if women 's dress shoes with heels of just 1.5 in ( 3.8 cm ) in height increases knee joint torques , which are thought to be relevant to the development and /or progression of knee osteoarthritis ( OA ) in both the medial and patellofemoral compartments . DESIGN R and omized controlled trial . SETTING A 3-dimensional motion analysis gait laboratory . PARTICIPANTS Twenty-nine healthy young women ( age , 26.7+/-5.0 y ) and 20 healthy elderly adult women ( age , 75.3+/-6.5 y ) . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Peak external varus knee torque in early and late stance and prolongation of flexor knee torque in early stance . Three-dimensional data on lower-extremity torques and motion were collected during walking while ( 1 ) wearing shoes with 1.5-in high heels and ( 2 ) wearing control shoes without any additional heel . Data were plotted and qualitatively compared ; major peak values and timing were statistically compared between the 2 conditions using paired t tests . RESULTS Peak knee varus torque during late stance was statistically significantly greater with the heeled shoes than with the controls , with increases of 14 % in the young women and 9 % in the elderly women . With the heeled shoes , the early stance phase knee flexor torque was significantly prolonged , by 19 % in the young women and by 14 % in elderly women . Also , the peak flexor torque was 7 % higher with the heeled shoe in the elderly women . CONCLUSIONS Even shoes with moderately high heels ( 1.5 in ) significantly increase knee torques thought to be relevant in the development and /or progression of knee OA . Women , particularly those who already have knee OA , should be advised against wearing these types of shoes OBJECTIVE Elevated dynamic joint loads have been associated with the severity and progression of osteoarthritis ( OA ) of the knee . This study compared the effects of a specialized shoe ( the mobility shoe ) design ed to lower dynamic loads at the knee with self-chosen conventional walking shoes and with a commercially available walking shoe as a control . METHODS Subjects with knee OA were evaluated in 2 groups . Group A ( n = 28 ) underwent gait analyses with both their self-chosen walking shoes and the mobility shoes . Group B ( n = 20 ) underwent gait analyses with a control shoe and the mobility shoe . Frontal plane knee loads were compared between the different footwear conditions . RESULTS Group A demonstrated an 8 % reduction in the peak external knee adduction moment with the mobility shoe compared with self-chosen walking shoes ( mean + /- SD 49 + /- 0.80 versus 2.71 + /- 0.84 % BW x H ; P < 0.05 ) . Group B demonstrated a 12 % reduction in the peak external knee adduction moment with the mobility shoe compared with the control shoe ( mean + /- SD 2.66 + /- 0.69 versus 3.07 + /- 0.75 % BW x H ; P < 0.05 ) . CONCLUSION Specialized footwear can effectively reduce joint loads in subjects with knee OA , compared with self-chosen shoes and control walking shoes . Footwear may represent a therapeutic target for the treatment of knee OA . The types of shoes worn by subjects with knee OA should be evaluated more closely in terms of their effects on the disease OBJECTIVES To examine the effectiveness of shock-absorbing insoles in the immediate reduction of knee joint load , as well as reductions in knee joint load , pain , and dysfunction after 1 month of wear , in individuals with knee osteoarthritis ( OA ) . DESIGN Pre-post design with participants exposed to 2 conditions ( normal footwear , shock-absorbing insoles ) with a 1-month follow-up . SETTING University laboratory for testing and general community for intervention . PARTICIPANTS Community-dwelling individuals ( N=16 ; 6 men , 10 women ) with medial compartment knee OA . INTERVENTION Participants were provided with sulcus length shock-absorbing insoles to be inserted into their everyday shoes . MAIN OUTCOME MEASURES Primary outcome measures included the peak , early stance peak , and late stance peak external knee adduction moment ( KAM ) ; the KAM impulse ( positive area under the KAM curve ) ; and peak tibial vertical acceleration . Secondary outcomes included walking pain , the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale and total score , and a timed stair climb task . RESULTS There was a significant reduction in the late stance peak KAM with shock-absorbing insoles ( P=.03 ) during follow-up compared with the baseline test session . No other immediate or longitudinal significant changes ( P>.05 ) in the other KAM parameters or peak tibial acceleration after use of a shock-absorbing insole were observed . However , significant improvements in all measures of pain and function ( P<.05 ) were observed . CONCLUSIONS Shock-absorbing insoles produced significant reductions in self-reported knee joint pain and physical dysfunction with 1 month of wear in patients with knee OA despite no consistent changes in knee joint load . Further research using r and omized controlled trials , with larger sample sizes and explorations into long-term use of shock-absorbing insoles and their effect on disease progression , is warranted This study aim ed to investigate the effects of walking surfaces and shoe features on gait variables associated with balance control and the risk of slips and trips in 10 young and 26 older adults . A systematic approach was adopted in which the features of a st and ard , Oxford-type shoe were individually modified . Subjects walked along a level ( control ) , irregular , and wet walkway in eight r and omised shoe conditions ( st and ard , elevated heel , soft sole , hard sole , high-collar , flared sole , bevelled heel and tread sole ) . Walking velocity , step length , step width , cadence , double-support time , heel horizontal velocity and shoe-floor angle at heel contact , and toe clearance at mid-swing were measured . Older people exhibited a more conservative walking pattern , especially on the irregular and wet surfaces . Compared to the st and ard shoes , the elevated heel shoes elicited increased double-support time , heel horizontal velocity at heel strike and toe clearance . On the wet surface , the soft sole shoes led to shorter steps and a flatter foot l and ing , gait adaptations which are associated with perceptions of shoe/surface slipperiness . Increasing collar height led to greater double-support time and step width . The results indicate that shoes with elevated heels or soft soles impair walking stability in older people , especially on wet floors , and that high-collar shoes of medium sole hardness provide optimal stability on level dry , irregular and wet floors OBJECTIVE To assess the efficacy of a lateral wedge insole with elastic strapping of the subtalar joint for conservative treatment of osteoarthritis ( OA ) of the knee . METHODS The efficacy of a novel insole with elastic subtalar strapping and a traditional shoe insert wedge insole was compared . Ninety female out patients with OA of the knee were treated with wedge insoles for 8 weeks . R and omization was performed according to birth date . St and ing radiographs with unilateral insole use were used to analyze the femorotibial and talar tilt angles for each patient with and without their respective insole . Visual analog scale ( VAS ) score for subjective knee pain at the final assessment was compared with that at baseline in both groups . RESULTS Participants wearing the elastically strapped insole ( n = 46 ) had significantly decreased femorotibial angle ( p < 0.0001 ) and talar tilt angle ( p = 0.005 ) and significantly improved VAS pain score ( p = 0.045 ) in comparison with baseline assessment s. These significant differences were not found in the group with the inserted insole ( n = 44 ) . CONCLUSION The novel strapped insole leads to valgus angulation of the talus , result ing in correction of the femorotibial angle in patients with knee OA with varus deformity , and may have a therapeutic effect similar to that of high tibial osteotomy To comprehensively evaluate the performance of the Assessment of Quality of Life ( AQoL ) instrument for measuring health‐related quality of life ( HRQOL ) in people with hip and knee joint disease ( arthritis or osteoarthritis )

Studies targeted at physicians more often described providers and interventions . Lack of method ological rigor limits the evidence for the impact of cultural competence training on minority health care quality .

PURPOSE To systematic ally examine the method ological rigor of studies using cultural competence training as a strategy to improve minority health care quality . To the authors ' knowledge , no prior studies of this type have been conducted .

BACKGROUND This study examined the nurse outcomes of a cancer pain education program for nurses of patients from 11 different ethnic groups . METHODS Four hundred ninety six home , hospital , and hospice nurses participated in a one-day workshop or two half-day workshops on cancer pain assessment and management . Of these , 116 were r and omized to participate in a bedside-precepted visit with an oncology nurse specialist with pain specialization and a focus group to discuss attitudinal issues . Eighty-six nurses served as controls . Pre- , post- and one-year follow-up tests were administered . RESULTS Attitudes , knowledge , and application skills significantly improved for workshop-only and enriched-model nurses relative to controls . CONCLUSION For postgraduate nurses , daylong cancer pain education workshops were , in the group studied , as effective as h and s-on experience in improving cancer pain knowledge and changing attitudes . Both the workshop-only and the enriched-model nurses relative to controls had significantly improved knowledge and changed attitudes towards optimal pain management Abstract The changes in attitudes towards cultural difference of seventeen participants in a three-week community health study abroad program to Nepal were compared with the changes in attitudes of a similar group who did not participate in the tour . Participants in the tour group were surveyed eight weeks prior to departure and in the last week of the tour using a twenty-six item question naire employing a six-point forced-choice response scale . The responses of participants in the lour group showed significant shifts in relation to eight items compared while the responses for the control group showed no significant shifts . Observed student advantages of participation in this study tour included the development of independent behaviour and positive cultural adjustment and adaptation The purpose of this two group intervention study ( N = 94 ) was to determine if RNs who participated in " culture school " improved levels of cultural competence to a greater extent than RNs who attended nursing informatics classes . The Giger and Davidhizar Transcultural Assessment Model/Theory ( GDTAMT ) was the study 's theoretical foundation ( Giger & Davidhizar , 1995 ) . A sample of 94 participants , was identified from a r and omized group of all Jefferson County , Alabama RNs . R and omly assigned participants ( stratified by race ) experienced 8.5 hours of either culture school or nursing informatics classes and completed survey tools in three phases ( pre-intervention , immediate post intervention , three week follow-up ) . The Cultural Self-Efficacy Scale ( CSES ) by Bernal and Froman ( 1987 ) , knowledge base questions by Rooda ( 1990 ) , and demographic profiles were used . Concepts empirically measured using these tools were analyzed by transcultural nursing experts for their congruence with GDTAMT . Using repeated measures analyses of convariance ( race ) , significant differences between groups for both scales were found . Culture school participants demonstrated significantly more cultural self-efficacy and cultural knowledge , and these improvements remained during phase three . Further research is recommended to allow for greater generalizability of findings , an examination of client perceptions , and actual nurse behaviors The objective of the present study was to prepare new doctors with an awareness of cultural and health issues to facilitate positive experiences with indigenous patients . The study incorporated the 1998 intern orientation programs in Queensl and public hospitals . The study method included tier one of the Three Tiered Plan , which was implemented and audited . Indigenous liaison officers , directors of clinical training and medical education officers were surveyed prior to this implementation to determine whether any or similar initiatives had been carried out in previous years and /or were planned . Post-implementation feedback from interns was obtained by using question naires . Follow-up telephone interviews with the directors of clinical training , medical education officers and indigenous hospital liaison officers detailed the format and content of tier one at each hospital . The results indicate that this active intervention improved the implementation rate of tier one from nine of 19 ( 47 % ) Queensl and public hospitals in 1997 to 17 ( 90 % ) in 1998 . The 14 indigenous hospital liaison officers ( 100 % ) involved in the intervention perceived it as beneficial . Forty-three ( 67 % ) of interns who responded to the survey indicated they had encountered an indigenous patient within the last 2 - 4 months . The level of knowledge of indigenous health and culture self-reported by interns was between the categories ' enough to get by ' and ' inadequate ' . In conclusion , it appears that tier one has been successful and is to be a formal component of intern orientations in Queensl and public hospitals . Further initiatives in indigenous health and culture targeting medical staff ( i.e. tier two and tier three ) , are needed

Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT , with a more marked increase in the risk of local adverse reactions . Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy . AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving ( i.e. desensitization ) and post-discontinuation of AIT . It is , however , associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions .

BACKGROUND The European Academy of Allergy and Clinical Immunology ( EAACI ) is developing Guidelines for Allergen Immunotherapy ( AIT ) for IgE-mediated Food Allergy . To inform the development of clinical recommendations , we sought to critically assess evidence on the effectiveness , safety and cost-effectiveness of AIT in the management of food allergy .

BACKGROUND Some children allergic to cow 's milk proteins ( CMPs ) experience exceptionally severe reactions after ingesting only trace amounts of antigen . Avoiding the food and carrying self-injectable epinephrine are the current strategies for their management . OBJECTIVE The aim of this study was to evaluate the safety and efficacy of specific oral tolerance induction ( SOTI ) for children with severe CMP-induced systemic reactions . METHODS Ninety-seven children aged 5 years or older with a history of severe allergic reactions and very high CMP-specific IgE levels were selected for a double-blind , placebo-controlled food challenge . Sixty had positive test results to very small amounts of milk and were r and omly divided in 2 different groups . Thirty children ( group A ) immediately began SOTI , whereas the remaining 30 ( group B ) were kept on a milk-free diet and followed for 1 year . RESULTS After 1 year , 11 ( 36 % ) of 30 children in group A had become completely tolerant , 16 ( 54 % ) could take limited amounts of milk ( 5 - 150 mL ) , and 3 ( 10 % ) were not able to complete the protocol because of persistent respiratory or abdominal complaints . In group B the result of the double-blind , placebo-controlled food challenge performed after a year was positive in all 30 cases ( P < .001 ) . CONCLUSIONS In this study SOTI was effective in a significant percentage of cases BACKGROUND Food allergy may be life-threatening , and patients affected need to receive accurate diagnoses and treatment . Hazelnut has often been implicated as responsible for allergic reactions , and trace quantities can induce systemic reactions . OBJECTIVE The aim of this study was to evaluate the efficacy and tolerance of sublingual immunotherapy with a st and ardized hazelnut extract in patients allergic to hazelnut . METHODS This was a r and omized , double-blind , placebo-controlled study . Inclusion criteria were a history of hazelnut allergy and positive skin prick test and double-blind placebo-controlled food challenge results . Patients were then r and omly assigned into 2 treatment groups ( hazelnut immunotherapy or placebo ) . Efficacy was assessed by double-blind , placebo-controlled food challenge after 8 to 12 weeks of treatment . Blood sample s were drawn for measurement of specific IgE , IgG(4 ) , and serum cytokines before and after treatment . RESULTS Twenty-three patients were enrolled and divided into 2 treatment groups . Twenty-two patients reached the planned maximum dose at 4 days . Systemic reactions were observed in only 0.2 % of the total doses administered . Mean hazelnut quantity provoking objective symptoms increased from 2.29 g to 11.56 g ( P = .02 ; active group ) versus 3.49 g to 4.14 g ( placebo ; NS ) . Moreover , almost 50 % of patients who underwent active treatment reached the highest dose ( 20 g ) , but only 9 % in the placebo . Laboratory data showed an increase in IgG(4 ) and IL-10 levels after immunotherapy in only the active group . CONCLUSION Our data confirm significant increases in tolerance to hazelnut after sublingual immunotherapy as assessed by double-blind , placebo-controlled food challenge , and good tolerance to this treatment Background : Oral immunotherapy ( OIT ) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted . Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment . Objective : We sought to test the safety , effectiveness , and feasibility of early OIT ( E‐OIT ) in the treatment of peanut allergy . Methods : We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy . Qualifying subjects reacted to peanut during an entry food challenge and were block‐r and omized 1:1 to receive E‐OIT at goal maintenance doses of 300 or 3000 mg/d in a double‐blinded fashion . The primary end point , sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy ( 4‐SU ) , was assessed by double‐blinded , placebo‐controlled food challenge either upon achieving 4 prespecified criteria , or after 3 maintenance years . Peanut‐specific immune responses were serially analyzed . Outcomes were compared with 154 matched st and ard‐care controls . Results : Of 40 consented subjects , 3 ( 7.5 % ) did not qualify . Overall , 29 of 37 ( 78 % ) in the intent‐to‐treat analysis achieved 4‐SU ( 300‐mg arm , 17 of 20 [ 85 % ] ; 3000 mg , 12 of 17 [ 71 % ] , P = .43 ) over a median of 29 months . Per‐ protocol , the overall proportion achieving 4‐SU was 29 of 32 ( 91 % ) . Peanut‐specific IgE levels significantly declined in E‐OIT‐treated children , who were 19 times more likely to successfully consume dietary peanut than matched st and ard‐care controls , in whom peanut‐specific IgE levels significantly increased ( relative risk , 19.42 ; 95 % CI , 8.7‐43.7 ; P < .001 ) . Allergic side effects during E‐OIT were common but all were mild to moderate . Conclusions : At both doses tested , E‐OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary re introduction BACKGROUND The mechanisms contributing to clinical immune tolerance remain incompletely understood . This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance . OBJECTIVE Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells , basophils , and antibodies in subjects undergoing oral immunotherapy ( OIT ) for peanut allergy . METHODS In a phase 1 single-site study , we studied participants ( n = 23 ) undergoing peanut OIT and compared them with age-matched allergic control subjects ( n = 20 ) undergoing st and ard of care ( abstaining from peanut ) for 24 months . Participants were operationally defined as clinical ly immune tolerant ( IT ) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal ( IT , n = 7 ) , whereas those who had an allergic reaction were categorized as nontolerant ( NT ; n = 13 ) . RESULTS Antibody and basophil activation measurements did not statistically differentiate between NT versus IT participants . However , T-cell function and demethylation of forkhead box protein 3 ( FOXP3 ) CpG sites in antigen-induced regulatory T cells were significantly different between IT versus NT participants . When IT participants were withdrawn from peanut therapy for an additional 3 months ( total of 6 months ) , only 3 participants remained classified as IT participants , and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced regulatory T cells . CONCLUSION In summary , modifications at the DNA level of antigen-induced T-cell subsets might be predictive of a state of operationally defined clinical immune tolerance during peanut OIT BACKGROUND There are presently no available therapeutic options for patients with peanut allergy . OBJECTIVE We sought to investigate the safety , efficacy , and immunologic effects of peanut sublingual immunotherapy ( SLIT ) . METHODS After a baseline oral food challenge ( OFC ) of up to 2 g of peanut powder ( approximately 50 % protein ; median successfully consumed dose [ SCD ] , 46 mg ) , 40 subjects , aged 12 to 37 years ( median , 15 years ) , were r and omized 1:1 across 5 sites to daily peanut or placebo SLIT . A 5-g OFC was performed after 44 weeks , followed by unblinding ; placebo-treated subjects then crossed over to higher dose peanut SLIT , followed by a subsequent crossover Week 44 5-g OFC . Week 44 OFCs from both groups were compared with baseline OFCs ; subjects successfully consuming 5 g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders . RESULTS After 44 weeks of SLIT , 14 ( 70 % ) of 20 subjects receiving peanut SLIT were responders compared with 3 ( 15 % ) of 20 subjects receiving placebo ( P < .001 ) . In peanut SLIT responders , median SCD increased from 3.5 to 496 mg . After 68 weeks of SLIT , median SCD significantly increased to 996 mg ( compared with Week 44 , P = .05 ) . The median SCD at the Week 44 Crossover OFC was significantly higher than baseline ( 603 vs 71 mg , P = .02 ) . Seven ( 44 % ) of 16 crossover subjects were responders ; median SCD increased from 21 to 496 mg among responders . Of 10,855 peanut doses through the Week 44 OFCs , 63.1 % were symptom free ; excluding oral-pharyngeal symptoms , 95.2 % were symptom free . CONCLUSIONS Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared with placebo . Longer duration of therapy showed statistically significant increases in the SCD BACKGROUND Cow 's milk allergy ( CMA ) in children is a important problem in medical practice . Oral desensitization has been proposed as a therapeutic approach , but current protocol s are time-consuming and impractical . OBJECTIVES To establish a patient-friendly desensitization regimen with weekly up-dosing and to evaluate it in a r and omized controlled trial . METHODS Thirty children with IgE-mediated CMA confirmed by double-blind placebo-controlled food challenge were equally r and omized to desensitization with CM or soy milk as control . The weekly up-dosing lasted 18 weeks . The occurrence and severity of reactions after each dose was evaluated , and the desensitization was stopped if severe reactions occurred . Specific IgE and IgG4 levels to CM were measured at baseline , after 8 weeks , and at the end of the study . The double-blind food challenge was repeated once the desensitization was completed or after premature discontinuation . RESULTS Two active and 1 control patient dropped out . Full tolerance to CM ( 200 mL ) was achieved in 10 active patients and partial tolerance in 1 . Two active patients discontinued the desensitization after experiencing severe reactions , whereas no reactions occurred in controls , whose sensitivity to CM remained unchanged . A significant increase in specific IgG4 levels was found only in the active group . CONCLUSIONS This weekly up-dosing desensitization protocol for CMA performed under medical supervision was effective and reasonably safe and induced consistent immunologic changes BACKGROUND Open-label oral immunotherapy ( OIT ) protocol s have been used to treat small numbers of patients with peanut allergy . Peanut OIT has not been evaluated in double-blind , placebo-controlled trials . OBJECTIVE To investigate the safety and effectiveness of OIT for peanut allergy in a double-blind , placebo-controlled study . METHODS In this multicenter study , children ages 1 to 16 years with peanut allergy received OIT with peanut flour or placebo . Initial escalation , build-up , and maintenance phases were followed by an oral food challenge ( OFC ) at approximately 1 year . Titrated skin prick tests ( SPTs ) and laboratory studies were performed at regular intervals . RESULTS Twenty-eight subjects were enrolled in the study . Three peanut OIT subjects withdrew early in the study because of allergic side effects . During the double-blind , placebo-controlled food challenge , all remaining peanut OIT subjects ( n = 16 ) ingested the maximum cumulative dose of 5000 mg ( approximately 20 peanuts ) , whereas placebo subjects ( n = 9 ) ingested a median cumulative dose of 280 mg ( range , 0 - 1900 mg ; P < .001 ) . In contrast with the placebo group , the peanut OIT group showed reductions in SPT size ( P < .001 ) , IL-5 ( P = .01 ) , and IL-13 ( P = .02 ) and increases in peanut-specific IgG(4 ) ( P < .001 ) . Peanut OIT subjects had initial increases in peanut-specific IgE ( P < .01 ) but did not show significant change from baseline by the time of OFC . The ratio of forkhead box protein 3 (FoxP3)(hi ) : FoxP3(intermediate ) CD4 + CD25 + T cells increased at the time of OFC ( P = .04 ) in peanut OIT subjects . CONCLUSION These results conclusively demonstrate that peanut OIT induces desensitization and concurrent immune modulation . The current study continues and is evaluating the hypothesis that peanut OIT causes long-term immune tolerance BACKGROUND There are no treatments currently available for peanut allergy . Sublingual immunotherapy ( SLIT ) is a novel approach to the treatment of peanut allergy . OBJECTIVE We sought to investigate the safety , clinical effectiveness , and immunologic changes with SLIT in children with peanut allergy . METHODS In this double-blind , placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind , placebo-controlled food challenge . RESULTS Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge . Dosing side effects were primarily oropharyngeal and uncommonly required treatment . During the double-blind , placebo-controlled food challenge , the treatment group safely ingested 20 times more peanut protein than the placebo group ( median , 1,710 vs 85 mg ; P = .011 ) . Mechanistic studies demonstrated a decrease in skin prick test wheal size ( P = .020 ) and decreased basophil responsiveness after stimulation with 10(-2 ) μg/mL ( P = .009 ) and 10(-3 ) μg/mL ( P = .009 ) of peanut . Peanut-specific IgE levels increased over the initial 4 months ( P = .002 ) and then steadily decreased over the remaining 8 months ( P = .003 ) , whereas peanut-specific IgG4 levels increased during the 12 months ( P = .014 ) . Lastly , IL-5 levels decreased after 12 months ( P = .015 ) . No statistically significant changes were found in IL-13 levels , the percentage of regulatory T cells , or IL-10 and IFN-γ production . CONCLUSION Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy , with evidence of immunologic changes suggesting a significant change in the allergic response . Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance No studies have evaluated the potential of egg oral immunotherapy ( egg‐OIT ) to induce sustained unresponsiveness after discontinuing therapy following short‐term treatments BACKGROUND Coadministration of a bacterial adjuvant with oral immunotherapy ( OIT ) has been suggested as a potential treatment for food allergy . OBJECTIVE To evaluate a combined therapy comprising a probiotic together with peanut OIT . METHODS We performed a double-blind , placebo-controlled r and omized trial of the probiotic Lactobacillus rhamnosus CGMCC 1.3724 and peanut OIT ( probiotic and peanut oral immunotherapy [ PPOIT ] ) in children ( 1 - 10 years ) with peanut allergy . The primary outcome was induction of sustained unresponsiveness 2 to 5 weeks after discontinuation of treatment ( referred to as possible sustained unresponsiveness ) . Secondary outcomes were desensitization , peanut skin prick test , and specific IgE and specific IgG4 measurements . RESULTS Sixty-two children were r and omized and stratified by age ( ≤5 and > 5 years ) and peanut skin test wheal size ( ≤10 and > 10 mm ) ; 56 reached the trial 's end . Baseline demographics were similar across groups . Possible sustained unresponsiveness was achieved in 82.1 % receiving PPOIT and 3.6 % receiving placebo ( P < .001 ) . Nine children need to be treated for 7 to achieve sustained unresponsiveness ( number needed to treat , 1.27 ; 95 % CI , 1.06 - 1.59 ) . Of the subjects , 89.7 % receiving PPOIT and 7.1 % receiving placebo were desensitized ( P < .001 ) . PPOIT was associated with reduced peanut skin prick test responses and peanut-specific IgE levels and increased peanut-specific IgG4 levels ( all P < .001 ) . PPOIT-treated participants reported a greater number of adverse events , mostly with maintenance home dosing . CONCLUSION This is the first r and omized placebo-controlled trial evaluating the novel coadministration of a probiotic and peanut OIT and assessing sustained unresponsiveness in children with peanut allergy . PPOIT was effective in inducing possible sustained unresponsiveness and immune changes that suggest modulation of the peanut-specific immune response . Further work is required to confirm sustained unresponsiveness after a longer period of secondary peanut elimination and to clarify the relative contributions of probiotics versus OIT Summary Background Small studies suggest peanut oral immunotherapy ( OIT ) might be effective in the treatment of peanut allergy . We aim ed to establish the efficacy of OIT for the desensitisation of children with allergy to peanuts . Methods We did a r and omised controlled crossover trial to compare the efficacy of active OIT ( using characterised peanut flour ; protein doses of 2–800 mg/day ) with control ( peanut avoidance , the present st and ard of care ) at the NIHR/Wellcome Trust Cambridge Clinical Research Facility ( Cambridge , UK ) . R and omisation ( 1:1 ) was by use of an audited online system ; group allocation was not masked . Eligible participants were aged 7–16 years with an immediate hypersensitivity reaction after peanut ingestion , positive skin prick test to peanuts , and positive by double-blind placebo-controlled food challenge ( DBPCFC ) . We excluded participants if they had a major chronic illness , if the care provider or a present household member had suspected or diagnosed allergy to peanuts , or if there was an unwillingness or inability to comply with study procedures . Our primary outcome was desensitisation , defined as negative peanut challenge ( 1400 mg protein in DBPCFC ) at 6 months ( first phase ) . Control participants underwent OIT during the second phase , with subsequent DBPCFC . Immunological parameters and disease-specific quality -of-life scores were measured . Analysis was by intention to treat . Fisher 's exact test was used to compare the proportion of those with desensitisation to peanut after 6 months between the active and control group at the end of the first phase . This trial is registered with Current Controlled Trials , number IS RCT N62416244 . Findings The primary outcome , desensitisation , was recorded for 62 % ( 24 of 39 participants ; 95 % CI 45–78 ) in the active group and none of the control group after the first phase ( 0 of 46 ; 95 % CI 0–9 ; p<0·001 ) . 84 % ( 95 % CI 70–93 ) of the active group tolerated daily ingestion of 800 mg protein ( equivalent to roughly five peanuts ) . Median increase in peanut threshold after OIT was 1345 mg ( range 45–1400 ; p<0·001 ) or 25·5 times ( range 1·82–280 ; p<0·001 ) . After the second phase , 54 % ( 95 % CI 35–72 ) tolerated 1400 mg challenge ( equivalent to roughly ten peanuts ) and 91 % ( 79–98 ) tolerated daily ingestion of 800 mg protein . Quality -of-life scores improved ( decreased ) after OIT ( median change −1·61 ; p<0·001 ) . Side-effects were mild in most participants . Gastrointestinal symptoms were , collectively , most common ( 31 participants with nausea , 31 with vomiting , and one with diarrhoea ) , then oral pruritus after 6·3 % of doses ( 76 participants ) and wheeze after 0·41 % of doses ( 21 participants ) . Intramuscular adrenaline was used after 0·01 % of doses ( one participant ) . Interpretation OIT successfully induced desensitisation in most children within the study population with peanut allergy of any severity , with a clinical ly meaningful increase in peanut threshold . Quality of life improved after intervention and there was a good safety profile . Immunological changes corresponded with clinical desensitisation . Further studies in wider population s are recommended ; peanut OIT should not be done in non-specialist setting s , but it is effective and well tolerated in the studied age group . Funding MRC-NIHR partnership The possibility of obtaining oral desensitization in patients with food allergy is still a matter of debate . We decided to evaluate the safety and efficacy of st and ardized protocol s for oral desensitization with the most common food allergens . Forty-two children ( ages up to 16 years ) diagnosed as affected by food allergy ( on the basis of clinical history , skin prick tests , measurement of specific IgE , and double-blind , placebo-controlled food challenge ) underwent a sublingual-oral desensitizing treatment according to new st and ardized protocol s. The control group consisted of 10 patients who followed an elimination diet . The treatment was successfully completed by 85.7 % of the patients . Specific IgE showed a significant decrease , while specific IgG4 showed a significant increase , in all treated patients . The immunological modifications observed in our patients lead us to hypothesize that oral tolerance may be mediated by the same mechanisms as those involved in traditional desensitizing treatments for respiratory and insect sting allergy BACKGROUND Cow 's milk protein (CMP)-specific IgG4 responses and the efficacy of oral desensitization in infants with cow 's milk allergy ( CMA ) warrant more clarification . OBJECTIVE To explore whether CMP-specific IgG4 responses develop during infancy and whether regular CM exposure is efficacious for inducing a CMP-specific IgG4 response accompanying CM desensitization in 7- to 12-month-old infants . METHODS CM-specific IgE and CMP ( α-lactalbumin , β-lactoglobulin , and casein)-specific IgG4 levels were measured in 262 CM-sensitized children . Of these , 31 infants 7 to 12 months old with challenge-proved CMA were r and omly assigned to oral desensitization or an elimination diet and evaluated 6 months later . RESULTS CMP-specific IgG4 levels in 7- to 12-month-old infants were higher than in those younger than 6 months but comparable to those in children older than 12 months . CMP-specific IgG4 levels in 7- to 12-month-old infants with CMA were significantly lower than in those without CMA . Fourteen of 16 patients receiving oral desensitization could accept daily doses of 200 mL of CM , whereas all but 3 dropout patients receiving the elimination diet still showed allergic symptoms at the follow-up food challenge . In patients who became desensitized , CM-specific IgE levels were lower than at baseline , whereas CMP-specific IgG4 levels were significantly increased . In patients receiving the elimination diet , CM-specific IgE and CMP-specific IgG4 levels remained unchanged . CONCLUSION CMP-specific IgG4 responses did not develop sufficiently in 7- to 12-month-old infants with CMA . Oral desensitization in 7- to 12-month-old infants with CMA was associated with the upregulation of CMP-specific IgG4 responses accompanying the alleviation of CMA symptoms Background : The possibility of inducing oral desensitization in patients with food allergy is still controversial and no st and ardized programmes are yet available Background Limited published evidence shows oral desensitization to be a potential intervention option for cow 's milk protein ( CMPs ) allergy INTRODUCTION Desensitisation or specific oral tolerance induction ( SOTI ) to food is a new topical-therapeutic approach of food allergy for those children who have not achieved tolerance spontaneously . The objective of this study is to induce clinical tolerance in children with persistent allergy using an oral desensitisation protocol with powdered pasteurised egg . METHODS Seventy-two patients with egg allergy confirmed by open oral challenge test were r and omly assigned to SOTI or elimination diet as a control group . Forty children ( 5 - 15 years ) underwent a SOTI beginning with 1 mg and increasing the dosage weekly until a dose of 10 g , equivalent to an egg . The control group included 32 patients ( 4 - 15 years ) . RESULTS The procedure 's average duration was 10 weeks ( range 4 - 28 weeks ) . Three patients were withdrawn from the protocol for persistent gastrointestinal symptoms . During SOTI , 21 children ( 52.5 % ) presented symptoms . In eight the symptoms were mild and required no treatment . In the other 13 ( 61.90 % ) , the reactions were more severe . Seventeen children finished the treatment over a year ago and 20 in the past 6 - 12 months . Thirty-seven patients ( 92.5 % ) in the active group achieved tolerance to egg , versus 21.8 % in the control group . We only found statistically significant differences ( p<0.05 ) for skin prick tests with powdered egg at various dilutions and IgG levels with egg white after SOTI . Specific IgE concentration did not change significantly . CONCLUSIONS Our SOTI protocol is a safe , effective treatment for food allergy and of reasonable duration , confirming that tolerance can be induced in children who have not achieved it spontaneously IgE-mediated cow 's milk allergy ( CMA ) is a heavy burden for patients , particularly for children and their families . Allergen avoidance represents the only therapeutic option , but oral desensitization protocol s have been suggested . Because of the long duration and complexity of these protocol s we examined the feasibility of an oral tolerance induction protocol using a weekly up-dosing schedule . Children with IgE-mediated food allergy to milk , confirmed by a double-blind placebo-controlled food challenge , were recruited . Six of them were r and omized to double-blind desensitization with milk or soy formula as placebo . Seven patients underwent the protocol in open fashion . The desensitization schedule started with one drop of whole CM diluted 1:25 every week . The dose was doubled weekly until the 18th week to achieve an intake of 200 mL in approximately 4 months . Of the 13 children enrolled , 10 children received CM and 3 control children received soy formula . Full tolerance ( 200 mL of milk ) was achieved in 7 children ; in 2 children this therapeutic approach failed , because severe reactions occurred during the procedure . One patient achieved a partial tolerance ( 64 mL of milk ) . The three control children receiving placebo still showed a positive food challenge at the end of the study . A weekly up-dosing oral tolerance induction could be a viable alternative to traditional protocol s for children with IgE-mediated CMA BACKGROUND Food allergy is treated by avoidance diets in order to prevent anaphylactic reactions and to cure chronic associated symptoms . However , the natural history is left unchanged . OBJECTIVE To search for a beneficial effect of an oral desensitization protocol to allergenic foods in IgE-dependent milk or egg allergies in children . METHODS 60 children with documented cow 's milk allergy ( 13 months-6.5 years ) , and 90 children with egg allergy ( 12 months-8 years ) , were consecutively included after 6 - 12 months of avoidance diet , if a SBPCFC to 60 ml milk ( 60 ml ) or to 965 mg of raw egg white was negative . They were r and omized for uninterrupted avoidance or oral desensitization ( group A or OD ) . Six months later , a new SBPCFC was performed with , up to 200 ml of milk or 7 g of raw egg white . Prick tests and specific IgE levels were carried out simultaneously . RESULTS Data were obtained for 57 children with CMA ( 30 A and 27 OD ) , and 84 children with EA ( 35 A and 49 OD ) . The two groups ( AD or OD group ) were similar with regard to means of ages , the size of PT wheals and the level of IgEs at baseline . MILK ALLERGY : A SBPCFC to milk was positive in 11.1 % of those following OD vs. 40 % after A ( p < .025 ) . The size of PT decreased after OD and increased after A ( -3.4 mm vs. + 0.84 mm ; p < .002 ) . EGG ALLERGY : The SBPCFC to egg was positive in 30.6 % after OD vs. 48.6 % after A ( p < .1 ) . After 6 months , in the OD group , the mean size of the PT and the level of specific IgE were significantly reduced compared to the A group . In the A group , the threshold of reactivity was often lower , or more serious symptoms were observed . CONCLUSION Oral desensitization helps the egg and milk allergic children to overcome their allergies . Since the avoidance of these foods is likely to increase sensitization as well as to lower the threshold of reactivity , an active treatment is required . Further attempts to st and ardize the procedures of oral desensitization are expected BACKGROUND / AIMS Food allergy in children is still an unresolved problem that merits investigation , particularly when the food is fundamental for the child 's growth . Reports in the literature that deal with the possibility of a desensitizing treatment are sporadic and often inconsistent , and no st and ardized protocol s are yet available . In this paper we propose a st and ardized oral desensitization program for food allergy in children . METHODOLOGY The treatment was carried out in 14 cases with allergy to food ( milk in 6 cases , egg in 5 , fish in 2 and apple in 1 case ) . The control group consisted of 10 age and sex matched allergic subjects ( 5 to milk , 4 to egg and 1 to fish ) , who underwent a strict elimination diet regimen . RESULTS Compliance to treatment was satisfactory , since 12 out of the 14 treated cases ( 85.7 % ) completed the program . Treatment was successful in 100 % of the cases that completed the program : all the treated patients are now able to tolerate any food with no untoward effects or need for preventive drugs . CONCLUSIONS The proposed st and ardized oral desensitization treatment may represent a safe and convenient alternative in the management of food-allergic subjects BACKGROUND Orally administered , food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals . OBJECTIVE We sought to determine whether milk oral immunotherapy ( OIT ) is safe and efficacious in desensitizing children with cow 's milk allergy . METHODS Twenty children were r and omized to milk or placebo OIT ( 2:1 ratio ) . Dosing included 3 phases : the build-up day ( initial dose , 0.4 mg of milk protein ; final dose , 50 mg ) , daily doses with 8 weekly in-office dose increases to a maximum of 500 mg , and continued daily maintenance doses for 3 to 4 months . Double-blind , placebo-controlled food challenges ; end-point titration skin prick tests ; and milk protein serologic studies were performed before and after OIT . RESULTS Nineteen patients , 6 to 17 years of age , completed treatment : 12 in the active group and 7 in the placebo group . One dropped out because of persistent eczema during dose escalation . Baseline median milk IgE levels in the active ( n = 13 ) versus placebo ( n = 7 ) groups were 34.8 kUa/L ( range , 4.86 - 314 kUa/L ) versus 14.6 kUa/L ( range , 0.93 - 133.4 kUa/L ) . The median milk threshold dose in both groups was 40 mg at the baseline challenge . After OIT , the median cumulative dose inducing a reaction in the active treatment group was 5140 mg ( range 2540 - 8140 mg ) , whereas all patients in the placebo group reacted at 40 mg ( P = .0003 ) . Among 2437 active OIT doses versus 1193 placebo doses , there were 1107 ( 45.4 % ) versus 134 ( 11.2 % ) total reactions , with local symptoms being most common . Milk-specific IgE levels did not change significantly in either group . Milk IgG levels increased significantly in the active treatment group , with a predominant milk IgG4 level increase . CONCLUSIONS Milk OIT appears to be efficacious in the treatment of cow 's milk allergy . The side-effect profile appears acceptable but requires further study BACKGROUND Hen 's egg allergy affects young children and can cause severe allergic reactions . Avoidance results in dietary limitations and can affect the quality of life , especially in cases where potentially life-threatening reactions exist . Our objective was to desensitize children with moderate-severe IgE-mediated hen 's egg allergy over a 6-month period , by introducing increasing and very gradual daily doses of raw hen 's egg in order to enable the children to assume 25ml of this food , or to induce tolerance to the highest possible dose . The protocol foresaw the egg re introduction in the home setting . METHODS In this r and omized , controlled open study , 20 hen 's egg allergic children ( 10 in the active group ) were admitted . A convincing history or a positive double-blind placebo-controlled food challenge confirmed the diagnosis . Oral desensitization was performed with increasing doses starting from 0.27 mg of hen 's egg proteins ( 1 drop of raw hen 's egg diluted 1:100 ) . We adopted an original , mathematically calculated protocol in order to ensure a constant , daily increment of doses . RESULTS 8/10 children ( 80 % ) in the active group achieved the daily intake of 25ml over a 6-month period . One child ( 10 % ) could tolerate up to 2ml/day while another child ( 10 % ) failed the desensitization . Six months after enrolment only 2 children in the control group ( 20 % ) could tolerate hen 's egg . CONCLUSIONS We successfully desensitized 8/10 children with IgE-mediated hen 's egg allergy in a 6-month period . The partial outcome in the child who could tolerate 2ml/day reduced the risk of severe reactions after unnoticed introduction of egg . A regular protocol that ensures a daily constant increase of doses helps to reduce possible adverse events , thus improving safety and effectiveness BACKGROUND Oral desensitization in children allergic to cow 's milk proteins is not risk free . The analysis of factors that may influence the outcome is of utmost importance . OBJECTIVE To analyze the efficacy and safety of the oral desensitization according to specific IgE ( sIgE ) level and adverse events during the maintenance phase . METHODS Thirty-six patients allergic to cow 's milk ( mean age , 7 years ) were included in an oral desensitization protocol . Patients were grouped according to sIgE levels ( ImmunoCAP ) into groups 1 ( sIgE < 3.5 kU/L ) , 2 ( 3.5 - 17 kU/L ) , and 3 ( > 17 - 50 kU/L ) . Nineteen children were included as a control group . Serum sIgE levels to cow 's milk and its proteins were determined at inclusion and 6 and 12 months after finishing the desensitization protocol . RESULTS Thirty-three of 36 patients were successfully desensitized ( 200 mL ) : 100 % of group 1 and 88 % of groups 2 and 3 . Desensitization was achieved in a median of 3 months ( range , 1 - 12 months ) ; 90 % of the patients in group 1 , 50 % of the patients in group 2 , and 30 % of the patients in group 3 achieved tolerance in less than 3 months ( P = .04 ) . In the control group only 1 child tolerated milk in oral food challenge after 1 year . During the induction phase , there were 53 adverse events in 27 patients ( 75 % ) . Patients of groups 2 and 3 had more severe adverse events compared with group 1 . During the maintenance phase , 20 of 33 patients ( 60 % ) had an adverse event . CONCLUSION Oral desensitization is efficacious . Tolerance is achieved earlier when sIgE is lower . Severe adverse events are frequent , especially in patients with higher sIgE levels BACKGROUND Oral immunotherapy ( OIT ) may be an effective treatment for food allergy in children . It is not clear if the OIT-induced effect is achieved by desensitization ( transient state dependent on regular antigen exposure ) , or by tolerance ( persistent condition where the ability to consume the food is retained even after a period of withdrawal ) . OBJECTIVE The aim of this study was to investigate the efficacy of OIT-egg desensitization in a double-blind placebo-controlled study , and to evaluate if , after desensitization , tolerance can be maintained . METHODS Children with egg allergy were r and omized to OIT or placebo for 4 months . At the end of the controlled phase , a double-blind food challenge was repeated to confirm the achieved desensitization . Those subjects found to be desensitized were placed on an egg-containing diet for 6 months , followed by an egg avoidance phase for 3 months , when the food challenge was repeated to determine the maintained tolerance . RESULTS A total of 31 children were r and omized to OIT with dehydrated egg white ( n = 17 ) or placebo ( n = 14 ) . Of the 17 active patients ( 1 dropout ) , 16 achieved desensitization and started the 6-month egg-containing diet . After 3-month of egg avoidance , 31 % remained tolerant . In the control group , only 1 passed the final food challenge . Egg-specific IgG4 increased only in the active group . Five active OIT patients had side effects . CONCLUSION Egg OIT results in desensitization in almost all subjects , although tolerance was maintained in only 1/3 of them after a 3-month period of withdrawal . Side effects were encountered , but the procedure appeared safe . In hen egg allergy , OIT is effective for desensitization BACKGROUND Treatment of severe egg allergy is avoidance of hen 's egg ( HE ) and carrying self-injectable epinephrine . Specific oral tolerance induction ( SOTI ) seems a promising alternative treatment . However , some aspects of SOTI are still considered experimental . METHODS We evaluated the efficacy and safety of an original 6-month SOTI protocol in children with very severe HE allergy using raw HE emulsion . Twenty children ( age range : 5 - 11 yr ) were r and omized equally into a SOTI treatment group and a control group . The treatment group started SOTI and underwent a second challenge 6 months later . Control children were kept on an egg-free diet for 6 months and then underwent a second challenge . RESULTS After 6 months , 9/10 children of the SOTI group ( 90 % ) achieved partial tolerance ( at least 10 ml , but < 40 ml of raw HE emulsion , in a single dose ) and 1 ( 10 % ) was able to tolerate only 5 ml ( no tolerance ) . After 6 months , nine control children tested positive to the second challenge at a dose ≤0.9 ml of raw HE emulsion , and one reacted to 1.8 ml ( SOTI vs. control group p<0.0001 ) . All children in the SOTI group had side effects , but no child had a grade 5 reaction according to the Sampson grading . CONCLUSION Six months of SOTI with raw HE emulsion result ed in partial tolerance , with regular intake , in a significant percentage of children with severe egg allergy Background The incidence of anaphylaxis might be increasing . Data for fatal anaphylaxis are limited because of the rarity of this outcome . Objective We sought to document trends in anaphylaxis admissions and fatalities by age , sex , and cause in Engl and and Wales over a 20-year period . Methods We extracted data from national data bases that record hospital admissions and fatalities caused by anaphylaxis in Engl and and Wales ( 1992 - 2012 ) and crosschecked fatalities against a prospect i ve fatal anaphylaxis registry . We examined time trends and age distribution for fatal anaphylaxis caused by food , drugs , and insect stings . Results Hospital admissions from all-cause anaphylaxis increased by 615 % over the time period studied , but annual fatality rates remained stable at 0.047 cases ( 95 % CI , 0.042 - 0.052 cases ) per 100,000 population . Admission and fatality rates for drug- and insect sting – induced anaphylaxis were highest in the group aged 60 years and older . In contrast , admissions because of food-triggered anaphylaxis were most common in young people , with a marked peak in the incidence of fatal food reactions during the second and third decades of life . These findings are not explained by age-related differences in rates of hospitalization . Conclusions Hospitalizations for anaphylaxis increased between 1992 and 2012 , but the incidence of fatal anaphylaxis did not . This might be due to increasing awareness of the diagnosis , shifting patterns of behavior in patients and health care providers , or both . The age distribution of fatal anaphylaxis varies significantly according to the nature of the eliciting agent , which suggests a specific vulnerability to severe outcomes from food-induced allergic reactions in the second and third decades

Even though the current review revealed that there are not many studies reporting data relevant to the analyzed topic , the data obtained suggest that the delayed positioning of implants should be considered more predictable than the immediate positioning .

The aim of this study was to compare success rates in immediate and delayed dental implant placement following guided bone regeneration or onlay bone block ridge augmentation .

Osseointegrated implants as anchors for various prosthetic reconstructions have become a predictable treatment alternative . It was expected that implants required submucosal placement during the healing period for successful tissue integration . However , it has been demonstrated that healing and long-term health of implants could be achieved with equal predictability in a 1-stage , non-submerged approach . This prospect i ve 5-year study not only calculates implant success by life table analysis , but also evaluates the correlation between observed bone level changes with clinical parameters as measured by suppuration , plaque indices , bleeding indices , probing depth , attachment level and mobility . A total of 112 ITI dental implants were inserted in different areas of the jaws . Clinical and radiographic parameters were evaluated annually for 5 years , whereas a portion of the study group for which 6-year evaluations were available were included in the life-table analysis . The overall success rate after 5 years in service was 99.1 % , while after 6 years it was reduced to 95.5 % due to the fracture of 3 implants in 1 patient . The mean crestal bone loss experienced during the first year was 0.6 mm followed by an annual yearly loss of approximately 0.05 mm . No significant differences could be found between the amount of bone loss measured at each of the yearly follow-up visits . This suggests that statistically the followed implants did not show any radiographically measurable bone loss following the initial period of bone loss associated with implant placement and osseointegration . Low levels of correlation between the individual and cumulative clinical parameters with radiographically measured bone loss suggests that these parameters are of limited clinical value in assessing and predicting future peri-implant bone loss Thirty patients with extremely resorbed maxillae had reconstructive bone grafts from the ala iliaca and endosseous implants in a one-stage procedure . The first ten patients constituted a development group and the following 20 patients a routine group . The marginal bone level and implants success rate was evaluated in a prospect i ve long-term follow-up for a minimum of 10 years ( 10 - 13 years ) . Clinical and radiographic examinations were performed at 6 months and then annually up to 5 years . The final examinations were performed at the 10-year follow-up . The bridges were removed at every clinical examination . Marginal bone loss was seen up to the 3-year examination , where it averaged 4.6 mm in the routine group . Between the 3- and 10-year follow-up no significant change was registered . The initial bone loss was probably due to the design of the 3.6 mm conical unthreaded marginal part of the implant . The implant success rate was 83.1 % in the routine group . Failures mostly occurred during the first 2 years ( 14 out of 20 ) . A substantial amount of bone can be gained in patients with extremely resorbed maxillae , when treated with bone graft according to the procedure described in this study The present follow-up study evaluated clinical and radiographic parameters of dental implants placed with simultaneous guided bone regeneration with exp and ed polytetrafluoroethylene ( e-PTFE ) membranes . All implants were functioning well 24 months after insertion . In all , 63 patients with a total of 91 e-PTFE-augmented implants were integrated in a regular maintenance protocol . Modified periodontal data of 85 implants in 59 patients were recorded at 24 months and indicated no difference to implants placed in sufficient pristine bone . The mean plaque score ( mplI ) was 0.29 , 74 % of the sites showed no plaque . The sulcular probing depth ranged from 1 to 7 mm with a mean of 2.6 mm ( SD + /- 0.8 ) . Of the sites 96.5 % were < or = 4 mm deep , in 49 % of them probing result ed in bleeding . Periotest values 6 and 24 months ( mean : -3.4 and -3.4 ) after placement revealed stable peri-implant conditions and sustained osseointegration . The radiographic evaluation performed 6 , 12 and 24 months post insertion yielded a mean bone loss of 0.93 , 1.36 and 1.51 mm ranging from 0 to 4 mm . The short-term results of our clinical study demonstrated stable peri-implant conditions 2 years after membrane-protected osseous regeneration . The newly formed bone seemed to be able to withst and functional loading in a predictable manner after 18 months OBJECTIVES The purpose s of this study were to compare : ( a ) autogenous bone grafts ( ABG ) and distraction osteogenesis ( DO ) for their ability in correcting vertically deficient m and ibular ridges and their capability in maintaining over time the vertical bone gain obtained before and after implant placement ; and ( b ) the survival and success rates of implants placed in the reconstructed or distracted areas . MATERIAL AND METHODS In a 2-year period ( 2001 - 2002 ) , 17 patients presenting with vertically atrophied partially edentulous m and ibles requiring implant-supported prosthetic rehabilitation , were included in this study . Patients were r and omly assigned to two groups . Eight patients ( group 1 ) were treated with ABG harvested from the m and ibular ramus , while nine patients ( group 2 ) were treated by means of DO . In group 1 , patients received implants 4 - 5 months after the reconstructive procedure , while in group 2 implants were placed at the time of distraction device removal ( approximately 3 months after the completion of distraction ) . A total of 19 endosseous implants were placed in group 1 , and 21 implants were placed in group 2 patients . For both groups , after an additional 3 - 5-month period , prosthetic rehabilitation was started . RESULTS Bone resorption before implant placement was significantly higher in group 1 ( P=0.01 ) , while no statistically significant differences were found between the two groups as far as survival and success rates of implants and peri-implant bone resorption after the start of prosthetic loading were concerned . CONCLUSION The results suggested that : ( a ) both techniques may effectively improve the deficit of vertically resorbed edentulous ridges ; ( b ) survival and success rates of implants placed in the reconstructed/distracted areas are consistent with those of implants placed in native bone In the present multi-center study , non-submerged ITI implants were prospect ively followed to evaluate their long-term prognosis in fully and partially edentulous patients . In a total of 1003 patients , 2359 implants were consecutively inserted . Following a healing period of 3 - 6 months , the successfully integrated implants were restored with 393 removable and 758 fixed restorations . Subsequently , all consecutive implants were documented annually up to 8 years . At each examination , the clinical status of all implants was evaluated according to predefined criteria of success . Therefore , the data base allowed the evaluation of 8-year cumulative survival and success rates for 2359 implants . In addition , cumulative success rates were calculated for implant subgroups divided per implant type , implant length , and implant location . Furthermore , the actual 5-year survival and success rates could be determined for 488 implants . During the healing period , 13 implants did not successfully integrate , whereas 2346 implants fulfilled the predefined criteria of success . This corresponds with an early failure rate of 0.55 % . During follow-up , 19 implants were classified as failures due to several reasons . In addition , 17 implants ( approximately 0.8 % ) demonstrated at the last annual examination a suppurative periimplant infection . Including 127 drop out implants (= 5.4 % drop out rate ) into the calculation , the 8-year cumulative survival and success rates result ed in 96.7 % and 93.3 % , respectively . The analysis of implant subgroups showed slightly more favorable cumulative success rates for screw type implants ( > 95 % ) compared to hollow-cylinder implants ( 91.3 % ) , and clearly better success rates for m and ibular implants ( approximately 95 % ) when compared to maxillary implants ( approximately 87 % ) . The actual 5-year survival and success rates of 488 implants with 98.2 % and 97.3 % , respectively , were slightly better than the estimated 5-year cumulative survival and success rates of 2359 implants indicating that the applied life table analysis is a reliable statistical method to evaluate the long-term prognosis of dental implants . It can be concluded that non-submerged ITI implants maintain success rates well above 90 % in different clinical centers for observation periods up to 8 years A total of 114 ITI solid-screw implants was consecutively placed in 55 partially edentulous patients and restored with 68 fixed prostheses . The patients were followed for at least 5 years in a prospect i ve study that focused on implant success and longitudinal reactions of the peri-implant hard and soft tissues . During the study period , 5 implants failed and 15 implants were lost to follow-up , result ing in a cumulative survival rate of 95.3 % after 5 years of loading . The success analysis included additional strictly defined events ( " first occurrence of marginal bone loss > or = 4 mm , " " first occurrence of pocket depth > or = 4 mm , " and " first occurrence of crevicular fluid volume > or = 2.5 mm " ) and result ed in a cumulative 5-year success rate of 89.0 % . Median loss of marginal bone , as observed on radiographs , was 0.7 mm between implant placement and prosthetic treatment and 0.5 mm between prosthesis placement and the 5-year evaluation . Compared to the previous year 's value , the annual increase in marginal bone loss did not reach a level of statistical significance between 1 and 5 years of function , so that a steady state prevailed . The incidence of lingual-palatal surfaces affected with remarkable plaque deposits increased from 13 % after prosthesis placement to 23 % after 5 years . Sulcus Bleeding index , probing depth , attachment level , and crevicular fluid volume were used to describe the health of the peri-implant soft tissues . The research parameters remained almost unchanged and indicated a soft tissue response within physiologic levels . Most mechanical complications were experienced during the first year of loading and were related to loosening of occlusal screws , which occurred in 8 ( 12 % ) of 68 restorations In this prospect i ve study 47 edentulous patients were treated with m and ibular fixed prostheses supported by osseointegrated Brånemark implants and followed for 12 to 15 years . Three ( 1 % ) of the 273 inserted implants were lost , two before and one six years after placement of the fixed prosthesis . The cumulative success rate ( CSR ) of the implants was 98.9 % both after 10 and 15 years . None of the fixed prostheses was lost and at the last follow-up , all patients had stable fixed prostheses in function ( CSR 100 % ) . The marginal bone loss around the implants was small , on average 0.5 mm during the first post surgical year and thereafter about 0.05 mm annually . More bone was lost around the anterior implants than around the most posterior ones . Smoking and poor oral hygiene had significant influence on bone loss , while occlusal loading factors such as maximal bite force , tooth clenching and length of cantilevers were of minor importance . It is concluded that the long-term results of the m and ibular implant treatment were extremely successful , regarding both the fixed prostheses and implant stability . Bone resorption around the implants , albeit limited , was influenced by several factors , smoking and oral hygiene appeared to be most important This report of the 1st 2 prospect i ve studies using the Astra Tech Implant System and fixed detachable bridges for rehabilitation of m and ibular edentulism , presents clinical and radiographic data at the 5-year follow-up . The original material comprised 109 subjects , 56 of whom had been included in the original study , using the 1st generation Astra Tech Implant . Two subjects were excluded and the 3-year follow-up report was based on the remaining 54 subjects and 310 fixtures . After some minor changes to the fixture and the abutment , the 2nd generation Astra Tech Implant was used in 53 subjects and 308 fixtures . In all 16 subjects were lost to follow-up and the 5-year results are based on the remaining 91 subjects with 517 fixtures in function : 5 fixtures were lost due to mobility at abutment installation and during the 1st year , 2 fixtures were removed due to pain , and after 4 years in situ 1 fixture failed . As no clinical or radiographic differences were obvious in the annual registration s of the 2 studies the results have been combined . The fixed bridges were removed at 3 and 5 years to test each fixture and none was mobile . The cumulative fixture survival rate at 5 years was 98.7 % and the bridge survival rate was 100 % . Of the sites 82 % were plaque free , and 96.8 % showed no signs of inflammation . Over the 5-year period after bridge insertion , i.e. from baseline registration , there was only minor deterioration in marginal bone levels as measured on st and ardized intraoral radiographs : the mean differences in mm and st and ard deviations ( SD ) were -0.09 ( 0.27 ) in the 1st year , -0.20 ( 0.40 ) in the 3rd year , and -0.26 ( 0.53 ) in the 5th year . According to the stringent clinical and radiographic criteria by Albrektsson and co-workers , the successful treatment outcome and the survival rate in 91 subject over 5 years , indicates that the Astra Tech Dental Implant System with fixed detachable bridges is an appropriate method for rehabilitation of m and ibular edentulism In 10 patients , 68 endosseous implants were inserted in the augmented edentulous maxilla using a one-stage implant placement technique . Three months before implant insertion , the width and height of the alveolar crest were augmented with autologous bone grafts from the iliac crest . In all cases , the result ing bone volume was sufficient for implant insertion . According to an early loading protocol , the implant-supported overdenture was fabricated 2 months after insertion of the implants . Evaluation was performed according to a st and ardised protocol immediately and 1 year after fabrication of the prosthetic construction . The protocol included assessment of both clinical ( bleeding score , pocket depth , implant mobility ) and radiographic ( marginal bone level on st and ardised radiographs ) parameters . Three implants in two patients in the upper jaw were lost ( survival rate : 95.6 % ) . The peri-implant tissues had a healthy appearance and bone loss was minimal . Overall , the patients were very satisfied with the prosthetic construction . From this preliminary study , it is concluded that in selected cases , early loading of implants may develop into a predictable treatment modality after augmentation of the maxilla This prospect i ve clinical study evaluated the 5-year survival and success rates of 66 titanium implants placed in bone that had been previously augmented with autografts and nonresorbable barrier membranes . During the observation period , three patients with five implants dropped out of the study . None of the remaining 61 implants were lost during the follow-up period ( implant survival rate of 100 % ) . One implant exhibited a periimplant infection , whereas 60 implants were considered clinical ly successful at the 5-year examination , result ing in a 5-year success rate of 98.3 % . It can be concluded that the clinical results of implants in regenerated bone are comparable to those of implants in nonregenerated bone PURPOSE Vastly different surgical techniques have been advocated for osseous reconstruction of the severely atrophic m and ible . Endosseous implants placed in autologous bone grafts have been proposed to minimize graft resorption and restore function ; however , sufficient bone must exist to support the implants and prevent pathologic fracture . The purpose of this retrospective analysis was to assess the efficacy of autologous bone grafting and the subsequent placement of endosteal implants as a staged procedure in patients with severely atrophic m and ibles . MATERIAL S AND METHODS The records of all patients presenting to The University of North Carolina for treatment from 1997 to 1999 with atrophic m and ibles ( vertical m and ibular height < 7 mm as measured on panoramic radiographs in at least 1 site at the m and ibular midline and at the thinnest portion of the m and ibular body ) were review ed . Bone height was assessed preoperatively , immediately postoperatively , at the time of implant placement ( 4 to 6 months ) , and again at 12 and 24 months after bone grafting from posterior iliac crest to the m and ible via an extraoral approach . Five endosteal implants were subsequently placed in each patient as a delayed procedure 4 to 6 months after bone grafting , and prosthetic rehabilitation was completed with implant supported prostheses . RESULTS Fourteen consecutive patients were identified with a median preoperative bone height of 9 mm ( interquartile range , 25th to 75th percentile [ IQ ] , 7 to 10 mm ) in the m and ibular midline and 5 mm ( IQ , 2 to 5 mm ) in the body region . There were no perioperative complications . Median estimated blood loss during the bone graft procedure , as estimated by the surgeon and the anesthesiologist , was 300 mL ( IQ , 150 to 1,100 mL ) , and 1 patient required blood transfusion secondary to symptomatic anemia . The mean loss of vertical bone height after grafting and during the 4 to 6 months before implant placement was 33 % . After implant placement and at 12 months , the vertical bone loss was negligible in the implant-supported region and less than 11 % in the body region . CONCLUSION Reconstruction of the severely atrophic m and ible using autogenous corticocancellous bone grafts followed by placement of osseointegrated implants in 4 to 6 months can restore and maintain m and ibular bone sufficient to support implants and facilitate successful restoration of occlusion . A prospect i ve study is planned to identify predictors of successful outcomes compared with other surgical/prosthetic treatment OBJECTIVE The aim of this prospect i ve study was to present the clinical outcome of immediately loaded dental implants placed in edentulous , severely atrophied m and ibles , after reconstruction with autogenous multilayered calvarial grafts . MATERIAL S AND METHODS Six patients , two males and four females , aged 40 - 67 years ( mean : 56 years ) presenting with severely atrophied edentulous m and ibles ( Cawood and Howell class VI ) , were reconstructed with multilayered calvarial bone grafts placed in the intraforaminal area of the m and ible . Five to 8 months afterwards , 23 dental implants were placed in the reconstructed areas ( three to four implants per patient ) and immediately loaded with implant-supported overdentures . Patients were followed with clinical and radiographic controls annually . RESULTS Recovery after the reconstruction was uneventful in all patients . All 23 implants were osseointegrated 1 - 3 years after the start of immediate loading . The survival and success rates of implants were 100 % and 95.7 % , respectively . CONCLUSION Results from this study showed that immediate loading of dental implants placed in severely atrophied edentulous m and ibles reconstructed with calvarial bone grafts is a predictable procedure , which permits a successful dental rehabilitation with a shortening of treatment times The aim of this study was to longitudinally follow up osseointegrated titanium implants in partially dentate patients by clinical , radiographic and microbiological parameters in order to evaluate possible changes in the peri-implant health over time . Fifteen individuals treated with titanium implants , ad modum Brånemark , and followed for ten years were included in the study . Before implant placement ten years previously , the individuals had been treated for advanced periodontal disease and thereafter been included in a maintenance care program . The survival rate of the implants after ten years was 94.7 % . The bone loss was 1.7 mm when using the abutment-fixture junction as a reference point . Of the individuals , 50 % were positive for plaque at the implants . Bleeding on sulcus probing was present at 61 % of the implant surfaces . Ten years previously , the individuals had been carriers of putative periodontal pathogens , such as Porphyromonas gingivalis , Prevotella intermedia , Actinobacillus actinomycetemcomitans , Capnocytophaga spp . and Campylobacter rectus , and were also carriers of these species at the current examination . The results of the present study suggest that the presence of these putative periodontal pathogens at implants may not be associated with an impaired implant treatment . These species are most likely part of the normal resident microbiota of most individuals and may therefore be found at r and om at both stable and progressing peri-implant sites The purpose of this prospect i ve study was to compare vertical guided bone regeneration ( GBR ) and vertical distraction osteogenesis ( DO ) for their ability in correcting vertically deficient alveolar ridges and their ability in maintaining over time the vertical bone gain obtained before and after implant placement . Eleven patients ( group 1 ) were treated by means of vertical GBR with autogenous bone and e-PTFE membranes , while 10 patients ( group 2 ) were treated by means of DO . In group 1 , six patients received implants at the time of GBR ( subgroup 1A ) , while five patients had implants placed at the time of membrane removal ( subgroup 1B ) . In group 2 , implants were placed at the time of distraction device removal . A total of 25 implants were placed in group 1 and 34 implants were placed in group 2 patients . Three to 5 months after implant placement , patients were rehabilitated with implant-borne dental prostheses . The following parameters were evaluated : ( a ) bone resorption of the regenerated ridges before and after implant placement ; ( b ) peri-implant clinical parameters 1 , 2 , and 3 years after prosthetic loading of implants ; ( c ) survival and success rates of implants . Bone resorption values before and after implant placement were significantly higher in group 1 . The results suggested that both techniques may improve the deficit of vertically resorbed edentulous ridges , although distraction osteogenesis seems to be more predictable as far as the long-term prognosis of vertical bone gain is concerned . Implant survival rates as well as peri-implant clinical parameters do not differ significantly between the two groups , whereas the success rate of implants placed in group 2 patients was higher than that obtained in group 1 patients The aim of this study was to analyse the clinical outcome of two different surgical methods for the reconstruction of narrow edentulous ridges before implant installation : guided bone regeneration with e-PTFE membranes and autologous bone chips or grafting of autologous bone blocks without e-PTFE membranes . Thirty partially edentulous patients , presenting insufficient bone width ( less than 4 mm ) in the edentulous sites for installation of screw-type titanium implants , were selected and assigned to two different treatment modalities . Fifteen patients ( group 1 ) were treated by means of guided bone regeneration with e-PTFE membranes supported by stainless steel screws and autologous bone chips taken from intraoral sites . Fifteen patients ( group 2 ) were treated by means of autologous bone blocks taken from intraoral or extraoral sites ( anterior iliac crest and calvaria ) and stabilized with titanium microscrews . Six to 8 months later , during re-entry for implant insertion , the gain of ridge width obtained was measured . In group 1 the average amount of bone gain was 2.7 mm , whereas in group 2 the value was 4.0 mm . Five to 6 months after implant placement prosthetic rehabilitation was started . The mean follow-up after prosthetic load has been 22.4 months . Success rates of implants according to Albrektsson criteria has been 93.3 % in group 1 , and 90.9 % in group 2 . Although a statistical comparison between the two treatment modalities may not be feasible , due to the bias result ing from the choice of treatment by the clinician and from the differences in donor sites and defect extension , some considerations can be made : 1 ) both methods are a reliable means for the correction of narrow edentulous ridges ; 2 ) both techniques necessitate overcorrection of the defect because of interposition of connective tissue beneath the membrane in the first group and bone resorption in the second one ; 3 ) the use of semipermeable barriers increases the costs of the surgical procedure , as compared to bone grafting without membranes ; 4 ) guided bone regeneration presents a higher risk of infection because of wound dehiscence and membrane exposure . Therefore , in case of wide edentulous areas , reconstruction of narrow ridges should be performed with bone blocks without membranes

Implication s for practice Due to only one study in children it is not possible to make recommendations for treatment or prevention of OC in children . Due to insufficient evidence no conclusion could be made about the effectiveness of clotrimazole , nystatin , amphotericin B , itraconazole or ketoconazole with regard to OC prophylaxis . In comparison to placebo , fluconazole is an effective preventative intervention . However , the potential for resistant C and ida organisms to develop , as well as the cost of prophylaxis , might impact the feasibility of implementation . Direction of findings suggests that ketoconazole , fluconazole , itraconazole and clotrimazole improved the treatment outcomes . There is also a strong need for more research to be done on the treatment and prevention of OC in children as it is reported that OC is the most frequent fungal infection in children and adolescents who are HIV positive .

BACKGROUND Oral c and idiasis ( OC ) associated with human immunodeficiency virus ( HIV ) infection occurs commonly and recurs frequently , often presenting as an initial manifestation of the disease . Left untreated these lesions contribute considerably to the morbidity associated with HIV infection . Interventions aim ed at preventing and treating HIV-associated oral c and idal lesions form an integral component of maintaining the quality of life for affected individuals . OBJECTIVES To determine the effects of any intervention in preventing or treating OC in children and adults with HIV infection .

Background Progressive cell-mediated immunodeficiency with decrease of CD4 + lymphocyte count to less than or equal to 200 cells/mm3 is a major risk factor for colonization with C and ida species and development of c and idiasis . Oropharyngeal c and idiasis may occur in up to 90 % of human immunodeficiency virus (HIV)-infected patients during the course of the disease . This study is to determine the effect of prolonged highly active antiretroviral therapy ( HAART ) on oropharyngeal colonization with C and ida species and oral c and idiasis . Methods A prospect i ve , longitudinal follow-up study in HIV-infected patients receiving HAART . Results The mean CD4 + count increased from 232.5 to 316 cells/mm3 and the proportion of patients whose CD4 + count less than 200 cells/mm3 decreased from 50.0 % to 28.9 % ( p = 0.0003 ) in patients receiving HAART for at least 2 years . The prevalence of oral c and idiasis decreased from 10.6 % to 2.1 % ( p = 0.004 ) . The decrease in C and ida colonization was less impressive , falling from 57.8 % to 46.5 % ( p = 0.06 ) . Of the 142 patients enrolled in at least two surveys , 48 ( 33.8 % ) remained colonized with C and ida and 42 ( 29.6 % ) remained negative . In the remaining 52 patients , 34 switched from culture positive to negative , and an increase in CD4 + lymphocytes was noted in 91.2 % of them . Among the 18 patients who switched from culture negative to positive , 61.1 % also demonstrated an increase in CD4 + lymphocyte count ( p = 0.01 ) . Conclusion These findings indicate that HAART is highly effective in decreasing oral c and idiasis in association with a rise in CD4 + lymphocyte counts , but only marginally effective in eliminating C and ida from the oropharynx Objective : To evaluate the efficacy of itraconazole cyclodextrin solution in fluconazole-refractory oropharyngeal c and idiasis ( OPC ) , and to correlate clinical outcome with in vitro susceptibility and serum azole levels . Design : A prospect i ve , open-label , intervention study . Setting : A university hospital , which serves as the provincial HIV referral center . Patients and interventions : Thirty-six HIV-infected individuals referred for fluconazole-refractory OPC were evaluated prospect ively between May 1993 and March 1995 , including clinical assessment , serum azole levels , and susceptibility testing of C and ida spp . isolates . Itraconazole solution was administered orally at a daily dose of 200 mg for 14 days , followed by suppressive therapy . Thirty-four patients were evaluable . Main outcome measure : Resolution of oral pseudomembranous lesions . Results : Initial isolates were C and ida albicans ( n = 33 ) , C. glabrata ( n = 1 ) , C. krusei ( n = 1 ) , and mixed infection with C. albicans and C. krusei ( n = 1 ) . Fluconazole serum levels obtained at the time of failed therapy ranged from 4.7 to 40 mg/l ( median , 12.9 mg/l ) . Itraconazole was generally well tolerated . Clinical responses were observed in 65 % ( 22 out of 34 ) of evaluable cases . Among the responders , relapse had occurred within 2 months for four ( 36 % ) out of 11 cases who continued with follow-up . The median fluconazole minimal inhibitory concentration ( MIC ) was 64 mg/l for isolates from fluconazole-refractory cases , compared with a median of 0.5 mg/l for control isolates ( P = 0.002 ) . The median itraconazole MIC for isolates from fluconazole-refractory cases was 1.25 mg/l , compared with a median of 0.078 mg/l for controls ( P = 0.011 ) . Conclusion : A correlation between clinical response and in vitro susceptibility was clearly demonstrated for fluconazole , but not for itraconazole . Itraconazole cyclodextrin solution may be effective for fluconazole-refractory OPC and should be considered prior to salvage therapy with intravenous amphotericin OBJECTIVES --To compare the tolerance , efficacy , and pharmacokinetics of amphotericin deoxycholate ( Fungizone ) prepared in a parenteral fat emulsion ( Intralipid 20 % ) or glucose in HIV patients with c and idiasis . DESIGN --Non-blind r and omised controlled trial . SETTING --University hospital ; tertiary clinical care . PATIENTS --22 HIV positive patients with oral c and idiasis . INTERVENTIONS --Amphotericin 1 mg/kg/day given on four consecutive days as a one hour infusion dissolved in either 5 % glucose ( amphotericin-glucose ) or parenteral fat emulsion at a final concentration of 2 g/l fat emulsion ( amphotericin-fat emulsion ) . MAIN OUTCOME MEASURES -- Clinical tolerance ( fever , chills , sweats , nausea , arterial pressure , and pulse rate ) ; biological tolerance ( serum creatinine , electrolyte , and magnesium values ) ; clinical score of c and idiasis ; and serum concentrations of amphotericin . RESULTS --11 patients were enrolled in each group . All the amphotericin-fat emulsion infusions were given without serious problem whereas four amphotericin-glucose infusions were stopped because of renal impairment ( n = 3 ) or severe chills ( n = 2 ) , or both . For patients completing the amphotericin-glucose treatment creatine concentration increased by 42 mumol/l ; four of seven patients had at least one creatinine value > or = 133 mumol/l versus one of 11 receiving amphotericin-fat emulsion . Magnesium concentration fell significantly with amphotericin-glucose but not with amphotericin-fat emulsion . Clinical side effects were noted in 36/38 infusions with amphotericin-glucose but 10/44 with amphotericin-fat emulsion . Oral c and idiasis score was reduced similarly in both groups . Serum amphotericin concentrations were significantly lower and the volume of distribution of the drug higher after infusion of amphotericin-fat emulsion than after amphotericin-glucose . CONCLUSIONS -- Clinical and renal toxicity of amphotericin are reduced when the drug is prepared in fat emulsion . Preparation is simple and cost effective . Its efficacy is similar to that of conventional amphotericin In an open multicentre study the efficacy and safety of fluconazole versus ketoconazole were evaluated in the treatment of 46 pediatric patients with oropharyngeal c and idiasis and AIDS or HIV infection . Twenty-four subjects received oral fluconazole in a dosage of 3 mg/kg/day and 22 subjects received oral ketoconazole in a dosage of 7 mg/kg/day . The treatment duration ranged from 5 to 49 days . Results showed that fluconazole and ketoconazole have comparable efficacy and safety in the treatment of oropharyngeal c and idiasis in HIV-infected children . Patients treated with fluconazole had higher clinical and mycological cure rates at the end of therapy ( 88 % and 71 % respectively ) than those treated with ketoconazole ( 81 % and 57 % respectively ) . One case of drug-related side effects ( diarrhea and abdominal pain ) in a patient receiving ketoconazole result ed in discontinuation of treatment . Follow-up examinations 2 and 4 weeks post-treatment showed a comparably high rate of relapse in both patient groups BACKGROUND We evaluated the efficacy and safety of oral posaconazole for human immunodeficiency virus (HIV)-infected subjects with oropharyngeal c and idiasis ( OPC ) and /or esophageal c and idiasis ( EC ) who were clinical ly refractory to treatment with oral fluconazole or itraconazole . METHODS Subjects with confirmed OPC or EC who did not improve after receiving st and ard courses of fluconazole or itraconazole treatment were eligible for study enrollment . Subjects received either oral posaconazole ( 400 mg twice daily ) for 3 days followed by oral posaconazole ( 400 mg once daily ) for 25 days ( regimen A ; 103 patients ) or oral posaconazole ( 400 mg twice daily ) for 28 days ( regimen B ; 96 patients ) . The primary end point was cure or improvement after 28 days . Primary efficacy analyses were performed on the subset of treated subjects with refractory disease ( e.g. , baseline culture positive for fluconazole- or itraconazole-resistant C and ida species or persistent or progressive clinical signs or symptoms consistent with treatment failure ) . RESULTS Of the modified intent-to-treat population , 132 ( 75 % ) of 176 subjects achieved a clinical response to posaconazole treatment . Clinical response rates were similar between regimen A recipients ( 75.3 % ) and regimen B recipients ( 74.7 % ) . Clinical responses occurred in 67 ( 73 % ) of 92 subjects with baseline isolates resistant to fluconazole , 49 ( 74 % ) of 66 subjects with baseline isolates resistant to itraconazole , and 42 ( 74 % ) of 57 subjects with isolates resistant to both . Clinical response was achieved in 32 ( 74.4 % ) of 43 subjects with endoscopically documented EC . The most common treatment-related adverse events were diarrhea ( 11 % ) , neutropenia ( 7 % ) , flatulence ( 6 % ) , and nausea ( 6 % ) . Eight subjects ( 4 % ) discontinued therapy as a result of a treatment-related adverse event . CONCLUSIONS Posaconazole offers a safe and effective treatment option for HIV-infected subjects with azole-refractory OPC and /or EC CONTEXT Multiple options are now available for prophylaxis of opportunistic infections related to the acquired immunodeficiency syndrome ( AIDS ) . However , because of differences in incidence rates as well as drug efficacy , toxicity , and costs , the role of different types of prophylaxis remains uncertain . OBJECTIVE To determine the clinical impact , cost , and cost-effectiveness of strategies for preventing opportunistic infections in patients with advanced human immunodeficiency virus ( HIV ) disease . DESIGN We developed a Markov simulation model to compare different strategies for prophylaxis of Pneumocystis carinii pneumonia ( PCP ) , toxoplasmosis , Mycobacterium avium complex ( MAC ) infection , fungal infections , and cytomegalovirus ( CMV ) disease in HIV-infected patients . Data for the model were derived from the Multicenter AIDS Cohort Study , r and omized controlled trials , and the national AIDS Cost and Services Utilization Survey . MAIN OUTCOME MEASURES Projected life expectancy , quality -adjusted life expectancy , total lifetime direct medical costs , and cost-effectiveness in dollars per quality -adjusted life-year ( QALY ) saved . RESULTS For patients with CD4 cell counts of 0.200 to 0.300 x 10(9)/L ( 200 - 300/microL ) who receive no prophylaxis , we projected a quality -adjusted life expectancy of 39.08 months and average total lifetime costs of $ 40288 . Prophylaxis for PCP and toxoplasmosis with trimethoprim-sulfamethoxazole for patients with CD4 cell counts of 0.200 x 10(9)/L ( 200/microL ) or less increased quality -adjusted life expectancy to 42.56 months , implying an incremental cost of $ 16000 per QALY saved . Prophylaxis for MAC for patients with CD4 cell counts of 0.050 x 10(9)/L ( 50/microL ) or less produced smaller gains in quality -adjusted life expectancy ; incremental cost-effectiveness ratios were $ 35000 per QALY saved for azithromycin and $ 74000 per QALY saved for rifabutin . Oral ganciclovir for the prevention of CMV infection was the least cost-effective prophylaxis ( $ 314000 per QALY saved ) . Results were most sensitive to the risk of developing an opportunistic infection , the impact of opportunistic infection history on long-term survival , and the cost of prophylaxis . CONCLUSIONS The cost-effectiveness of prophylaxis against HIV-related opportunistic infections varies widely , but prophylaxis against PCP or toxoplasmosis and against MAC delivers the greatest comparative value . In an era of limited re sources , these results can be used to set priorities and explore new alternatives for improving HIV patient care Over 37 months , we conducted a prospect i ve double-blind , r and omized study in a cohort of 138 HIV-infected patients to compare the effect of two different strategies on the prevention and treatment of oropharyngeal c and idiasis relapses and on the development of clinical and microbiological resistance to fluconazole . Each episode was treated with a 7 day course of fluconazole 200 mg/day , followed by secondary prophylaxis with fluconazole 150 mg once weekly matched to placebo . The duration of the double-blind phase of the study , from the day of r and omization to the first primary end-point , was 347 + /- 186 days for the fluconazole group and 196 + /- 128 days for the placebo group ( P < 0.001 ) . A total of 33 patients remained relapse-free during the course of the study . Clinical failure was observed in a total of five patients ( four in the fluconazole group , one in the placebo group ; P = 0.15 ) . Microbiological resistance was recorded in 12 patients ( eight in the fluconazole group , four in the placebo group ; P = 0.20 ) . There were no significant treatment group differences in microbiological resistance whether comparisons were made for all cases or for cases up to 1 month post- study . In the few patients who developed clinical and /or microbiological resistance , the cumulative dose of fluconazole before entry into the study was a mean value of 8.6 g ( compared with 2.9 g in patients without clinical and /or microbiological resistance ) . In summary , patients treated with secondary prophylaxis suffered fewer relapses of oropharyngeal c and idiasis . Development of resistant c and idiasis ( clinical and /or microbiological ) was rarely seen in either group and its incidence was not significantly different PURPOSE The effects of continuous or intermittent therapy with fluconazole on the recurrence of and the development of fluconazole resistance are not known . PATIENTS AND METHODS We studied human immunodeficiency virus (HIV)-positive patients with CD4 cell count < 350 x 10(6)/L and oropharyngeal c and idiasis in a prospect i ve , r and omized study . After initial treatment , 20 patients ( 16 of whom completed 3 months of follow-up ) received continuous fluconazole at 200 mg/day , and 48 patients ( 28 of whom completed follow-up ) received intermittent therapy at the time of symptomatic relapses . Oral sample s were obtained weekly during episodes of infection and quarterly as surveillance cultures . Development of resistance was defined as a fourfold rise in minimum inhibitory concentration ( MIC ) to at least 16 microg/mL from the initial culture in the same species , the emergence of new , resistant ( MIC > or = 16 microg/mL ) species , or a significant increase in the proportion of resistant isolates . RESULTS During a mean follow-up of 11 months , median annual relapse rates were lower in patients on continuous therapy ( 0 episodes/year ) than in patients on intermittent therapy ( 4.1 episodes/year ; P < 0.001 ) . Sterile cultures were seen in 6 of 16 ( 38 % ) patients on continuous therapy compared with 3 of 28 ( 11 % ) on intermittent therapy ( P = 0.04 ) . Microbiological resistance developed in 9 of 16 ( 56 % ) patients on continuous treatment , compared with 13 of 28 ( 46 % ) on intermittent treatment ( P = 0.75 ) . However , despite isolates with increased MICs , 42 of 44 patients responded to fluconazole in doses up to 800 mg/day . CONCLUSIONS In patients with frequent recurrences , continuous suppressive therapy significantly reduced relapses and colonization . Resistance occurred with both continuous and intermittent therapy ; however , therapeutic responses were excellent Objective : This multicentre study evaluated the clinical efficacy and tolerability of D0870 in treating oropharyngeal c and idiasis in HIV-positive patients who had no history of clinical resistance to fluconazole . Methods : Three regimens were evaluated in two phases . In phase I a 50 mg initial dose was followed by 10 mg for 4 days ( Group 1 ) . In phase II a 100 mg initial dose was followed by 25 mg for 4 days ( Group 2 ) , or 10 mg for 5 days ( Group 3 ) . Results : Clinical cure was obtained in 27 patients of a total of 35 ( 77 % ) and six other patients improved ( 17 % ) . Two patients at the lowest dose failed and both had very low plasma concentration of D0870 . No association was found between clinical outcome , minimum inhibitory concentration of D0870 pre-therapy for C and ida albicans , maximum recorded plasma D0870 concentration , cfu of culture or CD4 cell count at entry . Overall , 37 % of the patients experienced relapse during the 2 weeks post therapy . Tolerance was excellent . Mild adverse events possibly related to the study drug were recorded in five patients . Conclusion : D0870 demonstrates excellent efficacy at low doses in the treatment of HIV-related OPC and exhibits a favourable safety profile BACKGROUND In human immunodeficiency virus (HIV)-infected patients , fluconazole prophylaxis is associated with reductions in the rate of fungal infection . However , concerns exist with regard to the use of fluconazole prophylaxis and the risk of development of fluconazole treatment-refractory infections . METHODS We performed a r and omized , open-label trial that compared oral fluconazole given continuously ( 200 mg 3 times weekly ; the " continuous fluconazole arm " ) with fluconazole that was provided only for episodes of orophayngeal c and idiasis ( OPC ) or esophageal c and idiasis ( EC ) ( the " episodic fluconazole arm " ) in HIV-infected persons with CD4 + T cell counts of < 150 cells/mm3 and a history of OPC . The primary study end point was the time to development of fluconazole-refractory OPC or EC , which was defined as lack of response to 200 mg fluconazole given daily for 14 or 21 days , respectively . RESULTS A total of 413 subjects were r and omized to receive continuous fluconazole , and 416 were r and omized to receive episodic fluconazole . After 42 months , 17 subjects ( 4.1 % ) in the continuous fluconazole arm developed fluconazole-refractory OPC or EC infections , compared with 18 subjects ( 4.3 % ) in the episodic fluconazole arm , with no difference between treatment arms with regard to the time to development of a fluconazole-refractory infection within 24 months ( P=.88 , by log-rank test ) or before the end of the study ( P=.97 , by the log-rank test ) . Continuous fluconazole therapy was associated with fewer cases of OPC or EC ( 0.29 vs. 1.08 episodes per patient-year ; P<.0001 ) and fewer invasive fungal infections ( 15 vs. 28 episodes ; P=.04 , by chi2 test ) , but not with improved survival , compared with episodic fluconazole therapy . CONCLUSION Continuous fluconazole therapy is not associated with significant risk of fluconazole-refractory OPC or EC , compared with episodic fluconazole therapy , in HIV-infected patients with access to active antiretroviral therapy A r and omized un-blinded study on the treatment of oropharyngeal and esophageal c and idiasis was conducted in Kinshasa ( Zaire ) , among 141 in patients with AIDS and oropharyngeal c and idiasis , of whom 136 also had esophageal c and idiasis . The study compared the efficacy of gentian violet mouth washes ( 1.5 ml 0.5 % aqueous solution b.i.d . ) , oral ketoconazole ( 200 mg/day , after a meal ) and nystatin mouth washes ( 200.000 U oral suspension q.i.d . ) . Patients treated with mouth washes swallowed their medication after mouth washing . Patients enrolled in this study had a very high mortality ( probability of death : 41.6 % after 14 days ) . After 14 days , 72 patients could be evaluated . At that time , oropharyngeal lesions had disappeared in similar proportions of patients treated with gentian violet ( 11/26 , 42 % ) and ketoconazole ( 10/23 , 43 % ) , and in a lower proportion of patients treated with nystatin ( 2/23 , 9 % ; p less than 0.05 ) . In esophageal c and idiasis , ketoconazole seemed more efficient than both other treatments : esophageal lesions had disappeared in 5 ( 24 % ) of the 21 patients on ketoconazole , compared to less than 10 % of patients on both other treatments ( p = 0.07 ) . The suboptimal results observed with all 3 treatments could be explained by the profound immunosuppression of patients enrolled in the study . This study suggests that gentian violet is effective treatment for oropharyngeal c and idiasis . As it is very cheap ( 0.5 US$ /treatment course in Kinshasa ) , we suggest that its use should be assessed in larger studies To determine whether daily use of nystatin pastilles can prevent initial outbreak or recurrence of oral c and idiasis in HIV-infected patients and to identify factors associated with outbreaks during 20-week follow-up , a r and omized , double-blind , placebo-controlled clinical trial was conducted . Subjects were 128 HIV-infected men ( aged 27 - 60 years ) who either had had no documented episode of oral c and idiasis in the previous year or had been clinical ly clear of oral c and idiasis for at least 72 h before r and omization . Study arms were two placebo pastilles , one nystatin ( 200,000 U ) and one placebo pastille , or two nystatin pastilles daily for 20 weeks . The main outcome measure was time to oral c and idiasis , as determined by potassium hydroxide ( KOH ) smear and fungal culture . A multivariate proportional hazards model showed that four factors were significant ( p < 0.001 ) in predicting time to oral c and idiasis : nystatin treatment ( hazard ratio 0.59 ) , history of oral c and idiasis ( 3.58 ) , C and ida albicans carriage ( 2.79 ) , and CD4 count at r and omization ( 0.65 ) . In this small group of subjects , nystatin appeared to be effective in delaying onset of oral c and idiasis . Patients with CD4 counts < 200 who are carriers of C. albicans and have a history of oral c and idiasis may be most likely to benefit from antifungal prophylaxis ABSTRACT D0870 is a triazole with a broad antifungal spectrum , and it has been shown to have both in vitro and in vivo activities against wild-type and fluconazole-resistant strains of C and ida albicans . Twenty-two human immunodeficiency virus (HIV)-positive male subjects were enrolled in an open , nonr and omized trial investigating the pharmacokinetics of two different dosing regimens of D0870 and assessing the safety of multiple oral doses of D0870 in HIV-positive subjects and their ability to tolerate multiple oral doses . Nine subjects received an initial loading dose of 50 mg , followed by four once-daily maintenance doses of 10 mg . A further nine subjects received an initial 200-mg loading dose followed by four daily maintenance doses of 25 mg . All subjects were fasting . A single loading dose of 50 mg of D0870 result ed in a mean maximum concentration in serum ( Cmax ) of 107 ± 32 ng/ml . Concentrations in plasma were maintained by the 10-mg once-daily dosing regimen as seen by the similar values of the area under the concentration-time curve from 0 to 24 h following dosing on days 1 and 5 and a mean accumulation ratio close to unity ( 0.90 ) . The terminal plasma half-life of D0870 in plasma following dosing on day 5 ranged from 23 to 85 h ( mean , 49 h ) . A single loading dose of 200 mg of D0870 result ed in a Cmax of 431 ± 186 ng/ml . Concentrations in plasma were again maintained by the 25-mg daily dosing regimen , with the mean accumulation ratio being close to unity ( 1.17 ) . The terminal half-life of D0870 in plasma following dosing on day 5 of phase II of the study ranged from 34 to 137 h ( mean , 71 h ) . In addition , the concentrations achieved in the plasma of these HIV-positive subjects were similar to the values predicted from simulations based on data derived from normal , healthy subjects . D0870 was well tolerated . No serious adverse events were experienced during the course of the study , and all volunteers completed the trial . A total of 15 adverse events were reported , but none were considered to be related to the administration of D0870 and all had resolved by the end of the trial . No changes in the hematology , clinical chemistry , or urinalysis parameters were considered to be related to dosing with D0870 . No clinical ly significant changes in the electrocardiogram parameters were noted during the trial . The data generated in this trial support further investigation of these regimens with HIV-positive subjects with fluconazole-susceptible or -resistant oropharyngeal c and idosis Oral c and idiasis is a major problem in developing countries where antiretroviral therapy is available to a small percentage of the infected population . HIV patients are prone to xerostomia and predisposed to C and ida infection . Preventing oral c and idiasis is better than the frequent use of antifungals that may lead to the development of drug resistance . This study investigated the ability of commercial mouth rinses and sodium bicarbonate to reduce salivary C and ida and to improve the saliva flow of HIV-positive patients . One hundred fifty HIV patients without oral c and idiasis were examined for oral lesions initially and after 2 , 4 , and 12 weeks . Unstimulated saliva was collected ; the volume was measured and cultured for yeasts . Subjects were provided with mouth rinses containing either benzydamine hydrochloride , benzydamine hydrochloride with chlorhexidine gluconate , triclosan with sodium fluoride , 5 % sodium bicarbonate , or placebo and asked to rinse twice daily for 12 weeks . The effect of the mouth rinses and placebo on C and ida counts and saliva flow was analyzed using analysis of variance ( ANOVA ) . A total of 108 patients completed the trial , 35 missed appointments , 4 died , 2 developed oral c and idiasis , and 1 herpetic lesion . Triclosan/fluoride decreased the C and ida count more than the placebo ( p = 0.005 ) while chlorhexidine/benzydamine hydrochloride ( p = 0.001 ) and triclosan/fluoride mouthrinses ( p = 0.002 ) increased the salivary flow during the initial 4 weeks . The most effective mouth rinse triclosan/fluoride decreased oral C and ida counts and increased saliva flow . Studies are needed to determine the efficacy of these mouth rinses for the long-term prevention of clinical oral c and idiasis in adult HIV-positive patients BACKGROUND Oropharyngeal c and idiasis is the most common opportunistic infection affecting patients with human immunodeficiency virus ( HIV ) infection . Because of convenience , cost , and reluctance to complicate antiretroviral treatment regimens , single-dose fluconazole may be a favorable regimen for treatment of moderate to severe oropharyngeal c and idiasis . We conducted a prospect i ve , r and omized , double-blind , placebo-controlled trial to compare the clinical and mycological responses , relapse rates , and safety of a single 750-mg dose and a 14-day course of treatment with fluconazole . METHODS A total of 220 HIV-infected patients with clinical and mycological evidence of oropharyngeal c and idiasis were r and omly assigned in a 1:1 ratio to receive either a 750-mg single dose of orally administered fluconazole ( 110 patients ) or 150 mg of orally administered fluconazole once per day for 2 weeks ( 110 patients ) . The primary efficacy analysis was based on clinical and mycological responses at the end of treatment . Secondary parameters were safety and relapse rate . RESULTS Single-dose fluconazole was equivalent to a 14-day course of fluconazole in achieving clinical and mycological cure , with clinical cure rates of 94.5 % and 95.5 % , respectively ( odds ratio , 0.825 ; 95 % confidence interval , 0.244 - 2.789 ; P= .99 ) , and mycological cure rates of 84.5 % and 75.5 % , respectively ( odds ratio , 1.780 ; 95 % confidence interval , 0.906 - 3.496 ; P= .129 ) . Drug-related adverse events were uncommon and were not different between the treatment groups . CONCLUSION A single dose of 750 mg of fluconazole was safe , well tolerated , and as effective as the st and ard 14-day fluconazole therapy in patients with HIV infection and acquired immunodeficiency syndrome who had oropharyngeal c and idiasis coinfection BACKGROUND Oropharyngeal c and idiasis is the most common opportunistic infection among persons infected with human immunodeficiency virus ( HIV ) . Use of some agents is hampered by lack of efficacy , emergence of resistance , adverse events , and need for intravenous administration . Posaconazole is an extended-spectrum triazole with potent in vitro activity against C and ida species , including C and ida albicans , C and ida glabrata , and C and ida krusei ( including fluconazole-resistant strains ) . METHODS This multicenter , r and omized , evaluator-blinded study of subjects with HIV infection and oropharyngeal c and idiasis compared efficacy of posaconazole with that of fluconazole . Subjects received either 200 mg of posaconazole or fluconazole oral suspension on day 1 , followed by 100 mg/day for 13 days . The primary study end point-- clinical success ( cure or improvement ) on day 14 - -was evaluated for 329 subjects . Durability of clinical success was evaluated on day 42 . RESULTS Three hundred fifty subjects received posaconazole ( n = 178 ) or fluconazole ( n = 172 ) . Clinical success occurred in 155 ( 91.7 % ) of 169 posaconazole recipients and in 148 ( 92.5 % ) of 160 fluconazole recipients ( 95 % confidence interval , -6.61 % to 5.04 % ) , indicating that posaconazole was not inferior to fluconazole . On day 14 , mycological success was 68 % in both arms , but by day 42 , significantly more posaconazole recipients than fluconazole recipients continued to have mycological success ( 40.6 % vs. 26.4 % ; P=.038 ) . Fewer posaconazole recipients than fluconazole recipients experienced clinical relapse ( 31.5 % vs. 38.2 % ) . Adverse events were similar between treatment arms . CONCLUSIONS Results demonstrate that posaconazole was as effective as fluconazole in producing a successful clinical outcome . However , posaconazole was more effective in sustaining clinical success after treatment was stopped This double-blind trial compared the clinical and mycological efficacy and safety of itraconazole oral solution with those of fluconazole capsules in the treatment of oropharyngeal c and idiasis in patients with AIDS . A total of 244 patients were enrolled and r and omized to one of three groups for treatment with itraconazole oral solution ( 100 mg twice daily for 7 days or 100 mg once daily for 14 days ) or fluconazole capsules ( 100 mg once daily for 14 days ) . Among 194 evaluable cases , complete response ( clearance of all symptoms and signs ) or marked improvement was noted in 54 of 60 patients ( 90 % ) receiving once-daily itraconazole and in 65 of 72 fluconazole-treated patients ( 90 % ) at the end of treatment ; these results were statistically equivalent ( P = .0024 ) . Twice-daily itraconazole produced a clinical response in 51 of 62 patients ( 82 % ) . The groups were equivalent in terms of early relapse ( within the 18-day period studied ) ; 37 % of patients in the twice-daily itraconazole group , 35 % in the once-daily itraconazole group , and 34 % in the fluconazole group relapsed . Drug tolerability was comparable between the three groups . These results show that , in the treatment of oropharyngeal c and idiasis , itraconazole oral solution and fluconazole capsules at a 100-mg single daily dose for 14 days are equally effective Recurrent oropharyngeal c and idiasis is common in patients with acquired immunodeficiency syndrome and the acquired immunodeficiency syndrome-related complex . It causes local pain and discomfort , loss of taste , and aversion to food and may lead to secondary complications . We examined , in a double-blind study , whether recurrent thrush could be prevented by prophylaxis . Twenty-five patients with one to four previous thrush episodes who had no thrush at the outset of the study were r and omized to receive 100 mg of fluconazole or placebo daily for 12 weeks . If thrush occurred , prophylaxis was stopped and patients were treated conventionally , after which prophylaxis was resumed . After the r and omized study , some patients were given continuous fluconazole ( open phase ) . In the r and omized study , thrush occurred in eight of 13 placebo-treated patients and none of 12 fluconazole-treated patients . Possible side effects were not different between the groups . Dermatophytosis and onychomycosis and cryptococcuria also improved in the fluconazole-treated patients , and fungal colonization was significantly decreased . One episode of thrush occurred in the open phase in an intermittently compliant patient ( group total , 71.5 patient-months of fluconazole treatment ) ; in contrast , the 25 patients also had had two episodes of C and ida esophagitis , three of cryptococcosis , and 13 of dermatophytosis before entry . Subsequent to entry in the r and omized trial , in 92.3 patient-months without fluconazole , there were 35 episodes of thrush , one of esophagitis , one of cryptococcemia , and one of dermatophytosis , and preexisting dermatophytosis and onychomycosis were unchanged or worsened . Individual patients observed with and without fluconazole treatment also showed its efficacy . In conclusion , thrush can be prevented in patients with acquired immunodeficiency syndrome and the acquired immunodeficiency syndrome-related complex with negligible toxic effects . Larger trials to confirm prevention of all mycoses with prophylaxis should be considered Fluconazole , a newly available triazole , has been evaluated extensively as a treatment for thrush . It has been effective in the treatment of this condition in patients with HIV infection . Clotrimazole troches have been a common treatment for thrush in patients with HIV infection for several years . This study compared the efficacy and safety of fluconazole 100 mg tablets once per day versus clotrimazole 10 mg troches five times per day in the treatment of thrush in patients with HIV infection . Patients were evaluated at baseline , day 7 , 14 , 28 , and 42 . The following parameters were evaluated : clinical cure , colonization at the end of treatment , relapse at day 28 , and relapse at day 42 . Side effects including liver enzyme values were also monitored . Clinical cure was superior with fluconazole tablets than with clotrimazole troches . Also , rates of colonization at the end of therapy and relapse at days 28 and 42 were less with fluconazole tablets than with clotrimazole troches . However , these differences were not statistically significant . Patient compliance with fluconazole was superior to that of clotrimazole . This difference was statistically significant . Both fluconazole tablets and clotrimazole troches are effective in treating thrush in patients with HIV infection . The avoidance of multiple-per-day dosing would appear to favor fluconazole PURPOSE To evaluate the efficacy of alcohol-based and alcohol-free melaleuca oral solution in patients with AIDS and fluconazole-refractory oropharyngeal c and idiasis . METHOD We performed a prospect i ve , single-center , open-label study in a university-based inner city HIV/AIDS clinic . The study included 27 patients with AIDS and oral c and idiasis clinical ly refractory to fluconazole . Patients were r and omized 1:1 to receive either alcohol-based or alcohol-free melaleuca oral solution four times daily for 2 - 4 weeks . Thirteen patients were enrolled into cohort 1 , and 14 patients were enrolled into cohort 2 . The main outcome measure was resolution of clinical lesions of oral c and idiasis . Evaluations were performed at 2 and 4 weeks for clinical signs and symptoms of oral c and idiasis and quantitative yeast cultures . RESULTS All C. albicans isolates showed some degree of in vitro resistance to fluconazole . Overall , using a modified intent-to-treat analysis , 60 % of patients demonstrated a clinical response to the melaleuca oral solution ( 7 patients cured and 8 patients clinical ly improved ) at the 4-week evaluation . CONCLUSION Both formulations of the melaleuca oral solution appear to be effective alternative regimens for patients with AIDS suffering from oropharyngeal c and idiasis refractory to fluconazole This r and omized comparative study assessed the efficacy and safety of a 10-mg once-daily topical regimen of miconazole nitrate mucoadhesive buccal tablet ( n = 178 ) versus a 400-mg once-daily systemic regimen of ketoconazole ( n = 179 ) in HIV-positive patients with oropharyngeal c and idiasis . A total of 357 patients were treated for 7 or 14 days depending on response after 7 days of treatment . Clinical response was the primary outcome variable , and secondary outcomes included microscopy , time to cure , symptom scores , and safety outcomes . A per- protocol analysis of 332 patients demonstrated that miconazole nitrate was not statistically significantly inferior to ketoconazole treatment . At day 7 , the clinical response rate was 135 of 156 ( 87 % ) for miconazole nitrate and 137 of 153 ( 90 % ) for ketoconazole ( 90 % confidence interval of the treatment difference : [ −9 % ; 3 % ] ) . At the end of treatment , dysphagia was 1 % in both groups . Microscopic findings paralleled the clinical results . The mucoadhesive tablet was generally well tolerated . A higher incidence of gastrointestinal disorders and drug-related adverse events was seen during ketoconazole treatment . The low-dose 10-mg miconazole mucoadhesive tablet is not inferior to systemic antifungal treatment with ketoconazole in the treatment of AIDS-related oropharyngeal c and idiasis with and without dysphagia . It provides the first and only once-daily topical treatment option and should therefore be considered in first-line therapy for this condition , particularly in re source -poor setting s , where ease of use can help to guarantee the success of therapy To determine the efficacy and toxicity of two systemically active antifungal agents in the treatment of buccal and oesophageal c and idiasis 111 HIV-infected patients with microscopically-confirmed c and idiasis were r and omized to receive either 200 mg itraconazole once a day or 200 mg ketoconazole twice a day for 28 days in a double blind study . After 1 week of treatment , 75 and 82 % of the patients on itraconazole and ketoconazole , respectively , had responded clinical ly . After 4 weeks of treatment , this had risen to 93 % in each group . One patient discontinued itraconozole because of toxicity ( rash ) , five patients discontinued ketaconazole ( two nausea , two hepatotoxicity and one rash ) . Despite successful clinical and mycological clearance , 80 % patients had a further episode of c and idosis within the next 3 months In a r and omized , open study , the efficacy of fluconazole as a prophylaxis of recurrent oral c and idiasis in patients with advanced stages of HIV-infection ( CD4 cell count<100/mm3 ) was studied . For this purpose , the frequency of episodes of oral c and idiasis during two different prophylaxis regimens ( 50 mg/day vs. 100 mg/day ) were compared to an untreated control group . Sixty-five HIV-positive patients were included in the study from May , 1989 to January , 1990 . Of these , 58 were evaluated over an observation time of 137–215 days . Prophylaxis with fluconazole clearly reduced the occurrence of oral c and idiasis . In 20 out of 21 patients in the untreated control group , a total of 60 relapses occurred . In the prophylaxis group receiving 50 mg/day ( group 2 ) , two out of 18 patients had four relapses . In the group receiving 100 mg/day ( group 3 ) , four out of 19 patients had nine relapses in total . Of 3575 observation days in the control group , treatment due to oral c and idiasis was necessary on 393 days ( 28 % ) . In group 2 , on 57 of 3316 days ( 2 % ) , fluconazole in a higher dosage was administered for treatment . In group 3 , relapse treatment with fluconazole 200 mg/day , or treatment with ketoconazole , became necessary in 116 out of 3314 observation days ( 3 % ) . In all relapses , C and ida albicans cfu>103/ml were isolated in the oral wash-outs . As compared to the untreated control group , fluconazole prophylaxis in a daily dosage of 50 as well as 100 mg led to significantly less frequent relapses of oral c and idiasis ( p<0.01 ) . The lower dosage of 50 mg/day , as compared to the higher dosage of 100 mg/day , result ed in no significant difference in the frequency of relapses ( p=0.66 ) . The fact that the patient gains more quality of life by longer symptom-free periods outweighs the disadvantages emerging from increased drug intake and higher costs Multilocus enzyme electrophoresis ( MEE ) and in vitro antifungal susceptibility testing were used to investigate the C and ida albicans strain diversity in twenty nine AIDS patients from Abidjan ( Ivory Coast ) . All patients were monitored for a first episode of oropharyngeal c and idiasis and were r and omly clustered into three groups of therapy : ketoconazole , amphotericin B or nystatin . Oral swabs were collected before every treatment , 14 and 30 days after the initiation of the therapy ; a total of 67 isolates were investigated . No resistant or less susceptible isolate to any antifungal agent was found despite the emergence of clinical relapses , mainly for patients treated with nystatin or amphotericin B. The MEE analysis revealed 27 different electrophoretic types ( ETs ) . Genetic distances between ETs were statistically analyzed and represented on a dendrogram . The 27 ETs clustered into three groups ; in each group , ETs represented variants of the same strain . A segregation of the C. albicans isolates seemed to be as a function of the serotype Objective To determine the efficacy and safety of amphotericin B oral suspension ( ABOS ) for the treatment of fluconazole refractory oral c and idiasis in persons with HIV infection . Design and setting A prospect i ve , multicenter , open label trial at 25 study centers within the AIDS Clinical Trials Group . Patients and methods Individuals with diffuse oral c and idiasis after 14 days of treatment with 200 mg of fluconazole daily ( more than five plaques or a single plaque > 3 cm largest length ) were treated with ABOS , 100 mg/ml , 5 ml swish and swallow , four times daily for 14 days . Thereafter incomplete or non-responders received an additional 14 days of therapy and responders received maintenance ABOS twice daily for up to 6 months . Relapses during maintenance ABOS were treated by increasing the dose to four times daily . Main outcome measures To demonstrate an ABOS clinical response rate > 33 % and a treatment-limiting toxicity rate < 50 % . Clinical response was defined as the absence of mouth pain and the presence of less than five oral plaques , the largest being < 3 cm largest dimension . Results Fifty-eight subjects with a median age of 39 years and a median CD4 count of 10 × 106 cells/l were enrolled . Four subjects were excluded from the analysis because of inadequate follow-up after r and omization ( n = 3 ) or the presence of active esophageal disease ( n = 1 ) . Of the remaining 54 subjects , 23 ( 42.6 % ; 95 % lower confidence interval , 31.1 % ) were classified as responders after 28 days . Five subjects ( 9 % ) stopped treatment due to toxicity . Relapse occurred in 16 responders ( 70 % ) . Conclusions Amphotericin B oral suspension is well tolerated but has limited efficacy for the treatment of fluconazole refractory oral c and idiasis OBJECTIVE To determine if chlorhexidine can be used as an intervention to prolong the time to relapse of oral c and idiasis . SUBJECTS AND METHODS A double-blinded r and omized clinical trial was performed in 75 HIV/AIDS subjects with oral c and idiasis . Clotrimazole troche was prescribed , and the subjects were re-examined every 2 weeks until the lesions were completely eradicated . The subjects were then r and omly divided into two groups ; 0.12 % chlorhexidine ( n = 37 , aged 22 - 52 years , mean 34 years ) and 0.9 % normal saline ( n = 38 , aged 22 - 55 years , mean 38 years ) . They were re-examined every 2 weeks until the next episode was observed . RESULTS The time to recurrence of oral c and idiasis between the chlorhexidine and the saline group was not statistically significant ( P > 0.05 ) . The following variables were significantly associated with the time of recurrence ; frequency of antifungal therapy ( P = 0.011 ) , total lymphocyte ( P = 0.017 ) , alcohol consumption ( P = 0.043 ) , and c and idiasis on gingiva ( P = 0.048 ) . The subjects with lower lymphocyte showed shorter oral c and idiasis-free periods ( P = 0.034 ) . CONCLUSIONS Chlorhexidine showed a small but not statistically significant effect in maintenance of oral c and idiasis-free period . This lack of significance may be due to the small sample size . Further study should be performed to better assess the size of the effect , or to confirm our findings PURPOSE Oropharyngeal c and idasis ( thrush ) is the most common opportunistic infection in individuals who are positive for the human immunodeficiency virus ( HIV ) and those who have progressed to AIDS . Itraconazole has a broad in vitro spectrum of activity , including a wide variety of C and ida species . Our study determined the relative efficacy of a new oral solution formulation of itraconazole and fluconazole tablets in the treatment of oropharyngeal c and idiasis . PATIENTS AND METHODS This was a prospect i ve r and omized , third-party-blind , multicenter trial conducted at 12 centers in the United States . One hundred seventy-nine HIV-positive patients with mycologically documented oropharyngeal c and idiasis were treated with itraconazole oral solution 200 mg/ day for 7 or 14 days , or fluconazole tablets 100 mg/day for 14 days . Severity of disease was scored clinical ly before treatment and at clinical evaluations on days 3 , 7 , 14 , 21 , 35 , and 42 . Semi-quantitative cultures of mouth washings were also obtained on these days . RESULTS Both 14-day and 7-day regimens of itraconazole oral solution were equivalent to fluconazole for most efficacy parameters . The clinical response rate was 97 % after 14 days of itraconazole and 87 % after 14 days of fluconazole . Itraconazole oral solution given for 7 days was also equivalent to fluconazole treatment for 14 days . Approximately one half of patients in all three groups relapsed by 1 month after completion of treatment . There were few adverse reactions to either drug . CONCLUSION Itraconazole oral solution is well tolerated and offers an alternative at least as effective as fluconazole in the treatment of oropharyngeal c and idiasis This study was conducted to evaluate the efficacy of highly active anti-retroviral therapy ( HAART ) in preventing recurrence of oral c and idosis ( OC ) associated with HIV . A prospect i ve case-controlled observational study was performed in an inner-city university-hospital HIV/AIDS clinic . Ninety-three HIV-positive study subjects with a history of recurrent OC were divided into two groups : protease inhibitors (PI)-treated patients ( group 1 , n = 30 ) and non-PI-treated patients ( group 2 , n = 63 ) . Study subjects were matched for sex , age , stage of HIV infection , and peripheral CD4 + T-cell counts . The non-PI-treated group was further subdivided into the following three subgroups : HIV-positive study subjects treated with reverse transcriptase inhibitors ( RTI ; groups 2a and 2c ) and HIV-positive study subjects not treated with RTIs ( group 2b ) . Group 2c met the same inclusion criteria as group 2a had but was matched 6 months after the beginning of the study . We also assessed in vitro peripheral blood mononuclear cells ( P BMC ) and their lymphoproliferative response , as well as cutaneous delayed-type hypersensitivity ( DTH ) response to C and ida-associated antigens in a r and omly selected sample of study subjects divided into those treated with PIs and those who were not . During a 1-year follow-up , OC was diagnosed in 2 ( 7 % ) PI-treated and 23 ( 36 % ) non-PI-treated patients ( p<.001 ) . In addition to comparing findings in group 1 with those in group 2c , OC was detected in 14 ( 50 % ) non-PI-treated patients compared with no HAART-treated study subjects ( p<.001 ) . Only 41 % of PI-treated study subjects had positive lymphoproliferative response in P BMC s and none was positive in terms of DTH to C and ida antigens ( p = not significant versus non-PI-treated study subjects ) . While objective ly demonstrating a beneficial effect of HAART in preventing recurrence of OC infections , our findings suggest this effect can not be not fully accounted for by reconstitution of anti-C and ida cell-mediated immunity , given that other mechanisms , even of a nonimmune nature , could have some effect This prospect i ve study was design ed to compare the efficacy and safety of itraconazole oral solution with those of clotrimazole troche in the treatment of oropharyngeal c and idosis in acquired immunodeficiency syndrome ( AIDS ) patients . Patients were excluded if they had been treated with any antifungal agents 2 weeks prior to the study entry , were pregnant or nursing , or had significant liver disease . Twenty-nine patients ( 20 men and nine women ) , with a mean age of 32 years ( 15 - 62 years ) , were r and omly , observer-blind treated with clotrimazole troche ( 10 mg , five times daily ) or itraconazole oral solution ( 100 mg/10 mL , twice daily ) for 1 week . Clinical and mycologic assessment were carried out on four consecutive days , in week 1 , week 2 , and week 4 after the start of treatment . Clinical evaluation was assessed by a scoring method ( 0 - 3 , absent to severe ) as follows : soreness , change in taste , erythema , removable white plaque , and extent of lesions . Mycologic assessment was performed by KOH preparation and fungal culture . Global evaluation , which is a summary of clinical and mycologic assessment at the end of treatment , was classified as cure ( all signs and symptoms resolved with no evidence of infection ) , improvement ( decrease in clinical score without complete resolution ) , or failure ( lack of improvement or further deterioration ) . ( Pons V , Greenspan D , Debruin M. Therapy for oropharyngeal c and idiasis in HIV-infected patients : a r and omized , prospect i ve multicenter study of oral fluconazole versus clotrimazole troches . J Acquir Immune Defic Syndr 1993 ; 6 : 1311 - 1316 . ) Global evaluation at week 2 and week 4 was made in terms of no relapse or relapse . Any intercurrent medical events , whether human immunodeficiency virus (HIV)-related or not , were recorded . An intention-to-treat analysis was employed . Data were analyzed using the chi-squared test , Mann-Whitney U-test , and Student 's t-test Oropharyngeal c and idiasis is a frequent infection in cancer patients who receive cytotoxic drugs . In this study , the efficacy , safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal c and idiasis . Of 279 patients who were r and omised between the two treatment groups , 252 patients were considered to be eligible ( 126 in each group ) . The clinical cure rate was 74 % for fluconazole and 62 % for itraconazole ( P=0.04 , 95 % Confidence Interval ( CI ) : 0.5 - 23.3 % ) . The mycological cure rate was 80 % for fluconazole and 68 % for itraconazole ( P=0.03 , 95 % CI : 1.2 - 22.6 % ) . The safety and tolerance profile of both drugs were comparable . This study has shown that in patients with cancer and oropharyngeal c and idiasis , fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole The efficacy of oral fluconazole versus nystatin was evaluated as a treatment modality for oral c and idosis . Of the included patients ( n = 60 ) , two-thirds presented with an erythematous c and idosis , and the others showed clinical signs compatible with a pseudomembranous c and idosis . Predisposing factors were xerostomia ( n = 18 ) , HIV ( n = 5 ) , immunosuppression in conjunction with organ transplantation ( n = 10 ) , and wearing of dentures ( n = 14 ) . For the remaining patients no specific predisposing factors were found . One patient who was treated with nystatin was excluded owing to nausea that was related to the antifungal treatment . After 7 days of treatment with fluconazole ( 50 mg/day ) , the affected oral mucosa , assessed by the investigator , was cured or showed considerable improvement in 87 % of the patients ( n = 30 ) . The corresponding figure for the nystatin group ( n = 30 ) , rinsing with 1 mL 4 times a day for 21 days , was 80 % . Following treatment with fluconazole , 20 of 22 patients with symptoms at the start ( 91 % ) reported improvement . The comparable figures for the nystatin group were 10 of 12 patients ( 83 % ) . Half of the patients in the nystatin group reported inconvenience from taking the medication ( mean value = 25.9 ) compared with 23 % of the patients in the fluconazole group ( mean value = 6.6 ) . Eight patients in the fluconazole group and 12 patients in the nystatin group exhibited a relapse within 6 months . These differences were not found to be statistically significant . The patients in the fluconazole group reported less inconvenience from taking the medication , a finding that may have clinical implication s for compliance OBJECTIVE To assess the efficacy and tolerance of fluconazole ( 150 mg oral dose , once a week ) in the prevention of recurrent oropharyngeal c and idiasis in patients with moderate to severe human immunodeficiency virus ( HIV ) infection . DESIGN A r and omised , double-blind , placebo-controlled trial . PATIENTS Eighty-four patients with moderate to severe HIV infection who had successfully completed two to four weeks treatment with fluconazole for oropharyngeal c and idiasis were r and omly allocated to receive either placebo or fluconazole . Pre-treatment clinical and laboratory characteristics were similar in the two groups . OUTCOME MEASURES Success was classified as absence throughout the course of treatment of clinical evidence of oropharyngeal c and idiasis , and failure as recurrence or relapse of symptomatic oropharyngeal c and idiasis . RESULTS Of 73 evaluable patients the median time to relapse was > or = 168 days in the fluconazole group and 37 days in the placebo group ( P < 0.0001 ) . One patient in the placebo group and 18 patients in the fluconazole group completed six months ' treatment without clinical relapse ( P < 0.001 ) . CONCLUSION Fluconazole was well tolerated and prevented clinical relapse of oropharyngeal c and idiasis in 71 % of patients who completed three months of treatment ( 95 % confidence interval [ CI ] , 55 - 86 ) and 58 % ( 95 % CI , 41 - 75 ) who completed six months of treatment Thirty-nine adult patients with human immunodeficiency virus infection and oral c and idiasis were r and omly assigned to receive either one fluconazole capsule ( 100 mg ) or five clotrimazole troches ( 10 mg each ) daily for 14 days . Among 36 evaluable patients , clinical resolution rates were 100 and 65 % , respectively ( P = 0.018 ) . Mycological eradication rates were 75 and 20 % , respectively ( P = 0.004 ) . Fluconazole-treated patients were more likely to remain disease free during follow-up than those treated with clotrimazole ( P = 0.014 at 2 weeks ) . Prolonged clinical responses correlated with mycological eradication at the end of therapy ( P = 0.043 ) The aim of this study was to assess the role and the therapeutic efficacy of 2 azole antifungal drugs , fluconazole and itraconazole , in the treatment of endoscopically diagnosed C and ida esophagitis in patients with acquired immunodeficiency syndrome ( AIDS ) . The study involved 123 human immunodeficiency virus (HIV)-positive patients ( 70 males and 53 females , mean age 27 years ) at their first episode of esophageal c and idiasis diagnosed by endoscopy . The patients were r and omized in a double-blind design to receive either fluconazole ( 100 mb b.i.d . per os ) or itraconazole ( 100 mg b.i.d . per os ) . In order to evaluate the efficacy of treatment , clinical examinations were performed every week up to the end of follow-up ( 2 months ) ; endoscopic examination was performed at baseline , at the end of treatment ( 3 weeks ) and at the end of follow-up . At the end of the treatment , cure , as judged by endoscopy , was observed in 74 % of fluconazole-treated patients and in 47.2 % of itraconazole-treated patients ( p < 0.01 ) ; at the end of follow-up , cure was observed endoscopically in 71.7 % of fluconazole-treated patients and in 43.2 % of the itraconazole-treated patients ( p < 0.05 ) . As regards clinical cure , no statistically significant difference was observed between the groups , at the end of pharmacological treatment and at the end of follow-up . The results of this study demonstrate that both fluconazole and itraconazole are efficacious in the treatment of C and ida esophagitis in AIDS patients ; fluconazole is associated with higher rate of endoscopic cure than is itraconazole Objective : To evaluate the efficacy of melaleuca oral solution in AIDS patients with fluconazole‐resistant oropharyngeal c and ida infections . Design : A prospect i ve , single center , open‐labeled study . Setting : A university‐based inner‐city HIV/AIDS clinic . Patients : Thirteen patients with AIDS and oral c and idiasis documented to be clinical ly refractory to fluconazole , as defined by failure to respond to a minimum of 14 days of ≥ 400 mg fluconazole per day . Additionally , patients had in vitro resistance to fluconazole , defined by minimal inhibitory concentrations of ≥ 20 µg/ml . Interventions : Patients were given 15 ml melaleuca oral solution four times daily to swish and expel for 2–4 weeks . Main outcome measures : Resolution of clinical lesions of oral pseudomembranous c and idiasis lesions . Evaluations were performed weekly for 4 weeks and at the end of therapy for clinical signs of oral c and idiasis . Quantitative yeast cultures were performed at each evaluation . Results : A total of 13 patients were entered into the study , 12 were evaluable . At the 2‐week evaluation , seven out of 12 patients had improved , none were cured , and six were unchanged . At the 4‐week evaluation , eight out of 12 patients showed a response ( two cured , six improved ) , four were non‐responders , and one had deteriorated . A mycological response was seen in seven out of 12 patients . A followup evaluation 2–4 weeks after therapy was discontinued revealed that there were no clinical relapses in the two patients who were cured . Conclusions : Melaleuca oral solution appears to be effective as an alternative regimen for AIDS patients with oropharyngeal c and idiasis refractory to fluconazole Summary In an open phase-III study 103 HIV-positive patients with oral c and idiasis were treated with oral fluconazole 100 mg/day for 7–21 days ( mean 12.2 ± 6.1 days ) . Ninety per cent of the patients presented with the full clinical picture of AIDS , in 83 % CD4-lymphocytes were < 100/mm3 . Clinical and mycological ( smear and mouth rinsing ) examinations were performed at the start of therapy , after weeks 1 , 2 , and 3 , and at the end of therapy . The clinical findings showed fluconazole therapy to have achieved cure in 71 % of the patients and improvement in 16 % . Therapy failed in 13 % . Mycological tests revealed elimination in 57 % and reduction in colony counts in 23 % of patients . Therapy failure according to mycological criteria was observed in 20 % of all subjects . Adverse events were recorded for 26 % of all patients . A causal connection with study therapy was considered as “ unlikely ” in 20 cases , “ question able ” in 17 cases , and “ likely ” in three cases . Premature discontinuation of fluconazole therapy was required in seven patients , in three of them because of adverse events due to fluconazole . Even in patients with advanced HIV infection and consequently severe immunodeficiency , fluconazole is an important improvement of the therapeutic spectrum . ZusammenfassungIn einer offenen Phase-III-Studie wurden 103 HIV-positive Patienten mit oraler C and idiasis mit Fluconazol , 100 mg/Tag p. o. über 7–21 Tage ( Mittel 12,2±6,1 Tage ) beh and elt . Bei 90 % der Patienten lag das klinische Vollbild von Aids vor , bei 83 % lagen die CD4-Lymphozyten unter 100 pro mm3 . Klinische und mykologische Untersuchungen ( Abstrich und Mundspülung ) wurden vor Beginn der Therapie sowie nach 1 , 2 und 3 Wochen durchgeführt . Klinisch ließ sich mit Fluconazol bei 71 % der Patienten ein Therapieerfolg erzielen , zu einer Besserung kam es bei 16 % der Patienten . Die Rate der Therapieversager betrug 13 % . In 57 % der Fälle kam es zu einer Elimination und bei 23 % zu einer patiellen Elimination der Pilze . Nach mykologischen Kriterien lag in 20 % der Fälle ein Therapieversagen vor . Nebenwirkungen traten bei 26 % der Patienten auf , wobei der kausale Zusammenhang mit der Studienmedikation in 20 Fällen als unwahrscheinlich , in 17 Fällen als fraglich und in drei Fällen als wahrscheinlich beurteilt wurde . Bei sieben Patienten wurde die Fluconazol-Beh and lung vorzeitig beendet , bei drei Patienten aufgrund von Nebenwirkungen von Fluconazol . Insgesamt stellt Fluconazol auch bei Patienten mit HIV-Infektion i m fortgeschrittenen Stadium und entsprechend schwerer Abwehrschwäche eine wesentliche Bereicherung des therapeutischen Spektrums dar Objectives : To evaluate the efficacy and tolerance of D0870 in the treatment of HIV-related fluconazole-resistant oro-oesophageal c and idosis . Design : Multicentre open study . Patients : HIV-seropositive patients with oro-oesophageal c and idosis despite at least 7 days of treatment with fluconazole at doses of 100 mg per day or more . Methods : Patients received an initial dose of D0870 ( 150 mg ) , then 25 mg per day for 6 days . Symptoms and signs of c and idosis were compared at entry and on days 3 and 7 of treatment . At each visit , sample s were taken for safety monitoring and for in vitro susceptibility testing of C and ida isolates . Limited pharmacokinetic sample s were taken on days 1 and 7 . Results : Of 26 evaluable patients , 16 showed partial improvement , nine showed no improvement , and only one had full clearance of thrush by day 7 . In vitro testing of the cleared patient 's isolate suggested that it was susceptible to fluconazole . Symptoms of dysphagia cleared in 14 and improved in five of the 22 patients with presumptive oesophageal involvement at entry . Pharmacokinetic measurement showed wide variability in maximum D0870 levels recorded on day 1 ( range , 0.07–0.34 mg/l ) and susceptibility testing of isolates also showed a range of minimal inhibitory concentration values to D0870 ( range , < 0.06–8 mg/l ; median , 0.25 mg/l ) . When these data were combined with clinical response there was a strong suggestion that lack of symptomatic improvement was related to low plasma D0870 levels or to the presence of less D0870-susceptible isolates . Six patients were noted to have a fall in haemoglobin , three of whom were receiving concomitant therapy known to suppress bone marrow . Three patients reported headaches as adverse events that were attributed to study medication , but D0870 was well tolerated overall . Conclusions : D0870 shows promise in the treatment of fluconazole-resistant oro-oesophageal c and idosis and was well tolerated , although efficacy in this difficult- to-treat patient group was probably limited due to the inadequate plasma levels achieved in this pilot study with the low doses of D0870 administered OBJECTIVE To compare the efficacy , safety , and tolerance of fluconazole suspension versus nystatin in the treatment of oropharyngeal thrush in immunocompromised children . DESIGN Multicenter , r and omized , observer-masked trial . SETTING Thirty-two centers participated , including hospitals and ambulatory care clinics . PATIENTS We enrolled 182 immunocompromised infants and children , ages 5 months to 14 years , with signs of oral thrush and presence of yeasts on potassium hydroxide- or gram-stained preparations . Subjects were r and omly assigned to receive a single daily dose of fluconazole suspension , 2 to 3 mg/kg per day , or nystatin , 400,000 units four times daily for 14 days ; 159 patients , who had culture confirmation of thrush and received at least 7 days of study drug , were evaluated for efficacy ; all patients were evaluated for safety . RESULTS Clinical cure was demonstrated in 91 % of the subjects in the fluconazole group and 51 % of the subjects in the nystatin group ( p < 0.001 ) , and eradication of the organism cultured at entry occurred in 76 % and 11 % ( p < 0.001 ) , respectively . Gastrointestinal conditions developed in six patients who received fluconazole and in three who received nystatin ; two fluconazole recipients were subsequently withdrawn from the study . Laboratory abnormalities occurred with equal frequency in both groups . Clinical relapse rates were similar in both groups at 2 weeks ( 18 % and 24 % for fluconazole and nystatin , respectively ) and 1 month ( 28 % and 27 % , respectively ) after the completion of study drug . CONCLUSIONS Fluconazole suspension is more effective than nystatin in the treatment of thrush in immunocompromised children . Both regimens were well tolerated Fluconazole 50 mg daily for 14 - 28 days was effective in the treatment of patients with AIDS and AIDS-related complex with severe oropharyngeal and oesophageal c and idiasis . Of 24 patients entered , 17 ( 81 % ) , including seven with oesophageal c and idiasis , were clinical ly cured and two ( 9.5 % ) improved at the end of treatment . Following clinical cure , 14 patients were entered into the double-blind phase of the study , where fluconazole ( 150 mg ) or placebo capsules were given once weekly . Treatment was double blind . Fluconazole 150 mg once weekly was found to be effective in maintaining patients both clinical ly and mycologically free of oropharyngeal c and idiasis R and omised controlled trials are the best way to compare the effectiveness of different interventions . Only r and omised trials allow valid inferences of cause and effect . Only r and omised trials have the potential directly to affect patient care — occasionally as single trials but more often as the body of evidence from several trials , whether or not combined formally by meta- analysis . It is thus entirely reasonable to require higher st and ards for papers reporting r and omised trials than those describing other types of study . Like all studies , r and omised trials are open to bias if done badly.1 It is thus essential that r and omised trials are done well and reported adequately . Readers should not have to infer what was probably done , they should be told explicitly . Proper methodology should be used and be seen to have been used . Yet review s of published trials have consistently found major deficiencies in reporting,2 3 4 making the task OBJECTIVES To determine whether systemic or deep fungal infections can be prevented , a double-blind , placebo-controlled , phase III trial of itraconazole prophylaxis was undertaken in HIV-infected patients . METHODS HIV-1 infected patients with CD4 counts < 300 cells/microL were treated with itraconazole ( 200 mg per day ) or matching placebo and followed for 2 years . Development of deep fungal infections , episodes of mucocutaneous c and idiasis , change in CD4 count , survival and safety data were collected at each study visit . RESULTS Three hundred and seventy-four patients received study medication , 187 were given itraconazole and 187 matching placebo . Time to development of deep fungal infection did not differ between groups , in an intention to treat analysis . Low CD4 cell count and prior use of Pneumocystis carinii pneumonia ( PCP ) prophylaxis were significantly associated with a more rapid development of deep fungal infection ( P = 0.044 and 0.017 , respectively ) . Itraconazole treatment significantly reduced the incidence of oral c and idosis ( 25 % vs. 48 % P < 0.001 ) and time to development of oral c and idosis ( 508 vs. 413 days , P < 0.001 ) but not the number of deep fungal infections ( 11 vs. 13 ) . Survival did not differ significantly between groups ( nine vs. 14 deaths ) . CD4 counts decreased significantly over time in both study arms . Adverse events did not differ between groups ; 20 % vs. 23 % stopped study medication due to an adverse experience . CONCLUSIONS Although itraconazole prophylaxis significantly reduced the number and time to development of oral c and idosis , too few episodes of deep fungal infection were noted to determine whether itraconazole prophylaxis was effective for this condition . Chronic itraconazole treatment is well tolerated in HIV-infected patients with marked immunodeficiency BACKGROUND AND STUDY AIMS Contrasting opinions exist as to the pharmacological treatment of esophageal c and idiasis in human immunodeficiency virus (HIV)-positive patients . The aim of this study has been to evaluate the role , therapeutic efficacy , and the cost-benefit ratio of two antifungal drugs , fluconazole and flucytosine , compared with a placebo , in the treatment of endoscopically-diagnosed esophageal c and idiasis in patients with acquired immune deficiency syndrome ( AIDS ) . PATIENTS AND METHODS The study included 60 HIV-positive patients ( 38 males and 22 females , mean age 27 + /- 2 ) with a first episode of esophageal c and idiasis diagnosed by endoscopy ( grade s I-II of Kodsi 's endoscopic classification , and grade s I-IIa of Barbaro 's clinical classification ) . No other opportunistic infection of the esophagus was detected . In a double-blind procedure , patients were r and omized into three groups of 20 patients each , receiving either fluconazole ( 3 mg/kg/daily per os ) , flucytosine ( 100 mg/kg/daily per os ) or placebo . After two weeks of treatment , the patients previously assigned to receive the placebo were double-blindly r and omized to receive fluconazole ( eight patients ) or flucytosine ( nine patients ) . In order to evaluate the efficacy of pharmacological therapy , clinical examination was performed at weeks 2 and 5 , and then every week up to the end of follow-up ( three months ) ; endoscopic examination was performed at weeks 2 and 5 , and at the end of follow-up . RESULTS At week 2 , endoscopic cure ( grade 0 ) was observed in 13 patients ( 65 % ) of the fluconazole group and in three patients ( 15 % ) in the flucytosine group ( relative risk ratio : 0.23 ; 95 % C.I. : 0.10 - 0.48 ; p < 0.05 ) , and a partial endoscopic response ( grade I ) was observed in two patients ( 10 % ) in the placebo group . Complete clinical remission ( grade 0 ) was observed in 16 patients ( 80 % ) in the fluconazole group and 12 patients ( 60 % ) in the flucytosine group ( relative risk ratio : 0.75 ; 95 % C.I. : 0.42 - 0.89 ; p = n.s . ) , while six patients ( 30 % ) in the placebo group presented partial clinical remission ( grade I ) . At the end of follow-up , endoscopic cure was observed in 19 patients ( 70 % ) in the fluconazole group and in nine patients ( 33 % ) in the flucytosine group ( relative risk ratio : 0.47 ; 95 % C.I. : 0.19 - 0.65 ; p < 0.05 ) . Complete clinical remission was observed in 21 patients ( 77.7 % ) in the fluconazole group and in 17 patients ( 63 % ) in the flucytosine group ( relative risk ratio : 0.81 ; 95 % C.I. : 0.53 - 0.92 ; p = n.s . ) . No noticeable side-effects were observed in the patients in either treatment group , without a statistically significant difference in comparison with the placebo . CONCLUSIONS The results of this study have demonstrated that both fluconazole and flucytosine are safe and well tolerated in the treatment of esophageal c and idiasis in AIDS patients . Fluconazole showed greater therapeutic efficacy than flucytosine , with a difference that was statistically significant in terms of the rate of endoscopic cure This multicenter , open-label , third-party-masked trial compared the efficacy and safety of itraconazole oral solution ( 200 mg once daily ) and clotrimazole troches ( 10 mg five times daily ) in a population of immunocompromised subjects composed primarily of patients with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome ( AIDS ) . Patients were treated for 14 days ; patients who exhibited a clinical response were followed up for an additional month to document the occurrence of relapse . Efficacy was judged by changes from baseline in symptoms of oropharyngeal c and idiasis ( erythema , soreness/burning ) , extent of oral lesions , and the presence/absence of C and ida species on fungal culture . A total of 162 patients were r and omized , and 149 were evaluated for efficacy . The percentage of patients with negative cultures at the end of treatment was significantly greater in the itraconazole group than in the clotrimazole group ( 60 % vs 32 % , respectively ) . Negative culture plus clinical response was achieved in significantly more itraconazole-treated patients ( 53 % ) than clotrimazole-treated patients ( 30 % ) ; results were similar in the subgroup of patients with HIV/AIDS . Both drugs were well tolerated , with the most frequently reported adverse events for both agents involving the gastrointestinal system . In conclusion , systemic therapy with intraconazole oral solution is efficacious and well tolerated in immunocompromised patients , including those with HIV/AIDS , when administered once daily for 14 days for the treatment of oral c and idiasis In a prospect i ve , r and omized , double-blind trial , 149 patients with advanced human immunodeficiency virus ( HIV ) infection were r and omized to receive itraconazole capsules ( 200 mg daily ) and 146 to receive a matched placebo . Both groups were monitored for evidence of fungal infections . Baseline characteristics of the two groups were similar . Failure of prophylaxis occurred in 29 ( 19 % ) of the itraconazole recipients and 42 ( 29 % ) of the placebo recipients ( P = .004 ; log-rank test ) . There were 6 invasive fungal infections in the itraconazole group ( 4 , histoplasmosis ; 1 , cryptococcosis ; 1 , aspergillosis ) and 19 in the placebo group ( 10 , histoplasmosis ; 8 , cryptococcosis ; 1 , aspergillosis ) ( P = .0007 ; log-rank test ) . Itraconazole significantly delayed time to onset of histoplasmosis ( P = .03 ; log-rank test ) and cryptococcosis ( P = .0005 ; log-rank test ) . Prophylaxis failure due to recurrent or refractory mucosal c and idiasis occurred with similar frequency in the two groups ( itraconazole , 15 % ; placebo , 16 % ) . A survival benefit was not demonstrated . Itraconazole generally was well tolerated . Primary prophylaxis with itraconazole capsules prevents histoplasmosis and cryptococcosis in patients with HIV infection The demographic characteristics of the human immunodeficiency virus ( HIV ) epidemic in the United States have changed markedly in recent years . In 1994 , 18 % of new cases of acquired immunodeficiency syndrome ( AIDS ) occurred in women [ 1 ] ; AIDS is now the third leading cause of death in women of reproductive age [ 2 ] . C and idiasis is a frequent complication of HIV infection [ 3 - 5 ] . The risk for oropharyngeal and esophageal c and idiasis increases as the immune system becomes more suppressed . Vaginal c and idiasis is also common in HIV-infected women [ 6 , 7 ] . Because few HIV-infected women have been enrolled in clinical trials of therapy for and prophylaxis of fungal infections , few data have been recorded on the natural history , prevention , and treatment of mucosal c and idiasis in women . Fluconazole , a broad-spectrum systemic antifungal agent , has been used effectively for the treatment of c and idiasis in patients with HIV infection or AIDS and may result in a more rapid clinical and mycologic response than other azoles [ 8 ] . Although several regimens of fluconazole have been shown to prevent c and idiasis ( including recurrent episodes in persons with HIV infection ) , routine prophylaxis with fluconazole has not been recommended because of cost ; the possible emergence of resistant C and ida species ; and drug interactions with non-sedating antihistamines , warfarin , phenytoin , oral hypoglycemic agents , rifampin or rifabutin , and hydrochlorothiazide [ 9 - 11 ] . The Terry Beirn Community Programs for Clinical Research on AIDS ( CPCRA ) initiated this study in HIV-infected women to evaluate the effectiveness and safety of weekly fluconazole for the prevention of mucosal c and idiasis and to detect alterations in vaginal colonization by C and ida species [ 12 ] . A sub study was also done to investigate in vitro resistance to C and ida organisms . Methods Study Sample Patients were enrolled in the Women 's Fungal Study ( CPCRA 010 ) at 14 sites that were participating in the CPCRA [ 12 ] . The CPCRA is a consortium of community-based sites that provide primary health care to patients who are infected with HIV . Potentially eligible patients were identified by physicians who were participating in the consortium . Female patients with HIV infection who were 13 years of age or older were eligible if their CD4 + cell count did not exceed 300 cells/mm3 or 20 % of their total lymphocyte count . Patients were excluded if they had a history of C and ida esophagitis , were receiving systemic antifungal agents , had a known intolerance of azoles , or were pregnant or lactating . The protocol was approved by the internal review board at each site . Informed consent was obtained from all patients before they were assigned to a study group . Study Design In this double-blind trial , patients were r and omly assigned to receive weekly fluconazole or placebo using a permuted block scheme with r and omly mixed block sizes of two and four . R and omization was stratified by CPCRA site and was done through the CPCRA statistical center . The target sample size ( 400 patients ) and study duration ( 18 months ) were chosen to ensure that there would be 80 % power to detect a 50 % difference in the rate of episodes of c and idiasis between groups with a two-sided P value of 0.05 . We extended the follow-up period to obtain more information on clinical and in vitro resistance . Treatment Regimens Fluconazole was provided in 100-mg capsules ; patients received 200 mg of fluconazole per week or placebo . This dosage was used because pharmacologic studies by Houang and colleagues [ 13 ] indicated that therapeutic concentrations of fluconazole greater than the median minimal inhibitory concentration ( MIC ) of C and ida albicans were found in vaginal secretions and tissues for 96 hours after a fluconazole dose of 150 mg . Open-label daily fluconazole for prophylaxis was permitted after two episodes of oropharyngeal or vaginal c and idiasis or one episode of esophageal c and idiasis ( that is , prophylaxis failure ) . The relative severity of the c and idiasis was considered in defining prophylaxis failure . Therapy with the study drug was continued during episodes of oropharyngeal and vaginal c and idiasis but not during episodes of esophageal c and idiasis . Ongoing use of systemic antifungal agents required withdrawal of the study drug . Topical antifungal agents were recommended for the treatment of oropharyngeal and vaginal c and idiasis ; fluconazole was recommended for esophageal c and idiasis . End Points Episodes of c and idiasis were review ed by a committee that was blinded to treatment group . Several major clinical end points were specified : 1 ) first episode of confirmed vaginal c and idiasis , confirmed oropharyngeal c and idiasis , or confirmed or probable esophageal c and idiasis ; 2 ) prophylaxis failure , defined as the first episode of confirmed or probable esophageal c and idiasis or the second episode of confirmed vaginal or oropharyngeal c and idiasis ; and 3 ) confirmed or probable clinical resistance to fluconazole . Esophageal c and idiasis was confirmed by histologic or cytologic evidence on microscopy or evidence of c and idiasis on gross endoscopic inspection or at autopsy . Patients were considered to have had a probable episode of esophageal c and idiasis if they had recent onset of dysphagia or odynophagia and had either a confirmed diagnosis of oropharyngeal c and idiasis or a response to antifungal therapy . Oropharyngeal or vaginal c and idiasis was confirmed by a positive culture for C and ida species in the presence of two or more clinical signs or symptoms . Patients were considered to have had a probable episode of mucosal c and idiasis if 1 ) the culture was positive and they had one clinical sign or symptom [ other than white exu date s for oropharyngeal c and idiasis ] , 2 ) a potassium hydroxide preparation was positive and they had two or more clinical signs or symptoms , or 3 ) they responded to antifungal therapy and had two or more signs or symptoms . Confirmation of clinical resistance to fluconazole required all of the following : 1 ) confirmed or probable esophageal c and idiasis , confirmed vaginal c and idiasis , or confirmed oropharyngeal c and idiasis ; 2 ) no response to a previous course of antifungal therapy and the need for high-dose therapy with systemic azoles or intravenous amphotericin B ; and 3 ) no other identifiable cause of the symptoms . The patients were considered to have had probable clinical resistance if the first two criteria were met but other causes for the symptoms could not be ruled out . Adverse events were grade d on a five-point scale ( I through V ) . We recorded events that were at least grade IV , that were not caused by the progression of HIV infection , and that led to discontinuation of treatment while patients were receiving the study medication and for 8 weeks thereafter . Follow-up The trial ended on 30 November 1995 , which was 22 months after the last patient was r and omly assigned . The median length of follow-up was 29 months . Every 3 months , we ascertained symptoms of c and idiasis , collected a vaginal specimen for yeast culture , and documented concomitant treatments and new HIV-related diagnoses . Liver function tests were done and CD4 + cell counts were measured every 6 months . Sub study of in Vitro Resistance to Fluconazole A sub study examining in vitro resistance to fluconazole ( CPCRA 029 ) was started 1 year after the primary study began . After patients were enrolled , vaginal specimens that were obtained at scheduled follow-up visits every 3 months were analyzed for susceptibility to five antifungal agents . Isolates that had been obtained for other end points of the primary study were also analyzed . We used microtiter methods for in vitro susceptibility testing in accordance with National Committee for Clinical Laboratory St and ards [ 14 ] . In vitro resistance to fluconazole was defined as an MIC of 16 g/mL or less at 48 hours . Statistical Analysis Participating investigators were blinded to interim results . Treatment groups were compared according to each patient 's original assignment ( intention-to-treat analysis ) ; the comparison groups consisted of patients who received weekly fluconazole and patients who received placebo until prophylaxis failure , at which time daily fluconazole could be prescribed at the clinician 's discretion . Analyses were stratified by CPCRA site in accordance with the r and omization method . Baseline comparability was assessed using the Mantel-Haenszel chi-square or stratified analysis of variance [ 15 , 16 ] . For clinical end points and adverse events , time-to-event methods ( including Kaplan-Meier estimation , log-rank tests , and proportional hazards regression models ) were used to compare treatment groups [ 17 - 19 ] . We also compared two-sided P values and 95 % CIs for relative risks ( RRs ) of fluconazole with those of placebo . Natural history analyses could be done because our control group received placebo . For such analyses , a proportional hazards regression model was used to investigate the independent influence of the following baseline variables on risk for c and idiasis : ethnic group , injection drug use , CD4 + cell count , history of mucosal c and idiasis , presence of AIDS , prophylaxis for Pneumocystis carinii pneumonia , antiretroviral treatment , and result of vaginal yeast culture at baseline . Vaginal specimens were collected every 3 months and analyzed for colonization by C and ida species using a model for longitudinal binary data ; findings are summarized with relative odds estimates for fluconazole compared with placebo [ 20 ] . All analyses were done using SAS software ( SAS Institute , Cary , North Carolina ) . The National Institute of Allergies and Infectious Diseases ( NIAID ) supported the clinical sites and statistical center responsible for gathering and analyzing the data . Staff members from NIAID were also part of the protocol team but had no role in the decision to publish the results of the study . Results Study Sample Between May 1992 and January 1994 , 323 patients were enrolled in CPCRA 010 ; 162 were r and omly This open-label , multicenter trial evaluated the efficacy and safety of a new oral solution formulation of itraconazole in HIV+/AIDS patients with fluconazole-refractory oropharyngeal c and idiasis . Seventy-four HIV+/AIDS patients with mycologically confirmed oropharyngeal c and idiasis who failed fluconazole therapy ( 200 mg/day ) were treated with 100 mg of itraconazole oral solution administered twice daily ( 200 mg/day ) for 14 days . Patients who demonstrated an incomplete response to treatment were treated for an additional 14 days ( 28 days total ) . Clinical responders were eligible for participation in a separate 6-month maintenance protocol . If they declined further treatment , responders were monitored for 6 weeks posttreatment . The primary efficacy parameter was clinical response ( i.e. , no lesions or symptoms ) at end of treatment . Fungal cultures were performed at baseline and at the end of treatment . Among the 74 patients who had mycologically confirmed , fluconazole-unresponsive , oropharyngeal c and idiasis at baseline , 41 ( 55 % ) achieved a clinical response by day 28 . The median time to response was 7 days ( range , 7 to 28 days ) . C and ida albicans was the most common pathogen isolated , either alone ( 62 % ) or in combination with another C and ida species ( 31 % ) . All 22 patients who entered the optional , off-therapy , 6-week follow-up phase relapsed ; mean time to relapse was 13 days . Itraconazole oral solution was well-tolerated ; adverse events were predominantly gastrointestinal disturbances . This trial demonstrates that itraconazole oral solution is a useful therapy in the treatment of HIV-infected patients with fluconazole-refractory oropharyngeal c and idiasis C and idiasis of the oropharynx and oesophagus is one of the most common problems encountered in patients with HIV disease . Fluconazole is a bis‐triazole antifungal agent with a long serum half‐life . Sixteen anti‐HIV positive patients ( 15 haemophiliacs and one blood transfusion recipient ) with a clinical diagnosis of oropharyngeal c and idiasis were treated with 50 mg fluconazole daily for 14–28 days and then either 150 mg fluconazole or placebo weekly for 6 months in a prophylactic phase . Clinical cure occurred in all patients , and mycological cure occurred in 13/16 ( 81 % ) patients . In the prophylactic phase , there were 2/5 ( 40 % ) relapses in the placebo arm compared with 1/8 ( 12.5 % ) in the fluconazole arm , but this was not statistically significant by Fisher 's onesided exact test ( P= 0.31 ) . It is concluded that fluconazole is an effective treatment of oropharyngeal c and idiasis and has potential for prophylactic use ABSTRACT Caspofungin is an antifungal agent of the novel echinoc and in class . We investigated its efficacy , safety , and tolerability as therapy for oropharyngeal and /or esophageal c and idiasis in a phase II dose-ranging study . Patients were r and omized in a double-blind manner to receive either caspofungin acetate ( 35 , 50 , or 70 mg ) or amphotericin B ( 0.5 mg/kg of body weight ) intravenously once daily for 7 to 14 days . A favorable response required both complete resolution of symptoms and quantifiable improvement of mucosal lesions 3 to 4 days after discontinuation of study drug . Efficacy was assessed using a modified intent-to-treat analysis . No hypothesis testing of efficacy was planned or performed . Of 140 enrolled patients , 63 % had esophageal involvement and 98 % were infected with the human immunodeficiency virus ( HIV ) ( median CD4 count , 30/mm3 ) . A modestly higher proportion of patients in each of the caspofungin groups ( 74 to 91 % ) achieved favorable responses compared to amphotericin B recipients ( 63 % ) , but there was considerable overlap in the 95 % confidence intervals surrounding these point estimates . Similar trends were found in the subgroups with esophageal involvement , a history of fluconazole failure , and CD4 counts of ≤50/mm3 . A smaller proportion of patients receiving any dose of caspofungin experienced drug-related adverse events compared to patients given st and ard doses of conventional amphotericin B ( P < 0.01 ) . Caspofungin provided a generally well-tolerated parenteral therapeutic option for HIV-infected patients with oropharyngeal and /or esophageal c and idiasis in this study A total of 334 HIV-infected patients with oral c and idiasis were r and omly assigned to receive 14 days of treatment with either 100 mg of oral fluconazole once daily or 10 mg clotrimazole five times daily . Both treatments were clinical ly effective : 98 % of evaluable fluconazole-treated patients and 94 % of evaluable clotrimazole-treated patients were cured or showed improvement ( p = NS ) . Fluconazole was more effective than clotrimazole in eradicating C and ida from the oral flora by the end of therapy ( 65 % versus 48 % ) ( p = 0.005 ) . In addition , patients in the fluconazole-treated group were more likely to remain asymptomatic through the second week of follow-up ( 82.3 % versus 50.0 % ) ( p < 0.001 ) . This difference was no longer evident by the post-therapy visit during week 4 . Seven patients treated with clotrimazole and two patients treated with fluconazole discontinued therapy because of side effects . Two patients in the fluconazole group were withdrawn from therapy because of elevated serum glutamic-oxaloacetic transaminase levels , one considered possibly related to drug therapy . Fluconazole was as effective as clotrimazole in the treatment of oral c and idiasis and temporarily provided a more prolonged disease-free state . Future studies are needed to define the optimal regimen for both the treatment and prevention of recurrent oral c and idiasis in HIV-infected patients , addressing special attention to the issue of compliance , cost , and emergence of resistance A total of 167 human immunodeficiency virus (HIV)-infected patients with oropharyngeal c and idiasis were r and omly assigned to receive 14 days of therapy with liquid suspension fluconazole ( 100 mg once daily ) or liquid nystatin ( 500,000 U four times daily ) . At day 14 , 87 % of the fluconazole-treated patients were clinical ly cured , as opposed to 52 % in the nystatin-treated group ( P < .001 ) . Fluconazole eradicated C and ida organisms from the oral flora in 60 % , vs. a 6 % eradication rate with nystatin ( P < .001 ) . The fluconazole group had fewer relapses noted on day 28 ( 18 % , vs. 44 % in the nystatin group ; P < .001 ) . This relapse difference no longer existed by day 42 . Fluconazole oral suspension as a systemic therapy was more effective than liquid nystatin as a topical therapy in the treatment of oral c and idiasis in HIV-infected patients and provided a longer disease-free interval before relapse The primary aim of this study was to compare the efficacy and safety of single-dose fluconazole and a 7-day regimen of itraconazole for the treatment of oropharyngeal c and idiasis in human immunodeficiency virus (HlV)-positive patients . In this open-label trial , 40 HIV-positive patients with oropharyngeal c and idiasis were r and omized to receive either one dose of fluconazole 150 mg or seven daily doses of itraconazole 100 mg . Clinical condition was assessed at baseline , day 8 , and day 30 ( follow-up ) . In the fluconazole group , 15 of 20 ( 75 % ) patients were clinical ly cured on day 8 , three ( 15 % ) were clinical ly improved , and two ( 10 % ) were treatment failures . At follow-up , six ( 30 % ) patients experienced relapse . In the itraconazole group , four of 17 ( 24 % ) patients were clinical ly cured at 8 days , and two ( 12 % ) were clinical ly improved ; two patients relapsed by day 30 . Ten ( 50 % ) patients in the itraconazole group were taking concomitant medications that could potentially affect the bioavailability of itraconazole . After excluding the results from these patients , clinical response rates remained significantly higher in the fluconazole treatment arm . These results suggest that a single 150-mg dose of fluconazole may be a safe , effective , and convenient therapy for acquired immune deficiency syndrome-related oropharyngeal c and idiasis . The lower response rate in the patients who received itraconazole 100 mg daily for 7 days could be explained by drug interactions and the unpredictable absorption of itraconazole In a r and omised , double-blind study the efficacy and toxicity of oral fluconazole 50 mg daily and ketoconazole 200 mg daily were compared for the treatment of oropharyngeal c and idiasis in patients with acquired immunodeficiency syndrome ( AIDS ) and AIDS-related complex ( ARC ) . 20 episodes ( 18 patients ) were treated with fluconazole and 20 episodes ( 19 patients ) with ketoconazole . Pretreatment clinical features and laboratory test results were similar in both groups . 17 episodes ( 85 % ) in the fluconazole group and 16 ( 80 % ) in the ketoconazole group could be evaluated . There was clinical cure at the end of therapy in all fluconazole-treated and 12 of 16 ( 75 % ) ketoconazole-treated episodes . Cultures were negative at the end of therapy in 87 % of the fluconazole group and 69 % of the ketoconazole group . 1 patients stopped taking fluconazole because of severe nausea . 1 of 18 fluconazole-treated and 4 of 19 ketoconazole-treated patients had transient rises in alanine or aspartate aminotransferase . Fluconazole seemed more effective than ketoconazole in the treatment of oral thrush among AIDS and ARC patients The efficacy of oral itraconazole and ketoconazole in the treatment of oropharyngeal and /or esophageal c and idiasis , and the rate of post-treatment relapse , were compared in a multicenter , prospect i ve , double-blind , double-dummy , r and omized , parallel-group trial . A total of 143 adult HIV-positive patients with oropharyngeal and /or esophageal c and idiasis were assigned to receive either itraconazole or ketoconazole ( 200 mg/day ) . Patients with oropharyngeal and esophageal c and idiasis were treated for 2 and 4 weeks , respectively . Patients were evaluated clinical ly and mycologically after 1 , 2 and 4 ( for esophageal patients ) weeks of therapy , and relapses were compared in a 6-week post-treatment follow-up period . Of 129 evaluable patients , 98 had oropharyngeal c and idiasis and 31 esophageal infection . CDC classification , CD4 + cell counts , and number of previous episodes of oropharyngeal or esophageal c and idiasis were comparable in both groups . Oropharyngeal infection was cleared clinical ly at 21 days in 71 % of patients receiving itraconazole and 60 % receiving ketoconazole , and esophageal c and idiasis was cleared at 41 days in 100 % of patients receiving itraconazole and 91 % receiving ketoconazole . Marginally significant differences were found between itraconazole and ketoconazole in rates of clearing of infection clinical ly in patients with oropharyngeal and esophageal c and idiasis ( p = 0.0614 and 0.0781 , respectively ) . Mean rates of infection relapse were not statistically different in the two treatment groups . Adverse events were generally mild and not considered drug related . Itraconazole is marginally more efficacious than ketoconazole in the treatment of oropharyngeal and esophageal c and idiasis in HIV-positive patients and both drugs appear safe and well tolerated

Results The impact of physical activity upon gallbladder function remains unclear ; acute activity could augment emptying by stimulating cholecystokinin release , and one of two training experiments found a small increase in gallbladder motility . The largest and most recent cross-sectional and case-control trials show a reduced risk of gallbladder disease in active individuals . Conclusions Although there remains a need for further research , regular physical activity seems likely to reduce the risk of both gallstones and gallbladder cancer . A substantial number of individuals must be persuaded to exercise in order to avoid one case of gallbladder disease , but the attempt appears warranted because of the other health benefits of regular physical activity

Background Cholecystitis and gallstones affect a large segment of the population in developed nations , and a small proportion of affected individuals subsequently develop cancer of the gallbladder . However , little is known about the possible beneficial effects of physical activity . Objective Accordingly , a systematic review examined the influence of both acute and chronic exercise on gallbladder motility , and relationships were examined between habitual physical activity , gallbladder disease , and gallbladder cancer .

Abstract The longitudinal observations for ten years on 5209 men and women aged 30–62 in Framingham , Massachusetts , have been used for a prospect i ve investigation of the epidemiology of gallbladder disease . ‘ Definite ’ gallbladder disease was diagnosed in 427 persons on the evidence of pathology reports , surgery , X-ray and hospital admissions and 116 were ‘ doubtful ’ , having only the diagnosis suggested by a physician without further verification . The overall incidence of gallbladder disease was about twice as high in women as in men , and it increased with age in both sexes without any evidence of an excess in the forties . Gallbladder disease was not related to ‘ fairness ’ as measured by national origin . Increase in weight and number of pregnancies were each associated with increased incidence . Despite the presence of cholesterol in many gallstones and the elevation of serum cholesterol often noted with obesity and during pregnancy , no relationship was demonstrated between serum cholesterol level and gallbladder disease . Hemoglobin level was also not related in the population studied . Women with lower systolic blood pressures showed a somewhat reduced risk of gallbladder disease , but the possibility that a mutual relationship to weight could explain this has not been excluded . Slight negative correlations were noted between the disease incidence and height , and alcohol and cigarette consumption . These were small and in general not statistically significant . Dietary fat , protein and cholesterol intake , level of physical activity , age at menopause , marital status and precinct of residence were not related to gallbladder disease . Nor was an excess incidence noted in persons whose spouses had gallbladder disease . Persons entering the study with gallbladder disease showed no excess mortality . It is not yet clear whether such persons develop coronary heart disease at an excess rate . Potent environmental factors influencing the rate of development of gallbladder disease have yet to be identified . On the basis of present evidence , it would appear that more attention should be devoted to the anatomy and pathological physiology of the biliary tract in seeking a better underst and ing of the pathogenesis of gallbladder disease Ten healthy volunteers ( six men and four women , aged 22 - 41 years ) were studied in a crossover trial . The study was divided into three one week periods . During each period the subjects either ran on a treadmill , cycled on a bicycle ergometer , or rested in a chair for 1 hour every day . The exercise was performed at two thirds predicted maximum heart rate ( equivalent to 50 % VO2 max ) . The sequences were rotated ; no studies were performed in the perimenstrual period . Transit was measured by the method of measuring the excretion of a single dose of radio-opaque markers ; all stools were collected , weighed , and x rayed after the ingestion of radio-opaque markers . Dietary fibre and fluid intake were measured on the fourth day of each test period by 24 hour record . Lifestyle was otherwise unchanged . Transit time was dramatically accelerated by moderate exercise ( both jogging and cycling ) ; however , stool weight , defecation frequency , dietary fibre intake , and fluid intake did not change significantly . Whole gut transit changed from 51.2 hours ( 95 % confidence intervals 41.9 to 60.5 ) at rest to 36.6 hours ( 31.6 to 39.2 ) when riding and 34.0 hours ( 28.8 to 39.2 ) when jogging . Riding and running both differed significantly from resting ( p less than 0.01 ) ; the difference between riding and running was not significant PURPOSE Regular exercise reduces cardiovascular risk in humans by reducing cholesterol levels , but the underlying mechanisms have not been fully explored . Exercise might provoke changes in cholesterol and bile acid metabolism and thereby reduce cardiovascular risk . We examined whether voluntary wheel running in mice modulates cholesterol and bile acid metabolism . METHODS Male mice ( 10 wk old ) were r and omly assigned to have access to a voluntary running wheel for 2 wk ( RUN group ) or remained sedentary ( SED group ) . Running wheel activity was recorded daily . In a first experiment , fecal sterol outputs , fecal bile acid profiles , plasma parameters , and expression levels of genes involved in cholesterol and bile acid metabolism were determined . In a second experiment , bile flow , biliary bile acid profile , and biliary secretion rates of cholesterol , phospholipids , and bile acids were determined . RESULTS The RUN group ran an average of 10 km.d and displayed lower plasma cholesterol compared with SED ( P = 0.030 ) . Fecal bile acid loss was induced by approximately 30 % in running mice compared with SED ( P = 0.0012 ) . A approximately 30 % increase in fecal cholesterol output in RUN ( P = 0.014 ) was consistent with changes in parameters of cholesterol absorption , such as reduced plasma plant sterol-cholesterol ratio ( P = 0.044 ) and decreased jejunal expression of Npc1l1 ( P = 0.013 ) . Supportive of an increased cholesterol synthesis to compensate for fecal sterol loss were increased hepatic mRNA levels of HMGCoA reductase ( P = 0.006 ) and an increased plasma lathosterol-cholesterol ratio ( P = 0.0011 ) in RUN . CONCLUSIONS Voluntary wheel running increased cholesterol turnover in healthy mice owing to an increased fecal bile acid excretion and a decreased intestinal cholesterol absorption . Enhanced cholesterol turnover may contribute to the established reduction of cardiovascular risk induced by regular exercise Despite the high prevalence of gallbladder disease in industrialized countries , little is known about the predictors of the disease , especially in men . The authors prospect ively studied 16,785 alumni of Harvard University , aged 15 - 24 years , who were followed for up to 61 years . The health characteristics of these men were ascertained from their college entrance physical examination done in 1916 - 1950 , and up date d via mailed question naires in 1962 or 1966 ( 1962/1966 ) . Alumni subsequently self-reported physician-diagnosed gallbladder disease on further mailed question naires in 1972 or 1977 . Between college time and 1962/1966 , 371 gallbladder disease cases occurred . An additional 314 cases occurred after 1962/1966 . With respect to college characteristics , after adjustment for potential confounders , the authors found that body mass index ( BMI ) , smoking , physical activity , blood pressure , and consumption of alcohol , coffee , or tea were unrelated to risk . However , BMI in 1962/1966 was directly related to risk of subsequent gallbladder disease , as was BMI gain since college ( p , trend = 0.002 and 0.013 , respectively ) . Compared with men with BMI < 22.0 , men with BMI > or = 27.0 had a rate ratio of 2.71 ( 95 % confidence interval ( CI ) 1.57 - 4.66 ) for risk of contracting the disease . Men who gained > or = 6.0 BMI units since college had a rate ratio of 1.46 ( 95 % CI 0.86 - 2.46 ) compared with men who gained -0.9 to + 0.9 BMI units . Compared with never smokers , men who smoked pipes or cigars or < 1 pack of cigarettes daily in 1962/1966 had a rate ratio of 1.43 ( 95 % CI 1.00 - 2.06 ) , while heavier cigarette smokers had a rate ratio of 1.52 ( 95 % CI 1.03 - 2.24 ) . Neither physical activity nor physician-diagnosed hypertension or diabetes mellitus in 1962/1966 predicted risk Background Animal experiments have shown a protective effect of vitamin C on the formation of gallstones . Few data in humans suggest an association between reduced vitamin C intake and increased prevalence of gallstone disease . The aim of this study was to assess the possible association of regular vitamin C supplementation with gallstone prevalence . Methods An observational , population -based study of 2129 subjects aged 18 - 65 years r and omly selected from the general population in southern Germany was conducted . Abdominal ultrasound examination , completion of a st and ardized question naire , compilation of anthropometric data and blood tests were used . Data were collected in November and December 2002 . Data analysis was conducted between December 2005 and January 2006 . Results Prevalence of gallstones in the study population was 7.8 % ( 167/2129 ) . Subjects reporting vitamin C supplementation showed a prevalence of 4.7 % ( 11/232 ) , whereas in subjects not reporting regular vitamin C supplementation , the prevalence was 8.2 % ( 156/1897 ) . Female gender , hereditary predisposition , increasing age and body-mass index ( BMI ) were associated with increased prevalence of gallstones . Logistic regression with backward elimination adjusted for these factors showed reduced gallstone prevalence for vitamin C supplementation ( odds ratio , OR 0.34 ; 95 % confidence interval , CI 0.14 to 0.81 ; P = 0.01 ) , increased physical activity ( OR 0.62 ; 95 % CI , 0.42 to 0.94 ; P = 0.02 ) , and higher total cholesterol ( OR 0.65 ; 95 % CI , 0.52 to 0.79 ; P < 0.001 ) . Conclusion Regular vitamin C supplementation and , to a lesser extent , increased physical activity and total cholesterol levels are associated with a reduced prevalence of gallstones . Regular vitamin C supplementation might exert a protective effect on the development of gallstones BACKGROUND Gallstones are a highly prevalent condition ; however , the nutritional and lifestyle risk factors of this disease are not well understood . OBJECTIVE We evaluated the association between diet , physical activity , and incident cases of gallstones diagnosed by ultrasound in a population -based , case-control study . DESIGN One hundred patients with newly diagnosed gallstones and 290 r and omly selected control subjects without gallstones were enrolled in the study . The presence of gallstones was determined by ultrasonography . Both patients and control subjects completed a question naire about their usual diet and physical activity for the 12 mo before the ultrasonography . The association between diet and physical activity and risk of gallstone formation was analyzed by using multiple logistic regression . RESULTS Body mass index and intake of refined sugars were directly associated with risk of gallstone formation , whereas physical activity , dietary monounsaturated fats , dietary cholesterol , and dietary fibers from cellulose were inversely associated with risk of gallstone formation . Saturated fats were a risk factor for gallstone formation and the association appeared to be stronger for men than for women . CONCLUSION These findings suggest that a sedentary lifestyle and a diet rich in animal fats and refined sugars and poor in vegetable fats and fibers are significant risk factors for gallstone formation By means of loxiglumide , a potent and highly specific antagonist for cholecystokinin ( CCK ) , the effects of blocking CCK receptors on gastrointestinal motility were investigated in a placebo-controlled study in healthy young men ( aged 21 - 39 , mean 24 years ) . Gallbladder contraction stimulated by ingestion of a liquid test meal was completely abolished by oral administration of loxiglumide 30 min before the test meal . Gastric emptying of radio-opaque markers ingested with the test meal was significantly accelerated by loxiglumide ( area under the curve [ markers x h ] 33.3 [ SEM 3.8 ] vs 17.9 [ 2.7 ] after placebo ) . No effect of loxiglumide was found on small-bowel transit time , but 7 days ' treatment with oral loxiglumide ( 800 mg three times daily ) significantly shortened colonic transit time ( 29.4 [ 4.1 ] h after placebo , 15.0 [ 3.4 ] h after loxiglumide ) . It is concluded that CCK is an important mediator of meal-induced gallbladder contraction and is involved in the regulation of gastrointestinal motility in man Background The effects of vegetable preference and leisure-time physical activity ( LPA ) on cancer have been inconsistent . We examined the effects of dietary preference and physical activity , as well as their combined effect on cancer risk . Methods This prospect i ve cohort study included 444,963 men , older than 40 years , who participated in a national health examination program begun in 1996 . Based on the answer to the question " What kind of dietary preference do you have ? " we categorized dietary preference as ( 1 ) vegetables , ( 2 ) mixture of vegetables and meat , and ( 3 ) meats . We categorized LPA as low ( < 4 times/wk , < 30 min/session ) , moderate ( 2–4 times/wk , ≥ 30 min/session or ≥ 5 times/wk , < 30 min/session ) , or high ( ≥ 5 times/wk , ≥ 30 min/session ) . We obtained cancer incidence data for 1996 through 2002 from the Korean Central Cancer Registry . We used a st and ard Poisson regression model with a log link function and person-time offset to estimate incidence and relative risk .. Results During the 6-year follow-up period , we identified 14,109 cancer cases . Multivariate analysis revealed that a preference for vegetables or a mixture of vegetables and meat as opposed to a preference for meat played a significant protective role against lung cancer incidence ( aRR , 0.81 ; 95 % confidence interval [ CI ] , 0.68–0.98 ) . Compared with the low LPA group , subjects with moderate-high LPA had a significantly lower risk for stomach ( aRR , 0.91 ; 95%CI , 0.86–0.98 ) , lung ( aRR , 0.83 ; 95%CI , 0.75–0.92 ) , and liver ( aRR , 0.88 ; 95%CI , 0.81–0.95 ) cancer . Among current smokers , the combined moderate-high LPA and vegetable or mixture of vegetables and meat preference group showed a 40 % reduced risk of lung cancer ( aRR , 0.60 ; 95%CI , 0.47–0.76 ) compared with the combined low LPA and meat preference group . Among never/former smokers , subjects with moderate-high LPA and a preference for vegetables or a mixture of vegetables and meat showed reduced stomach cancer risk ( aRR , 0.72 ; 95%CI , 0.54–0.95 ) . Conclusion Our findings add to the evidence of the beneficial effects of vegetable preference on lung cancer risk and of physical activity on lung , stomach , and liver cancer risk . Additionally , vegetable preference combined with LPA might significantly reduce lung and stomach cancer risk It has been suggested that aerobic exercise influences gallstone disease pathogenesis through its effects on gallbladder motility . The purpose of the present investigation was to examine the effects of acute aerobic exercise on gallbladder emptying . Gallbladder function was evaluated , via cholescintigraphy , in 12 healthy females after undergoing two experimental trials [ i.e. , postpr and ial ( P ) and exercise + postpr and ial ( E + P ) ) ] . In the E + P trial , 60 min after injection of 99mTc disofenin , subjects exercised for 30 min at 65.3 + /- 0.9 % , ( mean + /- SEM ) of VO2 peak on a recumbent leg ergometer , and then ingested 8 oz of a liquid meal to promote gallbladder emptying . In the P trial the meal was administered at the same time relative to the E + P trial ; however , for the 30 min prior to meal ingestion subjects remained in a resting supine position . Postpr and ial gallbladder ejection fraction ( EF ) was nonsignificantly higher in the E + P trial ( 49.4 + /- 5.1 % ) than in the P trial ( 46.6 + /- 6.7 % ) . Results of this study also indicated that during a fasted state the gallbladder undergoes significant periods of spontaneous emptying both at rest EF = 25 + /- 5.6 % ( P < 0.02 ) and during exercise EF = 17 + /- 4.3 % ( P < 0.01 ) . In conclusion , the results of this study indicate that 30 min of aerobic exercise at 65 % of VO2 peak does not effect gallbladder motility in a healthy , premenopausal , female population A cross-sectional study of gallstone disease , ascertained by ultrasonography , comprised 4581 men and women of Danish origin , aged 30 , 40 , 50 , and 60 years , of whom 3608 ( 79 % ) took part in the investigation . The prevalence was assessed in relation to alcohol intake and number of daily meals . A r and omly chosen subgroup of 593 persons was interviewed about their dietary habits . Both in the univariate and the multivariate analysis , gallstone disease was significantly related to abstinence from alcohol but not to number of meals . There was a trend towards positive association between gallstones and intake of refined sugars and total fat , whereas a negative trend was found between gallstones and intake of fibres and polyunsaturated to saturated fat ratio . None of the associations were significant . The same relations were observed when gallstones less than 10 mm were used in the analysis . The problem of assessing diet in relation to gallstone prevalence is stressed PURPOSE Comparatively few prospect i ve studies have investigated the relationship between physical activity and gallbladder motility , and the results are controversial . Exercise may affect gallbladder motility via neural or hormonal mechanisms . The purpose of this study was to evaluate the possible effects of aerobic exercise on gallbladder motility in a group of obese women without gallstones . PATIENTS AND METHODS Twenty-three obese women ( age 41.2+/-10.3 years , body mass index 40.7+/-6.7 kg/m(2 ) ) were included in the study . Following an overnight fast , fasting and postpr and ial ( 15 , 30 , 45 , 60 , 75 , 90 , 120 , and 150 minute ) volumes and ejection fractions were evaluated with real-time ultrasonography before exercise . For all subjects , the exercise regimen consisted of daily 45-minute walking sessions at 60 - 80 % of maximum heart rate for 4 weeks except weekends . Gallbladder volume and ejection fraction were again evaluated after exercise . RESULTS Fasting and postpr and ial ( 15 , 30 , 45 , 60 , 75 , 90 , 120 , and 150 minute ) volumes were 38.6+/- 10.9 , 32.8+/- 8.8 , 27.6/- 8.1 , 22.7+/- 8.5 , 21.4+/- 7.2 , 20.8+/- 7.0 , 22.8+/- 7.3 , 29.6 + /- 7.0 , and 36.8+/- 6.2 cm(3 ) before the exercise period , respectively , and 40.8+/- 18.9 , 29.9+/-11.2 , 25.3+/- 9.2 , 22.4+/-8.5 , 19.6+/-7.8 , 17.7+/- 6.8 , 17.8+/- 7.3 , 23.1+/-10.8 , and 29.0+/-14.4 cm(3 ) after the exercise period , respectively . Postpr and ial ( 15 , 30 , 45 , 60 , 75 , 90 , 120 , and 150 minute ) ejection fractions were 13.5+/-15.9 , 27.4+/-15.4 , 39.5+/-20.0 , 43.2+/-16.7 , 44.3+/-17.3 , 37.5 + /- 23.5 , 23.5 + /-25.1 , and 5.5+/- 21.6 % before the exercise period , respectively , and 22.6+/- 20.1 , 34.6+/-14.5 , 42.0+/-13.6 , 49.2+/-12.6 , 53.1+/-14.1 , 52.6+/-16.1 , 43.6+/-17.0 , and 29.2+/- 26.5 % after exercise , respectively . After the exercise period , the 75 , 90 , 120 , and 150 minute volumes were lower ( p < 0.05 , p < 0.05 , p < 0.05 , p < 0.01 ) and the 90 , 120 , and 150 minute ejection fractions were higher than before exercise ( p < 0.05 , p < 0.05 , p < 0.01 ) . CONCLUSIONS Our study showed that exercise decreased late-phase postpr and ial gallbladder volume and increased late-phase postpr and ial gallbladder motility in these obese women PURPOSE Several prospect i ve studies have suggested that physical activity may decrease the risk for symptomatic gallbladder disease . None of these studies were able to include subjects with asymptomatic gallstones in their case group . METHODS This investigation examined the relationship between physical activity levels and the development of gallbladder disease determined by ultrasonography in a population -based cohort of 3143 men and women , 45 - 74 yr of age , from 13 American Indian communities . Participants were examined at baseline ( 1989 - 1992 ) , at which time physical activity levels , age , body mass index , waist circumference , smoking status , and diabetes status were determined . Gallbladder disease status was assessed in the entire cohort at follow-up ( 1993 - 1995 ) by ultrasonography . RESULTS Individuals who reported at baseline that they had gallbladder surgery or that a physician had told them that they had gallbladder disease were removed from the analyses . Out of the 2130 remaining , 650 individuals ( 403 women and 247 men ) were found to have gallbladder disease according to ultrasound or reported surgery by the follow-up clinic visit . After adjusting for potential confounders including body mass index , increased activity levels were inversely related to gallbladder disease status . These findings were maintained when the data were stratified by sex , but they were only significant in individuals without diabetes ( not in those with diabetes ) . CONCLUSIONS Physical activity seems to be significantly and inversely related to the development of gallbladder disease as assessed by ultrasonography in a population at high risk for gallbladder disease . These findings add to the evidence supporting a causal link between physical activity levels and a decreased risk of gallbladder disease , and they provide yet another reason to encourage the achievement and maintenance of a physically active lifestyle The aim of the study was to examine the relationship between the work load , evaluated by the occupational activity , and the incidence of cholelithiasis . In total 372 subjects ( 169 cholelithiasis patients examined using USG , and 203 controls ) , hospitalised in 1993 in the Department of Gastroenterology , Regional Hospital , Białystok , completed the question naire . Attention was also given to age , sex , permanent residence , education and physical activities after work . A moderate physical effort , both occupational and non-occupational , seemed to reduce the risk of cholelithasis Background and aims Physical activity may prevent gallstones formation by reducing bile stasis and plasma triglycerides and elevating high-density lipoprotein cholesterol levels . This prospect i ve study investigated the relationship of physical activity and symptomatic gallstones in both sexes , using a question naire vali date d against physiological measurements . Methods A total of 25 639 volunteers , aged 40–74 years , were recruited into the European Prospect i ve Investigation of Cancer , Norfolk and completed a question naire recording occupational and recreational physical activity . This question naire was vali date d earlier against measures of energy expenditure and cardio-respiratory fitness . Participants were ranked into four groups of physical activity . The cohort was monitored over 14 years for symptomatic gallstones . The primary outcome was hazard ratios ( HR ) of developing gallstones at 5 years , calculated using Cox regression modelling . HRs were adjusted for body mass index , alcohol , hormone replacement therapy and parity . Further analysis of a binary variable compared the highest level of physical activity against a combination of the lowest three levels . Results After 5 years of follow-up , 135 participants ( 69.6 % women ) developed symptomatic gallstones . Comparing the highest level of physical activity against the lowest three levels , the multivariable analysis at 5 years was HR=0.30 ( 95 % confidence interval=0.14–0.64 , P=0.002 ) . After 14 years the findings were attenuated ( HR=0.70 , 95 % confidence interval=0.49–1.01 , P=0.055 ) . Conclusion The highest level of physical activity was associated with a 70 % decreased risk of symptomatic gallstones after 5 years . This association may be causal as there are consistent experimental and epidemiological data for a protective effect . Physical activity should be accurately measured in studies investigating gallstones aetiology PURPOSE Aerobic exercise may influence gallstone disease pathogenesis through its effect on gallbladder motility . The purpose of this investigation was to examine the effects of exercise training on gallbladder emptying in obese women . METHODS Twenty-seven obese subjects were r and omized into one of two groups : exercise ( E ) ( five 45-min brisk walking sessions per week at 75.2 + /- 0.5 % of maximum heart rate ) and controls ( C ) . Gallbladder function via cholescintigraphy , cardiorespiratory fitness , and body composition were measured in all subjects before and after a 12-wk intervention period . In each cholescintigraphy trial subjects ingested an 8-oz liquid meal 45 min after injection of 99mTc disofenin to promote gallbladder emptying . Gallbladder areas were then scanned for 60 s and then every 5 min for 60 min . RESULTS VO2max increased significantly by 9 % for E when compared with that for C ( P < 0.001 ) . Within E postpr and ial gallbladder ejection fraction ( EF ) increased significantly after training ( 39.5 + /- 4.9 % to 54.7 + /- 6.5 % , P < 0.05 ) ; however , this 15.2 % increase in EF was not significantly greater than the change reported in the controls . CONCLUSIONS Results indicate that 12 wk of moderate exercise training does improve cardiorespiratory fitness but does not significantly effect gallbladder emptying in obese women The presence of gall stones diagnosed by ultrasonography in a cross sectional study was analysed in relation to relative weight , weight change since age 25 , slimming treatment , physical activity , smoking , consumption of coffee , and diabetes mellitus . The r and om sample comprised 4581 men and women of Danish origin , aged 30 , 40 , 50 , and 60 years , of whom 3608 ( 79 % ) attended the investigation . In women high body mass index , history of slimming treatment , and weight gain since the age of 25 of more than 5 body mass index units were each significantly associated with gall stones ( p less than 0.05 ) , while only body mass index was significant ( p less than 0.05 ) in a multivariate analysis . In men history of slimming treatment was significantly associated ( p less than 0.05 ) with gall stones in univariate and in multivariate analyses , where smoking also became significantly associated ( p less than 0.05 ) . No significant association was detected between gall stones and the other variables BACKGROUND Physical activity may play a role in preventing gallstone disease . METHODS The activity/gallstone relationship was examined in post-menopausal women from the Study of Osteoporotic Fractures ( SOF ; 1986 - 1988 ) , a prospect i ve study of fracture risk factors in 8010 women ( mean age = 71.1 years , SD = 4.9 ) . RESULTS Multivariate logistic regression indicated women in the lowest two quartiles of physical activity , according to question naire , had a 59 % { OR = 1.59 ( 1.11 - 2.29 ) , P = 0.02 } and a 57 % higher risk { OR = 1.57 ( 1.11 - 2.23 ) , P = 0.01 } of developing gallstone disease compared to women in the highest quartile of activity ( PTrend = < 0.0001 ) . Additionally , this relationship was examined in a cohort of 182 post-menopausal women ( mean age 74.2 years , SD = 4.1 ) who participated in a r and omized controlled trial of a walking intervention . Women in the r and omized clinical trial in the lowest tertile of physical activity determined by a physical activity monitor had a higher risk of developing gallstone disease than women in the highest tertile of physical activity , 13 % { OR-1.13 ( 1.01 - 1.28 ) , P = 0.05 , PTrend = < 0.04}. CONCLUSION Physical activity appears to be inversely related to the development of gallstone disease in post-menopausal women independent of body mass index BACKGROUND Physical activity may be an important determinant of the risk of gallstone disease in women , both independently and as a result of its role in maintaining body weight . METHODS We prospect ively studied recreational physical activity ( such as jogging , running , and bicycling ) and sedentary behavior ( such as spending hours watching television ) in relation to the risk of cholecystectomy , a surrogate for symptomatic cholelithiasis , in a cohort of 60,290 women who were 40 to 65 years of age in 1986 and had no history of gallstone disease . As part of the Nurses ' Health Study , the women reported on question naires mailed to them every two years both their activity level and whether they had undergone cholecystectomy . During a 10-year follow-up period ( 1986 to 1996 ) , 3257 cases of cholecystectomy were documented . RESULTS Recreational physical activity was inversely related to the risk of cholecystectomy . The multivariate relative risk for women in the highest as compared with the lowest quintile of physical activity was 0.69 ( 95 percent confidence interval , 0.61 to 0.78 ) . In contrast , sedentary behavior was independently related to an increased risk of cholecystectomy . As compared with women who spent less than 6 hours per week sitting while at work or driving , women who spent 41 to 60 hours per week sitting had a multivariate relative risk of 1.42 ( 95 percent confidence interval , 1.06 to 1.89 ) , and women who spent more than 60 hours per week sitting while at work or driving had a multivariate relative risk of 2.32 ( 95 percent confidence interval , 1.26 to 4.26 ) . These associations persisted after we controlled for body weight and weight change . CONCLUSIONS In women , recreational physical activity is associated with a decreased risk of cholecystectomy . The association is independent of other risk factors for gallstone disease , such as obesity and recent weight loss BACKGROUND & AIMS Insulin resistance is associated with prevalent gallstones , but its effect on initial gallstone formation is not well-understood . METHODS We conducted a nested case-control study to examine whether insulin resistance is a risk factor for initial gallbladder sludge and stone formation during pregnancy . Cases were 205 women with new gallbladder sludge and stones during pregnancy and the early postpartum . Controls were 443 r and omly selected women without sludge or stones during pregnancy . Gallbladder ultrasounds were obtained during each trimester and at 4 - 6 weeks post partum . Fasting serum glucose , lipids , and insulin were measured at 26 - 28 weeks gestation . Insulin resistance was measured by the homeostasis model . Logistic regression was used to identify independent risk factors for gallstone formation . RESULTS Insulin resistance was significantly greater in cases than in controls on univariate analysis ( P < .001 ) . Pre-pregnancy body mass index was strongly associated with gallstone formation on univariate analysis ( P < .001 ) , but this association was diminished after adjusting for insulin resistance ( P = .01 ) . On multivariate analysis , insulin resistance was significantly associated with gallstone formation ( P = .004 ) , even after adjustment for pre-pregnancy body mass index and other confounding factors including high-density lipoprotein cholesterol and physical activity . This association was strongest in women with pre-pregnancy body mass index < 30 kg/m(2 ) . CONCLUSIONS Insulin resistance is a risk factor for incident gallbladder sludge and stones during pregnancy , even after adjustment for body mass index . Insulin resistance might represent a causal link between obesity and overweight and gallstones

Results showed that ICBT has been tested for 25 different clinical disorders , whereas most r and omized controlled trials have been aim ed at depression , anxiety disorders and chronic pain . Effect sizes were large in the treatment of depression , anxiety disorders , severe health anxiety , irritable bowel syndrome , female sexual dysfunction , eating disorders , cannabis use and pathological gambling . For other clinical problems , effect sizes were small to moderate . Comparison to conventional CBT showed that ICBT produces equivalent effects . Cost-effectiveness data were relatively scarce but suggested that ICBT has more than 50 % probability of being cost effective compared with no treatment or to conventional CBT when willingness to pay for an additional improvement is zero . Although ICBT is a promising treatment option for several disorders , it can only be regarded as a well-established treatment for depression , panic disorder and social phobia . It seems that ICBT is as effective as conventional CBT for respective clinical disorder , that is , if conventional CBT works then ICBT works . The large effects and the limited therapist time required suggest that the treatment is highly cost effective for well-established indications

Internet-based cognitive behavior therapy ( ICBT ) is a promising treatment that may increase availability of cognitive behavior therapy ( CBT ) for psychiatric disorders and other clinical problems . The main objective of this study was to determine the applications , clinical efficacy and cost-effectiveness of ICBT .

The aim of this study was to investigate if cognitive behavior therapy ( CBT ) based on exposure and mindfulness exercises delivered via the Internet would be effective in treating participants with irritable bowel syndrome ( IBS ) . Participants were recruited through self-referral . Eighty-six participants were included in the study and r and omized to treatment or control condition ( an online discussion forum ) . One participant was excluded after r and omization . The main outcome measure was IBS-symptom severity and secondary measures included IBS-related quality of life , GI-specific anxiety , depression and general functioning . Participants were assessed at pre-treatment , post-treatment and 3 month follow-up ( treatment condition only ) . Four participants ( 5 % of total sample ) in the treatment condition did not participate in post-treatment assessment . Participants in the treatment condition reported a 42 % decrease and participants in the control group reported a 12 % increase in primary IBS-symptoms . Compared to the control condition , participants in the treatment group improved on all secondary outcome measures with a large between group effect size on quality of life ( Cohen 's d = 1.21 ) . We conclude that CBT-based on exposure and mindfulness delivered via the Internet can be effective in treating IBS- patients , alleviating the total burden of symptoms and increasing quality of life BACKGROUND Subthreshold depression is a highly prevalent condition and a risk factor for developing a major depressive episode . Internet-based cognitive behaviour therapy may be a promising approach for the treatment of subthreshold depression . The current study had two aims : ( 1 ) to determine whether an internet-based cognitive behaviour therapy intervention and a group cognitive behaviour therapy intervention are more effective than a waiting-list control group ; and ( 2 ) to determine whether the effect of the internet-based cognitive behaviour therapy differs from the group cognitive behaviour therapy intervention . METHOD A total of 191 women and 110 men with subthreshold depression were r and omized into internet-based treatment , group cognitive behaviour therapy ( Lewinsohn 's Coping With Depression course ) , or a waiting-list control condition . The main outcome measure was treatment response after 10 weeks , defined as the difference in pre- and post-treatment scores on the Beck Depression Inventory ( BDI ) . Missing data , a major limitation of this study , were imputed using the Multiple Imputation ( MI ) procedure Data Augmentation . RESULTS In the waiting-list control group , we found a pre- to post-improvement effect size of 0.45 , which was 0.65 in the group cognitive behaviour therapy condition and 1.00 within the internet-based treatment condition . Helmert contrasts showed a significant difference between the waiting-list condition and the two treatment conditions ( p=0.04 ) and no significant difference between both treatment conditions ( p=0.62 ) . CONCLUSIONS An internet-based intervention may be at least as effective as a commonly used group cognitive behaviour therapy intervention for subthreshold depression in people over 50 years of age The effectiveness of a therapist-supported Internet intervention program for tinnitus distress in an industrial setting was evaluated using a cluster r and omised design . Fifty-six Australian employees of two industrial organisations were r and omly assigned , based on their work site ( 18 work sites from BP Australia and five from BHP Billiton ) , to either a cognitive behavioural therapy ( CBT ) program or an information-only control program . Participants were assessed at pre- and postprogram , measuring tinnitus distress , depression , anxiety , stress , quality of life , and occupational health . The CBT program was not found to be superior to the information program for treating tinnitus distress . A high attrition rate and small sample size limit the generalisability of the findings , and further developments of the program and assessment process are needed to enhance engagement and compliance BACKGROUND Therapist-delivered online cognitive-behavioural therapy ( CBT ) has been found to be effective for depression in primary care . AIMS To determine the cost-effectiveness of online CBT compared with usual care . METHOD Economic evaluation at 8 months alongside a r and omised controlled trial . Cost to the National Health Service ( NHS ) , personal costs , and the value of lost productivity , each compared with outcomes based on the Beck Depression Inventory and quality -adjusted life-years ( QALYs ) . Incremental analysis indicated the NHS cost per QALY gain . RESULTS Online CBT was more expensive than usual care , although the outcomes for the CBT group were better . Cost per QALY gain based on complete case data was £ 17,173 , and £ 10,083 when missing data were imputed . CONCLUSIONS Online CBT delivered by a therapist in real time is likely to be cost-effective compared with usual care if society is willing to pay at least £ 20,000 per QALY ; it could be a useful alternative to face-to-face CBT The present study investigated the efficacy of self-help based on cognitive behaviour therapy in combination with Internet support in the treatment of bulimia nervosa and binge eating disorder . After confirming the diagnosis with an in-person interview , 73 patients were r and omly allocated to treatment or a waiting list control group . Treated individuals showed marked improvement after 12 weeks of self-help compared to the control group on both primary and secondary outcome measures . Intent-to-treat analyses revealed that 37 % ( 46 % among completers ) had no binge eating or purging at the end of the treatment and a considerable number of patients achieved clinical ly significant improvement on most of the other measures as well . The results were maintained at the 6-month follow-up , and provide evidence to support the continued use and development of self-help programmes BACKGROUND Although hypochondriasis is generally thought to be a chronic and stable condition with a relatively low remission rate , this disorder remains understudied . METHODS This is a 4- to 5-year prospect i ve case-control study of DSM-III-R hypochondriasis . Medical out patients meeting DSM diagnostic criteria for hypochondriasis completed an extensive research battery assessing hypochondriacal symptoms , medical and psychiatric comorbidity , functional status and role impairment , and medical care . A comparison group of nonhypochondriacal patients from the same setting underwent the same battery . Four to 5 years later , both cohorts were re-interviewed . RESULTS One hundred twenty hypochondriacal and 133 nonhypochondriacal comparison patients were originally studied . Follow-up was obtained on 73.5 % ( n = 186 ) of all patients . At follow-up , the hypochondriacal sample was significantly ( P<.001 ) less hypochondriacal and had less somatization ( P<.001 ) and disability than at inception , but 63.5 % ( n = 54 ) still met DSM-III-R diagnostic criteria . When compared with the comparison group using repeated measures multivariate analysis of variance , these changes remained statistically significant ( P<.0001 ) . Changes in medical and psychiatric comorbidity did not differ between the 2 groups . When hypochondriacal patients who did and did not meet diagnostic criteria at follow-up were compared , the latter had significantly less disease conviction ( P<.05 ) and somatization ( P<.01 ) at inception , and their incidence of major medical illness during the follow-up period was significantly ( P<.05 ) greater . CONCLUSIONS Hypochondriacal patients show a considerable decline in symptoms and improvement in role functioning over 4 to 5 years but two thirds of them still meet diagnostic criteria . Hypochondriasis , therefore , carries a very substantial , long-term burden of morbidity , functional impairment , and personal distress Online therapy offers many advantages over face-to-face therapy . Interapy includes psychoeducation , screening , effect measures , and a protocol -driven treatment via the Internet for people suffering from posttraumatic stress . The present article reports the results of a controlled trial on the Internet-driven treatment of posttraumatic stress and grief in a group of people who manifested mild to relatively severe trauma symptoms . Participants in the treatment condition ( n=69 ) improved significantly more than participants in the waiting-list control condition ( n=32 ) on trauma-related symptoms and general psychopathology . The effect sizes were large . On most subscales , more than 50 % of the treated participants showed reliable change and clinical ly significant improvement , with the highest percentages being found for depression and avoidance BACKGROUND Major depression can be treated by means of cognitive-behavioural therapy , but as skilled therapists are in short supply there is a need for self-help approaches . Many individuals with depression use the internet for discussion of symptoms and to share their experience . AIMS To investigate the effects of an internet-administered self-help programme including participation in a monitored , web-based discussion group , compared with participation in web-based discussion group only . METHOD A r and omised controlled trial was conducted to compare the effects of internet-based cognitive-behavioural therapy with minimal therapist contact ( plus participation in a discussion group ) with the effects of participation in a discussion group only . RESULTS Internet-based therapy with minimal therapist contact , combined with activity in a discussion group , result ed in greater reductions of depressive symptoms compared with activity in a discussion group only ( waiting-list control group ) . At 6 months ' follow-up , improvement was maintained to a large extent . CONCLUSIONS Internet-delivered cognitive cognitive-behavioural therapy should be pursued further as a complement or treatment alternative for mild-to-moderate depression This study evaluated a targeted intervention design ed to alleviate body image and eating problems in adolescent girls that was delivered over the internet so as to increase access to the program . The program consisted of six , 90-minute weekly small group , synchronous on-line sessions and was facilitated by a therapist and manual . Participants were 73 girls ( mean age=14.4 years , SD=1.48 ) who self-identified as having body image or eating problems and were r and omly assigned to an intervention group ( n=36 ) ( assessed at baseline , post-intervention and at 2- and 6-months follow-up ) or a delayed treatment control group ( n=37 ) ( assessed at baseline and 6–7 weeks later ) . Clinical ly significant improvements in body dissatisfaction , disordered eating , and depression were observed at post-intervention and maintained at follow-up . Internet delivery was enthusiastically endorsed . The program offers a promising approach to improve body image and eating problems that also addresses geographic access problems Background Self-help therapies are often effective in reducing mental health problems . We developed a new Web-based self-help intervention based on problem-solving therapy , which may be used for people with different types of comorbid problems : depression , anxiety , and work-related stress . Objective The aim was to study whether a Web-based self-help intervention is effective in reducing depression , anxiety , and work-related stress ( burnout ) . Methods A total of 213 participants were recruited through mass media and r and omized to the intervention ( n = 107 ) or a waiting list control group ( n = 106 ) . The Web-based course took 4 weeks . Every week an automated email was sent to the participants to explain the contents and exercises for the coming week . In addition , participants were supported by trained psychology students who offered feedback by email on the completed exercises . The core element of the intervention is a procedure in which the participants learn to approach solvable problems in a structured way . At pre-test and post-test , we measured the following primary outcomes : depression ( CES-D and MDI ) , anxiety ( SCL-A and HADS ) , and work-related stress ( MBI ) . Quality of life ( EQ-5D ) was measured as a secondary outcome . Intention-to-treat analyses were performed . Results Of the 213 participants , 177 ( 83.1 % ) completed the baseline and follow-up question naires ; missing data were statistically imputed . Of all 107 participants in the intervention group , 9 % ( n = 10 ) dropped out before the course started and 55 % ( n = 59 ) completed the whole course . Among all participants , the intervention was effective in reducing symptoms of depression ( CES-D : Cohen ’s d = 0.50 , 95 % confidence interval ( CI ) 0.22 - 0.79 ; MDI : d = 0.33 , 95 % CI 0.03 - 0.63 ) and anxiety ( SCL-A : d = 0.42 , 95 % CI 0.14 - 0.70 ; HADS : d = 0.33 , 95 % CI 0.04 - 0.61 ) as well as in enhancing quality of life ( d = 0.31 , 95 % CI 0.03 - 0.60 ) . Moreover , a higher percentage of patients in the intervention group experienced a significant improvement in symptoms ( CES-D : odds ratio [ OR ] = 3.5 , 95 % CI 1.9 - 6.7 ; MDI : OR = 3.7 , 95 % CI 1.4 - 10.0 ; SCL-A : OR = 2.1 , 95 % CI 1.0 - 4.6 ; HADS : OR = 3.1 , 95 % CI 1.6 - 6.0 ) . Patients in the intervention group also recovered more often ( MDI : OR = 2.2 ; SCL-A : OR = 2.0 ; HADS < 8) , although these results were not statistically significant . The course was less effective for work-related stress , but participants in the intervention group recovered more often from burnout than those in the control group ( OR = 4.0 , 95 % CI 1.2 - 13.5 ) . Conclusions We demonstrated statistically and clinical ly significant effects on symptoms of depression and anxiety . These effects were even more pronounced among participants with more severe baseline problems and for participants who fully completed the course . The effects on work-related stress and quality of life were less clear . To our knowledge , this is the first trial of a Web-based , problem-solving intervention for people with different types of ( comorbid ) emotional problems . The results are promising , especially for symptoms of depression and anxiety . Further research is needed to enhance the effectiveness for work-related stress . Trial Registration International St and ard R and omized Controlled Trial Number ( IS RCT N ) Background Many depressed people do not receive help for their symptoms , and there are various barriers that impede help-seeking . The Internet may offer interesting alternatives for reaching and helping people with depression . Depression can be treated effectively with Internet-based cognitive behavioral therapy ( CBT ) , but a short intervention based on problem solving therapy ( PST ) could constitute a worthwhile alternative to CBT . Objective In this study we evaluated the effectiveness of Internet-based CBT and Internet-based PST in comparison to a waiting list control group ( WL ) , and we determined the differences between the two treatments . Methods We conducted a 3-arm r and omized controlled trial to compare CBT , PST , and WL . The main inclusion criterion was presence of depressive symptoms ( ≥ 16 on the Center for Epidemiological Studies Depression scale ) . CBT and PST consisted of eight and five weekly lessons respectively . Participants were supported by email . Self-report measures of depression , anxiety , and quality of life were completed at pretest and after 5 , 8 , and 12 weeks . Results A total of 263 participants were r and omized to the three conditions ( CBT : n=88 ; PST : n=88 ; WL : n=87 ) . Of the 263 participants , 184 ( 70 % ) completed question naires after 5 weeks , 173 ( 66 % ) after 8 weeks , and 151 ( 57 % ) after 12 weeks . Between-group effect sizes for depressive symptoms were 0.54 for CBT after 8 weeks ( 95 % confidence interval ( CI ) : 0.25 - 0.84 ) and 0.47 for PST after 5 weeks ( 95 % CI : 0.17 - 0.77 ) . These effects were further improved at 12 weeks ( CBT : 0.69 , 95 % CI : 0.41 - 0.98 ; PST : 0.65 , 95 % CI : 0.36 - 0.95 ) . For anxiety , effect sizes were also at a medium level . Effect sizes for quality of life were low . The number of participants showing clinical ly significant change at 12 weeks was significantly higher for CBT ( n = 34 , 38.6 % ) and PST ( n = 30 , 34.1 % ) , compared to WL ( n = 0 ) . Conclusions Both Internet-based treatments are effective in reducing depressive symptoms , although the effect of PST is realized more quickly . Trial Registration International St and ard R and omized Controlled Trial Number ( IS RCT N ) : 16823487 ; http://www.controlled-trials.com/IS RCT N16823487/16823487 ( Archived by WebCite at http://www.webcitation.org/5cQsOj7xf ) BACKGROUND Internet-delivered self-help programmes with added therapist guidance have shown efficacy in social anxiety disorder , but unguided self-help has been insufficiently studied . AIMS To evaluate the efficacy of guided and unguided self-help for social anxiety disorder . METHOD Participants followed a cognitive-behavioural self-help programme in the form of either pure bibliotherapy or an internet-based treatment with therapist guidance and online group discussion s. A subsequent trial was conducted to evaluate treatment specificity . Participants ( n = 235 ) were r and omised to one of three conditions in the first trial , or one of four conditions in the second . RESULTS Pure bibliotherapy and the internet-based treatment were better than waiting list on measures of social anxiety , general anxiety , depression and quality of life . The internet-based therapy had the highest effect sizes , but directly comparable effects were noted for bibliotherapy augmented with online group discussion s. Gains were well maintained a year later . CONCLUSIONS Unguided self-help through bibliotherapy can produce enduring improvement for individuals with social anxiety disorder Internet-delivered psychological treatment of major depression has been investigated in several trials , but the role of personalized treatment is less investigated . Studies suggest that guidance is important and that automated computerized programmes without therapist support are less effective . Individualized e-mail therapy for depression has not been studied in a controlled trial . Eighty-eight individuals with major depression were r and omized to two different forms of Internet-delivered cognitive behaviour therapy ( CBT ) , or to a waiting-list control group . One form of Internet treatment consisted of guided self-help , with weekly modules and homework assignments . St and ard CBT components were presented and brief support was provided during the treatment . The other group received e-mail therapy , which was tailored and did not use the self-help texts i.e. , all e-mails were written for the unique patient . Both treatments lasted for 8 weeks . In the guided self-help 93 % completed ( 27/29 ) and in the e-mail therapy 96 % ( 29/30 ) completed the posttreatment assessment . Results showed significant symptom reductions in both treatment groups with moderate to large effect sizes . At posttreatment 34.5 % of the guided self-help group and 30 % of the e-mail therapy group reached the criteria of high-end-state functioning ( Beck Depression Inventory score below 9 ) . At six-month follow-up the corresponding figures were 47.4 % and 43.3 % . Overall , the difference between guided self-help and e-mail therapy was small , but in favour of the latter . These findings indicate that both guided self-help and individualized e-mail therapy can be effective Patients with phobic disorder ( mainly agoraphobics ) of minimum one year duration were treated by self-administered exposure in vivo treatment . Seventy-one patients were r and omly assigned to one of three groups : ( A ) book-instructed , ( B ) computer-instructed , or ( C ) therapist-instructed . All three groups improved significantly to a similar extent on various phobic measures at the end of the treatment and maintained their treatment gains at 6-month follow up . Mean clinicians ' time spent with each patient was 40 minutes , 4.2 hours and 3.2 hours in group A , B and C respectively . Similar small numbers of patients defaulted from each group Background Internet-based cognitive behavior therapy ( ICBT ) has shown promising effects in the treatment of irritable bowel syndrome ( IBS ) . However , to date no study has used a design where participants have been sample d solely from a clinical population . We aim ed to investigate the acceptability , effectiveness , and cost-effectiveness of ICBT for IBS using a consecutively recruited sample from a gastroenterological clinic . Methods Sixty-one patients were r and omized to 10 weeks of ICBT ( n = 30 ) or a waiting list control ( n = 31 ) . The ICBT was guided by an online therapist and emphasized acceptance of symptoms through exposure and mindfulness training . Severity of IBS symptoms was measured with the Gastrointestinal symptom rating scale - IBS version ( GSRS-IBS ) . Patients in both groups were assessed at pre- and post-treatment while only the ICBT group was assessed 12 months after treatment completion . Health economic data were also gathered at all assessment points and analyzed using bootstrap sampling . Results Fifty of 61 patients ( 82 % ) completed the post-treatment assessment and 20 of 30 patients ( 67 % ) in the ICBT group were assessed at 12-month follow-up . The ICBT group demonstrated significantly ( p < .001 ) larger improvements on the IBS-related outcome scales than the waiting list group . The between group effect size on GSRS-IBS was Cohen 's d = 0.77 ( 95 % CI : 0.19 - 1.34 ) . Similar effects were noted on measures of quality of life and IBS-related fear and avoidance behaviors . Improvements in the ICBT group were maintained at 12-month follow-up . The ICBT condition was found to be more cost-effective than the waiting list , with an 87 % chance of leading to reduced societal costs combined with clinical effectiveness . The cost-effectiveness was sustained over the 12-month period . Conclusions ICBT proved to be a cost-effective treatment when delivered to a sample recruited from a gastroenterological clinic . However , many of the included patients dropped out of the study and the overall treatment effects were smaller than previous studies with referred and self-referred sample s. ICBT may therefore be acceptable and effective for only a subset of clinical patients . Study dropout seemed to be associated with severe symptoms and large impairment . Objective and empirically vali date d criteria to select which patients to offer ICBT should be developed . Trial Registration Clinical Trials.gov : Tinnitus distress can be reduced by means of cognitive-behavior therapy ( CBT ) , and the treatment can be delivered in different ways . The most recent format is Internet-based self-help . The aim of this study was to compare this treatment ( n= 26 ) with st and ard group-based CBT ( n=25 ) in a r and omized controlled trial . Outcomes on self-report inventories measuring tinnitus distress were evaluated immediately after and 1 year after treatment . Results showed that both groups had improved , and there were few differences between them . The effect size for the Internet treatment was d=0.73 ( 95 % CI=0.16 - 1.30 ) and for the group treatment was d=0.64 ( 95 % CI=0.07 - 1.21 ) . The Internet treatment consumed less therapist time and was 1.7 times as cost-effective as the group treatment . At pretreatment patients rated the Internet treatment as less credible than the group treatment . In conclusion , Internet treatment for tinnitus distress merits further investigation , as the outcomes achieved are promising Fifty-five people with panic disorder ( PD ) were r and omised to internet-based cognitive behavioural panic treatment ( CBT ) ( with email contact ) , therapist-assisted CBT manual or information-only control ( both with telephone contact ) . Both CBT treatments were more effective in reducing PD symptomatology , panic-related cognition , negative affect , and number of GP visits and improving physical health ratings . Internet treatment was more effective than CBT manual in reducing clinician-rated agoraphobia and number of GP visits at post- assessment . At follow-up , these effects were maintained for both CBT groups , with internet CBT better at improving physical health ratings and reducing GP visits . This study provides support for the efficacy of internet-based CBT This study offers data about the efficacy of " Talk to Me , " an Internet-based telepsychology program for the treatment of fear of public speaking that includes the most active components in cognitive-behavior therapy ( CBT ) for social phobia ( exposure and cognitive therapies ) . One hundred twenty-seven participants with social phobia were r and omly assigned to three experimental conditions : ( a ) an Internet-based self-administered program ; ( b ) the same program applied by a therapist ; ( c ) a waiting-list control group . Results showed that both treatment conditions were equally efficacious . In addition , Talk to Me and the same treatment applied by a therapist were more efficacious than the waiting-list condition . Treatment gains were maintained at 1-year follow-up . The results from this study support the utility of Internet-delivered CBT programs in order to reach a higher number of people who could benefit from CBT . Internet-delivered CBT programs could also play a valuable role in the dissemination of CBT To engage more US combat veterans in PTSD treatment , we offered a psychological intervention that could be initiated in primary care and completed using the Internet . Participants ( n = 31 ) were r and omized to complete either Written Emotional Disclosure ( WED ) or time management narratives on a secure Internet website . In the WED group , participants wrote about their thoughts and emotions regarding one traumatic combat experience in three 20-min sessions . Writing instructions encouraged exposure to traumatic memories and cognitive processing of trauma . The intervention was found to be feasible and safe to implement . Although follow-up assessment s did not reveal significant group differences in PTSD symptoms , half of the WED participants reported symptom reductions . Content analyses revealed that participants who expressed more emotion and cognitions were significantly more likely to experience decreased PTSD symptoms . WED may have promise as a brief intervention for veterans with PTSD BACKGROUND Posttraumatic stress disorder ( PTSD ) is a severe and disabling condition and few receive appropriate care . Internet-based treatment of PTSD shows promise in reducing barriers to care and preliminary evidence suggests it is efficacious in treating symptoms of PTSD . METHODOLOGY Forty-two individuals with a diagnosis of PTSD confirmed by clinician interview completed a r and omized controlled comparison of Internet-based cognitive behavioral therapy ( CBT ) with a waitlist control condition . PRINCIPLE FINDINGS Large pre- to posttreatment effect sizes ( ESs ) were found for the Treatment group on measures of PTSD symptoms , depression , anxiety , and disability . A small between-group ES was found for PTSD symptoms and moderate between-group ESs were found for depression , anxiety , and disability . CONCLUSIONS Results provide preliminary support for Internet-based CBT as an efficacious treatment for individuals with a confirmed primary diagnosis of PTSD Objective : In two r and omized controlled trials Titov et al. demonstrated significant benefit from an Internet- and email-based treatment programme for social phobia : the Shyness programme . Data are presented about the longer term outcomes ( 6 months after treatment ) , cost-effectiveness relative to face-to-face treatment , and the acceptability of the programme to participants . Method : Participants completed outcome and acceptability question naires at 6 months after treatment . Repeated measures analyses of variance were calculated using an intention-to-treat design . Cost-effectiveness in years lived with disability averted were calculated based on between-group effect sizes . Results : A total of 59 % of treatment group participants completed the 6 month follow-up question naires . Between post-treatment and 6 month follow up participants continued to make improvements in symptoms of social phobia , while maintaining improvements in mood , psychological distress , and disability . At 6 month follow up the mean within-group effect size ( Cohen 's d ) for the two social phobia measures increased from 1.2 to 1.4 . Cost-effectiveness in years lived with disability ( YLD ) averted was calculated as one-quarter that of face-to-face group treatment , or $ AUD1495 for one YLD gained , compared to $ AUD5686/YLD gained . Participants rated the Internet treatment to be as effective and helpful as face-to-face treatment . Conclusions : The present results confirm the reliability of the short-term findings reported in the first two Shyness programmes . The procedure appears to be very cost-effective , and acceptable to participants . These data provide further support for the development of Internet-based virtual clinics for common mental disorders This study evaluated an Internet-delivered computer-assisted health education ( CAHE ) program design ed to improve body satisfaction and reduce weight/shape concerns -- concerns that have been shown to be risk factors for the development of eating disorders in young women . Participants were 60 women at a public university r and omly assigned to either an intervention or control condition . Intervention participants completed the CAHE program Student Bodies . Measures of body image and disordered eating attitudes were assessed at baseline , postintervention , and 3-month follow-up . At follow-up , intervention participants , compared with controls , reported a significant improvement in body image and a decrease in drive for thinness . This program provides evidence for the feasibility and effectiveness of providing health education by means of the Internet Clinician-guided Internet-based cognitive behavioural therapy ( iCBT ) programs are clinical ly effective at treating specific anxiety disorders . The present study examined the efficacy of a transdiagnostic Internet-based cognitive behavioural treatment ( iCBT ) program to treat more than one anxiety disorder within the same program ( the Anxiety Program ) . Eighty six individuals meeting diagnostic criteria for generalized anxiety disorder ( GAD ) , panic disorder , and /or social phobia were r and omly assigned to a treatment group , or to a waitlist control group . Treatment consisted of CBT based online educational lessons and homework assignments , weekly email or telephone contact from a clinical psychologist , access to a moderated online discussion forum , and automated emails . An intention-to-treat model using the baseline-observation-carried-forward principle was employed for data analyses . Seventy-five percent of treatment group participants completed all 6 lessons within the 8 week program . Post-treatment data was collected from 38/40 treatment group and 38/38 control group participants , and 3-month follow-up data was collected from 32/40 treatment group participants . Relative to controls , treatment group participants reported significantly reduced symptoms of anxiety as measured by the Generalized Anxiety Disorder - 7 Item , Social Phobia Screening Question naire , and the Panic Disorder Severity Rating Scale - Self Report Scale , but not on the Penn State Worry Question naire , with corresponding between-groups effect sizes ( Cohen 's d ) at post-treatment of 0.78 , 0.43 , 0.43 , and 0.20 , respectively . The clinician spent a total mean time of 46min per person over the program , participants rated the procedure as moderately acceptable , and gains were sustained at follow-up . Modifications to the Anxiety program , based on post-treatment feedback from treatment group participants , were associated with improved outcomes in the control group . These results indicate that transdiagnostic programs for anxiety disorders may be successfully administered via the Internet OBJECTIVE Comorbid depression is common in patients with type 1 and type 2 diabetes , adversely affecting quality of life , diabetes outcomes , and mortality . Depression can be effectively treated with cognitive behavior therapy ( CBT ) . The Internet is a new and attractive method for delivering CBT intervention on a large scale at relatively low costs . This study evaluated the effectiveness of Web-based CBT for depression treatment in adults with type 1 or type 2 diabetes , with minimal guidance . RESEARCH DESIGN AND METHODS A r and omized controlled trial was conducted in the Netherl and s in 255 adult diabetic patients with elevated depressive symptoms . Primary outcomes were depressive symptoms . Secondary outcomes were diabetes-specific emotional distress and glycemic control . Assessment s were at baseline , after treatment , and at the 1-month follow-up . RESULTS The Web-based CBT was effective in reducing depressive symptoms by intention-to-treat analyses ( P = 0.04 , d = 0.29 ; clinical improvement 41 % vs. 24 % P < 0.001 ) and by per- protocol analyses ( P < 0.001 , d = 0.70 ; clinical improvement , 56 % vs. 24 % P < 0.001 ) . The intervention reduced diabetes-specific emotional distress ( P = 0.03 ) but had no beneficial effect on glycemic control ( P > 0.05 ) . CONCLUSIONS Web-based CBT depression treatment is effective in reducing depressive symptoms in adults with type 1 and type 2 diabetes . In addition , the intervention reduces diabetes-specific emotional distress in depressed patients The goals of this study were to delineate the courses of social phobia and to determine whether the course of generalized and specific social phobia differed . In the Harvard/Brown Longitudinal Study of Anxiety Research Project , 66 specific and 74 generalized social phobic subjects were identified for whom adequate course data were available . These subjects had been followed prospect ively with a st and ardized follow-along measure of psychopathology . The probability of remission was calculated for each individual group and both groups combined . Demographics were the same for both groups except that the specific social phobia group had a marginally higher mean score on the Global Assessment Scale . Complete remission for the combined group was not different from that for either subgroup and was 0.11 at 65 weeks . Social phobia appears to be a disorder with considerable long-term morbidity . Surprisingly , both subtypes took a comparably long time to remit and were similar in their high level of psychosocial dysfunction Objective : To evaluate the effectiveness of a web-based multimedia health promotion program for the workplace , design ed to help reduce stress and to prevent depression , anxiety , and substance abuse . Methods : Using a r and omized controlled trial design , 309 working adults were r and omly assigned to the web-based condition or to a wait-list control condition . All participants were assessed on multiple self-reported outcomes at pretest and posttest . Results : Relative to controls , the web-based group reduced their stress , increased their knowledge of depression and anxiety , developed more positive attitudes toward treatment , and adopted a more healthy approach to alcohol consumption . Conclusions : We found that a brief and easily adaptable web-based stress management program can simultaneously reduce worker stress and address stigmatized behavioral health problems by embedding this prevention material into a more positive stress management framework Background Internet-based cognitive behavioural therapy ( iCBT ) for generalized anxiety disorder ( GAD ) has been shown to be effective when guided by a clinician . The present study sought to replicate this finding , and determine whether support from a technician is as effective as guidance from a clinician . Method R and omized controlled non-inferiority trial comparing three groups : Clinician-assisted vs. technician-assisted vs. delayed treatment . Community-based volunteers applied to the VirtualClinic ( www.virtualclinic.org.au ) research program and 150 participants with GAD were r and omized . Participants in the clinician- and technician-assisted groups received access to an iCBT program for GAD comprising six online lessons , weekly homework assignments , and weekly supportive contact over a treatment period of 10 weeks . Participants in the clinician-assisted group also received access to a moderated online discussion forum . The main outcome measures were the Penn State Worry Question naire ( PSWQ ) and the Generalized Anxiety Disorder-7 Item ( GAD-7 ) . Completion rates were high , and both treatment groups reduced scores on the PSWQ ( p<0.001 ) and GAD-7 ( p<0.001 ) compared to the delayed treatment group , but did not differ from each other . Within group effect sizes on the PSWQ were 1.16 and 1.07 for the clinician- and technician-assisted groups , respectively , and on the GAD-7 were 1.55 and 1.73 , respectively . At 3 month follow-up participants in both treatment groups had sustained the gains made at post-treatment . Participants in the clinician-assisted group had made further gains on the PSWQ . Approximately 81 minutes of clinician time and 75 minutes of technician time were required per participant during the 10 week treatment program . Conclusions Both clinician- and technician-assisted treatment result ed in large effect sizes and clinical ly significant improvements comparable to those associated with face-to-face treatment , while a delayed treatment/control group did not improve . These results provide support for large scale trials to determine the clinical effectiveness and acceptability of technician-assisted iCBT programs for GAD . This form of treatment has potential to increase the capacity of existing mental health services . Trial Registration Australian New Zeal and Clinical Trials Registry BACKGROUND Despite strong evidence for its effectiveness , cognitive-behavioural therapy ( CBT ) remains difficult to access . Computerised programs have been developed to improve accessibility , but whether these interventions are responsive to individual needs is unknown . We investigated the effectiveness of CBT delivered online in real time by a therapist for patients with depression in primary care . METHODS In this multicentre , r and omised controlled trial , 297 individuals with a score of 14 or more on the Beck depression inventory ( BDI ) and a confirmed diagnosis of depression were recruited from 55 general practice s in Bristol , London , and Warwickshire , UK . Participants were r and omly assigned , by a computer-generated code , to online CBT in addition to usual care ( intervention ; n=149 ) or to usual care from their general practitioner while on an 8-month waiting list for online CBT ( control ; n=148 ) . Participants , research ers involved in recruitment , and therapists were masked in advance to allocation . The primary outcome was recovery from depression ( BDI score < 10 ) at 4 months . Analysis was by intention to treat . This trial is registered , number IS RCT N 45444578 . FINDINGS 113 participants in the intervention group and 97 in the control group completed 4-month follow-up . 43 ( 38 % ) patients recovered from depression ( BDI score < 10 ) in the intervention group versus 23 ( 24 % ) in the control group at 4 months ( odds ratio 2.39 , 95 % CI 1.23 - 4.67 ; p=0.011 ) , and 46 ( 42 % ) versus 26 ( 26 % ) at 8 months ( 2.07 , 1.11 - 3.87 ; p=0.023 ) . INTERPRETATION CBT seems to be effective when delivered online in real time by a therapist , with benefits maintained over 8 months . This method of delivery could broaden access to CBT . FUNDING BUPA Foundation & NA ; Both pharmacological and non‐pharmacological interventions have demonstrated efficacy in the management of fibromyalgia ( FM ) . Non‐pharmacological interventions however are far less likely to be used in clinical setting s , in part due to limited access . This manuscript presents the findings of a r and omized controlled trail of an Internet‐based exercise and behavioral self‐management program for FM design ed for use in the context of a routine clinical care . 118 individuals with FM were r and omly assigned to either ( a ) st and ard care or ( b ) st and ard care plus access to a Web‐Enhanced Behavioral Self‐Management program ( WEB‐SM ) grounded in cognitive and behavioral pain management principles . Individuals were assessed at baseline and again at 6 months for primary endpoints : reduction of pain and an improvement in physical functioning . Secondary outcomes included fatigue , sleep , anxiety and depressive symptoms , and a patient global impression of improvement . Individuals assigned to the WEB‐SM condition reported significantly greater improvement in pain , physical functioning , and overall global improvement . Exercise and relaxation techniques were the most commonly used skills throughout the 6 month period . A no‐contact , Internet‐based , self‐management intervention demonstrated efficacy on key outcomes for FM . While not everyone is expected to benefit from this approach , this study demonstrated that non‐pharmacological interventions can be efficiently integrated into routine clinical practice with positive outcomes Background Internet administered cognitive behaviour therapy ( CBT ) is a promising new way to deliver psychological treatment , but its effectiveness in regular care setting s and in relation to more traditional CBT group treatment has not yet been determined . The primary aim of this study was to compare the effectiveness of Internet- and group administered CBT for panic disorder ( with or without agoraphobia ) in a r and omised trial within a regular psychiatric care setting . The second aim of the study was to establish the cost-effectiveness of these interventions . Methods Patients referred for treatment by their physician , or self-referred , were telephone-screened by a psychiatric nurse . Patients fulfilling screening criteria underwent an in-person structured clinical interview carried out by a psychiatrist . A total of 113 consecutive patients were then r and omly assigned to 10 weeks of either guided Internet delivered CBT ( n = 53 ) or group CBT ( n = 60 ) . After treatment , and at a 6-month follow-up , patients were again assessed by the psychiatrist , blind to treatment condition . Results Immediately after r and omization 9 patients dropped out , leaving 104 patients who started treatment . Patients in both treatment conditions showed significant improvement on the main outcome measure , the Panic Disorder Severity Scale ( PDSS ) after treatment . For the Internet treatment the within-group effect size ( pre-post ) on the PDSS was Cohen 's d = 1.73 , and for the group treatment it was d = 1.63 . Between group effect sizes were low and treatment effects were maintained at 6-months follow-up . We found no statistically significant differences between the two treatment conditions using a mixed models approach to account for missing data . Group CBT utilised considerably more therapist time than did Internet CBT . Defining effect as proportion of PDSS responders , the cost-effectiveness analysis concerning therapist time showed that Internet treatment had superior cost-effectiveness ratios in relation to group treatment both at post-treatment and follow-up . Conclusions This study provides support for the effectiveness of Internet CBT in a psychiatric setting for patients with panic disorder , and suggests that it is equally effective as the more widely used group administered CBT in reducing panic- and agoraphobic symptoms , as well as being more cost effective with respect to therapist time . Trial registration Clinical Trials.gov Background Internet-based cognitive behavioural therapy ( iCBT ) for depression is effective when guided by a clinician , less so if unguided . Question : Would guidance from a technician be as effective as guidance from a clinician ? Method R and omized controlled non-inferiority trial comparing three groups : Clinician-assisted vs. technician-assisted vs. delayed treatment . Community-based volunteers applied to the VirtualClinic ( www.virtualclinic.org.au ) research program , and 141 participants with major depressive disorder were r and omized . Participants in the clinician- and technician-assisted groups received access to an iCBT program for depression comprising 6 online lessons , weekly homework assignments , and weekly supportive contact over a treatment period of 8 weeks . Participants in the clinician-assisted group also received access to a moderated online discussion forum . The main outcome measures were the Beck Depression Inventory ( BDI-II ) and the Patient Health Question naire-9 Item ( PHQ-9 ) . Completion rates were high , and at post-treatment , both treatment groups reduced scores on the BDI-II ( p<0.001 ) and PHQ-9 ( p<0.001 ) compared to the delayed treatment group but did not differ from each other . Within group effect sizes on the BDI-II were 1.27 and 1.20 for the clinician- and technician-assisted groups respectively , and on the PHQ-9 , were 1.54 and 1.60 respectively . At 4-month follow-up participants in the technician group had made further improvements and had significantly lower scores on the PHQ-9 than those in the clinician group . A total of approximately 60 minutes of clinician or technician time was required per participant during the 8-week treatment program . Conclusions Both clinician- and technician-assisted treatment result ed in large effect sizes and clinical ly significant improvements comparable to those associated with face-to-face treatment , while a delayed treatment control group did not improve . These results provide support for large scale trials to determine the clinical effectiveness and acceptability of technician-assisted iCBT programs for depression . This form of treatment has potential to increase the capacity of existing mental health services . Trial Registration Australian New Zeal and Clinical Trials Registry Abstract Objective To evaluate the efficacy of two internet interventions for community-dwelling individuals with symptoms of depression — a psychoeducation website offering information about depression and an interactive website offering cognitive behaviour therapy . Design R and omised controlled trial . Setting Internet users in the community , in Canberra , Australia . Participants 525 individuals with increased depressive symptoms recruited by survey and r and omly allocated to a website offering information about depression ( n = 166 ) or a cognitive behaviour therapy website ( n = 182 ) , or a control intervention using an attention placebo ( n = 178 ) . Main outcome measures Change in depression , dysfunctional thoughts ; knowledge of medical , psychological , and lifestyle treatments ; and knowledge of cognitive behaviour therapy . Results Intention to treat analyses indicated that information about depression and interventions that used cognitive behaviour therapy and were delivered via the internet were more effective than a credible control intervention in reducing symptoms of depression in a community sample . For the intervention that delivered cognitive behaviour therapy the reduction in score on the depression scale of the Center for Epidemiologic Studies was 3.2 ( 95 % confidence interval 0.9 to 5.4 ) . For the “ depression literacy ” site ( BluePages ) , the reduction was 3.0 ( 95 % confidence interval 0.6 to 5.2 ) . Cognitive behaviour therapy ( MoodGYM ) reduced dysfunctional thinking and increased knowledge of cognitive behaviour therapy . Depression literacy ( BluePages ) significantly improved participants ' underst and ing of effective evidence based treatments for depression ( P < 0.05 ) . Conclusions Both cognitive behaviour therapy and psychoeducation delivered via the internet are effective in reducing symptoms of depression This study compared Panic Online ( PO ) , an internet-based CBT intervention , to best- practice face-to-face CBT for people with panic disorder with or without agoraphobia . Eighty-six people with a primary diagnosis of panic disorder were recruited from Victoria , Australia . Participants were r and omly assigned to either PO ( n=46 ) or best practice face-to-face CBT ( n=40 ) . Effects of the internet-based CBT program were found to be comparable to those of face-to-face CBT . Both interventions produced significant reductions in panic disorder and agoraphobia clinician severity ratings , self reported panic disorder severity and panic attack frequency , measures of depression , anxiety , stress and panic related cognitions , and displayed improvements in quality of life . Participants rated both treatment conditions as equally credible and satisfying . Participants in the face-to-face CBT treatment group cited higher enjoyment with communicating with their therapist . Consistent with this , therapists ' ratings for compliance to treatment and underst and ing of the CBT material was higher in the face-to-face CBT treatment group . PO required significantly less therapist time than the face-to-face CBT condition Background Anxiety disorders share common vulnerabilities and symptoms . Disorder-specific treatment is efficacious , but few access evidence -based care . Administering transdiagnostic cognitive-behavioral therapy via the internet ( iCBT ) may increase access to evidence -based treatment , with a recent r and omized controlled trial ( RCT ) providing preliminary support for this approach . This study extends those findings and aims to answer three questions : Is a transdiagnostic iCBT program for anxiety disorders efficacious and acceptable ? Does it result in change for specific disorders ? Can good clinical outcomes be obtained when guidance is provided via a Coach rather than a Clinician ? Method RCT ( N = 131 ) comparing three groups : Clinician-supported ( CL ) vs. Coach-supported ( CO ) vs. waitlist control ( Control ) . Individuals met DSM-IV criteria for a principal diagnosis of generalized anxiety disorder ( GAD ) , social phobia ( SP ) or panic disorder with or without agoraphobia ( Pan/Ag ) . Treatment consisted of an 8-lesson/10 week iCBT program with weekly contact from a Clinician or Coach , and follow-up at 3-months post-treatment . Results Outcomes for the pooled treatment groups ( CL+CO ) were superior to the Control group on measures of anxiety , depression and disability , were associated with medium to large effect sizes ( Cohen 's d = .76 – 1.44 ) ( response rate = 89–100 % ) , and were maintained at follow-up . Significant reductions were found on disorder-specific outcomes for each of the target diagnoses , and were associated with large effect sizes . CO participants achieved similar outcomes to CL participants at post-treatment , yet had significantly lower symptom severity scores on general anxiety , panic-disorder , depression and disability at follow-up ( d = .45 – .46 ) . Seventy-four percent of CO and 76 % of CL participants completed the program . Less than 70 minutes of Clinician or Coach time was required per participant during the program . Discussion This transdiagnostic iCBT course for anxiety appears to be efficacious , associated with significant change for three target disorders , and is efficacious when guided by either a Clinician or Coach . Trial Registration Australian New Zeal and Clinical Trials Registry Objective The aim of this study was to investigate if cognitive behavior therapy ( CBT ) provided via the Internet results in significant decreases of distress in individuals with tinnitus . Methods Participants were recruited through Web pages and newspaper articles and thereafter r and omly allocated to a CBT self-help manual in six modules or to a waiting-list control group ( WLC ) . All treatment and contact with participants were conducted via the Internet with Web pages and E-mail correspondence . Participants were 117 individuals with tinnitus of duration of more than 6 months . In the first r and omized controlled phase of the study , 26 completed all stages of treatment ( 51 % dropout ) , and 64 of the WLC group completed measures . At 1-year follow-up , all participants had been offered the program and 96 provided outcome measures ( 18 % dropout rate from baseline ) . Tinnitus-related problems were assessed before and after treatment and at the 1-year follow-up . Daily diary ratings were included for 1 week before and 1 week following the treatment period . Results Tinnitus-related distress , depression , and diary ratings of annoyance decreased significantly . Immediately following the r and omized controlled phase ( with a WLC ) , significantly more participants in the treatment group showed an improvement of at least 50 % on the Tinnitus Reaction Question naire . At the uncontrolled follow-up , 27 ( 31 % ) of all participants had achieved a clinical ly significant improvement . Conclusions CBT via the Internet can help individuals decrease annoyance associated with tinnitus . High dropout rates or delay in completing treatment can be a characteristic of treatment studies using the Internet but should be contrasted with the cost effectiveness and accessibility of the Internet BACKGROUND Women reporting initial eating disorder ( ED ) symptoms are at highest risk for the development of an eating disorder . Preventive interventions should , therefore , be specifically tailored for this subgroup . AIMS To adapt and evaluate the effects of the Internet-based prevention program " Student Bodies ™ " for women with symptoms of disordered eating and /or subthreshold eating disorder ( ED ) syndromes . METHOD 126 women , reporting subthreshold ED symptoms ( high weight and shape concerns and below threshold bingeing , purging , chronic dieting or several of these symptoms ) were r and omly assigned to a Student Bodies ™ + ( SB+ ) intervention or a wait-list control group and assessed at pre-intervention , post-intervention , and 6-month follow-up . " Student Bodies ™ " was adapted to be suitable for subthreshold EDs . Main outcome measures were attitudes and symptoms of disordered eating . Pre-follow-up data were analyzed by ANCOVAS with mixed effects . RESULTS At 6-month follow-up , compared to participants in the control group , participants in the intervention group showed significantly greater improvements on ED-related attitudes . Intervention participants also showed 67 % ( 95 % CI = 20 - 87 % ) greater reductions in combined rates of subjective and objective binges , and 86 % ( 95 % CI = 63 - 95 % ) greater reduction in purging episodes . Also , the rates of participants abstinent from all symptoms of disordered eating ( restrictive eating , binge eating and any compensatory behavior ) were significantly higher in the intervention group ( 45.1 % vs. 26.9 % ) . Post-hoc subgroup analyses revealed that for participants with binge eating the effect on EDE-Q scores was larger than in the pure restricting subgroup . CONCLUSION The adapted " SB+ " program represents an effective intervention for women with subthreshold EDs of the binge eating subtype OBJECTIVE To determine the feasibility of conducting a cluster r and omised trial in Australia of the effectiveness of general practitioner-supported delivery of internet-based cognitive behaviour therapy ( CBT ) and enhanced psychological care . DESIGN , SETTING AND PARTICIPANTS Cluster r and omised trial involving patients attending general practice s in Australia . Participating practice s were r and omly allocated to interventions . The study was conducted between January 2004 and January 2007 . INTERVENTIONS Enhanced GP care was delivered by doctors who had completed specific mental health training ; the experimental condition consisted of enhanced GP care plus MoodGYM , an internet-based CBT intervention . MAIN OUTCOME MEASURES Demographic and behavioural characteristics of patients , and demographic and practice characteristics of GPs ; time to resolution of psychological symptoms for patients involved in the longitudinal phase of the trial . RESULTS 1571 patients attending 90 GPs from 84 general practice s were identified as potentially suitable for recruitment . These patients had a mean age of 35 years , 76 % were female , 84 % had access to the internet for personal use , and 22 % reported high or very high levels of psychological distress on the Kessler Psychological Distress Scale . The 90 GPs had a mean age of 49 years , 53 % were female and 25 % had completed formal mental health training . Of the 1571 screened patients , 340 reported high levels of psychological distress , but only 140 of these could be further assessed for eligibility in the trial . Of these 140 , 83 patients with depression ( attending 10 GPs in eight general practice s ) proceeded to r and omisation . For these patients , the experimental intervention ( enhanced GP care plus MoodGYM ) tended to result in prompt and more sustained resolution of depressive symptoms . CONCLUSION Our capacity to conduct a definitive trial was limited by available re sources . Preliminary data suggest that primary care patients with depression may derive additional benefits from an internet-based CBT program delivered in conjunction with enhanced psychological care from GPs Objective : In two previous r and omized controlled trials Titov et al. demonstrated significant benefit from an Internet- and email-based treatment programme for social phobia . The present study ( Shyness 3 ) explores whether participants are able to complete this programme independently . Method : A total of 98 individuals with social phobia were r and omly assigned to a clinician-assisted computerized cognitive behavioural treatment ( CaCCBT ) group , a self-guided computerized CBT ( CCBT ) group , or to a waitlist control group . CaCCBT group participants completed the usual Shyness programme consisting of six online lessons , cognitive behavioural homework assignments , email contact with a therapist , and participation in an online discussion forum . CCBT group participants accessed the same re sources except for therapist emails . An intention-to-treat model was used for data analyses . Results : A total of 77 % of CaCCBT and 33 % of CCBT group participants completed all lessons . Significant differences were found after treatment between CaCCBT and control groups ( mean between-groups effect size ( ES ) for the social phobia measures = 1.04 ) , and between the CaCCBT and CCBT groups ( mean between-groups ES for the social phobia measures = 0.66 ) . No significant differences were found after treatment between the CCBT and control groups ( mean between-groups ES for the social phobia measures = 0.38 ) . CCBT participants , however , who completed the six lessons made good progress ( mean within-group ES for the social phobia measures = 0.62 ) . Quantitative and qualitative data indicate that both the CaCCBT and CCBT procedures were acceptable to participants . Conclusions : The reliability of this Internet-based treatment programme for social phobia has been confirmed . The therapist-guided condition was superior to the self-guided condition , but a subgroup of participants still benefited considerably from the latter . These data confirm that self-guided education or treatment programmes for common anxiety disorders can result in significant improvements Background The effectiveness of Internet-based treatments for depression has been demonstrated ; their cost-effectiveness , however , has been less well research ed . Objective Evaluating the relative cost-utility and cost-effectiveness of ( 1 ) Internet-based cognitive behavioral therapy , ( 2 ) Internet-based problem-solving therapy , and ( 3 ) a waiting list for adults with depressive symptoms . Methods A total of 263 participants with clinical ly significant depressive symptoms were r and omized to Internet-based cognitive behavioral therapy ( n = 88 ) , Internet-based problem-solving therapy ( n = 88 ) , and a waiting list ( n = 87 ) . End points were evaluated at the 12-week follow-up . Results Cost-utility analysis showed that cognitive behavioral therapy and problem-solving therapy had a 52 % and 61 % probability respectively of being more acceptable than waiting when the willingness to pay is € 30,000 for one quality -adjusted life-year . When society is prepared to pay € 10,000 for a clinical ly significant change from depression , the probabilities of cognitive behavioral therapy and problem-solving therapy being more acceptable than waiting are 91 % and 89 % , respectively . Comparing both Internet-based treatments showed no clear preference for one or the other of the treatments . Conclusions Both Internet-based treatments have a high probability of being cost-effective with a modest value placed on clinical ly significant change in depressive symptoms . Trial Registration IS RCT N16823487 ; http://www.controlled-trials.com/IS RCT N16823487 ( Archived by WebCite at http://www.webcitation.org/5u8slzhDE Objective : The present study ( Shyness 7 ) has two aims : Firstly , to replicate an earlier trial showing that a self-guided Internet treatment for social phobia is efficacious , and secondly , to examine whether the addition of self-guided motivational enhancement strategies improves completion rates and clinical outcomes . Method : R and omized controlled trial ( RCT ) of self-guided Internet-based cognitive behavioural treatment ( iCBT ) , or iCBT plus self-guided motivational enhancement strategies ( iCBT+MS ) , was conducted . An intention-to-treat and last observation carried forward model was used for data analyses . The participants consisted of 108 volunteers with social phobia . The iCBT intervention consisted of two online lessons about symptoms and treatment of anxiety disorders and six lessons about management of social phobia ( the Shyness programme ) with complex automated reminders . The motivational intervention was based on traditional techniques including underst and ing and exploring ambivalence about change using a cost – benefit analysis , developing and resolving discrepancy between values and symptoms , and enhancing self-efficacy for change . The main outcome measures were the Social Interaction Anxiety Scale and Social Phobia Scale . Results : More iCBT+MS group participants completed the eight lessons than iCBT group participants ( 75 % versus 56 % , respectively ) , but there were no between-group differences in outcome measures at post-treatment or at 3 month follow up . Large mean within-groups effect sizes ( Cohen 's d ) for the two social phobia measures were found for both the iCBT and iCBT+ MS groups ( 1.1 and 0.95 , respectively ) , which were sustained at 3 month follow up ( 1.06 and 1.07 , respectively ) . Both iCBT and iCBT+MS group participants reported that the procedures were highly acceptable . Conclusions : Both self-guided versions of the Shyness programme were reliably efficacious , confirming that people with social phobia may significantly benefit from a highly structured self-guided intervention . The addition of motivational techniques increased completion rates but did not improve clinical outcomes or acceptability Previous studies on Internet-based treatment with minimal to moderate therapist guidance have shown promising results for a number of specific diagnoses . The aim of this study was to test a new approach to Internet treatment that involves tailoring the treatment according to the patient 's unique characteristics and comorbidities . A total of 54 participants , regardless of specific anxiety diagnosis , were included after an in-person , semi-structured diagnostic interview and r and omized to a 10 week treatment program or to a control group . Treatment consisted of a number of individually-prescribed modules in conjunction with online therapist guidance . Significant results were found for all dependent measures both immediately following treatment and at 1 and 2 year intervals . Mean between-group effect size including measures of anxiety , depression and quality of life was Cohen 's d = 0.69 at post-treatment , while the mean within-group effect size was d = 1.15 at post-treatment and d = 1.13 and d = 1.04 at 1 and 2 year follow-up respectively . The tentative conclusion drawn from these results is that tailoring the Internet-based therapy can be a feasible approach in the treatment of anxiety in a homogeneous population Although effective therapies for pathological gambling exist , their uptake is limited to 10 % of the target population . To lower the barriers for help seeking , the authors tested an online alternative in a r and omized trial ( N = 66 ) . The participants were pathological gamblers not presenting with severe comorbid depression . A wait-list control was compared with an 8-week Internet-based cognitive behavior therapy program with minimal therapist contact via e-mail and weekly telephone calls of less than 15 min . Average time spent on each participant , including phone conversations , e-mail , and administration , was 4 hr . The Internet-based intervention result ed in favorable changes in pathological gambling , anxiety , depression , and quality of life . Composite between-group effect size ( Cohen 's d ) at posttreatment was 0.83 . Follow-ups carried out in the treatment group at 6 , 18 , and 36 months indicated that treatment effects were sustained ( ds = 2.58 , 1.96 , and 1.98 ) . This evidence is in support of Internet-delivered treatment for pathological gamblers . However , it is not clear how effective the treatment is for more severely depressed individuals Objective : There is a need for practical , efficient and broad-reaching diabetes self-management interventions that can produce changes in lifestyle behaviours such as healthy eating and weight loss . The objective of this study was to evaluate such a computer-assisted intervention . Methods : Type 2 diabetes primary care patients ( n=335 ) from fee-for-service and health maintenance organization setting s were r and omized to social cognitive theory-based tailored self-management ( TSM ) or computer-aided enhanced usual care ( UC ) . Intervention consisted of computer-assisted self-management assessment and feedback , tailored goal - setting , barrier identification , and problem-solving , followed by health counsellor interaction and follow-up calls . Outcomes were changes in dietary behaviours ( fat and fruit/vegetable intake ) , haemoglobin A1c ( HbA1c ) , lipids , weight , quality of life , and depression . Results : TSM patients reduced dietary fat intake and weight significantly more than UC patients at the 2-month follow-up . Among patients having elevated levels of HbA1c , lipids or depression at baseline , there were consistent directional trends favouring intervention , but these differences did not reach significance . The intervention proved feasible and was implemented successfully by a variety of staff . Conclusions : This relatively low-intensity intervention appealed to a large , generally representative sample of patients , was well implemented , and produced improvement in targeted behaviours . Implication s of this practical clinical trial for dissemination are discussed Generalized anxiety disorder ( GAD ) has been effectively treated with cognitive behavioural therapy ( CBT ) in face-to face setting s. Internet-delivered CBT could be a way to increase the accessibility and affordability of CBT for people suffering from GAD . The aim of this study was to evaluate the efficacy of guided Internet-delivered CBT for GAD in a controlled trial with a wait-list control group . A total of 89 participants were included following online screening and a structured psychiatric telephone interview . Participants were r and omized to either an 8-week treatment group ( n = 44 ) or a wait-list control group ( n = 45 ) . Treatment consisted of a self-help program based on CBT principles and applied relaxation along with therapist guidance . The main outcome measure was the Penn State Worry Question naire . Ratings of clinical improvement and symptoms were included as well as secondary outcome measures dealing with anxiety , depression , and quality of life . Among the treatment group participants , 13.6 % did not complete the posttreatment measures . The treatment group showed significant improvement compared with the control group on all outcome measures . Large effect sizes ( Cohen 's d>0.8 ) were found both within the treatment group and between the groups in favor of the treatment on all outcome measures except on a measure of quality of life . Results at 1- and 3-year follow-up indicated that treatment results improved or were maintained . The authors conclude that Internet-delivered CBT with therapist support can reduce symptoms and problems related to GAD OBJECTIVE The authors report an 8-week r and omized , controlled proof-of-concept trial of a new therapist-assisted , Internet-based , self-management cognitive behavior therapy versus Internet-based supportive counseling for posttraumatic stress disorder ( PTSD ) . METHOD Service members with PTSD from the attack on the Pentagon on September 11th or the Iraq War were r and omly assigned to self-management cognitive behavior therapy ( N=24 ) or supportive counseling ( N=21 ) . RESULTS The dropout rate was similar to regular cognitive behavior therapy ( 30 % ) and unrelated to treatment arm . In the intent-to-treat group , self-management cognitive behavior therapy led to sharper declines in daily log-on ratings of PTSD symptoms and global depression . In the completer group , self-management cognitive behavior therapy led to greater reductions in PTSD , depression , and anxiety scores at 6 months . One-third of those who completed self-management cognitive behavior therapy achieved high-end state functioning at 6 months . CONCLUSIONS Self-management cognitive behavior therapy may be a way of delivering effective treatment to large numbers with unmet needs and barriers to care Background : As many sufferers from phobic and panic ( phobia/panic ) disorders can not get to suitable therapists , routine aspects of therapy were delegated to internet-accessed computer-aided self-help with or without exposure instructions . Methods : Phobia/panic referrals were r and omised to computer-aided self-help via the internet at home in a 2:1 ratio either by self-exposure cognitive behaviour therapy ( CBT ) [ FearFighter ( FF ) , n = 45 ] or by minimal CBT without exposure [ Managing Anxiety ( MA ) , n = 23 ] . All had brief backup phone advice from a clinician concerning their computer guidance . Results : On self-ratings and blinded assessor ratings , patients improved equally with each form of self-help over 10 treatment weeks but significantly more on 5 out of 10 measures by week 14 ( 1-month follow-up ) when the self-help included self-exposure instructions than when it did not . In accord with this , st and ardised effect sizes ( Cohen ’s d ) indicated superiority of FF over MA on 5 measures by week 14 . Satisfaction with treatment in all patients pooled correlated positively with improvement after treatment and at 1-month follow-up . Conclusions : At the end of treatment , computer-aided CBT self-help at home via the internet plus brief live helpline support was effective with or without exposure instructions , and at 1-month follow-up it was more effective on some measures if exposure instructions had been included . Analysis is needed of how non-exposure CBT produced its shorter-term effect BACKGROUND Severe health anxiety is a common condition associated with functional disability , making it a costly disorder from a societal perspective . Internet-based cognitive behaviour therapy ( ICBT ) is a promising treatment but no previous study has assessed the cost-effectiveness or long-term outcome of ICBT for severe health anxiety . The aim of this study was to investigate the cost-effectiveness and 1-year treatment effects of ICBT for severe health anxiety . METHOD Cost-effectiveness and 1-year follow-up data were obtained from a r and omized controlled trial ( RCT ) comparing ICBT ( n = 40 ) to an attention control condition ( CC , n = 41 ) . The primary outcome measure was the Health Anxiety Inventory ( HAI ) . A societal perspective was taken and incremental cost-effectiveness ratios ( ICERs ) were calculated using bootstrap sampling . RESULTS The main ICER was -£1244 , indicating the societal economic gain for each additional case of remission when administering ICBT . Baseline to 1-year follow-up effect sizes on the primary outcome measure were large ( d = 1.71 - 1.95 ) . CONCLUSIONS ICBT is a cost-effective treatment for severe health anxiety that can produce substantial and enduring effects A r and omized trial was conducted of two different self-help programs for panic disorder ( PD ) on the Internet . After confirming the PD-diagnosis with an in-person structured clinical interview for DSM-IV ( SCID ) interview 22 participants were r and omized to either applied relaxation ( AR ) or a multimodal treatment package based on cognitive behavioral therapy ( CBT ) . Overall , the results suggest that Internet-administered self-help plus minimal therapist contact via e-mail has a significant medium to large effect ( Cohen 's d=0.71 for AR and d=0.42 for CBT ) . The results from this study generally provide evidence to support the continued use and development of Internet-distributed self-help programs The loss of a child during pregnancy can be a traumatic event associated with long-lasting grief and psychological distress . This study examined the efficacy of an internet-based cognitive behavioral therapy program for mothers after pregnancy loss . In a r and omized controlled trial with a waiting list control group , 83 participants who had lost a child during pregnancy were r and omly allocated either to 5 weeks of internet therapy or to a 5-week waiting condition . Within a manualized cognitive behavioral treatment program , participants wrote ten essays on loss-specific topics . Posttraumatic stress , grief , and general psychopathology , especially depression , were assessed pretreatment , posttreatment , and at 3-month follow-up . Intention-to-treat analyses and completer analyses were performed . Relative to controls , participants in the treatment group showed significant improvements in posttraumatic stress , grief , depression , and overall mental health , but not in anxiety or somatization . Medium to large effect sizes were observed , and the improvement was maintained at 3-month follow-up . This internet-based cognitive behavioral therapy program represents an effective treatment approach with stable effects for women after pregnancy loss . Implementation of the program can thus help to improve the health care provision for mothers in this traumatic loss situation Objective : The aim of the present study was to determine the efficacy of an Internet-based clinician-assisted computerized cognitive behavioural treatment ( CaCCBT ) programme for depression . Method : Forty-five individuals meeting diagnostic criteria for depression were r and omly assigned to the Sadness programme or to a waitlist control group . In the clinician-assisted Sadness programme , participants complete six online lessons , weekly homework assignments , receive weekly email contact from a clinical psychologist , and contribute to a moderated online discussion forum with other participants . An intention-to-treat model was used for data analyses . Results : A total of 20 ( 74 % ) treatment group participants completed all lessons within the 8 week programme , and post-treatment data were collected from 18/27 treatment group and 17/18 waitlist group participants . Treatment group participants reported significantly reduced symptoms of depression as measured by the Beck Depression Inventory – second edition and the Patient Health Question naire – Nine Item . Treatment group participants each received an average of eight email contacts ( 111 min of therapist time ] . Mean within- and between-group effect sizes ( Cohen 's d ) across the two measures of depressive symptoms were 0.98 and 0.75 , respectively . Participants found the treatment programme acceptable and satisfactory . Conclusions : These results replicate those from the pilot trial reported by Perini et al. and are consistent with literature indicating that Internet-based programmes for depression and other mental disorders combined with clinical guidance can result in clinical ly significant improvements . These data provide further support for the development of Internet-based treatment for common mental disorders After treatment for prostate cancer , multidisciplinary sexual rehabilitation involving couples appears more promising than traditional urologic treatment for erectile dysfunction ( ED ) . The authors of this report conducted a r and omized trial comparing traditional or internet‐based sexual counseling with waitlist ( WL ) control This study compared the efficacy of an Internet-based , 8-week self-help program for traumatic event-related consequences ( SHTC ) ( n = 13 ) to a wait-list ( WL ) condition ( n = 14 ) . The SHTC consisted of cognitive-behavioral modules that progressed from the least anxiety-provoking component ( i.e. , information ) to the most anxiety-provoking ( i.e. , exposure ) . Participants were those who had experienced a traumatic event and had been experiencing sub clinical levels of symptoms associated with the event . Participants mastered the material in each module before proceeding to the next module . Pre- and post-treatment assessment s revealed that SHTC participants decreased avoidance behavior , frequency of intrusive symptoms , state anxiety , and depressive symptoms , and increased coping skills and coping self-efficacy significantly more than WL participants . SHTC participants demonstrated more clinical ly significant improvement than WL individuals We r and omized , at two sites , 210 patients with Rome II diagnosed irritable bowel syndrome ( IBS ) , of at least moderate severity , to one of three conditions : group-based cognitive therapy ( CT ; n=120 ) , psychoeducational support groups ( n=46 ) as an active control , or intensive symptom and daily stress monitoring ( n=44 ) . One hundred eighty-eight participants completed the initial treatment . Those in symptom monitoring were then crossed over to CT . For an intent to treat analysis on a composite GI symptom measure derived from daily symptom diaries , both CT and the psychoeducational support groups were significantly more improved than those in the intensive symptom monitoring condition , but the CT and psychoeducational support group did not differ . Among treatment completers on the same composite measure of GI symptoms , again , both CT and psychoeducational support groups were statistically superior to symptom monitoring but did not differ on the symptom composite , or on any other measure . On individual IBS symptoms , both CT and psychoeducational support were statistically superior to symptom monitoring on reductions in abdominal pain and tenderness and for flatulence . Patient global ratings at the end of treatment showed the two active conditions statistically superior to symptom monitoring on change in Bowel Regularity , with CT superior to symptom monitoring on reduction in overall pain and in improvement in sense of well-being . Three-month follow-up data on 175 patients revealed maintenance of significant improvement or continued significant improvement on all IBS symptoms , including the McGill Pain Question naire . Group CT and psychoeducational support groups continued not to differ on any measure . We thus conclude that group CT is not superior to an attention placebo control condition OBJECTIVE To determine the efficacy of an Internet-based Arthritis Self-Management Program ( ASMP ) as a re source for arthritis patients unable or unwilling to attend small-group ASMPs , which have proven effective in changing health-related behaviors and improving health status measures . METHODS R and omized intervention participants were compared with usual care controls at 6 months and 1 year using repeated- measures analyses of variance . Patients with rheumatoid arthritis , osteoarthritis , or fibromyalgia and Internet and e-mail access ( n = 855 ) were r and omized to an intervention ( n = 433 ) or usual care control ( n = 422 ) group . Measures included 6 health status variables ( pain , fatigue , activity limitation , health distress , disability , and self-reported global health ) , 4 health behaviors ( aerobic exercise , stretching and strengthening exercise , practice of stress management , and communication with physicians ) , 5 utilization variables ( physician visits , emergency room visits , chiropractic visits , physical therapist visits , and nights in hospital ) , and self-efficacy . RESULTS At 1 year , the intervention group significantly improved in 4 of 6 health status measures and self-efficacy . No significant differences in health behaviors or health care utilization were found . CONCLUSION The Internet-based ASMP proved effective in improving health status measures at 1 year and is a viable alternative to the small-group ASMP This study evaluated the efficacy of a newly developed , home-based depression intervention for people with epilepsy . Based on mindfulness-based cognitive therapy ( MBCT ) , the eight-session , weekly intervention was design ed for group delivery via the Internet or telephone . Forty participants were r and omly assigned to intervention or waitlist . Depressive symptoms and other outcomes were measured at baseline , after intervening in the intervention group ( ~8 weeks ) , and after intervening in the waitlist group ( ~16 weeks ) . Depressive symptoms decreased significantly more in the intervention group than the waitlist group ; Internet and telephone did not differ . This effect persisted over the 8 weeks when those waitlisted received the intervention . Knowledge/skills increased significantly more in the intervention than the waitlist group . All other changes , though not significant , were in the expected direction . Findings indicate that distance delivery of group MBCT can be effective in reducing symptoms of depression in people with epilepsy . Directions for future research are proposed In this study conducted in the French-speaking part of Switzerl and , 52 individuals with social phobia were r and omly assigned either to an Internet-based cognitive-behavioral treatment with minimal contact with therapists via e-mail or to a waiting-list control group . Significant differences between the two groups were found at posttreatment on all primary outcome measures ( social anxiety measures ) and on two of the secondary outcome measures ( general symptomatology , therapy goal attainment ) . On average , within-groups effect sizes were large for the primary outcomes ( Cohen 's d=0.82 ) and for secondary outcomes ( Cohen 's d=1.04 ) . Moreover , subjects in the treatment group fulfilled the criteria of clinical ly significant improvement significantly more often than subjects in the control group on all measured dimensions ( 58 % vs. 20 % ) . Users ' acceptance of the program was high . The results from the present study lend further support to the hypothesis that Internet-delivered interventions with minimal therapist contact are a promising treatment approach to social phobia INTRODUCTION Men with erectile dysfunction are often worried about their condition , have interpersonal difficulties , and have a reduced quality of life . Internet-delivered cognitive behavior therapy ( ICBT ) has been shown effective for a number of health problems but evidence is limited concerning the treatment of erectile dysfunction . AIM The study investigated the effects of ICBT for erectile dysfunction . METHODS Seventy-eight men were included in the study and r and omized to either ICBT or to a control group , which was an online discussion group . Treatment consisted of a 7-week Web-based program with e-mail-based therapist support . Each therapist spent an average of 55 minutes per participant . MAIN OUTCOME MEASURE The International Index of Erectile Functioning five-item version was administered via the telephone at pretreatment , post-treatment , and 6 months after receiving ICBT . RESULTS At post-treatment , the treatment group had significantly greater improvements with regard to erectile performance compared with the control group . Between-group differences at post-treatment were small ( d = 0.1 ) , but increased at the 6-month follow-up ( d = 0.88 ) . CONCLUSIONS This study provides support for the use of ICBT as a possible treatment format for erectile dysfunction While cognitive-behavioral therapy for IBS is quite effective , the limited availability of competent therapists and lack of access to treatment remain problematic . This paper reports on a small , r and omized , controlled trial of a five week internet based cognitive-behavioral intervention for IBS with limited therapist feedback via e-mail . Fifty-four IBS patients were recruited via the internet and r and omly assigned to either immediate treatment or a wait-list control group . Thirty-one subjects completed the post-treatment assessment . 77 % of treatment completers also completed a 3-month follow-up assessment . Treatment completers experienced statistically and clinical ly significant declines in IBS symptoms and improvements in quality of life . Those gains were substantially maintained at follow-up . Treatment efficacy was partially mediated by reductions in the tendency to catastrophize the social and occupational implication s of symptoms , suggesting that catastrophizing may be an important target for treatment A r and omized trial was conducted comparing 10 individual weekly sessions of cognitive behaviour therapy for panic disorder ( PD ) with or without agoraphobia with a 10-module self-help program on the Internet . After confirming the PD diagnosis with an in-person structured clinical interview ( SCID ) 49 participants were r and omized . Overall , the results suggest that Internet-administered self-help plus minimal therapist contact via e-mail can be equally effective as traditional individual cognitive behaviour therapy . Composite within-group effect sizes were high in both groups , while the between-group effect size was small ( Cohen 's d=16 ) . One-year follow-up confirmed the results , with a within-group effect size of Cohen 's d=0.80 for the Internet group and d=0.93 for the live group . The results from this study generally provide evidence to support the continued use and development of Internet-distributed self-help programs UNLABELLED The Self-care Pain Management Project assessed the feasibility and efficacy of delivering online mind-body self-care techniques to 78 adults aged 55 and older with chronic pain . To assess feasibility , the study monitored use of the intervention and documented participant satisfaction . A r and omized trial with intervention ( n = 41 ) and waiting list comparison groups ( n = 37 ) was used to assess changes in pain intensity , limitations due to pain , pain self-efficacy , depression , anxiety , and awareness of responses to pain from baseline to follow-up at 6 weeks . There were statistically significant results for between-group difference in awareness of responses to pain , improvements in pain intensity and pain interference for both groups , and increases in confidence with using nonmedical self-care techniques to manage pain for the intervention group . Reductions in mean pain scores reported by the intervention group at log on and log off also suggest that the intervention may have an immediate impact on reducing pain . Findings document the feasibility of a relatively short-term , online mind-body pain management intervention that can have benefits for participants . The characteristics of those who volunteered for an online self-care pain management intervention also have implication s for identifying target population s for such interventions . PERSPECTIVE This article documents the outcomes of an Internet-based self-care pain management intervention that focused on mind-body exercises . The study suggests that the Internet can be an efficient mode for delivering self-care education to older adults with chronic pain and has potential benefits that complement clinical care Objectives Research has shown that cognitive and behavioral therapies can effectively improve quality of life in chronic pain patients . Unfortunately , many patients lack access to cognitive and behavioral therapy treatments . We developed a pilot version of an interactive online intervention to teach self-management skills for chronic lower back pain , a leading cause of disability and work absenteeism . The objective of this r and omized , controlled trial was to evaluate its efficacy . Methods Individuals with chronic lower back pain were recruited over the Internet , screened by phone , and r and omly assigned to receive access to the intervention ( Wellness Workbook ; WW ) either immediately ( intervention group ) or after a 3-week delay ( wait-list control ) . Participants ( n=141 , 83 % female , 23 % minority ) were asked to complete the WW over 3 weeks . Self-report measures of pain , disability , disabling attitudes and beliefs , self-efficacy for pain control , and mood regulation were completed at baseline , week 3 , and week 6 . Results Controlling for baseline individual differences in the outcome measures , multivariate analysis of covariance revealed that , at week 3 , the intervention group scored better than the wait-list control group on all outcomes , including pain severity ratings . At week 6 , after both groups had been exposed to the WW , there were no differences between groups . Discussion Use of this pilot intervention seems to have had positive effects on a number of pain-related outcomes , including disability . Future research will evaluate the effectiveness of the completed intervention , with particular attention to quality of life and disability BACKGROUND Internet-delivered treatment may reduce barriers to care in those unwilling or unable to access traditional forms of treatment . OBJECTIVE To assesses the efficacy of web-based therapist-assisted cognitive behavioral treatment ( web-CBT ) of panic symptoms . DESIGN A r and omized waiting-list controlled trial with an uncontrolled three-year follow-up . PARTICIPANTS A community sample of 58 participants with chronic panic symptoms of varying severity ( immediate treatment : n=27 , waiting-list control : n=31 ) . OUTCOME MEASURES The primary outcome measures were a one-week Panic Diary and the Panic Disorder Severity Scale - Self-Report ( PDSS-SR ) ; secondary measures were the Agoraphobic Cognitions Question naire ( ACQ ) , the Body Sensations Question naire ( BSQ ) , the Mobility Inventory - Alone subscale ( MI-AAL ) , and the Depression Anxiety Stress Scales ( DASS-42 ) . RESULTS In the RCT , 54 participants ( 93 % ) completed posttest measurements . With regard to the primary outcome measures , intention-to-treat ANCOVAs revealed that participants in the treatment condition improved more than the participants in the waiting-list control condition ( p<.03 ) , with a pooled between-group effect size of d=.7 . After three years ( n=47 ; 81 % study compliance ) , effects were more pronounced . CONCLUSION The results demonstrate the efficacy of therapist-assisted web-CBT in the treatment of panic symptoms OBJECTIVE There is a well-documented gap between diabetes care guidelines and the services received by patients in most health care setting s. This report presents 12-month follow-up results from a computer-assisted , patient-centered intervention to improve the level of recommended services patients received from a variety of primary care setting s. RESEARCH DESIGN AND METHODS A total of 886 patients with type 2 diabetes under the care of 52 primary care physicians participated in the Diabetes Priority Program . Physicians were stratified and r and omized to intervention or control conditions and evaluated on two primary outcomes : number of recommended laboratory screenings and recommended patient-centered care activities completed from the National Committee on Quality Assurance/American Diabetes Association Provider Recognition Program ( PRP ) . Secondary outcomes were evaluated using the Problem Areas in Diabetes 2 quality of life scale , lipid and HbA1c levels , and the Patient Health Question naire-9 depression scale . RESULTS The program was well implemented and significantly improved both the number of laboratory assays and patient-centered aspects of diabetes care patients received compared with those in the control condition . There was overall improvement on secondary outcomes of lipids , HbA1c , quality of life , and depression scores ; between-condition differences were not significant . CONCLUSIONS Staff in small , mixed-payer primary care offices can consistently implement a patient-centered intervention to improve PRP measures of quality of diabetes care . Alternative explanations for why these process improvements did not lead to improved outcomes , and suggested directions for future research are discussed Abstract The purpose of this study was to investigate the effects of an Internet‐based cognitive‐behavioral intervention with telephone support for chronic back pain . Participants who met the criteria for chronic back pain ( N=56 ) were r and omly assigned to either an Internet‐based cognitive behavioral self‐help treatment or to a waiting‐list control condition . The study period lasted 8 weeks and consisted of 1 week of self‐monitoring prior to the intervention , 6 weeks of intervention , and 1 week of post‐intervention assessment . Treatment consisted of education , cognitive skill acquisition , behavioral rehearsal , generalization and maintenance . The dropout rate was 9 % ( N=5 ) . Results showed statistically significant improvements in catastrophizing , control over pain and ability to decrease pain . Some improvement was found in both the control group and the treatment group . A follow‐up of 3 months after treatment termination was completed in 92 % ( N=47 ) of the participants who completed the treatment intervention . Follow‐up results showed that some improvement was maintained . Findings indicate that Internet‐based self‐help with telephone support , based on established psychological treatment methods , holds promise as an effective approach for treating disability in association with pain Objective : To determine the efficacy of an Internet-based clinician-assisted cognitive behavioural treatment program ( the Panic program ) for panic disorder ( with or without agoraphobia ) . Method : Fifty-nine individuals meeting diagnostic criteria for panic disorder with agoraphobia were r and omly assigned to a treatment group or to a waitlist control group . Treatment group participants completed the Panic program , comprising six on-line lessons , weekly homework assignments , received weekly email contact from a psychiatry registrar , and contributed to a moderated online discussion forum with other participants . An intention-to-treat model was used for data analyses . Results : Twenty-three ( 79 % ) of treatment group participants completed all lessons within the 8-week program , and post-treatment data were collected from 22/29 treatment group and 22/25 waitlist group participants . Compared to the control group , treatment group participants reported significantly reduced symptoms of panic as measured by the Panic Disorder Severity Scale , Body Sensation Question naire , and Agoraphobic Cognitions Question naires . Significant reductions were also reported on measures of disability and depression . The mean within- and between-group effect size ( Cohen 's d ) on the Panic Disorder Severity Scale was 0.93 and 0.59 , respectively , and effects were sustained at 1-month follow-up . Mean therapist time per participant was 75 minutes for the program . Conclusions : These results replicate those from the open trial of the Panic Program indicating the efficacy of the Internet-based clinician-assisted cognitive behavioural treatment program for panic disorder with agoraphobia The present study investigates the efficacy of an Internet-based cognitive-behavioral therapy program for bereaved people suffering complicated grief . The program combines established methods of psychotherapy with new technology– therapists and patients communicated exclusively by e-mail . Bereaved individuals diagnosed with complicated grief ( n = 55 ) were r and omly assigned to either the treatment group or a waiting list control condition . The 5-week intervention consisted of three modules : ( 1 ) exposure to bereavement cues ; ( 2 ) cognitive re appraisal ; and ( 3 ) integration and restoration . The Impact of Event Scale ( IES ) , a failure to adapt scale , and the depression and anxiety subscales of the Brief Symptom Inventory ( BSI ) were used to assess treatment outcomes . Participants in the treatment group ( n = 26 ) improved significantly relative to participants in the waiting condition on symptoms of intrusion , avoidance , maladaptive behavior , and general psychopathology , and showed a large treatment effect . Follow-up results show that this improvement was maintained after 3 months Infertility has been associated with stigma and negative psychosocial functioning . However , only a small proportion of this population actually receives care . Fertility patients predominantly use the Internet for information gathering , social support , and assistance with decision-making ; yet , available web re sources are unreliable sources of mental health care . Web-based alternatives also have the potential to assist with intervention access difficulties and may be of significant lower cost . This study evaluated the efficacy of a web-based approach to providing a cognitive behavioral intervention with 31 infertile women seeking medical reproductive technologies . Following r and omized assignment , participants using the web-based intervention were compared with those in a wait-list control condition on general and infertility-related psychological stress measures . Results were mixed regarding intervention efficacy . Significant declines in general stress were evidence d in the experimental group compared with a wait-list control group . However , website access did not result in statistically significant improvements on a measure of infertility-specific stress . These findings add to the literature on psychological interventions for women experiencing fertility problems . Moreover , despite the widespread use of the Internet by this population , the present study is one of the first to investigate the usefulness of the Internet to attenuate stress in this population . Preliminary results suggest general stress may be significantly reduced in infertile women using an online cognitive behavioral approach Sixty-four individuals with social phobia ( social anxiety disorder ) were assigned to a multimodal cognitive-behavioral treatment package or to a waiting list control group . Treatment consisted of a 9-week , Internet-delivered , self-help program that was combined with 2 group exposure sessions in real life and minimal therapist contact via e-mail . Results were analyzed on an intention-to-treat basis , including all r and omized participants . From pre- to posttest , treated participants in contrast to controls showed significant improvement on most measured dimensions ( social anxiety scales , general anxiety and depression levels , quality of life ) . The overall within- and between-groups effect sizes were Cohen 's d = 0.87 and 0.70 , respectively . Treatment gains were maintained at 1-year follow-up . The results from this study support the continued use and development of Internet-distributed , self-help programs for people diagnosed with social phobia The Internet can reach a large number of people at a low cost and offers the opportunity for 2-way communication . The present study was design ed to evaluate the effects of applied relaxation and problem solving in the treatment of recurrent headache when implemented via the Internet and E-mail . A group of 102 headache sufferers were r and omized to 2 conditions : a 6-week treatment condition or a waiting-list control . The dropout was proportionately large ( 56 % ) , and at the end of the study there were 20 participants in the treatment condition and 25 participants in the control condition . Results showed statistically significant reductions in headache for the treated participants . In 50 % of these , the reduction was clinical ly significant . The Internet has the potential to serve as a complement in the treatment of recurrent headache and deserves further study The aim of this study was to assess the effects of a 7‐week st and ardized cognitive behavioural treatment of work‐related stress conducted via e‐mail . A total of 342 people applied for treatment in reaction to a newspaper article . Initial screening reduced the sample to a heterogeneous ( sub ) clinical group of 239 participants . Participants were assigned r and omly to a waiting list condition ( n = 62 ) , or to immediate treatment ( n = 177 ) . A follow‐up was conducted 3 years after inception of the treatment . The outcome measures used were the Depression Anxiety Stress Scales ( DASS‐42 ) and the Emotional Exhaustion scale of the Maslach Burnout Inventory – General Survey ( MBI‐GS ) . Fifty participants ( 21 % ) dropped out . Both groups showed statistically significant improvements . Intention‐to‐treat analysis of covariance ( ANCOVAs ) revealed that participants in the treatment condition improved significantly more than those in the waiting control condition ( 0.001<p⩽0.025 ) . In the treatment group , the effects were large to moderate ( 0.9 (stress)⩾d⩾0.5 ( anxiety ) ) . The between‐group effects ranged from d = 0.6 ( stress ) to d = 0.1 ( anxiety ) . At follow‐up , the effects were more pronounced , but this result requires replication in view of high attrition at follow‐up . The results warrant further research on Internet‐driven st and ardized cognitive behavioural therapy for work‐related stress . Such research should include the direct comparison of this treatment with face‐to‐face treatment , and should address the optimal level of therapist contact in Internet‐driven treatment BACKGROUND Bulimic eating disorders are common among female students , yet the majority do not access effective treatment . Internet-based cognitive-behavioural therapy ( iCBT ) may be able to bridge this gap . METHOD Seventy-six students with bulimia nervosa ( BN ) or eating disorder not otherwise specified ( EDNOS ) were r and omly assigned to immediate iCBT with e-mail support over 3 months or to a 3-month waiting list followed by iCBT [ waiting list/delayed treatment control ( WL/DTC ) ] . ED outcomes were assessed with the Eating Disorder Examination ( EDE ) at baseline , 3 months and 6 months . Other outcomes included depression , anxiety and quality of life . RESULTS Students who had immediate iCBT showed significantly greater improvements at 3 and 6 months than those receiving WL/DTC in ED and other symptoms . CONCLUSIONS iCBT with e-mail support is efficacious in students with bulimic disorders and has lasting effects This study examined whether an online problem-solving intervention could improve parental adjustment following pediatric traumatic brain injury ( TBI ) . Families of children with moderate-to-severe TBI were recruited from the trauma registry of a large children 's hospital and r and omly assigned to receive online family problem solving therapy ( FPS ; n = 20 ) or Internet re sources ( IRC ; n = 20 ) in addition to usual care . The FPS group reported significantly less global distress , depressive symptoms , and anxiety at follow-up than did the IRC group after controlling for baseline symptoms . The FPS group also reported significant improvements in problem-solving skills , although the groups did not differ significantly at follow-up . Findings suggest that an online , skill-building approach can be effective in facilitating parental adaptation after TBI Chronic headache is a significant public health problem in Western nations . Although controlled trials demonstrate the efficacy and cost-effectiveness of face-to-face behavioral therapy , most headache sufferers have limited access to these treatments . Delivery of behavioral interventions using Internet technology has the potential to reach a larger number of headache sufferers and reduce the burden of disease . This r and omized controlled study evaluated an Internet-delivered behavioral regimen composed of progressive relaxation , limited biofeedback with autogenic training , and stress management versus a symptom monitoring waitlist control . Treatment led to a significantly greater decrease in headache activity than symptom monitoring alone . Thirty-nine percent of treated individuals showed clinical ly significant improvement on self-report measures of headache symptoms at post-treatment . At two-month follow-up , 47 % of participants maintained improvement . Treatment had a significant impact on general headache symptoms and headache-related disability . There was a 35 % within-group reduction of medication usage among the treated subjects . The Internet program was more time-efficient than traditional clinical treatment . Treatment and follow-up dropout rates , 38.1 % and 64.8 % , respectively , were typical of behavioral self-help studies . This approach to self-management of headache is promising ; however , several method ological and ethical challenges need to be addressed This study aim ed to evaluate the efficacy and patient acceptance of the first German- language Internet-based treatment for infertile patients . Infertile patients ( N = 124 ) were r and omly assigned to either an 8-week Internet-based cognitive-behavioral treatment , or to a waiting-list control group . Participants were assessed at treatment start , post-treatment , and at a 5-month follow-up . Outcome measures included mental health and pregnancy rate . From pre- to posttest , treated participants in contrast to controls did not show significant improvement , although between-group effect sizes were in favor of the intervention group on all mental health measures ( Cohen ’s d ranged from 0.16 to 0.38 ) . The intervention significantly reduced the depression level of clinical ly distressed and depressed participants . No effects were found regarding pregnancy rate . The treatment was assessed as positive or very positive by 80 % of the participants ; this finding coupled with the high dem and for such support confirm that Internet-based interventions are a promising new approach for infertile patients that needs more development and testing Objective : To compare the effectiveness of Internet cognitive behaviour therapy ( CBT ) with face-to-face CBT in social phobia . Methods : R and omized controlled trial of 75 patients with social phobia referred to an anxiety disorders clinic . A total of 37 patients participated , and post-treatment data was obtained from 25 Subjects ( Ss ) . An intention to treat analysis was used . The same therapist ( M.D. ) treated both groups . Results : Both groups made significant progress on symptoms and disability measures . There were no significant differences in outcome between the Internet and face-to-face groups . The total amount of therapist time required was 18 min per patient for the Internet group and 240 min per patient for the face-to-face group . Conclusions : Both forms of treatment were equally effective and this is consistent with previous findings in depression and panic disorder . The difference in clinician time required was substantial . If Internet CBT was offered as ‘ st and ard of care ’ the staff time saved would permit a stepped care model in which in-depth therapy for the difficult to recover patients could be provided without an increase in staff Social anxiety disorder ( SAD ) is highly prevalent and associated with a substantial societal economic burden , primarily due to high costs of productivity loss . Cognitive behavior group therapy ( CBGT ) is an effective treatment for SAD and the most established in clinical practice . Internet-based cognitive behavior therapy ( ICBT ) has demonstrated efficacy in several trials in recent years . No study has however investigated the cost-effectiveness of ICBT compared to CBGT from a societal perspective , i.e. an analysis where both direct and indirect costs are included . The aim of the present study was to investigate the cost-effectiveness of ICBT compared to CBGT from a societal perspective using a prospect i ve design . We conducted a r and omized controlled trial where participants with SAD were r and omized to ICBT ( n=64 ) or CBGT ( n=62 ) . Economic data were assessed at pre-treatment , immediately following treatment and six months after treatment . Results showed that the gross total costs were significantly reduced at six-month follow-up , compared to pre-treatment in both treatment conditions . As both treatments were equivalent in reducing social anxiety and gross total costs , ICBT was more cost-effective due to lower intervention costs . We conclude that ICBT can be more cost-effective than CBGT in the treatment of SAD and that both treatments reduce societal costs for SAD Increased access to therapy for body dissatisfaction and disordered eating is required . This pilot study compared a group intervention delivered face-to-face or synchronously over the Internet . Women with body dissatisfaction and disordered eating were r and omly assigned to a face-to-face ( N = 19 ) or Internet ( N = 21 ) group . Body dissatisfaction , disordered eating , and psychological variables were assessed at baseline , post-intervention , and two months follow-up . Significant improvements on all outcome variables were observed and maintained at follow-up in both groups . There were no significant differences between delivery modes . This program shows promise , and the Internet mode of delivery has potential to overcome geographical distance BACKGROUND Hypochondriasis , characterised by severe health anxiety , is a common condition associated with functional disability . Cognitive-behavioural therapy ( CBT ) is an effective but not widely disseminated treatment for hypochondriasis . Internet-based CBT , including guidance in the form of minimal therapist contact via email , could be a more accessible treatment , but no study has investigated internet-based CBT for hypochondriasis . AIMS To investigate the efficacy of internet-based CBT for hypochondriasis . METHOD A r and omised controlled superiority trial with masked assessment comparing internet-based CBT ( n = 40 ) over 12 weeks with an attention control condition ( n = 41 ) for people with hypochondriasis . The primary outcome measure was the Health Anxiety Inventory . This trial is registrated with Clinical Trials.gov ( NCT00828152 ) . RESULTS Participants receiving internet-based CBT made large and superior improvements compared with the control group on measures of health anxiety ( between-group Cohen 's d range 1.52 - 1.62 ) . CONCLUSIONS Internet-based CBT is an efficacious treatment for hypochondriasis that has the potential to increase accessibility and availability of CBT for hypochodriasis Disorder-specific cognitive behavioural therapy programs delivered over the internet ( iCBT ) with clinician guidance are effective at treating specific anxiety disorders and depression . The present study examined the efficacy of a transdiagnostic iCBT protocol to treat three anxiety disorders and /or depression within the same program ( the Wellbeing Program ) . Seventy-seven individuals with a principal diagnosis of major depression , generalised anxiety disorder , panic disorder , and /or social phobia were r and omly assigned to a Treatment or Waitlist Control group . Treatment consisted of CBT-based online educational lessons and homework assignments , weekly email or telephone contact from a clinical psychologist , access to a moderated online discussion forum , and automated emails . Eighty one percent of Treatment group participants completed all 8 lessons within the 10 week program . Post-treatment data were collected from 34/37 Treatment group and 35/37 Control group participants , and 3-month follow-up data were collected from 32/37 Treatment group participants . Relative to Controls , Treatment group participants reported significantly reduced symptoms of anxiety and depression as measured by the Depression Anxiety and Stress Scales-21 item , Patient Health Question naire-9 item , and Generalised Anxiety Disorder-7 item scales , with corresponding between-groups effect sizes ( Cohen 's d ) at post treatment of.56,.58 , and .52 , respectively . The clinician spent a mean time of 84.76 min ( SD=50.37 ) per person over the program . Participants rated the procedure as highly acceptable , and gains were sustained at follow-up . These results provide preliminary support for the efficacy of transdiagnostic iCBT in the treatment of anxiety and depressive disorders OBJECTIVE The aim of this study was to compare the outcomes following an eight-session , small group , therapist-led , intervention for body dissatisfaction , and disordered eating in adult women , delivered either in face-to-face or synchronous , internet mode . METHOD Community women with high body dissatisfaction and internet access were r and omly assigned to either face-to-face delivery ( N = 42 ) , internet delivery ( N = 37 ) , or delayed treatment control ( N = 37 ) . All groups were assessed at baseline and 8 - 9 weeks later . The intervention groups were reassessed at 6-months follow-up . RESULTS Both intervention groups showed large improvements in body dissatisfaction compared with the delayed treatment control and these improvements were maintained at follow-up . However , posttreatment improvements were greater in the face-to-face than internet intervention . CONCLUSION In adult women , it is desirable to deliver the body image intervention in a face-to-face mode , but the internet mode is effective and has the potential to increase access to therapy Forty-five participants who refused to fly during a screening test and who also met Diagnostic and Statistical Manual of Mental Disorders criteria for specific phobia , agoraphobia , or panic disorder with agoraphobia were r and omly assigned to 5 sessions of either virtual reality exposure ( VRE ) or attention-placebo group treatment ( GT ) . At posttreatment , 65 % of VRE participants and 57 % of GT participants flew during a test flight . Both groups showed significant improvement following treatment on st and ardized self-report measures of flight anxiety , with a better outcome for the VRE group on 4 of 5 of these measures . At 6-month follow-up , however , most group differences had disappeared ; VRE result ed in a better outcome on only 1 of 5 st and ardized flight anxiety measures This study investigates utilization of the Internet in the rehabilitation of people on long-term sick leave with chronic pain and /or burnout . Fifty-five people were r and omly assigned to two groups : a treatment group ( n=27 ) that participated in a rehabilitation course over the Internet and a waiting list group ( n=28 ) . The goals were to improve participants ' health and increase quality of life , and , for those who were not on permanent disability pensions , to increase work capacity , if possible . A 20-week program , based on 19 films on different themes , was supplemented with written material and a Socratic dialogue over the Internet . Upon completion of the rehabilitation course , statistically significant improvements were observed in the treatment group in comparison to the waiting list group , for variables such as depression , pain , vitality , social function , performance problems involving work or other activities due to physical illness and the presence of stress symptoms . Thirteen of 23 individuals ( 57 % ) also increased their work capacity . The number needed to treat regarding recovering from anxiety and depression was 2 . For increased work capacity , the number needed to treat was 3 . Rehabilitation of people on long-term sick leave carried out over the Internet is a good complement to other rehabilitation programs . Die vorliegende Studie befasst sich mit der Nutzung des Internets bei der Rehabilitation von Langzeitkranken mit chronischen Schmerzen und/oder Burnout-Syndrom . Zwei Gruppen wurden insgesamt 55 Studienteilnehmer r and omisiert zugeordnet , d. h. einer Therapiegruppe ( n=27 ) , die an einem Internet-basierten Reha-Kurs teilnahm , und einer Wartelistengruppe ( n=28 ) . Die Ziele waren die gesundheitliche Verbesserung der Teilnehmer und die Steigerung der Lebensqualität und – für diejenigen , die nicht permanent eine Erwerbsunfähigkeitsrente bezogen – nach Möglichkeit eine Steigerung der Arbeitsleistung . Ein 20-Wochen-Programm auf der Grundlage von 19 Filmen zu unterschiedlichen Themen wurde durch schriftliches Material und einen sokratischen Dialog per Internet ergänzt . Nach Beendigung des Reha-Kurses wurden in der Therapiegruppe verglichen mit der Wartelistengruppe statistisch signifikante Verbesserungen bei Variablen wie Depression , Schmerzen , Lebenskraft , gesellschaftliche Funktion , Leistungsprobleme bei der Arbeit oder and eren Aktivitäten infolge von körperlicher Krankheit und das Vorh and ensein von Stresssymptomen beobachtet . Dreizehn von 23 Teilnehmern ( 57 % ) steigerten zudem ihre Arbeitsleistung . Wegen der Rekonvaleszenz von Angstgefühlen und Depression mussten insgesamt zwei Teilnehmer beh and elt werden , bei der Steigerung der Arbeitsleistung lag die Zahl bei drei . Mit einer Internet-basierten Rehabilitation von Langzeitkranken lassen sich and ere Reha-Programme gut ergänzen . Este estudio investiga la utilización de Internet en la rehabilitación de individuos con ausencia prolongada al trabajo por enfermedad , por padecer dolor crónico o el síndrome del desgaste profesional , o ambos . Se distribuyeron a 55 individuos al azar en dos grupos : un grupo de tratamiento ( n=27 ) , quienes participaron en un curso de rehabilitación impartido mediante Internet , y un grupo en lista de espera ( n=28 ) . Los objetivos fueron mejorar la salud y calidad de vida de los participantes y , para aquellos que no estaban percibiendo pensión de invalidez permanente , aumentar la capacidad de trabajo , de ser posible . Se aplicó un programa de 20 semanas , por Internet , en el que se emplearon 19 películas sobre diferentes temas , complementadas con material es escritos y un diálogo socrático . Al terminar el curso de rehabilitación se hallaron mejorías estadísticamente significativas en el grupo sometido a tratamiento , a diferencia del grupo en la lista de espera , en relación con variables tales como la depresión , el dolor , la vitalidad , la función social , problemas de rendimiento en el trabajo o al realizar otras actividades debido a la presencia de enfermedades orgánicas , y la presencia de síntomas de estrés . Trece de los 23 individuos ( 57 % ) mejoraron su capacidad de trabajo . De estas personas , 2 recibieron el tratamiento como alivio a la ansiedad y depresión que padecían ; y 3 para mejorar su capacidad de trabajo . La rehabilitación de individuos con ausencia prolongada al trabajo por enfermedad , mediante Internet , es un buen complemento al resto de los programas de rehabilitación empleados . Cette étude s'intéresse à l'utilisation de l'Internet pour la rééducation des individus en congé maladie de longue durée souffrant de douleurs chroniques et/ou d'épuisement . Cinquante-cinq personnes ont été réparties de manière aléatoire dans deux groupes ; un groupe de traitement ( n=27 ) , qui a participé au stage de rééducation sur Internet , et un groupe sur liste d'attente ( n=28 ) . Les objectifs étaient d'améliorer la santé et la qualité de vie des participants et , pour les individus ne bénéficiant pas de pensions d'invalidité permanentes , d'accroître la capacité de travail dans la mesure du possible . Un programme sur 20 semaines , reposant sur 19 films consacrés à des thèmes différents , a été complété par des matériaux écrits et un dialogue socratique via l'Internet . À la fin du stage de rééducation , des améliorations statistiquement significatives ont été observées chez le groupe de traitement par rapport au groupe sur liste d'attente , notamment pour les variables comme la dépression , la douleur , la vitalité , la fonction sociale , les problèmes de performances dus à la maladie physique et impliquant le travail ou d'autres activités , et la présence de symptômes de stress . Treize des 23 participants ( 57 % ) ont également augmenté leur capacité de travail . Le nombre d'individus à traiter pour des problèmes d'anxiété et de dépression était de 2 . Pour l'augmentation de la capacité de travail , le nombre à traiter était de 3 . La rééducation des individus en congé maladie de longue durée via l'Internet constitue un bon complément aux autres programmes de rééducation OBJECTIVE To study the contribution of therapist-initiated telephone contact in the treatment of recurrent headache via the Internet . BACKGROUND Internet-based cognitive behavioral self-help is a promising new venue for the treatment of recurrent headache . While cost-effective , there are indications that this modality may be associated with high dropout rates . DESIGN AND METHODS The role of therapist-initiated contact was investigated in a r and omized controlled trial in which 44 self-recruited headache sufferers were r and omized to either a Web-based self-help program with e-mail support or to a group receiving , in addition , weekly individual telephone calls . An additional 8 control subjects were recruited to receive similar treatment outside of the study . RESULTS Dropout rates were 29 % in the telephone support group and 35 % in the control group , suggesting that the telephone calls did not affect dropout . Results showed significant reductions in headache-related disability , depression , maladaptive coping strategies , and perceived stress but little to indicate any superior performance in the Internet-only group and little improvement in the headache index . In short , therapist-initiated telephone calls did not influence the results . CONCLUSIONS Internet-based treatment for headache is not affected by minimal therapist-initiated telephone contact Background : Adapting to living with chronic conditions is a life-long psychosocial challenge . Objective : The purpose of this study was to report the effect of a computer intervention on the psychosocial adaptation of rural women with chronic conditions . Methods : A two-group study design was used with 309 middle-aged , rural women who had chronic conditions , r and omized into either a computer-based intervention or a control group . Data were collected at baseline , at the end of the intervention , and 6 months later on the psychosocial indicators of social support , self-esteem , acceptance of illness , stress , depression , and loneliness . Results : The impact of the computer-based intervention was statistically significant for five of six of the psychosocial outcomes measured , with a modest impact on social support . The largest benefits were seen in depression , stress , and acceptance . Discussion : The women-to-women intervention result ed in positive psychosocial responses that have the potential to contribute to successful management of illness and adaptation . Other components of adaptation to be examined are the impact of the intervention on illness management and quality of life and the interrelationships among environmental stimuli , psychosocial response , and illness management Objective : The purpose of the present study was to examine the effectiveness of an Internet-based clinician-assisted computerized cognitive behavioural therapy programme for social phobia . Method : A total of 105 individuals with social phobia were r and omly assigned to a six-lesson cognitive behavioural treatment programme or to a waitlist control group . Treatment consisted of four components : six online lessons ; homework assignments ; participation in an online discussion forum ; and regular email contact with a therapist . An intention-to-treat model was used for data analyses . Results : A total of 78 % of treatment group participants completed all lessons , and post-treatment data were obtained from 93/105 participants . Significant post-treatment differences between treatment and waitlist participants were found on two measures of symptoms of social phobia . Mean within- and between-group effect sizes ( Cohen 's d ) for the primary social phobia outcome measures were 1.15 , and 0.95 , respectively . Conclusions : These results were comparable with those obtained in exemplary face-to-face treatment programmes . They provide further positive data about the utility of Internet-based guided self-help programmes for people with common mental disorders Objective : In a r and omized controlled trial Titov et al. ( 2008 ) demonstrated significant benefit from an Internet- and email-based treatment programme for social phobia . The present study ( Shyness 2 ) seeks to replicate that finding and compares results with benchmark data . Method : Eighty-eight individuals with social phobia were r and omly assigned to a clinician-assisted computerized cognitive behavioural treatment programme or to a waitlist control group . Participants completed the same treatment programme used in Shyness 1 , consisting of six online lessons , cognitive behavioural homework assignments , email contact with a therapist , and participation in an online discussion forum . An intention-to-treat model was used for data analyses . Results : A total of 80 % of treatment group participants completed all lessons , and post-treatment data were obtained from 78/81 participants . Treatment group participants each had an average of 127 min of therapist contact over the 10 week programme , including an average of 22 email contacts plus therapist responses to forum postings . Pre- to post-treatment differences were seen between treatment and waitlist participants across two measures of symptoms of social phobia , and across a measure of disability . Mean within- and between-group effect sizes ( Cohen 's d ) across the two primary outcome measures were 1.18 , and 1.20 , respectively . Quantitative and qualitative data indicate that the procedure is very acceptable to participants . Conclusions : These results closely replicate those obtained in Shyness 1 , indicating that the treatment procedure is reliable . These results compare favourably with outcomes reported in benchmarking studies from high- quality face-to-face treatment programmes for social phobia . These results provide further positive data about the utility of Internet-based guided self-help programmes for people with social phobia BACKGROUND This study investigated the efficacy of an Internet-based self-help program with minimal therapist contact via e-mail for Swedish university students with social phobia and public speaking fears . The main objective was to test if the Internet-based self-help program would be more effective if five live group exposure sessions were added . METHODS Thirty-eight students meeting the diagnostic and statistical manual of mental disorders , 4th edition criteria for social phobia were r and omized into two different treatment groups : Internet delivered cognitive behavior therapy combined with five group exposure sessions ( ICBT+ exp ) or the Internet program alone ( ICBT ) . RESULTS Results were analyzed on an intention-to-treat basis . Both treatment groups showed significant improvement from pre- to post-test , and from pre-test to 1-year follow-up , on all measured dimensions ( social anxiety , general anxiety , depression levels , and quality of life ) . For both the groups , the average within-group effect sizes for the primary social anxiety scales , expressed as Cohen 's d , were comparable to those seen in traditionally administered cognitive behavioral therapy both at post-test and at 1- year follow-up . CONCLUSIONS The results suggest that the Internet-based self-help program on its own is efficient in the treatment of university students with social phobia . Adding group exposure sessions did not improve the outcome significantly Depression is common but undertreated . Web-based self-help provides a widely accessible treatment alternative for mild to moderate depression . However , the lack of therapist guidance may limit its efficacy . The authors assess the efficacy of therapist-guided web-based cognitive behavioural treatment ( web-CBT ) of mild to moderate depression . Fifty-four individuals with chronic , moderate depression participated in a r and omized wait-list controlled trial , with an 18-month follow-up ( immediate treatment : n = 36 , wait-list control : n = 18 ) . Primary outcome measures were the Beck Depression Inventory ( BDI-IA ) and the Depression scale of the Symptom Checklist-90-Revised ( SCL-90-R. DEP ) . Secondary outcome measures were the Depression Anxiety Stress Scales and the Well-Being Question naire . Five participants ( 9 % ) dropped out . Intention-to-treat analyses of covariance revealed that participants in the treatment condition improved significantly more than those in the wait-list control condition ( .011 < p < .015 ) . With regard to the primary measures , between-group effects ( d ) were 0.7 for the BDI-IA and 1.1 for the SCL-90-R DEP . Posttest SCL-90- R DEP scores indicated recovery of 49 % of the participants in the treatment group compared with 6 % in the control group ( odds ratio = 14.5 ; p < .004 ) . On average , the effects were stable up to 18 months ( n = 39 ) , although medication was a strong predictor of relapse . The results demonstrate the efficacy of web-CBT for mild to moderate depression and the importance of therapist guidance in psychological interventions In the last decade , several programs for the treatment of cannabis-related disorders were developed . Until now , no information is available on the efficacy of Internet-based counseling approaches for this target group . This article describes the evaluation of " quit the shit , " a web-based intervention developed to help young people to quit or reduce their cannabis use significantly . Cannabis users seeking web-based treatment were included in a two-arm controlled trial conducted on a website for drug-related information and prevention . After the baseline assessment , members of the treatment condition were r and omized to a 50-day intervention program . Other trial participants were put on a waiting list . A post-test was conducted 3 months after r and omization . Of all 1,292 subjects included in the trial , a total of 206 participants took part at the post-test . Per- protocol - and intention-to-treat analyses were conducted . Members of the treatment condition showed a significantly stronger reduction in cannabis use ( primary outcome ) than the control group . In the per- protocol analyses , moderate-to-strong effects were found for the reduction of the frequency and the reduction of the quantity of consumed cannabis . Small-to-moderate effects were observed on the secondary outcomes ( use-related self-efficacy , anxiety , depression , and life satisfaction ) . Despite limitations concerning the interpretation of the results , the intervention seems to offer an effective treatment option for persons with cannabis-related problems Background Internet programs for smoking cessation are widely available but few controlled studies demonstrate long-term efficacy . Purpose To determine the 13-month effectiveness of an Internet program presenting a set sequence of interactive steps , and the role of depressed affect . Methods In a r and omized controlled trial sponsored by the American Cancer Society , a treatment condition ( n = 1,106 ) was compared to a control site ( n = 1,047 ) . Results More treatment condition participants were abstinent ( 30-day point prevalence ) than control site participants ( 12.9 % vs. 10.1 % , p < .05 ) at 13 months . This effect was greater among participants not reporting depressed affect ( 15.0 % vs. 10.1 % , p < .01 ) . Among smokers who reported depressed affect , there was no difference in abstinence between the treatment and control conditions . Conclusions Data support the long-term efficacy of an Internet intervention for cessation modeled on a structured , in-person treatment approach , especially for participants not experiencing daily depressed affect

Taken together , these results suggested that CDA and ACDF are efficient and safe methods for dealing with cervical spondylosis . However , with respect to certain specific indicators , such as the reoperation rate of adjacent levels following surgery , the former has several advantages

Anterior cervical discectomy and fusion ( ACDF ) and cervical disc arthroplasty ( CDA ) are the most commonly used procedures in cervical spondylosis . However , only a few published studies exist in the literature comparing these two operation types , particularly its mid-term efficacy and safety . Furthermore , in those studies , even large sample trials , when compared , have elicited controversial results , making it inconvenient for clinicians to refer to them . The aim of the present study was to clarify the advantages and shortcomings of the two procedures .

Cervical artificial disc replacement ( ADR ) is indicated for the treatment of severe radiculopathy permitting neural decompression and maintenance of motion . We evaluated the clinical and radiographic outcomes in cervical ADR patients using the ProDisc-C device ( DePuy Synthes , West Chester , PA , USA ) with a 5 - 9 year follow-up . Data were collected through a prospect i ve registry , with retrospective analysis performed on 24 consecutive patients treated with cervical ADR by a single surgeon . All patients underwent single- or two-level ADR with the ProDisc-C device . Outcome measures included neck and arm pain ( visual analogue scale ) , disability ( neck disability index [ NDI ] ) , complications and secondary surgery rates . Flexion-extension cervical radiographs were performed to assess range of motion ( ROM ) of the device and adjacent segment disease ( ASD ) . Average follow-up was 7.7 years . Neck and arm pain improved 60 % and 79 % , respectively , and NDI had an improvement of 58 % . There were no episodes of device migration or subsidence . Mean ROM of the device was 6.4 ° . Heterotopic ossification was present in seven patients ( 37 % ) . Radiographic ASD below the device developed in four patients ( 21 % ) ( one single-level and three two-level ADR ) . No patient required secondary surgery ( repeat operations at the index level or adjacent levels ) . Fourteen out of 19 patients ( 74 % ) were able to return to employment , with a median return to work time of 1.3 months . The ProDisc-C device for cervical ADR is a safe option for patients providing excellent clinical outcomes , satisfactory return to work rates and maintenance of segmental motion despite radiographic evidence of heterotopic ossification and ASD on long-term follow-up Background Neck pain caused by cervical spondylosis has become a common health problem worldwide among > 40-year-old adults . Acupuncture intervention is one of the most popular treatment measures for this disorder . However , evidence for its efficacy in relieving neck pain and recovering neck physiological function has not been established in r and omized , placebo-controlled trials . The primary aim of this trial is to assess the efficacy and safety of active acupuncture compared with sham acupuncture intervention for neck pain caused by cervical spondylosis . Methods / Design We will conduct a r and omized , double-blind , parallel-group , placebo-controlled trial comparing active acupuncture with placebo ( sham acupuncture ) . A total of 456 patients with neck pain caused by cervical spondylosis who meet the eligibility criteria from outpatient clinics of the Second People ’s Hospital of Fujian Province and the Affiliated Rehabilitation Hospital , Fujian University of Traditional Chinese Medicine will be recruited and r and omized into an active acupuncture or sham acupuncture group . The participants will undergo treatment sessions with either active or sham acupuncture intervention five times a week for 2 weeks . Evaluation by blinded assessors at baseline and at intervention for 1 and 2 weeks will include demographic characteristics , vali date d question naires ( Northwick Park Neck Pain Question naire ( NPQ ) scale , Short-Form 36 ( SF-36 ) scale , and McGill pain scale ) , examination of neck physiological function , and adverse events . All included patients will be followed up and investigated for relapse of neck pain at 4 , 8 , and 12 weeks after intervention . Discussion This paper describes the rationale and design of a r and omized double-blind , placebo-controlled trial that aims to determine the efficacy and safety of acupuncture intervention for neck pain caused by cervical spondylosis . The primary outcomes are changes in the NPQ score and neck physiological function . Secondary outcome measures include quality of life , adverse events , and relapse of neck pain . If successful , this project will provide evidence of the efficacy and safety of acupuncture for neck pain caused by cervical spondylosis . Trial registration Chinese Clinical Trial Registry : ChiCTR-TRC-12002206 . Registration date : 11 May 2012 BACKGROUND CONTEXT Cervical total disc replacement ( TDR ) is intended to address radicular pain and preserve functional motion between two vertebral bodies in patients with symptomatic cervical disc disease ( SCDD ) . PURPOSE The purpose of this trial is to compare the safety and efficacy of cervical TDR , ProDisc-C ( Synthes Spine Company , L.P. , West Chester , PA ) , to anterior cervical discectomy and fusion ( ACDF ) surgery for the treatment of one-level SCDD between C3 and C7 . STUDY DESIGN / SETTING The study was conducted at 13 sites . A noninferiority design with a 1:1 r and omization was used . PATIENT SAMPLE Two hundred nine patients were r and omized and treated ( 106 ACDF ; 103 ProDisc-C ) . OUTCOME MEASURES Visual analog scale ( VAS ) pain and intensity ( neck and arm ) , VAS satisfaction , neck disability index ( NDI ) , neurological exam , device success , adverse event occurrence , and short form-36 ( SF-36 ) st and ardized question naires . METHODS A prospect i ve , r and omized , controlled clinical trial was performed . Patients were enrolled and treated in accordance with the US Food and Drug Administration ( FDA ) -approved protocol . Patients were assessed pre- and postoperatively at six weeks , 3 , 6 , 12 , 18 , and 24 months . RESULTS Demographics were similar between the two patient groups ( ProDisc-C : 42.1+/-8.4 years , 44.7 % males ; Fusion : 43.5 + /- 7.1 years , 46.2 % males ) . The most commonly treated level was C5-C6 ( ProDisc-C : 56.3 % ; Fusion=57.5 % ) . NDI and SF-36 scores were significantly less compared with presurgery scores at all follow-up visits for both the treatment groups ( p<.0001 ) . VAS neck pain intensity and frequency as well as VAS arm pain intensity and frequency were statistically lower at all follow-up timepoints compared with preoperative levels ( p<.0001 ) but were not different between treatments . Neurologic success ( improvement or maintenance ) was achieved at 24 months in 90.9 % of ProDisc-C and 88.0 % of Fusion patients ( p=.638 ) . Results show that at 24 months postoperatively , 84.4 % of ProDisc-C patients achieved a more than or equal to 4 degrees of motion or maintained motion relative to preoperative baseline at the operated level . There was a statistically significant difference in the number of secondary surgeries with 8.5 % of Fusion patients needing a re-operation , revision , or supplemental fixation within the 24 month postoperative period compared with 1.8 % of ProDisc-C patients ( p=.033 ) . At 24 months , there was a statistically significant difference in medication usage with 89.9 % of ProDisc-C patients not on strong narcotics or muscle relaxants , compared with 81.5 % of Fusion patients . CONCLUSIONS The results of this clinical trial demonstrate that ProDisc-C is a safe and effective surgical treatment for patients with disabling cervical radiculopathy because of single-level disease . By all primary and secondary measures evaluated , clinical outcomes after ProDisc-C implantation were either equivalent or superior to those same clinical outcomes after Fusion Study Design Prospect i ve , r and omized , controlled . Level 1 evidence . Objective To report functional outcomes at 48 months follow-up on prospect ively r and omized patients to either the Bryan cervical disc prosthesis or anterior cervical discectomy and fusion ( ACDF ) at a single site . Summary of Background Data Surgical treatment of cervical disc pathology can involve discectomy and fusion ( ACDF ) , the gold st and ard technique . The safety and effectiveness of this procedure has been established and demonstrated in the literature , however , limitations have evolved and alternatives such as disc replacement are being investigated . Intervertebral disc replacement is design ed to preserve motion , both at affected and adjacent levels avoiding limitations of fusion such as adjacent level degeneration . New onset degenerative changes and possible recurring neurologic symptoms may be deferred or eliminated with cervical disc replacement . A recent multicenter trial with 24 months follow-up has shown the Bryan disc to compare favorably with ACDF . Continued follow-up is needed to further evaluate and compare functional outcomes in both these cohorts . Methods A total of 47 patients were enrolled at our site as part of an ongoing multicenter prospect ively r and omized study investigating ACDF versus Bryan cervical disc prosthesis . Functional outcomes are now reported at 48 months follow-up for our cohort of participants . Neck disability index score ( NDI ) , VAS neck and arm and SF-36 both physical and mental as well as complications and reoperations will be reported . Results Functional outcome data collected at routine follow-up for 48-months has favorably demonstrated improved functional outcomes for NDI , neck/arm pain VAS scores , and the SF-36 physical/mental health component scores for the Bryan arthroplasty and ACDF cohorts . The NDI scores for the Bryan arthroplasty preoperatively was 51 and at 48 months 10 . For ACDF preoperative NDI score was also 51 and at 48 months 16.7 . At 48 months NDI success , measured by ≥15 points NDI improvement demonstrated a 93.3 % success for Bryan arthroplasty and an 82.4 % success for ACDF . VAS neck pain scores for the Bryan arthroplasty preoperatively was 76.2 and at 48 months was 13.6 . VAS neck pain scores for ACDF preoperatively was 80.6 and at 48 months was 28.1 . Arm Pain scores were also measured and for the Bryan arthroplasty preoperatively measured 78.8 and at 48 months 10.8 . For ACDF arm pain scores preoperatively measured 77.1 and at 48 months 21.7 . These outcomes have not been associated with any degradation of outcome measures from 2 to 4 years . During the 48 months of follow-up at our institution we also report 6 secondary surgeries in our control group ( ACDF ) and only 1 in our investigational group ( Bryan ) . Of the 6 surgeries in the control group performed , 3 or 12 % to date were for adjacent level degenerative disease and 1 or 4 % for remote level degenerative disc disease . The remaining 2 surgeries were performed on the same patient for a pseudarthrosis . In the investigational group there was only 1 secondary surgery performed to date for adjacent level disease 5 % . Conclusions At 48 months , cervical arthroplasty with the Bryan cervical disc prosthesis continues to compare favorably to ACDF at our institution . There has been no degradation of functional outcomes from 24 to 48 months for NDI , VAS of neck and arm , and SF-36 . There has been a lower incidence of secondary surgeries for the Bryan arthroplasty cohort to date OBJECT The purpose of this study was to determine long-term clinical outcomes in patients undergoing anterior cervical surgery in which a cervical disc prosthesis was used to treat single-level degenerative cervical disc disease . METHODS In this prospect i ve , nonblinded study , 541 patients at 32 investigational sites were r and omly assigned to 1 of 2 treatment groups . The results of the investigational group , in which patients received the Prestige disc prosthesis , were compared with those of the control group , in which patients underwent an instrumented interbody fusion . Data were collected preoperatively , intraoperatively , and at 1.5 , 3 , 6 , 12 , 24 , 36 , and 60 months postoperatively . To date , 271 patients have completed 5 years of clinical follow-up ( 144 investigational and 127 control patients ) . RESULTS Significant improvements in Neck Disability Index ( NDI ) scores , Physical Component Summary scores of the 36-Item Short-Form Health Survey , and neck and arm pain scores were achieved by 1.5 months in both groups and sustained at 5 years . The mean NDI improvements from preoperative scores were 35.4 , 36.3 , and 38.4 at 24 , 36 , and 60 months , respectively , in the investigational group . The corresponding mean NDI improvements were 33.9 , 31.3 , and 34.1 in the control group . The intergroup differences at both 36 and 60 months were significant ( p = 0.008 and 0.022 , respectively ) . The overall rates of maintenance or improvement in neurological status in the investigational group were 91.6 % , 92.8 % , and 95.0 % , respectively , at 24 , 36 , and 60 months compared with 83.6 % , 83.2 % , and 88.9 % in the control group ( p = 0.006 , 0.004 , and 0.051 , respectively ) . The implant effectively maintained angular motion , averaging more than 7.3 degrees at 36 months and 6.5 degrees at 60 months after surgery . No implant migration was observed up to 60 months . There were statistically significant differences between the investigational and control groups with regard to the rate of revision and supplemental fixation surgical procedures performed subsequent to the index procedure . Additional surgical procedures for adjacent-segment disease were observed in both treatment groups . Rates for surgery at adjacent levels trended lower in the investigational group ( 8 patients [ 11 surgeries ] ) compared with those in the control group ( 13 patients [ 16 surgeries ] ) , but the differences were not statistically significant ( p = 0.376 ) . Some of the second surgeries involved both index and adjacent levels . CONCLUSIONS The Prestige disc maintains improved clinical outcomes and segmental motion after implantation at 5-year follow-up OBJECT The purpose of this study was to evaluate the long-term results of cervical total disc replacement ( TDR ) and anterior cervical discectomy and fusion ( ACDF ) in the treatment of single-level cervical radiculopathy . METHODS The results of 2 separate prospect i ve , r and omized , US FDA Investigational Device Exemption pivotal trials ( Bryan Disc and Kineflex|C ) from a single investigational site were combined to evaluate outcomes at long-term follow-up . The primary clinical outcome measures included the Neck Disability Index ( NDI ) , visual analog scale ( VAS ) , and neurological examination . Patients were r and omized to receive cervical TDR in 2 separate prospect i ve , r and omized studies using the Bryan Disc or Kineflex|C cervical artificial disc compared with ACDF using structural allograft and an anterior plate . Patients were evaluated preoperatively ; at 6 weeks ; at 3 , 6 , and 12 months ; and then yearly for a minimum of 48 months . Plain radiographs were obtained at each study visit . RESULTS A total of 74 patients were enrolled and r and omly assigned to either the cervical TDR ( n = 41 ) or ACDF ( n = 33 ) group . A total of 63 patients ( 86 % ) completed a minimum of 4 years follow-up . Average follow-up was 6 years ( 72 months ) with a range from 48 to 108 months . In both the cervical TDR and ACDF groups , mean NDI scores improved significantly by 6 weeks after surgery and remained significantly improved throughout the minimum 48-month follow-up ( p < 0.001 ) . Similarly , the median VAS pain scores improved significantly by 6 weeks and remained significantly improved throughout the minimum 48-month follow-up ( p < 0.001 ) . There were no significant differences between groups in mean NDI or median VAS scores . The range of motion ( ROM ) in the cervical TDR group remained significantly greater than the preoperative mean , whereas the ROM in the ACDF group was significantly reduced from the preoperative mean . There was significantly greater ROM in the cervical TDR group compared with the ACDF group . There were 3 reoperations ( 7.3 % ) at index or adjacent levels in the cervical TDR group ; all were cervical laminoforaminotomies . There were 2 adjacent-level reoperations in the cervical TDR group ( 4.9 % ) . There was 1 reoperation ( 3.0 % ) in the ACDF group at an index or adjacent level ( a second ACDF at the adjacent level ) . There was no statistically significant difference in overall reoperation rate or adjacent-level reoperation rate between groups . CONCLUSIONS Both cervical TDR and ACDF groups showed excellent clinical outcomes that were maintained over long-term follow-up . Both groups showed low index-level and adjacent-level reoperation rates . Both cervical TDR and ACDF appear to be viable options for the treatment of single-level cervical radiculopathy Study Design / Setting Prospect i ve , r and omized , 3-center , clinical trial . Objective To prospect ively compare the outcomes of cervical arthroplasty with the BRYAN Cervical Disc Prosthesis ( Medtronic Sofamor Danek , Inc , Memphis , TN ) to anterior cervical discectomy and fusion ( ACDF ) . Summary of Background Data Surgical treatment of cervical disc pathology commonly involves techniques that employ discectomy and fusion ( ACDF ) . This “ gold-st and ard ” technique has demonstrated good clinical and radiographic outcomes . Common adverse effects of this procedure are associated with the adjacent level degeneration and bone-graft harvest . Several investigators have independently reported successful short-term outcomes with the BRYAN Cervical Disc Prosthesis . In addition , a significant body of knowledge has been collected regarding the wear patterns and adjacent level effects of this device in human and animal models . Methods As part of an FDA IDE trial , 3 centers collected prospect i ve outcomes data on 115 patients r and omized in a 1:1 ratio to ACDF ( Control group ) or arthroplasty with the BRYAN Cervical Disc Prosthesis ( Investigational group ) . Results Demographic and surgical data were generally similar in the 2 population s. Outcomes data collected at routine postoperative intervals for 24 months demonstrated that the Investigational group had statistically significant ( P<0.05 ) improvements as assessed by the Neck Disability Index , the Neck Pain Score , and SF-36 Physical component scores . The improvement in the Mental Component Subscore values for the BRYAN and control groups was equivalent at 24 months ( P=0.055 ) . Arm pain relief was similar in both groups ( P=0.152 ) . During the course of the 2-year follow-up , 4 patients in the Control group required surgical intervention and 3 patients in the Investigational group required ACDF for adjacent level disease . Conclusions At 24 months , cervical arthroplasty with the BRYAN Cervical Disc Prosthesis compares favorably with ACDF as defined by st and ard outcomes scores Background Cervical total disk replacement ( TDR ) is intended to address pain and preserve motion between vertebral bodies in patients with symptomatic cervical disk disease . Two-year follow-up for the ProDisc-C ( Synthes USA Products , LLC , West Chester , Pennsylvania ) TDR clinical trial showed non-inferiority versus anterior cervical discectomy and fusion ( ACDF ) , showing superiority in many clinical outcomes . We present the 4-year interim follow-up results . Methods Patients were r and omized ( 1:1 ) to ProDisc-C ( PDC-R ) or ACDF . Patients were assessed preoperatively , and postoperatively at 6 weeks and 3 , 6 , 12 , 18 , 24 , 36 , and 48 months . After the r and omized portion , continued access ( CA ) patients also underwent ProDisc-C implantation , with follow-up visits up to 24 months . Evaluations included Neck Disability Index ( NDI ) , Visual Analog Scale ( VAS ) for pain/satisfaction , and radiographic and physical/neurologic examinations . Results R and omized patients ( 103 PDC-R and 106 ACDF ) and 136 CA patients were treated at 13 sites . VAS pain and NDI score improvements from baseline were significant for all patients ( P < .0001 ) but did not differ among groups . VAS satisfaction was higher at all time points for PDC-R versus ACDF patients ( P = .0499 at 48 months ) . The percentage of patients who responded yes to surgery again was 85.6 % at 24 months and 88.9 % at 48 months in the PDC-R group , 80.9 % at 24 months and 81.0 % at 48 months in the ACDF group , and 86.3 % at 24 months in the CA group . Five PDC-R patients ( 48 months ) and no CA patients ( 24 months ) had index-level bridging bone . By 48 months , approximately 4-fold more ACDF patients required secondary surgery ( 3 of 103 PDC-R patients [ 2.9 % ] vs 12 of 106 ACDF patients [ 11.3 % ] , P = .0292 ) . Of these , 6 ACDF patients ( 5.6 % ) required procedures at adjacent levels . Three CA patients required secondary procedures ( 24 months ) . Conclusions Our 4-year data support that ProDisc-C TDR and ACDF are viable surgical options for symptomatic cervical disk disease . Although ACDF patients may be at higher risk for additional surgical intervention , patients in both groups show good clinical results at longer-term follow-up Study Design . R and omized controlled trial . Objective . Analyze the clinical outcomes at 5 years comparing cervical total disc replacement ( TDR ) with ProDisc-C ( Synthes Spine USA Products ; LLC , West Chester , PA ) with anterior cervical discectomy and fusion ( ACDF ) . Summary of Background Data . Previous reports of 2- and 4-year results have shown that ProDisc-C , a TDR for surgical treatment of patients experiencing single-level symptomatic cervical disc disease between C3 and C7 , is safe and effective . Methods . Two hundred nine patients ( 103 ProDisc-C and 106 ACDF ) from 13 sites were r and omized and treated . Results including neck disability index , visual analog scale ( VAS ) neck and arm pain , Short Form-36 ( SF-36 ) , neurological examination , device success , adverse event occurrence , and VAS patient satisfaction were analyzed . Results . Demographics were similar between the 2 patient groups ( ProDisc-C : 42.1 ± 8.4 yr , 44.7 % males ; ACDF : 43.5 ± 7.1 yr , 46.2 % males ) . Rates of follow-up at 2 years were 98.1 % ProDisc-C and 94.8 % ACDF , and at 5 years 72.7 % ProDisc-C and 63.5 % ACDF . For all clinical outcomes for both groups , there was a statistically and clinical ly significant improvement at 2 and 5 years compared with baseline . At 5 years , ProDisc-C patients had statistically significantly less neck pain intensity and frequency . Both groups scored high VAS satisfaction scores at 5 years , with ProDisc-C 86.56 and ACDF 82.74 . There were no reports of device failures or implant migration with ProDisc-C. The ProDisc-C patients maintained motion at their index level . At 5 years , the ProDisc-C patients had a statistically significantly lower rate of reoperation compared with ACDF patients ( 2.9 % vs. 11.3 % ) . Conclusion . Five-year results show that TDR with ProDisc-C is a safe and effective treatment of single-level symptomatic cervical disc disease . Clinical outcomes were comparable with ACDF . ProDisc-C patients maintained motion at the index level and had significantly less neck pain intensity and frequency as well as a lower probability of secondary surgery OBJECT A prospect i ve , r and omized clinical trial was conducted to compare the Prestige II Cervical Disc with anterior decompression and fusion for the treatment of single-level degenerative disease . St and ardized clinical outcome measures and radiographic examinations were used at prescribed postoperative intervals to compare the treatment groups . METHODS Patients with symptomatic single-level cervical disc disease who met the inclusion /exclusion criteria defined in the protocol were r and omized to receive the Prestige II disc or iliac crest autograft fusion . All patients underwent a st and ardized neurological and radiographic examination and completed outcomes question naires ( Neck Disability Index and Short Form-36 ) preoperatively and at each postoperative interval ( 6 weeks and 3 , 6 , 12 , and 24 months ) . Two independent radiologists review ed all x-ray films and assessed motion at the treated level and adjacent segments . St and ard statistical methods were used to compare all outcome measures . Preliminary results in 55 patients enrolled in the study are presented . Several patients have reached the final ( 24-month ) follow-up interval . Clinical and radiographic results are encouraging , with significant improvement seen in both treatment groups . Radiographic results show that the Prestige II disc maintains motion at the treated level without adjacent-segment compromise . CONCLUSIONS Cervical spine arthroplasty is an exciting and rapidly developing surgical treatment option . An objective comparison with fusion is important to advance this option . This is the first prospect i ve r and omized trial in which cervical arthroplasty is compared with fusion . The preliminary results from this limited number of patients indicate that the Prestige II disc is potentially a viable alternative to fusion for primary cervical disc disease ; however , further clinical studies with larger sample sizes will be required to show statistical equivalence Study Design . A prospect i ve , r and omized , multicenter study of surgical treatment of cervical disc disease . Objective . To assess the safety and efficacy of cervical disc arthroplasty using a new arthroplasty device at 24-months follow-up . Summary of Background Data . Cervical disc arthroplasty preserves motion in the cervical spine . It is an alternative to fusion after neurologic decompression , whereas anterior decompression and fusion provides a rigorous comparative benchmark of success . Methods . We conducted a r and omized controlled multicenter clinical trial enrolling patients with cervical disc disease . Ultimately 242 received the investigational device ( Bryan Cervical Disc ) , and 221 patients underwent a single-level anterior cervical discectomy and decompression and fusion as a control group . Patients completed clinical and radiographic follow-up examinations at regular intervals for 2 years after surgery . Results . Analysis of 12- and 24-month postoperative data showed improvement in all clinical outcome measures for both groups ; however , 24 months after surgery , the investigational group patients treated with the artificial disc had a statistically greater improvement in the primary outcome variables : Neck disability index score ( P = 0.025 ) and overall success ( P = 0.010 ) . With regard to implant- or implant/surgical-procedure-associated serious adverse events , the investigational group had a rate of 1.7 % and the control group , 3.2 % . There was no statistical difference between the 2 groups with regard to the rate of secondary surgical procedures performed subsequentto the index procedure . Patients who received the artificial cervical disc returned to work nearly 2 weeks earlier than the fusion patients ( P = 0.015 ) . Conclusion . Two-year follow-up results indicate that cervical disc arthroplasty is a viable alternative to anterior cervical discectomy and fusion in patients with persistently symptomatic , single-level cervical disc disease Study Design . Prospect i ve 10-year follow-up magnetic resonance imaging ( MRI ) study of patients who underwent anterior cervical decompression and fusion ( ACDF ) and healthy control subjects . Objective . To clarify the incidence of adjacent segment degeneration during 10 years after ACDF . Summary of Background Data . There have been few studies which investigated incidence of progression of degenerative changes at adjacent segments in patients treated by ACDF comparing with healthy subjects . Methods . Sixty-four patients who underwent ACDF ( 48 males , 16 females , mean age 47.3 years , mean follow-up 12.1 year ) and 201 asymptomatic volunteers who underwent MRI in our previous study ( 113 males , 88 females , mean age ; 41.1 year , mean follow-up ; 11.7 years ) were included in this study . The patients and control subjects underwent follow-up MRI in this study . Following MR findings were evaluated using a numerical grading system from C2–C3–C7–T1 : ( 1 ) Decrease in signal intensity of disc ( DSI ) , ( 2 ) Posterior disc protrusion ( PDP ) , ( 3 ) Disc space narrowing , and ( 4 ) Foraminal stenosis . When an increase in at least one grade in any of the radiographic parameters was detected between the 2 time points , progression of disc degeneration was judged as present at the level of interest . Results . Progression of DSI was significantly more frequent in ACDF group than in control group at C4–C5 , while progression of PDP was significantly more frequent in ACDF group than in control group at all levels except for C5–C6 . Progression of disc space narrowing and foraminal stenosis was significantly more frequent in ACDF group at C3–C4 and at C6–C7 , respectively . Conclusion . Although both ACDF patients and control subjects demonstrated progression of disc degeneration during 10 years , ACDF patients had significantly higher incidence of progression of disc degeneration at adjacent segments than control subjects , while progression of disc degeneration at adjacent segments was not always related to development of clinical symptoms OBJECTIVE : Heterotopic ossification ( HO ) is a well-known complication in joint replacements , but its occurrence and clinical effect on cervical artificial discs has not yet been studied . The purpose of this study was to investigate the incidence of HO in cervical disc replacement , to identify any associated risk factors for HO , and to examine the relationship of HO with clinical outcomes . METHODS : The patient data for this observational study were obtained from the original Bryan Disc Study by the European Consortium . Occurrence of HO was defined by the McAfee classification on the cervical lateral x-rays at 12 months after surgery . Secondary outcome measurements included Odom 's criteria and the Medical Outcomes Study Short-Form 36-Item Health Survey . RESULTS : Sixteen ( 17.8 % ) of the 90 studied patients experienced HO , and 6 ( 6.7 % ) of these patients experienced Grade 3 and 4 HO . Ten patients ’ ( 11 % ) artificial discs were shown to have movement of less than 2 degrees on flexion and extension cervical x-ray at 12 months , with 4 of these patients having HO of Grade 3 or 4 . Male sex ( & khgr;2 = 4.1 ; P = 0.0407 ) and older patients ( P = 0.023 ; odds ratio = 1.10 ; 95 % confidence interval = 1.01–1.19 ) were associated with development of HO . CONCLUSION : There is a strong association of the occurrence of HO with subsequent loss of movement of the implanted cervical artificial disc . We have found that sex and age are two possible risk factors in the development of HO after cervical disc replacement OBJECTIVE To compare the clinical outcomes of single level Bryan cervical disc replacement with traditional anterior cervical discectomy and fusion ( ACDF ) . METHODS From Dec 2003 to May 2005 , 59 patients with primary , single-level cervical radiculopathy and /or myelopathy were prospect ively r and omized into 2 groups : Bryan group with artificial disc replacement and ACDF group with traditional anterior cervical discectomy and fusion . Operation time , blood loss and hospitalization duration were compared between the 2 groups . Follow-up was taken at six weeks , 3 , 6 , 12 and 24 months after operation , and each case in both groups was evaluated with serial radiographic studies , neck disability indices ( NDI ) , visual analog scale scores ( VAS ) for arm and neck pain . RESULTS No difference was found in the operation time , intraoperative blood loss and hospital stay between the 2 groups . But at the follow-up of 6 weeks and 3 months after operation , significant difference in NDI and VAS of neck pain existed . All replaced segments remained normal range of motion in sagittal rotation , while no motion occurred in any of the fusion segments . In ACDF group movement of the whole cervical spine decreased but gradually recovered to preoperative level in 6 months after operation . In Bryan group , pre- and postoperative motion of the whole cervical spine remained unchanged at any of the follow-up time . CONCLUSIONS Bryan disc replacement can achieve similar clinical improvement compared with traditional ACDF . Arthroplasty has the advantages of motion maintenance for the cervical spine and short recovery time after operation A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis The purpose of this paper is to compare the new functional intervertebral cervical disc prosthesis replacement and the classical interbody fusion operation , including the clinical effect and maintenance of the stability and segmental motion of cervical vertebrae . Twenty-four patients with single C5 - 6 intervertebral disk hernias were specifically selected and divided r and omly into two groups : One group underwent artificial cervical disc replacement and the other group received interbody fusion . All patients were followed up and evaluated . The operation time for the single disc replacement was ( 130 ± 50 ) minutes and interbody fusion was ( 105 ± 53 ) minutes . Neurological or vascular complications were not observed during or after operation . There was no prosthesis subsidence or extrusion . The JOA score of the group with prosthesis replacement increased from an average of 8.6 to 15.8 . The JOA score of the group with interbody fusion increased from an average of 9 to 16.2 . The clinical effect and the ROM of the adjacent space of the two groups showed no statistical difference . The short follow-up time does not support the advantage of the cervical disc prosthesis . The clinical effect and the maintenance of the function of the motion of the intervertebral space are no better than the interbody fusion . At least 5 years of follow-up is needed to assess the long-term functionality of the prosthesis and the influence on adjacent levels . RésuméL’objectif de ce travail est de comparer les prothèses discales , cervicales à la classique arthrodèse intercorporéale , en analysant les aspects cliniques , la stabilité et la mobilité des vertèbres cervicales . 24 patients ayant présenté une hernie discale c5 c6 ont été sélectionnés et séparés en deux groupes r and omisés . Un groupe a bénéficié d’une prothèse discale et l’autre groupe d’une arthrodèse intercorporéale . Tous les patients ont été suivis et évalués . Résultats : le temps opératoire pour la prothèse discale a été de 50 à 130 minutes et le temps opératoire de l’arthrodèse de 53 à 105 minutes . Aucune complication neurologique ou vasculaire n’a été observée après les interventions . Le score JOA dans le groupe des prothèses a évolué de 8.6 à 15.8 et dans le groupe des arthrodèses de 9 à 16.2 . la symptopathologie clinique et la mobilité des espaces inter vertébraux adjacents à l’intervention chirurgicale ne montrent pas de différence statistique . En conclusion : ce suivi à court terme ne permet pas de mettre en évidence un avantage à la prothèse discale cervicale . Les résultats fonctionnels et la mobilité ne sont pas supérieurs à ceux d’une arthrodèse intercorporéale . Il faudra au moins cinq ans de suivi avant de mettre en évidence une éventuelle fonctionnalité à long terme des prothèses et leur influence bénéfique au niveau des espaces adjacents à l’intervention si tant est qu’il y en ait Study Design . This is a prospect i ve r and omized and controlled study , approved by the local ethical committee of Saarl and ( Germany ) . Objective . The aim of the current study was to analyze segmental motion following artificial disc replacement using disc prosthesis over 1 year . A second aim was to compare both segmental motion as well as clinical result to the current gold st and ard ( anterior cervical discectomy and fusion [ ACDF ] ) . Summary of Background Data . ACDF may be considered to be the gold st and ard for treatment of symptomatic degenerative disc disease within the cervical spine . However , fusion may result in progressive degeneration of the adjacent segments . Therefore , disc arthroplasty has been introduced . Among these , artifical disc replacement seems to be promising . However , segmental motion should be preserved . This , again , is very difficult to judge and has not yet been proven . Methods . A total of 49 patients with cervical disc herniation were enrolled and assigned to either study group ( receiving a disc prosthesis ) or control group ( receiving ACDF , using a cage with bone graft and an anterior plate ) . Roentgen stereometric analysis ( RSA ) was used to quantify intervertebral motion immediately as well as 3 , 6 , 12 , 24 , and 52 weeks after surgery . Also , clinical results were judged using visual analog scale and neuro-examination at even RSA follow-up . Results . Cervical spine segmental motion decreased over time in the presence of disc prosthesis or fusion device . However , the loss segmental motion is significantly higher in the fusion group , when looked at 3 , 6 , 12 , 24 , and 52 weeks after surgery . We observed significant pain reduction in neck and arm after surgery , without significant difference between both groups . Conclusion . Cervical spine disc prosthesis remains cervical spine segmental motion within the first 1 year after surgery . The clinical results are the same when compared with the early results following ACDF The object of this study is to compare radiographic outcomes of anterior cervical decompression and fusion ( ACDF ) versus cervical disc replacement using the Bryan Cervical Disc Prosthesis ( Medtronic Sofamor Danek , Memphis , TN ) in terms of range of motion ( ROM ) , Functional spinal unit ( FSU ) , overall sagittal alignment ( C2–C7 ) , anterior intervertebral height ( AIH ) , posterior intervertebral height ( PIH ) and radiographic changes at the implanted and adjacent levels . The study consisted of 105 patients . A total of 63 Bryan disc were placed in 51 patients . A single level procedure was performed in 39 patients and a two-level procedure in the other 12 . Fifty-four patients underwent ACDF , 26 single level cases and 28 double level cases . The Bryan group had a mean follow-up 19 months ( 12–38 ) . Mean follow-up for the ACDF group was 20 months ( 12–40 months ) . All patients were evaluated using static and dynamic cervical spine radiographs as well as MR imaging . All patients underwent anterior cervical discectomy followed by autogenous bone graft with plate ( or implantation of a cage ) or the Bryan artificial disc prosthesis . Clinical evaluation included the visual analogue scale ( VAS ) , and neck disability index ( NDI ) . Radiographic evaluation included static and dynamic flexion-extension radiographs using the computer software ( Infinitt PiviewSTAR 5051 ) program . ROM , disc space angle , intervertebral height were measured at the operative site and adjacent levels . FSU and overall sagittal alignment ( C2–C7 ) were also measured pre-operatively , postoperatively and at final follow-up . Radiological change was analyzed using χ2 test ( 95 % confidence interval ) . Other data were analyzed using the mixed model ( SAS enterprises guide 4.1 versions ) . There was clinical improvement within each group in terms of VAS and NDI scores from pre-op to final follow-up but not significantly between the two groups for both single ( VAS p = 0.8371 , NDI p = 0.2872 ) and double ( VAS p = 0.2938 , NDI p = 0.6753 ) level surgeries . Overall , ROM and intervertebral height was relatively well maintained during the follow-up in the Bryan group compared to ACDF . Regardless of the number of levels operated on , significant differences were noted for overall ROM of the cervical spine ( p < 0.0001 ) and all other levels except at the upper adjacent level for single level surgeries ( p = 0.2872 ) . Statistically significant ( p < 0.0001 and p = 0.0172 ) differences in the trend of intervertebral height measurements between the two groups were noted at all levels except for the AIH of single level surgeries at the upper ( p = 0.1264 ) and lower ( p = 0.7598 ) adjacent levels as well as PIH for double level surgeries at the upper ( p = 0.8363 ) adjacent level . Radiological change was 3.5 times more observed for the ACDF group . Clinical status of both groups , regardless of the number of levels , showed improvement . Although clinical outcomes between the two groups were not significantly different at final follow-up , radiographic parameters , namely ROM and intervertebral heights at the operated site , some adjacent levels as well as FSU and overall sagittal alignment of the cervical spine were relatively well maintained in Bryan group compared to ACDF group . We surmise that to a certain degree , the maintenance of these parameters could contribute to reduce development of adjacent level change . Noteworthy is that radiographic change was 3.5 times more observed for ACDF surgeries . A longer period of evaluation is needed , to see if all these radiographic changes will translate to symptomatic adjacent level disease Purpose Total cervical artificial disc replacement ( TDR ) simulates normal disc structure , thus avoiding the drawbacks of anterior cervical decompression and fusion ( ACDF ) . This prospect i ve , r and omized , controlled and multicentre study aim ed to evaluate clinical and radiographic outcomes by comparing cervical disc replacement using Mobi-C disc prostheses with ACDF . Methods This prospect i ve , r and omized , controlled and multicentre study consisted of 111 patients undergoing single-level Mobi-C disc prosthesis replacement ( TDR group , n = 55 ) or ACDF ( n = 56 ) from February 2008 to November 2009 at 11 medical centres across China . Patients were assessed before surgery , at seven days postoperation and one , three , six , 12 , 24 , 36 and 48 months postoperation . Clinical and neurological outcome was determined by measuring the Japanese Orthopaedic Association ( JOA ) scores , visual analogue scale ( VAS ) and Neck Disability Index ( NDI ) . Static and dynamic radiographs were obtained of the cervical curvature , the functional spinal unit ( FSU ) angle and range of motion ( ROM ) of the cervical spine , FSU angle and treated and adjacent segments . Results A total of 111 patients were included and r and omly assigned to either Mobi-C disc prosthesis replacement or ACDF . JOA , VAS and NDI showed statistically significant improvements 48 months after surgery ( P < 0.05 ) . ROM , FSU angle , treated segment and adjacent segments in the Mobi-C group were not significantly different before and after replacement ( p > 0.05 ) . ROM in the ACDF group was significantly reduced at one month and remained so throughout the follow-up . By 48-months , more ACDF patients required secondary surgery ( four of 56 patients ) . Conclusions Although ACDF may increase the risk of additional surgery , clinical outcomes indicated that both Mobi-C artificial cervical disc replacement and ACDF were reliable . Radiographic data showed that ROM of the cervical spine , FSU angle and treated and adjacent segments were relatively better reconstructed and maintained in the Mobi-C group compared with those in the ACDF group Study Design . Prospect i ve 6-center study . Objective . To evaluate outcomes of cervical disc replacement performed adjacent to a prior cervical fusion . Summary of Background Data . The use of disc replacement adjacent to a prior anterior cervical decompression and fusion ( ACDF ) is an attractive reconstructive option , obviating the need for a multilevel fusion . This study reports outcomes from patients with and without previous ACDF receiving the porous coated motion ( PCM ) artificial cervical disc in a United States Federal Drug Administration Investigational Device Exemption trials . Methods . Patients between ages of 18 and 65 with single-level cervical radiculopathy and /or myelopathy , unresponsive to at least 6 weeks of nonsurgical therapy , or experiencing progressive neurologic symptoms were enrolled . Clinical outcomes are compared for patients receiving a PCM disc at a level adjacent to a prior ACDF ( “ adjacent ” ) and those without having previously had fusion ( “ primary ” ) . Results . 126 PCM patients were primary ( mean age : 44.4 years . ) and 26 patients had previous “ adjacent level ” fusion surgery ( mean age : 46.4 years ) . Surgery time was similar in both groups ( 96 minutes and 98 minutes , respectively ; P = 0.761 ) , and mean blood loss was 76 mL and 66 mL in the 2 groups , respectively ( P = 0.491 ) . Clinical outcomes using Neck Disability Index and Visual Analog Scores neck and arm scores showed significant improvement after surgery and were similar between groups at all time points . Revision surgery occurred in 2 of 126 primary patients , and in 2 of 26 patients in the adjacent-to-fusion group . Conclusion . Although the level adjacent to a prior cervical fusion is subject to increased biomechanical forces , potentially leading to a higher risk of failure , the PCM disc was well tolerated in the short term . The early clinical results of disc replacement adjacent to a prior fusion are good and comparable to the outcomes after primary disc replacement surgery . However , in view of the small study population and short-term follow-up , continued study is m and atory Study Design . Prospect i ve , r and omized , controlled , multicenter clinical trial . Objective . To compare outcomes of cervical disc arthroplasty with those of anterior cervical decompression and fusion ( ACDF ) in a Chinese population . Summary of Background Data . Cervical disc arthroplasty has been found to be superior to ACDF for maintaining range of motion ( ROM ) at the index spinal segment and possibly will avoid abnormal stress to adjacent segments . Methods . A total of 120 patients from 3 large hospitals in China were r and omly assigned to treatment with cervical disc arthroplasty ( n = 60 ) using the BRYAN prosthesis or ACDF ( n = 60 ) and were observed postoperatively for 24 months . Results . The 2 groups had similar preoperative demographics and baseline characteristics including ROM , neck disability index , and visual analogue scale for neck and arm pain . The total disc replacement ( TDR ) group had a significantly longer operation time than the ACDF group ( P < 0.001 ) . Outcome data obtained after 24 months revealed a significant difference between the groups in mean change from baseline in ROM at the index level ( P < 0.001 ) ; ROM was maintained in the TDR group but reduced in the ACDF group . There were no significant between-group differences in the baseline changes in neck disability index or visual analogue scale scores for pain . One patient in the TDR group and 4 patients in the ACDF group required reoperations . Conclusion . At 24 months after surgery , the cervical disc prosthesis yielded good clinical results while maintaining ROM at the index level . Cervical disc arthroplasty appears to be a viable alternative to ACDF

Subgroup analyses indicated larger reduction was identified in the intake of low-dose of grape polyphenols ( < 733 mg/day , median level of the included studies ) or patients with metabolic syndrome . Contrarily , diastolic blood pressure was not significantly decreased in the grape polyphenols group as compared to controls . No significant heterogeneity or publication bias was detected in the meta- analysis of either systolic or diastolic blood pressure . CONCLUSIONS Daily grape polyphenol intake can significantly reduce the systolic blood pressure in humans , although the reduction is modest when compared with anti-hypertensive medications .

BACKGROUND The effect of grape polyphenols on blood pressure remains unclear , which we aim ed to address via a meta- analysis study .

The aim of our study was to evaluate the effect of a st and ardized formulation of a polyphenolic extract of grapes ( Leucoselect-Phytosome [ LP ] ) on low-density lipoprotein ( LDL ) susceptibility to oxidation in a group of heavy smokers . A r and omized , double-blind , crossover study was undertaken in 24 healthy male heavy smokers , aged > or = 50 years . Enrolled subjects were given 2 capsules twice daily for 4 weeks ( phase 1 ) . Each capsule contained 75 mg of a grape procyanidin extracts and soy-phosphatidlcholine or placebo consisiting of 75 mg lactose and soy-phosphatidlcholine . A wash out period of 3 weeks was then followed by 4 weeks of the opposite treatment ( phase 2 ) . Blood sample s were taken at baseline and at the end of each phase and assayed for plasma lipids and LDL susceptibility to oxidation . Compliance was good , and no adverse effects were recorded . Subjects did not show significant modification of total cholesterol ( TC ) , triglycerides ( TG ) , high-density lipoprotein-cholesterol ( HDL-C ) and LDL-C during LP treatment . Among oxidative indices , thiobarbituric acid reactive substances ( TBARS ) concentration was significantly reduced in subjects taking LP ( -14.7 % + /- 21.1 % v + 5.0 % + /- 18.1 % , P < .01 ) , and the lag phase prolonged ( + 15.4 % + /- 24.4 % v -0.1 % + /- 16.0 % , P < .05 ) compared with placebo and basal values . The antioxidant potential of grape seed extract polyphenols may prove effective in a model of oxidative stress ( smoking ) ; however more investigational data are needed before use in wider clinical setting Background Raisins are a significant source of dietary fiber and polyphenols , which may reduce cardiovascular disease ( CVD ) risk by affecting lipoprotein metabolism and inflammation . Walking represents a low intensity exercise intervention that may also reduce CVD risk . The purpose of this study was to determine the effects of consuming raisins , increasing steps walked , or a combination of these interventions on blood pressure , plasma lipids , glucose , insulin and inflammatory cytokines . Results Thirty-four men and postmenopausal women were matched for weight and gender and r and omly assigned to consume 1 cup raisins/d ( RAISIN ) , increase the amount of steps walked/d ( WALK ) or a combination of both interventions ( RAISINS + WALK ) . The subjects completed a 2 wk run-in period , followed by a 6 wk intervention . Systolic blood pressure was reduced for all subjects ( P = 0.008 ) . Plasma total cholesterol was decreased by 9.4 % for all subjects ( P < 0.005 ) , which was explained by a 13.7 % reduction in plasma LDL cholesterol ( LDL-C ) ( P < 0.001 ) . Plasma triglycerides ( TG ) concentrations were decreased by 19.5 % for WALK ( P < 0.05 for group effect ) . Plasma TNF-α was decreased from 3.5 ng/L to 2.1 ng/L for RAISIN ( P < 0.025 for time and group × time effect ) . All subjects had a reduction in plasma sICAM-1 ( P < 0.01 ) . Conclusion This research shows that simple lifestyle modifications such as adding raisins to the diet or increasing steps walked have distinct beneficial effects on CVD risk BACKGROUND Patients treated with hemodialysis frequently experience cardiovascular complications attributed , among other causes , to dyslipidemia , increased oxidative stress , and inflammation . OBJECTIVE The aim of the study was to study the effects of dietary supplementation with concentrated red grape juice ( RGJ ) , a source of polyphenols , on lipoprotein profile , antioxidant capacity , LDL oxidation , and inflammatory biomarkers . DESIGN Twenty-six patients receiving hemodialysis and 15 healthy subjects were instructed to drink 100 mL RGJ/d for 14 d. Blood was drawn at baseline , twice during RGJ supplementation , and twice during the 6-mo follow-up period . As a control , 12 other r and omly recruited hemodialysis patients not receiving RGJ were studied . Lipids , apolipoproteins , oxidized LDL , and antioxidant vitamins were measured in plasma . The bioavailability of RGJ polyphenols was assessed in healthy subjects . RESULTS The maximum plasma concentration of quercetin was achieved 3 h after RGJ ingestion , which indicates that supplement-derived polyphenols are rapidly absorbed . In both healthy subjects and hemodialysis patients , RGJ consumption increased the antioxidant capacity of plasma without affecting concentrations of uric acid or ascorbic acid ; reduced the concentration of oxidized LDL ; and increased the concentration of cholesterol-st and ardized alpha-tocopherol . RGJ supplementation also caused a significant decrease in LDL-cholesterol and apolipoprotein B-100 concentrations , while increasing the concentrations of HDL cholesterol and apolipoprotein A-I. In a further study in hemodialysis patients , RGJ supplementation for 3 wk significantly reduced plasma monocyte chemoattractant protein 1 , an inflammatory biomarker associated with cardiovascular disease risk . CONCLUSION Dietary supplementation with concentrated RGJ improves the lipoprotein profile , reduces plasma concentrations of inflammatory biomarkers and oxidized LDL , and may favor a reduction in cardiovascular disease risk To evaluate the effects of grape polyphenols on plasma lipids , inflammatory cytokines , and oxidative stress , 24 pre- and 20 postmenopausal women were r and omly assigned to consume 36 g of a lyophilized grape powder ( LGP ) or a placebo for 4 wk . The LGP consisted of 92 % carbohydrate and was rich in flavans , anthocyanins , quercetin , myricetin , kaempferol , and resveratrol . After a 3-wk washout period , subjects were assigned to the alternate treatment for an additional 4 wk . The placebo consisted of an equal ratio of fructose and dextrose and was similar in appearance and energy content ( 554 kJ ) to LGP . Plasma triglyceride concentrations were reduced by 15 and 6 % in pre- and postmenopausal women , respectively ( P < 0.01 ) after LGP supplementation . In addition , plasma LDL cholesterol and apolipoproteins B and E were lower due to LGP treatment ( P < 0.05 ) . Further , cholesterol ester transfer protein activity was decreased by approximately 15 % with intake of LGP ( P < 0.05 ) . In contrast to these beneficial effects on plasma lipids , LDL oxidation was not modified by LGP treatment . However , whole-body oxidative stress as measured by urinary F(2)-isoprostanes was significantly reduced after LGP supplementation . LGP also decreased the levels of plasma tumor necrosis factor-alpha , which plays a major role in the inflammation process . Through alterations in lipoprotein metabolism , oxidative stress , and inflammatory markers , LGP intake beneficially affected key risk factors for coronary heart disease in both pre- and postmenopausal women BACKGROUND Atherosclerotic cardiovascular disease is the most common cause of death among hemodialysis patients ; it has been attributed to increased oxidative stress , dyslipidemia , malnutrition , and chronic inflammation . Activation of neutrophils is a well-recognized feature in dialysis patients , and superoxide-anion production by neutrophil NADPH oxidase may contribute significantly to oxidative stress . OBJECTIVE The aim of the study was to compare the effects of dietary supplementation with concentrated red grape juice ( RGJ ) , a source of polyphenols , and vitamin E on neutrophil NADPH oxidase activity and other cardiovascular risk factors in hemodialysis patients . DESIGN Thirty-two patients undergoing hemodialysis were recruited and r and omly assigned to groups to receive dietary supplementation with RGJ , vitamin E , or both or a control condition without supplementation or placebo . Blood was obtained at baseline and on days 7 and 14 of treatment . RESULTS RGJ consumption but not vitamin E consumption reduced plasma concentrations of total cholesterol and apolipoprotein B and increased those of HDL cholesterol . Both RGJ and vitamin E reduced plasma concentrations of oxidized LDL and ex vivo neutrophil NADPH oxidase activity . These effects were intensified when the supplements were used in combination ; in that case , reductions in the inflammatory biomarkers intercellular adhesion molecule 1 and monocyte chemoattractant protein 1 also were observed . CONCLUSIONS Regular ingestion of concentrated RGJ by hemodialysis patients reduces neutrophil NADPH-oxidase activity and plasma concentrations of oxidized LDL and inflammatory biomarkers to a greater extent than does that of vitamin E. This effect of RGJ consumption may favor a reduction in cardiovascular risk Grape seed extract ( GSE ) has in vitro antioxidant activity but whether or not it works in vivo is not clear . In a fully r and omised , crossover trial with 4-week treatment periods on 36 men and women with above-average vascular risk , we aim ed to demonstrate that 2 g/day of GSE ( 1 g of polyphenols ) alone , or with 1 g/day of added quercetin in yoghurt , favourably alters vascular function , endothelial function , and degree of oxidative damage in comparison to a control yoghurt . GSE alone improved flow-mediated dilatation determined ultrasonically by an absolute 1.1 % compared with control . There was no effect of the combination of GSE with quercetin . No other blood or urine measure was altered . Thus sufficient polyphenols from GSE appear to be absorbed to influence endothelial nitric oxide production , and GSE has the potential to favourably influence vascular function OBJECTIVE The objective of the study was to evaluate the effects of a grape product rich in dietary fiber and natural antioxidants on cardiovascular disease risk factors . METHODS A r and omized , controlled parallel-group trial was carried out . Thirty-four non-smoking ( 21 normocholesterolemic and 13 hypercholesterolemic ) adults were supplemented for 16 wk with 7.5 g/d of grape antioxidant dietary fiber , a natural product containing 5.25 g of dietary fiber and 1400 mg of polyphenols . Nine non-supplemented non-smokers were followed as a control group . Fasting blood sample s , blood pressure , and anthropometric readings were obtained at baseline and at week 16 . Subjects were allowed to consume their regular diet , which was monitored weekly . RESULTS Grape antioxidant dietary fiber ( 7.5 g/d ) reduced significantly ( P < 0.05 ) total cholesterol ( 9 % ) , low-density lipoprotein cholesterol ( 9 % ) , and systolic and diastolic blood pressures ( 6 % and 5 % respectively ) . Greater reductions in total cholesterol ( 14.2 % ) and low-density lipoprotein cholesterol ( 11.6 % , P < 0.05 ) were observed in hypercholesterolemic subjects . No changes were observed in the control group . There was a reduction of 2.5 points in the Framingham Global Risk Score in the supplemented group . A significant reduction in triacylglycerol concentration took place in the supplemented hypercholesterolemic subjects ( 18.6 % , P < 0.05 ) . CONCLUSION Grape antioxidant dietary fiber showed significant reducing effects in lipid profile and blood pressure . The effects appear to be higher than the ones caused by other dietary fibers , such as oat fiber or psyllium , probably due to the combined effect of dietary fiber and antioxidants The aim of this study was to evaluate the effects of Eminol ® , the polyphenol-rich grape extract supplement ( 700 mg ) , on cardiovascular risk and oxidant stress indicators in a sample of volunteers . A r and omized , double-blind , placebo-controlled clinical trial was performed over 56 days and included 60 volunteers . Thirty volunteers took 700 mg of the grape extract , Eminol ® ( E ) , and 30 took the placebo ( P ) . On comparison of the results , a decrease in total cholesterol ( E : 213.77 ± 4.1 mg/dl and P : 245.57 ± 4.1 mg/dl ; p = 0.01 ) and LDL cholesterol ( E : 142.17 ± 3.1 mg/dl and P : 165.13 ± 3.1 mg/dl ; p = 0.02 ) levels as well as an increase in antioxidant capacity ( E : 65.63 ± 5.8 μmol TE/mg and P : 57.80 ± 7.7 μmol TE/mg ; p < 0.01 ) and vitamin E ( E : 11.46 ± 0.5 μg/ml and P : 9.06 ± 0.5 μg/ml ; p = 0.018 ) was observed . This result indicates that the grape extract Eminol ® modulated the lipid profile in terms of cardiovascular risk indicators , lowering total blood cholesterol and LDL cholesterol levels Obese individuals are at an increased risk of developing CVD , hypertension , type 2 diabetes , and bacterial and viral infections when compared with the normal-weight population . In a 9-week r and omised , double-blind , cross-over study , twenty-four obese subjects aged between 20 and 60 years and with a BMI between 30 and 45 kg/m2 were fed grape or placebo powder for 3-week intervals to determine the effects of dietary grapes on blood lipid profiles , plasma inflammatory marker concentrations and immune cell function . Blood sample s were collected on days 1 and 8 for obtaining baseline information and at weeks 3 , 4 , 8 and 9 . Comprehensive chemistry panels , lipid profile analyses by NMR , measurement of plasma inflammatory marker concentrations , and analyses of cytokine production by activated T lymphocytes and monocytes were performed for each blood draw . Dietary grape powder reduced the plasma concentrations of large LDL-cholesterol and large LDL particles compared with the placebo powder ( P < 0·05 ) . The concentrations of interferon-γ , TNF-α , IL-4 and IL-10 were measured in supernatants from peripheral blood mononuclear cells ( P BMC ) activated with anti-CD3/CD28 antibodies and those of TNF-α , IL-1β , IL-6 and IL-8 were measured in supernatants from P BMC activated with lipopolysaccharide ( LPS ) . No difference in the production of T-cell cytokines was observed between the two intervention groups . The production of IL-1β and IL-6 was increased in supernatants from LPS-activated P BMC in the grape powder group compared with the placebo powder group ( P < 0·05 ) . These data suggest that dietary grapes may decrease atherogenic lipid fractions in obese individuals and increase the sensitivity of monocytes in a population at a greater risk of developing infections A positive relationship between alcohol consumption and blood pressure ( BP ) is well-established but the relative effect of specific alcoholic beverages is controversial . This study aim ed to determine whether red wine may improve vascular function and have less of an impact on blood pressure because of its high content of antioxidant vasodilator polyphenolic compounds . Healthy normotensive men entered a 4-period crossover study comparing in r and om order 4 weeks of control – abstinence with similar periods of daily consumption of red wine ( 375 mL ; 39 grams alcohol ) , de-alcoholized red wine ( 375 mL ) , or beer ( 1125 mL ; 41 grams alcohol ) . Ambulatory systolic BP and diastolic BP and heart rate ( HR ) were measured together with vascular function as assessed by flow-mediated dilatation ( FMD ) and glyceryl trinitrate-mediated ( GTNMD ) dilatation of the brachial artery . The systolic and diastolic BP and HR were not different between control – abstinence and de-alcoholized red wine . However , compared with control – abstinence , both red wine and beer increased awake systolic BP ( 2.9 and 1.9 mm Hg , respectively ; P<0.05 ) and asleep HR ( 5.0 and 4.4 bpm ; P<0.05 ) . There were no specific effects of red wine , de-alcoholized red wine , or beer on FMD or GTNMD . Daily consumption of ≈40 grams alcohol as either red wine or beer for 4 weeks results in similar increases in systolic BP and HR . De-alcoholized red wine did not lower BP , and neither red wine nor de-alcoholized red wine influenced vascular function , suggesting that red wine polyphenolics do not have a significant role in mitigating the blood pressure-elevating effects of alcohol in men BACKGROUND Few studies have investigated the effect of dietary polyphenols on the complex human gut microbiota , and they focused mainly on single polyphenol molecules and select bacterial population s. OBJECTIVE The objective was to evaluate the effect of a moderate intake of red wine polyphenols on select gut microbial groups implicated in host health benefits . DESIGN Ten healthy male volunteers underwent a r and omized , crossover , controlled intervention study . After a washout period , all of the subjects received red wine , the equivalent amount of de-alcoholized red wine , or gin for 20 d each . Total fecal DNA was su bmi tted to polymerase chain reaction(PCR)-denaturing gradient gel electrophoresis and real-time quantitative PCR to monitor and quantify changes in fecal microbiota . Several biochemical markers were measured . RESULTS The dominant bacterial composition did not remain constant over the different intake periods . Compared with baseline , the daily consumption of red wine polyphenol for 4 wk significantly increased the number of Enterococcus , Prevotella , Bacteroides , Bifidobacterium , Bacteroides uniformis , Eggerthella lenta , and Blautia coccoides-Eubacterium rectale groups ( P < 0.05 ) . In parallel , systolic and diastolic blood pressures and triglyceride , total cholesterol , HDL cholesterol , and C-reactive protein concentrations decreased significantly ( P < 0.05 ) . Moreover , changes in cholesterol and C-reactive protein concentrations were linked to changes in the bifidobacteria number . CONCLUSION This study showed that red wine consumption can significantly modulate the growth of select gut microbiota in humans , which suggests possible prebiotic benefits associated with the inclusion of red wine polyphenols in the diet . This trial was registered at controlled-trials.com as IS RCT N88720134 High blood pressure ( BP ) variability , which may be an important determinant of hypertensive end-organ damage , is emerging as an important predictor of cardiovascular health . Dietary antioxidants can influence BP , but their effects on variability are yet to be investigated . The aim of the present study was to assess the effects of vitamin E , vitamin C and polyphenols on the rate of daytime and night-time ambulatory BP variation . To assess these effects , two r and omised , double-blind , placebo-controlled trials were performed . In the first trial ( vitamin E ) , fifty-eight individuals with type 2 diabetes were given 500 mg/d of RRR-α-tocopherol , 500 mg/d of mixed tocopherols or placebo for 6 weeks . In the second trial ( vitamin C-polyphenols ) , sixty-nine treated hypertensive individuals were given 500 mg/d of vitamin C , 1000 mg/d of grape-seed polyphenols , both vitamin C and polyphenols , or neither ( placebo ) for 6 weeks . At baseline and at the end of the 6-week intervention , 24 h ambulatory BP and rate of measurement-to-measurement BP variation were assessed . Compared with placebo , treatment with α-tocopherol , mixed tocopherols , vitamin C and polyphenols did not significantly alter the rate of daytime or night-time systolic BP , diastolic BP or pulse pressure variation ( P>0·05 ) . Treatment with the vitamin C and polyphenol combination result ed in higher BP variation : the rate of night-time systolic BP variation ( P= 0·022 ) and pulse pressure variation ( P= 0·0036 ) were higher and the rate of daytime systolic BP variation was higher ( P= 0·056 ) . Vitamin E , vitamin C or grape-seed polyphenols did not significantly alter the rate of BP variation . However , the increase in the rate of BP variation suggests that the combination of high doses of vitamin C and polyphenols could be detrimental to treated hypertensive individuals Background There is growing evidence that oxidative stress contributes to the pathogenesis of hypertension and endothelial dysfunction . Thus , dietary antioxidants may beneficially influence blood pressure ( BP ) and endothelial function by reducing oxidative stress . Objective To determine if vitamin C and polyphenols , alone or in combination , can lower BP , improve endothelial function and reduce oxidative stress in hypertensive individuals . Design A total of 69 treated hypertensive individuals with a mean 24-h ambulatory systolic blood pressure ≥ 125 mmHg participated in a r and omized , double-blind , placebo-controlled , factorial trial . Following a 3-week washout , participants received 500 mg/day vitamin C , 1000 mg/day grape-seed polyphenols , both vitamin C and polyphenols , or neither for 6 weeks . At baseline and post-intervention , 24-h ambulatory BP , ultrasound-assessed endothelium-dependent and -independent vasodilation of the brachial artery , and markers of oxidative damage , ( plasma and urinary F2-isoprostanes , oxidized low-density lipoproteins and plasma tocopherols ) , were measured . Results A significant interaction between grape-seed and vitamin C treatments for effects on BP was observed . Vitamin C alone reduced systolic BP versus placebo ( −1.8 ± 0.8 mmHg , P = 0.03 ) , while polyphenols did not ( −1.3 ± 0.8 mmHg , P = 0.12 ) . However , treatment with the combination of vitamin C and polyphenols increased systolic BP ( 4.8 ± 0.9 mmHg versus placebo ; 6.6 ± 0.8 mmHg versus vitamin C ; 6.1 ± 0.9 mmHg versus polyphenols mmHg , each P < 0.0001 ) and diastolic BP ( 2.7 ± 0.6 mmHg , P < 0.0001 versus placebo ; 1.5 ± 0.6 mmHg , P = 0.016 versus vitamin C ; 3.2 ± 0.7 mmHg , P < 0.0001 versus polyphenols ) . Endothelium-dependent and -independent vasodilation , and markers of oxidative damage were not significantly altered . Conclusion Although the mechanism remains to be eluci date d , these results suggest caution for hypertensive subjects taking supplements containing combinations of vitamin C and polyphenols Oxidation of low density lipoprotein cholesterol ( LDL-c ) is supposed to play a role in the generation of atherosclerotic lesions . Grape derived beverages supply a large number of nutritional antioxidants because of their high content of polyphenols . This might be one of the mechanisms behind the supposed beneficial effect of red wine . Wine also contains alcohol and its role in oxidation processes especially in vivo is unclear . In this study the effect of daily red wine consumption for 2 weeks on oxidizability status of LDL was investigated . The role of alcohol in LDL oxidation was further explored in in vitro experiments . After abstinence from alcoholic beverages , grape juices and tea for a week , seven healthy male volunteers consumed 375 ml of red wine ( 30 g alcohol ) per day during 2 weeks . At the start and end of the drinking period blood sample s were taken and the susceptibility of LDL-c to copper-induced oxidation was analyzed with the addition of distilled water ( control ) and dilutions of a 12 % alcohol solution , white wine and red wine . Although red wine at concentrations achievable in vivo caused a significant prolongation of the lag-time of metal ion dependent LDL oxidation in vitro ( 85.9+/-23.0 - 114.1+/-30.8 min , P<0 . 001 ) , a significant shortening of lag-time was found in vivo after the 2 weeks of wine consumption ( 56.3+/-13.0 min , P<0.001 ) . A shorter lag-time compared to the control was found for both alcohol and white wine in vitro . The changed oxidizability status of LDL after 2 weeks of wine consumption made it more susceptible for the in vitro antioxidant effect of red wine . At low dilutions red grape juice extended lag-time as well , which was not influenced by the addition of alcohol . Red wine has a strong inhibitory effect on copper-induced oxidation of LDL in vitro , while red grape juice has a minor effect , an effect which should be attributed to the non alcohol components in the beverages . In vivo , however , this effect can be overshadowed by the prooxidant influence of alcohol . The balance between alcohol and polyphenols of a wine may be critical for its in vivo effect on LDL oxidation Data suggest that polyphenol-rich products may improve endothelial function and other cardiovascular health risk factors . Grape and wine contain high amounts of polyphenols , but effects of these polyphenols have hardly been investigated in isolation in r and omized controlled studies . Our objective in this study was to test the chronic effect of polyphenol-rich solids derived from either a wine grape mix or grape seed on flow-mediated dilation ( FMD ) . Blood pressure and other vascular function measures , platelet function , and blood lipids were secondary outcomes . Thirty-five healthy males were r and omized in a double-blind , placebo-controlled crossover study consisting of three 2-wk intervention periods separated by 1-wk washout periods . The test products , containing 800 mg of polyphenols , were consumed as capsules . At the end of each intervention period , effects were measured after consumption of a low-fat breakfast ( ~751 kJ , 25 % fat ) and a high-fat lunch ( ~3136 kJ , 78 % fat ) . After the low-fat breakfast , the treatments did not significantly affect FMD . The absolute difference after the wine grape solid treatment was -0.4 % ( 95 % CI = -1.8 to 0.9 ; P = 0.77 ) and after grape seed solids , 0.2 % ( 95 % CI = -1.2 to 1.5 ; P = 0.94 ) compared with after the placebo treatment . FMD effects after the high-fat lunch and effects on secondary outcomes also showed no consistent differences between both of the grape solids and placebo treatment . In conclusion , consumption of grape polyphenols has no major impact on FMD in healthy men . Future studies should address whether grape polyphenols can improve FMD and other cardiovascular health risk factors in population s with increased cardiovascular risk Dietary polyphenols , such as those from grape products , may exert beneficial effects on cardiovascular health , including anti-hypertensive effects . We investigated the effect of a specific grape seed extract ( GSE ) rich in low-molecular-weight polyphenolic compounds on ambulatory blood pressure ( ABP ) in untreated subjects with pre- and stage I hypertension . In addition , potential mechanisms that could underlie the hypothesised effect of GSE on blood pressure ( BP ) , and platelet aggregation , were explored . The study was design ed as a double-blind , placebo-controlled , r and omised , parallel-group intervention study including seventy healthy subjects with systolic BP between 120 and 159 mmHg . A 1-week run-in period was followed by an 8-week intervention period , during which subjects consumed capsules containing either 300 mg/d of GSE or a placebo ( microcrystalline cellulose ) . Before and after the intervention , daytime ABP readings , 24 h urine sample s and fasting and non-fasting blood sample s were taken . The mean baseline systolic BP was 135.8 ( SE 1.3 ) mmHg and diastolic BP was 81.5 ( SE 0.9 ) mmHg . BP values were modestly , but not significantly , affected by the polyphenol-rich GSE treatment v. placebo with an effect of - 3.0 mmHg for systolic BP ( 95 % CI - 6.5 , 0.5 ) and - 1.4 mmHg for diastolic BP ( 95 % CI - 3.5 , 0.6 ) . Vasoactive markers including endothelin-1 , NO metabolites and asymmetric dimethylarginine , plasma renin activity and platelet aggregation were not affected by the GSE intervention . Our findings show that consumption of polyphenol-rich GSE does not significantly lower ABP in untreated subjects with pre- and stage I hypertension Background : Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function . Objectives : To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk . Design : In a r and omized , double-blind , placebo-controlled crossover trial , 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation ( 1300 mg daily ) and placebo for 4 weeks each , with a 4-week washout . Resting brachial diameter and brachial flow-mediated dilation ( FMD ) and biomarkers of inflammation , lipid peroxidation , and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models . Results : There was no evidence of improved FMD ( % change ) with muscadine grape seed ( muscadine grape seed : pre 5.2 % ± 0.3 % , post 4.6 % ± 0.3 % , p = 0.06 ; placebo : pre 5.3 % ± 0.4 % , post 5.2 % ± 0.4 % , p = 0.82 ; p for muscadine grape seed vs. placebo = 0.25 ) . However , there was a significant increase in baseline diameter ( mm ) with muscadine grape seed supplementation ( muscadine grape seed : pre 4.05 ± 0.09 , post 4.23 ± 0.10 , p = 0.002 ; placebo : pre 4.12 ± 0.11 , post 4.12 ± 0.10 , p = 0.93 ; p for muscadine grape seed vs. placebo = 0.026 ) . All other biomarkers were not significantly altered by muscadine grape seed supplementation . Conclusions : Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation , lipid peroxidation , or antioxidant capacity . However , the muscadine grape seed supplement did result in a significant increase in resting brachial diameter . The clinical significance of the effect on resting diameter is not yet established . More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits Many of the flavonoids found in grapes and grape products such as juice or wine have been known to exert antioxidant , anti‐inflammatory , platelet inhibitory and arterial relaxing effects either in vitro , in animal studies and in human trials . This study was design ed to test the effect of Concord grape juice consumption on altering blood pressure in hypertensive patients . Forty subjects were given 5.5 ml/kg body weight/day of either Concord grape juice ( CGJ ) or a calorie‐matched placebo drink every day for 8 weeks . Blood pressure ( BP ) was measured on weeks 0 , 4 and 8 . Compared to baseline , in the CGJ group systolic BP was reduced on average by 7.2 mm Hg ( p = 0.005 ) and diastolic BP was reduced on average by 6.2 mm Hg ( p = 0.001 ) at the end of 8 weeks . Comparable changes in the group getting the placebo product were ‐3.5 mm Hg ( NS ) and ‐3.2 mm Hg ( p = 0.05 ) Consuming Concord grape juice , which is high in polyphenolic compounds , may favorably affect BP in hypertensive individuals Hypertension is the most common condition seen in primary care and leads to myocardial infa rct ion , stroke , renal failure , and death if not detected early and treated appropriately . Patients want to be assured that blood pressure ( BP ) treatment will reduce their disease burden , while clinicians want guidance on hypertension management using the best scientific evidence . This report takes a rigorous , evidence -based approach to recommend treatment thresholds , goals , and medications in the management of hypertension in adults . Evidence was drawn from r and omized controlled trials , which represent the gold st and ard for determining efficacy and effectiveness . Evidence quality and recommendations were grade d based on their effect on important outcomes . There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg ; however , there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal , or in those younger than 30 years for a diastolic goal , so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion . The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease ( CKD ) as for the general hypertensive population younger than 60 years . There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor , angiotensin receptor blocker , calcium channel blocker , or thiazide-type diuretic in the nonblack hypertensive population , including those with diabetes . In the black hypertensive population , including those with diabetes , a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy . There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes . Although this guideline provides evidence -based recommendations for the management of high BP and should meet the clinical needs of most patients , these recommendations are not a substitute for clinical judgment , and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient

In patients with IgAN and normal or mildly impaired renal function , steroids significantly delay the progression to end stage kidney disease ( evidence from SR ) and improve proteinuria . Associating steroids and cytotoxic agents ( cyclophosphamide followed by oral azathioprine ) proves effective in patients with rapidly progressive renal disease ( evidence from RCT ) . Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers significantly improve proteinuria ( evidence from RCT ) , but there are no conclusive data on efficacy on hard patient level endpoints . There are no conclusive data available on the use of a therapy combining these agents . In IgAN patients current evidence supports the hypothesis that immunosuppressive agents delay the progression to end stage renal disease .

BACKGROUND The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic review s ( SR ) of r and omized trials ( RCT ) or RCT data only . In the present guideline , evidence of the use of immunosuppressive and non-immunosuppressive treatments in IgA nephropathy ( IgAN ) is presented .

Recently , our group has shown that a 3-month course of intravenous immunoglobulin ( 2 g/kg/monthly ) followed by 6 months of intramuscular immunoglobulins ( IMIG , 16.5 % , 0.35 ml/kg every 15 days ) was able to slow or to stop the decline in the glomerular filtration rate , to reduce proteinuria , hematuria , leukocyturia and the histological index of activity on renal biopsy in patients with severe forms of IgA nephropathy ( IGAN ) and Henoch-Schönlein purpura ( HSP ) . The aim of this open prospect i ve trial was to evaluate the efficacy and safety of low-dose immunoglobulin therapy in moderate IGAN and HSP with permanent proteinuria . Fourteen patients with moderate IGAN [ idiopathic IGAN : n = 11 ; chronic idiopathic HSP : n = 3 ] and permanent albuminuria were treated with polyvalent IMIG ( 16.5 % ) for 9 months ( 0.35 ml/kg once a week for 1 month , followed by 0.35 ml/kg every 15 days for a further 8 months ) . Eligibility criteria in the study were Lee histological stage I , II or III , albuminuria between 300 and 2,000 mg/day and a glomerular filtration rate > 70 ml/min/1.73 m2 . IMIG were well tolerated and only 1 patient withdrew from the trial . No viral , renal or immunological side effects were observed . IMIG induced a significant decrease in albuminuria as well as in the histological activity index in the 11 cases in which a follow-up biopsy was performed . There was also a decrease in serum IgA , serum beta 2-microglobulin and IgA immune complex levels , and an increase in serum IgG1 levels . Twelve of the 13 evaluable patients improved during treatment Protein trafficking across the glomerular capillary has a pathogenic role in subsequent renal damage . Despite evidence that angiotensin-converting enzyme ( ACE ) inhibitors improve glomerular size-selectivity , whether this effect is solely due to ANG II blocking or if other mediators also play a contributory role is not clear yet . We studied 20 proteinuric patients with IgA nephropathy , who received either enalapril ( 20 mg/day ) or the ANG II receptor blocker irbesartan ( 100 mg/day ) for 28 days in a r and omized double-blind study . Measurements of blood pressure , renal hemodynamics , and fractional clearance of neutral dextran of grade d sizes were performed before and after 28 days of treatment . Both enalapril and irbesartan significantly reduced blood pressure over baseline . This reduction reached the maximum effect 4 - 6 h after drug administration but did not last for the entire 24-h period . Despite transient antihypertensive effect , proteinuria was effectively reduced by both treatments to comparable extents . Neither enalapril nor irbesartan modified the sieving coefficients of small dextran molecules , but both effectively reduced transglomerular passage of large test macromolecules . Theoretical analysis of sieving coefficients showed that neither drug affected significantly the mean pore radius or the spread of the pore-size distribution , but both importantly and comparably reduced the importance of a nonselective shunt pathway . These data suggest that antagonism of ANG II is the key mechanism by which ACE inhibitors exert their beneficial effect on glomerular size-selective function and consequently on glomerular filtration and urinary output of plasma proteins IgA nephropathy is the world 's most common primary glomerulonephropathy . Recent evidence in a rat model implicated excessive production of oxygen-free radicals in the pathogenesis and suggested that vitamin E-treatment ameliorated progression . We studied this antioxidant therapy on the glomerular filtration rate ( GFR ) , proteinuria and hematuria in biopsy-proven IgA nephropathy in children . The duration of treatment or placebo was 2 years , with vitamin E treatment consisting of 400 IU/day in children weighing < 30 kg , and twice that dose for those > 30 kg . We measured GFR at entry , midpoint and exit . At baseline and at 4-month intervals after r and omization , urinary protein/creatinine ratios and urinalysis were examined . The mixed model procedure with log transformation was used in data analysis to test treatment difference as well as the potential time effect . Fifty-five patients were r and omized and 38 completed at least 1 year of follow-up . At entry , the clinical characteristics were not different between the treatment and placebo groups . There was a trend toward better preservation of GFR in vitamin E-treated versus placebo patients , 127±50 vs. 112±31 ml/min/1.73 m2 , respectively ( P=0.09 ) . The urinary protein/creatinine ratio was significantly lower in the vitamin E-treated group vs. placebo ; 0.24±0.38 vs. 0.61±1.37 ( P<0.013 ) . However , there was no difference in the prevalence of hematuria between the groups . Vitamin E treatment in our study patients was associated with significantly lower proteinuria , but no effect on hematuria . While there was a trend toward stabilization of GFR in the vitamin E-treated patients , long-term treatment and follow-up are needed to determine whether antioxidant therapy is associated with preservation of renal function in IgA nephropathy This study investigates the ability of low doses of angiotensin-converting-enzyme inhibitors , in combination with angiotensin II receptor blockers , to exert antiproteinuric effects in normotensive and proteinuric out patients with immunoglobulin A ( IgA ) nephropathy confirmed by biopsy . We performed a prospect i ve , r and omized , 6-month study of the effects of temocapril 1 mg ( n=10 ) , losartan 12.5 mg ( n=10 ) , and both ( n=11 ) on mild-to-moderate proteinuria 0.76+/-0.35 g/day ( range , 0.4 to 1.6 g/day ) and renal function . The study subjects comprised 31 normotensive and proteinuric out patients with IgA nephropathy accompanied by normal , or mild-to-moderately reduced but stable renal function ( glomerular filtration rate>50 ml/min ) without steroid or immunosuppressive therapy . We prospect ively evaluated blood pressure , proteinuria , renal function and biochemical parameters before and after 6 months of therapy . The combination therapy significantly reduced proteinuria ( 63.2 % ) compared with either temocapril or losartan alone ( 41.3 % and 36.6 % , respectively , p=0.04 and 0.01 , respectively ) . Blood pressure was most decreased in the group that received combination therapy . The reduced proteinuria did not correlate with reduced systolic or diastolic blood pressure or mean arterial pressure in any of the groups . The glomerular filtration rate fell during the first 3 months of combined therapy , but became reversible after a further 3 months of therapy . The combination significantly decreased angiotensin II ( p < 0.01 ) , and this decrease was greater than that by either drug alone . In conclusion , the effectiveness of the combined therapy may have been at least partly due to the greater inhibition of the action of angiotensin II in patients with IgA nephropathy . This strategy apparently reduced mild-to-moderate proteinuria in patients with normotensive IgA nephropathy Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme ( ACE ) inhibitors on the progression of IgA nephropathy ( IgAN ) , but prospect i ve and controlled studies demonstrating this effect are lacking . Forty-four patients with biopsy-proven IgAN , proteinuria > or = 0.5 g/d , and serum creatinine ( SCr ) < or = 1.5 mg/dl were r and omly assigned either to receive enalapril ( n = 23 ) or to a control group ( n = 21 ) in whom BP was controlled with antihypertensives other than ACE inhibitors . Primary outcome was renal survival estimated by a 50 % increase in baseline SCr . Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria . Baseline clinical findings were similar at baseline between enalapril-treated and control group , and there were no differences in BP control during follow-up . Mean follow-up was 78 + /- 37 mo in the enalapril group and 74 + /- 36 mo in the control group . Three patients ( 13 % ) in the enalapril group and 12 ( 57 % ) in the control group reached the primary end point ( P < 0.05 ) . Kaplan-Meier renal survival was significantly better in enalapril group than in control group : 100 % versus 70 % after 4 yr and 92 % versus 55 % after 7 yr ( P < 0.05 ) . Three patients in the enalapril group ( 13 % ) and 11 ( 52 % ) in the control group showed SCr > 1.5 mg/dl at the last visit ( P < 0.05 ) . Proteinuria significantly decreased in the enalapril group , whereas it tended to increase in the control group ( P < 0.001 between groups ) . In conclusion , ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function Twenty children and adolescents with IgA glomerulonephritis were enrolled in a crossover trial . Each received 12 weeks of prednisone therapy and 12 weeks of placebo dosing . Urinary protein and erythrocyte excretion were monitored during both courses . There was no evidence that , under the conditions of the study , corticosteroid therapy was effective in IgA nephropathy BACKGROUND Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy ( IgAN ) , a prospect i ve placebo-controlled r and omized study was started in patients with IgAN using mycophenolate mofetil ( MMF ) . METHODS A total of 34 patients with IgAN were treated with salt intake restriction , angiotensin-converting enzyme ( ACE ) inhibition and MMF 2 g per day ( N= 21 ) or placebo ( N= 13 ) . After 36 months of follow-up clinical , biochemical , and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis . RESULTS Therapy had to be stopped prematurely in five patients . Two patients ( MMF group ) evolved to end-stage renal disease ( ESRD ) . There was no difference between groups in the percentage of patients with a decrease of 25 % or more in the inulin clearance or with a serum creatinine increase of 50 % or more over 3 years . There was also no significant difference between groups in annualized rate of change of serum creatinine , computed by linear regression analysis . No significant difference was noted between groups for inulin clearance , serum creatinine , proteinuria , blood pressure , or other parameters of renal function . Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group . As a function of time , a significant decline in both groups was noted of proteinuria , parenchymal thickness of the kidneys and C3d . CONCLUSION In patients with IgAN at risk for progressive disease , no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/ outcome or proteinuria . However , larger r and omized studies are needed to confirm or reject these results The role of immunosuppressive therapy in the management of IgA nephropathy ( IgAN ) remains controversial . No consensushas yet emerged on the specific treatment of IgAN and this ismostly related to the lack of complete underst and ing of themultifactorial pathogenesis of the disease . Choice of appropriatetherapeutic agents is further limited by the difficulty inidentifying patients who would most likely benefit from therapy . Immunosuppressive therapy has not been recommended in patients with isolated hematuria and well preserved renal function becauseof their generally favourable prognosis and there are no clinical trials in this area . Considering that mild IgAN may be an earlystage of the disease and can be reversed by immunosuppressiveagents we have used prednisolone and azathioprine in patients with isolated hematuria in a prospect i ve , r and omized , controlled study since 1988 . In this prospect i ve study we have evaluated theeffect of prednisolone with azathioprine on the clinical courseof IgAN and its impact on histologic parameters and preventionof progression in patients with isolated hematuria . We studied 43biopsy-proven IgAN patients ( 29 males and 14 females , agedbetween 13–63 years , mean age 28 ± 6 ) with isolated hematuria and well-preserved renal function ( Ccr 89.2 ± 10.2 ml/min ) . The patients were assigned to two groups : 21 patients receivedprednisolone ( 40 mg/day ) and azathioprine ( 100 mg/day ) orally forfour months ( group A ) and 22 patients received no specifictreatment for IgAN and served as a control group ( group B ) . InGroup A prednisolone was reduced to 20 mg/day at the end of thesecond month , then slowly tapered over a two-month period and stopped . The median duration of follow-up was 60 months ( range12–120 months ) . At the end of the therapy hematuria disappearedin 17 patients . In three patients who did not respond to therapy , microscopic hematuria persisted . Of the 22 patients of group B , three had episodes of gross hematuria and proteinuria > 500mg/day . No significant changes in biochemical profile wereobserved in either group . Thirteen patients ( eight from thetreated , five from the untreated group ) underwent a repeat biopsyafter 12 ± 6 months ( range 10–25 ) . An improvement ofhistopathological features was noted in Group A , whiledeterioration was noted in Group B. We conclude that earlytreatment with prednisolone and azathioprine appears to bebeneficial in preventing the progression of immunologic renalinjury and in improving histopathological features in IgAN patients with isolated hematuria BACKGROUND It has been postulated that angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist ( ACEI/ATRA ) may decrease proteinuria in patients with glomerulonephritis by its action on the glomerular basement membrane . We therefore studied the relationship between the response of patients with IgA nephritis ( IgAN ) to ACEI/ATRA therapy by decreasing proteinuria and its effect on the selectivity index ( SI ) in these patients . METHODS Forty-one patients with biopsy-proven IgAN entered a control trial , with 21 in the treatment group and 20 in the control group . The entry criteria included proteinuria of 1 g or more and /or renal impairment . Patients in the treatment group received ACEI/ATRA or both with three monthly increases in dosage . In the control group , hypertension was treated with atenolol , hydrallazine , or methyldopa . The following tests were performed at three monthly intervals : serum creatinine , total urinary protein , SI , sodium dodecyl sulfate-polyacrylamide gel electrophoresis ( SDS-PAGE ) , and low molecular weight ( LMW ) proteinuria . RESULTS After a mean duration of therapy of 13 + /- 5 months , in the treatment group , there was no significant change in serum creatinine , proteinuria , or SI , but in the control group , serum creatinine deteriorated from 1.8 + /- 0.8 to 2.3 + /- 1.1 mg/dL ( P < 0.05 ) . Among the 21 patients in the treatment group , 10 responded to ACEI/ATRA therapy determined as a decrease in proteinuria by 30 % ( responders ) , and the other 11 did not respond ( nonresponders ) . Among the responders , SI improved from a mean of 0.26 + /- 0.07 to 0.18 + /- 0 . 07 ( P < 0.001 ) , indicating a tendency toward selective proteinuria . This was associated with an improvement in serum creatinine from mean 1.7 + /- 0.6 to 1.5 + /- 0.6 mg/dL ( P < 0.02 ) and a decrease in proteinuria from a mean of 2.3 + /- 1.1 to 0.7 + /- 0.5 g/day ( P < 0 . 001 ) . After treatment , proteinuria in the treatment group ( 1.8 + /- 1 . 6 g/day ) was significantly less than in the control group ( 2.9 + /- 1 . 8 g/day , P < 0.05 ) . The post-treatment SI in the responder group ( 0 . 18 + /- 0.07 ) was better than that of the nonresponder group ( 0.33 + /- 0.11 , P < 0.002 ) . Eight out of 21 patients in the treatment group who had documented renal impairment had improved renal function compared with two in the control group ( chi2 = 4.4 , P < 0 . 05 ) . Of the eight patients in the treatment group who improved their renal function , three normalized their renal function compared with one from the control group . CONCLUSION Our data suggest that ACEI/ATRA therapy may be beneficial in patients with IgAN with renal impairment and nonselective proteinuria , as such patients may respond to therapy with improvement in protein selectivity , decrease in proteinuria , and improvement in renal function . ACEI/ATRA therapy probably modifies pore size distribution by reducing the radius of large unselective pores , causing the shunt pathway to become less pronounced , result ing in less leakage of protein into the urine AIM In recent reports , some kinds of HMG-CoA reductase inhibitors were able to decrease proteinuria and to improve renal function . Here we aim ed to clarify the effect of fluvastatin ( an HMG-CoA reductase inhibitor ) on proteinuria and renal function in children with mild IgA nephropathy . PATIENTS AND METHODS We conducted a prospect i ve controlled study of 30 children who had been recently diagnosed with normocholesterolemic IgA nephropathy following the detection of a minor lesion or of focal mesangial proliferation and moderate proteinuria . The 30 patients were r and omly assigned to receive both of 20 mg of fluvastatin and 5 mg/kg of dipyridamole ( group 1 ) , or 5 mg/kg of dipyridamole only ( group 2 ) for 1 year . RESULTS By the end of the trial , urinary protein , hematuria , BUN and serum creatinine levels had significantly decreased in the patients of group 1 as compared to baseline . Serum total cholesterol , triglyceride and LDL cholesterol levels had significantly decreased , while serum total protein and albumin , and creatinine clearance had significantly increased in group 1 as compared to baseline and group 2 . The urinary protein level had significantly decreased in the group 2 patients as compared to baseline , but only slightly . CONCLUSIONS The results of this study suggest that fluvastatin and dipyridamole treatment yields an antiproteinuric effect and leads to the amelioration of renal function in moderately proteinuric patients with mild histological IgA nephropathy Cyclosporin 's known regulatory effects on the immune system suggest that it may be useful in treating patients with IgA nephropathy . A r and omised prospect i ve single blind study of 19 patients with IgA nephropathy and proteinuria ( greater than 1.5 g/day ) was conducted to determine the therapeutic value of cyclosporin . The patients were divided into two groups : nine patients were given oral cyclosporin ( 5 mg/kg/day ) for 12 weeks and 10 patients a placebo . The two groups were comparable in age of presentation , ratio of men to women , plasma creatinine and serum IgA concentrations , creatinine clearance , daily urinary protein excretion , severity of renal histopathological changes , and prevalence of hypertension . A significant reduction of proteinuria and an increase of plasma albumin concentration was observed with treatment with cyclosporin . Nevertheless , a significant rise of plasma creatinine concentration and a fall in creatinine clearance was found in patients after six weeks ' treatment with cyclosporin , although the plasma cyclosporin concentrations were maintained within a narrow therapeutic range . Serum IgA concentrations were reduced in seven patients . Renal function improved within eight weeks after treatment was stopped . Three months after treatment was stopped proteinuria remained less than half of the pretreatment values in three patients . No similar biochemical changes were observed in the controls . Short term cyclosporin therapy may be beneficial in reducing proteinuria in some patients with IgA nephropathy . As transient renal impairment was seen , despite cyclosporin concentrations being maintained within a narrow therapeutic range , indiscriminate use of cyclosporin in glomerulonephritis should be discouraged In several studies diets supplemented with fish oil containing a high proportion of omega-3-polyunsaturated fatty acids ( w-3-PUFA ) have been shown to produce beneficial effects , such as a reduction in blood pressure , lipid levels and inflammation , all of which may affect the course of IgA nephropathy . However , the results of hitherto published studies concerning IgA nephropathy have been inconclusive . We therefore carried out a prospect i ve , r and omized , placebo-controlled six-month study with a higher daily dose of w-3-PUFA than used in previous studies . Thirty-two adult patients with biopsy-proven IgA nephropathy and proteinuria completed the study : 15 were assigned to a fish-oil product with a high percentage of w-3-PUFA ( K 85 , with 55 % eicosapentenoic and 30 % docosahexenoic acid ) and 17 to corn oil , 6 g daily of either oil . At the start , no significant differences were found between the two groups ( K85 : 3 females/12 males , mean age 39 years ( range 22 - 64 ) , corn oil : 4 females/13 males , age 42 years ( range 26 - 68 ) . By six months , supplements of K85 result ed in a slight but significant reduction in glomerular filtration rate ( GFR ) compared to the start : 51Cr-EDTA : 63 + /- 22 to 59 + /- 21 ml/min/1.73 m2 ( p < 0.05 ) , creatinine clearance : 91 + /- 31 to 79 + /- 25 ml/min ( p < 0.01 ) , s-creatinine : 131 + /- 39 to 139 + /- 39 mumol/l , whereas no change in GFR was observed in the corn oil group . The urinary total protein and red blood cell excretions were not affected in any of the groups . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease . We aim ed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker , and monotherapy of each drug at its maximum dose , in patients with non-diabetic renal disease . METHODS 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan . After screening and an 18-week run-in period , 263 patients were r and omly assigned angiotensin-II receptor blocker ( losartan , 100 mg daily ) , angiotensin-converting-enzyme inhibitor ( tr and olapril , 3 mg daily ) , or a combination of both drugs at equivalent doses . Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease . Analysis was by intention to treat . FINDINGS Seven patients discontinued or were otherwise lost to follow-up . Ten ( 11 % ) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 ( 23 % ) of 85 on tr and olapril alone ( hazard ratio 0.38 , 95 % CI 0.18 - 0.63 , p=0.018 ) and 20 ( 23 % ) of 86 on losartan alone ( 0.40 , 0.17 - 0.69 , p=0.016 ) . Covariates affecting renal survival were combination treatment ( hazard ratio 0.38 , 95 % CI 0.18 - 0.63 , p=0.011 ) , age ( 1.30 , 1.03 - 2.29 , p=0.009 ) , baseline renal function ( 1.80 , 1.02 - 2.99 , p=0.021 ) , change in daily urinary protein excretion rate ( 0.58 , 0.24 - 0.88 , p=0.022 ) , use of diuretics ( 0.80 , 0.30 - 0.94 , p=0.043 ) , and antiproteinuric response to tr and olapril ( 0.81 , 0.21 - 0.91 , p=0.039 ) . Frequency of side-effects with combination treatment was the same as with tr and olapril alone . INTERPRETATION Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy . However , since some patients reached the combined primary endpoint on combined treatment , further strategies for complete management of progressive non-diabetic renal disease need to be research ed A multicentre , r and omized , placebo-controlled study was performed in 39 adult patients with biopsy-proven IgA nephropathy with the aim of comparing the effects of the ACE inhibitor fosinopril and placebo on proteinuria . All patients had normal blood pressure and normal renal function . Proteinuria ranged from 1.0 to 2.5 g/24 h. After a 3-month run-in period , fosinopril and placebo were r and omly administered in two 4-month sequences separated from cross-over treatment by a 1-month interval . The mean values of creatinine clearance did not change during either the placebo or the treatment sequences . The mean values of mean arterial pressure ( MAP ) were significantly lower during the fosinopril sequence ( 90.4 + /- 9.0 mmHg ) than in basal conditions ( 92.8 + /- 9.1 mmHg ) ( P = 0.034 ) . The mean basal values of proteinuria were 1.74 + /- 0.84 g/24 h. They were unchanged during the placebo sequence ( 1.79 + /- 1.20 ) and fell to 1.37 + /- 0.98 g/24 h after 4 months of fosinopril treatment . Using a multivariate statistical analysis , the treatment effect by time on proteinuria was significantly evident only in the fosinopril sequence ( Wilks test , P = 0.033 ) . Changes in protein excretion were not correlated with changes in MAP , baseline plasma renin activity , and urinary sodium excretion . This controlled study shows that fosinopril can significantly reduce proteinuria even in normotensive patients with IgA nephropathy . Obviously , the results of treatment with ACE inhibitors on long-term renal prognosis remain to be eluci date Proteinuria plays a causal role in the progression of IgA nephropathy ( IgAN ) . A previous controlled trial showed that steroids are effective in reducing proteinuria and preserving renal function in patients with IgAN . The objective of this study was to evaluate the long-term effectiveness of steroids in IgAN , examine the trend of proteinuria during follow-up ( starting from the hypothesis that the degree of reduction in proteinuria may influence IgAN outcome ) , and evaluate how histologic scores can influence steroid response . A secondary analysis of a multicenter , r and omized , controlled trial of 86 adult IgAN patients who were receiving supportive therapy or intravenous methylprednisolone plus oral prednisone for 6 mo was conducted . Ten-year renal survival was significantly better in the steroid than in the control group ( 97 % versus 53 % ; log rank test P = 0.0003 ) . In the 72 patients who did not reach the end point ( doubling in baseline serum creatinine ) , median proteinuria significantly decreased ( 1.9 g/24 h at baseline , 1.1 g/24 h after 6 mo , and 0.6 g/24 h after a median of 7 yr ) . In the 14 progressive patients , proteinuria increased from a median of 1.7 g/24 h at baseline to 2.0 g/24 h after 6 mo and 3.3 g/24 h after a median of 5 yr . Steroids were effective in every histologic class . Cox multivariate regression analyses showed that , in addition to steroids , a low baseline histologic score , a reduction in proteinuria after 6 mo , and no increase in proteinuria during follow-up all were independent predictors of a beneficial outcome . Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN . The histologic picture and proteinuria during early and late follow-up improve the prediction of outcome , but considerable variability remains outside the model This study was undertaken to clarify the effect of corticosteroids on the long-term clinical course of the early stage of progressive IgA nephropathy . The early stage of progressive IgA nephropathy was defined as having moderate proteinuria between 1 and 2 g/day , creatinine clearance values of 70 ml/min or more , and a histological severity score of 7 or more . The number of patients who fulfilled these three conditions during 12 years from 1972 and then were continuously followed up for 10 years or more in our renal unit was 46 . Twenty of them received steroid treatment for an average period of 18 months , and the remaining 26 patients had no steroid treatment . The initial data of proteinuria , creatinine clearance values , frequency of hypertensive cases , and histological scores of 7 or more were not different between the two groups : 1.4 + /- 0.4 vs. 1.3 + /- 0.3 g/day , 85 + /- 14 vs. 88 + /- 13 ml/min , 25 vs. 38 % , and 10.7 + /- 2.5 vs. 11.0 + /- 3.0 , respectively . During the follow-up period of 10 years , the renal survival rate was significantly different between the two groups ( 100 vs. 84 % 5 years after starting therapy and 80 vs. 34 % 10 years later ; p < 0.001 ) . The final creatinine clearance values were significantly different between the two groups ( 54 + /- 35 vs. 20 + /- 29 ml/min ; p < 0.005 ) . On the other h and , the patient groups with mild histological changes or decreased renal function due to moderate proteinuria showed no significant differences in the final outcome . These results indicate that corticosteroids are beneficial in stabilizing the renal function for a long time during the early stage of progressive IgA nephropathy , although this study was not a r and omized one Fifty-two pairs of patients with idiopathic diffuse mesangial proliferative glomerulonephritis entered a controlled 3-year prospect i ve trial of a combination regimen of cyclophosphamide , dipyridamole and warfarin . In the treatment group proteinuria decreased significantly ( p less than 0.01 ) and renal function remained stable , but in the control group there was no change in proteinuria and creatinine clearance ( Ccr ) decreased significantly ( p less than 0.01 ) . The time patients with renal impairment in the control group and those in the treatment group took to reach end stage renal failure was significantly different ( 6.1 years versus 8.9 years , p less than 0.02 ) . Among the patients with IgA nephritis , those in the treatment group ( n = 27 ) had stable renal function and a significant decrease in proteinuria ( p less than 0.01 ) but in the control group ( n = 21 ) there was a significant fall in Ccr ( p less than 0.01 ) and rise in serum creatinine ( p less than 0.02 ) with no change in proteinuria . Among 23 pairs of patients in the study who were matched for renal function and degree of glomerulosclerosis , those in the treatment group had stable renal function and decrease in proteinuria ( p less than 0.01 ) whereas those in the control group had decreased Ccr ( p less than 0.01 ) but no change in proteinuria OBJECTIVE To investigate the effectiveness safety and tolerance of mycophenolate mofeil(MMF ) in severe IgA nephropathy and evaluate the dosage adjustment and course for clinical treatment . METHODS 62 patients with IgA nephropathy diagnosed by renal biopsy as Lee 's grade IV and V with urinary protein > 2.0 g/d were enrolled r and omly in the trial . The initial dosage of MMF was 1.0 g/d ( body weight < 50 kg ) or 1.5 g/d ( body weight > 50 kg ) . The dosage was reduced to 0.75 approximately 1.0 g/d after 6 months treatment , the maintaining dosage was 0.5 approximately 0.75 g/d after 12 months . The total course of treatment lasted at least 12 months . Another 31 patients matched with age gender and severity of renal damage were given prednisone orally ( 0.8mg(;)kg(;)d ) ( control group).Blood and urinary tests hepatic and renal function plasma albumin serum triglyceride and cholesterol 24 h protein excretion urinary NAG enzyme , creatinine clearance(Ccr ) were performed before and 3 6 12 18 months after treatments in both groups 5 patients in MMF group received repeated renal biopsy . RESULTS ( 1 ) After 3 months treatment , decrease of urinary protein ( 1.9 g/24 h + /- 1.6 g/24 h vs 3.2 g/24 h + /- 1.7 g/24 h , P < 0.01 ) and improvement of plasma albumin ( 41 g/L + /- 6 g/L vs 37 g/L + /- 6 g/L , P < 0.01 ) were observed in MMF groups while in control group , no significant changes were found in uinary protein ( 2.3 g/24 h + /- 1.8 g/24 h vs 2.9 g/24 h + /- 1.5 g/24 h , P < 0.05 ) and plasma albumin ( 40 g/L + /- 6 g/L vs 37 g/L + /- 6 g/L , P < 0.05 ) . After treatment for 6 , 12 and 18 months , both group showed obvious alleviation of proteinuria and albumin . At the 12th and 18th month , the proteinuria in MMF group was significantly improved than that in control group ( 0.8 g/24 h + /- 0.8 g/24 h vs 1.4 g/24 h + /- 1.6 g/24 h and 0.6 g/24 h + /- 0.7 g/24 h vs 1.4 g/24 h + /- 1.3 g/24 h , P < 0.05 respectively ) . The remission rate and total effective rate of MMF group were higher than those of the control group ( 44.4 % vs 19.1 % and 88.9 % vs 61.9 % , P < 0.05 respectively ) . Patients were administered with MMF for 13.8 + /- 6.3 months ( 6 approximately 30 m ) . ( 2 ) Serum cholesterol and triglyceride were remarkably reduced after 6,12 and 18 months treatment in MMF group , no significant difference was found in control group(P < 0.05 ) . ( 3 ) For the 6 patients with renal insufficiency in MMF group , MMF treatment was significantly effective in 1 patient , effective in 2 patients , not effective in 3 patients with an overall effective rate of 50 % . For the 7 patients with renal insufficiency in control group , the treatment was significantly effective in 1 patient , effective in 1 patient , not effective in 5 patients and total effective rate is 28.6 % . ( 4 ) 5 patients in MMF group received repeated renal biopsy after 7 approximately 12 months treatment ( mean 9.8 + /- 2.3 m ) . The results showed that the interstitial lesions were alleviated . No special drug-induced renal damage was obtained . ( 5 ) Side effects : 3 patients in MMF group suffered from slight diarrhea , 1 patient herpes zoster , all of them got remission without drug withdrawal . 1 patient suffered nausea in the first weeks . No significant change was found in hepatic function ( P > 0.05 ) . CONCLUSIONS MMF is more effective in reducing proteinuria and serum lipid than the currently widespread use of prednisone therapy in IgA nephropathy patients with Lee SMK 's grade IV approximately V and urinary protein > 2.0 g/d . Treatment with MMF associates with less adverse effect and good tolerance BACKGROUND IgA nephropathy ( IgAN ) is the most common form of glomerulonephritis worldwide . Up to 40 % progress to end-stage renal disease ( ESRD ) over 10 - 20 years . Currently , treatment is limited . We studied the use of mycophenolate mofetil ( MMF ) vs placebo in a group of North American IgAN patients at high risk for progressive disease . METHODS Included were 32 patients aged 18 - 75 years from multiple centres who had their biopsies read at Columbia and who had at least 1 g of proteinuria per day plus at least two of the following risk factors : ( i ) male sex ; ( ii ) hypertension > 150/90 mmHg or requiring antihypertensive medications ; ( iii ) creatinine clearance , measured by 24 h urine collection , < 80 and > 20 ml/min at time of enrolment ; and ( iv ) presence of glomerulosclerosis or tubulointerstitial atrophy and fibrosis on renal biopsy . Patients were r and omized to either 1 year of MMF , titrated up to a dose of 1000 mg bid , or placebo . Total follow-up was 2 years . All patients received angiotensin inhibition medication . The primary outcome was a 50 % increase in baseline serum creatinine ( SCr ) . Secondary outcomes were an increase of 0.5 mg/dl SCr , ESRD and a 50 % reduction in proteinuria . RESULTS The mean baseline SCr was 2.4 mg/dl . No statistically significant differences were observed for any outcome . Five of 17 who received MMF vs two of 15 patients in the placebo group reached a 50 % increase in SCr ( P = 0.4 ) . In both groups , all patients who reached the primary outcome also reached ESRD . Ten who received MMF vs seven who received placebo had a 0.5 mg/dl increase in SCr ( P = 0.7 ) Only three MMF and two placebo patients had a 50 % reduction in 24 h proteinuria . No serious adverse events occurred in either group . CONCLUSION No benefit was seen in patients who received MMF in this high risk group , probably reflecting the relatively advanced stage of disease of our population . We conclude that MMF is probably not effective in patients with IgAN who already have moderate renal insufficiency In a single-center , multiple-referral source study , 38 patients with progressive IgA nephropathy and controlled hypertension were r and omized to treatment with prednisolone and cytotoxic agents , to therapy with low-dose cyclophosphamide then azathioprine , and to control groups . The follow-up period lasted 2 to 6 yr . Renal survival , as assessed by Kaplan-Meier analysis annually to 5 yr , showed significant preservation of function from 3 yr in the treatment group and 82 , 82 , 72 , and 72 % for 2 , 3 , 4 , and 5 yr , respectively , compared with 68 , 47 , 26 , and 6 % in controls . Rate of loss of renal function , evaluated objective ly by least-squares analyses of reciprocal serum creatinine , was reduced- and in one-third of the patients , arrested-during immunosuppressive treatment . Proteinuria , present in all patients at the time of entry into the trial , was reduced by treatment from 12 mo , compared with pretreatment levels or controls ; erythrocyturia was reduced from 6 mo . Histologic activity and chronicity indexes were determined in renal biopsies performed at trial entry . Multivariate analysis demonstrated that mesangial cell proliferation and matrix scores were highest in those patients with more rapidly progressive disease . No morphologic variable or residual renal function predicted response to immunosuppressive therapy at entry . Mean arterial pressures did not differ significantly between treatment and control groups . There was thus no explanation other than treatment for the improved outcome in patients who received immunosuppressive therapy . Morbidity attributable to treatment or to renal failure occurred in both groups ; an audit showed that benefits of therapy outweighed expected or minor side effects of drugs in this population at risk of end-stage renal failure . Patients selected for moderately progressive IgA nephropathy benefit from treatment with prednisolone and cytotoxic agents ; results are consistent with modulation of systemic immune response or nephritic injury , thus explaining improved outcome , and indicate that this therapy has an acceptably low risk of side effects Thirty-seven patients with biopsy proven mesangial IgA nephropathy were prospect ively allocated to either two years of treatment with eicosapentanoic acid ( EPA ) 10 g per day or no treatment . At entry treated and untreated patients with renal dysfunction ( Group A ) or patients with normal serum creatinine less than 0.12 mmol/l ( Group B ) did not differ in serum creatinine , creatinine clearance , urinary protein excretion , or quantitative urinary red cell counts . Compliance with EPA therapy was excellent as assessed by plasma fatty acid profiles . At the end of the trial creatinine clearance in treated patients had gone from 80 + /- 16 to 57 + /- 17 ml/min ( p less than 0.05 ) and in untreated patients from 76 + /- 18 to 55 + /- 14 ( p less than 0.05 ) . There were no beneficial effects in either Group A or Group B patients . The only two patients who had improvement in renal function were in the EPA treatment group . Although no side effects of treatment were noted , EPA does not alter the course of established mesangial IgA nephropathy Diffuse proliferative immunoglobulin A ( IgA ) nephropathy has the potential risk for end-stage renal disease . However , treatment of IgA nephropathy has not been well established . To determine whether early treatment with corticosteroids ameliorates the proliferative lesions of diffuse proliferative IgA nephropathy , we conducted a prospect i ve , r and omized , controlled trial . Inclusion criteria were as follows : duration of abnormal urinalysis results less than 36 months , proteinuria less than 1.5 g/d of protein , serum creatinine level less than 1.5 mg/dL , and mesangial cell proliferation or matrix accumulation involving more than 50 % of glomeruli . Twenty-one patients were r and omly assigned to two groups : the corticosteroid group and the antiplatelet group . After 1 year of treatment , repeated renal biopsy was performed in 19 patients . We evaluated glomerular filtration rate , blood pressure , proteinuria , and histological parameters , including light microscopic findings and staining of alpha-smooth muscle actin ( alphaSMA ) , as a marker of myofibroblast-like cells and fibronectin EDA ( EDA-FN ) as an indicator of renal fibrosis . After 1 year of treatment , proteinuria significantly decreased in the corticosteroid group . Histological findings , such as mesangial cell proliferation , mesangial matrix accumulation , and cellular crescents , showed significant improvement in the corticosteroid group but not in the antiplatelet group . Expression of alphaSMA in glomeruli significantly decreased in the corticosteroid group but not in the antiplatelet group . EDA-FN did not change in either group . We conclude that early treatment with corticosteroids for adult diffuse proliferative IgA nephropathy is effective in reducing renal injury BACKGROUND No accepted therapy has been established for progressive immunoglobulin A ( IgA ) nephropathy . METHODS A prospect i ve , r and omized , controlled trial of low-dose prednisolone therapy was performed in patients with IgA nephropathy with moderate histological characteristics . Forty-three patients in the steroid group and 47 patients in the control group were included in the study . The initial dose of prednisolone was 20 mg/d , gradually tapered to 5 mg/d during 2 years . RESULTS Baseline urine protein-creatinine ratio ( UP-UCR ) was significantly greater in the steroid group than in controls . Follow-up duration was 65 + /- 25 months in the steroid group and 64 + /- 23 months in controls . Changes in UP-UCR from baseline , ie , UP-UCR at last follow-up minus UP-UCR at baseline , were significantly lower in the steroid group than in controls ( steroid group , -0.84 + /- 1.78 ; controls , 0.26 + /- 1.65 ; P = 0.0034 ) . Kidney survival was similar in both groups . Patients were divided into two subgroups according to clinical course . There were 28 improved patients and 15 unimproved patients in the steroid group and 27 improved patients and 20 unimproved patients in the control group . In the steroid group , UP-UCR was significantly greater in the unimproved than improved subgroup ( 3.1 + /- 2.6 versus 1.8 + /- 1.5 ) . CONCLUSION These data suggest that our protocol had an antiproteinuric effect , but could not improve kidney survival . Because the effect of steroid therapy to prevent the progression of IgA nephropathy is believed to be linked closely to reduction in urinary protein , an insufficient dose of prednisolone in our protocol may be the reason for the discrepancy between the effect on proteinuria and kidney survival A r and omized prospect i ve study of 34 patients with IgA nephropathy and nephrotic syndrome was conducted to determine the therapeutic value of corticosteroid therapy . The patients were divided into two groups : Group A , 17 patients receiving oral prednisolone/prednisone for four months ; and Group B , 17 patients receiving no corticosteroid therapy and acting as controls . The groups are comparable in age of presentation , sex ratio , and duration of study . No difference in serum creatinine levels , creatinine clearance , serum IgA levels , severity of renal histopathological changes , incidence of hypertension or incidence of impaired renal function could be demonstrated but the Group A patients had significantly heavier proteinuria . During the mean study period of 38 months ( range 12 - 106 ) , no significant difference in serum creatinine levels and creatinine clearance was demonstrated between the two groups . Forty percent of the Group A patients developed complications related to steroid therapy . Despite the overall lack of therapeutic value in IgA nephropathy with nephrotic syndrome as reflected by change in renal function , corticosteroid treatment result ed in excellent remission of nephrotic syndrome in 80 % of patients with mild glomerular histopathological changes . Our findings suggest that corticosteroid therapy is only beneficial to selected groups of patients with IgA nephropathy and nephrotic syndrome but its indiscriminate use should be discouraged Angiotensin-converting enzyme ( ACE ) inhibitors and AT1-receptor antagonists ( ARAs ) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure . Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect , which may occur because ACE inhibitors do not completely reduce angiotensin II ( Ang II ) production . Ang II is also produced by chymase . Thus , combination therapy better antagonizes the effects of Ang II . The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure . Therefore , enalapril ( E ; 10 mg/d ) and losartan ( LOS ; 50 mg/d ) were r and omly administered alone and then in association ; initial dosages were doubled when drugs were administered alone and in association . To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria , both ambulatory and office blood pressures were recorded . E and LOS administered alone reduced proteinuria by the same extent ; no further reduction was observed when E and LOS alone were administered at a doubled dose . When E and LOS were coadministered , proteinuria decreased by a greater extent compared with E and LOS alone ; an additional reduction in proteinuria was observed when combined therapy doses were doubled . The reduction in proteinuria was not correlated with clinical through blood pressure ; however , reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria , as well as with creatinine clearance . In conclusion , this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure . In normotensive proteinuric patients , it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs BACKGROUND IgA nephropathy is progressive in most cases and has no established therapy . In this r and omised trial , we assessed the efficacy and safety of a 6-month course of steroids in this disorder . METHODS Between July , 1987 , and September , 1995 , we enrolled 86 consecutive patients from seven renal units in Italy . Eligible patients had biopsy-proven IgA nephropathy , urine protein excretion of 1.0 - 3.5 g daily , and plasma creatinine concentrations of 133 micromol/L ( 1.5 mg/dL ) or less . Patients were r and omly assigned either supportive therapy alone or steroid treatment ( intravenous methylprednisolone 1 g per day for 3 consecutive days at the beginning of months 1 , 3 , and 5 , plus oral prednisone 0.5 mg/kg on alternate days for 6 months ) . The primary endpoint was deterioration in renal function defined as a 50 % or 100 % increase in plasma creatinine concentration from baseline . Analyses were by intention to treat . FINDINGS Nine of 43 patients in the steroid group and 14 of 43 in the control group reached the primary endpoint ( a 50 % increase in plasma creatinine ) by year 5 of follow-up ( p<0.048 ) . Factors influencing renal survival were vascular sclerosis ( relative risk for 1-point increase in score 1.53 , p=0.0347 ) , female sex ( 0.22 , p=0.0163 ) , and steroid therapy ( 0.41 , p=0.0439 ) . All 43 patients assigned steroids completed the treatment without experiencing any important side-effects . INTERPRETATION A 6-month course of steroid treatment protected against deterioration in renal function in IgA nephropathy with no notable adverse effects during follow-up . An increase in urinary protein excretion could be a marker indicating the need for a second course of steroid therapy

REVIEW ERS ' CONCLUSIONS 1 . Oral colonization by respiratory pathogens , fostered by poor oral hygiene and periodontal diseases , appears to be associated with nosocomial pneumonia . 2 .

BACKGROUND Several recent studies provide evidence that the oral cavity may influence the initiation and /or the progression of lung diseases such as pneumonia and chronic obstructive pulmonary disease ( COPD ) . RATIONALE Studies have shown that poor oral hygiene and periodontal disease may foster colonization of the oropharyngeal region by respiratory pathogens , particularly in hospital or nursing home patients . If aspirated , these pathogens can cause pneumonia , one of the most common respiratory infections , especially in institutionalized subjects . Other cross-sectional epidemiologic studies point to an association between periodontal disease and COPD . This systematic review examines the literature to determine if interventions that improve oral hygiene reduce the rate of pneumonia in high-risk population s. FOCUSED QUESTION Do periodontal diseases or other indicators of poor oral health influence the initiation/progression of pneumonia or other lung diseases ?

OBJECTIVES To investigate the importance of medical and dental factors in aspiration pneumonia in an older veteran population . DESIGN Prospect i ve enrollment of subjects with retrospective analysis of data . SETTING Department of Veterans Affairs outpatient clinic , inpatient ward , and nursing home . PARTICIPANTS 358 veterans age 55 and older ; 50 subjects with aspiration pneumonia . MEASUREMENTS Demographic and medical data ; functional status ; health-related behaviors ; dental care utilization ; personal oral hygiene ; comprehensive dental examination ; salivary assays including IgA antibodies ; and cultures of saliva , throat , and dental plaques . RESULTS Two logistic regression models produced estimates of significant risk factors . One model using dentate patients included : requiring help with feeding ( odds ratio ( OR ) = 13.9 ) , chronic obstructive pulmonary disease ( COPD ) ( OR = 4.7 ) , diabetes mellitus ( OR = 3.5 ) , number of decayed teeth ( OR = 1.2 ) , number of functional dental units ( OR = 1.2 ) , presence of important organisms for decay , Streptococcus sobrinus in saliva ( OR = 6.2 ) , and periodontal disease , Porphyromonous gingivalis in dental plaque ( OR = 4.2 ) , and Staphylococcus aureus presence in saliva ( OR = 7.4 ) . The second model , containing both dentate and edentulous patients included : requiring help with feeding ( OR = 4.7 ) , COPD ( OR = 2.5 ) , diabetes mellitus ( OR = 1.7 ) , and presence of S. aureus in saliva ( OR = 8.3 ) . CONCLUSION This study supports the significance of oral and dental factors while controlling for established medical risk factors in aspiration pneumonia incidence Objective : To assess the prevalence of oral colonization by respiratory pathogens in a group of ICU patients , with specific attention to dental plaque and the oral mucosa . Design : Prospect i ve , nonr and omized study with age-matched controls . Setting s : Medical ICU in a tertiary-care Veterans Affairs Medical Center and a dental school outpatient preventive dentistry clinic . Patients : Nonconsecutive , unselected patients admitted to the medical ICU during a 2-month period ; controls were age-matched patients seen for the first time in the preventive dentistry clinic . Interventions : None . Measurements : Oral hygienic status was assessed in both groups using a semiquantitative system . Quantitative cultures of dental plaque and buccal mucosa were done within 12 hrs of medical ICU admission and every third day thereafter until discharge/death from the medical ICU . In controls , cultures of plaque and buccal mucosa were done on the initial visit only . Severity of illness of medical ICU patients was quantitated using the Acute Physiology and Chronic Health Evaluation ( APACHE II ) system and McCabe-Jackson criteria . Main Results : Oral hygiene of medical ICU patients was poor . These patients had a mean plaque score ( 1.9 ± 0.2 ) that was significantly greater than that same score seen in out patients of the preventive dentistry clinic ( 1.4 ± 0.1 ; p < .005 ) . Plaque and /or oral mucosa of 22 ( 65 % ) of 34 medical ICU patients were colonized by respiratory pathogens , in contrast to only four ( 16 % ) of 25 preventive dentistry clinic patients ( p < .005 ) . The potential respiratory pathogens cultured from medical ICU patients included methicillinresistant Staphylococcus aureus , Pseudomonas aeruginosa , and ten genera of Gram-negative bacilli . Colonization by respiratory pathogens was statistically associated with concomitant antibiotic therapy within the medical ICU group of patients , but not with severity of illness . Although medical ICU patients tended to have more dental plaque than preventive dentistry clinic patients , there was no statistically significant association noted between the presence of dental plaque and respiratory pathogen colonization . Conclusions : These findings suggest that bacteria commonly causing nosocomial pneumonia colonize the dental plaque and oral mucosa of intensive care patients . In many cases , this colonization occurs by large numbers of bacteria . Dental plaque may be an important reservoir of these pathogens in medical ICU patients . Efforts to improve oral hygiene in medical ICU patients could reduce plaque load and possibly reduce oropharyngeal colonization OBJECTIVE To study the dental status and colonization of dental plaque by aerobic pathogens and their relation with nosocomial infections in intensive care unit ( ICU ) patients . DESIGN A prospect i ve study in a medical ICU of a university-affiliated hospital . PATIENTS Consecutive patients admitted to the ICU during a 3-mo period . INTERVENTIONS Dental status was assessed by the same investigator using a score adapted from the " Caries-Absent-Occluded " ( CAO ) index ( referred to in the U.S. as DMFT [ Decayed-Missing-Filled Teeth ] index ) . The amount of dental plaque on premolars was assessed using a semiquantitative score . Quantitative cultures of dental plaque , nasal secretions , tracheal aspirates , and urine were done at admission ( day 0 ) and every fifth day until death or discharge . An additional study was done in eight patients to serially compare dental plaque , salivary , and tracheal aspirate cultures during a 2-wk period . MEASUREMENTS AND MAIN RESULTS Fifty-seven patients were included in the main study . Due to the variability in their ICU stay , 29 patients could be examined on day 0 only ( group A ) , 15 patients on days 0 and 5 ( group B ) , and 13 patients on days 0 , 5 , and 10 ( group C ) . The mean dental CAO score was 16 + /- 8 and did not change during the ICU stay . The dental plaque score was < or = 1 in 70 % of patients on day 0 ; > or = 2 in 50 % of patients on day 5 ; and > or = 2 in 90 % of patients on day 10 . Dental plaque cultures were positive at 10(3 ) colony-forming units/mL for aerobic pathogens in 23 % of patients on day 0 ; 39 % of patients on day 5 ; and 46 % of patients on day 10 . In groups B and C , mean dental plaque score and frequency of plaque colonization increased from days 0 to 5 and from days 5 to 10 . A high bacterial concordance was found between dental plaque and tracheal aspirate cultures , and in the additional study , between salivary and dental plaque cultures . Twenty-one patients developed a nosocomial infection in the ICU . Dental plaque colonization on days 0 and 5 was significantly associated with the occurrence of nosocomial pneumonia and bacteremia ( sensitivity 0.77 ; specificity 0.96 ; positive predictive value 0.87 ; negative predictive value 0.91 ; relative risk 9.6 ) . In six cases of nosocomial infection , the pathogen isolated from dental plaque was the first identified source of nosocomial infection . CONCLUSIONS The amount of dental plaque increased during the ICU stay . Colonization of dental plaque was either present on admission or acquired in 40 % of patients . A positive dental plaque culture was significantly associated with subsequent nosocomial infections . Dental plaque colonization by aerobic pathogens might be a specific source of nosocomial infection in ICU patients BACKGROUND Pneumonia is one of the most common nosocomial infections in hospitalized patients . The risk of nosocomial pneumonia increases with age , severity of acute illness and preexisting co-morbid conditions . Ventilator-associated pneumonia ( VAP ) significantly increases morbidity , length of stay , re source utilization and mortality . The purpose of this study was to determine whether adherence to a ventilator weaning protocol ( WP ) and the use of chlorhexidine gluconate ( CH ) oral rinse for oral hygiene would decrease the incidence of VAP in surgical ICU patients . METHODS A prospect i ve study was conducted over a period of 10 months ( October 1998-July 1999 ) in surgical ICU patients requiring mechanical ventilation ( n = 95 ) . During the first 5 months , a WP was applied to all patients requiring mechanical ventilation . During the following 5 months , a CH 0.12 % oral rinse administered twice daily was added to the protocol , initiated on ICU admission in all intubated patients . The data collection included age , gender , race , risk factors , co-morbid conditions , severity of the acute illness ( APACHE II ) at admission , duration of ventilation , ICU and total-hospital length of stay , and incidence of VAP and in-hospital mortality rates . Both WP and WP+CH groups were compared using the National Nosocomial Infection Surveillance ( NNIS ) and hospital data bases as historic controls . RESULTS The institution of the WP alone led only to a slight decrease in the incidence of VAP but a significant reduction in the median duration of mechanical ventilation by 40 % ( 4.5 days , p < 0.008 ) . The addition of CH to the WP led to a significant reduction and delay in the occurrence of VAP ( 37 % overall , 75 % for late VAP , p < 0.05 ) . The median duration of mechanical ventilation in this group was similar to that of the WP group . There was no significant difference in the overall hospital or ICU length of stay between the groups . CONCLUSIONS Improved oral hygiene via topical CH application in conjunction with the use of a WP is effective in reducing the incidence of VAP and the duration of mechanical ventilation in surgical ICU patients OBJECTIVES Aspiration of oral secretions and their bacteria is increasingly being recognized as an important factor in pneumonia . We investigated whether oral care lowers the frequency of pneumonia in institutionalized older people . DESIGN Survey . SETTING Eleven nursing homes in Japan . PARTICIPANTS Four hundred seventeen patients r and omly assigned to an oral care group or a no oral care group . INTERVENTION Nurses or caregivers cleaned the patients ' teeth by toothbrush after each meal . Swabbing with povidone iodine was additionally used in some cases . Dentists or dental hygienists provided professional care once a week . MEASUREMENTS Pneumonia , febrile days , death from pneumonia , activities of daily living , and cognitive functions . RESULTS During follow-up , pneumonia , febrile days , and death from pneumonia decreased significantly in patients with oral care . Oral care was beneficial in edentate and dentate patients . Activities of daily living and cognitive functions showed a tendency to improve with oral care . CONCLUSION We suggest that oral care may be useful in preventing pneumonia in older patients in nursing homes Abstract Objectives : To document in intensive care unit ( ICU ) patients the effect of dental plaque antiseptic decontamination on the occurrence of plaque colonization by aerobic nosocomial pathogens and nosocomial infections . Design : Single-blind r and omized comparative study . Setting : A 16-bed adult intensive care unit in a university hospital . Patients : Patients consecutively admitted in the ICU with a medical condition suggesting an ICU stay of 5 days and requiring mechanical ventilation . Interventions : After r and omization , the treated group received dental plaque decontamination with 0.2 % chlorhexidine gel , three times a day during the ICU stay . The control group received st and ard oral care . Specific measurements : Dental status was assessed by the Caries-Absent-Occluded index ; the amount of dental plaque was assessed by a semi-quantitative plaque index . Bacterial sampling of dental plaque , nasal and tracheal aspirate , blood , and urine cultures were done on days 0 , 5 , 10 , and every week . Main results : Sixty patients were included ; 30 in the treated group and 30 in the control one ( mean age : 51±16 years ; mean Simplified Acute Physiological Score II : 35±14 points ) . On admission , no significant differences were found between both groups for all clinical and dental data . Compared with the control group , the nosocomial infection rate and the incidence densities related to risk exposition were significantly lower in the treated group ( 18 vs 33‰ days in the ICU and 10.7 vs 32.3‰ days of mechanical ventilation ; P<0.05 ) . These results were consistent with a significant preventive effect of the antiseptic decontamination ( Odds Ratio : 0.27 ; 95 % CI : 0.09 ; 0.80 ) with a 53 % relative risk reduction . There was a trend to a reduction of mortality , length of stay , and duration of mechanical ventilation . Conclusions : An antiseptic decontamination of dental plaque with a 0.2 % chlorhexidine gel decreases dental bacterial colonization , and may reduce the incidence of nosocomial infections in ICU patients su bmi tted to mechanical ventilation BACKGROUND Decreasing the levels of bacteria in the oropharynx should reduce the prevalence of nosocomial pneumonia . OBJECTIVES To test the effectiveness of 0.12 % chlorhexidine gluconate oral rinse in decreasing microbial colonization of the respiratory tract and nosocomial pneumonia in patients undergoing open heart surgery . METHODS A prospect i ve , r and omized , case-controlled clinical trial design was used . Peridex ( 0.12 % chlorhexidine gluconate ) was the experimental drug , and Listerine ( phenolic mixture ) was the control drug . A total of 561 patients undergoing aortocoronary bypass or valve surgery requiring cardiopulmonary bypass were r and omized to an experimental ( n = 270 ) or a control ( n = 291 ) group . Nosocomial pneumonia was diagnosed by using the criteria established by the Centers for Disease Control and Prevention . RESULTS The overall rate of nosocomial pneumonia was reduced by 52 % ( 4/270 vs 9/291 ; P = .21 ) in the Peridex-treated patients . Among patients intubated for more than 24 hours who had cultures that showed microbial growth ( all pneumonias occurred in this group ) , the pneumonia rate was reduced by 58 % ( 4/19 vs 9/18 ; P = .06 ) in patients treated with Peridex . In patients at highest risk for pneumonia ( intubated > 24 hours , with cultures showing the most growth ) , the rate was 71 % lower in the Peridex group than in the Listerine group ( 2/10 vs 7/10 ; P = .02 ) . CONCLUSIONS Although rates of nosocomial pneumonia were lower in patients treated with Peridex than in patients treated with Listerine , the difference was significant only in those patients intubated more than 24 hours who had the highest degree of bacterial colonization BACKGROUND Associations between poor oral health and chronic lung disease have recently been reported . The present study evaluated these potential associations by analyzing data from the National Health and Nutrition Examination Survey III ( NHANES III ) , which documents the general health and nutritional status of r and omly selected United States subjects from 1988 to 1994 . METHODS This cross-sectional , retrospective study of the NHANES III data base included a study population of 13,792 subjects > or = 20 years of age with at least 6 natural teeth . A history of bronchitis and /or emphysema was recorded from the medical question naire , and a dichotomized variable combined those with either chronic bronchitis and /or emphysema , together considered as chronic obstructive pulmonary disease ( COPD ) . Subject lung function was estimated by calculating the ratio of forced expiratory volume ( FEV ) after 1 second (FEV1)/forced vital capacity ( FVC ) . Oral health status was assessed from the DMFS/T index ( summary of cumulative caries experience ) , gingival bleeding , gingival recession , gingival probing depth , and periodontal attachment level . Unweighted analyses were used for initial examination of the data , and a weighted analysis was performed in a final logistic regression model adjusting for age , gender , race and ethnicity , education , income , frequency of dental visits , diabetes mellitus , smoking , and alcohol use . RESULTS The mean age of all subjects was 44.4 + /- 17.8 years ( mean + /- SD ) : COPD = 51.2 + /- 17.9 years and subjects without COPD = 43.9 + /- 17.7 years . Subjects with a history of COPD had more periodontal attachment loss than subjects without COPD ( 1.48 + /- 1.35 mm versus 1.17 + /- 1.09 mm , P = 0.0001 ) . Subjects with mean attachment loss ( MAL ) > or = 3.0 mm had a higher risk of COPD than those having MAL < 3.0 mm ( odds ratio , 1.45 ; 95 % CI , 1.02 to 2.05 ) . A trend was noted in that lung function appeared to diminish with increasing periodontal attachment loss . CONCLUSIONS The findings of the present analysis support recently published reports that suggest an association between periodontal disease and COPD UNLABELLED Colonization of the intestinal tract has been assumed to be important in the pathogenesis of ventilator-associated pneumonia ( VAP ) , but relative impacts of oropharyngeal , gastric , or intestinal colonization have not been eluci date d. Our aim was to prevent VAP by modulation of oropharyngeal colonization , without influencing gastric and intestinal colonization and without systemic prophylaxis . In a prospect i ve , r and omized , placebo-controlled , double-blind study , 87 patients received topical antimicrobial prophylaxis ( gentamicin/ colistin/vancomycin 2 % in Orabase , every 6 h ) in the oropharynx and 139 patients , divided over two control groups , received placebo ( 78 patients were studied in the presence of patients receiving topical prophylaxis [ control group A ] and 61 patients were studied in an intensive care unit where no topical prophylaxis was used [ control group B ] ) . Baseline characteristics were comparable in all three groups . Topical prophylaxis eradicated colonization present on admission in oropharynx ( 75 % in study group versus 0 % in control group A [ p < 0.00001 ] and 9 % in control group B patients [ p < 0.00001 ] ) and in trachea ( 52 % versus 22 % in A [ p = 0.03 ] and 7 % in B [ p = 0.004 ] ) . Moreover , topical prophylaxis prevented acquired oropharyngeal colonization ( 10 % versus 59 % in A [ p < 0.00001 ] and 63 % in B [ p < 0.00001 ] ) . Colonization rates in stomach and intestine were not affected . Incidences of VAP were 10 % in study patients , 31 % in Group A , and 23 % in Group B patients ( p = 0.001 and p = 0.04 , respectively ) . This was not associated with shorter duration s of ventilation or ICU stay or better survival . Oropharyngeal colonization is of paramount importance in the pathogenesis of VAP , and a targeted approach to prevent colonization at this site is a very effective method of infection prevention . KEYWORDS cross infection , prevention and control ; respiration , artificial , adverse effects ; antibiotics , administration and dosage infection control methods ; pneumonia , etiology , prevention and control ; intubation , intratracheal , adverse OBJECTIVE We evaluated the effectiveness of professional oral health care ( POHC ) given by dental hygienists once a week for 24 months to 141 elderly persons needing daily care and living in 2 nursing homes . STUDY DESIGN Elderly subjects with POHC and without POHC living in 2 nursing homes were examined for 24 months to detect any fevers of 37.8 degrees C or more and the prevalence of fatal aspiration pneumonia . The numbers of Staphylococcus species and C and ida albicans in swab sample s from oral cavities were compared between the POHC group and the non-POHC group . The amounts of methylmercaptan exhaled in the POHC group were determined and compared with those in the non-POHC group . RESULTS The prevalence of fevers of 37.8 degrees C or more in the subjects receiving POHC was significantly lower than in the non-POHC group ( P < .05 ) . We found that the ratio of fatal aspiration pneumonia in the POHC group during the 24 months was significantly lower than in the non-POHC group ( P < .05 ) . Numbers of C albicans species in sample s obtained from the oral cavity after 6 months of POHC were significantly lower than those in the non-POHC group ( P < .01 ) . POHC result ed in the reduction of the presence of Staphylococcus but not to a statistically significant extent . The amounts of methylmercaptan exhaled by the POHC group were significantly less than those of the non-POHC group ( P < .05 ) . CONCLUSION This study showed that POHC administered by dental hygienists to a group of elderly patients needing daily nursing care was associated with a reduction in prevalence of fever and fatal pneumonia The authors present a study that tests the effectiveness of oropharyngeal decontamination on nosocomial infections in a group of patients undergoing heart surgery . This was a prospect i ve , r and omized , double blind , placebo-controlled study . Consecutive patients undergoing primary artery bypass grafting , valve surgery , and other open heart procedures were enrolled . All the patients were operated on by the same group of surgeons . Patients were excluded if they died intraoperatively , if they had preoperative infection or intubation , if they were pregnant , if they had received a heart or lung transplantation , or if they had known hypersensitivity to chlorhexidine . The placebo consisted of material that looked and tasted similar to the test solution of chlorhexidine . The alcohol content of the chlorhexidine was 3–2 % compared with that of the chlorhexidine solution , which was 11.6 % . The chlorhexidine and placebo were used as an oropharyngeal rinse or rigorously applied by the nursing staff to the buccal , pharyngeal , gingival , tongue , and tooth surfaces for 30 seconds twice a day . The patients were not allowed to ingest the chlorhexidine . Prophylactic antibiotics consisted of cefuroxime 1.5 g IV every 12 hours preoperatively and for 48 hours postoperatively . All the patients received ranitidine 15 mg IV twice a day as stress ulcer prophylaxis while in the intensive care unit . Infections were diagnosed using the Centers for Disease Control definition of nosocomial infections . A total of 353 patients were included in the analysis . There were 173 r and omized to chlorhexidine and 180 to the placebo group . There did not appear to be any statistically significant difference in the two groups in regard to age , sex , type of surgery , preoperative pulmonary risk factors , preoperative white count , cardiopulmonary bypass time , and number of emergency or reoperative procedures . There was also no difference between the two groups in the average duration of mechanical ventilatory assistance , reintubation rate , or length of stay in the hospital . The incidence of nosocomial infection was significantly lower in the chlorhexidine-treated group , and this was exclusively due to a decrease of total number of respiratory tract infections . There was no difference in the number of nosocomial infections between the two groups when wound , blood , and urinary tract infections were compared . These authors were also able to demonstrate a reduction in mortality in the chlorhexidine-treated patients . Chlorhexidine-treated patients had a 1.16 % mortality compared to a 5.56 % mortality in the placebo-treated patients Abstract . Aspiration pneumonia is a major cause of morbidity and mortality among the elderly who are hospitalized or in nursing homes . Multiple risk factors for pneumonia have been identified , but no study has effectively compared the relative risk of factors in several different categories , including dysphagia . In this prospect i ve outcomes study , 189 elderly subjects were recruited from the outpatient clinics , inpatient acute care wards , and the nursing home care center at the VA Medical Center in Ann Arbor , Michigan . They were given a variety of assessment s to determine oropharyngeal and esophageal swallowing and feeding status , functional status , medical status , and oral/dental status . The subjects were followed for up to 4 years for an outcome of verified aspiration pneumonia . Bivariate analyses identified several factors as significantly associated with pneumonia . Logistic regression analyses then identified the significant predictors of aspiration pneumonia . The best predictors , in one or more groups of subjects , were dependent for feeding , dependent for oral care , number of decayed teeth , tube feeding , more than one medical diagnosis , number of medications , and smoking . The role that each of the significant predictors might play was described in relation to the pathogenesis of aspiration pneumonia . Dysphagia was concluded to be an important risk for aspiration pneumonia , but generally not sufficient to cause pneumonia unless other risk factors are present as well . A dependency upon others for feeding emerged as the dominant risk factor , with an odds ratio of 19.98 in a logistic regression model that excluded tube-fed patients

This systematic review found positive effects of PMX-DHP on mean arterial pressure and dopamine/ dobutamine use , PaO2/FiO2 ratio , endotoxin removal , and mortality . The EUPHAS study , a multicenter RCT performed in ten Italian intensive care units in 2009 , found that PMX-DHP improved 28-day survival , blood pressure , vasopressor requirement , and degree of organ failure .

Since direct hemoperfusion with polymyxin B immobilized fiber ( PMX-DHP ) received its product certification for use in Europe in 1998 , several prospect i ve r and omized controlled trials ( RCTs ) have been conducted in European countries . The first RCT , performed in six European academic medical centers in 2005 , concluded that PMX-DHP is associated with improved hemodynamic status and cardiac function . Subsequently , a meta- analysis of PMX-DHP was presented in Italy in 2007 .

Background / Aims : We investigated whether urinary podocytes are present in septic patients with methicillin-resistant Staphylococcus aureus (MRSA)-associated glomerulonephritis and whether polymyxin B-immobilized fiber ( PMX-F ) treatment affects proteinuria and urinary podocyte excretion in these patients . Methods : Twenty septic patients with MRSA-associated glomerulonephritis ( mean age : 63.7 years ) and 80 septic patients whose MRSA infection was not followed by glomerulonephritis ( mean age : 60.5 years ) were included in this study . All septic patients were treated with fosfomycin sodium , β-lactams , arbekacin sulfate , and teicoplanin , or a combination of these . Twenty septic patients with MRSA-associated glomerulonephritis were r and omly assigned to one of two treatments : PMX-F treatment ( group A , n = 10 ) and conventional treatment ( group B , n = 10 ) . PMX-F treatment was repeated twice . Results : Urinary podocytes and urinary protein excretion were not detected in MRSA septic patients without glomerulonephritis . However , urinary podocytes ( 1.7 ± 0.6 cells/ml ) and proteinuria ( 2.6 ± 0.6 g/d ) were detected in the 20 septic patients with MRSA-associated glomerulonephritis . Plasma endotoxin levels were decreased from 13.6 ± 4.6 pg/ml to 6.6 ± 2.2 pg/ml ( p < 0.05 ) in group A. Levels in group B , however , showed little difference after treatment . Urinary podocytes were reduced in group A ( from 1.8 ± 0.6 cells/ml to 0.4 ± 0.2 cells/ml , p < 0.01 ) as was urinary protein excretion ( from 3.0 ± 0.5 g/d to 0.8 ± 0.4 g/d , p < 0.01 ) but urinary podocytes and protein excretion levels showed little difference after treatment in group B. Conclusion : PMX-F treatment may be effective in reducing urinary protein and urinary podocyte excretion in septic patients with MRSA-associated glomerulonephritis Introduction The objective of this study was to clarify the efficacy and mechanism of action of direct hemoperfusion with an immobilized polymyxin B fiber column ( DHP-PMX ) in patients with acute lung injury or acute respiratory distress syndrome caused by sepsis . Method Thirty-six patients with sepsis were included . In each patient a thermodilution catheter was inserted , and the oxygen delivery index and oxygen consumption index were measured . DHP-PMX was performed in patients with a normal oxygen delivery index and oxygen consumption index ( > 500 ml/minute per m2 and > 120 ml/minute per m2 , respectively ) . The Acute Physiology and Chronic Health Evaluation II score was used as an index of the severity of sepsis , and survival was assessed after 1 month . The humoral mediators measured were the chemokine IL-8 , plasminogen activator inhibitor-1 , and neutrophil elastase ( NE ) . These mediators were measured before DHP-PMX treatment , and at 24 , 48 , and 78 hours after the start of treatment . The arterial oxygen tension (PaO2)/fractional inspired oxygen ( FiO2 ) ratio was measured before DHP-PMX treatment and at 24 , 48 , 72 , 92 , and 120 hours after the start of treatment . Results All patients remained alive after 1 month . Before DHP-PMX treatment , the Acute Physiology and Chronic Health Evaluation II score was 24 ± 2.0 , the IL-8 level was 54 ± 15.8 pg/ml , plasminogen activator inhibitor-1 was 133 ± 28.1 ng/ml , and NE was 418 ± 72.1 μg/l . These three humoral mediators began to decrease from 24 hours after DHP-PMX treatment , and the decline became significant from 48 hours onward . The PaO2/FiO2 ratio was 244 ± 26.3 before DHP-PMX treatment but improved significantly from 96 hours onward . There were significant negative correlations between the PaO2/FiO2 ratio and blood levels of NE and IL-8 . Conclusion The mechanism of action of DHP-PMX is still not fully understood , but we report the following findings . The mean blood levels of plasminogen activator inhibitor-1 , NE , and IL-8 were significantly decreased from 48 hours after DHP-PMX treatment . The mean PaO2/FiO2 ratio was significantly improved from 96 hours after DHP-PMX treatment . Improvement in the PaO2/FiO2 ratio appeared to be related to the decreases in blood NE and IL-8 levels OBJECTIVE the aim of the present study was to determine whether serum neopterin and soluble interleukin (IL)-2 receptor levels were related to the development of septic shock and whether polymyxin B-immobilized fibre ( PMX-F ) treatment affects these levels . METHODS we examined 24 patients admitted to our intensive care unit with Gram-negative septic shock . Serum neopterin and soluble IL-2 receptor levels were measured using commercially available test kits . Patients were treated with direct hemoperfusion using PMX-F columns . RESULTS fifteen out of 24 patients ( 63 % ) survived and were discharged from our hospitals within 30 days after PMX-F treatment . Blood endotoxin levels decreased significantly from 49.2+/-8.6 pg/ml to 13.2+/-4.4 pg/ml after PMX-F treatment . The pretreatment serum concentrations of neopterin and IL-2 receptor were significantly higher in the nine non-surviving patients with septic shock than in the 15 surviving patients ( P<0.01 ) and 20 control subjects ( P<0.001 ) . Serum concentrations of neopterin and IL-2 receptor in patients with septic shock decreased significantly after PMX-F treatment ( P<0.01 ) . CONCLUSIONS these data suggest that serum neopterin and IL-2 receptor concentrations may be prognostic indicators in patients with septic shock . PMX-F treatment may be effective for reducing serum neopterin and IL-2 receptor concentrations Endotoxin plays an important role in the pathogenesis of septic shock . Exposure of endothelial cells to endotoxin activates endothelial cells and increases the surface expression of adhesion molecules , markers of endothelial damage in organ dysfunction . Endotoxin adsorption therapy by polymyxin B-immobilized fiber column ( PMX ) hemoperfusion has been used for the treatment of septic shock patients . In this study , we measured plasma concentrations of endotoxin and soluble adhesion molecules in septic shock patients before and after the PMX treatment then observed on the relationships between actual duration of use and various outcomes . Sixteen patients with septic shock were studied . The 28-day mortality rate was 50 % . The elevated plasma concentrations of endotoxin decreased after the PMX treatment in the survivors but not in the nonsurvivors . The norepinephrine dose and plasma concentrations of soluble endothelial leukocyte adhesion molecule 1 and soluble intercellular adhesion molecule 1 significantly ( P < 0.05 ) decreased in the PMX greater-than-2-h ( prolonged ) group than in the PMX 2-h ( conventional ) group ( −17.8 ± 14.6 vs. −1.8 ± 2.7 & mgr;g/min , −143.0 ± 111.0 vs. 0 ± 2.8 ng/mL , and −126.2 ± 144.9 vs. 16.5 ± 108.1 ng/mL , respectively ) . Changes in the PaO2-FiO2 ratio and the Sequential Organ Failure Assessment score were significantly ( P < 0.05 ) more improved in the PMX greater-than-2-h group than in the PMX 2-h group ( 75.4 ± 80.7 vs. 1.2 ± 49.2 and −0.8 ± 1.8 vs. 2.2 ± 1.9 torr , respectively ) . We thus suggest that a longer duration of PMX treatment may improve the pulmonary oxygenation associated with decreased adhesion molecules in septic shock Background : CD16 + CD14 + monocytes dramatically increase in number in patients with severe infection . Hemoperfusion with PMX-F ( direct hemoperfusion with polymyxin B immobilized fibers ) has been reported to be a safe and effective treatment for patients with septic shock , although the molecular mechanism that accounts for its effectiveness is still unclear . The purpose of this study was to quantify the number of CD16+CD14 + monocytes in patients with an intra-abdominal infection and to evaluate the effects of PMX-F treatment on clinical parameters and leukocyte surface antigen expression in these patients . Material s and Methods : Seventeen septic patients who had an intra-abdominal infection were enrolled in this study ; 7 of these patients received PMX-F treatment . Peripheral blood sample s were obtained immediately after admission , and were also collected from the above 7 patients before , during , and immediately after their PMX-F treatment . The expression of CD14 , CD16 , and Toll-like receptor (TLR)-4 on these patients ' monocytes was evaluated using flow cytometry . In addition , lipopolysaccharide (LPS)-induced production of TNF-α and IL-1β by these cells was measured by ELISA . Results : Monocytic expression of CD16 and TLR-4 was significantly greater in septic patients than in healthy controls , and their proportion of CD16+CD14 + monocytes was similarly elevated . LPSinduced production of TNF-α and IL-1β by peripheral blood mononuclear cells ( P BMC s ) of septic patients was significantly reduced compared to controls . Furthermore , there was a reduction in the proportion of CD 16+CD 14 + monocytes during PMX-F treatment , and in the expression of TLR-4 on monocytes after PMX-F treatment . Conclusions : These results showed that the number of peripheral blood CD16+CD14 + monocytes and monocytic TLR-4 expression were markedly increased , and the production of pro-inflammatory cytokines in response to LPS significantly reduced in patients with sepsis . PMX-F treatment was found to be effective in reducing the number of CD 16+CD 14 + monocytes and in decreasing the monocytic expression of TLR-4 in patients with septic shock Objective : To determine the impact of a thyroid hormone infusion ( T4 ) on the vasopressor requirements in children with cessation of neurologic function ( i.e. , brain death ) during evaluation for organ recovery Design : Retrospective cohort study . Setting : The 1998–2002 data base of a regional organ recovery program . Patients : Children ≤18 yrs with cessation of neurologic function during evaluation for organ recovery ( n = 171 ) were included . The treated group ( n = 91 ) received a weight-based bolus and continuous infusion of T4 according to the organ procurement agency protocol . All other children ( n = 80 ) were considered untreated . Interventions : T4 was administered at the clinician ’s discretion . All children ( treated and untreated ) had identical goals for fluids , blood pressure , and organ function criteria . Vasopressor score ( [ dopamine × 1 ] + [ dobutamine × 1 ] + [ epinephrine × 100 ] + [ norepinephrine × 100 ] + [ phenylephrine × 100 ] ) at the time of the program ’s involvement ( T0 ) and at organ recovery ( TOR ) were recorded . The Wilcoxon rank sum and Student ’s two- sample t-test were used to compare the average vasopressor score at T0 vs. TOR . The Wilcoxon signed rank test was used to analyze the difference in median vasopressor score at T0 vs. TOR . Multivariable linear regression was used to assess the impact of T4 on the ability to wean vasopressor support while accounting for the effects of several potential confounders . Measurements and Main Results : One hundred seventy-one subjects were included in the final analysis . T4 administration was associated with an unadjusted decrease in the vasopressor score of 32 ( 95 % confidence interval , 12–53 ; p = .002 ) . After adjusting for steroid administration , fluid balance , and baseline vasopressor score , T4 administration was associated with a decrease in vasopressor score of 24 ( 95 % confidence interval , 6–43 ; p = .011 ) . Conclusions : T4 reduced vasopressor needs in children with cessation of neurologic function and hemodynamic instability . A prospect i ve study of T4 in critically ill and hemodynamically unstable children appears warranted Objective To analyze the effects of polymyxin B-immobilized fiber ( PMX-F ) on bone resorption in septic patients . Design and setting Observational prospect i ve study in intensive care units of a general hospital . Patients and participants 25 patients with severe sepsis and 20 healthy controls . Measurements and results Septic patients were r and omly assigned to two groups : PMX-F treatment group ( n=15 ) and conventional treatment group ( n=10 ) . Total pyridinium crosslink pyridinoline ( PYD ) and deoxypyridinoline ( DPD ) in urine were determined by modified high-performance liquid chromatography . Nitric oxide production was assessed by measuring the ratio of the nitric oxide breakdown products to urinary creatinine ( NOx/Cr ) . Plasma endotoxin levels were determined by endospecy test . The blood albumin , ionized calcium , and parathyroid hormone were also measured . PMX-F treatment was performed twice separated by 24 h. Urinary NOx/Cr , PYD/Cr , and DPD/Cr were significantly increased in septic patients compared with those in healthy controls . Blood ionized calcium in septic patients was lower than in healthy controls , while parathyroid hormone levels in septic patients were higher than in healthy controls ( P<0.01 ) . PMX-F treatment reduced plasma endotoxin , urinary NOx/Cr , PYD/Cr , DPD/Cr , and serum parathyroid hormone levels and increased blood ionized calcium significantly ; however , conventional treatment did not affect these levels . Conclusions Septic patients increased nitric oxide production and bone resorption , and PMX-F treatment is effective in reducing nitric oxide levels and bone resorption markers Endotoxin is an important pathogenic trigger for sepsis . The polymyxin B-immobilized endotoxin removal hemoperfusion cartridge , Toraymyxin ( hereafter PMX ) , has been shown to remove endotoxin in pre clinical and open-label clinical studies . In a multicenter , open-label , pilot , r and omized , controlled study conducted in the intensive care unit in six academic medical centers in Europe , 36 postsurgical patients with severe sepsis or septic shock secondary to intra-abdominal infection were r and omized to PMX treatment of 2 h ( n = 17 ) or st and ard therapy ( n = 19 ) . PMX was well tolerated and showed no significant side effects . There were no statistically significant differences in the change in endotoxin levels from baseline to 6 to 8 h after treatment or to 24 h after treatment between the two groups . There was also no significant difference in the change in interleukin (IL)-6 levels from baseline to 6 to 8 h after treatment or to 24 h after treatment between the two groups . Patients treated with PMX demonstrated significant increases in cardiac index ( CI ; P = 0.012 and 0.032 at days 1 and 2 , respectively ) , left ventricular stroke work index ( LVSWI , P = 0.015 at day 2 ) , and oxygen delivery index ( DO2I , P = 0.007 at day 2 ) compared with the controls . The need for continuous renal replacement therapy ( CRRT ) after study entry was reduced in the PMX group ( P = 0.043 ) . There was no significant difference between the groups in organ dysfunction as assessed by the Sequential Organ Failure Assessment ( SOFA ) scores from day 0 ( baseline ) to day 6 . Treatment using the PMX cartridge is safe and may improve cardiac and renal dysfunction due to sepsis or septic shock . Further studies are needed to prove this effectiveness The aim of the present study was to determine whether treatment with polymyxin B-immobilized fibre ( PMX-F ) haemoperfusion , teicoplanin , or both in combination is effective in patients with methicillin-resistant Staphylococcus aureus ( MRSA ) sepsis . Sixty patients with MRSA sepsis were r and omly assigned to one of four treatments : ( A ) PMX-F treatment ( N=15 ) , ( B ) teicoplanin treatment ( N=15 ) , ( C ) PMX-F and teicoplanin in combination ( N=20 ) and ( D ) conventional therapy ( N=10 ) . PMX-F treatment was repeated twice . Teicoplanin was administered by intravenous injection . Plasma endotoxin levels were determined by endospecy test . Plasma endotoxin levels were reduced in groups A and C ( P<0.05 ) . Survival rates were 53 , 47 , 90 , and 20 % in groups A , B , C and D , respectively ( group C versus group A , P<0.05 ; group C versus group B , P<0.01 ; group C versus group D , P < 0.001 ) . The mean duration of stay was 44 , 42 , 28 and 56 days in groups A , B , C and D , respectively . Our data suggest that combination therapy with PMX-F and teicoplanin is effective for sepsis caused by MRSA In a previously conducted trial of human monoclonal antibody HA-1A [ 1 ] among 102 patients with gram-negative bacteremia and shock , the all-cause mortality rate 28 days after treatment was reduced from 56 % in patients receiving placebo to 33 % in those receiving HA-1A ( chi-square P value = 0.020 ) . At day 14 in the same group , the mortality rate was reduced from 48 % in the placebo group to 24 % in the HA-1A group ( chi-square P value = 0.012 ) . That was an explanatory trial [ 1 ] intended to confirm the findings previously reported with J5 antiserum [ 2 ] and was conducted using stringent selection criteria at medical centers expert in conducting clinical trials in sepsis . An explanatory trial [ 3 , 4 ] tries to determine if a treatment is beneficial under an ideal or constrained set of clinical circumstances . Other trials , defined as pragmatic or management trials , try to determine the safety and efficacy of a treatment in clinical circumstances as close as possible to those actually or usually encountered . To analyze the effects of commonly used practice s to prevent death from frequently encountered diseases , large , simple , r and omized trials have theoretical and practical advantages in a management trial [ 5 ] . To our knowledge , this design has not been used previously in infectious disease and particularly not to study sepsis . Because death at day 14 in patients with shock and gram-negative bacteremia was not a primary end point in the trial by Ziegler and colleagues [ 1 ] , we wanted to determine if these results could be reproduced in st and ard clinical practice at many types of hospitals . We chose a large , simple trial design to test the use of septic shock as an indication for HA-1A treatment . Methods The primary objective of the Centocor : HA-1A Efficacy in Septic Shock ( CHESS ) trial was to compare the effectiveness of 100 mg of HA-1A and placebo in reducing the 14-day all-cause mortality rate in patients with septic shock who had gram-negative bacteremia . The secondary objective was to assess the safety of 100 mg of HA-1A in patients with septic shock who did not have gram-negative bacteremia . To be eligible for enrollment in the trial , patients had to 1 ) be in shock within 6 hours before enrollment ; 2 ) have gone into shock within the 24 hours before enrollment ; 3 ) have a presumptive clinical diagnosis of gram-negative infection that was judged to have caused the septic shock episode ; and 4 ) have a physician who was committed to providing full , supportive care for the patient and did not contemplate withdrawing support . Shock was defined as the presence of either systolic blood pressure less than 90 mm Hg after adequate fluid challenge or use of dopamine , dobutamine , norepinephrine , or epinephrine as vasopressive agents to maintain blood pressure . ( Dopamine used at low doses solely to improve renal blood flow was not considered a vasopressive agent . ) An adequate fluid challenge was an intravenous infusion of isotonic fluid , colloid , or blood products to restore the effective circulating blood volume . Excluded were 1 ) patients younger than 18 years ; 2 ) patients who were pregnant ; 3 ) patients who , because they had rapidly fatal underlying disease , were not expected to live more than 3 months ; 4 ) patients who had an organ or bone marrow transplant within the preceding 6 months ; 5 ) patients with a total leukocyte count less than 500 cells/mm3 ; 6 ) patients with a body surface area burn injury greater than 10 % within the preceding 2 months ; 7 ) patients who previously received any antiendotoxin monoclonal antibody ; 8) patients with do not resuscitate orders ; and 9 ) patients who , at enrollment , were participating in other clinical trials of investigational drugs to treat sepsis or septic shock . Patients were considered enrolled in the trial after all of the enrollment criteria had been met and a vial of study material was prepared for infusion . Patients were followed for 14 days after infusion . An independent r and omization and interim analysis center prepared a treatment allocation schedule that r and omly assigned patients to receive 100 mg of HA-1A or placebo ( human serum albumin ) in equal proportions . The treatment allocation schedule was assigned in a manner unknown to the sponsor and the participating investigators . The r and omization center labeled the study material with sequential vial numbers according to the allocation schedule . The sponsor and the participating investigators could not determine the treatment allocation from a patient 's vial number . Prospect i ve data collected from each patient were limited to 1 ) conformity with enrollment criteria ; 2 ) gram-negative bacteremia status within 48 hours of enrollment ; 3 ) death at day 14 after enrollment ; and 4 ) the occurrence of spontaneously reported adverse events . The primary efficacy end point was 14-day all-cause death for this specified patient cohort . The primary safety end points were 14-day all-cause death for patients without gram-negative bacteremia and adverse events in all patients infused . No other clinical information was obtained . We estimated that we needed 1500 patients to detect an 18 % proportionate decrease in mortality rate at day 14 after treatment from 49 % in the placebo group to 40 % in the HA-1A group , with a type I error rate of 0.05 and a power of 90 % . Patients who met all enrollment criteria , had gram-negative bacteremia , and received HA-1A or placebo were defined prospect ively as the group of primary interest . Because therapy must be instituted immediately in septic shock , patients were treated presumptively before the results of blood cultures were known . Given the difficulty in identifying patients with gram-negative bacteremia on clinical grounds , to accrue the target population of 1500 patients with gram-negative bacteremia , we expected to enroll 3400 to 7500 patients with shock and a presumptive diagnosis of gram-negative infection . As specified in the protocol , an interim analysis was planned after the data were available for 500 and 1000 patients with shock and gram-negative bacteremia who received HA-1A or placebo . At the interim analysis , the safety and efficacy monitoring committee could recommend stopping 1 ) if , among patients with septic shock and gram-negative bacteremia , the HA-1A-treated patients had a lower mortality rate at day 14 [ P < 0.010 ; Fisher two-tailed exact test ] than did patients given placebo ; or 2 ) if , among patients with septic shock without gram-negative bacteremia , the HA-1A-treated patients had a higher mortality rate ( P < 0.1 ; Fisher one-tailed exact test ) than did patients given placebo . The safety stopping rule was purpose fully design ed to be sensitive and to serve as an early warning of potential toxicity in patients not expected to benefit from HA-1A treatment . Results Figure 1 shows the distribution of patients into those enrolled , those meeting all enrollment criteria , and those in the prospect ively specified primary efficacy group ( gram-negative bacteremia ) . Among patients who met all enrollment criteria and who were given HA-1A or placebo , 621 of 2199 ( 28.2 % ) had gram-negative bacteremia and 1578 did not . Figure 1 . CHESS trial patient distribution . We stopped the trial at the first interim analysis because the all-cause mortality rate for patients treated with HA-1A who did not have gram-negative bacteremia ( 42 % ; 244 of 577 ) exceeded that of the patients given placebo ( 38 % ; 230 of 608 ) by an amount greater than that in the prespecified safety stopping rule ( P = 0.09 ; Fisher one-tailed exact test ) . Between the performance of the interim analysis and closure of the trial , additional patients were enrolled . These patients were included in the final analysis . Table 1 shows the results for patients with and without gram-negative bacteremia and the results in all patients treated . Table 1 . Final Analysis of the 14-Day Mortality Rate in Patients Who Were Given HA-1A or Placebo and Met All Enrollment Criteria The incidence of spontaneously reported adverse events classified as severe or life-threatening was 41 of 1199 ( 3.4 % ) for placebo and 41 of 1228 ( 3.3 % ) for HA-1A . Table 2 shows events categorized as possibly , probably , or definitely related to infusion of placebo or HA-1A ; no previously unreported events were identified . Hypotension was noted in 25 of 1199 patients given placebo ( 2.1 % ) and in 31 of 1228 patients receiving HA-1A ( 2.5 % ) ( P = 0.47 ) . For all treated patients for whom data are available , the incidence of any adverse effect , regardless of severity , was 534 of 1199 ( 45 % ) for placebo and 583 of 1228 ( 47 % ) for HA-1A treatment . For all treated patients without gram-negative bacteremia for whom data are available , the incidence of any adverse effect , regardless of severity , was 320 of 726 ( 44 % ) for placebo and 458 of 1017 ( 45 % ) for HA-1A treatment . Table 2 . Spontaneously Reported Adverse Events Possibly , Probably , or Definitely Related to Treatment in all Patients Infused with Placebo or HA-1A Discussion The results of this trial do not indicate any reduction in 14-day mortality rate with HA-1A treatment in patients with gram-negative bacteremia and septic shock . In the study by Ziegler and colleagues [ 1 ] , the 14-day mortality rate was reduced from 48 % with placebo to 24 % with HA-1A in similar patients . Several possible explanations could account for the disparity of these results : 1 ) The patients treated differed from those treated by Ziegler and colleagues [ 1 ] and were less likely to respond to HA-1A treatment ; 2 ) the patients treated with HA-1A were more severely ill than the patients given placebo ; 3 ) the treatment effect of HA-1A was obscured by the difference in mortality rates among the many participating hospitals ; 4 ) the HA-1A used in this trial was inactive or less active than the HA-1A used in the previous trial ; 5 ) the trial was terminated prematurely and its power to detect the expected reduction in mortality rate was low ; and 6 ) the conclusions of the previous trial were incorrect , and Objective : To find out whether polymyxin B-immobilized fiber ( PMX-F ) treatment affects the clinical parameters and plasma concentrations of erythropoietin ( EPO ) and interleukin (IL)-6 . Design : A prospect i ve case series study . Setting : Intensive care unit of the Department of Internal Medicine , Misato Junshin Hospital , Saitama , and Koto Hospital , Tokyo , Japan . Patients : 17 consecutive patients ( 10 men , 7 women ; mean age 54.6 years ) with clinical ly defined septic shock and 20 healthy volunteers ( 12 men , 8 women ; mean age 52.2 years ) . Main results : Of the 17 patients with septic shock , 9 ( 53 % ) survived . The systolic blood pressure increased significantly from 78 ± 6 to 106 ± 8 mm Hg 2 h after PMX-F treatment in patients with septic shock . Plasma endotoxin levels decreased significantly after treatment , from 40 ± 6 to 12 ± 4 pg/ml . The pretreatment plasma concentrations of EPO and IL-6 were significantly higher in the 8 nonsurviving patients with septic shock ( EPO : 400 ± 36 mlU/ml ; IL-6 : 6260 ± 1180 pg/ml ) than in the 9 surviving patients ( EPO : 120 ± 22 mlU/ml ; IL-6 : 680 ± 138 pg/ml ) and the 20 control subjects ( EPO , 12 ± 6 mlU/ml ; IL-6 , 8 ± 2 pg/ml ) . Plasma concentrations of EPO and IL-6 in patients with septic shock decreased significantly after PMX-F treatment ( EPO , nonsurviving : 320 ± 28 mlU/ml , p < 0.05 ; survivors : 26 ± 8 mlU/ml , p < 0.001 ; IL-6 , nonsurviving : 3860 ± 840 pg/ml , p < 0.01 ; survivors : 84 ± 20 pg/ml , p < 0.001 ) . Conclusions : Plasma concentrations of EPO and IL-6 may be prognostic indicators in patients with septic shock : PMX-F treatment may be effective in reducing the plasma concentrations of EPO and IL-6 in patients with septic shock Objective : To clarify whether plasma concentrations of soluble P-selectin , platelet factor-4 ( PF-4 ) and β-thromboglobulin ( βTG ) are altered in patients with septic shock and whether polymyxin B-immobilized fiber ( PMX-F ) treatment affects these changes.¶Subjects : Thirty patients with septic shock who were treated with PMX-F ( group A ) , 20 such patients who received conventional therapies ( group B ) and 20 healthy control subjects ( group C).¶ Methods : ELISA using commercial kits . Endotoxin elimination by direct hemoperfusion using PMX-F.¶ Results : Blood endotoxin levels decreased significantly from 49.4 ± 8.8 pg/ml to 13.0 ± 4.5 pg/ml after PMX-F treatment . The pretreatment plasma concentrations of soluble P-selectin , PF-4 and βTG in patients in groups A and B were significantly higher than those in group C ( p < 0.001 ) . Plasma concentrations of these factors decreased significantly in group A after PMX-F treatment ( p < 0.01 ) ; however , the concentrations in group B were not altered after conventional treatment . The survival rate of group A ( 60 % ) was higher than that of group B (30%).¶ Conclusions : Our findings suggest that soluble P-selectin , PF-4 and βTG may be associated with septic shock and that PMX-F is effective in reducing these markers in patients with septic shock BACKGROUND HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia . METHODS To evaluate the efficacy and safety of HA-1A , we conducted a r and omized , double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection . The patients received either a single 100-mg intravenous dose of HA-1A ( in 3.5 g of albumin ) or placebo ( 3.5 g of albumin ) . Other interventions , including the administration of antibiotics and fluids , were not affected by the study protocol . RESULTS Of 543 patients with sepsis who were treated , 200 ( 37 percent ) had gram-negative bacteremia as proved by blood culture . For the patients with gram-negative bacteremia followed to death or day 28 , there were 45 deaths among the 92 recipients of placebo ( 49 percent ) and 32 deaths among the 105 recipients of HA-1A ( 30 percent ; P = 0.014 ) . For the patients with gram-negative bacteremia and shock at entry , there were 27 deaths among the 47 recipients of placebo ( 57 percent ) and 18 deaths among the 54 recipients of HA-1A ( 33 percent ; P = 0.017 ) . Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients . Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death , 45 of the 93 given placebo ( 48 percent ) were discharged alive , as compared with 65 of the 103 treated with HA-1A ( 63 percent ; P = 0.038 ) . No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia . For all 543 patients with sepsis who were treated , the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A ( P = 0.24 ) . All patients tolerated HA-1A well , and no anti-HA-1A antibodies were detected . CONCLUSIONS HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia We investigated whether microalbuminuria/urinary creatinine ratio ( MACR ) is increased in septic patients with trauma and whether polymyxin B immobilized fiber ( PMX-F ) treatment decreases MACR . Twelve trauma patients without sepsis , 18 trauma patients with sepsis , and 10 healthy controls were included in this study . The 18 trauma patients with sepsis were r and omly assigned to one of two groups , PMX-F treatment or conventional treatment . Urinary microalbumin and creatinine were measured before and after treatment . Plasma endotoxin levels were determined by endospecy test . Hemoperfusion with PMX-F was carried out twice , for 2 hours , at a flow rate of 100 ml/min . MACR increased in the 30 trauma patients ( 5.2 ± 2.2 mg/mmol ) in comparison to that in the healthy controls ( 1.0 ± 0.6 mg/mmol , p < 0.01 ) . In the 18 trauma patients with sepsis , MACR after sepsis ( 16.6 ± 4.8 mg/mmol ) was significantly greater than that before sepsis ( 5.5 ± 2.3 mg/mmol , p < 0.01 ) . There was a significant correlation between plasma endotoxin levels and MACR in septic trauma patients ( p < 0.001 ) . MACR was reduced from 17.0 ± 5.0 mg/mmol to 4.2 ± 1.5 mg/mmol ( p < 0.01 ) with PMX-F , and plasma endotoxin levels were also reduced from 34.5 ± 18.5 pg/ml to 10.8 ± 6.6 pg/ml ( p < 0.01 ) . Neither MACR nor plasma endotoxin levels were affected by conventional treatment , however . In summary , trauma patients with sepsis appear to show increased MACR , and PMX-F therapy may be effective for attenuating the increase in MACR Acute respiratory distress syndrome ( ARDS ) is characterized by a high mortality rate . We have studied whether direct hemoperfusion using a polymyxin B immobilized fiber column ( PMX-DHP ) is effective for acute lung injury ( ALI ) and ARDS . Two ALI and eighteen ARDS patients were evaluated , four congestive heart failure ( CHF ) patients were evaluated as cardiogenic pulmonary edema , and we retrospectively compared the outcome with ten patients with ARDS who had been hospitalized between 1990 and 1998 as the untreated group . PMX-DHP was carried out twice at a rate of 80 - 100 ml/minute for 2 hours , with a time interval of approximately 24 hours . We monitored systolic blood pressure ( BP ) , diastolic BP , and the PaO(2)/FIO(2 ) ( PF ) ratio before and after PMX-DHP treatment . The mortality was classified if patients were alive at day 30 after initiating PMX-DHP . The mortality of ARDS patients was approximately 20 % . Systolic BP increased significantly from 106 + /- 20 to 135 + /- 21 and to 125 + /- 20 mmHg on the following day . Diastolic BP increased from 61 + /- 16 to 78 + /- 15 , and to 72 + /- 12 mmHg . The PF ratio increased significantly from 125 + /- 54 to 153 + /- 73 , and 163 + /- 78 Torr . CHF patients did not reveal improvement of systolic , diastolic BP , and PF ratio after PMX-DHP . Eight of ten patients in the untreated group died through exacerbated ARDS . In ARDS patients , PMX-DHP improved circulatory disturbance and oxygenation despite the underlying diseases . The mortality improved compared with that before induction of PMX-DHP BACKGROUND The neurological morbidity associated with prolonged periods of circulatory arrest has led some cardiac surgical teams to promote continuous low-flow cardiopulmonary bypass as an alternative strategy . The nonneurological postoperative effects of both techniques have been previously studied only in a limited fashion . METHODS AND RESULTS We compared the hemodynamic profile ( cardiac index and systemic and pulmonary vascular resistances ) , intraoperative and postoperative fluid balance , and perioperative course after deep hypothermia and support consisting predominantly of total circulatory arrest or low-flow cardiopulmonary bypass in a r and omized , single-center trial . Eligibility criteria included a diagnosis of transposition of the great arteries and a planned arterial switch operation before the age of 3 months . Of the 171 patients , 129 ( 66 assigned to circulatory arrest and 63 to low-flow bypass ) had an intact ventricular septum and 42 ( 21 assigned to circulatory arrest and 21 to low-flow bypass ) had an associated ventricular septal defect . There were 3 ( 1.8 % ) hospital deaths . Patients assigned to low-flow bypass had significantly greater weight gain and positive fluid balance compared with patients assigned to circulatory arrest . Despite the increased weight gain in the infants assigned to low-flow bypass , the duration of mechanical ventilation , stay in the intensive care unit , and hospital stay were similar in both groups . Hemodynamic measurements were made in 122 patients . During the first postoperative night , the cardiac index decreased ( 32.1 + /- 15.4 % , mean + /- SD ) , while pulmonary and systemic vascular resistance increased . The measured cardiac index was < 2.0 L.min-1.m-2 in 23.8 % of the patients , with the lowest measurement typically occurring 9 to 12 hours after surgery . Perfusion strategy assignment was not associated with postoperative hemodynamics or other nonneurological postoperative events . CONCLUSIONS After heart surgery in neonates and infants , both low-flow bypass and circulatory arrest perfusion strategies have comparable effects on the nonneurological postoperative course and hemodynamic profile Background : Sepsis and septic shock are still major causes of morbidity and mortality in spite of the availability of powerful and broadly active antibiotics . Methods : A prospect i ve , open and r and omized trial of the effect of immobilized polymyxin fibers ( PMX-F ) on the survival of patients with sepsis throughout a follow-up period of 28 days or until discharge , if earlier , was carried out . Ninety-eight patients were included who met at least 4 of the criteria for systemic inflammatory response syndrome due to infection . The patients were classified into three groups based on their Acute Physiology and Chronic Health Evaluation ( APACHE ) II score . Results : The overall survival rate was significantly improved by using PMX-F compared to the control group ( 41 vs. 11 % ) ( p = 0.002 ) . In patients with an APACHE II score less than 20 , treatment with PMX-F was shown to improve outcome ( 65 vs. 19 % ) ( p = 0.01 ) . In cases of more severe sepsis with an APACHE II score of 20–29 , PMX-F still maintained efficacy in improving outcome ( 40 vs. 11 % ) ( p = 0.04 ) . However , PMX-F treatment did not improve the survival rate in patients with an APACHE II score of greater than 30 ( survival rate 7 vs. 0 % ) ( p = 0.59 ) . Conclusion : From these results , it is concluded that treatment with PMX-F in patients with sepsis is effective and prolongs the survival rate when applied at an early stage of sepsis . However , in severe sepsis , this therapy does not improve the survival rate Despite the use of potent antibiotics and intensive supportive care , the mortality among patients with sepsis and Gram-negative bacteremia remains high . In recent years , endotoxin adsorption therapy ( PMX-DHP , polymyxin-direct hemoperfusion ) has been widely used in Japan to remove endotoxin , a causative agent of sepsis . In septic patients whose clinical condition may change at any moment , the decision of when to perform blood purification in addition to conventional intensive care is a critical factor in the therapeutic strategy and prognosis . In the present study , we investigated the effect over time of PMX-DHP in sepsis . The subjects were 16 patients with systemic inflammatory response syndrome ( SIRS ) who required surgical treatment including a surgical operation and drainage . The following six parameters were compared between the first and second PMX-DHP : mean blood pressure and time-restricted urine at four time points - at baseline and at 6 , 24 and 72 h after PMX-DHP ; and white blood cell count , platelet count , base excess and Septic Severity Score ( SSS ) at 24 and 72 h after PMX-DHP . Mean blood pressure improved over time up to 24 h after both the first and second PMX-DHP . Time-restricted urine volume improved only at 6 h after the first PMX-DHP . White blood cell count improved over time up to 24 h after both the first and second PMX-DHP . The SSS improved at all time points studied except for 3 days after the second PMX-DHP . We conclude that PMX-DHP is expected to have important implication s in terms of ( i ) correction of clinical conditions ( by severity assessment ) ; ( ii ) improvement of hemodynamics ; ( iii ) possible anti-inflammatory effect ; and ( iv ) possible improvement of oxygen metabolism in tissues A prospect i ve clinical study was performed to evaluate a new method of treatment of endotoxin shock , a column containing polystyrene fibers with covalently bound immobile polymyxin B. Direct hemoperfusion using the column removes circulating endotoxin by adsorption . All of the patients studied , 37 in the treatment group and 33 in the control group , had endotoxemia and failure of 1 or more organs . The perfusion was performed 1 - 7 times per patient , 2 h/session . The survival rate was significantly higher in the treatment group ( 54 % ) than in the controls ( 36.4 % ) . The mean plasma endotoxin concentration was significantly lowered by the treatment from 83.7 pg/ml before perfusion to 56.4 pg/ml immediately after and 28.5 pg/ml the day after the treatment , and the posttreatment level was much lower in those who survived ( mean , 18.8 pg/ml ) compared to those who died ( mean , 88 pg/ml ) . Various parameters of cardiac function also improved after the treatment Severe sepsis is known to cause multiple organ failure , including renal dysfunction . During sepsis , endotoxin targets the renal proximal tubular cells , the function of which can be evaluated on the basis of urinary N-acetyl-&bgr;-glucosaminidase ( NAG ) . We investigated whether urinary NAG activity is altered in patients with severe sepsis and whether treatment with polymyxin B immobilized fibers ( PMX-F ) affects this activity . Subjects of this study were 120 patients with severe sepsis and 60 healthy volunteers matched for age and gender . Patients were r and omly assigned to one of two treatments : PMX-F treatment ( n = 70 ) or conventional treatment ( n = 50 ) . The plasma endotoxin level was significantly reduced , from 34.6 ± 10.2 to 6.8 ± 2.4 pg/ml ( p < 0.01 ) in patients treated with PMX-F , and the urinary NAG/creatinine ratio was reduced from 46.5 ± 26.8 U/gm to 18.6 ± 13.6 U/gm ( p < 0.01 ) . The plasma endotoxin level and urinary NAG/creatinine ratio were unchanged in patients who received conventional treatment . The increased urinary NAG/creatinine ratio in patients with severe sepsis may reflect proximal tubular dysfunction . PMX-F is effective in reducing proximal tubular dysfunction , in part owing to reduced plasma endotoxin levels In this study , we examined the effects of direct hemoperfusion through filters with immobilized polymyxin B ( PMX-DHP ) on leukocyte function and plasma levels of cytokines in patients with septic shock . We found that PMX-DHP caused increased expression of C-X-C chemokine receptor 1 ( CXCR1 ) and CXCR2 , along with decreased expression of CD64 and CD11b , by circulating neutrophils in patients with septic shock . Plasma levels of cytokines , including interleukin 6 ( IL-6 ) , IL-8 , IL-10 , and high-mobility group box 1 , were elevated in patients with septic shock compared with healthy controls , but cytokine levels were not altered by PMX-DHP . These results suggest that PMX-DHP influences neutrophils via a mechanism that does not involve cytokine . Ex vivo perfusion of heparinized blood from patients with sepsis and septic shock through PMX filters in a laboratory circuit caused a significant decrease in neutrophil and monocyte counts . After 120 min of perfusion , neutrophils , monocytes , and lymphocytes were decreased by 78 % , 70 % , and 10 % , respectively , compared with baseline values . Flow cytometric analysis indicated that activated neutrophils with high levels of CD11b/CD64 expression and low levels of CXCR1/CXCR2 expression showed preferential adhesion to PMX filters . Neutrophils isolated from the blood after ex vivo PMX perfusion caused less damage to an endothelial cell monolayer than cells from sham-treated blood , whereas neutrophil phagocytosis of opsonized Escherichia coli was unaffected . These results indicate that PMX-DHP selectively removes activated neutrophils and reduces the ability of circulating cells to cause endothelial damage . Selective removal of activated neutrophils using PMX-DHP may improve the systemic inflammatory response in patients with septic shock

For haematological toxicities , such as neutropenic fever and anaemia , there was no clear evidence that risks differed between groups , while trastuzumab seemed to raise the risk of neutropenia . The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens . The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens , and patients treated as first-line or subsequent lines . Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer , but it also increased the risk of cardiac toxicities , such as congestive heart failure and LVEF decline .

BACKGROUND Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 ( known as HER2-positive ) or not ( HER2-negative ) . Typically , patients with HER2-positive disease have a worse prognosis . Trastuzumab is a selective treatment that targets the HER2 pathway . The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and , although the efficacy results seem to support its use , other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system . OBJECTIVES To assess the evidence on the efficacy and safety of therapy with trastuzumab ( overall ) and in relation to the type of co-administered regimen and the line of treatment , i.e. first-line or beyond progression , in women with HER2-positive metastatic breast cancer .

BACKGROUND Pertuzumab ( P ) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer . We assessed the tolerability , with particular focus on cardiac safety , of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer . PATIENTS AND METHODS In this multicenter , open-label phase II study , patients with operable , locally advanced , or inflammatory breast cancer were r and omized 1 : 1 : 1 to receive six neoadjuvant cycles q3w ( Arm A : 5-fluorouracil , epirubicin , cyclophosphamide [ FEC ] + H + P ×3 → docetaxel [ T ] + H + P ×3 ; Arm B : FEC ×3 → T + H + P ×3 ; Arm C : T + carboplatin + H [TCH]+P ×6 ) . pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS Two hundred twenty-five patients were r and omized . During neoadjuvant treatment , two patients ( 2.7 % ; Arm B ) experienced symptomatic left ventricular systolic dysfunction ( LVSD ) and 11 patients ( Arm A : 4 [ 5.6 % ] ; Arm B : 4 [ 5.3 % ] ; Arm C : 3 [ 3.9 % ] ) had declines in left ventricular ejection fraction of ≥10 % points from baseline to < 50 % . Diarrhea was the most common adverse event . pCR ( ypT0/is ) was reported for 61.6 % ( Arm A ) , 57.3 % ( Arm B ) , and 66.2 % ( Arm C ) of patients . CONCLUSION The combination of P with H and st and ard chemotherapy result ed in low rates of symptomatic LVSD BACKGROUND Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30 - 65 % of patients . We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy . METHODS This r and omised trial was done at 36 centres in the USA and Puerto Rico . Women with operable HER2-positive invasive breast cancer were r and omly assigned ( 1:1 ) with a biased coin minimisation algorithm , stratified for age , tumour size , and hormone receptor status . Neither patients nor investigators ( except for a cardiac safety review panel ) were masked to treatment assignment . Patients r and omly assigned to sequential treatment received fluorouracil 500 mg/m(2 ) , epirubicin 75 mg/m(2 ) , and cyclophosphamide 500 mg/m(2 ) ( FEC-75 ) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2 ) and trastuzumab 2 mg/kg ( after a 4 mg/kg loading dose ) once per week for 12 weeks , while those r and omly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 ( on day 1 of each 21-day cycle ) and once-weekly trastuzumab , in the same doses as the sequential group . Surgery , including evaluation of the axilla , was done within 6 weeks of completion of neoadjuvant treatment . The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population . The study is registered with Clinical Trials.gov , number NCT00513292 . FINDINGS From Sept 15 , 2007 , to Dec 15 , 2011 , 282 women were enrolled ( 140 in the sequential group , 142 in the concurrent group ) . Two patients in the sequential group withdrew consent before starting treatment . 78 of 138 ( 56·5 % , 95 % CI 47·8 - 64·9 ) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 ( 54·2 % , 95 % CI 45·7 - 62·6 ) who received concurrent treatment ( difference 2·3 % , 95 % CI -9·3 to 13·9 ) . No treatment-related deaths occurred . The most common severe toxic effects were neutropenia ( 35 [ 25·3 % ] of 138 patients in the sequential group vs 45 [ 31·7 % ] of 142 patients in the concurrent group ) and fatigue ( six [ 4·3 % ] vs 12 [ 8·5 % ] ) . Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one ( 0·8 % ) of 130 patients who received sequential treatment and four ( 2·9 % ) of 137 patients who received concurrent treatment ; by week 24 , it had dropped below this limit in nine ( 7·1 % ) of 126 patients and in six ( 4·6 % ) of 130 patients , respectively . INTERPRETATION Concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted . FUNDING US National Cancer Institute PURPOSE This study sought to estimate cardiac dysfunction ( CD ) risk for patients receiving trastuzumab ; to characterize observed CD by severity , treatment , and clinical outcome ; to assess effects of baseline clinical risk factors on CD ; and to assess effects of cumulative doses of anthracyclines and trastuzumab on CD . PATIENTS AND METHODS A retrospective review of records for patients enrolled onto any of seven phase II and III trastuzumab clinical trials was performed . Predefined criteria were used for the diagnosis , and the New York Heart Association functional classification system was used to document CD severity . Product-limit estimates were used to summarize the cumulative anthracycline and trastuzumab doses at the time of CD onset . RESULTS Patients treated with trastuzumab were found to be at an increased risk for CD . The incidence was greatest in patients receiving concomitant trastuzumab and anthracycline plus cyclophosphamide ( 27 % ) . The risk was substantially lower in patients receiving paclitaxel and trastuzumab ( 13 % ) or trastuzumab alone ( 3 % to 7 % ) ; however , most of these patients had received prior anthracycline therapy . CD was noted in 8 % of patients receiving anthracycline plus cyclophosphamide and 1 % receiving paclitaxel alone . Most trastuzumab-treated patients developing CD were symptomatic ( 75 % ) , and most improved with st and ard treatment for congestive heart failure ( 79 % ) . CONCLUSION Trastuzumab is associated with an increased risk of CD , which is greatest in patients receiving concurrent anthracyclines . In most patients with metastatic breast cancer , the risk of CD can be justified given the improvement in overall survival previously reported with trastuzumab Background A r and omized Phase II study evaluated the activity of weekly paclitaxel versus its combination with trastuzumab for treatment of patients with advanced breast cancer overexpressing HER-2 . Patients and methods Among 124 patients r and omized , 123 are assessable for toxicity and 118 for response . Patients received weekly paclitaxel single agent ( 80 mg/m2 ) or combined with trastuzumab ( 4 mg/kg loading dose , then weekly 2 mg/kg ) . HER-2 overexpression was determined by immunohistochemistry ( IHC ) . Patients with 2+/3 + IHC scores were eligible . IHC was compared with HER-2 serum extracellular domain ( ECD ) . Results Patient characteristics were similar in the two arms . Both treatments were feasible and well tolerated with no grade 4 hematologic toxicity . No patient developed cardiac toxicity . The combined treatment was statistically significant superior for overall response rate ( ORR ) ( 75 % vs. 56.9 % ; P = 0.037 ) , particularly in the subset of IHC 3 + patients ( 84.5 % vs. 47.5 % ; P = 0.00050 ) . A statistically significant better median time to progression was seen in the subgroup with IHC 3 + ( 369 vs. 272 days ; P = 0.030 ) and visceral disease ( 301 vs. 183 days ; P = 0.0080 ) treated with combination . Multivariable analysis of predictive factors showed that only IHC score retained statistically significant value for ORR ( P = 0.0035 ) . Conclusion Weekly paclitaxel plus trastuzumab is highly active and safe and it is superior to paclitaxel alone in patients with IHC score of 3 + Despite important progress in underst and ing the molecular factors underlying the development of cancer and the improvement in response rates with new drugs , long-term survival is still disappointing for most common solid tumours . This might be because very little of the modest gain for patients is the result of the new compounds discovered and marketed recently . An assessment of the regulatory agencies ' performance may suggest improvements . The present analysis summarizes and evaluates the type of studies and end points used by the EMEA to approve new anticancer drugs , and discusses the application of current regulations . This report is based on the information available on the EMEA web site . We identified current regulatory requirements for anticancer drugs promulgated by the agency and retrieved them in the relevant directory ; information about empirical evidence supporting the approval of drugs for solid cancers through the central ised procedure were retrieved from the European Public Assessment Report ( EPAR ) . We surveyed documents for drug applications and later extensions from January 1995 , when EMEA was set up , to December 2004 . We identified 14 anticancer drugs for 27 different indications ( 14 new applications and 13 extensions ) . Overall , 48 clinical studies were used as the basis for approval ; r and omised comparative ( clinical ) trial ( RCT ) and Response Rate were the study design and end points most frequently adopted ( respectively , 25 out of 48 and 30 out of 48 ) . In 13 cases , the EPAR explicitly reported differences between arms in terms of survival : the range was 0–3.7 months , and the mean and median differences were 1.5 and 1.2 months . The majority of studies ( 13 out of 27 , 48 % ) involved the evaluation of complete and /or partial tumour responses , with regard to the end points supporting the 27 indications . Despite the recommendations of the current EMEA guidance documents , new anticancer agents are still often approved on the basis of small single arm trials that do not allow any assessment of an ‘ acceptable and extensively documented toxicity profile ’ and of end points such as response rate , time to progression or progression-free survival which at best can be considered indicators of anticancer activity and are not ‘ justified surrogate markers for clinical benefit ’ . Anticipating an earlier than ideal point along the drug approval path and the use of not fully vali date d surrogate end points in nonr and omised trials looks like a dangerous shortcut that might jeopardise consumers ' health , leading to unsafe and ineffective drugs being marketed and prescribed . The present Note for Guidance for new anticancer agents needs revising . Drugs must be rapidly released for patients who need them but not be at the expense of adequate knowledge about the real benefit of the drugs PURPOSE Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer . In the German Breast Group 26/Breast International Group 03 - 05 trial , we investigated if trastuzumab treatment should be continued beyond progression . METHODS Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were r and omly assigned to receive capecitabine ( 2,500 mg/m(2 ) body-surface area on days 1 through 14 [ 1,250 mg/m(2 ) semi-daily ] ) alone or with continuation of trastuzumab ( 6 mg/kg body weight ) in 3-week cycles . The primary end point was time to progression . RESULTS We r and omly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab . Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up . Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 ( 95 % CI , 0.48 to 0.97 ; two-sided log-rank P = .0338 ) . Overall survival rates were 20.4 months ( 95 % CI , 17.8 to 24.7 ) in the capecitabine group and 25.5 months ( 95 % CI , 19.0 to 30.7 ) in the capecitabine-plus-trastuzumab group ( P = .257 ) . Overall response rates were 27.0 % with capecitabine and 48.1 % with capecitabine plus trastuzumab ( odds ratio , 2.50 ; P = .0115 ) . Continuation of trastuzumab beyond progression was not associated with increased toxicity . CONCLUSION Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment PURPOSE This is a noncomparative , r and omized , phase II trial of preoperative taxane-anthracycline in combination with trastuzumab , lapatinib , or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 ( HER2 ) -positive , stage II to IIIA operable breast cancer . The primary aim was to estimate the percentage of pathologic complete response ( pCR ; no invasive tumor in breast and axillary nodes ) . PATIENTS AND METHODS In the three arms , chemotherapy consisted of weekly paclitaxel ( 80 mg/m(2 ) ) for 12 weeks followed by fluorouracil , epirubicin , and cyclophosphamide for four courses every 3 weeks . The patients r and omly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly ; in arm B patients received lapatinib 1,500 mg orally ( PO ) daily ; and in arm C , patients received trastuzumab and lapatinib 1,000 mg PO daily . RESULTS A total of 121 patients were r and omly assigned . Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib . No episodes of congestive heart failure were observed . The rates of breast-conserving surgery were 66.7 % , 57.9 % , and 68.9 % in arms A , B and C , respectively . The pCR rates were 25 % ( 90 % CI , 13.1 % to 36.9 % ) in arm A , 26.3 % ( 90 % CI , 14.5 % to 38.1 % ) in arm B , and 46.7 % ( 90 % CI , 34.4 % to 58.9 % ) in arm C ( exploratory P = .019 ) . CONCLUSION The primary end point of the study was met , with a relative increase of 80 % in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib . These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer BACKGROUND Continuation of trastuzumab plus capecitabine ( XH ) showed a significantly improved overall response rate and time to progression compared with capecitabine ( X ) alone in women with HER2-positive breast cancer progressing during trastuzumab treatment . Here , we report the final analysis on overall survival . PATIENTS AND METHODS Patients with HER2-positive , advanced breast cancer who progressed during treatment with trastuzumab with or without 1st-line metastatic chemotherapy were prospect ively r and omised to X ( 2500mg/m(2 ) on days 1 - 14 , q3w ) or XH ( 6 (8)mg/kg , q3w ) . Overall survival was a pre-specified secondary end-point . RESULTS Median follow-up at June 2010 was 20.7months . Fifty nine of 74 and 60 of 77 patients died in the X and XH arm , respectively . Median overall survival was 20.6 and 24.9months with X and XH , respectively ( HR=0.94 [ 0.65 - 1.35 ] ; p=0.73 ) . Performance status and metastatic site were independent prognosticators for overall survival . No difference between treatment arms was observed for patients who achieved clinical response or clinical benefit , respectively . Patients who continued/restarted anti-HER2 treatment ( trastuzumab or lapatinib ) after 2nd progression ( N=52 ) had a post-progression survival of 18.8 compared with 13.3months for those who did not receive 3rd line treatment with anti-HER2 agents ( N=88 ) ( HR 0.63 ; p=0.02 ) . CONCLUSIONS Final overall survival analysis of the GBG-26 study did not demonstrate a significant survival benefit for treatment beyond progression with trastuzumab . However , in a post-hoc analysis , patients receiving anti-HER2 treatment as 3rd line therapy showed a better post-progression survival than those not receiving this targeted treatment

Although CBPR trials examined a wide range of behavioral and clinical outcomes , such trials had very high success rates in recruiting and retaining minority participants and achieving significant intervention effects . CONCLUSIONS Significant publication gaps remain between CBPR and other interventional research methods . CBPR may be effective in increasing participation of racial and ethnic minority subjects in research and may be a powerful tool in testing the generalizability of effective interventions among these population s. CBPR holds promise as an approach that may contribute greatly to the study of health care delivery to disadvantaged population

OBJECTIVE To examine the effectiveness of current community-based participatory research ( CBPR ) clinical trials involving racial and ethnic minorities .

Background Research and practice partnerships have the potential to enhance the translation of research findings into practice . Purpose This paper describes such a partnership in the development of Walk Kansas ( WK ) and highlights individual and organizational level outcomes . Method Phase 1 examined : ( a ) the reach of WK , ( b ) physical activity changes , and ( c ) maintenance of physical activity changes 6 months after the program was completed . Phase 2 explored WK adoption and sustainability over 5 years . Results WK attracted a large number of participants who were more likely to be female , more active , and older than the adult population within the counties where they resided . Inactive or insufficiently active participants at baseline experienced significant increases in both moderate ( p < 0.001 ) and vigorous ( p < 0.001 ) physical activity . A r and om selection of participants who were assessed 6 months post-program did not demonstrate a significant decrease in moderate or vigorous activity between program completion and 6-month follow-up . The number of counties adopting the program increased across years , peaking at 97 in 2006 and demonstrated the sustainability of the WK over 5 years . Conclusions WK is effective , has a broad reach , and enables participants to maintain increased activity . It also shows promise for broad adoption and sustainability It is becoming increasingly common for community teams or coalitions to implement programming for children and families design ed to promote positive youth development and prevent adolescent problem behaviors . However , there has been only limited rigorous study of the effectiveness of community teams ’ programming efforts to produce positive outcomes . This study employed a community-level r and omized control design to examine protective parent and youth skills outcomes of evidence -based preventive interventions selected from a menu and delivered by community teams supported by a community – university partnership model called PROSPER . Twenty-eight rural communities in two states were r and omized across intervention and control conditions . Data were collected through written question naires that were completed by approximately 12,000 middle school students in the fall of the 6th grade , prior to intervention delivery , and again in the spring of the 7th , 8th , and 9th grade s. Positive intervention effects were found for youth , parent , and family outcomes ( e.g. , association with antisocial peers , child management , parent – child affective quality ) at each post-intervention assessment point . Improvements in these family and youth skill outcomes are expected to support long-term reductions of adolescent problem behaviors , such as substance abuse . Editors ’ Strategic Implication s : In this important and well controlled trial , the authors demonstrate that university partnership-supported community teams , especially when supported with ongoing technical assistance , can continue to produce positive outcomes even after much of the control over delivery of programs is turned over to representatives of the communities in which they are implemented This study examined the longitudinal predictors of quality of functioning of community prevention teams during the “ operations ” phase of team development . The 14 community teams were involved in a r and omized-trial of a university-community partnership project , PROSPER ( Spoth et al. , Prevention Science , 5(1 ) : 31–39 , 2004b ) , that implements evidence -based interventions intended to support positive youth development and reduce early substance use , as well as other problem behaviors . The study included a multi-informant approach to measurement of constructs , and included data from 137 team members , 59 human service agency directors and school administrators , 16 school principals , and 8 Prevention Coordinators ( i.e. technical assistance providers ) . We examined how community demographics and social capital , team level characteristics , and team member attributes and attitudes are related to local team functioning across an 18-month period . Findings indicate that community demographics ( poverty ) , social capital , team member attitudes towards prevention , and team members ’ views of the acceptability of teen alcohol use played a substantial role in predicting various indicators of the quality of team functioning 18 months later BACKGROUND If positive- outcome bias exists , it threatens the integrity of evidence -based medicine . METHODS We sought to determine whether positive- outcome bias is present during peer review by testing whether peer review ers would ( 1 ) recommend publication of a " positive " version of a fabricated manuscript over an otherwise identical " no-difference " version , ( 2 ) identify more purpose fully placed errors in the no-difference version , and ( 3 ) rate the " Methods " section in the positive version more highly than the identical " Methods " section in the no-difference version . Two versions of a well- design ed r and omized controlled trial that differed only in the direction of the finding of the principal study end point were su bmi tted for peer review to 2 journals in 2008 - 2009 . Of 238 review ers for The Journal of Bone and Joint Surgery and Clinical Orthopaedics and Related Research r and omly allocated to review either a positive or a no-difference version of the manuscript , 210 returned review s. RESULTS Review ers were more likely to recommend the positive version of the test manuscript for publication than the no-difference version ( 97.3 % vs 80.0 % , P < .001 ) . Review ers detected more errors in the no-difference version than in the positive version ( 0.85 vs 0.41 , P < .001 ) . Review ers awarded higher methods scores to the positive manuscript than to the no-difference manuscript ( 8.24 vs 7.53 , P = .005 ) , although the " Methods " sections in the 2 versions were identical . CONCLUSIONS Positive- outcome bias was present during peer review . A fabricated manuscript with a positive outcome was more likely to be recommended for publication than was an otherwise identical no-difference manuscript Using community-based participatory research methods , a community- research coalition in Santa Clara County , California ( SCC ) conducted a quasi-experimental , controlled trial to increase Pap test receipt and to build community capacity among Vietnamese-American women . From 1999 to 2004 , the Coalition planned and implemented an Action Plan with six components : multimedia campaign , lay health worker outreach , Vietnamese Pap clinic with patient navigation , registry and reminder system , continuing medical education for Vietnamese physicians , and restoring a Breast and Cervical Cancer Control Program site . Components were evaluated individually . Community-wide , cross-sectional telephone surveys of Vietnamese women in SCC ( intervention community ) and Harris County , Texas ( comparison community ) measured overall project impact . Receipt and currency of Pap tests increased significantly in the intervention compared with the comparison community . Community involvement , system changes , community and research capacity building , dissemination of results , and program sustainability were also demonstrated . Community-based participatory research is feasible and effective in Vietnamese-American communities BACKGROUND Traditional research approaches frequently fail to yield representative numbers of people of color in research . Community-based participatory research ( CBPR ) may be an important strategy for partnering with and reaching population s that bear a greater burden of illness but have been historically difficult to engage . The Community Action Board , consisting of 20 East Harlem residents , leaders , and advocates , used CBPR to compare the effectiveness of various strategies in recruiting and enrolling adults with prediabetes into a peer-led , diabetes prevention intervention . METHODS The board created five recruitment strategies : recruiting through clinicians ; recruiting at large public events such as farmers markets ; organizing special local recruitment events ; recruiting at local organizations ; and recruiting through a partner-led approach , in which community partners developed and managed the recruitment efforts at their sites . RESULTS In 3 months , 555 local adults were approached ; 249 were appropriate c and i date s for further evaluation ( overweight , nonpregnant , East Harlem residents without known diabetes ) ; 179 consented and returned in a fasting state for 1/2 day of prediabetes testing ; 99 had prediabetes and enrolled in a pilot r and omized trial . The partner-led approach was highly successful , recruiting 68 % of those enrolled . This strategy was also the most efficient ; 34 % of those approached through partners were ultimately enrolled , versus 0%-17 % enrolled through the other four strategies . Participants were predominantly low-income , uninsured , undereducated , Spanish-speaking women . CONCLUSIONS This CBPR approach highlights the value of partner-led recruitment to identify , reach out to , and motivate a vulnerable population into participation in research , using techniques that may be unfamiliar to research ers but are nevertheless rigorous and effective Many promising technology-based programs design ed to promote healthy behaviors such as physical activity and healthy eating have not been adapted for use with diverse communities , including Latino communities . We design ed a community-based health kiosk program for English- and Spanish-speaking Latinos . Users receive personalized feedback on nutrition , physical activity , and smoking behaviors from computerized role models that guide them in establishing goals in 1 or more of these 3 areas . We found significant improvements in nutrition and physical activity among 245 Latino program users ; however , no changes were observed with respect to smoking behaviors . The program shows promise for extending the reach of chronic disease prevention and self-management programs OBJECTIVES Our community-academic partnership employed community-based participatory research to develop and pilot a simple , peer-led intervention to promote weight loss , which can prevent diabetes and eliminate racial/ethnic disparities in incident diabetes among overweight adults with prediabetes . METHODS We recruited overweight adults at community sites , performed oral glucose tolerance testing to identify persons with blood glucose levels in the prediabetes range , and r and omized eligible people to a peer-led lifestyle intervention group or delayed intervention in 1 year . Outcomes , including weight , blood pressure , and health behaviors , were measured at baseline and 3 , 6 , and 12 months . RESULTS More than half of those tested ( 56 % , or 99 of 178 ) had prediabetes and enrolled in the study . Participants were predominantly Spanish-speaking , low-income , undereducated women . The intervention group lost significantly more weight than the control group and maintained weight loss at 12 months ( 7.2 versus 2.4 pounds ; P < .01 ) . One fourth ( 24 of 99 ) of participants progressed to diabetes . CONCLUSIONS In underserved minority communities , prediabetes prevalence may be higher than previously reported . Low-cost , community-based interventions can succeed in encouraging weight loss to prevent diabetes This study investigated the effectiveness of a community-academic health center partnership , utilizing nurse-supervised indigenous community health workers , in decreasing the blood pressure in an urban African-American population . A four-year r and omized clinical trial was conducted in the S and town-Winchester community , which has an excess prevalence of high blood pressure , in order to test the effectiveness of 2 different levels of intervention intensity on increasing the control of high blood pressure . Community health workers were trained and certified in blood pressure management , monitoring , education and counseling , social support mobilization , and community outreach and follow up . The primary results were a significant decrease in mean systolic and diastolic pressures after both levels of intervention , and a significant increase in the percentage of individuals with controlled high blood pressure . Surprisingly , no differences in results were observed between the 2 levels of intervention intensity . This study supports the use of community-based partnership efforts , and the utilization of indigenous health workers , to enhance the control of high blood pressure in a high-risk , African-American urban population This project evaluated an intervention for preventing peer rejection in middle school that promoted social acceptance in the classroom environment . The systems-level and preventive focus of this intervention differed markedly from traditional interventions that target putative deficits within individual rejected children . In collaboration with 24 teachers and their classrooms , the intervention team led mixed groups of accepted and rejected children in cooperative games that required teamwork and mutual respect among all members in order to succeed . To reinforce these alliances between children , as well as to prevent future peer rejection , teachers were encouraged to use cooperative , teamwork-based group activities for academic instruction . The intervention was evaluated using a r and omized control ( waitlist ) design . Results suggested that the intervention reduced the amount of self-reported peer rejection in classrooms . Implication s for the further development and evaluation of systems-level interventions to prevent peer rejection are discussed . Editors ’ Strategic Implication s : The use of a systems-based prevention program shows promise for the prevention of children ’s perceived peer rejection . The authors demonstrate a model of university-community collaboration with a plan for sustainability and a focus on low-income and minority population s. Educators , school administrators , and research ers will be intrigued by the positive experiences of non-rejected peers and teachers in promoting a socially accepting school climate There has been relatively little research on effects of interventions aim ed directly at improving internal community coalition functioning , particularly in the area of planning for adoption of evidence -based prevention programs . The current study investigated the effect of Project STEP , a prevention diffusion trial , on three factors hypothesized to improve coalition prevention planning ( quality of coalition plans , extent of plan implementation , and committee internal functioning in meetings ) . Cities were r and omly assigned to one of three conditions ( televised training with limited technical assistance , televised training alone , or control ; n = 24 ) . Results demonstrated that at 1.5 year follow-up , coalitions in the two intervention groups showed more effective prevention plans , plan implementation , and functioning in meetings than control coalitions . Group differences were maintained at 3-year follow-up , albeit at decreased levels , for quality of planning and implementation . The findings suggest that building coalition capacity to diffuse evidence -based prevention programs works at least partially by increasing the effectiveness of coalition functioning , and that booster training may be warranted within 3 years after initial training Nearly 2 million children live or work on America 's farms and ranches . Despite the increasing mechanization of production agriculture in the United States , children still constitute a considerable portion of the work force on farms and ranches . When adjusted for actual work exposure time , adolescent injury rates on agricultural establishments surpass those of adults ( Castillo , D. N. , L and en , D. D. , & Layne , L. A. ( 1994 ) . American Journal of Public Health , 84 , 646 - 649 ) . This project , headed by two public health nurses , developed and tested an agricultural safety curriculum [ Agricultural Disability Awareness and Risk Education ( AgDARE ) ] for use in high school agriculture classes . Students who participated in AgDARE scored significantly higher in farm safety attitude and intent to change work behavior than the control group . School and public health nurses , working together with agriculture teachers , may make an effective team in reducing injuries among teen agricultural workers BACKGROUND This article describes the process and results of a smoking cessation intervention r and omized clinical trial ( RCT ) that was conducted as a community-based participatory research project . This RCT tested whether outcomes are improved by adding social justice and tobacco industry targeting messages to a smoking cessation program conducted among African American adults within a low-income community in San Francisco , California . This study provides lessons for future similar research projects that focus on urban low-income population s. METHODS Participants were r and omly allocated to receive a smoking-cessation program ( control group [ CG ] ) or CG care plus tobacco industry and media ( IAM ) messages . Primary interventions were behavioral . At intake , participants reporting severe withdrawal or smoking > or = 25 cigarettes daily were offered free nicotine replacement therapy . Baseline data were from an in-person interview . Outcome measures included self-reported smoking status ; validation of quitting was by salivary cotinine assays . RESULTS Of 87 participants providing baseline data , 31 % ( 27 ) did not join the RCT . Proportions quitting in the CG and IAM group were 11.5 % and 13.6 % at 6 months and 5.3 % and 15.8 % at 12 months , respectively . CONCLUSION African Americans in underserved inner-city neighborhoods can be recruited into RCTs with community participatory approaches . Differences between the CG and IAM in proportions who quit were 2.1 % and 10.5 % at 6 and 12 months , respectively . More than 3 years with adequate funding , high staffing ratios , and intense outreach and follow-up schedules are needed to achieve recruitment and study goals This pilot study used a community-based participatory research approach to recruit and train five licensed cosmetologists from two beauty salons to deliver health promotion messages to their customers . Stylists attended a 4-hr workshop to develop skills for delivering targeted health messages . Educational displays in the salons reinforced these messages . Qualitative and quantitative methods assessed satisfaction , readiness to change , and self-reported health behavior changes in customers immediately postintervention and at 12 months . Trained stylists reported they would continue delivering health messages after the 7-week pilot was completed ; 81 % of customers read the educational displays , and 86 % of customers talked with their cosmetologist about the Bringing Education and Underst and ing to You Project . At 12 months , 55 % of customers reported making changes in their health because of the conversations they had with their cosmetologist . Customers who spoke more often with their cosmetologists about health also reported a higher percentage of self-reported behavior changes . It appears that trained licensed cosmetologists are effective in promoting health messages to their customers Despite multidisciplinary efforts to control the nation 's obesity epidemic , obesity has persisted as one of the U.S. 's top public health problems , particularly among African Americans . Innovative approaches to address obesity that are sensitive to the unique issues of African Americans are needed . Thus , a faith-based weight-loss intervention using a community-based participatory research approach was developed , implemented , and evaluated with a rural African American faith community . A two-group , quasi-experimental , delayed intervention design was used , with church as the unit of assignment ( treatment n = 2 , control n = 2 ) and individual as the unit of observation ( treatment n = 36 , control n = 37 ) . Weekly small groups led by trained community members met for 8 weeks and emphasized healthy nutrition , physical activity , and faith 's connection with health . The mean weight loss of the treatment group was 3.60 ± 0.64 lbs . compared to the 0.59 ± 0.59-lb loss of the control group The objectives of this study were : 1 ) to evaluate the acceptance , effectiveness , and sustainability of a promotora ( community health worker ) pilot program to improve hypertension control among medically underserved Mexican Americans of the El Paso , Texas area , and 2 ) to demonstrate improvements in clinical measures of blood pressure , BMI and waist circumference , self-reported behaviors and changes in attitudes and beliefs about blood pressure among Mexican American hypertensives . Participants were eligible if they had been diagnosed with hypertension and if they were willing to be r and omized as either participants in the intervention or as controls . A total of 58 participants enrolled in the intervention group and 40 participants served as controls . This was a 9-week promotora intervention . Health behavior constructs and clinical data were measured pre-post intervention . Perceived benefits , and two heart-healthy behaviors ( salt and sodium , and cholesterol and fat ) were shown to be statistically significantly different between the intervention and control groups

Intraoperative goal directed hemodynamic therapy with minimally invasive monitoring decreases postoperative complications in noncardiac surgery , although it was not able to show a significant decrease in mortality rate

BACKGROUND The goal directed hemodynamic therapy is an approach focused on the use of cardiac output and related parameters as end-points for fluids and drugs to optimize tissue perfusion and oxygen delivery . Primary aim : To determine the effects of intraoperative goal directed hemodynamic therapy on postoperative complications rates .

BACKGROUND Some observational studies suggest that the use of pulmonary-artery catheters to guide therapy is associated with increased mortality . METHODS We performed a r and omized trial comparing goal -directed therapy guided by a pulmonary-artery catheter with st and ard care without the use of a pulmonary-artery catheter . The subjects were high-risk patients 60 years of age or older , with American Society of Anesthesiologists ( ASA ) class III or IV risk , who were scheduled for urgent or elective major surgery , followed by a stay in an intensive care unit . Outcomes were adjudicated by observers who were unaware of the treatment-group assignments . The primary outcome was in-hospital mortality from any cause . RESULTS Of 3803 eligible patients , 1994 ( 52.4 percent ) underwent r and omization . The base-line characteristics of the two treatment groups were similar . A total of 77 of 997 patients who underwent surgery without the use of a pulmonary-artery catheter ( 7.7 percent ) died in the hospital , as compared with 78 of 997 patients in whom a pulmonary-artery catheter was used ( 7.8 percent)--a difference of 0.1 percentage point ( 95 percent confidence interval , -2.3 to 2.5 ) . There was a higher rate of pulmonary embolism in the catheter group than in the st and ard-care group ( 8 events vs. 0 events , P=0.004 ) . The survival rates at 6 months among patients in the st and ard-care and catheter groups were 88.1 and 87.4 percent , respectively ( difference , -0.7 percentage point [ 95 percent confidence interval , -3.6 to 2.2 ] ; negative survival differences favor st and ard care ) ; at 12 months , the rates were 83.9 and 83.0 percent , respectively ( difference , -0.9 percentage point [ 95 percent confidence interval , -4.3 to 2.4 ] ) . The median hospital stay was 10 days in each group . CONCLUSIONS We found no benefit to therapy directed by pulmonary-artery catheter over st and ard care in elderly , high-risk surgical patients requiring intensive care Introduction Several studies have shown that goal -directed hemodynamic and fluid optimization may result in improved outcome . However , the methods used were either invasive or had other limitations . The aim of this study was to perform intraoperative goal -directed therapy with a minimally invasive , easy to use device ( FloTrac/Vigileo ) , and to evaluate possible improvements in patient outcome determined by the duration of hospital stay and the incidence of complications compared to a st and ard management protocol . Methods In this r and omized , controlled trial 60 high-risk patients scheduled for major abdominal surgery were included . Patients were allocated into either an enhanced hemodynamic monitoring group using a cardiac index based intraoperative optimization protocol ( FloTrac/Vigileo device , GDT-group , n = 30 ) or a st and ard management group ( Control-group , n = 30 ) , based on st and ard monitoring data . Results The median duration of hospital stay was significantly reduced in the GDT-group with 15 ( 12 - 17.75 ) days versus 19 ( 14 - 23.5 ) days ( P = 0.006 ) and fewer patients developed complications than in the Control-group [ 6 patients ( 20 % ) versus 15 patients ( 50 % ) , P = 0.03 ] . The total number of complications was reduced in the GDT-group ( 17 versus 49 complications , P = 0.001 ) . Conclusions In high-risk patients undergoing major abdominal surgery , implementation of an intraoperative goal -directed hemodynamic optimization protocol using the FloTrac/Vigileo device was associated with a reduced length of hospital stay and a lower incidence of complications compared to a st and ard management protocol .Trial Registration Clinical trial registration information : Unique identifier : BACKGROUND Patients with proximal femoral fracture ( PFF ) are at high risk of postoperative complications . Goal -directed haemodynamic treatment ( GDHT ) in other high-risk surgical patients reduces postoperative complications . We aim ed to compare effects of GDHT and routine fluid treatment ( RFT ) on postoperative outcomes after PFF surgery . METHODS PFF patients ( ≥70 yr ) were enrolled in this single-centre , open , r and omized , controlled , parallel-group superiority trial with concealed allocation using computer-generated r and omization . TREATMENTS ( i ) GDHT to attain oxygen delivery index > 600 ml min(-1 ) m(-2 ) using fluids and dobutamine and ( ii ) a protocol -guided RFT . After 150 enrolled patients , the trial was stopped due to slow recruitment . The short-term primary outcome measure was the relative risk ( RR ) of postoperative complications ; secondary measures were ( i ) administered fluid levels , ( ii ) vasopressor requirements , and ( iii ) haemodynamic responses . RESULTS For the GDHT group , 74 and for the RFT group 75 patients were design ated . The RR of postoperative complications ( GDHT vs RFT ) was 0.79 ( 95 % confidence interval 0.54 - 1.16 ) ; the volumes of i.v . fluids decreased ( 1078 vs 1440 ml , P=0.01 ) ; fewer patients required treatment of hypotension ( 18.5 % vs 75 % , P<0.005 ) ; there were more patients with increased oxygen delivery at the end of operation ( 28 % vs 8 % , P=0.04 ) , but the haemodynamic goal was achieved in only 27 % of patients in the GDHT group . CONCLUSIONS The magnitude of risk reduction of postoperative complications is clinical ly relevant , but the trial was underpowered and the null hypothesis can not be rejected Introduction Little is known about mortality rates following general surgical procedures in the United Kingdom . Deaths are most common in the ' high-risk ' surgical population consisting mainly of older patients , with coexisting medical disease , who undergo major surgery . Only limited data are presently available to describe this population . The aim of the present study was to estimate the size of the high-risk general surgical population and to describe the outcome and intensive care unit ( ICU ) re source use . Methods Data on inpatient general surgical procedures and ICU admissions in 94 National Health Service hospitals between January 1999 and October 2004 were extracted from the Intensive Care National Audit & Research Centre data base and the CHKS data base . High-risk surgical procedures were defined prospect ively as those for which the mortality rate was 5 % or greater . Results There were 4,117,727 surgical procedures ; 2,893,432 were elective ( 12,704 deaths ; 0.44 % ) and 1,224,295 were emergencies ( 65,674 deaths ; 5.4 % ) . A high-risk population of 513,924 patients was identified ( 63,340 deaths ; 12.3 % ) , which accounted for 83.8 % of deaths but for only 12.5 % of procedures . This population had a prolonged hospital stay ( median , 16 days ; interquartile range , 9–29 days ) . There were 59,424 ICU admissions ( 11,398 deaths ; 19 % ) . Among admissions directly to the ICU following surgery , there were 31,633 elective admissions with 3,199 deaths ( 10.1 % ) and 24,764 emergency admissions with 7,084 deaths ( 28.6 % ) . The ICU stays were short ( median , 1.6 days ; interquartile range , 0.8–3.7 days ) but hospital admissions for those admitted to the ICU were prolonged ( median , 16 days ; interquartile range , 10–30 days ) . Among the ICU population , 40.8 % of deaths occurred after the initial discharge from the ICU . The highest mortality rate ( 39 % ) occurred in the population admitted to the ICU following initial postoperative care on a st and ard ward . Conclusion A large high-risk surgical population accounts for 12.5 % of surgical procedures but for more than 80 % of deaths . Despite high mortality rates , fewer than 15 % of these patients are admitted to the ICU Background Our aim was to determine whether substitution of goal -directed fluid therapy ( GDT ) ( perioperative fluid administration ) for traditional therapy to manage elderly patients with coronary heart disease scheduled for gastrointestinal ( GI ) surgery was advantageous . We determined if it would reduce cardiac complications and shorten time to recovery and discharge . Methods Altogether , 60 of these elderly patients were r and omized into GDT ( n = 30 ) and control ( n = 30 ) groups . In the GDT group , fluid management was carried out under guidance of hemodynamic status indicators . Types and quantities of fluids administered , blood loss , intraoperative urine output , time of extubation , intensive care unit ( ICU ) stay , hospital stay , postoperative adverse cardiac events , and GI complications were recorded . Results Total fluids infused were 2,910 ± 645 ml ( GDT group ) and 3,640 ± 771 ml ( control group ) ( p < 0.05 ) . Numbers of adverse cardiac events in the two groups were not significantly different ( p = 0.121 ) . Return of GI function was significantly faster in the GDT group ( p < 0.001 ) . Median ICU stay was 32.5 h in the GDT group and 47.5 h in the control group ( p < 0.001 ) . Median hospital stay was 18 days in the GDT group and 22 days in the control group ( p < 0.001 ) . Conclusions GDT was associated with shorter ICU stay and time to discharge and faster return of GI function compared to traditional fluid therapy . The number of adverse cardiac events was similar in the two groups OBJECTIVES : This pilot study was design ed to utilize stroke volume variation and cardiac index to ensure fluid optimization during one-lung ventilation in patients undergoing thoracoscopic lobectomies . METHODS : Eighty patients undergoing thoracoscopic lobectomy were r and omized into either a goal -directed therapy group or a control group . In the goal -directed therapy group , the stroke volume variation was controlled at 10%±1 % , and the cardiac index was controlled at a minimum of 2.5 L.min-1.m-2 . In the control group , the MAP was maintained at between 65 mm Hg and 90 mm Hg , heart rate was maintained at between 60 BPM and 100 BPM , and urinary output was greater than 0.5 mL/kg-1/h-1 . The hemodynamic variables , arterial blood gas analyses , total administered fluid volume and side effects were recorded . RESULTS : The PaO2/FiO2-ratio before the end of one-lung ventilation in the goal -directed therapy group was significantly higher than that of the control group , but there were no differences between the goal -directed therapy group and the control group for the PaO2/FiO2-ratio or other arterial blood gas analysis indices prior to anesthesia . The extubation time was significantly earlier in the goal -directed therapy group , but there was no difference in the length of hospital stay . Patients in the control group had greater urine volumes , and they were given greater colloid and overall fluid volumes . Nausea and vomiting were significantly reduced in the goal -directed therapy group . CONCLUSION : The results of this study demonstrated that an optimization protocol , based on stroke volume variation and cardiac index obtained with a FloTrac/Vigileo device , increased the PaO2/FiO2-ratio and reduced the overall fluid volume , intubation time and postoperative complications ( nausea and vomiting ) in thoracic surgery patients requiring one-lung ventilation BACKGROUND A prospect i ve , r and omized controlled trial comparing conventional intraoperative fluid management with two differing methods of invasive haemodynamic monitoring to optimize intraoperative fluid therapy , in patients undergoing proximal femoral fracture repair under general anaesthesia . METHODS Ninety patients r and omized to three groups ; conventional intraoperative fluid management ( Gp CON , n=29 ) , and two groups receiving additional repeated colloid fluid challenges guided by central venous pressure ( Gp CVP , n=31 ) or oesophageal Doppler ultrasonography ( Gp DOP , n=30 ) . Primary outcome measures were time to medical fitness to discharge , hospital stay and postoperative morbidity . RESULTS The fluid challenge result ed in significantly greater perioperative changes in central venous pressure between Gp CVP and Gp CON ( mean 5 ( 95 % confidence interval 3 - 7 ) mm Hg ) ( P<0.0001 ) . Important perioperative changes were also shown in Gp DOP with increases of 49.4 ms ( 19.7 - 79.1 ms ) in the corrected flow time , 13.5 ml ( 7.4 - 19.6 ml ) in stroke volume , and 0.9 ( 0.49 - 1.39 ) litre min(-1 ) in cardiac output . As a result , fewer patients in Gp CVP and Gp DOP experienced severe intraoperative hypotension ( Gp CON 28 % ( 8/29 ) , Gp CVP 9 % ( 3/31 ) , Gp DOP 7 % ( 2/30 ) , P=0.048 ( chi-squared , 2 degrees of freedom ( df ) . No differences were seen between the three groups when major morbidity and mortality were combined , P=0.24 ( chi-squared , 2 df ) . Postoperative recovery for survivors , as defined by time to be deemed medically fit for discharge , was significantly faster , in comparison with Gp CON , in both the Gp CVP ( 10 vs 14 ( 95 % confidence interval 8 - 12 vs 12 - 17 ) days , P=0.008 ( t-test ) ) , and Gp DOP ( 8 vs 14 ( 95 % confidence interval 6 - 12 vs 12 - 17 ) days , P=0.023 ( t-test ) . There were no significant differences between groups , for survivors , with respect to acute orthopaedic hospital and total hospital stay . CONCLUSIONS Invasive intraoperative haemodynamic monitoring with fluid challenges during repair of femoral fracture under general anaesthetic shortens time to being medically fit for discharge This systematic review and meta- analysis summarizes the clinical effects of increasing perioperative blood flow using fluids with or without inotropes/vasoactive drugs to explicit defined goals in adults . We included r and omized controlled trials of adult patients ( aged 16 years or older ) undergoing surgery . We included 31 studies of 5292 participants . There was no difference in mortality at the longest follow-up : 282/2615 ( 10.8 % ) died in the control group and 238/2677 ( 8.9 % ) in the treatment group , RR of 0.89 ( 95 % CI : 0.76 - 1.05 ; P=0.18 ) . However , the results were sensitive to analytical methods and withdrawal of studies with method ological limitations . The intervention reduced the rate of three morbidities ( renal failure , respiratory failure , and wound infections ) but not the rates of arrhythmia , myocardial infa rct ion , congestive cardiac failure , venous thrombosis , and other types of infections . The number of patients with complications was also reduced by the intervention . Hospital length of stay was reduced in the treatment group by 1.16 days . There was no difference in critical care length of stay . The primary analysis of this review showed no difference between groups but this result was sensitive to the method of analysis , withdrawal of studies with method ological limitations , and was dominated by a single large study . Patients receiving this intervention stayed in hospital 1 day less with fewer complications . It is unlikely that the intervention causes harm . The balance of current evidence does not support widespread implementation of this approach to reduce mortality but does suggest that complications and duration of hospital stay are reduced Introduction Total hip replacement is one of the most commonly performed major orthopaedic operations . Goal -directed therapy ( GDT ) using haemodynamic monitoring has previously demonstrated outcome benefits in high-risk surgical patients under general anaesthesia . GDT has never been formally assessed during regional anaesthesia . Methods Patients undergoing total hip replacement while under regional anaesthesia were r and omised to either the control group ( CTRL ) or the protocol group ( GDT ) . Patients in the GDT group , in addition to st and ard monitoring , were connected to the FloTrac sensor/Vigileo monitor haemodynamic monitoring system , and a GDT protocol was used to maximise the stroke volume and target the oxygen delivery index to > 600 mL/minute/m2 . Results Patients r and omised to the GDT group were given a greater volume of intravenous fluids during the intraoperative period ( means ± st and ard deviation ( SD ) : 6,032 ± 1,388 mL vs. 2,635 ± 346 mL ; P < 0.0001 ) , and more of the GDT patients received dobutamine ( 0 of 20 CTRL patients vs. 11 of 20 GDT patients ; P < 0.0003 ) . The GDT patients also received more blood transfused during the intraoperative period ( means ± SD : 595 ± 316 mL vs. 0 ± 0 mL ; P < 0.0001 ) , although the CTRL group received greater volumes of blood replacement postoperatively ( CTRL patients 658 ± 68 mL vs. GDT patients 198 ± 292 mL ; P < 0.001 ) . Overall blood consumption ( intraoperatively and postoperatively ) was not different between the two groups . There were an increased number of complications in the CTRL group ( 20 of 20 CTRL patients ( 100 % ) vs. 16 of 20 GDT patients ( 80 % ) ; P = 0.05 ) . These outcomes were predominantly due to a difference in minor complications ( 20 of 20 CTRL patients ( 100 % ) vs. 15 of 20 GDT patients ( 75 % ) ; P = 0.047 ) . Conclusions GDT applied during regional anaesthesia in patients undergoing elective total hip replacement changes intraoperative fluid management and may improve patient outcomes by decreasing postoperative complications . Larger trials are required to confirm our findings .Trial registration S RCT Introduction Several single-center studies and meta-analyses have shown that perioperative goal -directed therapy may significantly improve outcomes in general surgical patients . We hypothesized that using a treatment algorithm based on pulse pressure variation , cardiac index trending by radial artery pulse contour analysis , and mean arterial pressure in a study group ( SG ) , would result in reduced complications , reduced length of hospital stay and quicker return of bowel movement postoperatively in abdominal surgical patients , when compared to a control group ( CG ) . Methods 160 patients undergoing elective major abdominal surgery were r and omized to the SG ( 79 patients ) or to the CG ( 81 patients ) . In the SG hemodynamic therapy was guided by pulse pressure variation , cardiac index trending and mean arterial pressure . In the CG hemodynamic therapy was performed at the discretion of the treating anesthesiologist . Outcome data were recorded up to 28 days postoperatively . Results The total number of complications was significantly lower in the SG ( 72 vs. 52 complications , p = 0.038 ) . In particular , infection complications were significantly reduced ( SG : 13 vs. CG : 26 complications , p = 0.023 ) . There were no significant differences between the two groups for return of bowel movement ( SG : 3 vs. CG : 2 days postoperatively , p = 0.316 ) , duration of post anesthesia care unit stay ( SG : 180 vs. CG : 180 minutes , p = 0.516 ) or length of hospital stay ( SG : 11 vs. CG : 10 days , p = 0.929 ) . Conclusions This multi-center study demonstrates that hemodynamic goal -directed therapy using pulse pressure variation , cardiac index trending and mean arterial pressure as the key parameters leads to a decrease in postoperative complications in patients undergoing major abdominal surgery . Trial registration Clinical Trial.gov , NCT01401283 Introduction Post-operative outcomes may be improved by the use of flow related end-points for intra-venous fluid and /or low dose inotropic therapy . The mechanisms underlying this benefit remain uncertain . The objective of this study was to assess the effects of stroke volume guided intra-venous fluid and low dose dopexamine on tissue microvascular flow and oxygenation and inflammatory markers in patients undergoing major gastrointestinal surgery . Methods R and omised , controlled , single blind study of patients admitted to a university hospital critical care unit following major gastrointestinal surgery . For eight hours after surgery , intra-venous fluid therapy was guided by measurements of central venous pressure ( CVP group ) , or stroke volume ( SV group ) . In a third group stroke volume guided fluid therapy was combined with dopexamine ( 0.5 mcg/kg/min ) ( SV & DPX group ) . Results 135 patients were recruited ( n = 45 per group ) . In the SV & DPX group , increased global oxygen delivery was associated with improved sublingual ( P < 0.05 ) and cutaneous microvascular flow ( P < 0.005 ) ( sublingual microscopy and laser Doppler flowmetry ) . Microvascular flow remained constant in the SV group but deteriorated in the CVP group ( P < 0.05 ) . Cutaneous tissue oxygen partial pressure ( PtO2 ) ( Clark electrode ) improved only in the SV & DPX group ( P < 0.001 ) . There were no differences in serum inflammatory markers . There were no differences in overall complication rates between the groups although acute kidney injury was more frequent in the CVP group ( CVP group ten patients ( 22 % ) ; pooled SV and SV & DPX groups seven patients ( 8 % ) ; P = 0.03 ) ( post hoc analysis ) . Conclusions Stroke volume guided fluid and low dose inotropic therapy was associated with improved global oxygen delivery , microvascular flow and tissue oxygenation but no differences in the inflammatory response to surgery . These observations may explain improved clinical outcomes associated with this treatment in previous trials . Trial registration numberIS RCT N Objective : To evaluate the influence of stroke volume variation (SVV)-based goal -directed therapy ( GDT ) on splanchnic organ functions and postoperative complications in orthopedic patients . Subjects and Methods : Eighty patients scheduled for major orthopedic surgery under general anesthesia were r and omly allocated to one of two equal groups to receive either intraoperative volume therapy guided by SVV ( GDT ) or st and ard fluid management ( control ) . In the SVV group , patients received colloid boluses of 4 ml/kg to maintain an SVV < 10 % when in the supine position or an SVV < 14 % if prone . In the control group , fluids were given to maintain a mean arterial pressure > 65 mm Hg , a heart rate < 100 bpm , a central venous pressure of 8 - 14 mm Hg , and a urine output > 0.5 ml/kg/h . Intraoperative organ perfusion , hemodynamic data , hospitalization , postoperative complications , and mortality were recorded . Results : The heart rate at the end of surgery was significantly lower ( p < 0.05 ) , there were fewer hypotensive episodes ( p < 0.05 ) , the arterial and gastric intramucosal pH were higher ( p < 0.05 for both ) , the gastric intramucosal PCO2 was lower ( p < 0.05 ) , the intraoperative infused colloids and the total infused volume were lower ( p < 0.05 for both ) , and the postoperative time to flatus was shorter ( p < 0.05 ) in the GDT group than in the control group . No differences in the length of hospital stay , complications , or mortality were found between the groups . Conclusion : SVV-based GDT during major orthopedic surgery reduced the volume of the required intraoperative infused fluids , maintained intraoperative hemodynamic stability , and improved the perioperative gastrointestinal function Objective To evaluate the effects of maximizing the oxygen delivery on morbidity and mortality in patients > 60 yrs of age and /or with chronic diseases of vital organs who underwent major elective surgery . Design Prospect i ve , r and omized , controlled trial . Setting A 24-bed general intensive care unit of a teaching hospital . Patients Thirty-seven high-risk patients who underwent major surgery . Interventions The hemodynamic and oxygen transport variables and outcomes in 18 patients ( control group ) treated to maintain normal values of oxygen delivery were compared with 19 patients ( protocol group ) treated to maintain “ supranormal ” values . Therapy in both groups consisted of volume expansion and , when necessary , dobutamine to reach target values , during the surgery and 24 hrs postoperatively . Measurements and Main Results We interrupted the study because of a significant difference in the 60-day mortality rate . The mortality rate in the control group was significantly higher when compared with the protocol group ( 9/18 [ 50 % ] vs. 3/19 [ 15.7 % ] , p < .05 ) . The prevalence of clinical and infectious complications was higher in the control group than in the protocol group ( 67 % and 31 % respectively ; relative risk , 0.47 ; 95 % confidence interval , 0.226–0.991;p < .05 ) and there was a trend toward more severe organ dysfunction in nonachievers patients ( 17/24 [ 71 % ] vs. 6/13 [ 46 % ] , relative risk , 0.65 ; 95 % confidence interval , 0.343–1.237 ; NS ) . Conclusion Older patients with existing cardiorespiratory illness undergoing major surgery have a reduced morbidity and mortality when dobutamine is used to maximize oxygen transport BACKGROUND We aim ed to investigate whether fluid therapy with a goal of near-maximal stroke volume ( SV ) guided by oesophageal Doppler ( ED ) monitoring result in a better outcome than that with a goal of maintaining bodyweight ( BW ) and zero fluid balance in patients undergoing colorectal surgery . METHODS In a double-blinded clinical multicentre trial , 150 patients undergoing elective colorectal surgery were r and omized to receive fluid therapy after either the goal of near-maximal SV guided by ED ( Doppler , D group ) or the goal of zero balance and normal BW ( Zero balance , Z group ) . Stratification for laparoscopic and open surgery was performed . The postoperative fluid therapy was similar in the two groups . The primary endpoint was postoperative complications defined and divided into subgroups by protocol . Analysis was performed by intention-to-treat . The follow-up was 30 days . The trial had 85 % power to show a difference between the groups . RESULTS The number of patients undergoing laparoscopic or open surgery and the patient characteristics were similar between the groups . No significant differences between the groups were found for overall , major , minor , cardiopulmonary , or tissue-healing complications ( P-values : 0.79 ; 0.62 ; 0.97 ; 0.48 ; and 0.48 , respectively ) . One patient died in each group . No significant difference was found for the length of hospital stay [ median ( range ) Z : 5.00 ( 1 - 61 ) vs D : 5.00 ( 2 - 41 ) ; P=0.206 ] . CONCLUSIONS Goal -directed fluid therapy to near-maximal SV guided by ED adds no extra value to the fluid therapy using zero balance and normal BW in patients undergoing elective colorectal surgery Background Intraoperative hypovolemia is common and is a potential cause of organ dysfunction , increased postoperative morbidity , length of hospital stay , and death . The objective of this prospect i ve , r and omized study was to assess the effect of goal -directed intraoperative fluid administration on length of postoperative hospital stay . Methods One hundred patients who were to undergo major elective surgery with an anticipated blood loss greater than 500 ml were r and omly assigned to a control group ( n = 50 ) that received st and ard intraoperative care or to a protocol group ( n = 50 ) that , in addition , received intraoperative plasma volume expansion guided by the esophageal Doppler monitor to maintain maximal stroke volume . Length of postoperative hospital stay and postoperative surgical morbidity were assessed . Results Groups were similar with respect to demographics , surgical procedures , and baseline hemodynamic variables . The protocol group had a significantly higher stroke volume and cardiac output at the end of surgery compared with the control group . Patients in the protocol group had a shorter duration of hospital stay compared with the control group : 5 ± 3 versus 7 ± 3 days ( mean ± SD ) , with a median of 6 versus 7 days , respectively ( P = 0.03 ) . These patients also tolerated oral intake of solid food earlier than the control group : 3 ± 0.5 versus 4.7 ± 0.5 days ( mean ± SD ) , with a median of 3 versus 5 days , respectively ( P = 0.01 ) . Conclusions Goal -directed intraoperative fluid administration results in earlier return to bowel function , lower incidence of postoperative nausea and vomiting , and decrease in length of postoperative hospital stay Introduction Several studies have shown that maximizing stroke volume ( or increasing it until a plateau is reached ) by volume loading during high-risk surgery may improve post-operative outcome . This goal could be achieved simply by minimizing the variation in arterial pulse pressure ( ΔPP ) induced by mechanical ventilation . We tested this hypothesis in a prospect i ve , r and omized , single-centre study . The primary endpoint was the length of postoperative stay in hospital . Methods Thirty-three patients undergoing high-risk surgery were r and omized either to a control group ( group C , n = 16 ) or to an intervention group ( group I , n = 17 ) . In group I , ΔPP was continuously monitored during surgery by a multiparameter bedside monitor and minimized to 10 % or less by volume loading . Results Both groups were comparable in terms of demographic data , American Society of Anesthesiology score , type , and duration of surgery . During surgery , group I received more fluid than group C ( 4,618 ± 1,557 versus 1,694 ± 705 ml ( mean ± SD ) , P < 0.0001 ) , and ΔPP decreased from 22 ± 75 to 9 ± 1 % ( P < 0.05 ) in group I. The median duration of postoperative stay in hospital ( 7 versus 17 days , P < 0.01 ) was lower in group I than in group C. The number of postoperative complications per patient ( 1.4 ± 2.1 versus 3.9 ± 2.8 , P < 0.05 ) , as well as the median duration of mechanical ventilation ( 1 versus 5 days , P < 0.05 ) and stay in the intensive care unit ( 3 versus 9 days , P < 0.01 ) was also lower in group I. Conclusion Monitoring and minimizing ΔPP by volume loading during high-risk surgery improves postoperative outcome and decreases the length of stay in hospital . Trial registration BACKGROUND The concept of drug titration emerged recently for intraoperative fluid administration during Fast-Track colonic surgery to avoid hypovolemia as well as excessive crystalloid administration . The Pleth Variability Index ( PVI ) is an oximeter-derived parameter . It allows a continuous monitoring of the respiratory variation of the perfusion index . OBJECTIVE To investigate if applying the concept of fluid titration with PVI-guided colloid administration conjointly with restricted crystalloids administration changes the amount of fluid administered . DESIGN , SETTING S AND PATIENTS : Twenty one ASA 2 patients scheduled for Fast-Track colonic surgery were r and omized in two groups : the PVI-guided the fluid management group and the the control group . INTERVENTION AND MAIN OUTCOME MEASURES After the induction of general anesthesia , the PVI group received a 10 mL.kg- 1.h-1 infusion of crystalloid during the first hour , reduced to 2 mL.kg-1.h-1 thereafter . Colloids 250 mL were administered if necessary to maintain a PVI value of 10 to 13 % . In the control group , a 10 mL.kg-1.h-1 infusion of crystalloid during the first hour was followed by a 5 mL.kg-1.h-1 infusion . Boluses of 250 mL of colloids were administered if required to maintain the mean arterial pressure above 65 mmHg . RESULTS Intraoperative crystalloids infused volume were significantly lower in the PVI group ( 925+/-262 mL vs 1129+/- 160 mL ; P=0.04 ) . In contrast , the infused amounts of colloids was higher in the PVI group ( 725+/-521 mL vs 250+/-224 mL ; P=0.01 ) . Interestingly , total fluid amount infused intra- ant postoperatively were similar between the groups ( 1650+/- 807 mL vs 1379+/-186 mL ; P=0.21 ) . CONCLUSION PVI-guided fluid management in Fast-Track colonic surgery is not necessarily associated with different total volume infused Introduction Stroke volume variation ( SVV ) is a good and easily obtainable predictor of fluid responsiveness , which can be used to guide fluid therapy in mechanically ventilated patients . During major abdominal surgery , inappropriate fluid management may result in occult organ hypoperfusion or fluid overload in patients with compromised cardiovascular reserves and thus increase postoperative morbidity . The aim of our study was to evaluate the influence of SVV guided fluid optimization on organ functions and postoperative morbidity in high risk patients undergoing major abdominal surgery . Methods Patients undergoing elective intraabdominal surgery were r and omly assigned to a Control group ( n = 60 ) with routine intraoperative care and a Vigileo group ( n = 60 ) , where fluid management was guided by SVV ( Vigileo/FloTrac system ) . The aim was to maintain the SVV below 10 % using colloid boluses of 3 ml/kg . The laboratory parameters of organ hypoperfusion in perioperative period , the number of infectious and organ complications on day 30 after the operation , and the hospital and ICU length of stay and mortality were evaluated . The local ethics committee approved the study . Results The patients in the Vigileo group received more colloid ( 1425 ml [ 1000 - 1500 ] vs. 1000 ml [ 540 - 1250 ] ; P = 0.0028 ) intraoperatively and a lower number of hypotensive events were observed ( 2[1 - 2 ] Vigileo vs. 3.5[2 - 6 ] in Control ; P = 0.0001 ) . Lactate levels at the end of surgery were lower in Vigileo ( 1.78 ± 0.83 mmol/l vs. 2.25 ± 1.12 mmol/l ; P = 0.0252 ) . Fewer Vigileo patients developed complications ( 18 ( 30 % ) vs. 35 ( 58.3 % ) patients ; P = 0.0033 ) and the overall number of complications was also reduced ( 34 vs. 77 complications in Vigileo and Control respectively ; P = 0.0066 ) . A difference in hospital length of stay was found only in per protocol analysis of patients receiving optimization ( 9 [ 8 - 12 ] vs. 10 [ 8 - 19 ] days ; P = 0.0421 ) . No difference in mortality ( 1 ( 1.7 % ) vs. 2 ( 3.3 % ) ; P = 1.0 ) and ICU length of stay ( 3 [ 2 - 5 ] vs. 3 [ 0.5 - 5 ] ; P = 0.789 ) was found . Conclusions In this study , fluid optimization guided by SVV during major abdominal surgery is associated with better intraoperative hemodynamic stability , decrease in serum lactate at the end of surgery and lower incidence of postoperative organ complications . Trial registration Current Controlled Trials IS RCT N95085011 BACKGROUND Evidence for the benefit of an intraoperative use of a goal -directed haemodynamic management has grown . We compared the oesophageal Doppler monitor ( ODM , CardioQ-ODM ™ ) with a calibrated pulse contour analysis ( PCA , PiCCO2 ™ ) with regard to assessment of stroke volume ( SV ) changes after volume administration within a goal -directed haemodynamic algorithm during non-cardiac surgery . METHODS The data were obtained prospect ively in patients with metastatic ovarian carcinoma undergoing cytoreductive surgery . During surgery , fluid challenges were performed as indicated by the goal -directed haemodynamic algorithm guided by the ODM . Monitors were compared regarding precision and trending . Clinical characteristics associated with trending were studied by extended regression analysis . RESULTS A total of 762 fluid challenges were performed in 41 patients result ing in 1524 paired measurements . The precision of ODM and PCA was 5.7 % and 6.0 % ( P=0.80 ) , respectively . Polar plot analysis revealed a poor trending between ODM and PCA with an angular bias of -7.1 ° , radial limits of agreement of -58.1 ° to 43.8 ° , and an angular concordance rate of 67.8 % . Dose of norepinephrine ( NE ) ( scaled 0.1 µg kg(-1 ) min(-1 ) ) [ adjusted odds ratio ( OR ) 0.606 ( 95 % confidence interval , CI : 0.404 - 0.910 ) ; P=0.016 ] and changes in mean arterial pressure ( MAP ) to a fluid challenge ( scaled 10 % ) [ adjusted OR 0.733 ( 95 % CI : 0.635 - 0.845 ) ; P<0.001 ] were associated with trending between ODM and PCA , whereas there was no relation to type of i.v . solution . CONCLUSIONS Despite a similar precision , ODM and PCA were not interchangeable with regard to measuring SV changes within a goal -directed haemodynamic algorithm . A decrease in interchangeability coincided with increasing NE levels and greater changes of MAP to a fluid challenge OBJECTIVE : The optimal strategy for fluid management during gastrointestinal surgery remains unclear . Minimizing the variation in arterial pulse pressure , which is induced by mechanical ventilation , is a potential strategy to improve postoperative outcomes . We tested this hypothesis in a prospect i ve , r and omized study with lactated Ringer 's solution and 6 % hydroxyethyl starch solution . METHOD : A total of 60 patients who were undergoing gastrointestinal surgery were r and omized into a restrictive lactated Ringer 's group ( n = 20 ) , a goal -directed lactated Ringer 's group ( n = 20 ) and a goal -directed hydroxyethyl starch group ( n = 20 ) . The goal -directed fluid treatment was guided by pulse pressure variation , which was recorded during surgery using a simple manual method with a Date x Ohmeda S/5 Monitor and minimized to 11 % or less by volume loading with either lactated Ringer 's solution or 6 % hydroxyethyl starch solution ( 130/0.4 ) . The postoperative flatus time , the length of hospital stay and the incidence of complications were recorded as endpoints . RESULTS : The goal -directed lactated Ringer 's group received the greatest amount of total operative fluid compared with the two other groups . The flatus time and the length of hospital stay in the goal -directed hydroxyethyl starch group were shorter than those in the goal -directed lactated Ringer 's group and the restrictive lactated Ringer 's group . No significant differences were found in the postoperative complications among the three groups . CONCLUSION : Monitoring and minimizing pulse pressure variation by 6 % hydroxyethyl starch solution ( 130/0.4 ) loading during gastrointestinal surgery improves postoperative outcomes and decreases the discharge time of patients who are grade d American Society of Anesthesiologists physical status I/II Background : The optimal amount and method for monitoring intravenous fluid in surgical patients is unresolved . Central venous oxygen saturation ( Scvo2 ) has been used to guide therapy and predict outcome in high-risk and intensive-care patients . The aim of this prospect i ve , r and omized trial was to compare the rate of postoperative complications in patients receiving fluid therapy guided by Scvo2 and those treated with a traditional effluent fluid scheme . Methods : Patients undergoing open colorectal and lower intestinal surgery ( n = 241 ) were r and omized to the Scvo2 group or the control group . The Scvo2 group received perioperatively crystalloid infusion 100 ml/h . When Scvo2 was less than 75 % , a bolus of 3 ml/kg hydroxyethyl starch was given . The bolus was repeated if Scvo2 increased by 1 percentage point or more . The control group was maintained with crystalloid 800 ml/h and given extra fluid if there were clinical signs of hypovolemia . The participating surgeon , unaware of the group allocation , registered complications within day 30 . Results : Until 8:00 am on the first postoperative day , the Scvo2 group had received 3,869 ± 992 ml ( mean ± SD ) intravenous fluid compared with 6,491 ± 1,649 ml in the control group . Increase in weight was 0.8 ± 1.8 kg and 2.5 ± 1.6 kg in the two groups , respectively . The postoperative complication rate was 42 % in both groups . Conclusion : Clinical outcomes among patients receiving Scvo2-guided perioperative fluid therapy were similar to those for patients treated with a traditional fluid regimen . Limitations in study design prevent full interpretation of these findings , and further large trials of this treatment algorithm are still required BACKGROUND Occult hypovolaemia is a key factor in the aetiology of postoperative morbidity and may not be detected by routine heart rate and arterial pressure measurements . Intraoperative gut hypoperfusion during major surgery is associated with increased morbidity and postoperative hospital stay . We assessed whether using intraoperative oesophageal Doppler guided fluid management to minimize hypovolaemia would reduce postoperative hospital stay and the time before return of gut function after colorectal surgery . METHODS This single centre , blinded , prospect i ve controlled trial r and omized 128 consecutive consenting patients undergoing colorectal resection to oesophageal Doppler guided or central venous pressure (CVP)-based ( conventional ) intraoperative fluid management . The intervention group patients followed a dynamic oesophageal Doppler guided fluid protocol whereas control patients were managed using routine cardiovascular monitoring aim ing for a CVP between 12 and 15 mm Hg . RESULTS The median postoperative stay in the Doppler guided fluid group was 10 vs 11.5 days in the control group P<0.05 . The median time to resuming full diet in the Doppler guided fluid group was 6 vs 7 for controls P<0.001 . Doppler patients achieved significantly higher cardiac output , stroke volume , and oxygen delivery . Twenty-nine ( 45.3 % ) control patients suffered gastrointestinal morbidity compared with nine ( 14.1 % ) in the Doppler guided fluid group P<0.001 , overall morbidity was also significantly higher in the control group P=0.05 . CONCLUSIONS Intraoperative oesophageal Doppler guided fluid management was associated with a 1.5-day median reduction in postoperative hospital stay . Patients recovered gut function significantly faster and suffered significantly less gastrointestinal and overall morbidity BACKGROUND Dynamic variables , for example , systolic pressure variation ( SPV ) , are superior to filling pressures for assessing fluid responsiveness . We analysed the effects of SPV-guided intraoperative fluid management on organ function and perfusion when compared with routine care . METHODS Eighty patients ( 44 female and 36 male ) undergoing elective major abdominal surgery were r and omly assigned to a control group [ n=40 , mean age 66 ( sd 10 ) , range 40 - 84 yr ] or SPV group [ n=40 , age 61 ( 16 ) , range 26 - 100 yr ] in which intraoperative fluid management was guided by SPV ( trigger : SPV>10 % ) . Central venous O2 saturation ( ScvO2 ) , lactate and bilirubin , creatinine , indocyanine green plasma disappearance rate ( ICG-PDR ) , and gastric mucosal CO(2 ) tension were measured after induction of anaesthesia , after 3 , 6 , 12 , and 24 h. RESULTS Patient characteristics , duration of surgery [ 5.8 ( 2.5 ) vs 5.4 ( 2.5 ) h ] , and infusion volumes ( median 4865 vs 4330 ml ) were comparable between the groups . At 3 and 6 h , SPV ( P=0.04 , P=0.01 ) and Deltadown ( P=0.005 , P=0.01 ) were significantly higher in the control group . Oxygen transport and organ function were comparable : baseline and 24 h values for ICG-PDR : 28.5 ( 7.9 ) and 22.7 ( 7.8 ) vs 23.9 ( 6.9 ) and 26.1 (5.9)% min(-1 ) , 77.7 ( 6.6 ) and 72.6 ( 5.5 ) vs 79.3 ( 7.1 ) and 72.8 (6.7)% for ScvO2 and 1.0 ( 0.4 ) and 1.2 ( 0.6 ) vs 0.9 ( 0.2 ) and 1.3 ( 0.5 ) mmol litre(-1 ) for lactate . Length of mechanical ventilation , ICU stay , and mortality were comparable . CONCLUSIONS In comparison with routine care , intraoperative SPV-guided treatment was associated with slightly increased fluid adminstration whereas organ perfusion and function was similar Background and objective We hypothesized that , in vascular surgery patients , the application of a goal -directed strategy based on a pulse contour-derived cardiac index would be associated with a better haemodynamic status than the application of routine perioperative care and that the amount of fluid and /or inotropes required in such a goal -directed therapy depended on the general anaesthetic technique used . Methods Patients undergoing peripheral arterial bypass grafting were r and omly assigned to three groups . In group 1 , haemodynamic management was performed according to routine clinical practice . In the two other groups ( groups 2 and 3 ) a goal -directed therapy was applied aim ing to maintain the pulse contour-derived cardiac index above 2.5 l m−2 min−1 . Patients in groups 1 and 2 received sevoflurane-based anaesthesia and patients in group 3 propofol-based anaesthesia . Haemodynamic variables , amount of fluid and administration of inotropes were assessed at different time intervals . Results The amount of fluid administered was not significantly different between the groups . Two patients in group 1 , 13 patients in group 2 and 12 patients in group 3 were treated with dobutamine ( P < 0.001 ) . None of the patients anaesthetized with sevoflurane ( groups 1 and 2 ) experienced postoperative cardiovascular complications , whereas four patients in the total intravenous group ( group 3 ) experienced major postoperative cardiovascular complications ( P = 0.005 ) . Conclusion In the conditions of the present study , the application of a goal -directed therapy aim ing to maintain the cardiac index above 2.5 l min−1 m−2 did not result in a higher tissue oxygen delivery than when applying the st and ard haemodynamic strategy nor did it depend on the anaesthetic technique used A r and omized controlled trial was conducted to test the hypothesis that there is no difference in complications in patients receiving intravenous ( iv ) water and electrolyte , based on either stroke volume or clinical indicators at bowel surgery Objectives To determine CO and gastric mucosal perfusion in patients during elective major surgery ; to seek a relationship with subsequent outcome . Design Prospect i ve descriptive study . Setting University hospital . Patients 51 patients undergoing elective major surgery of an anticipated duration of greater than 2 h who were at risk of developing gut mucosal hypoperfusion and postoperative organ failure . Measurements and results CO was determined by oesophageal Doppler measurement of aortic blood flow . Gastric mucosal perfusion was determined by tonometric assessmment of gastric mucosal pH ( pHi ) . Blood pressure and urine flow were measured . At the end of surgery no patients were oliguric or hypotensive . Post-operatively morbidity , mortality , duration and cost of stay in the ITU and hospital were assessed . There were 32 patients with evidence of gastric mucosal ischaemia at the end of surgery ( pHi<7.32 ) despite maintenance of CO . This group of patients spent a mean of 4.7 ( range 0–33 ) days in the ITU , 14 developed major complications ( 7 with multiple organ failure [ MOF ] and 6 died . In 19 patients gut mucosal perfusion was maintained during surgery ( pHi≥7.32 ) ; these patients demonstrated an increase in CO of 48.4 % ( 95 % confidence interval 21.3–75.6 ) and spent a mean of 1.0 ( range 0–4 ) days in the ITU . Only one developed a major complication and none died . The total cost of post-operative care for the 51 patients was estimated at £ 356650 . Mean cost per patient in the low pHi group was significantly greater at £ 8 845 ( range £ 600–£42 700 ) compared to £ 3 874 ( range £ 2 600–£9 600 ) in the normal pHi group . The total·cost of post-operative care for the 7 patients who developed MOF was £ 171 450 i.e. 48 % of the total cost . Conclusion A low gastric pHi measured during the intraoperative period in a group of patients undergoing major ( mainly cardiovascular ) surgery is associated with increased post-operative complications and cost Perioperative hemodynamic optimisation improves postoperative outcome for patients undergoing high-risk surgery ( HRS ) . In this prospect i ve r and omized multicentre study we studied the effects of an individualized , goal -directed fluid management based on continuous stroke volume variation ( SVV ) and stroke volume ( SV ) monitoring on postoperative outcomes . 64 patients undergoing HRS were r and omized either to a control group ( CON , n = 32 ) or a goal -directed group ( GDT , n = 32 ) . In GDT , SVV and SV were continuously monitored ( FloTrac/Vigileo ) and patients were brought to and maintained on the plateau of the Frank-Starling curve ( SVV < 10 % and SV increase < 10 % in response to fluid loading ) . Organ dysfunction was assessed using the SOFA score and re source utilization using the TISS score . Patients were followed up to 28 days for postoperative complications . Main outcome measures were the number of complications ( infectious , cardiac , respiratory , renal , hematologic and abdominal post-operative complications ) , maximum SOFA score and cumulative TISS score during ICU stay , duration of mechanical ventilation , length of ICU stay , and time until fit for discharge . 12 patients had to be excluded from final analysis ( 6 in each group ) . During surgery , GDT received more colloids than CON ( 1,589 vs. 927 ml , P < 0.05 ) and SVV decreased in GDT ( from 9.0 to 8.0 % , P < 0.05 ) but not in CON . The number of postoperative wound infections was lower in GDT ( 0 vs. 7 , P < 0.01 ) . Although not statistically significant , the proportion of patients with at least one complication ( 46 vs. 62 % ) , the number of postoperative complications per patient ( 0.65 vs. 1.40 ) , the maximum sofa score ( 5.9 vs. 7.2 ) , and the cumulative TISS score ( 69 vs. 83 ) tended to be lower . This multicentre study shows that fluid management based on a SVV and SV optimisation protocol is feasible and decreases postoperative wound infections . Our findings also suggest that a goal -directed strategy might decrease postoperative organ dysfunction Patients with limited cardiac reserve are less likely to survive and develop more complications following major surgery . By augmenting oxygen delivery index ( DO2I ) with a combination of intravenous fluids and inotropes ( goal directed therapy ( GDT ) ) , postoperative mortality and morbidity of high-risk patients may be reduced . However , although most studies suggest that GDT may improve outcome in high-risk surgical patients , it is still not widely practice d. We set out to test the hypothesis that GDT results in greatest benefit in terms of mortality and morbidity in patients with the highest risk of mortality and have undertaken a systematic review of the current literature to see if this is correct . We performed a systematic search of Medline , Embase and CENTRAL data bases for r and omized controlled trials ( RCTs ) and review s of GDT in surgical patients . To minimize heterogeneity we excluded studies involving cardiac , trauma , and paediatric surgery . Extremely high risk , high risk and intermediate risks of mortality were defined as > 20 % , 5 to 20 % and < 5 % mortality rates in the control arms of the trials , respectively . Meta analyses were performed and Forest plots drawn using RevMan software . Data are presented as odd ratios ( OR ; 95 % confidence intervals ( CI ) , and P-values ) . A total of 32 RCTs including 2,808 patients were review ed . All studies reported mortality . Five studies ( including 300 patients ) were excluded from assessment of complication rates as the number of patients with complications was not reported . The mortality benefit of GDT was confined to the extremely high-risk group ( OR = 0.20 , 95 % CI 0.09 to 0.41 ; P < 0.0001 ) . Complication rates were reduced in all subgroups ( OR = 0.45 , 95 % CI 0.34 to 0.60 ; P < 0.00001 ) . The morbidity benefit was greatest amongst patients in the extremely high-risk subgroup ( OR = 0.27 , 95 % CI 0.15 to 0.51 ; P < 0.0001 ) , followed by the intermediate risk subgroup ( OR = 0.43 , 95 % CI 0.27 to 0.67 ; P = 0.0002 ) , and the high-risk subgroup ( OR 0.56 , 95 % CI 0.36 to 0.89 ; P = 0.01 ) . Despite heterogeneity in trial quality and design , we found GDT to be beneficial in all high-risk patients undergoing major surgery . The mortality benefit of GDT was confined to the subgroup of patients at extremely high risk of death . The reduction of complication rates was seen across all subgroups of GDT patients BACKGROUND Postoperative organ failures commonly occur after major abdominal surgery , increasing the utilization of re sources and costs of care . Tissue hypoxia is a key trigger of organ dysfunction . A therapeutic strategy design ed to detect and reverse tissue hypoxia , as diagnosed by an increase of oxygen extraction ( O2ER ) over a predefined threshold , could decrease the incidence of organ failures . The primary aim of this study was to compare the number of patients with postoperative organ failure and length of hospital stay between those r and omized to conventional vs a protocol ized strategy design ed to maintain O2ER < 27 % . METHODS A prospect i ve , r and omized , controlled trial was performed in nine hospitals in Italy . One hundred thirty-five high-risk patients scheduled for major abdominal surgery were r and omized in two groups . All patients were managed to achieve st and ard goals : mean arterial pressure > 80 mm Hg and urinary output > 0.5 mL/kg/h . The patients of the " protocol group " ( group A ) were also managed to keep O2ER < 27 % . MEASUREMENTS AND MAIN RESULTS In group A , fewer patients had at least one organ failure ( n = 8 , 11.8 % ) than in group B ( n = 20 , 29.8 % ) [ p < 0.05 ] , and the total number of organ failures was lower in group A than in group B ( 27 failures vs 9 failures , p < 0.001 ) . Length of hospital stay was significantly lower in the protocol group than in the control group ( 11.3 + /- 3.8 days vs 13.4 + /- 6.1 days , p < 0.05 ) . Hospital mortality was similar in both groups . CONCLUSIONS Early treatment directed to maintain O2ER at < 27 % reduces organ failures and hospital stay of high-risk surgical patients . Clinical trials.gov reference No. NCT00254150 BACKGROUND Intraoperative fluid therapy regimens using oesophageal Doppler monitoring ( ODM ) to optimize stroke volume ( SV ) ( goal -directed fluid therapy , GDT ) have been associated with a reduction in length of stay ( LOS ) and complication rates after major surgery . We hypothesized that intraoperative GDT would reduce the time to surgical readiness for discharge ( RfD ) of patients having major elective colorectal surgery but that this effect might be less marked in aerobically fit patients . METHODS In this double-blinded controlled trial , 179 patients undergoing major open or laparoscopic colorectal surgery were characterized as aerobically ' fit ' ( n=123 ) or ' unfit ' ( n=56 ) on the basis of their performance during a cardiopulmonary exercise test . Within these fitness strata , patients were r and omized to receive a st and ard fluid regimen with or without ODM-guided intraoperative GDT . RESULTS GDT patients received an average of 1360 ml of additional intraoperative colloid . The mean cardiac index and SV at skin closure were significantly higher in the GDT group than in controls . Times to RfD and LOS were longer in GDT than control patients but did not reach statistical significance ( median 6.8 vs 4.9 days , P=0.09 , and median 8.8 vs 6.7 days , P=0.09 , respectively ) . Fit GDT patients had an increased RfD ( median 7.0 vs 4.7 days ; P=0.01 ) and LOS ( median 8.8 vs 6.0 days ; P=0.01 ) compared with controls . CONCLUSIONS Intraoperative SV optimization conferred no additional benefit over st and ard fluid therapy . In an aerobically fit subgroup of patients , GDT was associated with detrimental effects on the primary outcome . TRIAL REGISTRY UK NIHR CRN 7285 , IS RCT N 14680495 . http://public.ukcrn.org.uk/ Search / Study Detail.aspx ? Study ID=7285 BACKGROUND : Dynamic variables predict fluid responsiveness and may improve fluid management during surgery . We investigated whether displaying the variability in the pulse oximeter plethysmogram ( pleth variability index ; PVI ) would guide intraoperative fluid management and improve circulation as assessed by lactate levels . METHODS : Eighty-two patients scheduled for major abdominal surgery were r and omized into 2 groups to compare intraoperative PVI-directed fluid management ( PVI group ) versus st and ard care ( control group ) . After the induction of general anesthesia , the PVI group received a 500-mL crystalloid bolus and a crystalloid infusion of 2 mL · kg−1 · h−1 . Colloids of 250 mL were administered if the PVI was > 13 % Vasoactive drug support was given to maintain the mean arterial blood pressure above 65 mm Hg . In the control group , an infusion of 500 mL of crystalloids was followed by fluid management on the basis of fluid challenges and their effects on mean arterial blood and central venous pressure . Perioperative lactate levels , hemodynamic data , and postoperative complications were recorded prospect ively . RESULTS : Intraoperative crystalloids and total volume infused were significantly lower in the goal -directed PVI group . Lactate levels were significantly lower in the PVI group during surgery and 48 hours after surgery ( P < 0.05 ) . CONCLUSIONS : PVI-based goal -directed fluid management reduced the volume of intraoperative fluid infused and reduced intraoperative and postoperative lactate levels Summary Oesophageal Doppler monitoring allows non‐invasive estimation of stroke volume and cardiac output . We studied the impact of Doppler guided fluid optimisation on haemodynamic parameters , peri‐operative morbidity and hospital stay in patients undergoing major bowel surgery . Fifty‐seven patients were r and omly assigned to Doppler ( D ) or control ( C ) groups . All patients received intra‐operative fluid therapy at the discretion of the non‐investigating anaesthetist . In addition , Group D were given fluid challenges ( 3 ml.kg−1 ) guided by oesophageal Doppler . Group D received significantly more intra‐operative colloid than Group C ( mean 28 ( SD 16 ) vs. 19.4 ( SD 14.7 ) ml.kg−1 , p = 0.02 ) . Cardiac output increased significantly for Group D whilst that of controls remained unchanged . The mean difference between the groups in final cardiac output was 0.87 l.min−1 ( 95 % confidence interval 0.31–1.43 l.min−1 , p = 0.003 ) . Five control patients required postoperative critical care admission . Fluid titration using oesophageal Doppler during bowel surgery can improve haemodynamic parameters and may reduce critical care admissions postoperatively A new quantitative method for measuring the prognosis and severity of illness in terms of probability of survival was developed from 224 studies in an index population of 220 critically ill surgical patients . Patients were selected preoperatively to eliminate pre-existing cardiac disease , cirrhosis , nutritional debility , shock or sepsis , in order to evaluate the physiologic relationships of surgical trauma to outcome free of confounding associated medical disorders . The empirically derived numeric severity index was calculated from the probability of survival for each of 28 hemodynamic and oxygen transport variables at each time period after surgery . The score correctly indicated patient outcome in 96 % of the index population and 94 % of an independent , prospect i ve population . The survivors ' score consistently predicted survival within 21.6 ± 4.4 ( SEM ) h after the end of surgery . The severity score of those who died consistently predicted nonsurvival within 37 ± 11 ( SEM ) h after the end of surgery . We conclude that the score provides a useful , objective , physiologic measure of the severity of illness and prognosis Abstract Objectives : To assess whether intraoperative intravascular volume optimisation improves outcome and shortens hospital stay after repair of proximal femoral fracture . Design : Prospect i ve , r and omised controlled trial comparing conventional intraoperative fluid management with repeated colloid fluid challenges monitored by oesophageal Doppler ultrasonography to maintain maximal stroke volume throughout the operative period . Setting : Teaching hospital , London . Subjects : 40 patients undergoing repair of proximal femoral fracture under general anaesthesia . Interventions : Patients were r and omly assigned to receive either conventional intraoperative fluid management ( control patients ) or additional repeated colloid fluid challenges with oesophageal Doppler ultrasonography used to maintain maximal stroke volume throughout the operative period ( protocol patients ) . Main outcome measures : Time declared medically fit for hospital discharge , duration of hospital stay ( in acute bed ; in acute plus long stay bed ) , mortality , perioperative haemodynamic changes . Results : Intraoperative intravascular fluid loading produced significantly greater changes in stroke volume ( median 15 ml ( 95 % confidence interval 10 to 21 ml ) ) and cardiac output ( 1.2 l/min ( 0.1 to 2.3 l/min ) ) than in the conventionally managed group ( −5 ml ( −10 to 1 ml ) and −0.4 l/min ( −1.0 to 0.2 l/min ) ) ( P<0.001 and P<0.05 , respectively ) . One protocol patient and two control patients died in hospital . In the survivors , postoperative recovery was significantly faster in the protocol patients , with shorter times to being declared medically fit for discharge ( median 10 ( 9 to 15 ) days v 15 ( 11 to 40 ) days , P<0.05 ) and a 39 % reduction in hospital stay ( 12 ( 8 to 13 ) days v 20 ( 10 to 61 ) days , P<0.05 ) . Conclusions : Proximal femoral fracture repair constitutes surgery in a high risk population . Intraoperative intravascular volume loading to optimal stroke volume result ed in a more rapid postoperative recovery and a significantly reduced hospital stay . Key messages Patients undergoing hip fracture repair constitute a high risk group with considerable mortality and morbidity and an often protracted postoperative hospital stay These patients often have depleted intravascular volume in the perioperative period and rarely receive either invasive haemodynamic monitoring or high dependency care Haemodynamic optimisation guided by pulmonary artery catheter in the perioperative period has been shown to improve outcome in high risk patients undergoing major surgery , but this is not considered routinely practicable for hip fracture repair Intravascular volume optimisation directed by minimally invasive oesophageal Doppler monitoring in the intraoperative period significantly reduces hospital

IV regadenoson and IC nitroprusside produce similar pressure-derived FFR measurements compared to IV adenosine and have a favorable side effect profile . Both can be considered as alternative agents to IV adenosine for FFR measurement .

BACKGROUND FFR is useful in defining the physiological significance of intermediate coronary stenosis and requires induction of maximal hyperemia and measurement of pressure proximal and distal to the stenosis . Hyperemia normally is induced by either IV or IC adenosine , a medication associated with short-term side effects . IV regadenoson and IC nitroprusside have been suggested as viable alternatives . This meta- analysis aims to identify all studies comparing use of intravenous ( IV ) regadenoson or intracoronary ( IC ) nitroprusside with IV adenosine to determine differences related to the agent utilized for assessment of fractional flow reserve ( FFR ) .

OBJECTIVES The purpose of this study was to investigate the 2-year outcome of percutaneous coronary intervention ( PCI ) guided by fractional flow reserve ( FFR ) in patients with multivessel coronary artery disease ( CAD ) . BACKGROUND In patients with multivessel CAD undergoing PCI , coronary angiography is the st and ard method for guiding stent placement . The FAME ( Fractional Flow Reserve Versus Angiography for Multivessel Evaluation ) study showed that routine FFR in addition to angiography improves outcomes of PCI at 1 year . It is unknown if these favorable results are maintained at 2 years of follow-up . METHODS At 20 U.S. and European medical centers , 1,005 patients with multivessel CAD were r and omly assigned to PCI with drug-eluting stents guided by angiography alone or guided by FFR measurements . Before r and omization , lesions requiring PCI were identified based on their angiographic appearance . Patients r and omized to angiography-guided PCI underwent stenting of all indicated lesions , whereas those r and omized to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was < or=0.80 . RESULTS The number of indicated lesions was 2.7+/-0.9 in the angiography-guided group and 2.8+/-1.0 in the FFR-guided group ( p=0.34 ) . The number of stents used was 2.7+/-1.2 and 1.9+/-1.3 , respectively ( p<0.001 ) . The 2-year rates of mortality or myocardial infa rct ion were 12.9 % in the angiography-guided group and 8.4 % in the FFR-guided group ( p=0.02 ) . Rates of PCI or coronary artery bypass surgery were 12.7 % and 10.6 % , respectively ( p=0.30 ) . Combined rates of death , nonfatal myocardial infa rct ion , and revascularization were 22.4 % and 17.9 % , respectively ( p=0.08 ) . For lesions deferred on the basis of FFR>0.80 , the rate of myocardial infa rct ion was 0.2 % and the rate of revascularization was 3.2 % after 2 years . CONCLUSIONS Routine measurement of FFR in patients with multivessel CAD undergoing PCI with drug-eluting stents significantly reduces mortality and myocardial infa rct ion at 2 years when compared with st and ard angiography-guided PCI . ( Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [ FAME ] ; NCT00267774 ) Background Regadenoson is a selective A2A adenosine receptor agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging . This study characterized the dose dependence of regadenoson-induced coronary hyperemia . Methods and Results An open-label , dose-escalation study of regadenoson ( 10–500μg , rapid intravenous bolus ) was performed in 34 subjects ; in 4 additional subjects , the effect of aminophylline to reverse the response to regadenoson was determined . Intracoronary peak blood flow velocity in either the left anterior descending or left circumflex artery was measured by continuous Doppler , signal recording , heart rate , central aortic blood pressure , and adverse effects were recorded . Regadenoson increased peak blood flow velocity by up to 3.4-fold in a dose-dependent manner . The mean duration of the increase in flow velocity of 2.5-fold or greater caused by 400 to 500 μg of regadenoson was 2.3 to 2.4 minutes . Regadenoson ( 400–500 μg ) increased heart rate by up to 21±6 beats/min and decreased systolic blood pressure ( −5±8 mm Hg to −24±16 mm Hg ) and diastolic blood pressure ( −8±4 mm Hg to −15±14 mm Hg ) . Aminophylline ( 100 mg ) attenuated the increase in peak flow velocity but not tachycardia caused by 400 μg of regadenoson . Conclusion The results of this study demonstrate the utility of regadenoson as a coronary vasodilator for myocardial perfusion imaging OBJECTIVES The purpose of this study was to investigate the appropriateness of stenting a functionally nonsignificant stenosis . BACKGROUND Percutaneous coronary intervention ( PCI ) of an intermediate stenosis without evidence of ischemia is often performed , but its benefit is unproven . Coronary pressure-derived fractional flow reserve ( FFR ) is an invasive index used to identify a stenosis responsible for reversible ischemia . METHODS In 325 patients scheduled for PCI of an intermediate stenosis , FFR was measured just before the planned intervention . If FFR was > or = 0.75 , patients were r and omly assigned to deferral ( Defer group ; n = 91 ) or performance ( Perform group ; n = 90 ) of PCI . If FFR was < 0.75 , PCI was performed as planned ( Reference group ; n = 144 ) . Clinical follow-up was 5 years . RESULTS There were no differences in baseline clinical characteristics between the 3 groups . Complete follow-up was obtained in 98 % of the patients . Event-free survival was not different between the Defer and Perform groups ( 80 % and 73 % , respectively ; p = 0.52 ) , but was significantly worse in the Reference group ( 63 % ; p = 0.03 ) . The composite rate of cardiac death and acute myocardial infa rct ion in the Defer , Perform , and Reference groups was 3.3 % , 7.9 % , and 15.7 % , respectively ( p = 0.21 for Defer vs. Perform group ; p = 0.003 for the Reference vs. both other groups ) . The percentage of patients free from chest pain at follow-up was not different between the Defer and Perform groups . CONCLUSIONS Five-year outcome after deferral of PCI of an intermediate coronary stenosis based on FFR > /=0.75 is excellent . The risk of cardiac death or myocardial infa rct ion related to this stenosis is < 1 % per year and not decreased by stenting Background Earlier phase 1 and 2 studies have shown that regadenoson has desirable features as a stress agent for myocardial perfusion imaging . Methods and Results This multicenter , double-blinded phase 3 trial involved 784 patients at 54 sites . Each patient underwent 2 sets of gated single photon emission computed tomography myocardial perfusion imaging studies : an initial qualifying study with adenosine and a subsequent r and omized study with either regadenoson ( 2/3 of patients ) or adenosine . Regadenoson was administered as a rapid bolus ( < 10 seconds ) of 400 μg . The primary endpoint was to demonstrate noninferiority by showing that the difference in the strength of agreement in detecting reversible defects , based on blinded reading , between sequential adenosine-regadenoson images and adenosine-adenosine images , lay above a prespecified noninferiority margin . Other prospect ively defined safety and tolerability comparisons and supporting analyses were also performed . The average agreement rate based on the median of 3 independent blinded readers was 0.63±0.03 for regadenoson-adenosine and 0.64±0.04 for adenosine-adenosine — a 1 % absolute difference with the lower limit of the 95 % confidence interval lying above the prespecified noninferiority margin . Side-by-side interpretation of regadenoson and adenosine images provided comparable results for detecting reversible defects . The peak increase in heart rate was greater with regadenoson than adenosine , but the blood pressure nadir was similar . A summed symptom score of flushing , chest pain , and dyspnea was less with regadenoson than adenosine ( P=.013 ) . Conclusions This phase 3 trial shows that regadenoson provides diagnostic information comparable to a st and ard adenosine infusion . There were no serious drug-related side effects , and regadenoson was better tolerated than adenosine OBJECTIVES To compare the effects of age , gender , body mass index , and diabetes on the safety and efficacy of regadenoson stress myocardial perfusion imaging , and to assess the noninferiority of regadenoson to adenosine for the detection of reversible myocardial perfusion defects . BACKGROUND Previous reports have shown that a fixed unit bolus of regadenoson is safe and noninferior to adenosine for the detection of reversible perfusion defects by radionuclide imaging . METHODS Using a data base of 2,015 patients , we evaluated the effects of age , gender , body mass index , and diabetes on the safety and efficacy of regadenoson compared to adenosine . RESULTS For detection of ischemia relative to adenosine , noninferiority was demonstrated for all patients ( agreement rate difference 0 % , 95 % CI -6.2 % to + 6.8 % ) . The average agreement rate between adenosine-adenosine and adenosine-regadenoson were 0.62 + /- 0.03 and 0.63 + /- 0.02 . Detection of ischemia was also comparable in specific subgroups . Agreement was less for both agents in women versus men with moderate and large areas of ischemia . Compared to adenosine , regadenoson had a lower combined symptom score and less chest pain , flushing , and throat , neck , or jaw pain , but more headache and gastrointestinal discomfort . This was true in nearly all subgroups . Regadenoson patients reported feeling more comfortable ( 1.7 + /- .02 vs. 1.9 + /- 0.03 , p < 0.001 ) . Based on the overall tolerability score , women felt less comfortable than men with both stress agents . Image quality was rated good or excellent in 92 % for both agents . CONCLUSIONS Regadenoson can be safely administered as a fixed unit bolus and is as efficacious as adenosine in detecting ischemia regardless of age , gender , body mass index , and diabetes . Regadenoson is better tolerated overall and across various subgroups Background . Patients with reactive airways are at risk for adenosine-induced bronchoconstriction , mediated via A2B and /or A3 adenosine receptors . Methods and Results . In this r and omized , double-blind , placebo-controlled crossover trial , we examined the safety of regadenoson , a selective adenosine A2A receptor agonist , in patients with moderate chronic obstructive pulmonary disease ( COPD ) ( n=38 ) and patients with severe COPD ( n=11 ) with a baseline mean forced expiratory volume in 1 second ( FEV1 ) of 1.74±0.50 L and 1.0±0.35 L , respectively , 37 % of whom had dyspnea during activities of daily living . Patients receiving glucocorticoids or oxygen and those with pretreatment wheezing were included . Short-acting bronchodilators were withheld for at least 8 hours before treatment . No differences emerged between regadenoson and placebo on multiple lung function parameters , including repeated FEV1 and forced vital capacity , respiratory rate , pulmonary examinations , and oxygen saturation . The mean maximum decline in FEV1 was 0.11±0.02 L and 0.12±0.02 L ( P=.55 ) in patients after regadenoson and placebo , respectively , and new-onset wheezing was observed in 6 % and 12 % , respectively ( P=.33 ) . No patient required acute treatment with bronchodilators or oxygen . Conclusions . This pilot study showed the overall safety of regadenoson in 49 compromised out patients with clinical ly stable moderate and severe chronic obstructive pulmonary disease AIMS The aim of this study was to compare the hyperaemic effect of a single bolus regadenoson injection to a central venous adenosine infusion for inducing hyperaemia in the measurement of fractional flow reserve ( FFR ) . METHODS AND RESULTS One hundred patients scheduled for FFR measurement were enrolled . FFR was first measured by IV adenosine ( 140 µg/kg/min ) , thereafter by IV bolus regadenoson injection ( 400 µg ) , followed by another measurement by IV adenosine and bolus injection of regadenoson . The regadenoson injections were r and omised to central or peripheral intravenous . Hyperaemic response and duration of steady state maximum hyperaemia were studied , central versus peripheral venous regadenoson injections were compared , and safety and reproducibility of repeated injections were investigated . Mean age was 66±8 years , 75 % of the patients were male . The target stenosis was located in the LM , LAD , LCX , and RCA in 7 % , 54 % , 20 % and 19 % , respectively . There was no difference in FFR measured by adenosine or by regadenoson ( ΔFFR=0.00±0.01 , r=0.994 , p<0.001 ) . Duration of maximum hyperaemia after regadenoson was variable ( 10 - 600 s ) . No serious side effects of either drug were observed . CONCLUSIONS Maximum coronary hyperaemia can be achieved easily , rapidly , and safely by one single intravenous bolus of regadenoson administered either central ly or peripherally . Repeated regadenoson injections are safe . The hyperaemic plateau is variable . Clinical Trial Registration : http:// clinical trials.gov/ct2/ show/ study /NCT01809743?term = NCT01809743&rank=1 ( Clinical Trials.gov Identifier : NCT01809743 ) OBJECTIVES The aim of this study was to evaluate the efficacy of regadenoson , in comparison with adenosine , for assessing fractional flow reserve ( FFR ) of intermediate coronary artery stenoses ( CAS ) . BACKGROUND Fractional flow reserve is an established invasive method for assessing the physiological significance of CAS . Regadenoson , a selective A(2A ) receptor agonist , is an approved hyperemic agent for pharmacological stress imaging , but its role for measuring FFR is unknown . METHODS This prospect i ve , single-center study enrolled 25 consecutive patients with intermediate CAS discovered during elective angiography ( 25 lesions ) . In each patient , FFR of the CAS was measured first by IV adenosine ( 140 μg/kg/min ) , followed by IV regadenoson ( 400 μg bolus ) . The intrapatient FFR correlation between adenosine and regadenoson was evaluated . RESULTS The mean age was 63 ± 11 years , and mean left ventricular ejection fraction was 58 ± 11 % . Most patients were male ( 52 % ) and had hypertension ( 84 % ) and dyslipidemia ( 84 % ) , with 24 % having diabetes mellitus and 20 % chronic obstructive pulmonary disease . The CAS was visually estimated during angiography ( mean 58 ± 9 % ) and most often found in the left anterior descending coronary artery ( 48 % ) . A strong , linear correlation of FFR was noted with adenosine and regadenoson ( r = 0.985 , p < 0.001 ) . A hemodynamically significant lesion ( FFR ≤ 0.80 ) was present in 52 % with no reclassification of significance between adenosine and regadenoson . No serious events occurred with administration of either drug . CONCLUSIONS Our results suggest that a single IV bolus of regadenoson is as effective as an intravenous infusion of adenosine for measuring FFR and , given its ease of use , should be considered for FFR measurement in the catheterization laboratory BACKGROUND We hypothesized that in patients with stable coronary artery disease and stenosis , percutaneous coronary intervention ( PCI ) performed on the basis of the fractional flow reserve ( FFR ) would be superior to medical therapy . METHODS In 1220 patients with stable coronary artery disease , we assessed the FFR in all stenoses that were visible on angiography . Patients who had at least one stenosis with an FFR of 0.80 or less were r and omly assigned to undergo FFR-guided PCI plus medical therapy or to receive medical therapy alone . Patients in whom all stenoses had an FFR of more than 0.80 received medical therapy alone and were included in a registry . The primary end point was a composite of death from any cause , nonfatal myocardial infa rct ion , or urgent revascularization within 2 years . RESULTS The rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group ( 8.1 % vs. 19.5 % ; hazard ratio , 0.39 ; 95 % confidence interval [ CI ] , 0.26 to 0.57 ; P<0.001 ) . This reduction was driven by a lower rate of urgent revascularization in the PCI group ( 4.0 % vs. 16.3 % ; hazard ratio , 0.23 ; 95 % CI , 0.14 to 0.38 ; P<0.001 ) , with no significant between-group differences in the rates of death and myocardial infa rct ion . Urgent revascularizations that were triggered by myocardial infa rct ion or ischemic changes on electrocardiography were less frequent in the PCI group ( 3.4 % vs. 7.0 % , P=0.01 ) . In a l and mark analysis , the rate of death or myocardial infa rct ion from 8 days to 2 years was lower in the PCI group than in the medical-therapy group ( 4.6 % vs. 8.0 % , P=0.04 ) . Among registry patients , the rate of the primary end point was 9.0 % at 2 years . CONCLUSIONS In patients with stable coronary artery disease , FFR-guided PCI , as compared with medical therapy alone , improved the outcome . Patients without ischemia had a favorable outcome with medical therapy alone . ( Funded by St. Jude Medical ; FAME 2 Clinical Trials.gov number , NCT01132495 . ) Background . Patients with reactive airways are at risk for adenosine-induced bronchocon-striction , mediated via A2B and /or A3 adenosine receptors . Methods and Results . To examine the effects of regadenoson , a selective adenosine A2A receptor agonist , on airway resistance , we conducted a r and omized , double-blind , placebo-controlled crossover trial in asthmatic patients with a positive adenosine monophosphate challenge test . The mean ratio of the forced expiratory volume in 1 second ( FEV1 ) at each tested time point relative to the baseline FEV1 was significantly higher after treatment with regadenoson compared with placebo from 10 to 60 minutes after treatment . One patient had a substantial but asymptomatic FEV1 reduction ( −36.2 % ) after regadenoson that reversed spontaneously . The most common adverse events with regadenoson were tachycardia ( 66 % ) , dizziness ( 53 % ) , headache ( 45 % ) , and dyspnea ( 34 % ) . The mean heart rate significantly increased with regadenoson ( maximum of + 10.4 beats/min ) versus placebo . Conclusions . In this pilot safety study of 48 patients with mild or moderate asthma who had bronchial reactivity to adenosine monophosphate , regadenoson was safe and well tolerated

Conclusion Evidence supports potential anti-inflammatory effects from α2 agonists , but the relevance to clinical ly important outcomes is uncertain .

Background The α2 agonists , dexmedetomidine and clonidine , are used as sedative drugs during critical illness . These drugs may have anti-inflammatory effects , which might be relevant to critical illness , but a systematic review of published literature has not been published . We review ed animal and human studies relevant to critical illness to summarise the evidence for an anti-inflammatory effect from α2 agonists .

We have compared the effects of dexmedetomidine and propofol on endocrine , metabolic , inflammatory and cardiovascular responses in patients in the intensive care unit ( ICU ) after major surgery . Twenty patients who were expected to require 8 h of post-operative sedation and ventilation were allocated r and omly to receive either an infusion of dexmedetomidine 0.2 - 2.5 microg kg(-1 ) h(-1 ) or propofol 1 - 3 mg kg(-1 ) h(-1 ) . Arterial pressure , heart rate and sequential concentrations of circulating cortisol , adrenocorticotrophic hormone ( ACTH ) , growth hormone , prolactin , insulin , glucose and interleukin 6 were measured . An ACTH stimulation test was performed in all patients who received dexmedetomidine . Heart rate was significantly lower in the dexmedetomidine patients . There were no differences in arterial pressure , cortisol , ACTH , prolactin and glucose concentrations between the two groups . A positive response to the ACTH stimulation test varied depending on the diagnostic criteria used . The insulin concentration was significantly lower in the dexmedetomidine group at 2 h ( P=0.021 ) , although this did not affect blood glucose concentrations . Growth hormone concentrations were significantly higher in dexmedetomidine-treated patients overall ( P=0.036 ) , but circulating concentrations remained in the physiological range . Interleukin 6 decreased in the dexmedetomidine group . We conclude that dexmedetomidine infusion does not inhibit adrenal steroidogenesis when used for short-term sedation after surgery Introduction Sepsis , a systemic inflammatory response to infective etiologies , has a high mortality rate that is linked both to excess cytokine activity and apoptosis of critical immune cells . Dexmedetomidine has recently been shown to improve outcome in a septic cohort of patients when compared to patients r and omized to a benzodiazepine-based sedative regimen . We sought to compare the effects of dexmedetomidine and midazolam , at equi-sedative doses , on inflammation and apoptosis in an animal model of severe sepsis . Methods After central venous access , Sprague Dawley rats underwent cecal ligation and intestinal puncture ( CLIP ) with an 18 G needle without antibiotic cover and received either saline , or an infusion of comparable volume of saline containing midazolam ( 0.6 mg.kg-1.h-1 ) or dexmedetomidine ( 5 ug.kg-1.h-1 ) for 8 hours . Following baseline measurements and CLIP , blood was sample d for cytokine measurement ( tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 ; n = 4 - 6 per group ) at 2 , 4 and 5 hours , and animal mortality rate ( MR ) was monitored ( n = 10 per group ) every 2 hours until 2 hours had elapsed . In addition , spleens were harvested and apoptosis was assessed by immunoblotting ( n = 4 per group ) . Results The 24 hour MR in CLIP animals ( 90 % ) was significantly reduced by sedative doses of either dexmedetomidine ( MR = 20 % ) or midazolam ( MR = 30 % ) . While both sedatives reduced systemic levels of the inflammatory cytokine TNF-alpha ( P < 0.05 ) ; only dexmedetomidine reduced the IL-6 response to CLIP , though this narrowly missed achieving significance ( P = 0.05 ) . Dexmedetomidine reduced splenic caspase-3 expression ( P < 0.05 ) , a marker of apoptosis , when compared to either midazolam or saline . Conclusions Sedation with midazolam and dexmedetomidine both improve outcome in polymicrobial severely septic rats . Possible benefits conveyed by one sedative regimen over another may become evident over a more prolonged time-course as both IL-6 and apoptosis were reduced by dexmedetomidine but not midazolam . Further studies are required to evaluate this hypothesis Background Some studies have demonstrated dexmedetomidine has anti-inflammatory effect on septic rats . However , the mechanism of how dexmedetomidine exerts these effects is still remained unknown . This study was design ed to investigate the mechanism of how dexmedetomidine inhibits the production of inflammatory mediators in cecal ligation and puncturinduced septic rats . Methods 48 Sprague-Dawley rats were r and omly divided into six groups : sham-operated ( sham ) group , cecal ligation and puncture ( CLP ) group , dexmedetomidine 5 μg/kg ( DEX5 ) group , dexmedetomidine 10 μg/kg ( DEX10 ) group , dexmedetomidine + yohimbine ( DEX10 + Yoh ) group and yohimibine group ( Yoh ) . Blood , bronchoalveolarlavage fluid ( BALF ) and lung tissues in each group were collected at six hours after dexmedetomidine or yohimbine treatment , . Tumor necrosis factor-α ( TNF-α ) and interleukin-6 ( IL-6 ) in BALF and plasma were measured by enzyme-linked immunosorbent assay ( ELISA ) . Toll-like receptor-4(TLR4 ) and myeloid differerntiation factor(MyD88 ) expression were measuredby quantitative PCR , and extracellular signal-regulated kinase ( ERK ) 1/2 phosphorylation were determined by western blott . Results Compared with CLP group , dexmedetomidine significantly decreased not only the production of TNF-α and IL-6 both in plasma and BALF , but also inhibited the expression of TLR4 and MyD88 in mRNA level and the activation of ERK1/2 and NF-κB in the lung tissues of CLP-induced septic rats . All these effects could not be reversed by yohimibine . Conclusions Dexmedetomidine treatment can effectively reduce the generation of inflammatory mediators in the plasma and BALF of CLP-induced septic rats . These effects of dexmedetomidine rely on TLR4/MyD88/MAPK/ NF-κB signaling pathway and are independent of α2-adrenoceptor Rationale : Dexmedetomidine is associated with less delirium than benzodiazepines and better sleep architecture than either benzodiazepines or propofol ; its effect on delirium and sleep when administered at night to patients requiring sedation remains unclear . Objectives : To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill adults . Methods : This two‐center , double‐blind , placebo‐controlled trial r and omized 100 delirium‐free critically ill adults receiving sedatives to receive nocturnal ( 9:30 p.m. to 6:15 a.m. ) intravenous dexmedetomidine ( 0.2 & mgr;g/kg/h , titrated by 0.1 & mgr;g /kg/h every 15 min until a goal Richmond Agitation and Sedation Scale score of −1 or maximum rate of 0.7 & mgr;g/kg/h was reached ) or placebo until ICU discharge . During study infusions , all sedatives were halved ; opioids were unchanged . Delirium was assessed using the Intensive Care Delirium Screening Checklist every 12 hours throughout the ICU admission . Sleep was evaluated each morning by the Leeds Sleep Evaluation Question naire . Measurements and Main Results : Nocturnal dexmedetomidine ( vs. placebo ) was associated with a greater proportion of patients who remained delirium‐free during the ICU stay ( dexmedetomidine [ 40 ( 80 % ) of 50 patients ] vs. placebo [ 27 ( 54 % ) of 50 patients ] ; relative risk , 0.44 ; 95 % confidence interval , 0.23‐0.82 ; P = 0.006 ) . The average Leeds Sleep Evaluation Question naire score was similar ( mean difference , 0.02 ; 95 % confidence interval , 0.42‐1.92 ) between the 34 dexmedetomidine ( average seven assessment s per patient ) and 30 placebo ( six per patient ) group patients able to provide one or more assessment s. Incidence of hypotension , bradycardia , or both did not differ significantly between groups . Conclusions : Nocturnal administration of low‐dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay ; patient‐reported sleep quality appears unchanged . Clinical trial registered with www . clinical trials.gov ( NCT01791296 ) The aim was to verify that dexmedetomidine ( DEX ) can attenuate CLP-induced intestinal injury via inhibition of inflammation . Male Sprague-Dawley ( SD ) rats were r and omly allocated into Sham group and the other three CLP model groups , in terms of different treatments : placebo , DEX , and yohimbine plus DEX ( DEX + YOH ) groups . Pathology examination was conducted with HE stain . To identify differences among groups , the levels of DAO , and D-lactate in serum were measured by spectrophotometry , and the levels of TNF-α , IL-1β , and IL-6 in serum and organ were measured by ELISA . The expressions of occludin and TLR4 in tissue were detected by Western blot . The survival rate of an additional group of animals within 7 d was recorded . In DEX group , mortality was lower , histology change was minor , DAO , and D-lactate levels were reduced , and occludin expression was increased ; the expressions of TNF-α , IL-1β , IL-6 , and TLR4 were also decreased in DEX group . These results indicated that acute intestinal injury induced by CLP was mitigated by DEX treatment . However , these effects of DEX were significantly attenuated by yohimbine in DEX + YOH group . Our study indicated the protective effects of DEX on CLP-induced injury , which may be associated with the inhibition of inflammation via modulating TLR4 pathway and can be blocked by yohimbine Background : Dexmedetomidine , an & agr;-2 adrenergic receptor agonist , has already been used in septic patients although few studies have examined its effects on microcirculatory dysfunction , which may play an important role in perpetuating sepsis syndrome . Therefore , the authors have design ed a controlled experimental study to characterize the microcirculatory effects of dexmedetomidine in an endotoxemia rodent model that allows in vivo studies of microcirculation . Methods : After skinfold chamber implantation , 49 golden Syrian hamsters were r and omly allocated in five groups : ( 1 ) control animals ; ( 2 ) nonendotoxemic animals treated with saline ; ( 3 ) nonendotoxemic animals treated with dexmedetomidine ( 5.0 & mgr;g kg−1 h−1 ) ; ( 4 ) endotoxemic ( lipopolysaccharide 1.0 mg/kg ) animals treated with saline ; and ( 5 ) endotoxemic animals treated with dexmedetomidine . Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables and venular leukocyte rolling and adhesion . Mean arterial blood pressure , heart rate , arterial blood gases , and lactate concentrations were also documented . Results : Lipopolysaccharide administration increased leukocyte rolling and adhesion and decreased capillary perfusion . Dexmedetomidine significantly attenuated these responses : compared with endotoxemic animals treated with saline , those treated with dexmedetomidine had less leukocyte rolling ( 11.8 ± 7.2 % vs. 24.3 ± 15.0 % ; P < 0.05 ) and adhesion ( 237 ± 185 vs. 510 ± 363 ; P < 0.05 ) and greater functional capillary density ( 57.4 ± 11.2 % of baseline values vs. 45.9 ± 11.2 % ; P < 0.05 ) and erythrocyte velocity ( 68.7 ± 17.6 % of baseline values vs. 54.4 ± 14.8 % ; P < 0.05 ) at the end of the experiment . Conclusions : Dexmedetomidine decreased lipopolysaccharide-induced leukocyte – endothelial interactions in the hamster skinfold chamber microcirculation . This was accompanied by a significant attenuation of capillary perfusion deficits , suggesting that dexmedetomidine yields beneficial effects on endotoxemic animals ’ microcirculation BACKGROUND Dexmedetomidine reduced mortality and inhibited the inflammatory response during endotoxemia in rats . The aim of this study was to clarify the effect of dexmedetomidine-regulating inflammation on a noninfectious , ventilator-induced lung injury ( VILI ) in dogs . METHODS Thirty healthy Beagles weighing between 8 and 12 kg were r and omly divided into five groups : control group ( group C , n = 6 ) , mechanical ventilation ( group MV , n = 6 ) , and three different doses of dexmedetomidine group ( group DEX1 - 3 , n = 6 ) . VILI was induced by high-tidal volume ventilation ( tidal volume 20 mL/kg ; respiratory rate 15 breaths/min ; FiO2 0.5 ) . Group DEX received intravenous Dex 20 min before endotracheal intubation ( 0.5 , 1.0 , and 2.0 μg/kg Dex was infused within 20 min and then a maintenance dose of 0.5 , 1.0 , and 2.0 μg/kg/h Dex was infused intravenously ) . Arterial blood sample s were obtained from femoral artery at base state , MV1h , MV2h , and MV4h for blood gas analysis . After being mechanically ventilated for 4 h , dogs were killed and the levels of pulmonary inflammatory response and polymorphonuclear neutrophils ( PMNs ) count in bronchoalveolar lavage fluid were evaluated . RESULTS Histologic findings of the MV , DEX1 , DEX2 , and DEX3 groups revealed severe , moderate , mild , and normal to minimal inflammation , respectively . Myeloperoxidase level , PMNs/alveoli ratio , nuclear factor-κB messenger RNA ( mRNA ) , tumor necrosis factor-alpha mRNA , and inducible nitric oxide synthase mRNA expression in lung tissues of the DEX2 and DEX3 were significantly lower than those of the MV group . Partial pressures of oxygen was decreased significantly at MV4h as compared with the baseline . There was no statistical significance in partial pressures of oxygen between MV and DEX2 group as well as between group MV and group DEX3 . CONCLUSIONS Dexmedetomidine could mitigate pulmonary inflammatory response induced by VILI in dogs Dexmedetomidine , a specific selective α2-adrenergic agonist , does not only have the characteristics of being a sedative and analgesic , but also exhibits a protective role in brain ischemia-reperfusion injury and inhibits the inflammation in animals with sepsis . The objective of the present study was to investigate whether dexmedetomidine is capable of attenuating rat pulmonary damage induced by ischemia-reperfusion injury , which is a type of acute sterile lung injury . Sprague-Dawley rats were r and omly assigned into six groups : The sham-operated ( sham ) group , the lung ischemia-reperfusion ( I/R ) group , intravenous injection of dexmedetomidine 2.5 μg/kg/h ( Dex2.5 ) or 5 μg/kg/h ( Dex5 ) for 1 h prior to ischemia , combination of α2-adrenergic antagonist yohimbine prior to dexmedetomidine pre-treatment ( Dex+Yoh ) and pre-administration of yohimbine alone ( Yoh ) prior to ischemia . Lung injury was assessed by the histopathological changes , arterial blood gas , wet/dry ( w/d ) weight ratio and myeloperoxidase ( MPO ) activity of the lung . The concentration of tumor necrosis factor-α ( TNF-α ) , interleukin-6 ( IL-6 ) and monocyte chemoattractant protein-1 ( MCP-1 ) in bronchoalveolar lavage fluid ( BALF ) was measured by an enzyme-linked immunosorbent assay . The expression of toll-like receptor-4 ( TLR4 ) and myeloid differentiation factor 88 ( MyD88 ) mRNA in the lung were determined by quantitative PCR , and phosphorylated levels of c-Jun N-terminal kinase ( JNK ) and extracellular signal-regulated kinase (ERK)1/2 were determined by western blotting . Pre-treatment with dexmedetomidine significantly reduced the lung injury , w/d weight ratio and MPO activity , and decreased the concentration of TNF-α , IL-6 and MCP-1 in BALF compared with the I/R group . The expression of TLR4 and MyD88 mRNA and the levels of phosphorylated JNK and ERK1/2 in the lung tissue were markedly downregulated by intravenous injection of dexmedetomidne for 1 h prior to lung I/R. The protective effects of dexmedetomidine on the lung were not completely reversed by the α2-adrenergic antagonist , yohimbine . Pre-treatment with dexmedetomidine is capable of reducing pulmonary damage and inhibiting sterile inflammation induced by lung I/R injury . TLR4/MyD88/mitogen-activated protein kinase ( MAPK ) signaling is involved in the protective mechanism of dexmedetomidine through α2-adrenoceptor independence Introduction One of the main causes of death in European and US intensive care units is sepsis . It involves a network of pro-inflammatory cytokines such as TNF-α , IL-1β and IL-6 . Furthermore , there is an up regulation of transcription factors such as nuclear factor ( NF ) κB. It has previously been shown that clonidine is able to significantly reduce pro-inflammatory cytokines in surgical patients . We therefore hypothesise that the clinical ly used central alpha-2 agonist clonidine has the ability to improve survival in experimental sepsis by inhibiting the sympathetic tone and consequently inhibiting the pro-inflammatory cytokine release . Methods To investigate this therapeutic potential of clonidine in a prospect i ve r and omised laboratory investigation we used a murine model of caecal ligation and puncture ( CLP ) induced sepsis . Animals receiving pre-emptive injections were treated with either clonidine ( 5 μg/kg ) or dexmedetomidine ( 40 μg/kg ) 12 and 1 hours before the operation , as well as 1 , 6 and 12 hours afterwards . Another group of animals only received clonidine ( 5 μg/kg ) 1 , 6 and 12 hours after the operation , while the pre-emptive injections were normal saline . The control groups received solvent injections at the respective time points . Results Pre-emptive administration of a central sympatholytic significantly reduced mortality ( clonidine : p = 0.015 ; dexmedetomidine : p = 0.029 ) , although postoperative administration of clonidine failed to significantly prolong survival . Furthermore pre-emptive administration of clonidine significantly attenuated the cytokine response after CLP-induced sepsis ( mIL-1beta : p = 0.017 ; mIL-6 : p < 0.0001 ; mTNF-α : p < 0.0001 ) , preserved blood pressure control ( p = 0.024 ) and down-regulated the binding activity of NF-κB. There were no changes in the pro-inflammatory cytokine response when peripheral blood was incubated with lipopolysaccharide alone compared with incubation with clonidine ( 10 - 4 M ) plus LPS ( p > 0.05 ) . Conclusions Our results demonstrate that the pre-emptive administration of either clonidine or dexmedetomidine have the ability to successfully improve survival in experimental sepsis . Furthermore , there seems to be a connection between the central muscarinic network and the vagal cholinergic response . By down-regulating pro-inflammatory mediators sympatholytics may be a useful adjunct sedative in patients with a high risk for developing sepsis Approximately 42 % of patients with sepsis undergo acute kidney injury ( AKI ) , which evidently influences patient survival . However , effective therapy strategies are lacking , thus , the present study investigated the protective effects of dexmedetomidine ( DEX ) , a highly selective α-2 adrenoceptor agonist , in rat sepsis models . Rat sepsis models were generated through lipopolysaccharide injection ( LPS ; 5 mg/kg ) in the tail vein . Rats were pretreated with DEX ( 10 µg/kg ) 10 min before LPS injection to observe its protective effects . Of note , a unique α-2-adrenergic receptor antagonist , yohimbine ( YOH ; 1 mg/kg , intraperitoneally ) , was also used to antagonize the protective effects of DEX 30 min before DEX exposure . Thirty-two male Sprague Dawley rats were r and omly divided into the Sham , LPS , DEX + LPS and YOH + DEX + LPS groups ( n=8/group ) . All the rats were sacrificed 4 h later to observe the pathological changes of renal tissue , including plasma creatinine ( Cr ) , blood urea nitrogen ( BUN ) , kidney injury molecule-1 ( KIM-1 ) and high mobility group protein 1 ( HMGB-1 ) expression . Interleukin 6 ( IL-6 ) , IL-18 and tumor necrosis factor α ( TNF-α ) were all determined to examine the mechanisms of LPS-induced AKI relative to inflammatory reaction . The results indicated that AKI induced by LPS was serious . Renal pathological injury , plasma Cr , BUN , IL-6 , IL-18 and TNF-α were all evidently increased in varying degrees . KIM-1 and HMGB-1 expression was upregulated in the LPS group ( P<0.05 vs. Sham group ) . However , when rats were pretreated with DEX , AKI induced by LPS was decreased significantly . Renal pathological injury , plasma Cr , BUN , IL-6 , IL-18 , TNF-α , and KIM-1 and HMGB-1 expression were all reduced ( P<0.05 vs. LPS group ) . In addition , exposure of the α-2-adrenergic receptor antagonist , YOH , eliminated this reduction . In conclusion , DEX protected against sepsis-induced AKI through depressing the inflammatory reaction , mechanisms of which may be associated with α-2 receptors inhibition Previous studies have shown that dexmedetomidine exerted anti-inflammatory effect on several animal models with inflammation , but the mechanism is not clear . This study intends to eluci date the anti-inflammatory mechanism of dexmedetomidine through the cholinergic anti-inflammatory pathway . To investigate this therapeutic potential of dexmedetomidine , a murine model of endotoxemia was established induced by lipopolysaccharide ( LPS ) . Animals were assigned to one of four protocol s. Protocol one : animals were r and omly assigned to control group , dexmedetomidine group , and sterile saline group ( n = 20 each ) , and these animals were used for survival analysis . The survival rate was assessed up to 120 h after endotoxin injection . Protocol two : animals were r and omly assigned to one of four groups ( n = 16 each ) : group 1 ( group Saline ) , treated with sterile saline 15 min prior to endotoxin treatment ( 10 mg kg−1 over 2 min ) ; group 2 ( group Dex ) , treated with dexmedetomidine 15 min prior to endotoxin treatment ; group 3 ( group αBGT + Dex ) , treated with alpha-7 nicotinic acetylcholine receptors ( α7nAChR ) antagonist alpha-bungarotoxin ( αBGT , 1 μg/kg ) 15 min prior to dexmedetomidine treatment ; group 4 ( group saline + Dex ) , treated with equivalent sterile saline 15 min prior to dexmedetomidine treatment . Protocol three : animals were r and omly assigned to one of two groups ( n = 16 each ) : vagotomy group ( group VNX + Dex ) , right cervical vagus nerve was exposed and transected ; sham-operated group ( group SHAM + Dex ) , the cervical vagus nerve was visualized , but was neither isolated from the surrounding tissues nor transected . Protocol four : animals were treated with dexmedetomidine ( 40 μg/kg ) and sterile saline to observe the discharge activity of cervical vagus nerves by using BL-420F data acquisition and analysis system ( n = 16 each ) . In the survival analysis groups , the survival rate of dexmedetomidine group was significantly higher than that of the endotoxemia group ( 65 versus 25 % , P < 0.01 ) . Preemptive administration of dexmedetomidine significantly attenuated the cytokine response after lipopolysaccharide ( LPS ) induced endotoxemia ( TNF-alpha , IL-1beta , IL-6 , P < 0.01 , respectively ) . However , preemptive administration of dexmedetomidine failed to suppress cytokine response in α-bungarotoxin group and vagotomy group ( TNF-alpha , IL-1beta , IL-6 , P > 0.05 , respectively ) . Furthermore , preemptive administration of dexmedetomidine significantly increased the discharge frequency of cervical vagus nerves in comparison with sterile saline treatment ( P < 0.01).Our results demonstrate that the preemptive administration of dexmedetomidine increases the activity of cervical vagus nerve and have the ability to successfully improve survival in experimental endotoxemia by inhibiting the inflammatory cytokines release . However , administration of dexmedetomidine to vagotomy or α7 nAChR antagonist pretreatment mice failed to suppress TNF levels , indicating that the vagus nerve and α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of dexmedetomidine . These findings show that central alpha-2 agonist dexmedetomidine suppresses systemic inflammation through vagal- and α7nAChR-dependent mechanism Introduction Benzodiazepines and α2 adrenoceptor agonists exert opposing effects on innate immunity and mortality in animal models of infection . We hypothesized that sedation with dexmedetomidine ( an α2 adrenoceptor agonist ) , as compared with lorazepam ( a benzodiazepine ) , would provide greater improvements in clinical outcomes among septic patients than among non-septic patients . Methods In this a priori-determined subgroup analysis of septic vs non-septic patients from the MENDS double-blind r and omized controlled trial , adult medical/surgical mechanically ventilated patients were r and omized to receive dexmedetomidine-based or lorazepam-based sedation for up to 5 days . Delirium and other clinical outcomes were analyzed comparing sedation groups , adjusting for clinical ly relevant covariates as well as assessing interactions between sedation group and sepsis . Results Of the 103 patients r and omized , 63 ( 31 dexmedetomidine ; 32 lorazepam ) were admitted with sepsis and 40 ( 21 dexmedetomidine ; 19 lorazepam ) without sepsis . Baseline characteristics were similar between treatment groups for both septic and non-septic patients . Compared with septic patients who received lorazepam , the dexmedetomidine septic patients had 3.2 more delirium/coma-free days ( DCFD ) on average ( 95 % CI for difference , 1.1 to 4.9 ) , 1.5 ( -0.1 , 2.8 ) more delirium-free days ( DFD ) and 6 ( 0.3 , 11.1 ) more ventilator-free days ( VFD ) . The beneficial effects of dexmedetomidine were more pronounced in septic patients than in non-septic patients for both DCFDs and VFDs ( P-value for interaction = 0.09 and 0.02 respectively ) . Additionally , sedation with dexmedetomidine , compared with lorazepam , reduced the daily risk of delirium [ OR , CI 0.3 ( 0.1 , 0.7 ) ] in both septic and non-septic patients ( P-value for interaction = 0.94 ) . Risk of dying at 28 days was reduced by 70 % [ hazard ratio 0.3 ( 0.1 , 0.9 ) ] in dexmedetomidine patients with sepsis as compared to the lorazepam patients ; this reduction in death was not seen in non-septic patients ( P-value for interaction = 0.11 ) . Conclusions In this subgroup analysis , septic patients receiving dexmedetomidine had more days free of brain dysfunction and mechanical ventilation and were less likely to die than those that received a lorazepam-based sedation regimen . These results were more pronounced in septic patients than in non-septic patients . Prospect i ve clinical studies and further pre clinical mechanistic studies are needed to confirm these results .Trial Registration NCT00095251 Aims To investigate whether dexmedetomidine ( DEX ) preconditioning could alleviate the inflammation caused by myocardial ischemia/reperfusion ( I/R ) injury by reducing HMGB1-TLR4-MyD88-NF-кB signaling . Methods Seventy rats were r and omly assigned into five groups : sham group , myocardial I/R group ( I/R ) , DEX+I/R group ( DEX ) , DEX+yohimbine+I/R group ( DEX/YOH ) , and yohimbine+I/R group ( YOH ) . Animals were subjected to 30 min of ischemia induced by occluding the left anterior descending artery followed by 120 min of reperfusion . Myocardial infa rct size and histological scores were evaluated . The levels of IL-6 and TNF-α in serum and myocardium were quantified by enzyme-linked immunosorbent assay , and expression of HMGB1 , TLR4 , MyD88 , IκB and NF-κB in the myocardial I/R area were determined with Western blot and immunocytochemistry . Results Myocardial infa rct sizes , histological scores , levels of circulating and myocardial IL-6 and TNF-α , the expression of HMGB1 , TLR4 , MyD88 and NF-κB , and the degradation of IκB were significantly increased in the I/R group compared with the sham group ( P<0.01 ) . DEX preconditioning significantly reduced the myocardial infa rct size and histological scores ( P<0.01 vs. I/R group ) . Similarly , the serum and myocardial levels of IL-6 and TNF-α , the expression of HMGB1 , TLR4 , MyD88 and NF-κB , and the degradation of IκB were significantly reduced in the DEX group ( P<0.01 vs. I/R group ) . These effects were partly reversed by yohimbine , a selective α2-adrenergic receptor antagonist , while yohimbine alone had no significant effect on any of the above indicators . Conclusion DEX preconditioning reduces myocardial I/R injury in part by attenuating inflammation , which may be attributed to the downregulation of the HMGB1-TLR4-MyD88-NF-кB signaling pathway mediated by the α2-adrenergic receptor activation BACKGROUND In this pilot study , we aim ed to investigate the effect of dexmedetomidine on liver tissues during experimental sepsis by histopathological examination . METHODS The animals were allocated r and omly to four groups , two of which received endotoxin . In the Sepsis Group ( n:10 ) and Dexmedetomidine/Sepsis Group ( n:10 ) , endotoxemia was induced by E. coli lipopolysaccharide derived from E. coli 0111 : B4 . Animals in the Control Group ( n:10 ) received an infusion of 0.9 % saline ( 1.0 mL x kg(-1 ) x hr(-1 ) ) intravenously . The Dexmedetomidine Group ( n:10 ) and Dexmedetomidine/Sepsis Group received a bolus injection of 0.9 % saline ( 1.0 mL/kg ) , followed by dexmedetomidine administration ( infusion at 5 microg x kg(-1 ) x hr(-1 ) ) . All rats were euthanized at the 8th hour of endotoxin infusion . Histopathological examinations were performed on liver tissues . RESULTS In the liver , central venous congestion , congestion and dilation of the hepatic sinusoids and inflammation of the portal tracts were noted in the Sepsis Group . These parameters were seen slightly in the Sepsis/Dexmedetomidine group . There was a statistically significant difference between the Sepsis and Sepsis/Dexmedetomidine Groups ( p<0.001 ) . CONCLUSION Dexmedetomidine has a protective effect on liver tissues during experimental sepsis in the rat . We propose that dexmedetomidine sedation may be useful in the therapy of the liver dysfunction associated with sepsis and in other diseases related to local or systemic inflammation STUDY OBJECTIVE To compare the effects of an intravenous infusion of propofol and the alpha-2 adrenoceptor , dexmedetomidine , on inflammatory responses and intraabdominal pressure ( IAP ) in severe sepsis after abdominal surgery , specifically , serum cytokine levels ( interleukin [IL]-1 , IL-6 , and tumor necrosis factor [TNF]-alpha ) and IAP . DESIGN Prospect i ve , single-center study . SETTING University hospital . PATIENTS 40 adult ICU patients who had undergone ileus surgery and who were expected to require postoperative sedation and ventilation . INTERVENTIONS Patients received either a loading dose infusion of propofol ( Group P ; n = 20 ) one mg/kg over 15 minutes followed by a maintenance dose of one to three mg/kg/hr ( n = 20 , Group P ) or a loading dose of dexmedetomidine of one microg/kg over 10 minutes followed by a maintenance dose of 0.2 - 2.5 microg/kg/h ( n = 20 , Group D ) at the 24th hour . MEASUREMENTS Biochemical and hemodynamic parameters , cytokine levels , and IAP were recorded before the start of the study and at the 24th and 48th hours . MAIN RESULTS TNF-alpha levels were significantly lower at the 24th hour ( 14.66 + /- 4.40 pg/mL vs. 21.21 + /- 11.37 pg/mL , respectively ) and at the 48th hour ( 21.25 + /- 15.85 pg/mL vs. 46.55 + /- 35.99 pg/mL , respectively ) in Group D. IL-1 levels were significantly lower at the 24th hour ( 5.03 + /- 0.15 pg/mL vs. 6.23 + /- 2.09 pg/mL , respectively ) and the 48th hour ( 5.01 + /- 0.37 pg/mL vs. 6.42 + /- 2.76 pg/mL , respectively ) in Group D. IL-6 levels were significantly lower at the 24th hour ( 253.1 + /- 303.6 pg/mL and 511.3 + /- 374.8 pg/mL , respectively ) and at the 48th hour ( 343.5 + /- 393.4 pg/mL and 503.7 + /- 306.4 pg/mL , respectively ) in Group D. Intraabdominal pressure also was significantly lower at the 24th hour ( 12.35 + /- 5.84 mmHg vs. 18.1 + /- 2.84 mmHg , respectively ) and the 48th hour ( 13.9 + /- 6.15 mmHg vs. 18.7 + /- 3.46 mmHg , respectively ) in Group D. CONCLUSION Dexmedetomidine infusion decreases TNF-a , IL-1 , and IL-6 levels and IAP more than a propofol infusion OBJECTIVE To investigate the protective functions of dexmedetomidine on lipopolysaccharide-induced acute lung injury in the lung tissues of rats . METHODS The experiment was conducted from May 2008 to December 2009 in Zhongshan Hospital , Shanghai , China . Forty Sprague Dawley rats were r and omized into a normal group ( NS group ) , a lipopolysaccharide model group ( LPS group ) , and dexmedetomidine groups in high dosages ( HD ) , moderate dosages ( MD ) , and low dosages ( LD ) . After the acute lung injury model was duplicated by lipopolysaccharide , the rats in the LD , MD , and HD groups were injected with 0.5 ug/kg , 1.5 ug/kg , and 4.5 ug/kg of dexmedetomidine . The rats in the NS group were injected with normal saline . Immuno-histochemical and reverse transcription polymerase chain reaction techniques were used to assess the damage of lung tissue in each group . RESULTS The nuclear factor-KappaB and Toll-like receptor 4 messenger RNA expression in the lung tissues of the rats in the MD and HD groups were inhibited compared to the LPS group . The amount of tumor necrosis factor-beta , interleukin-1beta , and interleukin-6 as well as the lung tissue wet to dry weight ratio were also reduced in the MD and HD groups . CONCLUSION The inflammatory reactions in lung tissues can be effectively inhibited at doses ranging from 1.5 - 4.5 ug/kg , result ing in a protective effect on lung tissue STUDY OBJECTIVES To investigate the effect of dexmedetomidine on T helper 1 ( Th1 ) and T helper 2 ( Th2 ) cytokines and their ratio during and after surgery . DESIGN Single-blinded , r and omized , placebo-controlled clinical comparison study . SETTING Academic medical center . PATIENTS 46 adult , ASA physical status 1 and 2 patients scheduled for laparoscopic cholecystectomy . INTERVENTIONS Patients were r and omized to two groups : the dexmedetomidine group ( n = 23 ) , in which dexmedetomidine was infused with a 1.0 μg/kg loading dose followed by infusion of 0.5 μg/kg/h ; or the saline group ( n = 23 ) . MEASUREMENTS Interferon-gamma ( IFN-gamma ) and interleukin-4 ( IL-4 ) as Th1 and Th2 cytokines , respectively , were quantified three times : after induction of anesthesia ( T0 ) , at the end of peritoneal closure ( T1 ) , and 60 minutes after surgery ( T2 ) . The IFN-gamma/IL-4 ratio was then calculated . MAIN RESULTS The dexmedetomidine group displayed higher levels of IFN-gamma at T1 and T2 ( 42.30 pg/dL vs 6.91 pg/dL at T1 [ P = 0.025 ] ; 40.51 pg/dL vs 8.29 pg/dL at T2 [ P = 0.030 ] ) than the saline group . The dexmedetomidine group was also associated with higher ratios of IFN-gamma/IL-4 ( 1.22 vs 0.32 , respectively , at T1 [ P = 0.012 ] ; 1.53 vs 0.13 , respectively , at T2 [ P = 0.012 ] ) . CONCLUSIONS Dexmedetomidine plays an immunomodulatory role , shifting the Th1/Th2 cytokine balance toward Th1 in patients with surgical and anesthetic stress PURPOSE This study aim ed to explore effects of dexmedetomidine pretreatment on heme oxygenase-1 ( HO-1 ) expression and oxidative stress during one-lung ventilation ( OLV ) in lung cancer patients . METHODS Fifty patients with lung carcinoma ( ASA I-II , 40 - 65 years old , body mass index [ BMI ] < 30 kg/m2 ) undergoing pulmonary lobectomy were enrolled . They were divided r and omly into two equal groups before anaesthesia induction to receive either intravenous injection of 1 μg/kg dexmedetomidine for 20 min ( Dexmedetomidine ) or not ( Control ) . RESULTS The results showed no difference in heart rate ( HR ) , mean arterial pressure ( MAP ) and bispectral index ( BIS ) between the two groups , as well as liquid intake and output volume ( LIO ) , duration of OLV and time from surgery beginning to excision of pathological tissues ( P>0.05 ) . Levels of tumor necrosis factor ( TNF-α ) and malondialdehyde ( MDA ) in Dexmedetomidine group were lower than that of Control at OLV 60 and 90 ( P<0.05 ) . Superoxide dismutase ( SOD ) activity and the expression level of HO-1 were higher in Dexmedetomidine group than in Control ( P<0.05 ) . CONCLUSIONS Dexmedetomidine pretreatment could upregulated expression of HO-1 in lung tissue and reduce oxidative stress and inflammation during OLV . Thus dexmedetomidine played a role in protecting lung injury by promoting HO-1 expression Background : Dexmedetomidine reduces cytokine production in septic patients and reduces inflammation and mortality in experimental models of endotoxemia and sepsis . This study investigated whether dexmedetomidine attenuates endothelial dysfunction , intestinal microcirculatory dysfunction , and intestinal epithelial barrier disruption in endotoxemic rats . Methods : Ninety-two male Wistar rats were r and omly assigned to the following four groups : ( 1 ) Sham ; ( 2 ) lipopolysaccharide , received IV lipopolysaccharide 15 and 10 mg/kg at 0 and 120 min ; ( 3 ) dexmedetomidine , received IV dexmedetomidine for 240 min ; and ( 4 ) lipopolysaccharide + dexmedetomidine , received both lipopolysaccharide and dexmedetomidine . Sidestream dark-field videomicroscope , tissue oxygen monitor , and full-field laser perfusion image were used to investigate the microcirculation of the terminal ileum . Serum endocan level was measured . The Ussing chamber permeability assay , lumen-to-blood gadodiamide passage by magnetic resonance imaging , and bacterial translocation were conducted to determine epithelial barrier function . Mucosal apoptotic levels and tight junctional integrity were also examined . Results : The density of perfused small vessels in mucosa , serosal muscular layer , and Peyer patch in the lipopolysaccharide + dexmedetomidine group was higher than that of the lipopolysaccharide group . Serum endocan level was lower in the lipopolysaccharide + dexmedetomidine group than in the lipopolysaccharide group . Mucosal ratio of cleaved to full-length occludin and spleen bacterial counts were significantly lower in the lipopolysaccharide + dexmedetomidine group than in the lipopolysaccharide group . Conclusion : The study finding suggests that dexmedetomidine protects against intestinal epithelial barrier disruption in endotoxemic rats by attenuating intestinal microcirculatory dysfunction and reducing mucosal cell death and tight junctional damage . ( Anesthesiology 2016 ; 125:355 - 67 Purpose Our previous study demonstrated that dexmedetomidine drastically reduced mortality and inhibited the inflammatory response during endotoxemia in rats . The aim of this study was to clarify the dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxemia in rats . Methods Male Wistar rats ( n = 96 ) were anesthetized intraperitoneally with pentobarbital sodium and assigned to one of two protocol s : one representing the dose-related effects of dexmedetomidine , and the other , the time-related effects of dexmedetomidine . To evaluate the dose-related effects , the animals were r and omly assigned to one of four groups ( n = 15 each ) : endotoxemic group ( group E ) , receiving intravenous Escherichia coli endotoxin ( 15 mg·kg−1 over 2 min ) ; small-dose group ( group S ) , treated with a small dose of dexmedetomidine ( 2.5 μg·kg−1·h−1 , IV ) ; medium-dose group ( group M ) , treated with a medium dose ( 5 μg·kg−1·h−1 , IV ) ; and large-dose group ( group L ) , treated with a large dose ( 10 μg·kg−1·h−1 , IV ) . To evaluate the time-related effects , the animals were r and omly assigned to one of three groups ( n = 12 per group ) : endotoxemic group ; early posttreatment group , treated with 10 μg·kg−1·h−1 dexmedetomidine at 1 h after endotoxin injection ; and late posttreatment group , treated with 10 μg·kg−1·h−1 at 2 h after endotoxin injection . Hemodynamics and arterial blood gases were recorded and plasma cytokine concentrations were measured throughout the observation period . The mortality rate was assessed up to 8 h after endotoxin injection . Results In the dose-related study , the mortality rates at 8 h after endotoxin injection were 81 % , 26 % , 32 % , and 20 % for groups E , S , M , and L , respectively . Plasma tumor necrosis factor-alpha ( TNF ) concentrations were lower in groups M and L than in group E at 2 h after endotoxin injection . Plasma interleukin-6 ( IL-6 ) concentrations were lower in groups M and L than in group E at 4 and 5 h after endotoxin injection . In the time-related study , the mortality rates at 8 h after the endotoxin injection were 83 % , 33 % , and 58 % for the endotoxemic , early posttreatment , and late posttreatment groups , respectively . The TNF concentration was lower in the early posttreatment group than in the endotoxemic group at 2 h after endotoxin injection , and the IL-6 concentration was lower in the early posttreatment group than in the endotoxemic group at 5 h after endotoxin injection . Conclusion Dexmedetomidine dose-dependently attenuated extremely high mortality rates and increases in plasma cytokine concentrations after endotoxin injection . Moreover , the early administration of dexmedetomidine drastically reduced the high mortality rate and inhibited cytokine responses in endotoxin-exposed rats . These findings suggest that dexmedetomidine administration may be effective during sepsis Objectives : The aim of this study was to document the effects of a new sedative agent , dexmedetomidine , on the mortality rate and inflammatory responses to endotoxin-induced shock in rats . Design : R and omized laboratory study . Setting : University experimental laboratory . Subjects : Fifty-seven male rats . Interventions : The animals were r and omly assigned to one of four groups . The endotoxemic group ( n = 16 ) received intravenous Escherichia coli endotoxin ( 15 mg/kg over 2 mins ) . The saline control group ( n = 10 ) was given saline alone . The dexmedetomidine alone group ( n = 15 ) was treated identically to the control group but also received dexmedetomidine ( infusion at 5 μg·kg−1·hr−1 ) immediately after the injection of 0.9 % saline . The dexmedetomidine-endotoxin group ( n = 16 ) was treated identically to the endotoxemic group with the additional administration of dexmedetomidine ( infusion at 5 μg·kg−1·hr−1 ) immediately after endotoxin injection . Measurements and Main Results : Hemodynamics and arterial blood gases were recorded and plasma cytokine concentrations measured during the observation . The mortality rate was assessed up to 8 hrs after endotoxin or saline injection . In addition , microscopic findings of lung tissue for each group were obtained at necropsy . Mortality rates 8 hrs after endotoxin injection were 94 % , 10 % , 0 % , and 44 % for the endotoxemic , saline control , dexmedetomidine alone , and dexmedetomidine-endotoxin groups , respectively . Hypotension and increases in plasma cytokine ( tumor necrosis factor-&agr ; and interleukin-6 ) concentrations and infiltration of neutrophils in the airspace or vessel walls of the lungs were less in the dexme-detomidine-endotoxin group than in the endotoxemic group . Conclusions : Dexmedetomidine reduced mortality rate and had an inhibitory effect on inflammatory response during endotoxemia . These findings suggest that dexmedetomidine administration may inhibit the inflammatory response Cardiac surgery with cardiopulmonary bypass is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs . We hypothesised that the highly selective α2‐adrenergic agonist , dexmedetomidine , attenuates the systemic inflammatory response . Forty‐two patients were r and omly assigned to receive dexmedetomidine or saline after aortic cross‐clamping ) . The mean ( SD ) levels of the nuclear protein plasma high‐mobility group box 1 increased significantly from 5.1 ( 2.2 ) ng.ml−1 during ( 16.6 ( 7.3 ) ng.ml−1 ) and after ( 14.3 ( 8.2 ) ng.ml−1 ) cardiopulmonary bypass in the saline group . In the dexmedetomidine group , the levels increased significantly only during cardiopulmonary bypass ( 4.0 ( 1.9 ) ng.ml−1 baseline vs 10.8 ( 2.7 ) ng.ml−1 ) but not after ( 7.4 ( 3.8 ) ng.ml−1 ) . Dexmedetomidine infusion also suppressed the rise in mean ( SD ) interleukin‐6 levels after cardiopulmonary bypass ( a rise of 124.5 ( 72.0 ) pg.ml−1 vs 65.3 ( 30.9 ) pg.ml−1 ) . These suppressive effects of dexmedetomidine might be due to the inhibition of nuclear factor kappa B activation and suggest that intra‐operative dexmedetomidine may beneficially inhibit inflammatory responses associated with ischaemia‐reperfusion injury during cardiopulmonary bypass Objectives : Propofol-based sedation may increase hemodynamic instability by decreasing vascular tone and venous return . Incremental exogenous catecholamines doses may be required to counteract such effects , aggravating the deleterious effects of sympathetic overstimulation . & agr;-2 adrenergic agonists have been reported to decrease norepinephrine requirements in experimental septic shock . The aim of the present study is to test the hypothesis that switching from sedation with propofol to the & agr;-2 agonist dexmedetomidine may decrease norepinephrine doses in septic shock . Design : Prospect i ve open-label crossover study . Setting s : University hospital , ICU . Patients : Thirty-eight septic shock patients requiring norepinephrine to maintain adequate mean arterial pressure and needing deep sedation with propofol and remifentanil to maintain a Richmond Agitation-Sedation Scale score between –3 and –4 . Interventions : An initial set of measurements including hemodynamics , norepinephrine doses , and depth of sedation were obtained during sedation with propofol . Propofol was then replaced by dexmedetomidine and a second set of data was obtained after 4 hours of dexmedetomidine infusion . Sedation was switched back to propofol , and a final set of measurements was obtained after 8 hours . A Richmond Agitation-Sedation Scale score between –3 and –4 was maintained during the study period . Measurements and Main Results : Norepinephrine requirements decreased from 0.69 ± 0.72 & mgr;g/kg/min before dexmedetomidine to 0.30 ± 0.25 & mgr;g/kg/min 4 hours after dexmedetomidine infusion , increasing again to 0.42 ± 0.36 & mgr;g/kg/min while on propofol 8 hours after stopping dexmedetomidine ( p < 0.005 ) . Dexmedetomidine dosage was 0.7 ± 0.2 & mgr;g/kg/hr . Before and after dexmedetomidine infusion , sedative doses remained unchanged ( propofol 2.6 ± 1.2 vs 2.6 ± 1.2 mg/kg/hr ; p = 0.23 and remifentanil 1.27 ± 0.17 vs 1.27 ± 0.16 & mgr;g/kg/hr ; p = 0.52 , respectively ) . Richmond Agitation-Sedation Scale was –4 ( –4 to –3 ) before , –4 ( –4 to –3 ) during , and –4 ( –4 to –4 ) after dexmedetomidine ( p = 0.07 ) . Conclusions : For a comparable level of sedation , switching from propofol to dexmedetomidine result ed in a reduction of catecholamine requirements in septic shock patients OBJECTIVE To assess the effects of dexmedetomidine ( Dex ) on CD42a+/CD14+，HLADR+/CD14 + and inflammatory cytokine levels in patients undergoing multilevel spinal fusion . Patients and methods Forty ASA I-II patients undergoing multilevel spinal fusion were r and omly divided into Dex and control groups ( n=20 ) . A continuous intravenous infusion of Dex ( 0.5μg/kg/h ) or normal saline was started 10min prior to induction and was stopped 15min before operation completion . Serum levels of CD42a+/CD14 + , HLADR+/CD14 + , WBC , PLT , CRP , IL-6 , IL-10 , and TNF-α were measured before induction ( T1 ) , 30min ( T2 ) after operation initiation , and 60min ( T3 ) , 1d ( T4 ) , 3d ( T5 ) , and 5d ( T6 ) post-operation . VAS values were obtained at T3 , T4 , T5 and T6 , as well as hospital days . RESULTS Treatment with Dex significantly decreased CD42a+/CD14 + at T2 , T3 , and T4 , and markedly increased HLADR+/CD14 + at T4 and T5 when compared with controls . CRP and WBC were markedly decreased at T2 , T3 , T4 and T5 ( P<0.01 or P<0.05 ) . Serum IL-6 and TNF-α level in Dex group was significantly increased at T3 and T4 ( P<0.05 ) , and IL-6 and TNF-α level in control group was significantly increased at T2 , T3 , T4 and T5 ( P<0.05 ) when compared with their respective preoperative levels ( T1 ) . IL-6 and TNF-α levels at T2 , T3 , T4 and T5 in Dex group were significantly lower than those in control group ( P<0.05 ) . There were no significant differences in operation time , hospital days or VAS values between the two groups ( P>0.05 ) . CONCLUSION Dex can inhibit the inflammatory response and reduce immunosuppression in patients undergoing multilevel spinal fusion Importance Dexmedetomidine provides sedation for patients undergoing ventilation ; however , its effects on mortality and ventilator-free days have not been well studied among patients with sepsis . Objectives To examine whether a sedation strategy with dexmedetomidine can improve clinical outcomes in patients with sepsis undergoing ventilation . Design , Setting , and Participants Open-label , multicenter r and omized clinical trial conducted at 8 intensive care units in Japan from February 2013 until January 2016 among 201 consecutive adult patients with sepsis requiring mechanical ventilation for at least 24 hours . Interventions Patients were r and omized to receive either sedation with dexmedetomidine ( n = 100 ) or sedation without dexmedetomidine ( control group ; n = 101 ) . Other agents used in both groups were fentanyl , propofol , and midazolam . Main Outcomes and Measures The co– primary outcomes were mortality and ventilator-free days ( over a 28-day duration ) . Sequential Organ Failure Assessment score ( days 1 , 2 , 4 , 6 , 8) , sedation control , occurrence of delirium and coma , intensive care unit stay duration , renal function , inflammation , and nutrition state were assessed as secondary outcomes . Results Of the 203 screened patients , 201 were r and omized . The mean age was 69 years ( SD , 14 years ) ; 63 % were male . Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group ( 19 patients [ 22.8 % ] vs 28 patients [ 30.8 % ] ; hazard ratio , 0.69 ; 95 % CI , 0.38 - 1.22 ; P = .20 ) . Ventilator-free days over 28 days were not significantly different between groups ( dexmedetomidine group : median , 20 [ interquartile range , 5 - 24 ] days ; control group : median , 18 [ interquartile range , 0.5 - 23 ] days ; P = .20 ) . The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation ( range , 17%-58 % vs 20%-39 % ; P = .01 ) ; other outcomes were not significantly different between groups . Adverse events occurred in 8 ( 8 % ) and 3 ( 3 % ) patients in the dexmedetomidine and control groups , respectively . Conclusions and Relevance Among patients requiring mechanical ventilation , the use of dexmedetomidine compared with no dexmedetomidine did not result in statistically significant improvement in mortality or ventilator-free days . However , the study may have been underpowered for mortality , and additional research may be needed to evaluate this further . Trial Registration clinical trials.gov Identifier : BACKGROUND Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit ( ICU ) . The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied . METHODS In an open-label , r and omized trial , we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care ( propofol , midazolam , or other sedatives ) . The target range of sedation-scores on the Richmond Agitation and Sedation Scale ( which is scored from -5 [ unresponsive ] to + 4 [ combative ] ) was -2 to + 1 ( lightly se date d to restless ) . The primary outcome was the rate of death from any cause at 90 days . RESULTS We enrolled 4000 patients at a median interval of 4.6 hours between eligibility and r and omization . In a modified intention-to-treat analysis involving 3904 patients , the primary outcome event occurred in 566 of 1948 ( 29.1 % ) in the dexmedetomidine group and in 569 of 1956 ( 29.1 % ) in the usual-care group ( adjusted risk difference , 0.0 percentage points ; 95 % confidence interval , -2.9 to 2.8 ) . An ancillary finding was that to achieve the prescribed level of sedation , patients in the dexmedetomidine group received supplemental propofol ( 64 % of patients ) , midazolam ( 3 % ) , or both ( 7 % ) during the first 2 days after r and omization ; in the usual-care group , these drugs were administered as primary sedatives in 60 % , 12 % , and 20 % of the patients , respectively . Bradycardia and hypotension were more common in the dexmedetomidine group . CONCLUSIONS Among patients undergoing mechanical ventilation in the ICU , those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that in the usual-care group and required supplemental sedatives to achieve the prescribed level of sedation . More adverse events were reported in the dexmedetomidine group than in the usual-care group . ( Funded by the National Health and Medical Research Council of Australia and others ; SPICE III Clinical Trials.gov number , NCT01728558 . )

Results : An overall effect size of 1.06 ( 95 % CI = 0.76 - 1.36 , p < 0.00001 ) was obtained , demonstrating that upper limbs assistive devices significantly improve the performance in activities of daily living in people with neuromuscular diseases .

Background : This systematic review summarizes the current evidence about the effectiveness of wearable assistive technologies for upper limbs support during activities of daily living for individuals with neuromuscular diseases .

Distinguishing cohort studies from case series is difficult . We propose a conceptualization of cohort studies in systematic review s of comparative studies . The main aim of this conceptualization is to clarify the distinction between cohort studies and case series . We discuss the potential impact of the proposed conceptualization on the body of evidence and workload . All studies with exposure-based sampling gather multiple exposures ( with at least two different exposures or levels of exposure ) and enable calculation of relative risks that should be considered cohort studies in systematic review s , including non-r and omized studies . The term “ enables/can ” means that a predefined analytic comparison is not a prerequisite ( i.e. , the absolute risks per group and /or a risk ratio are provided ) . Instead , all studies for which sufficient data are available for re analysis to compare different exposures ( e.g. , sufficient data in the publication ) are classified as cohort studies .There are possibly large numbers of studies without a comparison for the exposure of interest but that do provide the necessary data to calculate effect measures for a comparison . Consequently , more studies could be included in a systematic review . Therefore , on the one h and , the outlined approach can increase the confidence in effect estimates and the strengths of conclusions . On the other h and , the workload would increase ( e.g. , additional data extraction and risk of bias assessment , as well as reanalyses ) Gravity compensation ( GC ) of the arm is used to facilitate arm movements in conventional therapy as well as in robot-assisted rehabilitation of neurologically impaired persons . Positive effects of GC on Range of Motion ( ROM ) have been demonstrated in stroke . In Multiple Sclerosis ( MS ) , research regarding this topic is lacking . Since an active participation of the patient is required for effective training , full support of the arm might not be advisable . The present study reports on the development of a procedure to measure actively the individual need for GC and to estimate the influence of GC on ROM during reaching , lifting and transporting in severely affected Persons with MS ( PwMS ) . Ten PwMS were tested with the procedure for determination of GC . Maximal reaching movements were performed in a 3D space in three conditions : No support ( NS ) , with GC by the HapticMaster ( GC-HM ) and with GC by the HapticMaster combined with a sling suspension system ( GC-HMS ) . For the total sample , significant correlations were found between the amount of GC and clinical tests for upper limb function . In four subjects with severe arm dysfunction it was found that mean ROM is larger in the GC-HMS condition compared to the GC-HM condition , and in the GC-HM condition compared to the NS condition , suggesting positive effects of GC on active ROM in PwMS . Therefore , GC could have a positive effect on arm rehabilitation by enabling the PwMS to actively reach a larger ROM during training The objective of this study was to determine the utility of a passive gravity-balanced arm orthosis , the Wilmington robotic exoskeleton ( WREX ) , for patients with neuromuscular diseases . The WREX , a four-degrees-of-freedom functional orthosis , is energized by rubber b and s to eliminate gravity and is attached to the wheelchair . The development and clinical testing of WREX is described in this report . Seventeen patients ( 14 boys and 3 girls ) with muscular disabilities participated in the study . Ages ranged from 4 to 20 years . Criteria for inclusion included a weakened arm , use of a wheelchair , the ability to grasp and release objects , and the ability to provide feedback on device use . Testing consisted of administering the Jebsen test of h and function without WREX and then testing again after approximately two weeks of wearing the WREX orthosis . The timed results of each task within the test then were compared . Specific tasks related to vertical movement required less time to perform with the WREX . A large number of subjects were able to perform the Jebsen tasks with the WREX , where they were unable to perform the task without the WREX . Patients can benefit from WREX because it increases their performance in daily living activities and makes many tasks possible . The range-of-motion in the patients ' arms increased considerably , while the time required to complete some of the Jebsen test tasks decreased . Most patients were very receptive to WREX , although a few were ambivalent Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies Therapeutic trials in muscular dystrophy have often been inconclusive . A protocol has been design ed which selects patients with Duchenne muscular dystrophy and permits accurate measurement of their status . An integral part of the protocol is a system for checking on the consistency of the data obtained using a computer program OBJECTIVE To provide guidance on how systematic review authors , guideline developers , and health technology assessment practitioners should approach the use of the risk of bias in nonr and omized studies of interventions ( ROBINS-I ) tool as a part of GRADE 's certainty rating process . STUDY DESIGN AND SETTING The study design and setting comprised iterative discussion s , testing in systematic review s , and presentation at GRADE working group meetings with feedback from the GRADE working group . RESULTS We describe where to start the initial assessment of a body of evidence with the use of ROBINS-I and where one would anticipate the final rating would end up . The GRADE accounted for issues that mitigate concerns about confounding and selection bias by introducing the upgrading domains : large effects , dose-effect relations , and when plausible residual confounders or other biases increase certainty . They will need to be considered in an assessment of a body of evidence when using ROBINS-I. CONCLUSION The use of ROBINS-I in GRADE assessment s may allow for a better comparison of evidence from r and omized controlled trials ( RCTs ) and nonr and omized studies ( NRSs ) because they are placed on a common metric for risk of bias . Challenges remain , including appropriate presentation of evidence from RCTs and NRSs for decision-making and how to optimally integrate RCTs and NRSs in an evidence assessment

Nevertheless , the application of non-invasive brain stimulation techniques , especially transcranial direct current stimulation , over the right PFC seemed to reduce violent reactions in these individuals by interfering with the interpretation of the unfavourable situations ( e.g. , threating signals ) or inner states that evoked anger . The main conclusion of these studies was that bilateral stimulation of the PFC satisfactorily reduced anger and irritability only in inmates , patients with autism spectrum disorders ( ASD ) , people who suffered a closed-head injury , and agitated patients with Alzheimer 's disease . Moreover , combining these techniques with risperidone considerably reduced aggressiveness in these patients .

The field of neurocriminology has proposed several treatments ( e.g. , pharmacological , brain surgery , and rogen-deprivation therapy , neurofeedback ) to reduce violence proneness , but unfortunately , their effectiveness has been limited due to their side-effects . Therefore , it is necessary to explore alternative techniques to improve patients ' behavioural regulation with minimal undesirable effects . In this regard , non-invasive brain stimulation techniques , which are based on applying changing magnetic fields or electric currents to interfere with cortical excitability , have revealed their usefulness in alleviating the symptomatology of several mental disorders . However , to our knowledge , there are no review s that assess whether these techniques are useful for reducing violence proneness .

Background Prefrontal repetitive transcranial magnetic stimulation ( rTMS ) has been used to induce side-specific mood changes in volunteers and patients . To clarify inconsistencies between reports that used different stimulation frequencies , we conducted a controlled study with a low ( 1 Hz ) frequency , comparing left with right-sided stimulation Methods Nineteen healthy volunteers received r and omised left or right prefrontal rTMS at a frequency of 1 Hz and 100 % of motor threshold in two sessions two weeks apart . Results There were significant improvements with TMS for performance in the digit symbol substitution and verbal fluency tests , but no change of mood on a number of measures . There was also a reduction of pulse rate after TMS . The only side-specific TMS-effect was on mean arterial pressure , which decreased pressure after left , but not after right prefrontal TMS . Conclusions Apart from the unexpected and so far unreplicated effect on mean arterial pressure , there were no side-specific effects on mood in volunteers . It is unlikely that a simple laterality model of mood together with the assumed activating effect of higher and ' quenching ' effect of lower stimulation frequency can account for the effects of TMS on mood Background Behavioral and psychological symptoms of dementia ( BPSD ) occur in 70 - 90 % of patients at different stages of Alzheimer ’s Disease ( AD ) , but the available methods for managing these problems are of limited effectiveness . Aim Assess the effects of high-frequency repetitive transcranial magnetic stimulation ( rTMS ) , applied over the left dorsolateral prefrontal cortex ( DLPFC ) , on BPSD and cognitive function in persons with AD . Methods Fifty-four patients with AD and accompanying BPSD were r and omly divided into an intervention group ( n=27 ) and a control group ( n=27 ) . In addition to st and ard antipsychotic treatment , the intervention group was treated with 20Hz rTMS five days a week for four weeks , while the control group was treated with sham rTMS.The Behavioral Pathology in Alzheimer 's Disease Rating Scale ( BEHAVE-AD ) , the Alzheimer 's Disease Assessment Scale-Cognitive ( ADAS-Cog ) , and the Treatment Emergent Symptom Scale ( TESS ) were administered by raters who were blind to the group assignment of patients before and after four weeks of treatment . Results Twenty-six subjects from each group completed the study . After four weeks of antipsychotic treatment with adjunctive real or sham rTMS treatment , the mean ( sd ) total BEHAVE-AD scores and mean total ADAS-Cog scores of both groups significantly decreased from baseline . After adjusting for baseline values , the intervention group had significantly lower scores ( i.e. , greater improvement ) than the control group on the BEHAVE-AD total score , on five of the seven BEHAVE-AD factor scores ( activity disturbances , diurnal rhythm , aggressiveness , affective disturbances , anxieties and phobias ) , on the ADAS-Cog total score , and on all four ADAS-Cog factor scores ( memory , language , constructional praxis , and attention ) . The proportion of individuals whose behavioral symptoms met a predetermined level of improvement ( i.e. , a drop in BEHAVE-AD total score of > 30 % from baseline ) in the intervention group was greater than that in the control group ( 73.1 % vs.42.3 % , X2=5.04 , p=0.025 ) . Conclusion Compared to treatment of AD with low-dose antipsychotic medications alone , the combination of low-dose antipsychotic medication with adjunctive treatment with high frequency rTMS can significantly improve both cognitive functioning and the behavioral and psychological symptoms that often accompany AD Cranial electrotherapy stimulation ( CES ) is reported to aid in relieving symptoms of depression and anxiety , though the mechanism underlying this effect remains unclear . Therefore , the present study aim ed to evaluate changes in the hypothalamic-pituitary-adrenal ( HPA ) axis response and levels of neurotrophic factors , as well as changes in mood state , in patients undergoing CES therapy . Fifty healthy postmenopausal women were r and omly assigned to either a Sham CES group ( n = 25 ) or an Active CES group ( n = 25 ) . CES treatment was conducted in 20-minute sessions , three times per week for 8 weeks , using a micro current cranial electrotherapy stimulator . Blood sample s were collected prior to and following the 8-week treatment period for measurement of cortisol , adrenocorticotropic hormone ( ACTH ) , brain-derived neurotrophic factor ( BDNF ) , and nerve growth factor ( NGF ) levels . Changes in mood state were also examined at the time of blood collection using the Profile of Mood States ( POMS ) . No significant differences in cortisol , ACTH , BDNF , or NGF were observed between the two participant groups ( p > 0.05 ) following the treatment period . However , those in the Active CES group exhibited significantly decreased Tension-Anxiety and Depression-Dejection scores on the POMS relative to pre-treatment scores ( p < 0.05 ) . Furthermore , Depression-Dejection scores following treatment were significantly lower in the Active CES group than in the Sham CES group ( p < 0.05 ) . No significant differences were observed in any other POMS scores such as Anger-Hostility , Vigor-Activity , Fatigue-Inertia , and Confusion-Bewilderment ( p > 0.05 ) . These results suggest that 8 weeks of CES treatment does not induce changes in blood levels of neurotrophic factors or HPA-axis-related hormones , though such treatment may be effective in treating symptoms of anxiety and depression Background : Data from the human motor cortex suggest that , depending on polarity , direct current ( DC ) brain polarization can depress or activate cortical neurons . Activating effects on the frontal lobe might be beneficial for patients with frontal lobe disorders . This phase 1 study tested the safety of frontal DC , including its effects on frontal and other brain functions . Methods : The authors applied 20 minutes of anodal , cathodal , or sham DC to the left prefrontal cortex in three groups of right-h and ed subjects and looked for effects on global measures of processing and psychomotor speed , emotion , and verbal fluency , a measure of local cortical function . In one experiment ( n = 30 ) , the authors tested before and after 1 mA DC and monitored EEG in 9 subjects . In two other experiments using 1 mA ( n = 43 ) and 2 mA ( n = 30 ) , the authors tested before and then starting 5 minutes after the onset of DC . Results : All subjects tolerated DC well . There were no significant effects on performance with 1 mA DC . At 2 mA , verbal fluency improved significantly with anodal and decreased mildly with cathodal DC . There were no clinical ly significant effects on the other measures . Conclusions : Limited exposure to direct current polarization of the prefrontal cortex is safe and can enhance verbal fluency selectively in healthy subjects . As such , it deserves consideration as a procedure to improve frontal lobe function in patients Research has demonstrated that left-prefrontal cortical activity is associated with positive affect , or approach motivation , and that right-prefrontal cortical activity is associated with negative affect , or withdrawal motivation . In past research , emotional valence ( positive-negative ) has been confounded with motivational direction ( approach-withdrawal ) , such that , for instance , the only emotions examined were both positive and approach related . Recent research has demonstrated that trait anger , a negative but approach-related emotion , is associated with increased left-prefrontal and decreased right-prefrontal activity , suggesting that prefrontal asymmetrical activity is associated with motivational direction and not emotional valence . The present experiment tested whether state-induced anger is associated with relative left-prefrontal activity and whether this prefrontal activity is also associated with aggression . Results supported these hypotheses The central nervous system seems to have an important role in fatigue and exercise tolerance . Novel noninvasive techniques of neuromodulation can provide insights on the relationship between brain function and exercise performance . The purpose of this study was to determine the effects of transcranial direct current stimulation ( tDCS ) on physical performance and physiological and perceptual variables with regard to fatigue and exercise tolerance . Eleven physically active subjects participated in an incremental test on a cycle simulator to define peak power output . During 3 visits , the subjects experienced 3 stimulation conditions ( anodal , cathodal , or sham tDCS — with an interval of at least 48 h between conditions ) in a r and omized , counterbalanced order to measure the effects of tDCS on time to exhaustion at 80 % of peak power . Stimulation was administered before each test over 13 min at a current intensity of 2.0 mA. In each session , the Brunel Mood State question naire was given twice : after stimulation and after the time-to-exhaustion test . Further , during the tests , the electromyographic activity of the vastus lateralis and rectus femoris muscles , perceived exertion , and heart rate were recorded . RM-ANOVA showed that the subjects performed better during anodal primary motor cortex stimulation ( 491 ± 100 s ) compared with cathodal stimulation ( 443 ± 11 s ) and sham ( 407 ± 69 s ) . No significant difference was observed between the cathodal and sham conditions . The effect sizes confirmed the greater effect of anodal M1 tDCS ( anodal x cathodal = 0.47 ; anodal x sham = 0.77 ; and cathodal x sham = 0.29 ) . Magnitude-based inference suggested the anodal condition to be positive versus the cathodal and sham conditions . There were no differences among the three stimulation conditions in RPE ( p = 0.07 ) or heart rate ( p = 0.73 ) . However , as hypothesized , RM- ANOVA revealed a main effect of time for the two variables ( RPE and HR : p < 0.001 ) . EMG activity also did not differ during the test accross the different conditions . We conclude that anodal tDCS increases exercise tolerance in a cycling-based , constant-load exercise test , performed at 80 % of peak power . Performance was enhanced in the absence of changes in physiological and perceptual variables Aggressive behavior is aim ed at causing damage or pain to another individual . Aggression has been associated with structural and functional deficits in numerous brain areas , including the dorsolateral region of the prefrontal cortex ( DLPFC ) , typically related to inhibition and impulse control . In this study , we used inhibitory continuous theta-burst magnetic stimulation ( cTBS ) to explore the role of the right and left DLPFC in aggression . Sixteen healthy right-h and ed volunteers underwent two sessions involving r and om , real and sham , right and left DLPFC stimulations . These sessions were followed by the Social Orientation Paradigm ( SOP ) , a monetary task that was specially design ed to assess participants ' aggressive tendencies by measuring the patterns of their reactive aggression ( a response to a perceived provocation ) and proactive aggression ( an aggressive act with goal -oriented purpose s ) . Results indicate that using cTBS to target the left DLPFC was associated with a greater increase in aggressive responses than right DLPFC stimulation . This pattern of results was found for both reactive and proactive types of aggressive reactions . It is concluded that DLPFC asymmetry is involved in modulating reactive and proactive aggression . Our results are in line with recent studies suggesting that the left DLPFC plays a major role in aggressive behavior Clinical and functional imaging studies suggest that the cerebellar vermis is involved in the regulation of a range of nonsomatic functions including cardiovascular control , thirst , feeding behavior , and primal emotions . Cerebello-hypothalamic circuits have been postulated to be a potential neuroanatomical substrate underlying this modulation . We tested this putative relationship between the cerebellar vermis and nonsomatic functions by stimulating the cerebellum noninvasively via neuronavigated transcranial magnetic stimulation . In this r and omized , counter-balanced , within-subject study , intermittent theta burst stimulation ( TBS ) was applied on three different days to the vermis and the right and left cerebellar hemispheres of 12 right-h and ed normal subjects with the aim of modulating activity in the targeted cerebellar structure . TBS-associated changes were investigated via cardiovascular monitoring , a series of emotionally arousing picture stimuli , subjective analog scales for primal emotions , and the Profile of Mood States test . All 36 sessions of cerebellar stimulation were tolerated well without serious adverse events . Cardiovascular monitoring pointed to a mild but significant decrease in heart rate subsequent to vermal stimulation ; no changes were detected in systolic or diastolic blood pressure measurements . Subjective ratings detected a significant increase in Thirst and a trend toward increased Appetite following vermal stimulation . These observations are consistent with existing neurophysiological and neuroimaging data indicating a role for the cerebellum in the regulation of visceral responses . In conjunction with the modulatory function of the cerebellum , our results suggest a role for the vermis in somatovisceral integration likely through cerebello-hypothalamic pathways . Further research is warranted to eluci date the potential mechanisms underlying the cerebellar modulation of nonsomatic functions Although negative results have been reported , an important aspect of the physiology of repetitive transcranial magnetic stimulation ( rTMS ) could be related to the endocrinological response of the hypothalamic-pituitary-adrenal ( HPA ) axis , such as cortisol secretion . Because endocrinological responses are influenced by anxiety states , this could influence the effect of rTMS in healthy individuals . In this sham-controlled , " single blind " crossover study , we examined whether one session of HF-rTMS could affect the HPA-system , when taking into account individual state anxiety scores based on the State-Trait Anxiety Inventory ( STAI ) . Twenty-four healthy rTMS naïve females received one sham-controlled high frequency (HF)-rTMS session delivered on the right dorsolateral prefrontal cortex ( DLPFC ) . The Profile of Mood States ( POMS ) question naire , together with salivary cortisol sample s , was collected before , just after and 30 min post HF-rTMS . To examine whether state anxiety could influence endocrinological outcome measurements , we administered the STAI-state just before each HF-rTMS experiment started . Based on the POMS question naire , no mood changes were observed . Without taking individual state anxiety scores into account , one sham-controlled right-sided HF-rTMS session did not influence the HPA-system . When taking into account individual STAI-state scores , we found that healthy women scoring higher on the STAI-state displayed a significantly more sensitive HPA-system , result ing in salivary cortisol concentration increases after real HF-rTMS , compared to those scoring lower on this anxiety scale . Our results indicate that healthy women scoring high on state anxiety display a more sensitive HPA-system when receiving one right-sided HF-rTMS session . Our findings suggest that the incorporation of individual anxiety states in experimental rTMS research could add further information about its neurobiological influences on the HPA-system Research has shown that exposure to violent media increases aggression . However , the neural underpinnings of violent-media-related aggression are poorly understood . Additionally , few experiments have tested hypotheses concerning how to reduce violent-media-related aggression . In this experiment , we focused on a brain area involved in the regulation of aggressive impulses — the right ventrolateral prefrontal cortex ( rVLPFC ) . We tested the hypothesis that brain polarization through anodal transcranial direct current stimulation ( tDCS ) over rVLPFC reduces aggression related to violent video games . Participants ( N = 79 ) were r and omly assigned to play a violent or a nonviolent video game while receiving anodal or sham stimulation . Afterward , participants aggressed against an ostensible partner using the Taylor aggression paradigm ( Taylor Journal of Personality , 35 , 297–310 , 1967 ) , which measures both unprovoked and provoked aggression . Among those who received sham stimulation , unprovoked aggression was significantly higher for violent-game players than for nonviolent-game players . Among those who received anodal stimulation , unprovoked aggression did not differ for violent- and nonviolent-game players . Thus , anodal stimulation reduced unprovoked aggression in violent-game players . No significant effects were found for provoked aggression , suggesting tit-for-tat responding . This experiment sheds light on one possible neural underpinning of violent-media-related aggression — the rVLPFC , a brain area involved in regulating negative feelings and aggressive impulses Background High frequency repetitive transcranial magnetic stimulation ( rTMS ) of the left dorsolateral prefrontal cortex ( DLPFC ) has shown significant efficiency in the treatment of resistant depression . However in healthy subjects , the effects of rTMS remain unclear . Objective Our aim was to determine the impact of 10 sessions of rTMS applied to the DLPFC on mood and emotion recognition in healthy subjects . Design In a r and omised double-blind study , 20 subjects received 10 daily sessions of active ( 10 Hz frequency ) or sham rTMS . The TMS coil was positioned on the left DLPFC through neuronavigation . Several dimensions of mood and emotion processing were assessed at baseline and after rTMS with clinical scales , visual analogue scales ( VASs ) , and the Ekman 60 faces test . Results The 10 rTMS sessions targeting the DLPFC were well tolerated . No significant difference was found between the active group and the control group for clinical scales and the Ekman 60 faces test . Compared to the control group , the active rTMS group presented a significant improvement in their adaptation to daily life , which was assessed through VAS . Conclusion This study did not show any deleterious effect on mood and emotion recognition of 10 sessions of rTMS applied on the DLPFC in healthy subjects . This study also suggested a positive effect of rTMS on quality of life The influence of repetitive transcranial magnetic stimulation ( rTMS ) on mood in healthy people is uncertain , as former studies show divergent results . Previous studies in healthy volunteers focused exclusively on the immediate effect of a single session of rTMS . In contrast the aim of this r and omised sham-controlled study was to analyse the influence on mood of a series of 9 High Frequency ( HF ) rTMS stimulations of the left dorsolateral prefrontal cortex ( DLPFC ) . 44 young healthy male volunteers were r and omly assigned to receive 9 sessions of active HF-rTMS ( n = 22 ) or sham rTMS ( n = 22 ) over the left DLPFC . Each session in the active group consisted of 15 trains of 25 Hz starting with 100 % of motor threshold . Sham stimulation was performed following the same protocol , but using a sham coil . The variables of interest were the Beck Depression Inventory ( BDI ) and six Visual Analogue Scales ( VAS ) which quantified " mood " , " enjoyment " and " energy " . We found a significant reduction of the BDI sum score in the active group ( GLM , p < 0.001 ) whereas no significant changes of the BDI sum score were caused by sham stimulation ( GLM , p = 0.109 ) . The BDI single item analyses revealed within and between group differences supporting the modifying effect of rTMS on BDI . According to the employed VAS we did not find significant differences caused by active or sham stimulation in five of six VAS . In the VAS labelled lively/gloomy the active group was found to be more " gloomy " ( p = 0.0111 ) immediately after stimulation . Our data show that a 9-day long series of HF-rTMS of the left DLPFC improves mood , analysed by BDI in healthy young men , whereas no significant long-term changes were found in VAS This double-blind study sought to discover if cranial electrotherapy stimulation ( CES ) , which is a known treatment of depression , anxiety and insomnia in non-head-injured patients , could be an effective , drug-free treatment of stress-related symptoms in the closed-head-injured ( CHI ) patient . In this study 10 CHI patients treated for 45 min daily , 4 days a week for 3 weeks , responded significantly on all negative mood factors of the Profile Of Mood States , while five sham-treated and six placebo controls did not . While the majority of the patients were known seizure cases , no patient suffered a seizure during CES therapy . No placebo effects were found , nor were any negative effects from CES treatment seen PURPOSE This study was design ed to evaluate the therapeutic effect of low-frequency repetitive transcranial magnetic stimulation ( rTMS ) on patients with refractory partial epilepsy . METHODS Sixty-four patients with refractory focal epilepsy were screened and 60 patients were r and omly divided into two groups by stimulation intensity : 90 % ( group 1 ) or 20 % ( group 2 ) of resting motor threshold ( rMT ) . Seizure frequency and interictal EEG epileptic discharges were compared between the baseline and follow-up periods . KEY FINDINGS Seizures significantly decreased following 2-weeks high intensity ( 90 % rMT ) rTMS treatment compared with baseline level ( p < 0.05 ) . rTMS also decreased interictal epilepsy discharges and improved the scales of Symptom Checklist-90 significantly ( p < 0.05 ) . Seizures and spikes in the follow-up period in the patients who received low intensity ( 20 % rMT ) rTMS did not show any difference compared with baseline data ( p > 0.05 , respectively ) . SIGNIFICANCE Low-frequency high intensity rTMS ( 90 % rMT ) delivered into the epileptogenic zone had a significant antiepileptic effect on patients with refractory partial seizures . rTMS treatment can also reduce the interictal epileptic discharge frequency and improve the psychological condition of these patients BACKGROUND High Frequency repetitive Transcranial Magnetic Stimulation ( HF-rTMS ) is currently used as an experimental tool to induce mood changes in normal volunteers and as a treatment option for depression . However , HF-rTMS , mostly performed on the left dorsolateral prefrontal cortex ( DLPFC ) , has yielded divergent results and effects on mood which seem to be oppositely lateralized between these two groups . The inconsistent results that have been reported might be explained by method ological heterogeneity and drawbacks . METHODS In this sham-controlled , single blind , crossover study , we tried to reproduce previous HF-rTMS findings of a negative mood induction in 28 healthy female subjects . To exclude individual anatomical differences , the left DLPFC was localised under magnetic resonance guidance ( MRI ) . Mood assessment was performed before and just after HF-rTMS with Visual Analogue Scales and the Profile of Mood States . To detect possible delayed mood changes , ratings were also performed 30 min post HF-rTMS . RESULTS We were unable to demonstrate significant mood changes from baseline after one single active HF-rTMS session on the left DLPFC . CONCLUSIONS Although this study controlled for several method ological problems , the hypothesis that one single session of HF-rTMS on the left DLPFC has negative mood effects in healthy female volunteers was not supported Although prefrontal brain impairments are one of the best-replicated brain imaging findings in relation to aggression , little is known about the causal role of this brain region . This study tests whether stimulating the dorsolateral prefrontal cortex using transcranial direct current stimulation ( tDCS ) reduces the likelihood of engaging in aggressive acts , and the mechanism underlying this relationship . In a double-blind , stratified , placebo-controlled , parallel-group , r and omized trial , 81 human adults ( 36 males , 45 females ) were r and omly assigned to an active ( N = 39 ) or placebo ( N = 42 ) condition , and then followed up 1 d after the experiment session . Intentions to commit aggressive acts and behavioral aggression were assessed using hypothetical vignettes and a behavioral task , respectively . The secondary outcome was the perception of the moral wrongfulness of the aggressive acts . Compared with the sham controls , participants who received anodal stimulation reported being less likely to commit physical and sexual assault ( p < 0.01 ) . They also judged aggressive acts as more morally wrong ( p < 0.05 ) . Perceptions of greater moral wrongfulness regarding the aggressive acts accounted for 31 % of the total effect of tDCS on intentions to commit aggression . Results provide experimental evidence that increasing activity in the prefrontal cortex can reduce intentions to commit aggression and enhance perceptions of the moral wrongfulness of the aggressive acts . Findings shed light on the biological underpinnings of aggression and theoretically have the potential to inform future interventions for aggression and violence . SIGNIFICANCE STATEMENT Aggressive behaviors pose significant public health risks . Underst and ing the etiology of aggression is paramount to violence reduction . Investigations of the neural basis of aggression have largely supported correlational , rather than causal , interpretations , and the mediating processes underlying the prefrontal – aggression relationship remain to be well eluci date d. Through a double-blind , stratified , placebo-controlled , parallel-group , r and omized trial , this study tested whether upregulation of the prefrontal cortex reduces the likelihood of engaging in aggression . Results provide experimental evidence that increasing prefrontal cortical activity can reduce intent to commit aggressive acts . They also shed light on moral judgment as one mechanism that may link prefrontal deficits to aggression and , in theory , have the potential to inform future approaches toward reducing aggression The mechanisms by which transcranial direct current stimulation ( tDCS ) influences emotional processing - and whether this is related to individual vulnerability for psychopathology - are still poorly understood . The present study aim ed to investigate if one prefrontal tDCS session modulates mood and neural functional connectivity after being exposed to negative information differently in individuals low or high in perceived criticism ( PC ) , which has been related to vulnerability for psychiatric illness . In a r and omized cross-over design , one session of MRI-compatible prefrontal tDCS ( neuronavigated placement of the anodal electrode at the left dorsolateral prefrontal cortex and the cathodal electrode at the right supraorbital region ; vs. sham ) was administered to healthy females , prior to listening to self-referential criticism . PC-dependent ( low vs. high PC ) changes in mood and resting-state functional connectivity patterns following tDCS and after hearing criticism were explored . After being criticized all females ( low and high PC ) felt angrier and more depressed , both in the active tDCS or sham tDCS condition . However , in contrast to low PC females , in high PC females prefrontal tDCS reduced connectivity between the left dorsal anterior cingulate cortex and the right dorsomedial prefrontal cortex following criticism . Despite having no differential effects on self-reported mood , prefrontal tDCS reduces medial prefrontal neural connectivity after being criticized in high PC females compared to low PC females . Depending on individual vulnerability for psychopathology , a single tDCS session differentially affects neural processing of negative emotional information , especially in brain regions involved in monitoring , experiencing and appraising/evaluating emotional material Transcranial static magnetic field stimulation ( tSMS ) is a novel non-invasive brain stimulation technique that has been shown to locally increase alpha power in the parietal and occipital cortex . We investigated if tSMS locally increased alpha power in the left or right prefrontal cortex , as the balance of left/right prefrontal alpha power ( frontal alpha asymmetry ) has been linked to emotional processing and mood disorders . Therefore , altering frontal alpha asymmetry with tSMS may serve as a novel treatment to psychiatric diseases . We performed a crossover , double-blind , sham-controlled pilot study to assess the effects of prefrontal tSMS on neural oscillations . Twenty-four right-h and ed healthy participants were recruited and received left dorsolateral prefrontal cortex ( DLPFC ) tSMS , right DLPFC tSMS , and sham tSMS in a r and omized order . Electroencephalography data were collected before ( 2 min eyes-closed , 2 min eyes-open ) , during ( 10 min eyes-open ) , and after ( 2 min eyes-open ) stimulation . In contrast with our hypothesis , neither left nor right tSMS locally increased frontal alpha power . However , alpha power increased in occipital cortex during left DLPFC tSMS . Right DLPFC tSMS increased post-stimulation fronto-parietal theta power , indicating possible relevance to memory and cognition . Left and right DLPFC tSMS increased post-stimulation left hemisphere beta power , indicating possible changes to motor behavior . Left DLPFC tSMS also increased post-stimulation right frontal beta power , demonstrating complex network effects that may be relevant to aggressive behavior . We concluded that DLPFC tSMS modulated the network oscillations in regions distant from the location of stimulation and that tSMS has region specific effects on neural oscillations Reduced activity of the frontal lobes , and particularly of the prefrontal cortex , has been related with violent behavior , aggression and crime . The causal importance of prefrontal cortex activity for aggressive behaviors and the self-perception of aggressiveness needs however to be clarified . The aim of this study was to explore the effect of an anodal transcranial direct current stimulation protocol ( tDCS , 1.5 mA , 15 min ) , which , according to previous studies , enhances cortical excitability , applied bilaterally over the prefrontal cortex on self-reported aggressiveness . Two imprisoned violent offender cohorts , discerned by the degree of aggressiveness ( murderers vs. non-murderers ) , were included in this single-blind sham-controlled study . Self-reported aggressiveness was recorded before and after 3 tDCS sessions ( one session per day ) . Four dimensions of aggression were evaluated by means of the st and ardized Buss-Perry Aggression Question naire ( BAQ ) . In both inmate groups the results revealed an aggression-reducing effect of tDCS on the Physical aggression , Anger , and Verbal aggression dimensions of the BAQ . In the Hostility dimension , tDCS significantly reduced aggression only in the group of murderers . These results suggest that modulation of prefrontal cortex excitability by 3 consecutive sessions of tDCS reduces self-reported aggressiveness similarly in murderer and non-murderer sample BACKGROUND The prefrontal cortex is crucial for top-down regulation of aggression , but the neural underpinnings of aggression are still poorly understood . Past research showed the transcranial direct current stimulation ( tDCS ) over the ventrolateral prefrontal cortex ( VLPFC ) modulates aggression following exposure to risk factors for aggression ( e.g. , social exclusion , violent media ) . Although frustration is a key risk factor for aggression , no study to date has examined the modulatory role of tDCS on frustration-induced aggression . OBJECTIVES By exploring the VLPFC involvement in frustration-aggression link , we tested the hypothesis that the anodal tDCS over right and left VLPFC modulates frustration-induced aggression . We also explored whether tDCS interacts with gender to influence frustration-induced aggression . METHODS 90 healthy participants ( 45 men ) were r and omly assigned to receive anodal or sham tDCS over the right or left VLPFC before being frustrated by an accomplice . To increase reliability , several tasks were used to measure aggression . RESULTS We found that anodal tDCS over the left VLPFC , compared to sham stimulation , increased aggression . Unexpectedly , no main effect was found following tDCS of right VLPFC . However , we also found a significant interaction between gender and tDCS , showing that males were more aggressive than females following sham stimulation , but females became as aggressive as males following active tDCS . CONCLUSION Overall , these results shed light on the neural basis of frustration-induced aggression , providing further evidence for the involvement of VLPFC in modulating aggressive responses , and on gender differences in aggression . Future research should further investigate the role of stimulating the VLPFC on frustration-induced aggression

EEN reduced infectious complications in unselected critically ill patients , in patients with severe acute pancreatitis , and after GI surgery . We did not detect any evidence of superiority for early PN or delayed EN over EEN . Conclusions We suggest using EEN in the majority of critically ill under certain pre caution s. In the absence of evidence , we suggest delaying EN in critically ill patients with uncontrolled shock , uncontrolled hypoxaemia and acidosis , uncontrolled upper GI bleeding , gastric aspirate > 500 ml/6 h , bowel ischaemia , bowel obstruction , abdominal compartment syndrome , and high-output fistula without distal feeding access

Purpose To provide evidence -based guidelines for early enteral nutrition ( EEN ) during critical illness . Methods We aim ed to compare EEN vs. early parenteral nutrition ( PN ) and vs. delayed EN .

Introduction Early protein and energy feeding in critically ill patients is heavily debated and early protein feeding hardly studied . Methods A prospect i ve data base with mixed medical-surgical critically ill patients with prolonged mechanical ventilation ( > 72 hours ) and measured energy expenditure was used in this study . Logistic regression analysis was used to analyse the relation between admission day-4 protein intake group ( with cutoffs 0.8 , 1.0 , and 1.2 g/kg ) , energy overfeeding ( ratio energy intake/measured energy expenditure > 1.1 ) , and admission diagnosis of sepsis with hospital mortality after adjustment for APACHE II ( Acute Physiology and Chronic Health Evaluation II ) score . Results A total of 843 patients were included . Of these , 117 had sepsis . Of the 736 non-septic patients 307 were overfed . Mean day-4 protein intake was 1.0 g/kg pre-admission weight per day and hospital mortality was 36 % . In the total cohort , day-4 protein intake group ( odds ratio ( OR ) 0.85 ; 95 % confidence interval ( CI ) 0.73 to 0.99 ; P = 0.047 ) , energy overfeeding ( OR 1.62 ; 95%CI 1.07 to 2.44 ; P = 0.022 ) , and sepsis ( OR 1.77 ; 95%CI 1.18 to 2.65 ; P = 0.005 ) were independent risk factors for mortality besides APACHE II score . In patients with sepsis or energy overfeeding , day-4 protein intake was not associated with mortality . For non-septic , non-overfed patients ( n = 419 ) , mortality decreased with higher protein intake group : 37 % for < 0.8 g/kg , 35 % for 0.8 to 1.0 g/kg , 27 % for 1.0 to 1.2 g/kg , and 19 % for ≥1.2 g/kg ( P = 0.033 ) . For these , a protein intake level of ≥1.2 g/kg was significantly associated with lower mortality ( OR 0.42 , 95%CI 0.21 to 0.83 , P = 0.013 ) . Conclusions In non-septic critically ill patients , early high protein intake was associated with lower mortality and early energy overfeeding with higher mortality . In septic patients early high protein intake had no beneficial effect on mortality OBJECTIVES To describe current enteral nutrition-prescribing practice s for critically ill patients , and to identify factors associated with initiation of , and tolerance to , enteral nutrition . DESIGN A prospect i ve , cohort study . SETTING Two tertiary care medical-surgical intensive care units ( ICU ) in Ontario , Canada . PATIENTS We enrolled 99 consecutive patients who were expected to stay in the ICU for > 3 days and who were unable to tolerate oral nutrition . We followed patients for 21 days or until they tolerated enteral nutrition , tolerated oral nutrition , were discharged from the ICU , or died . MEASUREMENTS AND MAIN RESULTS We recorded time elapsed from ICU admission to initiation and tolerance of enteral feedings , and examined factors associated with these events . We defined tolerance as receiving 90 % of estimated daily energy requirements for > 48 hrs without gastrointestinal dysfunction ( i.e. , high gastric residuals , vomiting , diarrhea , abdominal distention ) . Seventy-three ( 74 % ) of 99 patients were started on enteral feedings an average 3.1 days ( range 1 to 18 ) after ICU admission . Of 26 patients never started on enteral nutrition , three ( 12.5 % ) patients eventually tolerated oral nutrition , 14 ( 54.0 % ) patients were discharged from the ICU , and seven ( 27.0 % ) patients died . Reasons for not initiating enteral nutrition included absence of bowel sounds ( 27.0 % ) , high nasogastric drainage ( 16.9 % ) , contraindication to enteral nutrition ( 16.7 % ) , tolerance of oral nutrition ( 6.8 % ) , and no apparent reason ( 5.1 % ) . Abdominal surgery , use of vasoactive drugs , and admission to one hospital made initiation of enteral nutrition less likely , whereas presence of bowel sounds and admission to the other hospital made initiation of enteral nutrition more likely . Thirty-five ( 42.9 % ) of 73 patients started on enteral nutrition achieved tolerance of the regimen . The average time from ICU admission to tolerance of feedings was 5.8 days ( range 1 to 14 ) . Once started on enteral nutrition , the most common reasons for decreasing or discontinuing feedings included high gastric residuals ( 51.0 % ) , mechanical feeding tube problems ( 15.4 % ) , medical or surgical procedures ( 5.4 % ) , and vomiting ( 5.1 % ) . Use of paralytic agents and the presence of high gastric residuals were associated with intolerance . Of 38 patients who did not achieve tolerance , 20 ( 52.6 % ) patients were discharged from the ICU , eight ( 21.0 % ) patients died , and eight ( 21.0 % ) patients eventually tolerated oral nutrition . CONCLUSIONS Enteral nutrition is not started in all eligible ICU patients . Approximately half of those patients receiving enteral nutrition achieved tolerance of the regimen . Gastrointestinal dysfunction causing intolerance to enteral nutrition is a common reason for not starting , or discontinuing , feedings BACKGROUND Our goal is to define nutrition therapy in critically ill patients after surgical repair of acute ruptured or dissecting aortic aneurysm to identify opportunities for quality improvement . METHODS International , prospect i ve studies in 2007 - 2009 and 2011 were combined . Sites provided institutional and patient characteristics including from intensive care units ( ICUs ) admission to ICU discharge for a maximum of 12 days . We selected patients with aortic aneurysmal rupture or acute dissection staying in the ICU for ≥ 3 days . RESULTS There were 104 eligible patients from 72 distinct ICUs analyzed . Overall , 86.5 % received artificial nutrition . There were 50.0 % patients who received enteral nutrition ( EN ) only , 29.8 % patients received a combination of EN and parenteral nutrition ( PN ) , 6.7 % patients received PN only , and 13.5 % did not receive any nutrition . The mean time from admission to initiation of EN was 3.0 days ( SD ± 2.4 days ) . The adequacy of calories from nutrition support was 46.8 % ( range 0%-111 % ) with a mean of 10.0 kcal/kg/day . Of the total of 83 patients who received EN , 53 patients ( 63.8 % ) had interruption of EN . The reasons included fasting , intolerance , patients deemed too sick for enteral feeding , and loss of enteral feeding route . For patients with gastrointestinal intolerance , 3/30 patients ( 10 % ) received small bowel feeding and 23/30 patients ( 76.7 % ) of patients received motility agents . CONCLUSION Postoperative critically ill patients with aortic aneurysmal rupture or acute dissection are at high risk for inadequate nutrition therapy , and there may be inadequate utilization of strategies to improve nutrition uptake BACKGROUND The open abdomen is a requisite component of a damage control operation and treatment of abdominal compartment syndrome . Enteral nutrition ( EN ) has proven beneficial for patients with critical injury , but its application in those with an open abdomen has not been defined . The purpose of this study was to analyze the use of EN for patients with an open abdomen after trauma and the effect of EN on fascial closure rates and nosocomial infections . METHODS We review ed patients with an open abdomen after injury from January 2002 to January 2009 from 11 trauma centers . RESULTS During the 7-year study period , 597 patients required an open abdomen after trauma . Most were men ( 77 % ) sustaining blunt trauma ( 72 % ) , with a mean ( SD ) age of 38 ( 0.7 ) years , an Injury Severity Score of 31 ( 0.6 ) , an abdominal injury score of 3.8 ( 0.1 ) , and an Abdominal Trauma Index score of 26.8 ( 0.6 ) . Of the patients , 548 ( 92 % ) had an open abdomen after a damage control operation , whereas the remainder experienced an abdominal compartment syndrome . Of the 597 patients , 230 ( 39 % ) received EN initiated before the closure of the abdomen at mean ( SD ) day 3.6 ( 1.2 ) after injury . EN was started with an open abdomen in one quarter of the 290 patients with bowel injuries . For the 307 patients without a bowel injury , logistic regression indicated that EN is associated with higher fascial closure rates ( odds ratio [ OR ] , 5.3 ; p < 0.01 ) , decreased complication rates ( OR , 0.46 ; p = 0.02 ) , and decreased mortality ( OR , 0.30 ; p = 0.01 ) . For the 290 patients who experienced a bowel injury , regression analysis showed no significant association between EN and fascial closure rate ( OR , 0.6 ; p = 0.2 ) , complication rate ( OR , 1.7 ; p = 0.19 ) , or mortality ( OR , 0.79 ; p = 0.69 ) . CONCLUSION EN in the open abdomen after injury is feasible . For patients without a bowel injury , EN in the open abdomen is associated with increased fascial closure rates , decreased complication rates , and decreased mortality . EN should be initiated in these patients once resuscitation is completed . Although EN for patients with bowel injuries did not seem to affect the outcome in this study , prospect i ve r and omized controlled trials would further clarify the role of EN in this subgroup . LEVEL OF EVIDENCE Therapeutic study , level III BACKGROUND The purpose of this study was to determine the effects of early postoperative tube feeding on outcomes of liver transplant recipients . METHODS Fifty transplant patients were r and omized prospect ively to receive enteral formula via nasointestinal feeding tubes ( tube-feeding [ TF ] group ) or maintenance i.v . fluid until oral diets were initiated ( control group ) . Thirty-one patients completed the study . Resting energy expenditure , nitrogen balance , and grip strength were measured on days 2 , 4 , 7 , and 12 after liver transplantation . Calorie and protein intakes were calculated for 12 days posttransplant . RESULTS Tube feeding was tolerated in the TF group ( n = 14 ) . The TF patients had greater cumulative 12-day nutrient intakes ( 22,464 + /- 3554 kcal , 927 + /- 122 g protein ) than did the control patients ( 15,474 + /- 5265 kcal , 637 + /- 248 g protein ) ( p < .002 ) . Nitrogen balance was better in the TF group on posttransplant day 4 than in the control group ( p < .03 ) . There was a rise in the overall mean resting energy expenditure in the first two posttransplant weeks from 1487 + /- 338 to 1990 + /- 367 kcal ( p = .0002 ) . Viral infections occurred in 17.7 % of control patients compared with 0 % of TF patients ( p = .05 ) . Although other infections tended to occur more frequently in the control group vs the TF group ( bacterial , 29.4 % vs 14.3 % ; overall infections , 47.1 % vs 21.4 % ) , these differences were not statistically significant . Early posttransplant tube feeding did not influence hospitalization costs , hours on the ventilator , lengths of stay in the intensive care unit and hospital , rehospitalizations , or rejection during the first 21 posttransplant days . CONCLUSIONS Early posttransplant tube feeding was tolerated and promoted improvements in some outcomes and should be considered for all liver transplant patients This document represents the first collaboration between 2 organizations — the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine — to describe best practice s in nutrition therapy in critically ill children . The target of these guidelines is intended to be the pediatric critically ill patient ( > 1 month and 2–3 days in a PICU admitting medical , surgical , and cardiac patients . In total , 2032 citations were scanned for relevance . The PubMed / MEDLINE search result ed in 960 citations for clinical trials and 925 citations for cohort studies . The EMBASE search for clinical trials culled 1661 citations . In total , the search for clinical trials yielded 1107 citations , whereas the cohort search yielded 925 . After careful review , 16 r and omized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline . We used the GRADE criteria ( Grading of Recommendations , Assessment , IMPORTANCE Monitoring of residual gastric volume is recommended to prevent ventilator-associated pneumonia ( VAP ) in patients receiving early enteral nutrition . However , studies have challenged the reliability and effectiveness of this measure . OBJECTIVE To test the hypothesis that the risk of VAP is not increased when residual gastric volume is not monitored compared with routine residual gastric volume monitoring in patients receiving invasive mechanical ventilation and early enteral nutrition . DESIGN , SETTING , AND PATIENTS R and omized , noninferiority , open-label , multicenter trial conducted from May 2010 through March 2011 in adults requiring invasive mechanical ventilation for more than 2 days and given enteral nutrition within 36 hours after intubation at 9 French intensive care units ( ICUs ) ; 452 patients were r and omized and 449 included in the intention-to-treat analysis ( 3 withdrew initial consent ) . INTERVENTION Absence of residual gastric volume monitoring . Intolerance to enteral nutrition was based only on regurgitation and vomiting in the intervention group and based on residual gastric volume greater than 250 mL at any of the 6 hourly measurements and regurgitation or vomiting in the control group . MAIN OUTCOME MEASURES Proportion of patients with at least 1 VAP episode within 90 days after r and omization , as assessed by an adjudication committee blinded to patient group . The prestated noninferiority margin was 10 % . RESULTS In the intention-to-treat population , VAP occurred in 38 of 227 patients ( 16.7 % ) in the intervention group and in 35 of 222 patients ( 15.8 % ) in the control group ( difference , 0.9 % ; 90 % CI , -4.8 % to 6.7 % ) . There were no significant between-group differences in other ICU-acquired infections , mechanical ventilation duration , ICU stay length , or mortality rates . The proportion of patients receiving 100 % of their calorie goal was higher in the intervention group ( odds ratio , 1.77 ; 90 % CI , 1.25 - 2.51 ; P = .008 ) . Similar results were obtained in the per- protocol population . CONCLUSION AND RELEVANCE Among adults requiring mechanical ventilation and receiving early enteral nutrition , the absence of gastric volume monitoring was not inferior to routine residual gastric volume monitoring in terms of development of VAP . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01137487 Introduction Prone position is effective in mechanically ventilated patients to improve oxygenation . It is unknown if prone position affects gastric emptying and the ability of continued enteral feeding . Aim To determine tolerance of enteral feeding by measuring gastric residual volumes in enterally fed patients during supine and prone positions . Methods Consecutive mechanically ventilated intensive care patients who were turned to prone position were included . All patients were studied for 6 hours in supine position , immediately followed by 6 hours in prone position , or visa versa . The rate of feeding was unchanged during the study period . Gastric residual volume was measured by suctioning the naso-gastric tube after 3 and 6 hours in the same position . Wilcoxon test and regression analysis were used for analysis . Results The median volume of administered enteral feeds was 95 ml after 6 hours in supine position and 110 ml after 6 hours in prone position ( P = 0.85 ) . In 10 patients , a greater gastric residual volume was found in prone position . In eight others a greater volume was found in supine position . In 18 of 19 patients , gastric residual volumes in both positions were ≥ 150 ml in 6 hours or ≤ 150 ml in 6 hours . Significantly more sedatives were used in prone position . Regression analysis excluded dopamine dose and the starting position as confounders . Conclusion Our results suggest that enteral feeding can be continued when a patient is turned from supine to prone position or vice versa . The results indicate that patients with a clinical ly significant gastric residual volume in one position are likely to have a clinical ly significant gastric residual volume in the other position Introduction Diarrhoea is frequently reported in the ICU . Little is known about diarrhoea incidence and the role of the different risk factors alone or in combination . This prospect i ve observational study aims at determining diarrhoea incidence and risk factors in the first 2 weeks of ICU stay , focusing on the respective contribution of feeding , antibiotics , and antifungal drugs . Methods Out of 422 patients consecutively admitted into a mixed medical – surgical ICU during a 2-month period , 278 patients were included according to the following criteria : ICU stay > 24 hours , no admission diagnosis of gastrointestinal bleeding , and absence of enterostomy or colostomy . Diarrhoea was defined as at least three liquid stools per day . Diarrhoea episodes occurring during the first day in the ICU , related to the use of laxative drugs or Clostridium difficile infection , were not analysed . Multivariate and stratified analyses were performed to determine diarrhoea risk factors , and the impact of the combination of enteral nutrition ( EN ) with antibiotics or antifungal drugs . Results A total of 1,595 patient-days were analysed . Diarrhoea was observed in 38 patients ( 14 % ) and on 83 patient-days ( incidence rate : 5.2 per 100 patient-days ) . The median day of diarrhoea onset was the sixth day , and 89 % of patients had ≤4 diarrhoea days . The incidence of C. difficile infection was 0.7 % . Diarrhoea risk factors were EN covering > 60 % of energy target ( relative risk = 1.75 ( 1.02 to 3.01 ) ) , antibiotics ( relative risk = 3.64 ( 1.26 to 10.51 ) ) and antifungal drugs ( relative risk = 2.79 ( 1.16 to 6.70 ) ) . EN delivery per se was not a diarrhoea risk factor . In patients receiving > 60 % of energy target by EN , diarrhoea risk was increased by the presence of antibiotics ( relative risk = 4.8 ( 2.1 to 13.7 ) ) or antifungal drugs ( relative risk = 5.0 ( 2.8 to 8.7 ) ) . Conclusion Diarrhoea incidence during the first 2 weeks in a mixed population of patients in a tertiary ICU is 14 % . Diarrhoea risk factors are EN covering > 60 % of energy target , use of antibiotics , and use of antifungal drugs . The combination of EN covering > 60 % of energy target with antibiotics or antifungal drugs increases the incidence of diarrhoea INTRODUCTION Enteral nutrition within 48 hours of intensive care unit ( ICU ) admission is recommended for the ICU population . Major vascular surgery patients have a higher incidence of pre- and postoperative malnutrition compared with the general surgical population . Our objectives were to determine if early feeding ( within 48 hours of admission ) is achievable and well tolerated , identify factors that predict early feeding , and determine if there is an association between early feeding and in-hospital mortality among abdominal aortic aneurysm ( AAA ) repair patients . METHODS A retrospective cohort study was conducted among 145 postsurgical AAA repair patients admitted to the ICU within 48 hours of surgery . Kaplan-Meier methods and Cox proportional hazard multiple regression were used to analyze the data . RESULTS Only 35 ( 24 % ) patients received early feeding . Patients were more likely to be fed early if they were male ( adjusted hazard ratio [ aHR ] = 2.3 ; 95 % confidence interval [ CI ] , 0.8 - 6.7 ; P = .13 ) , had endovascular AAA repair ( aHR = 2.9 ; 95 % CI , 1.4 - 6.2 ; P = .006 ) , had less blood loss ( < 4 L ) during surgery ( aHR = 2.3 ; 95 % CI , 0.7 - 7.2 ; P = .14 ) , and had shorter length of ventilation ( < 48 hours ) ( aHR = 2.2 ; 95 % CI , 1.1 - 4.8 ; P = .048 ) . Of 44 patients fed via enteral nutrition ( EN ) , 27 ( 61 % ) achieved nutrition adequacy ( > 80 % EN goal ) during ICU admission . After controlling for other factors , 14-day mortality was not related to feeding time ( aHR = 1.1 ; P = .88 ) . CONCLUSION Early feeding was achieved in a minority of patients following AAA repair , was related to type of surgery and duration of mechanical ventilation , and was tolerated as well as later introduced feedings . R and omized trials are needed to determine safety and benefits of early feeding in this patient group Objective To assess the tolerance of early enteral nutrition in critically ill patients receiving invasive mechanical ventilation in the prone position . Design Prospect i ve , comparative study . Setting General intensive care unit in a university-affiliated hospital . Patients A total of 71 consecutive patients receiving invasive mechanical ventilation with early nasogastric enteral nutrition were studied for 5 days while being treated continuously in the supine position ( supine position group , n = 37 ) or with intermittent prone positioning for severe hypoxemia ( prone position group , n = 34 ) . Interventions Inclusion occurred within 24 hrs of mechanical ventilation initiation . Daily 18-hr enteral nutrition via a 14F gastric tube was initiated . Prone position patients were turned every 6 hrs as long as Pao2/Fio2 remained at < 150 , with a Fio2 of 0.6 and positive end-expiratory pressure of 10 ; the head was slightly elevated . When supine , patients in both groups were semirecumbent . Residual gastric volume was measured every 6 hrs , and enteral nutrition was discontinued if it exceeded 250 mL or vomiting occurred . Measurements and Main Results The groups were similar for age , sex , Simplified Acute Physiology Score II , mortality , and risk factors for enteral nutrition intolerance . At baseline , Pao2/Fio2 was lower in prone position patients than in supine position patients ( 127 ± 55 vs. 228 ± 102 ; p < .001 ) . As compared with supine position patients , prone position patients had significantly greater residual gastric volumes on days 1 , 2 , and 4 and experienced more vomiting episodes ( median , 1 [ interquartile range , 0–2 ] vs. 0 [ interquartile range , 0–1 ] ; p < .05 ) . Enteral nutrition was stopped in 82 % of prone position patients and 49 % of supine position patients ( p < .01 ) so that daily enteral nutrition volumes were lower with prone position patients . In the prone position group , vomiting occurred more frequently in the prone than in the supine position ( relative risk , 2.5 ; 95 % confidence interval , 1.5–4.0 ; p < .001 ) . Conclusion In critically ill patients receiving invasive mechanical ventilation in the prone position , early enteral nutrition is poorly tolerated . Prokinetic agents or transpyloric feeding and semirecumbency should be considered to enhance gastric emptying and to prevent vomiting in patients receiving mechanical ventilation in the prone position Background : Gastrointestinal ( GI ) problems are not uniformly assessed in intensive care unit ( ICU ) patients and respective data in available literature are insufficient . We aim ed to describe the prevalence , risk factors and importance of different GI symptoms BACKGROUND Undernutrition is common in patients admitted with stroke . We aim ed to establish whether the timing and route of enteral tube feeding after stroke affected patients ' outcomes at 6 months . METHODS The FOOD trials consist of three pragmatic multicentre r and omised controlled trials , two of which included dysphagic stroke patients . In one trial , patients enrolled within 7 days of admission were r and omly allocated to early enteral tube feeding or no tube feeding for more than 7 days ( early versus avoid ) . In the other , patients were allocated percutaneous endoscopic gastrostomy ( PEG ) or nasogastric feeding . The primary outcome was death or poor outcome at 6 months . Analysis was by intention to treat . FINDINGS Between Nov 1 , 1996 , and July 31 , 2003 , 859 patients were enrolled by 83 hospitals in 15 countries into the early versus avoid trial . Early tube feeding was associated with an absolute reduction in risk of death of 5.8 % ( 95 % CI -0.8 to 12.5 , p=0.09 ) and a reduction in death or poor outcome of 1.2 % ( -4.2 to 6.6 , p=0.7 ) . In the PEG versus nasogastric tube trial , 321 patients were enrolled by 47 hospitals in 11 countries . PEG feeding was associated with an absolute increase in risk of death of 1.0 % ( -10.0 to 11.9 , p=0.9 ) and an increased risk of death or poor outcome of 7.8 % ( 0.0 to 15.5 , p=0.05 ) . INTERPRETATION Early tube feeding might reduce case fatality , but at the expense of increasing the proportion surviving with poor outcome . Our data do not support a policy of early initiation of PEG feeding in dysphagic stroke patients Introduction Glucagon-like peptide-1 ( GLP-1 ) originates from the gastrointestinal system in response to the presence of nutrition in the intestinal lumen and potentiates postpr and ial insulin secretion . Also , it acts as an immune-modulator which has influences on cell-mediated immunity . The aim of this study was to determine the impact of early enteral nutrition versus late enteral nutrition on plasma GLP-1 levels and the relationship between GLP-1 changes and cell-mediated immunity . Material s and methods The study was design ed as a prospect i ve , single-blinded study and carried out in the neurology intensive care unit ( ICU ) of a university hospital . Twenty-four naive patients with acute thromboembolic cerebrovascular events , with National Institute of Health ( NIH ) stroke scores between 12 and 16 , were included . Any condition interfering with GLP-1 and immunity was regarded as exclusion criterion . Two patients died , and two dropped out of the study due to complicating conditions . Patients were r and omly subjected to early enteral feeding within the first 24 hours ( Group 1 ) , or late enteral feeding , beginning 48 hours after admission ( Group 2 ) via a nasogastric tube . Calculated daily energy requirement was supplemented with parenteral nutrition , starting on the first study day for both groups . Blood sample s were obtained before , and at 5 , 15 , 30 , 60 and 120 minutes after the first enteral feeding for GLP-1 assays ; this procedure was repeated on the third day . Before and 24 hours after the first enteral feeding , sample s were also taken for immunological analysis . Clinical observations were recorded . Pre- and post-feeding plasma GLP-1 changes between the two groups and within groups were evaluated . Lymphocyte subgroup changes before and 24 hours after the first enteral feeding in relation to GLP-1 changes were sought as well . Results Group 1 and Group 2 exhibited similar GLP-1 levels in the pre-feeding and post-feeding periods for both the first time and the third day of enteral feeding . Also , no significant change in pre-/post-feeding GLP-1 levels was observed within groups . T-helper and T-regulatory cells increased , T-cytotoxic cells decreased significantly in Group 1 ( P = 0.02 ; P = 0.036 ; P = 0.0019 ) , but remained the same in Group 2 after enteral feeding . Positive but statistically insignificant clinical effects in terms of predisposition to infections ( 10 % vs 40 % ) and median time of ICU stay ( 10 vs 15 days ) were observed in Group 1 . Conclusions Depending on our findings , we propose that early enteral feeding may cause amelioration in cell-mediated immunity via factors other than GLP-1 in ICU patients with acute thromboembolic stroke . However , the possible deleterious effects of parenteral nutrition can not be ruled out Objective To evaluate the effect of initial low energy permissive underfeeding ( “ trophic feeding ” ) versus full energy enteral feeding ( “ full feeding ” ) on physical function and secondary outcomes in patients with acute lung injury . Design Prospect i ve longitudinal follow-up evaluation of the NHLBI ARDS Clinical Trials Network ’s EDEN trial Setting 41hospitals in the United States . Participants 525 patients with acute lung injury . Interventions R and omised assignment to trophic or full feeding for up to six days ; thereafter , all patients still receiving mechanical ventilation received full feeding . Measurements Blinded assessment of the age and sex adjusted physical function domain of the SF-36 instrument at 12 months after acute lung injury . Secondary outcome measures included survival ; physical , psychological , and cognitive functioning ; quality of life ; and employment status at six and 12 months . Results After acute lung injury , patients had substantial physical , psychological , and cognitive impairments , reduced quality of life , and impaired return to work . Initial trophic versus full feeding did not affect mean SF-36 physical function at 12 months ( 55 ( SD 33 ) v 55 ( 31 ) , P=0.54 ) , survival to 12 months ( 65 % v 63 % , P=0.63 ) , or nearly all of the secondary outcomes . Conclusion In survivors of acute lung injury , there was no difference in physical function , survival , or multiple secondary outcomes at 6 and 12 month follow-up after initial trophic or full enteral feeding . Trial Registration NCT No UNLABELLED The aim of the present study was the comparison of calculated and measured values of the energy expenditure of critically ill patients during the different phases of therapeutic mild hypothermia . PATIENTS AND METHODS Five patients ( mean age 40.6 years , range 23 to 68 years , 2 females ) suffering from severe acute cerebral injuries who underwent mild hypothermia were prospect ively included into the study . Indirect calorimetry measurements were made at intervals of 3 - 4 hours and subsequently , during the steady state , at least every 12 hours . The results were compared with the basal metabolic rate calculated by the Harris-Benedict equation . RESULTS A close linear correlation between body temperature and basal metabolism could be observed across a wide range of temperatures from 30.5 degrees C to 38.3 degrees C ( r=0.82 , p<0.001 ) . One degree drop in temperature led to a 5.9 % reduction in energy . During mild hypothermia , oxygen consumption was reduced by 71 mL/min ( 95 % confidence interval 57 to 86 mL/min ; p<0.001 ) as compared to base line . The basal metabolism rate was decreased by 30.3 % ( 95 % confidence interval 24.7 to 35.9 % , p<0.001 ) . The average value recorded was 16.7 % below the values calculated in accordance with the Harris-Benedict equation ( 95 % confidence interval 12.8 to 20.6 % ) . CONCLUSION The immediate reduction in oxygen requirements achieved by hypothermia is linearly correlated with the reduction in temperature and the hypothermia induced reduction in oxygen requirement recorded by indirect calorimetry is considerably below that calculated in accordance with the Harris-Benedict equation . If indirect calorimetry should not be available and the Harris-Benedict equation is used , a corrective factor is therefore needed to avoid an inaccurate calorie administration Background Recent prospect i ve controlled trials of induced moderate hypothermia ( 32–34 ° C ) for relatively short periods ( 24–48 h ) in patients with severe head injury have suggested improvement in intracranial pressure control and outcome . It is possible that increased benefit might be achieved if hypothermia was maintained for more periods longer than 48 h , but there is little in the literature on the effects of prolonged moderate hypothermia in adults with severe head injury . We used moderate induced hypothermia ( 30–33 ° C ) in 43 patients with severe head injury for prolonged periods ( mean 8 days , range 2–19 days ) . Results Although nosocomial pneumonia ( defined in this study as both new chest radiograph changes and culture of a respiratory pathogen from tracheal aspirate ) was quite common ( 45 % ) , death from sepsis was rare ( 5 % ) . Other findings included hypokalaemia on induction of hypothermia and a decreasing total white cell and platelet count over 10 days . There were no major cardiac arrhythmias . There was a satisfactory neurological outcome in 20 out of 43 patients ( 47 % ) . Conclusion Moderate hypothermia may be induced for more prolonged periods , and is a relatively safe and feasible therapeutic option in the treatment of selected patients with severe traumatic brain injury . Thus , further prospect i ve controlled trials using induced hypothermia for longer periods than 48 h are warranted INTRODUCTION We sought to investigate the energy requirements for patients under therapeutic hypothermia , and the relationship of energy fulfillment to patient outcome . PATIENTS AND METHODS Adult patients admitted to our ICU after successful resuscitation from cardiac arrest for post resuscitation therapeutic hypothermia from April , 2012 to March , 2014 were enrolled . Body temperature was managed using the surface cooling device ( A rct ic Sun ( ® ) , IMI ) . Calorimeter module on the ventilator ( Engström carestation ( ® ) , GE ) was used for indirect calorimetry . Energy expenditure ( EE ) and respiratory quotient ( RQ ) were recorded continuously , as the average of the recent 2h . Measurements were started at the hypothermic phase and continued until the rewarming was completed . Cumulative energy deficit was calculated as the sum of difference between EE and daily energy provision for the 4 days during hypothermia therapy . RESULTS Seven patients were eligible for analysis . Median EE for the hypothermic phase ( day 1 ) was 1557.0kcald(-1 ) . EE was elevated according with the rise in body temperature , reaching 2375kcald(-1 ) at normothermic phase . There was significant association between cumulative energy deficit and the length of ICU stay , among patients with good neurologic recovery ( cerebral performance category ( CPC ) : 1 - 3 ) . CONCLUSION The EE for patients under therapeutic hypothermia was higher than expected . Meeting the energy dem and may improve patient outcome , as observed in the length of ICU stay for the present study . A larger , prospect i ve study is awaited to vali date the results of our study Objective To evaluate the effects of sedation with morphine and midazolam ( M&M ) versus propofol on gastric emptying in critically ill patients . Design Descriptive study . Setting Mixed medical and surgical intensive care unit . Patients Thirty-six unselected , mechanically ventilated , critically ill patients . Interventions Gastric scintigraphic data were analysed retrospectively according to whether patients were receiving M&M ( n = 20 ; 14 M , 6F ) or propofol ( n = 16 ; 7 M , 9F ) . Measurements were performed over 4 h after administration of 100 ml of Ensure ® , labelled with 20 MBq Tc99 m . Measurements and results Gastric half-emptying time ( t1/2 ) and total and regional ( proximal and distal stomach ) meal retention ( % ) were assessed . The median t1/2 of patients receiving M&M ( 153 ( IQR : 72–434 ) min ) was significantly longer than that of patients receiving propofol ( 58 ( 34–166 ) min , p = 0.02 ) . Total gastric retention was greater in patients receiving M&M compared to those receiving propofol ( p < 0.01 ) . Proximal ( p = 0.02 ) but not distal ( p = 0.80 ) gastric retention was greater in patients who received M&M. Patients who received M&M were more likely to have ≥ 5 % meal retention at 240 min than thosetreated with propofol ( 95 % ( 19/20 ) vs. 56 % ( 9/16 ) ; p = 0.01 ) . Changes in blood glucose concentrations during the study were similar in the two groups . Conclusions In critical illness , patients receiving M&M for sedation are more likely to have slow gastric emptying , and proximal meal retention than those receiving propofol . The apparent beneficial effects of propofol-based sedation need confirmation by a prospect i ve r and omised controlled study Objective : This study evaluated the usefulness of plasma intestinal fatty-acid binding protein ( IFABP ) levels in the early identification of intestinal necrosis ( IN ) in patients undergoing different types of aortic surgery . Background : Intestinal compromise greatly contributes to postoperative adverse outcome . IN is the most detrimental form of intestinal compromise and is notoriously difficult to diagnose . IFABP is a small protein exclusively expressed by mature enterocytes and a promising marker of intestinal damage . Methods : Plasma IFABP concentrations were measured in blood sample s taken perioperatively from 55 patients undergoing open thoracic or thoracoabdominal aneurysm repair [ OR-TAA(A ) ] , 25 patients undergoing conventional open abdominal aneurysm repair ( OR-abdominal aortic aneurysm [ AAA ] ) , and 16 patients undergoing endovascular aneurysm repair ( EVAR ) . Data were compared with perioperative changes in arterial pH and serum lactate levels . Results : IFABP levels increased in all patients undergoing OR-TAA(A ) and OR-AAA reaching peak levels shortly after surgery ; 281 ± 33 to 2,298 ± 490 pg/mL ( P < 0.001 ) and 187 ± 31 to 641 ± 176 pg/mL ( P < 0.05 ) respectively . IFABP levels were significantly higher in patients undergoing OR-TAA(A ) ( P < 0.001 ) . IFABP levels in EVAR patients remained at baseline concentrations throughout the study . Four patients [ 2 OR-AAA , 2 OR-TAA(A ) ] developed fatal postoperative intestinal ischemia on day 2 or 3 . High levels of plasma IFABP at the end of surgery had 100 % sensitivity and 98.1 % specificity for the identification of patients developing IN . In OR-AAA patients , arterial pH and lactate levels were of additional discriminating value . Complete discrimination between patients with and without IN using plasma IFABP could be made on the first postoperative day . Conclusions : Analysis of plasma IFABP levels is of additional value to other current plasma markers in the diagnosis of IN , and it enables early identification of patients with IN after aortic surgery days before clinical diagnosis Objective To study the frequency of and risk factors for increased gastric aspirate volume ( GAV ) and upper digestive intolerance and their complications during enteral nutrition ( EN ) in critically ill patients . Design Prospect i ve observational study . Setting Intensive care unit ( ICU ) in a general hospital . Patients A total of 153 patients with nasogastric tube feeding . Interventions None . Measurements and Main Results Upper digestive intolerance was considered when GAV was between 150 and 500 mL at two consecutive measurements , when it was > 500 mL , or when vomiting occurred . Forty-nine patients ( 32 % ; 95 % confidence interval [ CI ] , 25%–42 % ) presented increased GAV after a median EN duration of 2 days ( range , 1–16 days ) , and 70 patients ( 46 % ; 95 % CI , 38%–54 % ) presented upper digestive intolerance . Independent risk factors for high GAV were GAV > 20 mL before the start of EN ( odds ratio [ OR ] , 2.16 ; 95 % CI , 1.11–4.18;p = .02 ) , GAV > 100 mL during EN ( OR , 1.49 ; 95 % CI , 1.01–2.19;p < .05 ) , sedation during EN ( OR , 1.78 ; 95 % CI , 1.17–2.71;p = .007 ) , use of catecholamines during EN ( OR , 1.81 ; 95 % CI , 1.21–2.70;p = .004 ) . Complications related to high GAV were a lower feed intake ( 15 ± 7 vs. 19 ± 8 kcal/kg/day;p = .0004 ) and vomiting ( 53 % vs. 23%;p = .0002 ) . Complications related to upper digestive intolerance were the development of pneumonia ( 43 % vs. 24%;p = .01 ) , a longer ICU stay ( 23 ± 21 vs. 15 ± 16 days;p = .007 ) , and a higher ICU mortality ( 41 % vs. 25%;p = .03 ) , even after adjustment for Simplified Acute Physiology Score II ( OR , 1.48 ; 95 % CI , 1.04–2.10;p = .028 ) . Conclusion In ICU patients receiving nasogastric tube feeding , high gastric aspirate volume was frequent , occurred early , and was more frequent in patients with sedation or catecholamines . High gastric aspirate volume was an early marker of upper digestive intolerance , which was associated with a higher incidence of nosocomial pneumonia , a longer ICU stay , and a higher ICU mortality Objective To compare the effects of increasing the limit for gastric residual volume ( GRV ) in the adequacy of enteral nutrition . Frequency of gastrointestinal complications and outcome variables were secondary goals . Design An open , prospect i ve , r and omized study . Setting Twenty-eight intensive care units in Spain . Patients Three hundred twenty-nine intubated and mechanically ventilated adult patients with enteral nutrition ( EN ) . Interventions EN was administered by nasogastric tube . A protocol for management of EN-related gastrointestinal complications was used . Patients were r and omized to be included in a control ( GRV = 200 ml ) or in study group ( GRV = 500 ml ) . Measurements and results Diet volume ratio ( diet received/diet prescribed ) , incidence of gastrointestinal complications , ICU-acquired pneumonia , days on mechanical ventilation and ICU length of stay were the study variables . Gastrointestinal complications were higher in the control group ( 63.6 vs. 47.8 % , P = 0.004 ) , but the only difference was in the frequency of high GRV ( 42.4 vs. 26.8 % , P = 0.003 ) . The diet volume ratio was higher for the study group only during the 1st week ( 84.48 vs. 88.20 % ) ( P = 0.0002 ) . Volume ratio was similar for both groups in weeks 3 and 4 . Duration of mechanical ventilation , ICU length of stay or frequency of pneumonia were similar . Conclusions Diet volume ratio of mechanically ventilated patients treated with enteral nutrition is not affected by increasing the limit in GRV . A limit of 500 ml is not associated with adverse effects in gastrointestinal complications or in outcome variables . A value of 500 ml can be equally recommended as a normal limit for GRV Objective To assess gastrointestinal function in critically ill patients receiving muscle relaxant and to test clinical tolerance to enteral nutrition . Design and setting Prospect i ve study in an intensive care unit . Patients 20 critically ill patients requiring sedation with muscle relaxant to obtain adequate mechanical ventilation . Measurements and results Patients were r and omly selected to receive infusions of opioid sedation during the first session ( session 1 ) and the same sedation with muscle relaxation ( cisatracurium ) during the second session ( session 2 ) . Gastric emptying was assessed by the paracetamol absorption technique . Following the paracetamol absorption 200 ml enteral feed was given , and the residual gastric volume was measured 1 and 2 h after feeding . The maximum plasma concentration ( Cmax ) was 14 mg/l ( range 5–26 ) when patients received sedation , and 12 mg/l ( range 5–30 ) when they received muscle relaxant . The target time for reaching the maximum plasma concentration ( Tmax ) was 30 min ( range 20–60 ) and 35 min ( range 20–60 ) , respectively , in sessions 1 and 2 . There was no significant difference between the two session as regards Tmax , Cmax , or AUC0–120 . The residual volumes were 110±65 ml ( H1 ) and 95±76 ml ( H2 ) during session 1 and 125±85 ml ( H1 ) and 105±90 ml ( H2 ) during session 2 . Conclusions Enteral feeding is one of the most effective methods of supporting nutritional needs in the critically ill patient . We conclude that in critically ill patients requiring sedation gastric emptying is not improved by neuromuscular blocking agent A retrospective analysis of prospect ively collected data was performed to compare the frequency of upper gastrointestinal bleeding ( GIB ) in seriously burned patients treated with either cimetidine and antacids or enteral nutrition for ulcer prophylaxis . Five hundred and twenty-six seriously burned patients admitted to the burn intensive care unit of the BG Trauma Centre Ludwigshafen during a 4-year period were included into the study . All patients admitted to the burn unit from 1989 to 1991 received i.v . cimetidine ( 400 mg q4 ) for ulcer prophylaxis . If the intragastric pH dropped below 3.5 , gastric pH was titrated with antacids up to > or = 4 via nasogastric tube . During the second 2-year period ( 1992 - 1993 ) early enteral nutrition alone was regarded to be ulcer protective and no further interventions for ulcer prophylaxis were routinely performed . Signs of overt upper GIB were monitored and documented through the entire study period . The overall occurrence rate of upper GIB in the cimetidine/antacids ( C/A ) group ( n = 253 ) was 8.3 per cent with six cases of serious bleeding in five patients ( 1.98 per cent ) . In the enteral nutrition ( EN ) group ( n = 273 ) the overall incidence of GIB was 3.3 per cent with two cases of serious bleeding ( 0.73 per cent ) . There were no deaths directly related to ulcer haemorrhage . The difference in the overall frequency of overt GIB between the groups studied was statistically significant ( < 0.05 ) . In our experience , early enteral nutrition is effective in the prevention of stress haemorrhage in the upper gastrointestinal tract . Additional medicinal prophylaxis is not required in burn patients OBJECTIVE To assess the incidence of diarrhoea in intensive care patients with a length of stay ( LOS ) greater than 3 days who were receiving any type of enteral tube feeding , and to measure the effect of implementing a bowel management protocol . DESIGN A 2-year prospect i ve audit , with an intervention after 12 months . Diarrhoea was defined as bowel activity exceeding three stools of any consistency per day , or three or more unformed stools ( or 300 mL ) per day , for two consecutive days . SETTING A tertiary referral intensive care unit ( ICU ) in a large public hospital . SAMPLE Six hundred fifty-six consecutive patients admitted to ICU with a LOS > 3 days . INTERVENTION A bowel management protocol was implemented to address both diarrhoea and constipation . MAIN OUTCOME MEASURES Number of patients who experienced diarrhoea during their ICU stay ; number of ICU patient-days on which diarrhoea occurred . RESULTS After the protocol was implemented , diarrhoea was experienced by 13 % fewer patients ( p = 0.0002 ) and occurred on 8 % fewer ICU days ( p < 0.0001 ) . CONCLUSION Use of an evidence -based protocol , and improved monitoring and reporting of bowel activity , can decrease the incidence of diarrhoea in ICU patients BACKGROUND Nonocclusive bowel necrosis ( NOBN ) has been associated with early enteral nutrition ( EN ) . The purpose of this study was to determine the incidence of this complication in our trauma intensive care unit population and to define a typical patient profile vulnerable to NOBN . METHODS Thirteen cases of NOBN were identified among 4,311 patients ( 0.3 % ) over a 64-month period ending October 1998 . Their charts were analyzed for a variety of clinical data , including prospect i ve EN tolerance data in 4 . RESULTS Twelve ( 92 % ) patients were enterally fed prior to diagnosis for 10 + /- 8 days ( range 3 to 21 ) . Tachycardia ( n = 12 , 92 % ) ; fever/hypothermia , ( n = 12 , 92 % ) , and an abnormal white blood cell count ( n = 11 , 85 % ) were consistently present . Abdominal distention was common but tended to be a late sign ( n = 12 ) . Seven ( 56 % ) survived . In 4 patients with tolerance data , 3 reached the goal rate of feeds prior to diagnosis . Two became distended at > 12 hours from diagnosis . Gastric tonometry demonstrated a decreased NgpHi ( < 7.30 ) after starting EN in all 3 in whom it was monitored . CONCLUSIONS NOBN developed in 0.3 % of our trauma patients . Onset occurs in the second week in high-acuity patients who have had a period of EN tolerance . Clinical findings resemble bacterial sepsis with tachycardia , fever , and leukocytosis . Gastrointestinal specific signs are not consistent or occur late . Thus , we could not identify an early , useful clinical indicator . Gastric carbon dioxide tonometry may detect a vulnerable subgroup of patients Multiple trauma is associated with altered metabolism , wasting of the lean body mass and compromised wound healing . Nutritional support is one way to improve the condition of these critically ill patients . We performed a prospect i ve r and omized study on the effect of early nutritional support in severely injured patients admitted to the Division of Traumatic Surgery , Siriraj Hospital between June 1992 and January 1994 . Thirty-eight severe traumatic patients with ISS between 20 - 40 were r and omly divided into control and study group . The 17 patients in the control group were treated in the conventional method with administration of hypo caloric intravenous regimen and supplement with oral diet as soon as the bowel function was returned . The 21 patients of the study group were fed either by enteral or parenteral feeding or both with an appropriate caloric and protein requirement as soon as hemodynamic status was stabilized . We found the study group had a lower mortality rate , a lower complication rate , a shorter period of ICU stay , and an earlier weaning from the ventilator than the control group . The study group also lost less weight than the control group . Nitrogen balance in the study group was significantly lower than the control group OBJECTIVE To evaluate the incidence and risk factors for clinical ly important upper gastrointestinal bleeding in critically ill patients requiring mechanical ventilation . DESIGN In duplicate , blinded adjudicators determined the presence of clinical ly important gastrointestinal bleeding using a priori criteria , evaluating relevant clinical , laboratory , and diagnostic data . Cox proportional hazards regression analyses were used to examine baseline and time-dependent risk factors for bleeding . SETTING Sixteen university-affiliated intensive care units ( ICUs ) in Canada . PATIENTS A total of 1,077 critically ill ICU patients ventilated for at least 48 hrs . INTERVENTIONS Patients were r and omized to stress ulcer prophylaxis with intravenous ranitidine or nasogastric sucralfate ; otherwise , management was at the discretion of the ICU team . MEASUREMENTS AND MAIN RESULTS Demographic data included patient characteristics , Acute Physiology and Chronic Health Evaluation II score , and multiple organ dysfunction ( MOD ) score . Each day in the ICU , physiologic measurements including MOD score , feeding , and other treatment variables were recorded . The significant risk factors for upper gastrointestinal bleeding in the univariable analyses were low platelet count , maximum serum creatinine , maximum MOD score , maximum pulmonary component of the MOD score , maximum hepatic component of the MOD score , maximum renal component of the MOD score , enteral nutrition , and stress ulcer prophylaxis with ranitidine . The only independent predictors of bleeding in the multivariable analysis were maximum serum creatinine ( relative risk = 1.16 [ 95 % confidence interval = 1.02 - 1.32 ] ) , enteral nutrition ( relative risk = 0.30 [ 95 % confidence interval = 0.13 - 0.67 ] ) , and ranitidine administration ( relative risk = 0.39 [ 95 % confidence interval = 0.17 - 0.83 ] ) . CONCLUSIONS In critically ill ventilated patients , renal failure was independently associated with an increased risk of clinical ly important gastrointestinal bleeding , whereas enteral nutrition and stress ulcer prophylaxis with ranitidine conferred significantly lower bleeding rates Steroids are recommended in severe alcohol-induced hepatitis , but some data suggest that artificial nutrition could also be effective . We conducted a r and omized trial comparing the short- and long-term effects of total enteral nutrition or steroids in these patients . A total of 71 patients ( 80 % cirrhotic ) were r and omized to receive 40 mg/d prednisolone ( n = 36 ) or enteral tube feeding ( 2,000 kcal/d ) for 28 days ( n = 35 ) , and were followed for 1 year or until death . Side effects of treatment occurred in 5 patients on steroids and 10 on enteral nutrition ( not significant ) . Eight enterally fed patients were prematurely withdrawn from the trial . Mortality during treatment was similar in both groups ( 9 of 36 vs. 11 of 35 , intention-to-treat ) but occurred earlier with enteral feeding ( median 7 vs. 23 days ; P = .025 ) . Mortality during follow-up was higher with steroids ( 10 of 27 vs. 2 of 24 intention-to-treat ; P = . 04 ) . Seven steroid patients died within the first 1.5 months of follow-up . In contrast to total enteral nutrition ( TEN ) , infections accounted for 9 of 10 follow-up deaths in the steroid group . In conclusion , enteral feeding does not seem to be worse than steroids in the short-term treatment of severe alcohol-induced hepatitis , although death occurs earlier with enteral nutrition . However , steroid therapy is associated with a higher mortality rate in the immediate weeks after treatment , mainly because of infections . A possible synergistic effect of both treatments should be investigated BACKGROUND Enteral nutrition ( EN ) is controversial in patients with circulatory compromise . This study assesses the feasibility and safety of EN given early after cardiac surgery in patients with hemodynamic failure . METHODS Prospect i ve observational study conducted in a surgical intensive care unit ( ICU ) of a tertiary hospital over 17 months . INCLUSION CRITERIA Cardiac surgery patients with hemodynamic failure ( dependence on 2 or more vasoactive drugs and /or mechanical circulatory support ) requiring more than 24 hours of mechanical ventilation . Variables Examined : Descriptive data , daily hemodynamic data , and variables related to the efficacy and safety of EN . EN was performed according to our EN protocol . RESULTS Of 642 patients admitted to the ICU , 37 ( 5.8 % ) met the inclusion criteria . Of these , 11 ( 29.7 % ) required mechanical circulatory support , and 25 ( 68.0 % ) met the criteria for early multiorgan dysfunction . Mortality was 13.5 % . Mean EN duration was 12.3 days ( 95 % confidence interval [ CI ] , 9.6 - 15.0 ) . The mean EN diet volume delivered/patient/d was 1199 mL ( 95 % CI , 1118.7 - 1278.8 ) , and mean EN energy delivered/patient/d was 1228.4 kcal ( 95 % CI , 1145.8 - 1311 ) . The set energy target was achieved in 15 patients ( 40.4 % ) . The most common EN-related complication was constipation . No case of mesenteric ischemia was detected . CONCLUSIONS Our findings indicate that early EN is feasible in this type of patients and not associated with serious complications . However , it is difficult to attain an appropriate energy target by EN alone . These observations point to a need for monitoring of daily energy delivery and balance , as well as careful monitoring of warning signs of intestinal ischemia BACKGROUND Routine practice after major GI surgery has been to keep patient nil per oral till the return of bowel sound with a belief that this will prevent post operative nausea and vomiting and protect the anastomotic site where as the trend has been changing to encourage enteral feeding as soon as possible as various studies has shown early enteral feeding to be beneficial in terms of nutritional , immunological aspect and for faster recovery of patient . METHODS Patients undergoing major elective GI surgery in department of Surgery , Kathm and u Medical college Teaching Hospital who were given early enteral feeding ( within 24 hrs of operation ) were studied prospect ively and were compared retrospectively with historical control who underwent similar procedure . RESULTS Early enteral feeding in patient undergoing major G.I surgery showed early return of bowel movement , decreased ICU and hospital stay with a significant reduction in postoperative cost . CONCLUSIONS Early enteral feeding promotes faster recovery while reducing hospital stay and treatment cost in patient undergoing major GI surgery CONTEXT The amount of enteral nutrition patients with acute lung injury need is unknown . OBJECTIVE To determine if initial lower-volume trophic enteral feeding would increase ventilator-free days and decrease gastrointestinal intolerances compared with initial full enteral feeding . DESIGN , SETTING , AND PARTICIPANTS The EDEN study , a r and omized , open-label , multicenter trial conducted from January 2 , 2008 , through April 12 , 2011 . Participants were 1000 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart , Lung , and Blood Institute ARDS Clinical Trials Network . INTERVENTIONS Participants were r and omized to receive either trophic or full enteral feeding for the first 6 days . After day 6 , the care of all patients who were still receiving mechanical ventilation was managed according to the full feeding protocol . MAIN OUTCOME MEASURES Ventilator-free days to study day 28 . RESULTS Baseline characteristics were similar between the trophic-feeding ( n = 508 ) and full-feeding ( n = 492 ) groups . The full-feeding group received more enteral calories for the first 6 days , about 1300 kcal/d compared with 400 kcal/d ( P < .001 ) . Initial trophic feeding did not increase the number of ventilator-free days ( 14.9 [ 95 % CI , 13.9 to 15.8 ] vs 15.0 [ 95 % CI , 14.1 to 15.9 ] ; difference , -0.1 [ 95 % CI , -1.4 to 1.2 ] ; P = .89 ) or reduce 60-day mortality ( 23.2 % [ 95 % CI , 19.6 % to 26.9 % ] vs 22.2 % [ 95 % CI , 18.5 % to 25.8 % ] ; difference , 1.0 % [ 95 % CI , -4.1 % to 6.3 % ] ; P = .77 ) compared with full feeding . There were no differences in infectious complications between the groups . Despite receiving more prokinetic agents , the full-feeding group experienced more vomiting ( 2.2 % vs 1.7 % of patient feeding days ; P = .05 ) , elevated gastric residual volumes ( 4.9 % vs 2.2 % of feeding days ; P < .001 ) , and constipation ( 3.1 % vs 2.1 % of feeding days ; P = .003 ) . Mean plasma glucose values and average hourly insulin administration were both higher in the full-feeding group over the first 6 days . CONCLUSION In patients with acute lung injury , compared with full enteral feeding , a strategy of initial trophic enteral feeding for up to 6 days did not improve ventilator-free days , 60-day mortality , or infectious complications but was associated with less gastrointestinal intolerance . TRIAL REGISTRATION clinical trials.gov Identifiers : NCT00609180 and NCT00883948

There is little evidence that educational curriculum‐based programmes alone are effective in improving sexual and reproductive health outcomes for adolescents .

Abstract Background School‐based sexual and reproductive health programmes are widely accepted as an approach to reducing high‐risk sexual behaviour among adolescents . Many studies and systematic review s have concentrated on measuring effects on knowledge or self‐reported behaviour rather than biological outcomes , such as pregnancy or prevalence of sexually transmitted infections ( STIs ) . Objectives To evaluate the effects of school‐based sexual and reproductive health programmes on sexually transmitted infections ( such as HIV , herpes simplex virus , and syphilis ) , and pregnancy among adolescents . Authors ' conclusions There is a continued need to provide health services to adolescents that include contraceptive choices and condoms and that involve them in the design of services . Schools may be a good place in which to provide these services .

Background Adolescents need access to effective sexual and reproductive health ( SRH ) interventions , but face barriers accessing them through traditional health systems . School-based approaches might provide accessible , complementary strategies . We investigated whether a 21-session after-school SRH education programme and school health service attracted adolescents most at risk for adverse SRH outcomes and explored motivators for and barriers to attendance . Methods Grade 8 adolescents ( average age 13 years ) from 20 schools in the intervention arm of an HIV prevention cluster r and omised controlled trial in the Western Cape Province of South Africa , were invited to participate in an after-school SRH program and to attend school health services . Using a longitudinal design , we surveyed participants at baseline , measured their attendance at weekly after-school sessions for 6 months and surveyed them post-intervention . We examined factors associated with attendance using bivariate and multiple logistic and Poisson regression analyses , and through thematic analysis of qualitative data . Results The intervention was fully implemented in 18 schools with 1576 trial participants . The mean attendance of the 21-session SRH programme was 8.8 sessions ( S.D. 7.5 ) among girls and 6.9 ( S.D. 7.2 ) among boys . School health services were visited by 17.3 % ( 14.9 % of boys and 18.7 % of girls ) . Adolescents who had their sexual debut before baseline had a lower rate of session attendance compared with those who had not ( 6.3 vs 8.5 , p < .001 ) . Those who had been victims of sexual violence or intimate partner violence ( IPV ) , and who had perpetrated IPV also had lower rates of attendance . Participants were motivated by a wish to receive new knowledge , life coaching and positive attitudes towards the intervention . The unavailability of safe transport and domestic responsibilities were the most common barriers to attendance . Only two participants cited negative attitudes about the intervention as the reason they did not attend . Conclusions Reducing structural barriers to attendance , after-school interventions are likely to reach adolescents with proven-effective SRH interventions . However , special attention is required to reach vulnerable adolescents , through offering different delivery modalities , improving the school climate , and providing support for adolescents with mental health problems and neurodevelopmental academic problems . Trial registration Current Controlled Trials IS RCT N56270821 ; Registered 13 February 2013 Recent evidence suggests that conditional cash transfer programs for schooling are effective in raising school enrollment and attendance . However , there is also reason to believe that such programs can affect other outcomes , such as the sexual behavior of their young beneficiaries . Zomba Cash Transfer Program is a r and omized , ongoing conditional cash transfer intervention targeting young women in Malawi that provides incentives ( in the form of school fees and cash transfers ) to current schoolgirls and recent dropouts to stay in or return to school . An average offer of US$ 10/month conditional on satisfactory school attendance – plus direct payment of secondary school fees – led to significant declines in early marriage , teenage pregnancy , and self-reported sexual activity among program beneficiaries after just one year of program implementation . For program beneficiaries who were out of school at baseline , the probability of getting married and becoming pregnant declined by more than 40 percent and 30 percent , respectively . In addition , the incidence of the onset of sexual activity was 38 percent lower among all program beneficiaries than the control group . Overall , these results suggest that conditional cash transfer programs not only serve as useful tools for improving school attendance , but may also reduce sexual activity , teen pregnancy , and early marriage Background Only four out of 31 completed r and omized controlled trials ( RCTs ) of HIV prevention strategies against sexual transmission have shown significant efficacy . Poor adherence may have contributed to the lack of effect in some of these trials . In this paper we explore the impact of various levels of adherence on measured efficacy within an RCT . Analysis We used simple quantitative methods to illustrate the impact of various levels of adherence on measured efficacy by assuming a uniform population in terms of sexual behavior and the binomial model for the transmission probability per partnership . At 100 % adherence the measured efficacy within an RCT is a reasonable approximation of the true biological efficacy . However , as adherence levels fall , the efficacy measured within a trial substantially under-estimates the true biological efficacy . For example , at 60 % adherence , the measured efficacy can be less than half of the true biological efficacy . Conclusion Poor adherence during a trial can substantially reduce the power to detect an effect , and improved methods of achieving and maintaining high adherence within trials are needed . There are currently 12 ongoing HIV prevention trials , all but one of which require ongoing user-adherence . Attention must be given to methods of maximizing adherence when piloting and design ing RCTs and HIV prevention programmes A seven-year r and omized evaluation suggests education subsidies reduce adolescent girls ' dropout , pregnancy , and marriage but not sexually transmitted infection ( STI ) . The government 's HIV curriculum , which stresses abstinence until marriage , does not reduce pregnancy or STI . Both programs combined reduce STI more , but cut dropout and pregnancy less , than education subsidies alone . These results are inconsistent with a model of schooling and sexual behavior in which both pregnancy and STI are determined by one factor ( unprotected sex ) , but consistent with a two-factor model in which choices between committed and casual relationships also affect these outcomes Objective To assess the impact of a theoretically based sex education programme ( SHARE ) delivered by teachers compared with conventional education in terms of conceptions and terminations registered by the NHS . Design Follow-up of cluster r and omised trial 4.5 years after intervention . Setting NHS records of women who had attended 25 secondary schools in east Scotl and . Participants 4196 women ( 99.5 % of those eligible ) . Intervention SHARE programme ( intervention group ) v existing sex education ( control group ) . Main outcome measure NHS recorded conceptions and terminations for the achieved sample linked at age 20 . Results In an “ intention to treat ” analysis there were no significant differences between the groups in registered conceptions per 1000 pupils ( 300 SHARE v 274 control ; difference 26 , 95 % confidence interval −33 to 86 ) and terminations per 1000 pupils ( 127 v 112 ; difference 15 , −13 to 42 ) between ages 16 and 20 . Conclusions This specially design ed sex education programme did not reduce conceptions or terminations by age 20 compared with conventional provision . The lack of effect was not due to quality of delivery . Enhancing teacher led school sex education beyond conventional provision in eastern Scotl and is unlikely to reduce terminations in teenagers . Trial registration IS RCT N48719575 An exigent need exists for HIV prevention intervention research targeting young men who have sex with men (MSM)-a group of young adults that , despite composing the highest and most racially disproportionate rates of HIV incidence , have been least often the focus of behavioral intervention research . This pilot study tested a group-based HIV primary prevention intervention for young MSM to evaluate its initial efficacy , feasibility , and acceptability . Participants were r and omized ( N = 101 ; aged 16–20 years ) to one of two group-level , HIV and STI education programs : controls participated in a non-interactive , lecture-based program , while intervention participants took part in a highly interactive program tailored to young MSM aged 16–20 . Sexual risk and social cognitive outcomes were assessed at baseline , 6- , and 12-weeks post-intervention . Over the entire follow-up period , intervention participants were less likely than controls to engage in any sexual behavior while under the influence of substances ( p < .05 ) , and a decreasing trend in unprotected anal sex while under the influence of substances was also observed in this group ( p = .08 ) . Follow-up differences between groups on social cognitive outcomes favored the intervention group , though these differences were non-significant . Acceptability ratings were modest . A 6-session behavioral intervention tailored to young MSM , aged 16–20 , is feasible , acceptable , and demonstrates evidence of preliminary efficacy in reducing sexual risk , specifically sexual risk while under the influence of substances Abstract Objective : To determine whether a theoretically based sex education programme for adolescents ( SHARE ) delivered by teachers reduced unsafe sexual intercourse compared with current practice . Design : Cluster r and omised trial with follow up two years after baseline ( six months after intervention ) . A process evaluation investigated the delivery of sex education and broader features of each school . Setting : Twenty five secondary schools in east Scotl and . Participants : 8430 pupils aged 13 - 15 years ; 7616 completed the baseline question naire and 5854 completed the two year follow up question naire . Intervention : SHARE programme ( intervention group ) versus existing sex education ( control programme ) . Main outcome measures : Self reported exposure to sexually transmitted disease , use of condoms and contraceptives at first and most recent sexual intercourse , and unwanted pregnancies . Results : When the intervention group was compared with the conventional sex education group in an intention to treat analysis there were no differences in sexual activity or sexual risk taking by the age of 16 years . However , those in the intervention group reported less regret of first sexual intercourse with most recent partner ( young men 9.9 % difference , 95 % confidence interval −18.7 to −1.0 ; young women 7.7 % difference , −16.6 to 1.2 ) . Pupils evaluated the intervention programme more positively , and their knowledge of sexual health improved . Lack of behavioural effect could not be linked to differential quality of delivery of intervention . Conclusions : Compared with conventional sex education this specially design ed intervention did not reduce sexual risk taking in adolescents OBJECTIVE To evaluate the efficacy of an abstinence-only intervention in preventing sexual involvement in young adolescents . DESIGN R and omized controlled trial . SETTING Urban public schools . PARTICIPANTS A total of 662 African American students in grade s 6 and 7 . INTERVENTIONS An 8-hour abstinence-only intervention targeted reduced sexual intercourse ; an 8-hour safer sex-only intervention targeted increased condom use ; 8-hour and 12-hour comprehensive interventions targeted sexual intercourse and condom use ; and an 8-hour health-promotion control intervention targeted health issues unrelated to sexual behavior . Participants also were r and omized to receive or not receive an intervention maintenance program to extend intervention efficacy . OUTCOME MEASURES The primary outcome was self-report of ever having sexual intercourse by the 24-month follow-up . Secondary outcomes were other sexual behaviors . RESULTS The participants ' mean age was 12.2 years ; 53.5 % were girls ; and 84.4 % were still enrolled at 24 months . Abstinence-only intervention reduced sexual initiation ( risk ratio [ RR ] , 0.67 ; 95 % confidence interval [ CI ] , 0.48 - 0.96 ) . The model-estimated probability of ever having sexual intercourse by the 24-month follow-up was 33.5 % in the abstinence-only intervention and 48.5 % in the control group . Fewer abstinence-only intervention participants ( 20.6 % ) than control participants ( 29.0 % ) reported having coitus in the previous 3 months during the follow-up period ( RR , 0.94 ; 95 % CI , 0.90 - 0.99 ) . Abstinence-only intervention did not affect condom use . The 8-hour ( RR , 0.96 ; 95 % CI , 0.92 - 1.00 ) and 12-hour comprehensive ( RR , 0.95 ; 95 % CI , 0.91 - 0.99 ) interventions reduced reports of having multiple partners compared with the control group . No other differences between interventions and controls were significant . CONCLUSION Theory-based abstinence-only interventions may have an important role in preventing adolescent sexual involvement . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00640653 INTRODUCTION With the rising threat of HIV in India , youth are an important group to reach for prevention education . This pilot study tested the efficacy of STEP ( School-based Teenage Education Program focusing on HIV Prevention ) for school children . METHOD This pilot study r and omized 25 schools in Mumbai to receive STEP ( N = 1846 ) . We trained forty two undergraduates from local colleges to deliver the , ( six-session ) program over a six-week period to eighth grade rs ( age 13 - 15 years ) . Outcome measures collected at six weeks were HIV knowledge , attitudes toward abstinence/condom use , peer pressure , and confidence in dealing with risky social situations . A repeated measures analysis of variance was conducted with pretest and posttest scores with knowledge , beliefs , attitudes , and confidence as the within-group measures and gender as the between-group measure . RESULTS Both boys and girls significantly improved on knowledge , attitudes , and beliefs regarding HIV/AIDS and in their confidence level in dealing with risky behavior . However girls increased more on knowledge ( P < .05 ) , agreement with abstinence ( P < .05 ) , and agreement with condom use ( P < .001 ) . Girls had significantly less need to follow peers ( P < .05 ) , better underst and ing of pre caution s against HIV ( P < .001 ) , and a higher confidence level in dealing with risky social situations ( P < .05 ) . CONCLUSIONS Overall , girls benefited more from the STEP intervention than boys . The literature documents strong gender disparities in HIV/AIDS knowledge , information sources , and consequences of sex for youth in India . However , more work is needed to define and document the reasons for the differences Background Fostering adolescents ’ communication on sexuality issues with their parents and other significant adults is often assumed to be an important component of intervention programmes aim ed at promoting healthy adolescent sexual practice s. However , there are few studies describing the relationship between such communication and sexual practice s , particularly in sub-Saharan Africa . This study examined the relationships between adolescents ’ communication with significant adults and their condom use in three sites in this region . Methods Data stem from a multi-site r and omized controlled trial of a school-based HIV prevention intervention implemented in Cape Town and Mankweng , South Africa and Dar es Salaam , Tanzania . Only data from comparison schools were used . The design is therefore a prospect i ve panel study with three waves of data collection s. Data were collected in 2004 from 6,251 participants in 40 schools . Associations between adolescents ’ communication with adults about sexuality issues and their use of condoms were analysed cross-sectionally using analysis of variance , as well as prospect ively using multiple ordinal logistic regression analysis . Results Cross-sectional analyses showed that consistent condom users had significantly higher mean scores on communication ( across topics and communication partners ) than both occasional users and never-users , who had the lowest scores . After controlling for condom use at the first data collection occasion in each model as well as for possible confounders , communication scores significantly predicted consistent condom use prospect ively in all three ordinal logistic regression models ( Model R2 = .23 to .31 ) . Conclusion The findings are consistent with the assertion that communication on sexuality issues between adolescents and significant adults results in safer sexual practice s , as reflected by condom use , among in-school adolescents . The associations between communication variables and condom use might have been stronger if we had measured additional aspects of communication such as whether or not it was initiated by the adolescents themselves , the quality of advice provided by adults , and if it took place in a context of positive adult-adolescent interaction . Studies with experimental design s are needed in order to provide stronger evidence of causality This study evaluates the efficacy of Keepin ' It Safe , a theory-based , gender-specific , CD-ROM-mediated HIV prevention program for urban , early adolescent girls . Intervention effects were examined in a r and omized , pretest-posttest wait-list control-group design . Changes in HIV/AIDS knowledge , protective attitudes , and skills for reducing HIV risk-related sexual behaviors were tested using linear regression models that were controlled for baseline values of each outcome . Recruited through youth services agencies located in the greater New York City area , study participants comprised 204 adolescent girls aged 11 - 14 years . Girls exposed to Keepin ' It Safe , relative to wait-list control girls , increased their HIV/AIDS knowledge , perceived efficacy and enjoyment of abstinence , perceived efficacy and enjoyment of condoms , and sexual assertiveness , suggesting that a theory-based , gender-specific , CD-ROM-mediated HIV prevention program can enhance knowledge , protective attitudes , and skills for reducing HIV risk-related sexual behaviors among urban early-adolescent girls PURPOSE To evaluate the efficacy of an abstinence-centered sex education program in adolescent pregnancy prevention , the TeenSTAR Program was applied in a high school in Santiago , Chile . METHODS A total of 1259 girls from a Santiago high school were divided into three cohorts depending on the year they started high school : the 1996 cohort of 425 students , which received no intervention ; the 1997 cohort , in which 210 students received an intervention and 213 ( control group ) did not ; and the 1998 cohort , in which 328 students received an intervention and 83 ( control group ) did not . Students were r and omly assigned to control and intervention groups in these cohorts , before starting with the program . We conducted a prospect i ve , r and omized study using the application of the TeenSTAR sex education program during the first year of high school to the intervention groups in the 1997 and 1998 cohorts . All cohorts were followed up for 4 years ; pregnancy rates were recorded and subsequently contrasted in the intervention and control groups . Pregnancy rates were measured and Risk Ratio with 95 % confidence interval were calculated for intervention and control groups in each cohort . RESULTS Pregnancy rates for the intervention and control groups in the 1997 cohort were 3.3 % and 18.9 % , respectively ( RR : 0.176 , CI : 0.076 - 0.408 ) . Pregnancy rates for the intervention and control groups in the 1998 cohort were 4.4 % and 22.6 % , respectively ( RR 0.195 , CI : 0.099 - 0.384 ) . CONCLUSIONS The abstinence-centered TeenSTAR sex education intervention was effective in the prevention of unintended adolescent pregnancy Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background : HIV prevention among young people in southern Africa is a public health priority . There is little rigorous evidence of the effectiveness of different intervention approaches . We describe findings of a cluster r and omized trial of a community-based , multicomponent HIV , and reproductive health intervention aim ed at changing social norms for adolescents in rural Zimbabwe . Methods : Thirty rural communities were r and omized to early or deferred implementation of the intervention in 2003 . Impact was assessed in a representative survey of 18–22-year-olds after 4 years . Participants self-completed a question naire and gave a dried blood spot sample for HIV and herpes simplex virus-2 ( HSV-2 ) antibody testing . Young women had a urinary pregnancy test . Analyses were by intention-to-treat and were adjusted for clustering . Findings : Four thous and six hundred and eighty-four , 18–22-year-olds participated in the survey ( 97.1 % of eligible c and i date s , 55.5 % women ) . Just over 40 % had been exposed to at least 10 intervention sessions . There were modest improvements in knowledge and attitudes among young men and women in intervention communities , but no impact on self-reported sexual behavior . There was no impact of the intervention on prevalence of HIV or HSV-2 or current pregnancy . Women in intervention communities were less likely to report ever having been pregnant . Interpretation : Despite an impact on knowledge , some attitudes , and reported pregnancy , there was no impact of this intervention on HIV or HSV-2 prevalence , further evidence that behavioral interventions alone are unlikely to be sufficient to reverse the HIV epidemic . The challenge remains to find effective HIV prevention approaches for young people in the face of continued and unacceptably high HIV incidence , particularly among young women This paper describes the rationale , design , methods , and baseline results of a r and omized controlled trial to evaluate the impact of an adapted evidence -based intervention ( EBI ) , “ Respecting the Circle of Life ” ( RCL ) to reduce behavioral risks for HIV/AIDS among American Indian ( AI ) adolescents . A participatory approach shaped intervention adaptation and study design . A total of 267 participants ( aged 13–19 ) were r and omized by peer groups of the same sex to receive the RCL intervention or a control condition . Self-report assessment s were administered at four intervals . The sample was predominately female ( 57 % ) , had low HIV knowledge prevention scores , early sexual initiation ( mean 14.6 years ) , and 56 % reported intention to use a condom at next sex . Baseline characteristics were evenly distributed between groups with the exception of age and extrinsic reward scores . This is the first rigorous evaluation of an adapted EBI for HIV/AIDS prevention among AI adolescents , an at-risk and understudied population PURPOSE The Centers for Disease Control and Prevention highlights the importance of evaluating interventions rigorously and recommends evaluating new interventions against interventions with established efficacy . Competencias para adolescentes con una sexualidad saludable ( COMPAS ) is a school-based HIV prevention program that has been shown to be effective in reducing sexual risk behaviors among adolescents in Spain . This study evaluates the efficacy of COMPAS program compared with a Spanish-culture adapted version of ¡ Cuí date ! ( Take Care of Yourself ) , an evidence -based HIV prevention curriculum design ed for Latino adolescents in the US . METHODS This cluster r and omized controlled trial involved 1,563 adolescents attending 18 public high schools located in 5 provinces of Spain . The schools invited to participate were enrolled and r and omly assigned to the three experimental conditions : COMPAS , ¡ Cuí date ! , and control group ( CG ; no intervention ) . RESULTS Generalized estimating equation analyses revealed that both interventions improved attitudes toward people living with human immunodeficiency syndrome (HIV)/AIDS and the HIV test and increased HIV/sexually transmitted infection knowledge and intention to engage in safer sex behaviors compared with the CG . Although only COMPAS increased participants ' sexual risk perception and attitude toward condom use compared with the CG , the two interventions did not significantly differ on any outcome . CONCLUSIONS When compared with an established program , COMPAS was at least as effective at increasing the intention to engage in safer sex behaviors as the evidence -based intervention Background While many Ghanaian adolescents encounter sexual and reproductive health problems , their usage of services remains low . A social learning intervention , incorporating environment , motivation , education , and self-efficacy to change behaviour , was implemented in a low-income district of northern Ghana to increase adolescent services usage . This study aim ed to assess the impact of this intervention on usage of sexual and reproductive health services by young people . Methods Twenty-six communities were r and omly allocated to ( i ) an intervention consisting of school-based curriculum , out-of-school outreach , community mobilisation , and health-worker training in youth-friendly health services , or ( ii ) comparison consisting of community mobilisation and youth-friendly health services training only . Outcome measures were usage of sexually-transmitted infections ( STIs ) management , HIV counselling and testing , antenatal care or perinatal services in the past year and reported service satisfaction . Data was collected , at baseline and three years after , from a cohort of 2,664 adolescents aged 15–17 at baseline . Results Exposure was associated with over twice the odds of using STI services ( AOR 2.47 ; 95%CI 1.78–3.42 ) , 89 % greater odds of using perinatal services ( AOR 1.89 ; 95%CI 1.37–2.60 ) and 56 % greater odds of using antenatal services ( AOR 1.56 ; 95%CI 1.10–2.20 ) among participants in intervention versus comparison communities , after adjustment for baseline differences . Conclusions The addition of targeted school-based and outreach activities increased service usage by young people more than community mobilisation and training providers in youth-friendly services provision alone PURPOSE This study tested the effects of a theory-based , middle-school human immunodeficiency virus , STI , and pregnancy prevention program , It 's Your Game : Keep it Real ( IYG ) , in delaying sexual behavior . We hypothesized that the IYG intervention would decrease the number of adolescents who initiated sexual activity by the ninth grade compared with those in the comparison schools . METHODS The target population consisted of English-speaking middle school students from a large , urban , predominantly African-American and Hispanic school district in Southeast Texas . Ten middle schools were r and omly assigned either to receive the intervention or to the comparison condition . Seventh- grade students were recruited and followed through ninth grade . The IYG intervention comprises 12 seventh- grade and 12 eighth- grade lessons that integrate group-based classroom activities with computer-based instruction and personal journaling . Ninth- grade follow-up surveys were completed by 907 students ( 92 % of the defined cohort ) . The primary hypothesis tested was that the intervention would decrease the number of adolescents who initiated sexual activity by the ninth grade compared with those in the comparison schools . RESULTS Almost one-third ( 29.9 % , n=509 ) of the students in the comparison condition initiated sex by ninth grade compared with almost one-quarter ( 23.4 % , n=308 ) of those in the intervention condition . After adjusting for covariates , students in the comparison condition were 1.29 times more likely to initiate sex by the ninth grade than those in the intervention condition . CONCLUSIONS A theory-driven , multi-component , curriculum-based intervention can delay sexual initiation up to 24 months ; can have impact on specific types of sexual behavior such as initiation of oral and anal sex ; and may be especially effective with females . Future research must explore the generalizabilty of these results Objective To evaluate the effectiveness of a complex intervention implementing best practice guidelines recommending clinicians screen and counsel young people across multiple psychosocial risk factors , on clinicians ’ detection of health risks and patients ’ risk taking behaviour , compared to a didactic seminar on young people ’s health . Design Pragmatic cluster r and omised trial where volunteer general practice s were stratified by postcode advantage or disadvantage score and billing type ( private , free national health , community health centre ) , then r and omised into either intervention or comparison arms using a computer generated r and om sequence . Three months post-intervention , patients were recruited from all practice s post-consultation for a Computer Assisted Telephone Interview and followed up three and 12 months later . Research ers recruiting , consenting and interviewing patients and patients themselves were masked to allocation status ; clinicians were not . Setting General practice s in metropolitan and rural Victoria , Australia Participants General practice s with at least one interested clinician ( general practitioner or nurse ) and their 14–24 year old patients . Intervention This complex intervention was design ed using evidence based practice in learning and change in clinician behaviour and general practice systems , and included best practice approaches to motivating change in adolescent risk taking behaviours . The intervention involved training clinicians ( nine hours ) in health risk screening , use of a screening tool and motivational interviewing ; training all practice staff ( receptionists and clinicians ) in engaging youth ; provision of feedback to clinicians of patients ’ risk data ; and two practice visits to support new screening and referral re sources . Comparison clinicians received one didactic educational seminar ( three hours ) on engaging youth and health risk screening . Outcome Measures Primary outcomes were patient report of ( 1 ) clinician detection of at least one of six health risk behaviours ( tobacco , alcohol and illicit drug use , risks for sexually transmitted infection , STI , unplanned pregnancy , and road risks ) ; and ( 2 ) change in one or more of the six health risk behaviours , at three months or at 12 months . Secondary outcomes were likelihood of future visits , trust in the clinician after exit interview , clinician detection of emotional distress and fear and abuse in relationships , and emotional distress at three and 12 months . Patient acceptability of the screening tool was also described for the intervention arm . Analyses were adjusted for practice location and billing type , patients ’ sex , age , and recruitment method , and past health risks , where appropriate . An intention to treat analysis approach was used , which included multilevel multiple imputation for missing outcome data . Results 42 practice s were r and omly allocated to intervention or comparison arms . Two intervention practice s withdrew post allocation , prior to training , leaving 19 intervention ( 53 clinicians , 377 patients ) and 21 comparison ( 79 clinicians , 524 patients ) practice s. 69 % of patients in both intervention ( 260 ) and comparison ( 360 ) arms completed the 12 month follow-up . Intervention clinicians discussed more health risks per patient ( 59.7 % ) than comparison clinicians ( 52.7 % ) and thus were more likely to detect a higher proportion of young people with at least one of the six health risk behaviours ( 38.4 % vs 26.7 % , risk difference [ RD ] 11.6 % , Confidence Interval [ CI ] 2.93 % to 20.3 % ; adjusted odds ratio [ OR ] 1.7 , CI 1.1 to 2.5 ) . Patients reported less illicit drug use ( RD -6.0 , CI -11 to -1.2 ; OR 0·52 , CI 0·28 to 0·96 ) , and less risk for STI ( RD -5.4 , CI -11 to 0.2 ; OR 0·66 , CI 0·46 to 0·96 ) at three months in the intervention relative to the comparison arm , and for unplanned pregnancy at 12 months ( RD -4.4 ; CI -8.7 to -0.1 ; OR 0·40 , CI 0·20 to 0·80 ) . No differences were detected between arms on other health risks . There were no differences on secondary outcomes , apart from a greater detection of abuse ( OR 13.8 , CI 1.71 to 111 ) . There were no reports of harmful events and intervention arm youth had high acceptance of the screening tool . Conclusions A complex intervention , compared to a simple educational seminar for practice s , improved detection of health risk behaviours in young people . Impact on health outcomes was inconclusive . Technology enabling more efficient , systematic health-risk screening may allow providers to target counselling toward higher risk individuals . Further trials require more power to confirm health benefits . Trial Registration IS RCT N.com IS RCT N16059206 Background Systematic review s represent one of the most important tools for knowledge translation but users often struggle with underst and ing and interpreting their results . GRADE Summary -of- Findings tables have been developed to display results of systematic review s in a concise and transparent manner . The current format of the Summary -of- Findings tables for presenting risks and quality of evidence improves underst and ing and assists users with finding key information from the systematic review . However , it has been suggested that additional methods to present risks and display results in the Summary -of- Findings tables are needed . Methods / Design We will conduct a non-inferiority parallel-armed r and omized controlled trial to determine whether an alternative format to present risks and display Summary -of- Findings tables is not inferior compared to the current st and ard format . We will measure participant underst and ing , accessibility of the information , satisfaction , and preference for both formats . We will invite systematic review users to participate ( that is clinicians , guideline developers , and research ers ) . The data collection process will be undertaken using the online ' Survey Monkey ' system . For the primary outcome underst and ing , non-inferiority of the alternative format ( Table A ) to the current st and ard format ( Table C ) of Summary -of- Findings tables will be cl aim ed if the upper limit of a 1-sided 95 % confidence interval ( for the difference of proportion of participants answering correctly a given question ) excluded a difference in favor of the current format of more than 10 % . Discussion This study represents an effort to provide systematic review ers with additional options to display review results using Summary -of- Findings tables . In this way , review authors will have a variety of methods to present risks and more flexibility to choose the most appropriate table features to display ( that is optional columns , risks expressions , complementary methods to display continuous outcomes , and so on).Trials registration NCT02022631 ( 21 December 2013 Objective To assess the impact of Stepping Stones , a HIV prevention programme , on incidence of HIV and herpes simplex type 2 ( HSV-2 ) and sexual behaviour . Design Cluster r and omised controlled trial . Setting 70 villages ( clusters ) in the Eastern Cape province of South Africa . Participants 1360 men and 1416 women aged 15 - 26 years , who were mostly attending schools . Intervention Stepping Stones , a 50 hour programme , aims to improve sexual health by using participatory learning approaches to build knowledge , risk awareness , and communication skills and to stimulate critical reflection . Villages were r and omised to receive either this or a three hour intervention on HIV and safer sex . Interviewers administered question naires at baseline and 12 and 24 months and blood was tested for HIV and HSV-2 . Main outcome measures Primary outcome measure : incidence of HIV . Other outcomes : incidence of HSV-2 , unwanted pregnancy , reported sexual practice s , depression , and substance misuse . Results There was no evidence that Stepping Stones lowered the incidence of HIV ( adjusted incidence rate ratio 0.95 , 95 % confidence interval 0.67 to 1.35 ) . The programme was associated with a reduction of about 33 % in the incidence of HSV-2 ( 0.67 , 0.46 to 0.97 ; P=0.036)—that is , Stepping Stones reduced the number of new HSV-2 infections over a two year period by 34.9 ( 1.6 to 68.2 ) per 1000 people exposed . Stepping Stones significantly improved a number of reported risk behaviours in men , with a lower proportion of men reporting perpetration of intimate partner violence across two years of follow-up and less transactional sex and problem drinking at 12 months . In women desired behaviour changes were not reported and those in the Stepping Stones programme reported more transactional sex at 12 months . Conclusion Stepping Stones did not reduce incidence of HIV but had an impact on several risk factors for HIV — notably , HSV-2 and perpetration of intimate partner violence . Trial Registration Clinical Trials NCT00332878 Objective The authors evaluated the use of conditional cash transfers as an HIV and sexually transmitted infection prevention strategy to incentivise safe sex . Design An unblinded , individually r and omised and controlled trial . Setting 10 villages within the Kilombero/Ulanga districts of the Ifakara Health and Demographic Surveillance System in rural south-west Tanzania . Participants The authors enrolled 2399 participants , aged 18–30 years , including adult spouses . Interventions Participants were r and omly assigned to either a control arm ( n=1124 ) or one of two intervention arms : low-value conditional cash transfer ( eligible for $ 10 per testing round , n=660 ) and high-value conditional cash transfer ( eligible for $ 20 per testing round , n=615 ) . The authors tested participants every 4 months over a 12-month period for the presence of common sexually transmitted infections . In the intervention arms , conditional cash transfer payments were tied to negative sexually transmitted infection test results . Anyone testing positive for a sexually transmitted infection was offered free treatment , and all received counselling . Main outcome measures The primary study end point was combined prevalence of the four sexually transmitted infections , which were tested and reported to subjects every 4 months : Chlamydia trachomatis , Neisseria gonorrhoeae , Trichomonas vaginalis and Mycoplasma genitalium . The authors also tested for HIV , herpes simplex virus 2 and syphilis at baseline and month 12 . Results At the end of the 12-month period , for the combined prevalence of any of the four sexually transmitted infections , which were tested and reported every 4 months ( C trachomatis , N gonorrhoeae , T vaginalis and M genitalium ) , unadjusted RR for the high-value conditional cash transfer arm compared to controls was 0.80 ( 95 % CI 0.54 to 1.06 ) and the adjusted RR was 0.73 ( 95 % CI 0.47 to 0.99 ) . Unadjusted RR for the high-value conditional cash transfer arm compared to the low-value conditional cash transfer arm was 0.76 ( 95 % CI 0.49 to 1.03 ) and the adjusted RR was 0.69 ( 95 % CI 0.45 to 0.92 ) . No harm was reported . Conclusions Conditional cash transfers used to incentivise safer sexual practice s are a potentially promising new tool in HIV and sexually transmitted infections prevention . Additional larger study would be useful to clarify the effect size , to calibrate the size of the incentive and to determine whether the intervention can be delivered cost effectively . Trial registration number NCT00922038 Clinical Trials.gov Background Peer-led sex education is widely believed to be an effective approach to reducing unsafe sex among young people , but reliable evidence from long-term studies is lacking . To assess the effectiveness of one form of school-based peer-led sex education in reducing unintended teenage pregnancy , we did a cluster ( school ) r and omised trial with 7 y of follow-up . Methods and Findings Twenty-seven representative schools in Engl and , with over 9,000 pupils aged 13–14 y at baseline , took part in the trial . Schools were r and omised to either peer-led sex education ( intervention ) or to continue their usual teacher-led sex education ( control ) . Peer educators , aged 16–17 y , were trained to deliver three 1-h classroom sessions of sex education to 13- to 14-y-old pupils from the same schools . The sessions used participatory learning methods design ed to improve the younger pupils ' skills in sexual communication and condom use and their knowledge about pregnancy , sexually transmitted infections ( STIs ) , contraception , and local sexual health services . Main outcome measures were abortion and live births by age 20 y , determined by anonymised linkage of girls to routine ( statutory ) data . Assessment of these outcomes was blind to sex education allocation . The proportion of girls who had one or more abortions before age 20 y was the same in each arm ( intervention , 5.0 % [ 95 % confidence interval ( CI ) 4.0%–6.3 % ] ; control , 5.0 % [ 95 % CI 4.0%–6.4 % ] ) . The odds ratio ( OR ) adjusted for r and omisation strata was 1.07 ( 95 % CI 0.80–1.42 , p = 0.64 , intervention versus control ) . The proportion of girls with one or more live births by 20.5 y was 7.5 % ( 95 % CI 5.9%–9.6 % ) in the intervention arm and 10.6 % ( 95 % CI 6.8%–16.1 % ) in the control arm , adjusted OR 0.77 ( 0.51–1.15 ) . Fewer girls in the peer-led arm self-reported a pregnancy by age 18 y ( 7.2 % intervention versus 11.2 % control , adjusted OR 0.62 [ 95 % CI 0.42–0.91 ] , weighted for non-response ; response rate 61 % intervention , 45 % control ) . There were no significant differences for girls or boys in self-reported unprotected first sex , regretted or pressured sex , quality of current sexual relationship , diagnosed sexually transmitted diseases , or ability to identify local sexual health services . Conclusion Compared with conventional school sex education at age 13–14 y , this form of peer-led sex education was not associated with change in teenage abortions , but may have led to fewer teenage births and was popular with pupils . It merits consideration within broader teenage pregnancy prevention strategies . Trial registration : IS RCT N ( IS RCT N94255362 ) Background Chlamydia is the most commonly diagnosed sexually transmitted infection ( STI ) in Engl and and has serious public health consequences . Young people carry a disproportionate burden of infection . A number of social cognition models identify risk appraisal as a primary motivator of behaviour suggesting that changing risk appraisal s for STIs may be an effective strategy in motivating protective behaviour . Meta-analytic evidence indicates that the relationship between risk appraisal and health behaviour is small , but studies examining this relationship have been criticised for their many conceptual and method ological weaknesses . The effect of risk appraisal on health behaviour may therefore be of larger size . The proposed study aims to examine the efficacy of an intervention to increase condom use intentions and behaviour amongst young people through changing chlamydia risk and coping appraisal s. Coping appraisal is targeted to avoid the intervention being counterproductive amongst recipients who do not feel able to perform the behaviour required to reduce the threat . An experimental design with follow-up , a conditional measure of risk appraisal , and analysis which controls for past behaviour , enable the relationship between risk appraisal and protective behaviour to be accurately assessed . Methods / Design The proposed study is a two-arm cluster r and omised controlled trial using a waiting-list control design to test the efficacy of the intervention compared to a control group . Participants will be school pupils aged 13–16 years old recruited from approximately ten secondary schools . Schools will be r and omised into each arm . Participants will receive their usual teaching on STIs but those in the intervention condition will additionally receive a single-session sex education lesson on chlamydia . Measures will be taken at baseline , post-intervention and at follow-up three months later . The primary outcome measure is intention to use condoms with casual sexual partners . Discussion As far as the authors are aware , this is the first controlled trial testing the efficacy of an intervention to increase condom use intentions and behaviour through changing chlamydia risk appraisal s. It is one of few experimental studies to accurately test the relationship between risk appraisal and pre caution ary sexual behaviour using a conditional measure of risk appraisal and controlling for past behaviour Background Low caste adolescent girls living in rural northern Karnataka are at increased risk of school drop-out , child marriage , and entry into sex-work , which enhances their vulnerability to HIV , early pregnancy and adverse maternal and child health outcomes . This protocol describes the evaluation of Samata , a comprehensive , multi-level intervention design ed to address these structural drivers of HIV risk and vulnerability . Methods / Design The Samata study is a cluster r and omised controlled trial that will be conducted in eighty village clusters ( 40 intervention ; 40 control ) in Bijapur and Bagalkot districts in northern Karnataka . The intervention seeks to reach low caste girls and their families ; adolescent boys ; village communities ; high school teachers and school governing committees ; and local government officials . All low caste ( scheduled caste/tribe ) adolescent girls attending 7th st and ard ( final year of primary school ) will be recruited into the study in two consecutive waves , one year apart . Girls ( n = 2100 ) , their families ( n = 2100 ) and school teachers ( n = 650 ) will be interviewed at baseline and at endline . The study is design ed to assess the impact of the intervention on four primary outcomes : the proportion of low caste girls who ( i ) enter into secondary school ; ( ii ) complete secondary school ; ( iii ) marry before age 15 ; and ( iv ) engage in sex before age 15 . Observers assessing the outcomes will be blinded to group assignment . The primary outcome will be an adjusted , cluster-level intention to treat analysis , comparing outcomes in intervention and control villages at follow-up . We will also conduct survival analyses for the following secondary outcomes : marriage , sexual debut , pregnancy and entry into sex work . Complementary monitoring and evaluation , qualitative and economic research will be used to explore and describe intervention implementation , the pathways through which change occurs , and the cost-effectiveness of the intervention . Discussion This is an innovative trial of a comprehensive intervention to improve the quality of life and reduce HIV vulnerability among marginalised girls in northern Karnataka . The findings will be of interest to programme implementers , policy makers and evaluation research ers working in the development , education , and sexual and reproductive health fields . Trial registration Clinical Trials . Gov NCT01996241 . 16th November 2013 OBJECTIVE Little research has tested HIV/sexually transmitted infection ( STI ) risk-reduction interventions ' effects on early adolescents as they age into middle and late adolescence . This study tested whether intervention-induced reductions in unprotected intercourse during a 12-month period endured over a 54-month period and whether the intervention reduced the prevalence of STIs , which increase risk for HIV . METHOD Grade 6 learners ( mean age = 12.4 years ) participated in a 12-month trial in Eastern Cape Province , South Africa , in which 9 matched pairs of schools were r and omly selected and within pairs r and omized to a theory-based HIV/STI risk-reduction intervention or an attention-control intervention . They completed 42- and 54-month postintervention measures of unprotected intercourse ( the primary outcome ) , other sexual behaviors , theoretical constructs , and , at 42- and 54-month follow-up only , biologically confirmed curable STIs ( chlamydial infection , gonorrhea , and trichomoniasis ) and herpes simplex virus 2 . RESULTS The HIV/STI risk-reduction intervention reduced unprotected intercourse averaged over the entire follow-up period ( OR = 0.42 , 95 % CI [ 0.22 , 0.84 ] ) , an effect not significantly reduced at 42- and 54-month follow-up compared with 3- , 6- , and 12-month follow-ups . The intervention caused positive changes on theoretical constructs averaged over the 5 follow-ups , although most effects weakened at long-term follow-up . Although the intervention 's main effect on STIs was nonsignificant , an Intervention Condition × Time interaction revealed that it significantly reduced curable STIs at 42-month follow-up in adolescents who reported sexual experience . CONCLUSION These results suggest that theory-based behavioral interventions with early adolescents can have long-lived effects in the context of a generalized severe HIV epidemic Abstract Young women in South Africa are at high risk for HIV infection . Cash transfers offer promise to reduce HIV risk . We present the design and baseline results from HPTN 068 , a phase III , individually r and omized trial to assess the effect of a conditional cash transfer on HIV acquisition among South African young women . A total of 2533 young women were r and omized to receive a monthly cash transfer conditional on school attendance or to a control group . A number of individual- , partner- , household- and school-level factors were associated with HIV and HSV-2 infection . After adjusting for age , all levels were associated with an increased odds of HIV infection with partner-level factors conveying the strongest association ( aOR 3.05 95 % CI 1.84–5.06 ) . Interventions like cash transfers that address structural factors such as schooling and poverty have the potential to reduce HIV risk in young women in South Africa Considering the prevalence and consequences of health-risking sexual behaviors ( HRSBs ) and STDs among young adults , their prevention is a public health priority . Emerging etiological and prevention outcome literature s suggested study of the long-term effects of universal family-focused interventions on young adult HRSBs and STDs . Although earlier studies have demonstrated intervention impact on adolescent substance misuse , no study has examined universal family-focused intervention effects on young adult HRSBs and STDs via reductions in adolescent misuse . Sixth grade students and their families enrolled in 33 rural Midwestern schools were r and omly assigned to experimental conditions . Self-report question naires provided data at pretest ( Ns = 238 , 221 , and 208 for the Iowa Strengthening Families Program [ ISFP ] , Preparing for the Drug Free Years [ PDFY ] , and control groups , respectively ) , with seven data points through young adulthood ( age 21 ) . In latent growth modeling , three young adult HRSB measures ( number of sexual partners , condom use , substance use with sex ) and lifetime STDs were specified as distal outcomes mediated by adolescent substance initiation growth factors ( average level and rate of change ) . Results showed that the models fit the data and , except for condom use , there were significant indirect effects , with a higher frequency of significant findings for ISFP . The model additions of direct intervention effects on young adult outcomes generally were not supported , consistent with a model positing that long-term intervention effects on young adult HRSBs and STDs outcomes are indirect . As an indication of the practical significance of long-term effects , analyses revealed relative reduction rates ranging from 6 % to 46 % for significant outcomes Objectives : This paper review s the potential intervention approaches that have been used to prevent HIV through reducing risky sexual behaviours , summarizes the evidence on their effectiveness , primarily from trials , and discusses the way forward both in terms of research and programmes . Methods : An up date of a recent systematic review of HIV prevention interventions , focusing on trials that have included HIV as an outcome . Results : Five major intervention approaches have been used : community-wide sexual health education , adolescent sexual health interventions , interventions among groups most at risk , promotion of HIV testing and counseling , and interventions among HIV-positive individuals . The latter have often been underemphasized in programmes and research . Effective targeting of interventions to prevent HIV acquisition requires an underst and ing of HIV incidence by age and sex , whereas HIV prevalence patterns are critical for targeting interventions to reduce HIV transmission ( positive prevention ) . Unfortunately , none of the nine behavioural r and omized trials with HIV outcomes have shown a significant impact on HIV . Sometimes this has clearly been due to issues in trial design such as inadequate sample size or low coverage , but not always . Although more encouraging , trials with behavioural outcomes only can not be used to assume an impact on HIV due to the potential for misreporting and biases in reported sexual behaviour . Conclusion : Future research and programmes should place greater emphasis on interventions to reduce HIV transmission as well as acquisition , the sexual norms of the wider population , include a focus on concurrency , and on greatly increasing community acceptance and use of condoms The objectives of this study were to examine ( 1 ) whether the onset of sexually transmitted infections ( STI ) through age 30 differed for youths who received a social developmental intervention during elementary grade s compared to those in the control condition ; ( 2 ) potential social-developmental mediators of this intervention ; and ( 3 ) the extent to which these results differed by ethnicity . A nonr and omized controlled trial followed participants to age 30 , 18 years after the intervention ended . Three intervention conditions were compared : a full-intervention group , assigned to intervention in grade s 1 through 6 ; a late intervention group , assigned to intervention in grade s 5 and 6 only ; and a no-treatment control group . Eighteen public elementary schools serving diverse neighborhoods including high-crime neighborhoods of Seattle are the setting of the study . Six hundred eight participants in three intervention conditions were interviewed from age 10 through 30 . Interventions include teacher training in classroom instruction and management , child social and emotional skill development , and parent workshops . Outcome is the cumulative onset of participant report of STI diagnosis . Adolescent family environment , bonding to school , antisocial peer affiliation , early sex initiation , alcohol use , cigarette use , and marijuana use were tested as potential intervention mechanisms . Complementary log – log survival analysis found significantly lower odds of STI onset for the full-intervention compared to the control condition . The lowering of STI onset risk was significantly greater for African Americans and Asian Americans compared to European Americans . Family environment , school bonding , and delayed initiation of sexual behavior mediated the relationship between treatment and STI hazard . A universal intervention for urban elementary school children , focused on classroom management and instruction , children ’s social competence , and parenting practice s may reduce the onset of STI through age 30 , especially for African Americans BACKGROUND Lack of education and an economic dependence on men are often suggested as important risk factors for HIV infection in women . We assessed the efficacy of a cash transfer programme to reduce the risk of sexually transmitted infections in young women . METHODS In this cluster r and omised trial , never-married women aged 13 - 22 years were recruited from 176 enumeration areas in the Zomba district of Malawi and r and omly assigned with computer-generated r and om numbers by enumeration area ( 1:1 ) to receive cash payments ( intervention group ) or nothing ( control group ) . Intervention enumeration areas were further r and omly assigned with computer-generated r and om numbers to conditional ( school attendance required to receive payment ) and unconditional ( no requirements to receive payment ) groups . Participants in both intervention groups were r and omly assigned by a lottery to receive monthly payments ranging from US$ 1 to $ 5 , while their parents were independently assigned with computer-generated r and om numbers to receive $ 4 - 10 . Behavioural risk assessment s were done at baseline and 12 months ; serology was tested at 18 months . Participants were not masked to treatment status but counsellors doing the serologic testing were . The primary outcomes were prevalence of HIV and herpes simplex virus 2 ( HSV-2 ) at 18 months and were assessed by intention-to-treat analyses . The trial is registered , number NCT01333826 . FINDINGS 88 enumeration areas were assigned to receive the intervention and 88 as controls . For the 1289 individuals enrolled in school at baseline with complete interview and biomarker data , weighted HIV prevalence at 18 month follow-up was 1·2 % ( seven of 490 participants ) in the combined intervention group versus 3·0 % ( 17 of 799 participants ) in the control group ( adjusted odds ratio [ OR ] 0·36 , 95 % CI 0·14 - 0·91 ) ; weighted HSV-2 prevalence was 0·7 % ( five of 488 participants ) versus 3·0 % ( 27 of 796 participants ; adjusted OR 0·24 , 0·09 - 0·65 ) . In the intervention group , we noted no difference between conditional versus unconditional intervention groups for weighted HIV prevalence ( 3/235 [ 1 % ] vs 4/255 [ 2 % ] ) or weighted HSV-2 prevalence ( 4/233 [ 1 % ] vs 1/255 [ < 1 % ] ) . For individuals who had already dropped out of school at baseline , we detected no significant difference between intervention and control groups for weighted HIV prevalence ( 23/210 [ 10 % ] vs 17/207 [ 8 % ] ) or weighted HSV-2 prevalence ( 17/211 [ 8 % ] vs 17/208 [ 8 % ] ) . INTERPRETATION Cash transfer programmes can reduce HIV and HSV-2 infections in adolescent schoolgirls in low-income setting s. Structural interventions that do not directly target sexual behaviour change can be important components of HIV prevention strategies . FUNDING Global Development Network , Bill & Melinda Gates Foundation , National Bureau of Economic Research Africa Project , World Bank 's Research Support Budget , and several World Bank trust funds ( Gender Action Plan , Knowledge for Change Program , and Spanish Impact Evaluation fund ) BACKGROUND We examined the differential impact of a well-established human immunodeficiency virus (HIV)/sexually transmitted infections ( STIs ) curriculum , Be Proud ! Be Responsible ! , when taught by school nurses and health education classroom teachers within a high school curricula . METHODS Group-r and omized intervention study of 1357 ninth and tenth grade students in 10 schools . Twenty-seven facilitators ( 6 nurses , 21 teachers ) provided programming ; nurse-led classrooms were r and omly assigned . RESULTS Students taught by teachers were more likely to report their instructor to be prepared , comfortable with the material , and challenged them to think about their health than students taught by a school nurse . Both groups reported significant improvements in HIV/STI/condom knowledge immediately following the intervention , compared to controls . Yet , those taught by school nurses reported significant and sustained changes ( up to 12 months after intervention ) in attitudes , beliefs , and efficacy , whereas those taught by health education teachers reported far fewer changes , with sustained improvement in condom knowledge only . CONCLUSIONS Both classroom teachers and school nurses are effective in conveying reproductive health information to high school students ; however , teaching the technical ( eg , condom use ) and interpersonal ( eg , negotiation ) skills needed to reduce high-risk sexual behavior may require a unique set of skills and experiences that health education teachers may not typically have PURPOSE The purpose of this study was to evaluate the impact of a rights-based sexuality education curriculum on adolescents ' sexual health behaviors and psychosocial outcomes 1 year after participation . METHODS Within 10 urban high schools , ninth- grade classrooms were r and omized to receive a rights-based curriculum or a basic sex education ( control ) curriculum . The intervention was delivered across two school years ( 2011 - 2012 , 2012 - 2013 ) . Surveys were completed by 1,447 students at pretest and 1-year follow-up . Multilevel analyses examined curriculum effects on behavioral and psychosocial outcomes , including four primary outcomes : pregnancy risk , sexually transmitted infection risk , multiple sexual partners , and use of sexual health services . RESULTS Students receiving the rights-based curriculum had higher scores than control curriculum students on six of nine psychosocial outcomes , including sexual health knowledge , attitudes about relationship rights , partner communication , protection self-efficacy , access to health information , and awareness of sexual health services . These students also were more likely to report use of sexual health services ( odds ratio , 1.37 ; 95 % confidence interval , 1.05 - 1.78 ) and more likely to be carrying a condom ( odds ratio , 1.97 ; 95 % confidence interval , 1.39 - 2.80 ) relative to those receiving the control curriculum . No effects were found for other sexual health behaviors , possibly because of low prevalence of sexual activity in the sample . CONCLUSIONS The curriculum had significant , positive effects on psychosocial and some behavioral outcomes 1 year later , but it might not be sufficient to change future sexual behaviors among younger adolescents , most of whom are not yet sexually active . Booster education sessions might be required throughout adolescence as youth initiate sexual relationships OBJECTIVES We ( 1 ) evaluated the impact of an evidence -based HIV prevention program with and without a parent component among mid-adolescents living in the Caribbean and ( 2 ) determined the effect of prior receipt of a related intervention during preadolescence on intervention response . METHODS A r and omized , controlled 4-cell trial of a 10-session , theory-based HIV prevention intervention involving 2564 Bahamian grade -10 youths ( some of whom had received a comparable intervention in grade 6 ) was conducted ( 2008 - 2011 ) . R and omization occurred at the level of the classroom with follow-up at 6 , 12 , and 18 months after intervention . The 3 experimental conditions all included the youths ' curriculum and either a youth-parent intervention emphasizing adolescent-parent communication , a parent-only goal - setting intervention , or no parent intervention . RESULTS An intervention delivered to mid-adolescents in combination with a parent-adolescent sexual-risk communication intervention increased HIV/AIDS knowledge , condom-use skills , and self-efficacy and had a marginal effect on consistent condom use . Regardless of prior exposure to a similar intervention as preadolescents , youths benefited from receipt of the intervention . CONCLUSIONS Preadolescents and mid-adolescents in HIV-affected countries should receive HIV prevention interventions that include parental participation Objective A sexual health survey among rural Zimbabwean youth was used to compare the validity and reliability of sexual behaviour measures between four question naire delivery modes . Methods Using a r and om permuted block design , 1495 youth were r and omised to one of four question naire delivery modes : self-administered question naire ( SAQ=373 ) ; SAQ accompanied by an audio soundtrack ( Audio-SAQ=376 ) ; face-to-face interview with sensitive questions placed in a confidential voting box ( Informal confidential voting interview ; ICVI=365 ) ; and audio computer-assisted survey instrument ( ACASI=381 ) . Key questions were selected a priori to compare item non-response and rates of reporting of sensitive behaviours between question naire delivery modes . Qualitative data were collected on perceived method acceptability ( n=115 ) . Results Item non-response was significantly higher with SAQ and Audio-SAQ than with ICVI and ACASI ( p<0.001 ) . After adjusting for covariates , the odds of reporting sexual activity among Audio-SAQ and ACASI users were twice as high as the odds for SAQ users ( Audio-SAQ AOR=2.05 ( 95 % CI 1.2 to 3.4 ) ; ACASI AOR=2.0 ( 95 % CI 1.2 to 3.2 ) ) , with no evidence of reporting difference between ICVI and SAQ users ( ICVI AOR=1.0 ( 95 % CI 0.6 to 1.8 ) ) . ACASI users reported a lower age at first intercourse and were more likely to report a greater number of partners ( mean difference=1.06 ; 95 % CI 0.33 to 1.78 ; p=0.004 ) . They reported an increased ability to answer questions honestly ( p=0.004 ) and believed their answers would be kept secret . Participants cl aim ed increased comprehension when hearing questions while reading them . ICVI users expressed difficulty answering sensitive questions , despite underst and ing that their answers were unknown to the interviewer . Conclusion ACASI appears to reduce bias significantly , and is feasible and acceptable in re source -poor setting s with low computer literacy . Its increased use would likely improve the quality of question naire data in general and sexual behaviour data specifically PURPOSE Familias Unidas is an efficacious and effective family-based intervention for preventing and reducing substance use and unsafe sexual behaviors among Latino youth . To facilitate its dissemination , Familias Unidas was shortened from a 12-week intervention to a 6-week intervention and evaluated . We hypothesized that brief Familias Unidas would be efficacious in reducing substance use and unsafe sexual behaviors relative to a comparison condition . METHODS We r and omized 160 ninth- grade Latino adolescents and their families to brief Familias Unidas or a community practice control condition . Adolescents were surveyed at baseline and 6 , 12 , and 24 months after baseline . RESULTS At 24 months , youth r and omized to brief Familias Unidas had a significantly lower sexual initiation rate ( 34.0 % ) relative to control ( 55.0 % ) , p = .02 . Brief Familias Unidas also increased positive parenting . Moderation analyses revealed that brief Familias Unidas was significantly associated with decreased substance use initiation among girls ( 30.4 % vs. 64.0 % , respectively ; p = .02 ) , but not boys ( 28.0 % vs. 26.7 % , respectively ; p = .91 ) . Brief Familias Unidas was also significantly associated with reduced unsafe sex among adolescents aged 15 years or less ( p < .001 ) , but not among older adolescents ( p = .37 ) . Moderating effects were also found for family-level variables . CONCLUSIONS Brief Familias Unidas was efficacious in reducing sex initiation and improving positive parenting . Moderation analyses suggested that brief Familias Unidas was efficacious in reducing substance use initiation and unsafe sex for certain Hispanic adolescent subgroups , highlighting the importance of conducting moderation analyses , and of targeting interventions for specific subgroups BACKGROUND Competencies for adolescents with a healthy sexuality ( COMPAS ) is the only school-based sexual health promotion program in Spain that has been found to be as effective as an evidence -based intervention ( ¡ Cuí date ! ) in the short term . This study 's aim was to compare data from a 12-month follow-up evaluation on the effects of COMPAS on adolescents ' sexual risks ( knowledge , attitudes , perceived norms , sexual risk perception and intentions ) and sexual behaviours ( age of the first sex , consistent condom use and multiple partners ) with an evidence -based intervention ( ¡ Cuí date ! ) and a control group . METHODS Eighteen schools from five provinces of Spain were r and omly assigned to one of three conditions : COMPAS , ¡ Cuí date ! and a control group . The adolescents ( N = 1563 ; 34 % attrition ) were evaluated 1 week before and after the program , and 1 year post-program implementation . RESULTS We found that the COMPAS program was as effective as ¡ Cuí date ! , the evidence -based program , in increasing the adolescents ' knowledge about sexually transmitted infections and in fostering favourable attitudes about condom use and people living with HIV/AIDS . COMPAS was more effective than ¡ Cuí date ! in increasing the adolescents ' perceptions of their peer 's consistent condom use and the age delay of their first vaginal intercourse . However , it was less effective in maintaining the adolescents ' intentions to use condoms and in delaying the age of their first oral sex experience . CONCLUSION COMPAS was as effective as ¡ Cuí date ! in reducing sexual risk among adolescents Abstract African American women at increased risk of HIV/sexually transmitted infection ( STI ) may engage in risky sex as a coping mechanism for depressed economic conditions . This study examines the association between high-risk sexual behavior and structural determinants of sexual health among a sample of young African American women . 237 young African American women ( 16–19 years old ) from economically disadvantaged neighborhoods in North Carolina were enrolled into a r and omized trial testing the efficacy of an adapted HIV/STI prevention intervention . Logistic regression analyses predicted the likelihood that young women reporting lack of food at home , homelessness and low future prospect s would also report sexual risk behaviors . Young women reporting a lack of food at home ( 22 % ) , homelessness ( 27 % ) , and low perceived education/employment prospect s ( 19 % ) had between 2.2 and 4.7 times the odds as those not reporting these risk factors of reporting multiple sex partners , risky sex partners including older men and partners involved in gangs , substance use prior to sex , and exchange sex . Self-reported structural determinants of sexual health were associated with myriad sexual risk behaviors . Diminished economic conditions among these young women may lead to sexual risk due to hopelessness , the need for survival or other factors Controlled trials of HIV prevention and care interventions are susceptible to contamination . In a r and omized controlled trial of a social network peer education intervention among people who inject drugs and their risk partners in Philadelphia , PA and Chiang Mai , Thail and , we tested a contamination measure based on recall of intervention terms . We assessed the recall of test , negative and positive control terms among intervention and control arm participants and compared the relative odds of recall of test versus negative control terms between study arms . The contamination measures showed good discriminant ability among participants in Chiang Mai . In Philadelphia there was no evidence of contamination and little evidence of diffusion . In Chiang Mai there was strong evidence of diffusion and contamination . Network structure and peer education in Chiang Mai likely led to contamination . Recall of intervention material s can be a useful method to detect contamination in experimental interventions .ResumenEnsayos controlados de intervenciones de prevención y atención del VIH son susceptibles a la contaminación . En un ensayo controlado aleatorio de una red social intervención de educación inter pares entre personas que se inyectan drogas y sus socios de riesgo en Filadelfia , PA y Chiang Mai , Tail and ia , probamos una medida contaminación basada en el recuerdo de los términos de intervención . Se evaluó el recuerdo de la prueba , las condiciones de control negativos y positivos entre los participantes de la intervención y del brazo de control y se compararon las probabilidades relativas ( OR ) de retirada de prueba vs. términos de control negativo entre los brazos del estudio . Las medidas de contaminación mostraron buena capacidad discriminante entre los participantes en Chiang Mai . En Filadelfia no había pruebas de contaminación y poca evidencia de la difusión . En Chiang Mai hubo una fuerte evidencia de la difusión y la contaminación . Estructura de la red y la educación entre pares en Chiang Mai probablemente llevaron a la contaminación . Llamada a revisión de material es de intervención puede ser un método útil para detectar la contaminación en las intervenciones experimentales CONTEXT African American adolescent girls are at high risk for human immunodeficiency virus ( HIV ) infection , but interventions specifically design ed for this population have not reduced HIV risk behaviors . OBJECTIVE To evaluate the efficacy of an intervention to reduce sexual risk behaviors , sexually transmitted diseases ( STDs ) , and pregnancy and enhance mediators of HIV-preventive behaviors . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial of 522 sexually experienced African American girls aged 14 to 18 years screened from December 1996 through April 1999 at 4 community health agencies . Participants completed a self-administered question naire and an interview , demonstrated condom application skills , and provided specimens for STD testing . Outcome assessment s were made at 6- and 12-month follow-up . INTERVENTION All participants received four 4-hour group sessions . The intervention emphasized ethnic and gender pride , HIV knowledge , communication , condom use skills , and healthy relationships . The comparison condition emphasized exercise and nutrition . MAIN OUTCOME MEASURES The primary outcome measure was consistent condom use , defined as condom use during every episode of vaginal intercourse ; other outcome measures were sexual behaviors , observed condom application skills , incident STD infection , self-reported pregnancy , and mediators of HIV-preventive behaviors . RESULTS Relative to the comparison condition , participants in the intervention reported using condoms more consistently in the 30 days preceding the 6-month assessment ( unadjusted analysis , intervention , 75.3 % vs comparison , 58.2 % ) and the 12-month assessment ( unadjusted analysis , intervention , 73.3 % vs comparison , 56.5 % ) and over the entire 12-month period ( adjusted odds ratio , 2.01 ; 95 % confidence interval [ CI ] , 1.28 - 3.17 ; P = .003 ) . Participants in the intervention reported using condoms more consistently in the 6 months preceding the 6-month assessment ( unadjusted analysis , intervention , 61.3 % vs comparison , 42.6 % ) , at the 12-month assessment ( unadjusted analysis , intervention , 58.1 % vs comparison , 45.3 % ) , and over the entire 12-month period ( adjusted odds ratio , 2.30 ; 95 % CI , 1.51 - 3.50 ; P<.001 ) . Using generalized estimating equation analyses over the 12-month follow-up , adolescents in the intervention were more likely to use a condom at last intercourse , less likely to have a new vaginal sex partner in the past 30 days , and more likely to apply condoms to sex partners and had better condom application skills , a higher percentage of condom-protected sex acts , fewer unprotected vaginal sex acts , and higher scores on measures of mediators . Promising effects were also observed for chlamydia infections and self-reported pregnancy . CONCLUSION Interventions for African American adolescent girls that are gender-tailored and culturally congruent can enhance HIV-preventive behaviors , skills , and mediators and may reduce pregnancy and chlamydia infection Postponing Sexual Involvement ( PSI ) is a widely implemented middle school curriculum design ed to delay the onset of sexual intercourse . In an evaluation of its effectiveness among seventh and eighth grade rs in California , 10,600 youths from schools and community-based organizations statewide were recruited and participated in r and omly assigned intervention or control groups ; the curriculum was implemented by either adult or youth leaders . Survey data were collected before the program was implemented , and at three months and 17 months afterward . At three months , small but statistically significant changes were found in fewer than half of the measured attitudes , behaviors and intentions related to sexual activity ; at 17 months , none of these significant positive effects of the PSI program had been sustained . At neither follow-up were there significant positive changes in sexual behavior ; Youths in treatment and control groups were equally likely to have become sexually active , and youths in treatment groups were not less likely than youths in control groups to report a pregnancy or a sexually transmitted infection . The evaluation suggests that PSI may be too modest in length and scope to have an impact on youths ' sexual behavior BACKGROUND Improvement of sex education in schools is a key part of the UK government 's strategy to reduce teenage pregnancy in Engl and . We examined the effectiveness of one form of peer-led sex education in a school-based r and omised trial of over 8000 pupils . METHODS 29 schools were r and omised to either peer-led sex education ( intervention ) or to continue their usual teacher-led sex education ( control ) . In intervention schools , peer educators aged 16 - 17 years delivered three sessions of sex education to 13 - 14 year-old pupils from the same schools . Primary outcome was unprotected ( without condom ) first heterosexual intercourse by age 16 years . Analysis was by intention to treat . FINDINGS By age 16 years , significantly fewer girls reported intercourse in the peer-led arm than in the control arm , but proportions were similar for boys . The proportions of pupils reporting unprotected first sex did not differ for girls ( 8.4 % intervention vs 8.3 % control ) or for boys ( 6.2 % vs 4.7 % ) . Stratified estimates of the difference between arms were -0.4 % ( 95 % CI -3.7 % to 2.8 % , p=0.79 ) for girls and -1.4 % ( -4.4 % to 1.6 % , p=0.36 ) for boys . At follow-up ( mean age 16.0 years [ SD 0.32 ] ) , girls in the intervention arm reported fewer unintended pregnancies , although the difference was borderline ( 2.3 % vs 3.3 % , p=0.07 ) . Girls and boys were more satisfied with peer-led than teacher-led sex education , but 57 % of girls and 32 % of boys wanted sex education in single-sex groups . INTERPRETATION Peer-led sex education was effective in some ways , but broader strategies are needed to improve young people 's sexual health . The role of single-sex sessions should be investigated further BACKGROUND Young people who engage in substance use are at risk for becoming infected with HIV and diseases with similar transmission dynamics . Effective disease prevention programs delivered by prevention specialists exist but are rarely provided in systems of care due to staffing/re source constraints and operational barriers- and are thus of limited reach . Web-based prevention interventions could possibly offer an effective alternative to prevention specialist-delivered interventions and may enable widespread , cost-effective access to evidence -based prevention programming . Previous research has shown the HIV/disease prevention program within the Web-based therapeutic education system ( TES ) to be an effective adjunct to a prevention specialist-delivered intervention . The present study was the first r and omized , clinical trial to evaluate the comparative effectiveness of this Web-based intervention as a st and alone intervention relative to a traditional , prevention specialist-delivered intervention . METHODS Adolescents entering outpatient treatment for substance use participated in this multi-site trial . Participants were r and omly assigned to either a traditional intervention delivered by a prevention specialist ( n=72 ) or the Web-delivered TES intervention ( n=69 ) . Intervention effectiveness was assessed by evaluating changes in participants ' knowledge about HIV , hepatitis , and sexually transmitted infections , intentions to engage in safer sex , sex-related risk behavior , self-efficacy to use condoms , and condom use skills . FINDINGS Participants in the TES intervention achieved significant and comparable increases in HIV/disease-related knowledge , condom use self-efficacy , and condom use skills and comparable decreases in HIV risk behavior relative to participants who received the intervention delivered by a prevention specialist . Participants rated TES as easier to underst and . CONCLUSION This study indicates that TES is as effective as HIV/disease prevention delivered by a prevention specialist . Because technology-based interventions such as TES have high fidelity , are inexpensive and scalable , and can be implemented in a wide variety of setting s , they have the potential to greatly increase access to effective prevention programming Objective : The impact of a multicomponent intervention programme on the sexual health of adolescents was assessed in rural Tanzania . Design : A community-r and omized trial . Methods : Twenty communities were r and omly allocated to receive either a specially design ed programme of interventions ( intervention group ) or st and ard activities ( comparison group ) . The intervention had four components : community activities ; teacher-led , peer-assisted sexual health education in years 5–7 of primary school ; training and supervision of health workers to provide ‘ youth-friendly ’ sexual health services ; and peer condom social marketing . Impacts on HIV incidence , herpes simplex virus 2 ( HSV2 ) and other sexual health outcomes were evaluated over approximately 3 years in 9645 adolescents recruited in late 1998 before entering years 5 , 6 or 7 of primary school . Results : The intervention had a significant impact on knowledge and reported attitudes , reported sexually transmitted infection symptoms , and several behavioural outcomes . Only five HIV seroconversions occurred in boys , whereas in girls the adjusted rate ratio ( intervention versus comparison ) was 0.75 [ 95 % confidence interval ( CI ) 0.34 , 1.66 ] . Overall HSV2 prevalences at follow-up were 11.9 % in male and 21.1 % in female participants , with adjusted prevalence ratios of 0.92 ( CI 0.69 , 1.22 ) and 1.05 ( CI 0.83 , 1.32 ) , respectively . There was no consistent beneficial or adverse impact on other biological outcomes . The beneficial impact on knowledge and reported attitudes was confirmed by results of a school examination in a separate group of students in mid-2002 . Conclusion : The intervention substantially improved knowledge , reported attitudes and some reported sexual behaviours , especially in boys , but had no consistent impact on biological outcomes within the 3-year trial period Parent involvement in prevention efforts targeting adolescents increases the impact of such programs . However , the majority of risk-reduction intervention programs that are implemented through schools do not include parents , in part because most existing parental interventions require significant time commitment by parents . We design ed a brief parent-adolescent sexual risk communication intervention to be delivered with an effective HIV prevention intervention as part of a r and omized , controlled trial among 2,564 grade 10 students and their parents in the Bahamas . Mixed effects modeling analysis was conducted to evaluate the effect of the brief parent-adolescent communication intervention using four waves of longitudinal data . Results indicate that a brief parent-adolescent communication intervention is effective in improving parent-adolescent communication on sex-related issues and perceived parental monitoring as well as the youth 's condom use skills and self-efficacy . There is a marginal effect on consistent condom use . In addition , there is an apparent dose effect of the brief parent intervention on perceived parent-adolescent sexual risk communication and adolescent outcomes . These findings suggest that adolescent risk reduction interventions should include a brief parent-adolescent communication intervention that should be reinforced by periodic boosters in order to enhance the impact of adolescent HIV prevention programs PURPOSE To evaluate a health systems intervention to increase adolescents ' receipt of high- quality sexual and reproductive health care services . METHODS Quasi experimental design . Twelve high schools in a large public school district were matched into pairs . Within each pair , schools were assigned to condition so that no control school shared a geographic border with an intervention school . Five yearly surveys ( T1 , T2 , … , T5 ) were administered from 2005 to 2009 ( N = 29,823 ) to students in r and omly selected classes in grade s 9 - 12 . Community-based providers of high- quality sexual and reproductive health care services were listed on a referral guide for use by school nurses to connect adolescents to care . RESULTS Statistically significant effects were found for intervention school females on three outcomes , relative to controls . Relative to T1 , receipt of birth control in the past year was greater at T4 ( adjusted odds ratio [ AOR ] = 1.85 ; 95 % confidence interval [ CI ] , 1.09 - 3.15 ) and T5 ( AOR = 2.22 ; 95 % CI , 1.32 - 3.74 ) . Increases in sexually transmitted disease testing and /or treatment in the past year were greater in T1-T3 ( AOR = 1.78 ; 95 % CI , 1.05 - 3.02 ) , T1-T4 ( AOR = 1.73 ; 95 % CI , 1.01 - 2.97 ) , T1-T5 ( AOR = 1.97 ; 95 % CI , 1.17 - 3.31 ) , and T2-T5 ( AOR = 1.76 ; 95 % CI , 1.06 - 2.91 ) . Increases in ever receiving an HIV test were greater in T1-T4 ( AOR = 2.14 ; 95 % CI , 1.08 - 4.26 ) . Among males , no intervention effects were found . CONCLUSIONS A school-based structural intervention can improve female adolescents ' receipt of services The present study evaluated the efficacy of Familias Unidas + Parent-Preadolescent Training for HIV Prevention ( PATH ) , a Hispanic-specific , parent-centered intervention , in preventing adolescent substance use and unsafe sexual behavior . Two hundred sixty-six 8th- grade Hispanic adolescents and their primary caregivers were r and omly assigned to 1 of 3 conditions : Familias Unidas + PATH , English for Speakers of Other Language s ( ESOL ) + PATH , and ESOL + HeartPower ! for Hispanics ( HEART ) . Participants were assessed at baseline and at 6 , 12 , 24 , and 36 months postbaseline . Results showed that ( a ) Familias Unidas + PATH was efficacious in preventing and reducing cigarette use relative to both control conditions ; ( b ) Familias Unidas + PATH was efficacious , relative to ESOL + HEART , in reducing illicit drug use ; and ( c ) Familias Unidas + PATH was efficacious , relative to ESOL + PATH , in reducing unsafe sexual behavior . The effects of Familias Unidas + PATH on these distal outcomes were partially mediated by improvements in family functioning . These findings suggest that strengthening the family system , rather than targeting specific health behaviors , may be most efficacious in preventing and /or reducing cigarette smoking , illicit drug use , and unsafe sex in Hispanic adolescents Southeast Michigan accounts for over 70 % of all HIV/STI cases in the state , with young men who have sex with men ( YMSM ) between the ages of 13 and 24 encumbering the largest burden in HIV/STI incidence . Using community-based participatory research principles , we developed and pilot tested a web-based , r and omized control trial seeking to promote HIV/STI testing ( “ Get Connected ! ” ) among YMSM ( N = 130 ; ages 15–24 ) . R and omized participants completed a baseline assessment and shown a test-locator condition ( control ) or a tailored , personalized site ( treatment ) . At 30-day follow-up , we found high acceptability among YMSM in both conditions , yet higher credibility of intervention content among YMSM in the treatment group ( d = .55 ) . Furthermore , 30 participants reported testing by following , with the majority of these participants ( 73.3 % ; n = 22 ) completing the treatment condition , a clinical ly meaningful effect ( d = .34 ) suggesting preliminary efficacy for the intervention . These results demonstrate the potential of the intervention , and suggest that a larger efficacy trial may be warranted . ResumenEl Sudeste de Michigan contiene más del 70 % de todos los casos de VIH/ETS en el estado , con JHCH ( jóvenes hombres que tienen sexo con hombres ) entre las edades de 13 y 24 sufriendo la mayor incidencia de VIH/ETS . Utiliz and o los principios de investigación participativa y comunitaria , hemos desarrollado y examinado un proyecto piloto , con diseñode ensayo aleatorizado de control basado en promover la prueba de VIH/ETS ( “ Get Connected ! ” ) entre JHCH ( N = 130 entre los 15 y 24 años ) . Los JHCH completaron un cuestionario inicial y asignados a una condición control ( acceso a un localizador de pruebas ) o a un grupo de tratamiento ( un sitio web personalizado ) . A los 30 días de seguimiento , encontramos una alta aceptación a ambas condiciones de la intervención ; sin embargo , encontramos una mayor credibilidad al contenido entre los JHCH en el grupo de tratamiento ( d = .55 ) . Treinta participantes se reportaron haberse hecho una prueba de VIH/ETS durante el seguimiento , con la mayoría de los participantes ( 73.3 % , n = 22 ) siendo parte de la condición de tratamiento , un efecto clínicamente significativo ( d = .34 ) que sugiere la eficacia preliminar de la intervención . Estos result ados demuestran el potencial de laintervención , y sugieren un estudio de eficacia con una muestra más gr and e de JHCH OBJECTIVES We tested the efficacy of an intervention among 11- to 14-year-old adolescent boys to promote delay of sexual intercourse , condom use among those who were sexually active , and communication on sexuality between fathers ( or father figures ) and sons . METHODS Sites were r and omly assigned to the intervention and control groups . Assessment s were conducted prior to the intervention and at 3- , 6- , and 12-month follow-up interviews . RESULTS A total of 277 fathers and their sons completed baseline assessment s. Most participants were African American , and most fathers lived with their sons . Significantly higher rates of sexual abstinence and condom use and of intent to delay initiation of sexual intercourse were observed among adolescent boys whose fathers participated in the intervention . Fathers in the intervention group reported significantly more discussion s about sexuality and greater intentions to discuss sexuality than did control-group fathers . CONCLUSIONS The study demonstrates that fathers can serve as an important educator on HIV prevention and sexuality for their sons Early coital debut is a risk factor for HIV . In this paper we investigate the predictors of young adolescents ' transition to first intercourse using a social cognition theoretical framework . The analyses reported here were based on a longitudinal study of 2,360 students in the schools allocated to the control arm of a cluster-r and omized controlled trial to investigate the effect of a school-based HIV prevention programme among Grade 8 students in Cape Town . Structural equation modelling was performed with Mplus version 3.11 . Of the 1440 students who were virgins at baseline , 1,144 remained virgins 15 months later and 296 ( 20.6 % ) reported having had their first sexual intercourse . Transition to first sexual intercourse was more likely among males than females , among older students and among students with a lower socio-economic status . Transition to first sexual intercourse was significantly associated with intentions to have sexual intercourse , poor self-efficacy to negotiate delayed sex and intimate partner violence . The model predicted 35 % of the variance in intentions and 16 % of the variance in transition . These findings indicate some of the factors that influence young adolescent 's transition to first intercourse and that need to be addressed when design ing effective interventions OBJECTIVE To assess the effectiveness of a community-based HIV prevention intervention for adolescents in terms of its impact on ( 1 ) HIV and Herpes simplex virus type 2 ( HSV-2 ) incidence and on rates of unintended pregnancy and ( 2 ) reported sexual behaviour , knowledge and attitudes . METHODS Cluster r and omised trial of a multi-component HIV prevention intervention for adolescents based in rural Zimbabwe . Thirty communities were selected and r and omised in 2003 to early or deferred intervention implementation . A baseline bio-behavioural survey was conducted among 6791 secondary school pupils ( 86 % of eligibles ) prior to intervention implementation . RESULTS Baseline prevalences were 0.8 % ( 95 % CI : 0.6 - 1.0 ) for HIV and 0.2 % ( 95 % CI : 0.1 - 0.3 % ) for HSV-2 . Four girls ( 0.12 % ) were pregnant . There was excellent balance between study arms . Orphans who made up 35 % of the cohort were at increased risk of HIV [ age-sex adjusted odds ratio 3.4 ( 95 % CI : 1.7 - 6.5 ) ] . 11.9 % of young men and 2.9 % of young women reported that they were sexually active ( P < 0.001 ) ; however , there were inconsistencies in the sexual behaviour data . Girls were less likely to know about reproductive health issues than boys ( P < 0.001 ) and were less likely to have used and to be able to access condoms ( P < 0.001 ) . CONCLUSION This is one of the first rigorous evaluations of a community-based HIV prevention intervention for young people in southern Africa . The low rates of HIV suggest that the intervention was started before this population became sexually active . Inconsistency and under-reporting of sexual behaviour re-emphasise the importance of using externally vali date d measures of sexual risk reduction in behavioural intervention studies BACKGROUND Effective interventions to reduce the incidence of HIV , other sexually transmitted infections ( STIs ) and unwanted pregnancy among adolescents in sub-Saharan Africa are urgently needed . This paper describes the rationale and design of a r and omised trial of the impact of an innovative sexual health intervention among adolescents in rural Mwanza Region , Tanzania . METHODS The MEMA kwa Vijana intervention comprises a teacher-led , peer-assisted sexual health education programme for students in the last 3 years of primary school , training and supervision of health workers in the provision of youth-friendly health services , peer condom promotion and distribution , and wider community activities . Detailed process evaluation was conducted and the impact of the intervention was evaluated through a community-r and omised trial in which a cohort of 9645 adolescents was followed up for 3 years . Both process and impact evaluation used multiple assessment methods . Impact measures included incidence and prevalence of HIV and other STIs , pregnancy rates , knowledge and reported attitudes and sexual behaviour , as well as qualitative assessment s. RESULTS Results of the baseline survey of the cohort have been presented previously . The outcome of the trial will be reported separately . CONCLUSIONS Behaviour change interventions among adolescents have been widely advocated , but there have been few rigorously design ed trials of their effectiveness , particularly in developing countries , and measurement of sexual behaviour is particularly problematic in this age group . The MEMA kwa Vijana trial was undertaken to address these problems and to collect rigorous evidence on the effectiveness of an innovative intervention , design ed to be implemented on a very large scale PURPOSE Few computer-based HIV , sexually transmitted infection ( STI ) , and pregnancy prevention programs are available , and even fewer target early adolescents . In this study , we tested the efficacy of It 's Your Game (IYG)-Tech , a completely computer-based , middle school sexual health education program . The primary hypothesis was that students who received IYG-Tech would significantly delay sexual initiation by ninth grade . METHODS We evaluated IYG-Tech using a r and omized , two-arm nested design among 19 schools in a large , urban school district in southeast Texas ( 20 schools were originally r and omized ) . The target population was English-speaking eighth- grade students who were followed into the ninth grade . The final analytic sample included 1,374 students . Multilevel logistic regression models were used to test for differences in sexual initiation between intervention and control students , while adjusting for age , gender , ethnicity , time between measures , and family structure . RESULTS There was no significant difference in the delay of sexual activity or in any other sexual behavior between intervention and control students . However , there were significant positive between-group differences for psychosocial variables related to STI and condom knowledge , attitudes about abstinence , condom use self-efficacy , and perceived norms about sex . Post hoc analyses conducted among intervention students revealed some significant associations : " full exposure " ( completion of all 13 lessons ) and " mid-exposure " ( 5 - 8 lessons ) students were less likely than " low exposure " ( 1 - 4 lessons ) students to initiate sex . CONCLUSIONS Collectively , our findings indicate that IYG-Tech impacts some determinants of sexual behavior , and that additional efficacy evaluation with full intervention exposure may be warranted OBJECTIVES This study evaluated the long-term effectiveness of Draw the Line/Respect the Line , a theoretically based curriculum design ed to reduce sexual risk behaviors among middle school adolescents . METHODS The r and omized controlled trial involved 19 schools in northern California . A cohort of 2829 sixth grade rs was tracked for 36 months . RESULTS The intervention delayed sexual initiation among boys , but not girls . Boys in the intervention condition also exhibited significantly greater knowledge than control students , perceived fewer peer norms supporting sexual intercourse , had more positive attitudes toward not having sex , had stronger sexual limits , and were less likely to be in situations that could lead to sexual behaviors . Psychosocial effects for girls were limited . CONCLUSIONS The program was effective for boys , but not for girls OBJECTIVE To assess the feasibility of conducting a large r and omised controlled trial ( RCT ) of peer led intervention in schools to reduce the risk of HIV/STD and promote sexual health . METHODS Four secondary schools in Greater London were r and omly assigned to receive peer led intervention ( two experimental schools ) or to act as control schools . In the experimental schools , trained volunteers aged 16 - 17 years ( year 12 ) delivered the peer led intervention to 13 - 14 year old pupils ( year 9 ) . In the control schools , year 9 pupils received the usual teacher led sex education . Question naire data collected from year 9 pupils at baseline included views on the quality of sex education/intervention received , and knowledge and attitudes about HIV/AIDS and other sexual matters . Focus groups were also conducted with peer educators and year 9 pupils . Data on the process of delivering sex education/intervention and on attitudes to the RCT were collected for each of the schools . Analysis focused on the acceptability of a r and omised trial to schools , parents , and pupils . RESULTS Nearly 500 parents were informed about the research and invited to examine the study question naire ; only nine raised questions and only one pupil was withdrawn from the study . Question naire completion rates were around 90 % in all schools . At baseline , the majority of year 9 pupils wanted more information about a wide range of sexual matters . Focus group work indicated considerable enthusiasm for peer led education , among peer educators and year 9 pupils . Class discipline was the most frequently noted problem with the delivery of the peer led intervention . CONCLUSION Evaluation of a peer led behavioural intervention through an RCT can be acceptable to schools , pupils , and parents and is feasible in practice . In general , pupils who received the peer led intervention responded more positively than those in control schools . A large RCT of the long term ( 5 - 7 year ) effects of this novel intervention on sexual health outcomes is now under way African American women in the United States experience significant HIV health disparities . The majority of evidence -based risk reduction interventions do not incorporate HIV testing , and most are targeted only to narrow segments of the population such as women who are pregnant or seen in STI clinics . This pilot study assessed the feasibility and efficacy of The Girlfriends Project ( TGP ) , a community developed and community evaluated HIV risk reduction and testing intervention . A group r and omized wait-list design was used to recruit 149 women and to compare findings for intervention group versus control group participants . Women in the intervention group demonstrated statistically-significant increases in HIV knowledge scores and in condom use during vaginal sex . Eighty-seven percent of participants accessed HIV testing with a 100 % return rate for results . Study findings suggest that TGP has the potential to be an effective intervention and to increase number of African American women who access HIV testing OBJECTIVE This secondary data analysis sought to determine what mediated reductions in self-reported sexual initiation over the 24-month postintervention period in early adolescents who received " Promoting Health among Teens , " a theory-based , abstinence-only intervention ( Jemmott , Jemmott , & Fong , 2010 ) . METHOD African American Grade 6 and 7 students at inner-city public middle schools were r and omized to 1 of 5 interventions grounded in social-cognitive theory and the theory of reasoned action : 8-hr abstinence-only targeting reduced sexual intercourse ; 8-hr safer-sex-only targeting increased condom use ; 8-hr and 12-hr comprehensive interventions targeting sexual intercourse and condom use ; 8-hr control intervention targeting physical activity and diet . Primary outcome was self-report of vaginal intercourse by 24 months postintervention . Potential mediators , assessed immediately postintervention , were theory-of-reasoned-action variables , including behavioral beliefs about positive consequences of abstinence and negative consequences of sex , intention to have sex , normative beliefs about sex , and HIV and sexually transmitted infection ( STI ) knowledge . We tested single and serial mediation models using the product-of-coefficients approach . RESULTS Of 509 students reporting never having vaginal intercourse at baseline ( 324 girls and 185 boys ; mean age = 11.8 years , SD = 0.8 ) , 500 or 98.2 % were included in serial mediation analyses . Consistent with the theory of reasoned action , the abstinence-only intervention increased positive behavioral beliefs about abstinence , which reduced intention to have sex , which in turn reduced sexual initiation . Negative behavioral beliefs about sex , normative beliefs about sex , and HIV/STI knowledge were not mediators . CONCLUSIONS Abstinence-only interventions should stress the gains to be realized from abstinence rather than the deleterious consequences of sexual involvement PURPOSE To evaluate the efficacy of two , theory-based , multimedia , middle school sexual education programs in delaying sexual initiation . METHODS Three-armed , r and omized controlled trial comprising 15 urban middle schools ; 1,258 predominantly African American and Hispanic seventh grade students followed into ninth grade . Both programs included group and individualized , computer-based activities addressing psychosocial variables . The risk avoidance ( RA ) program met federal abstinence education guidelines ; the risk reduction ( RR ) program emphasized abstinence and included computer-based condom skills-training . The primary outcome assessed program impact on delayed sexual initiation ; secondary outcomes assessed other sexual behaviors and psychosocial outcomes . RESULTS Participants were 59.8 % females ( mean age : 12.6 years ) . Relative to controls , the RR program delayed any type of sexual initiation ( oral , vaginal , or anal sex ) in the overall sample ( adjusted odds ratio [ AOR ] : .65 , 95 % CI : .54-.77 ) , among females ( AOR : .43 , 95 % CI : .31-.60 ) , and among African Americans ( AOR : .38 , 95 % CI : .18-.79 ) . RR students also reduced unprotected sex at last intercourse ( AOR : .67 , 95 % CI : .47-.96 ) , frequency of anal sex in the past 3 months ( AOR : .53 , 95 % CI : .33-.84 ) , and unprotected vaginal sex ( AOR : .59 , 95 % CI : .36-.95 ) . The RA program delayed any sexual initiation among Hispanics ( AOR : .40 , 95 % CI : .19-.86 ) , reduced unprotected sex at last intercourse ( AOR : .70 , 95 % CI : .52-.93 ) , but increased the number of recent vaginal sex partners ( AOR : 1.69 , 95 % CI : 1.01 - 2.82 ) . Both programs positively affected psychosocial outcomes . CONCLUSIONS The RR program positively affected sexually inexperienced and experienced youth , whereas the RA program delayed initiation among Hispanics and had mixed effects among sexually experienced youth This article reports on a combined family-based substance abuse and HIV-prevention intervention targeting families with 13–14-year-old children in Bangkok , Thail and . Families ( n = 340 ) were r and omly and proportionally selected from 7 districts in Bangkok with half r and omly assigned to an experimental or control condition . Families in the intervention condition were exposed to 5 interactive booklets about adolescent substance use and risky sexual behavior . Trained health educators followed up by phone to encourage completion of each booklet . Primary outcomes reported in this article include whether the intervention increased the frequency of parent – child communication in general or about sexual risk taking in particular as well as whether the intervention reduced discomfort discussing sexual issues . The authors also tested to see whether booklet completion was associated with communication outcomes at the 6-month follow-up . Multivariate findings indicate that the intervention had a significant impact on the frequency of general parent – child communication on the basis of child reports . The intervention had a marginal impact on the frequency of parent – child communication about sexual issues on the basis of parent reports . Booklet completion was associated with reduced discomfort discussing sex and was marginally associated with frequency of parent – child discussion of sex on the basis of parent reports only . These findings indicate that a family-based program can influence communication patterns Fuzzy-trace theory is a theory of memory , judgment , and decision making , and their development . We applied advances in this theory to increase the efficacy and durability of a multicomponent intervention to promote risk reduction and avoidance of premature pregnancy and sexually transmitted infections . Seven hundred and thirty-four adolescents from high schools and youth programs in 3 states ( Arizona , Texas , and New York ) were r and omly assigned to 1 of 3 curriculum groups : RTR ( Reducing the Risk ) , RTR+ ( a modified version of RTR using fuzzy-trace theory ) , and a control group . We report effects of curriculum on self-reported behaviors and behavioral intentions plus psychosocial mediators of those effects : namely , attitudes and norms , motives to have sex or get pregnant , self-efficacy and behavioral control , and gist/verbatim constructs . Among 26 outcomes , 19 showed an effect of at least 1 curriculum relative to the control group : RTR+ produced improvements for 17 outcomes and RTR produced improvements for 12 outcomes . For RTR+ , 2 differences ( for perceived parental norms and global benefit perception ) were confined to age , gender , or racial/ethnic subgroups . Effects of RTR+ on sexual initiation emerged 6 months after the intervention , when many adolescents became sexually active . Effects of RTR+ were greater than RTR for 9 outcomes , and remained significantly greater than controls at 1-year follow-up for 12 outcomes . Consistent with fuzzy-trace theory , results suggest that by emphasizing gist representations , which are preserved over long periods and are key memories used in decision making , the enhanced intervention produced larger and more sustained effects on behavioral outcomes and psychosocial mediators of adolescent risk taking

Conclusions High rates of missing outcome data are present in the majority of CRTs , yet h and ling missing data in practice remains suboptimal .

Background Cluster r and omized trials ( CRTs ) r and omize participants in groups , rather than as individuals and are key tools used to assess interventions in health research where treatment contamination is likely or if individual r and omization is not feasible . Two potential major pitfalls exist regarding CRTs , namely h and ling missing data and not accounting for clustering in the primary analysis . The aim of this review was to evaluate approaches for h and ling missing data and statistical analysis with respect to the primary outcome in CRTs .

Reports of cluster r and omised trials require additional information to allow readers to interpret them accurately The effective reporting of r and omised controlled trials has received useful attention in recent years . Many journals now require that reports conform to the guidelines in the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement , first published in 1996 and revised in 2001 . The statement includes a checklist of items that should be included in the trial report . These items are evidence based whenever possible and are regularly review ed . The statement also recommends including a flow diagram to show the flow of participants from group assignment through to the final analysis . The CONSORT statement focused on reporting parallel group r and omised trials in which individual participants are r and omly assigned to study groups . However , in some situations it is preferable to r and omly assign groups of individuals ( such as families or medical practice s ) rather than individuals . Reasons include the threat of contamination of some interventions ( such as dietary interventions ) if individual r and omisation is used . 5 Also , in certain setting s r and omisation by group may be the only feasible method of conducting a trial . Trials with this design are variously known as field trials , community based trials , place based trials , or ( as in this paper ) cluster r and omised trials . In an earlier discussion paper we considered the implication s of the CONSORT statement for the reporting of cluster r and omised trials . Here we present up date d guidance , based on the 2001 revision of the CONSORT statement IMPORTANCE In sub-Saharan Africa , malaria is a leading cause of childhood morbidity and iron deficiency is among the most prevalent nutritional deficiencies . In 2006 , the World Health Organization and the United Nations Children 's Fund released a joint statement that recommended limiting use of iron supplements ( tablets or liquids ) among children in malaria-endemic areas because of concern about increased malaria risk . As a result , anemia control programs were either not initiated or stopped in these areas . OBJECTIVE To determine the effect of providing a micronutrient powder ( MNP ) with or without iron on the incidence of malaria among children living in a high malaria-burden area . DESIGN , SETTING , AND PARTICIPANTS Double-blind , cluster r and omized trial of children aged 6 to 35 months ( n = 1958 living in 1552 clusters ) conducted over 6 months in 2010 in a rural community setting in central Ghana , West Africa . A cluster was defined as a compound including 1 or more households . Children were excluded if iron supplement use occurred within the past 6 months , they had severe anemia ( hemoglobin level < 7 g/dL ) , or severe wasting ( weight-for-length z score < -3 ) . INTERVENTIONS Children were r and omized by cluster to receive a MNP with iron ( iron group ; 12.5 mg/d of iron ) or without iron ( no iron group ) . The MNP with and without iron were added to semiliquid home-prepared foods daily for 5 months followed by 1-month of further monitoring . Insecticide-treated bed nets were provided at enrollment , as well as malaria treatment when indicated . MAIN OUTCOMES AND MEASURES Malaria episodes in the iron group compared with the no iron group during the 5-month intervention period . RESULTS In intention-to-treat analyses , malaria incidence overall was significantly lower in the iron group compared with the no iron group ( 76.1 and 86.1 episodes/100 child-years , respectively ; risk ratio ( RR ) , 0.87 [ 95 % CI , 0.79 - 0.97 ] ) , and during the intervention period ( 79.4 and 90.7 episodes/100 child-years , respectively ; RR , 0.87 [ 95 % CI , 0.78 - 0.96 ] ) . In secondary analyses , these differences were no longer statistically significant after adjusting for baseline iron deficiency and anemia status overall ( adjusted RR , 0.87 ; 95 % CI , 0.75 - 1.01 ) and during the intervention period ( adjusted RR , 0.86 ; 95 % CI , 0.74 - 1.00 ) . CONCLUSION AND RELEVANCE In a malaria-endemic setting in which insecticide-treated bed nets were provided and appropriate malaria treatment was available , daily use of a MNP with iron did not result in an increased incidence of malaria among young children . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01001871 In a cluster r and omized controlled trial , Anthony Shakeshaft and colleagues measure the effectiveness of a multi-component community-based intervention for reducing alcohol-related harm Loss to follow-up is often hard to avoid in r and omised trials . This article suggests a framework for intention to treat analysis that depends on making plausible assumptions about the missing data and including all participants in sensitivity Abstract s Background The objective of this simulation study is to compare the accuracy and efficiency of population -averaged ( i.e. generalized estimating equations ( GEE ) ) and cluster-specific ( i.e. r and om-effects logistic regression ( RELR ) ) models for analyzing data from cluster r and omized trials ( CRTs ) with missing binary responses . Methods In this simulation study , clustered responses were generated from a beta-binomial distribution . The number of clusters per trial arm , the number of subjects per cluster , intra-cluster correlation coefficient , and the percentage of missing data were allowed to vary . Under the assumption of covariate dependent missingness , missing outcomes were h and led by complete case analysis , st and ard multiple imputation ( MI ) and within-cluster MI strategies . Data were analyzed using GEE and RELR . Performance of the methods was assessed using st and ardized bias , empirical st and ard error , root mean squared error ( RMSE ) , and coverage probability . Results GEE performs well on all four measures — provided the downward bias of the st and ard error ( when the number of clusters per arm is small ) is adjusted appropriately — under the following scenarios : complete case analysis for CRTs with a small amount of missing data ; st and ard MI for CRTs with variance inflation factor ( VIF ) <3 ; within-cluster MI for CRTs with VIF≥3 and cluster size>50 . RELR performs well only when a small amount of data was missing , and complete case analysis was applied . Conclusion GEE performs well as long as appropriate missing data strategies are adopted based on the design of CRTs and the percentage of missing data . In contrast , RELR does not perform well when either st and ard or within-cluster MI strategy is applied prior to the analysis Background Intention-to-treat analysis is used in the analysis of r and omized controlled trials to preserve trial power in the presence of missing subject data as well as to control for both known and unknown confounding factors . One form of intention-to-treat analysis is last-observation-carried-forward ( LOCF ) . Concerns exist regarding whether it is appropriate to use LOCF in analyses involving progressive conditions or in situations where missing data are non-r and om ( e.g. , subjects drop out because of treatment side effects or differing disease severity ) . Objective To examine the use of intention-to-treat imputation of missing data techniques , and specifically LOCF , in r and omized controlled trials of the use of cholinesterase inhibitors and memantine to treat Alzheimer ’s disease , vascular dementia , mixed dementia and mild cognitive impairment . Methods We conducted a systematic electronic search of MEDLINE and the Cochrane Central Register of Controlled Trials from 1984 to 2008 for double-blinded , r and omized controlled trials of cholinesterase inhibitors or memantine that examined progressive symptoms in Alzheimer ’s disease , vascular dementia , mixed dementia and mild cognitive impairment . We collected data on the use of intention-to-treat and non-intention-to-treat analyses and on contraindications to the use of LOCF analysis and we performed quality assessment s of included trials . Results Of the 57 studies that met the inclusion criteria , 12 did not report intention-to-treat analyses . Of the 34 studies that employed LOCF as the only form of intention-to-treat analysis , 24 reported conditions that could produce biased LOCF analyses favouring the drug under study . The latter finding was more common in cholinesterase inhibitor trials than in memantine studies . Conclusions The published results of some r and omized controlled trials of dementia drugs may be inaccurate ( i.e. , drug effectiveness may be exaggerated ) or invalid ( i.e. , there may be false-positive results ) because of bias introduced through the inappropriate use of LOCF analyses . This bias favours cholinesterase inhibitors , potentially preventing funding of and patient access to less toxic treatment options such as memantine . Licensing agencies should consider whether to accept LOCF analyses in research on dementias and other chronic progressive conditions BACKGROUND Cluster r and omized trials increasingly are being used in health services research and in primary care , yet the majority of these trials do not account appropriately for the clustering in their analysis . OBJECTIVES We review the main implication s of adopting a cluster r and omized design in primary care and highlight the practical application of appropriate analytical techniques . METHODS The application of different analytical techniques is demonstrated through the use of empirical data from a primary care-based case study . CONCLUSION Inappropriate analysis of cluster trials can lead to the presentation of inaccurate results and hence potentially misleading conclusions . We have demonstrated that adjustment for clustering can be applied to real-life data and we encourage more routine adoption of appropriate analytical techniques Background Attrition , which leads to missing data , is a common problem in cluster r and omized trials ( CRTs ) , where groups of patients rather than individuals are r and omized . St and ard multiple imputation ( MI ) strategies may not be appropriate to impute missing data from CRTs since they assume independent data . In this paper , under the assumption of missing completely at r and om and covariate dependent missing , we compared six MI strategies which account for the intra-cluster correlation for missing binary outcomes in CRTs with the st and ard imputation strategies and complete case analysis approach using a simulation study . Method We considered three within-cluster and three across-cluster MI strategies for missing binary outcomes in CRTs . The three within-cluster MI strategies are logistic regression method , propensity score method , and Markov chain Monte Carlo ( MCMC ) method , which apply st and ard MI strategies within each cluster . The three across-cluster MI strategies are propensity score method , r and om-effects ( RE ) logistic regression approach , and logistic regression with cluster as a fixed effect . Based on the community hypertension assessment trial ( CHAT ) which has complete data , we design ed a simulation study to investigate the performance of above MI strategies . Results The estimated treatment effect and its 95 % confidence interval ( CI ) from generalized estimating equations ( GEE ) model based on the CHAT complete data set are 1.14 ( 0.76 1.70 ) . When 30 % of binary outcome are missing completely at r and om , a simulation study shows that the estimated treatment effects and the corresponding 95 % CIs from GEE model are 1.15 ( 0.76 1.75 ) if complete case analysis is used , 1.12 ( 0.72 1.73 ) if within-cluster MCMC method is used , 1.21 ( 0.80 1.81 ) if across-cluster RE logistic regression is used , and 1.16 ( 0.82 1.64 ) if st and ard logistic regression which does not account for clustering is used . Conclusion When the percentage of missing data is low or intra-cluster correlation coefficient is small , different approaches for h and ling missing binary outcome data generate quite similar results . When the percentage of missing data is large , st and ard MI strategies , which do not take into account the intra-cluster correlation , underestimate the variance of the treatment effect . Within-cluster and across-cluster MI strategies ( except for r and om-effects logistic regression MI strategy ) , which take the intra-cluster correlation into account , seem to be more appropriate to h and le the missing outcome from CRTs . Under the same imputation strategy and percentage of missingness , the estimates of the treatment effect from GEE and RE logistic regression models are similar Sometimes interventions in r and omized clinical trials are not allocated to individual patients , but rather to patients in groups . This is called cluster allocation , or cluster r and omization , and is particularly common in health services research . Similarly , in some types of observational studies , patients ( or observations ) are found in naturally occurring groups , such as neighborhoods . In either situation , observations within a cluster tend to be more alike than observations selected entirely at r and om . This violates the assumption of independence that is at the heart of common methods of statistical estimation and hypothesis testing . Failure to account for the dependence between individual observations and the cluster to which they belong can have profound implication s on the design and analysis of such studies . Their p-values will be too small , confidence intervals too narrow , and sample size estimates too small , sometimes to a dramatic degree . This problem is similar to that caused by the more familiar " unit of analysis error " seen when observations are repeated on the same subjects , but are treated as independent . The purpose of this paper is to provide an introduction to the problem of clustered data in clinical research . It provides guidance and examples of methods for analyzing clustered data and calculating sample sizes when planning studies . The article concludes with some general comments on statistical software for cluster data and principles for planning , analyzing , and presenting such studies Introduction Cluster r and omised trials ( CRTs ) r and omise participants in groups , rather than as individuals , and are key tools used to assess interventions in health research where treatment contamination is likely or if individual r and omisation is not feasible . Missing outcome data can reduce power in trials , including in CRTs , and is a potential source of bias . The current review focuses on evaluating methods used in statistical analysis and h and ling of missing data with respect to the primary outcome in CRTs . Methods and analysis We will search for CRTs published between August 2013 and July 2014 using PubMed , Web of Science and PsycINFO . We will identify relevant studies by screening titles and abstract s , and examining full-text articles based on our predefined study inclusion criteria . 86 studies will be r and omly chosen to be included in our review . Two independent review ers will collect data from each study using a st and ardised , prepiloted data extraction template . Our findings will be summarised and presented using descriptive statistics . Ethics and dissemination This method ological systematic review does not need ethical approval because there are no data used in our study that are linked to individual patient data . After completion of this systematic review , data will be immediately analysed , and findings will be disseminated through a peer- review ed publication and conference presentation Introduction To counteract the recently observed increase in forearm fractures in children worldwide , an educational programme to improve fall skills was developed . In this 8-week programme children learned basic martial arts falling techniques in their physical education classes . In this study , the effectiveness of this educational programme to improve fall skills was evaluated . Methods A cluster r and omised controlled trial was conducted in 33 primary schools . The intervention group received the educational programme to improve falling skills during their physical education ( PE ) classes whereas the control group received their regular PE curriculum . At baseline ( October 2009 ) and follow-up ( May 2010 ) , a question naire was completed by the children about their physical activity behaviours . Furthermore , fall-related injuries were registered continuously during an entire school-year . Results A total of 36 incident injuries was reported in the intervention group , equalling an injury incidence density ( IID ) of 0.14 fall-related injuries per 1000 h of physical activity ( 95 % CI 0.09 to 0.18 ) . In contrast , 96 injuries were reported by the control group corresponding to an IID of 0.26 ( 95 % CI 0.21 to 0.32 ) . However , because intracluster correlation was high ( ICC=0.46 ) , differences in injury incidence were not statistically significant . When activity level was taken into account , a trend was shown suggesting that the ‘ falling is a sport ’ programme was effective in decreasing falling-related injury risk , but only in the least active children . Discussion and conclusion Although results did not reach significance because of strong clustering effects , a trend was found suggesting that a school-based educational programme to improve falling skills may be more beneficial for the prevention of falling-related injuries in children with low levels of habitual physical activity Patient-reported outcomes are increasingly used in health research , including r and omized controlled trials and observational studies . However , the validity of results in longitudinal studies can crucially hinge on the h and ling of missing data . This paper considers the issues of missing data at each stage of research . Practical strategies for minimizing missingness through careful study design and conduct are given . Statistical approaches that are commonly used , but should be avoided , are discussed , including how these methods can yield biased and misleading results . Methods that are valid for data which are missing at r and om are outlined , including maximum likelihood methods , multiple imputation and extensions to generalized estimating equations : weighted generalized estimating equations , generalized estimating equations with multiple imputation , and doubly robust generalized estimating equations . Finally , we discuss the importance of sensitivity analyses , including the role of missing not at r and om models , such as pattern mixture , selection , and shared parameter models . We demonstrate many of these concepts with data from a r and omized controlled clinical trial on renal cancer patients , and show that the results are dependent on missingness assumptions and the statistical approach The design and analysis of cluster r and omized trials has been a recurrent theme in Statistics in Medicine since the early volumes . In celebration of 25 years of Statistics in Medicine , this paper review s recent developments , particularly those that featured in the journal . Issues in design such as sample size calculations , matched paired design s , cohort versus cross-sectional design s , and practical design problems are covered . Developments in analysis include modification of robust methods to cope with small numbers of clusters , generalized estimation equations , population averaged and cluster specific models . Finally , issues on presenting data , some other clustering issues and the general problem of evaluating complex interventions are briefly mentioned Cluster r and omised trials , where groups of patients rather than individuals are r and omised , are increasingly being used in health services research . R and omisation by individual is inappropriate for evaluating some interventions , such as organisational changes , where it may not be feasible to r and omise at the patient level . In such cases cluster r and omisation at the level of the health professional or organisation is necessary . Such r and omisation can also minimise the potential for contamination between treatments when trial patients are managed within the same setting . The main consequence of adopting a cluster design is that the outcome for each patient can no longer be assumed to be independent of that for any other patient ( which is the case in an individually r and omised trial ) . Patients within any one cluster are more likely to have similar outcomes . For example , the management of patients within a single general practice is more likely to be consistent

Conclusion The pivot shift test is an important test following ACL reconstruction , and it correlates with functional outcomes

Purpose To identify and evaluate the evidence for the pivot shift test as an outcome measure following ACL reconstruction . Achieving rotatory control of the knee post anterior cruciate ligament ( ACL ) reconstruction has been shown to increase patient satisfaction , decrease functional instability and potentially delay the development of osteoarthritis . The pivot shift is able to assess this rotatory component of knee laxity and appears to have the potential to become a benchmark in gauging the success of ACL surgery . Multiple confounding factors and discrepancies in performing the maneuver itself however put its usefulness in question . Thus , the literature was review ed to assess whether the pivot shift was able to correlate with final functional outcomes .

Objective To analyze the clinical outcomes of arthroscopic anterior cruciate ligament ( ACL ) reconstruction with irradiated bone-patellar tendon-bone ( BPTB ) allograft compared with non-irradiated allograft and autograft . Methods All BPTB allografts were obtained from a single tissue bank and the irradiated allografts were sterilized with 2.5 mrad of irradiation prior to distribution . A total of 68 patients undergoing arthroscopic ACL reconstruction were prospect ively r and omized consecutively into one of the two groups ( autograft and irradiated allograft groups ) . The same surgical technique was used in all operations done by the same senior surgeon . Before surgery and at the average of 31 months of follow-up ( ranging from 24 to 47 months ) , patients were evaluated by the same observer according to objective and subjective clinical evaluations . Results Of these patients , 65 ( autograft 33 , irradiated allograft 32 ) were available for full evaluation . When the irradiated allograft group was compared to the autograft group at the 31-month follow-up by the Lachman test , the anterior drawer test ( ADT ) , the pivot shift test , and KT-2000 arthrometer test , statistically significant differences were found . Most importantly , 87.8 % of patients in the autograft group and just only 31.3 % in the irradiated allograft group had a side-to-side difference of less than 3 mm according to KT-2000 . The failure rate of the ACL reconstruction with irradiated allograft ( 34.4 % ) was higher than that with autograft ( 6.1 % ) . The anterior and rotational stabilities decreased significantly in the irradiated allograft group . According to the overall International Knee Documentation Committee ( IKDC ) , functional and subjective evaluations , and activity level testing , no statistically significant differences were found between the two groups . Besides , patients in the irradiated allograft group had a shorter operation time and a longer duration of postoperative fever . When the patients had a fever , the laboratory examinations of all patients were almost normal . Blood routine was normal , the values of erythrocyte sedimentation rate ( ESR ) were 5∼16 mm/h and the contents of C reactive protein ( CRP ) were 3∼10 mg/L. Conclusion We conclude that the short term clinical outcomes of the ACL reconstruction with irradiated BPTB allograft were adversely affected . The less than satisfactory results led the senior authors to discontinue the use of irradiated BPTB allograft in ACL surgery and not to advocate using the gamma irradiation as a secondary sterilizing method Delayed rather than early reconstruction of the anterior cruciate ligament is the current recommended treatment for injury to this ligament since it is thought to give a better functional outcome . We r and omised 105 consecutive patients with injury associated with chondral lesions no more severe than grade s 1 and 2 and /or meniscal tears which only required trimming , to early ( < two weeks ) or delayed ( > four to six weeks ) reconstruction of the anterior cruciate ligament using a quadrupled hamstring graft . All operations were performed by a single surgeon and a st and ard rehabilitation regime was followed in both groups . The outcomes were assessed using the Lysholm score , the Tegner score and measurement of the range of movement . Stability was assessed by clinical tests and measurements taken with the KT-1000 arthrometer , with all testing performed by a blinded uninvolved experienced observer . A total of six patients were lost to follow-up , with 48 patients assigned to the delayed group and 51 to the early group . None was a competitive athlete . The mean interval between injury and the surgery was seven days ( 2 to 14 ) in the early group and 32 days ( 29 to 42 ) in the delayed group . The mean follow-up was 32 months ( 26 to 36 ) . The results did not show a statistically significant difference for the Lysholm score ( p = 0.86 ) , Tegner activity score ( p = 0.913 ) or the range of movement ( p = 1 ) . Similarly , no distinction could be made for stability testing by clinical examination ( p = 0.56 ) and measurements with the KT-1000 arthrometer ( p = 0.93 ) . Reconstruction of the anterior cruciate ligament gave a similar clinical and functional outcome whether performed early ( < two weeks ) or late at four to six weeks after injury The Losee repair controls rotational subluxation of the lateral femoral condyle , or pivot shift , but does not reliably eliminate Lachman laxity . Despite this surgical limitation , many patients who were operated on continued to do high-dem and activities at the last followup . We hypothesized that Lachman findings alone did not predict poor surgical outcome or progression to osteoarthritis . We report on 87 patients evaluated at an average of 9 years ( range , 5 - 21 years ) postoperatively . Prospect ively collected examinations and radiographic , subjective , and objective outcome measures were recorded and statistically evaluated . The presence of a postoperative pivot shift or residual varus laxity correlated with poor patient subjective evaluations and poor scoring outcomes . Lachman laxity with an absent pivot shift had no correlation with the outcome measures or onset of radiographic progression to osteoarthritis . Meniscectomy , additional knee surgery , increased valgus or varus laxity , and time from injury until the final radiograph positively correlated with the onset of osteoarthritis . Elimination of the pivot shift was necessary to achieve successful relief of symptoms and functional outcome . In the absence of a pivot shift , Lachman laxity was not solely predictive of poor outcomes . Level of Evidence : Prognostic study , Level II-1 ( retrospective study ) . See the Guidelines for Authors for a complete description of levels of evidence The purpose of this study is to clinical ly evaluate hamstring tendon anterior cruciate ligament (ACL)-reconstruction using femoral fixation with bioresorbable interference screws and with a bioresorbable transfixation device . The ACL-reconstruction using the transfixation device at the femoral side leads to less knee laxity and therefore to a better clinical outcome for the patient . Prospect i ve r and omized clinical outcome study . From February 2002 to December 2002 , a total of 68 patients with hamstring ACL reconstruction using a femoral fixation once with TransFix ( n=38 ; m:22 and f:16 ; median age=28.5 range 15–47 ) and the second with bioscrew ( BS ) ( n=30 ; m:20 , f:10 ; median age=25.5 range 13–61 ) completed the follow-up period . Patients in each group got a clinical assessment at 3 , 6 , and 12 months after surgery . The measurement of anterior translation of the tibia has been performed using the Rolimeter ® device . No significant differences in the knee laxity testing using the Rolimeter device were seen between both groups and over time within these groups . Ninety percent of all patients had functionally normal or near normal International Knee Documentation Committee ( IKDC ) knee ligament ratings . The TF-group included 17 grade A , 19 grade B , and 2 grade C knees , and the BS-group had 12 grade A , 13 grade B , and 5 grade C knees . The IKDC rating , the OAK-score , the Tegner-activity-score , and the Lysholm-score did not show significant differences between the TF-group and the BS-group . We disproved our hypothesis that the transfixation technique leads to less laxity and therefore to a better clinical outcome when compared to the use of BS . The clinical results in this study clarified that this technique is an effective and safe method for femoral hamstring fixation in ACL-reconstruction . However , this technique revealed no advantage compared to the bioscrew fixation technique within the short-term follow-up BACKGROUND There are no controlled , prospect i ve studies comparing the 10-year outcomes of anterior cruciate ligament ( ACL ) reconstruction using patellar tendon ( PT ) and 4-str and hamstring tendon ( HT ) autografts . HYPOTHESIS Comparable results are possible with HT and PT autografts . STUDY DESIGN Cohort study ; Level of evidence , 2 . METHODS One hundred eighty ACL-deficient knees that met inclusion criteria underwent ACL reconstruction ( 90 HT autograft , 90 PT autograft ) by one surgeon and were treated with an accelerated rehabilitation program . All knees were observed in a prospect i ve fashion with subjective , objective , and radiographic evaluation at 2 , 5 , 7 , and 10-year intervals . RESULTS At 10 years , there were no differences in graft rupture rates ( 7/90 PT vs. 12/90 HT , P = .24 ) . There were 20 contralateral ACL ruptures in the PT group , compared with 9 in the HT group ( P = .02 ) . In all patients , graft rupture was associated with instrumented laxity > 2 mm at 2 years ( P = .001 ) . Normal or near-normal function of the knee was reported in 97 % of patients in both groups . In the PT group , harvest-site symptoms ( P = .001 ) and kneeling pain ( P = .01 ) were more common than in the HT group . More patients reported pain with strenuous activities in PT knees than in HT knees ( P = .05 ) . Radiographic osteoarthritis was more common in PT knees than the HT-reconstructed knees ( P = .04 ) . The difference , however , was composed of patients with mild osteoarthritis . Other predictors of radiographic osteoarthritis were < 90 % single-legged hop test at 1 year and the need for further knee surgery . An " ideal " outcome , defined as an overall International Knee Documentation Committee grade of A or B and a radiographic grade of A at 10 years after ACL reconstruction , was associated with <3 mm of instrumented laxity at 2 years , the absence of additional surgery in the knee , and HT grafts . CONCLUSIONS It is possible to obtain excellent results with both HT and PT autografts . We recommend HT reconstructions to our patients because of decreased harvest-site symptoms and radiographic osteoarthritis Introduction Correct placement of both tibial and femoral tunnels is one of the main factors for a favorable clinical outcome after anterior cruciate ligament ( ACL ) reconstruction . We used an original system of computer assisted surgery ( CAS ) . The system , based on fluoroscopic guidance combined with special graphical software of image analyzing , showed to the surgeon , before drilling , the recommended placement of tibial and femoral tunnel centers . We compared the first anatomical and clinical results of this procedure to the usual one single incision technique . Material s and methods We conducted a prospect i ve study on 73 patients ; 37 patients were operated on with CAS and 36 without CAS , by the same senior surgeon . The mean age was 27 years for both groups . Every patient was review ed at an average of 2.2 years ( range 1–4.5 ) by an independent observer , using IKDC scoring system , KT-1000 , and passive stress radiographs . Results Time between ACL rupture and reconstruction averaged 30 months for both groups . CAS needed 9.3 min extra surgery time . Clinical evaluation was grade d from A to C as per the IKDC scoring system : 67.6 % A , 29.7 % B , 2.7 % C with CAS ; and 60 % A , 37.1 % B , 2.9 % C without CAS . IKDC subjective knee evaluation score averaged 89.7 with CAS and 89.5 without CAS . Pre operative KT-1000 maxi manual differential laxity averaged 7 . At revision time , all the patients after CAS had a differential laxity less than 2 and 97.7 % without CAS . Stress X-rays differential laxity averaged 2.4 mm with CAS and 3 mm without CAS . The area of dispersion of the tunnels ’ center was smaller on the femoral side using the CAS method . There was no statistically significant difference between both groups using IKDC score , KT-1000 and passive stress radiographs . Conclusions The CAS method provided a more accurate and reproducible tunnels placement without clinical significant effect PURPOSE The aim of this study was to evaluate whether a change in the femoral graft insertion site between the 1-o'clock ( high ) and 2-o'clock ( low ) positions could change the laxity , the score on the 2000 International Knee Documentation Committee ( IKDC ) Knee Examination Form , or the score on the 2000 subjective IKDC Knee Evaluation Form in the anterior cruciate ligament (ACL)-reconstructed knee . METHODS The study was design ed as a prospect i ve , r and omized , double-blind investigation . We r and omized 30 patients to the low tunnel position group and 30 to the high tunnel position group . Four-str and ed semitendinosus and gracilis single-bundle grafts were used . At follow-up , the patients were examined according to the IKDC evaluation form and the IKDC examination form . The exact measurements of laxity at 25 degrees and 70 degrees were performed by use of the Rolimeter ( Aircast , Boca Raton , FL ) . St and ardized radiographs were evaluated . RESULTS In total , 26 patients in the low tunnel position group and 25 in the high tunnel position group completed the study . At follow-up , we found no significant difference in the laxity at 25 degrees and 70 degrees or scores on the IKDC examination form . We found a significant difference in the scores on the IKDC evaluation form , favoring the low position , with a subjective score of 82.8 versus 70.4 . CONCLUSIONS A change in the femoral tunnel placement from 1 o'clock to 2 o'clock did not result in a detectable change in the sagittal laxity at 25 degrees and 70 degrees , on the pivot-shift test , or on the IKDC examination form scores . However , we found a significant difference between the two groups in the scores on the IKDC evaluation form , most evident in the subgroups dealing with the patient 's subjective knee stability . We conclude that it is possible to improve the clinical result in 1-bundle ACL reconstruction by lowering the tibial tunnel angle and thereby lowering the femoral tunnel toward the 2-o'clock position . LEVEL OF EVIDENCE Level I , therapeutic prospect i ve r and omized trial The effect of using gamma irradiation to sterilize bone-patellar tendon-bone ( BPTB ) allograft on the clinical outcomes of anterior cruciate ligament ( ACL ) reconstruction with irradiated allograft remains controversial . Our study was aim ed to analyze the clinical outcomes of arthroscopic ACL reconstruction with irradiated BPTB allograft compared with non-irradiated allograft and autograft . All BPTB allografts were obtained from a single tissue bank and the irradiated allografts were sterilized with 2.5 Mrad of irradiation prior to distribution . A total of 102 patients undergoing arthroscopic ACL reconstruction were prospect ively r and omized consecutively into three groups . The same surgical technique was used in all operations done by the same senior surgeon . Before surgery and at the average of 31 months follow-up ( range 24–47 months ) patients were evaluated by the same observer according to objective and subjective clinical evaluations . Of these patients , 99 ( autograft 33 , non-irradiated allograft 34 , irradiated allograft 32 ) were available for full evaluation . When compared the irradiated allograft group to non-irradiated allograft group or autograft group at 31 months follow-up by the Lachman test , ADT , pivot shift test and KT-2000 arthrometer testing , statistically significant differences were found . Most importantly , 87.8 % of patients in the Auto group , 85.3 % in the Non-Ir-Auto group and just only 31.3 % in the Ir-Allo group had a side-to-side difference of less than 3 mm according to KT-2000 . The failure rate of the ACL reconstruction with irradiated allograft ( 34.4 % ) was higher than that with autograft ( 6.1 % ) and non-irradiated allograft ( 8.8 % ) . The anterior and rotational stability decreased significantly in the irradiated allograft group . According to the overall IKDC , functional , subjective evaluations and activity level testing , no statistically significant differences were found between the three groups . However , there was a trend that the functional and activity level decreased and the patients felt uncomfortable more often in the irradiated allograft group . The statistical analysis showed no significant difference between the non-irradiated allograft group and the autograft group according to the aforementioned evaluations , except that patients in the allograft group had a shorter operation time and a longer duration of postoperative fever . When comparing the postoperative duration of fever of the two allograft groups , there was also a trend that the irradiated allograft group was longer than the non-irradiated allograft group , but no significant difference was found . When the patients had a fever , the laboratory examinations of all patients were almost normal ( Blood routine was normal , the values of ESR were 5 ~ 16 mm/h , CRP were 3 ~ 10 mg/l ) . On the basis of our study , we concluded that patients undergoing ACL reconstruction with BPTB non-irradiated allograft or autograft had similar clinical outcomes . Non-irradiated BPTB allograft is a reasonable alternative to autograft for ACL reconstruction . While the short term clinical outcomes of the ACL reconstruction with irradiated BPTB allograft were adversely affected with an increased failure rate . The less than satisfactory results led the senior authors to discontinue the use of irradiated BPTB allograft in ACL surgery and not to advocate that gamma irradiation be used as a secondary sterilizing method . Further research into alternatives to gamma irradiation is needed PURPOSE The purpose of this study was to compare the clinical results of a double-bundle anterior cruciate ligament ( ACL ) reconstruction with 4 str and s versus 8 str and s of hamstring tendon graft . METHODS Seventy-six patients with chronic ACL rupture were r and omly separated into two groups for double-bundle ACL reconstruction . In the 4-str and hamstring graft ( 4SHG ) group , the semitendinosus tendon was used to make two 2-str and ed hamstring tendon grafts , whereas in the 8-str and hamstring graft ( 8SHG ) group , the semitendinosus tendon was used to make one 4SHG and the gracilis tendon was used to make the other 4SHG . The 4SHG group comprised 33 patients and the 8SHG group comprised 35 patients , with a minimum follow-up of 2 years . International Knee Documentation Committee ( IKDC ) and Lysholm scales were used to evaluate the clinical results . RESULTS In the 4SHG group the side-to-side difference was less than 3 mm in 26 patients ( 78.8 % ) , 3 to 5 mm in 4 patients ( 12.1 % ) , and 6 to 10 mm in 3 patients ( 9.0 % ) , with a mean value of 2.8 + /- 0.5 mm ; the pivot-shift test was negative in 29 patients ( 89.9 % ) and positive in 4 ( 12.1 % ) . In the 8SHG group the side-to-side difference was less than 3 mm in 32 patients ( 91.4 % ) , 3 to 5 mm in 2 patients ( 5.7 % ) , and 6 mm in 1 patient ( 2.9 % ) ( P = .004 ) , with a mean value of 1.3 + /- 0.4 mm ( P = .0003 ) ; the pivot-shift test was negative in 34 patients ( 97.1 % ) and positive in 1 ( 2.9 % ) . According to the IKDC scale , 29 patients ( 87.9 % ) in the 4SHG group and 33 patients ( 94.3 % ) in the 8SHG group had a grade of normal or nearly normal . In the 4SHG and 8SHG groups the mean IKDC subjective knee evaluation results were 86.4 + /- 4.2 and 96.3 + /- 2.8 ( P = .0007 ) , respectively , and the mean Lysholm scores were 89.6 + /- 3.7 and 96.5 + /- 2.9 ( P = .0006 ) , respectively . CONCLUSIONS On the basis of KT-1000 examination ( MEDmetric , San Diego , CA ) and clinical measures , double-bundle ACL reconstruction with 8SHG yields significantly better results than double-bundle ACL reconstruction with 4SHG , with a mean side-to-side difference in anterior knee laxity of 1.3 + /- 0.4 mm versus 2.8 + /- 0.5 mm ( P = .0003 ) , IKDC subjective result of 96.3 + /- 2.8 versus 86.4 + /- 4.2 ( P = .0007 ) , and Lysholm score of 96.5 + /- 2.9 versus 89.6 + /- 3.7 ( P = .0006 ) . LEVEL OF EVIDENCE Level II , lesser- quality r and omized controlled trial Background New devices for graft fixation in anterior cruciate ligament reconstruction are released to clinical use without clinical follow-up data . Hypothesis There is similar clinical outcome after either cross-pin or absorbable interference screw fixation in anterior cruciate ligament reconstruction with hamstring tendons . Study Design R and omized controlled clinical trial ; Level of evidence , 1 . Methods A total of 120 patients were r and omized into 4 different groups ( 30 each ) for anterior cruciate ligament reconstruction with hamstring tendons : femoral Rigidfix cross-pin and Intrafix tibial expansion sheath with a tapered expansion screw ; Rigidfix femoral and BioScrew interference screw tibial fixation , BioScrew femoral and Intrafix tibial fixation ; or BioScrew fixation into both tunnels . The evaluation methods were clinical examination , knee scores , and instrumented laxity measurements . Results Ten patients were completely lost to follow-up and 3 revisions were done before the 2-year follow-up , leaving 107 of 120 ( 89 % ) patients for analysis . No statistically significant differences between the groups were seen 2 years postoperatively , and all but 2 patients in the Rigidfix/Intrafix and Rigidfix/BioScrew groups , respectively , were classified into International Knee Documentation Committee A or B categories . A revision reconstruction was performed before the 2-year follow-up in 2 cases after a high-energy injury caused a rerupture ( 1 in Rigidfix/Intrafix and 1 in BioScrew/BioScrew groups ) . In addition , there were 4 nontraumatic failures revised before the 2-year follow-up ( 2 in Rigidfix/Intrafix and 1 each in Rigidfix/BioScrew and BioScrew/BioScrew ) . Conclusion There were no statistically or clinical ly relevant differences in the results 2 years postoperatively , and all 4 techniques improved patient performance Although allograft use for primary anterior cruciate ligament reconstruction has continued to increase during the last 10 years , concerns remain regarding the long-term function of allografts ( primarily that they may stretch with time ) and clinical efficacy compared with autograft tendons . We attempted to address these issues by prospect ively comparing identical quadrupled hamstring autografts with allograft constructs for primary anterior cruciate ligament reconstruction in patients with a minimum followup of 3 years . Eighty-four patients ( 37 with autografts and 47 with allografts ) were enrolled ; the mean followup was 52 ± 11 months for the autograft group and 48 ± 8 months for the allograft group . Outcome measurements included objective and subjective International Knee Documentation Committee scores , Lysholm scores , Tegner activity scales , and KT-1000 arthrometer measurements . The two cohorts were similar in average age , acute or chronic nature of the anterior cruciate ligament rupture , and incidence of concomitant meniscal surgeries . At final followup , we found no difference in terms of Tegner , Lysholm , KT-1000 , or International Knee Documentation Committee scores . Five anterior cruciate ligament reconstructions failed : three in the autograft group and two in the allograft group . Our data suggest laxity is not increased in allograft tendons compared with autografts and clinical outcome scores 3 to 6 years after surgery are similar . Level of Evidence : Level II , therapeutic study . See the Guidelines for Authors for a complete description of levels of evidence The aim of this study was to evaluate whether anterior cruciate ligament ( ACL ) reconstruction using the double bundle technique ( DB ) improves stability in the knee compared with the single bundle technique ( SB ) with the femoral tunnel in a more horizontal position ( 2 or 10 o’clock ) . We conducted a r and omized , prospect i ve study . Forty patients were r and omized to the DB group ( 20 patients ) and the SB group ( 20 patients ) . Four-str and ed semitendinosus and gracilis autologous grafts were used in the SB group and in the DB group the conventional four tunnel technique was carried out using the same tendons . The IKDC complete form was used for the preoperative evaluation , and in the follow-up the IKDC subjective knee evaluation form , IKDC current health assessment form and IKDC knee examination form were used . Anteroposterior ( AP ) laxity was evaluated by st and ardised and forced radiology in all patients . No significant preoperative between-group differences were found . During the follow-up , no differences were found between groups , except for significant between-group differences ( P < 0.05 ) between the preoperative and postoperative evaluations . The IKDC index also showed significant differences in the 2-year follow-up . Median scores increased from 48 ( range 41–54 ) to 81 ( range 75–87 ) ( P = 0.01 ) in the SB group and from 52 ( range 46–58 ) to 80 ( range 72–88 ) ( P = 0.02 ) in the DB group . There were no significant differences between the groups in terms of functional scores . In conclusion , the 2 and 10 o’clock placements showed no significant differences between SB and DB techniques in the pivot-shift test , manual and radiological anterior posterior laxity and IKDC scores . However , significant between-group differences were found between the preoperative and postoperative evaluations Background The choice of different graft types and surgical techniques used when reconstructing a torn anterior cruciate ligament may influence the long-term prevalence of osteoarthritis and functional outcomes . Hypothesis There are no differences in the prevalence of knee osteoarthritis or knee function in patients undergoing reconstruction of a torn anterior cruciate ligament with 4-str and hamstring autograft versus patellar tendon — bone autograft . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Seventy-two patients with subacute or chronic rupture of the anterior cruciate ligament were r and omly assigned to autograft reconstruction with 4-str and gracilis and semitendinosus tendon ( HAM ) ( N = 37 ) or with patellar tendon — bone ( PTB ) ( N = 35 ) from the ipsilateral side . Outcome measurements were the Cincinnati knee score , single-legged hop tests , isokinetic muscle strength tests , pain , knee joint laxity test ( KT-1000 arthrometer ) , and a radiologic evaluation ( Kellgren and Lawrence ) at 10-year follow-up . Results At 10 years , 57 patients ( 79 % ) were eligible for evaluation—29 in the HAM group and 28 in the PTB group . No differences were found between the 2 graft groups with respect to the Cincinnati knee score , the single-legged hop tests , pain , muscle strength measurements , or knee joint laxity . Fifty-five percent and 64 % of the patients had osteoarthritis corresponding to Kellgren and Lawrence grade 2 or more in the HAM and the PTB groups , respectively ( P = .27 ) . For the uninvolved knee , the corresponding numbers were 28 % and 22 % ( P = .62 ) . Conclusion At 10 years postoperatively , no statistically significant differences in clinical outcome between the 2 graft types were found . The prevalence of osteoarthritis was significantly higher in the operated leg than in the contralateral leg , but there were no significant differences between the 2 groups . The results indicate that the choice of graft type after an anterior cruciate ligament injury has minimal influence on the prevalence of osteoarthritis 10 years after surgery Twenty-six patients with anteroposterior ( AP ) laxity of the knee , associated with torn anterior cruciate ligament ( ACL ) , were prospect ively r and omized for arthroscopic lower femoral tunnel placed single- or double-bundle reconstruction using hamstring tendons . We evaluated AP and rotational stabilities under regular loads ( a 100-N anterior load and a 1.5-N m external – internal load ) before and after ACL reconstruction , comparing single- and double-bundle reconstruction with our original device for applying quantitative tibial rotation and the navigation system intraoperatively . No significant differences were found between the two groups in AP displacement and total range of tibial rotation at 30 ° and 60 ° of knee flexion . We found that a lower femoral tunnel placed single-bundle reconstruction reproduced AP and rotational stability as well as double-bundle reconstruction after reconstruction intraoperatively OBJECTIVE Many r and omized clinical trials demonstrated that 4-str and hamstring tendon grafts have comparable results both subjectively and objective ly with the patellar tendon grafts . The authors hypothesized that the increment of hamstring tendons strength with 6-str and graft could improve the knee stability compared to the result from using the gold st and ard patellar tendon . MATERIAL AND METHOD Thirty-four patients were prospect ively r and omized into two groups for arthroscopic anterior cruciate ligament reconstruction . Seventeen patients underwent reconstruction with 6-str and hamstring tendons and the remaining seventeen were treated with bone-patellar tendon-bone graft . Patients were followed-up under the similar rehabilitation protocol for at least 12 months . At the time of final follow-up , all the patients in both groups were evaluated in terms of patient 's satisfaction , activity level , and knee stability . RESULTS Fifteen patients in bone-patellar tendon-bone graft ( two lost to follow-up ) and thirteen patients used 6-str and hamstring tendons ( four were converted to 4-str and hamstring tendons ) were evaluated at a mean of 19 months ( range 12 - 31 months ) . The mean of KT-2000 side-to-side laxity measurement in 6-str and hamstring group ( 0.96 mm ) is less than BPTB group ( 1.22 mm ) significantly ( p < 0.05 ) . Eleven of 13 patients ( 84.62 % ) that received the 6-str and hamstring tendons could return to sport activities compared to 10 of 15 patients ( 66.67 % ) that received BPTB graft . Hamstring group have a lower prevalence of donor-site morbidity result ing in less difficult in kneeling . CONCLUSION The authors concluded that using 6-str and hamstring tendons could improve knee stability in the early clinical outcomes . With no difference in subjective assessment , anterior cruciate ligament reconstruction used hamstring tendons have less donor-site morbidity , which is more compatible to Asian life-style Background : R and omized controlled trials after anterior cruciate ligament reconstructions with long-term follow-up including assessment of health-related quality of life are rare . Purpose : To compare clinical outcome and health-related quality of life 8 years after anterior cruciate ligament reconstruction using 2 types of graft . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Long-term follow-up of 164 patients with anterior cruciate ligament injury r and omized to arthroscopic reconstruction with a quadrupled semitendinosus graft or a bone – patellar tendon – bone graft was undertaken . After a mean 8 years , 153 patients were available for follow-up , including instrumented laxity , 1-legged hop test , a knee-walking test , and assessment with International Knee Documentation Committee , Lysholm , Tegner , and patellofemoral pain score . Health-related quality of life was assessed with Knee Osteoarthritis Outcome Score and Short Form–36 . Results : Patients in both graft groups retained the same stability , knee function , and health-related quality of life . The patellofemoral pain score was similar for both groups ; the bone – patellar tendon – bone group had more donor site morbidity from kneeling and knee walking . In the bone – patellar tendon – bone group , 19 patients had no kneeling problems , 23 slight problems , 31 moderate problems , and 5 unable to kneel . Corresponding figures for the semitendinosus group were 25 , 32 , 16 , and 2 ( P < .001 ) . Patients with early reconstructions ( < 5 months ) had a lower risk for meniscal injuries ( 37 % ) than did later reconstructed ( 62 % , P = .008 ) . Health-related quality of life regarding physical functioning in Short Form–36 was better for the early-reconstructed patients than for the later reconstructed ( 92 vs 85 ; P = .014 ) . Patients without medial meniscal surgery had higher Knee Osteoarthritis Outcome Scores for all subscales than did patients with medial meniscal surgery , with most significant difference for sport and recreation ( 63 vs 75 , P = .008 ) . Conclusion : In the long term , the semitendinosus graft provided similar stability , knee function , and health-related quality of life but with less kneeling morbidity than did the bone – patellar tendon – bone graft We conducted a prospect i ve r and omised study of anatomical single-bundle ( A-SB group ) versus double-bundle ( A-DB group ) anterior cruciate ligament ( ACL ) reconstruction using the hamstrings tendons . Twenty patients with unilateral ACL deficiency were r and omised into two groups . We created the bone tunnels at the position of the original insertion of the anteromedial bundle footprint and posterolateral bundle footprint in the A-DB group and at the central position between these two bundles in the A-SB group . All of the patients were tested before ACL reconstruction and one year after surgery . The KT-1000 measurements , isokinetic muscle peak torque and heel-height difference were evaluated and the general knee condition was assessed by Lysholm score . For pre- and postoperative stability assessment , we used the six-degrees-of-freedom of knee kinematic measurement system using an electromagnetic device ( the EMS ) for quantitative assessment during the Lachman test and the pivot shift test . There were no significant differences in the KT-1000 measurements , isokinetic muscle peak torque , heel-height difference , and Lysholm score at one-year follow-up between these two groups . The EMS data showed there were significant differences in the acceleration of the pivot shift test between the operated knee and the contralateral normal knees in the A-SB group . In conclusion , clinical outcomes were equally good in both groups . However , the EMS data showed the anatomical double-bundle ACL reconstruction tended to be biomechanically superior to the single-bundle reconstruction The aims of the study were to analyse the change in knee laxity over time after anterior cruciate ligament ( ACL ) reconstruction , using either bone – patellar – tendon – bone ( BPTB ) or hamstring ( HS ) tendon autografts , and to compare the knee laxity measurements between the study groups both pre-operatively and on multiple follow-up occasions . Another aim was to compare the radiographic findings in terms of degenerative changes between the study groups . A r and omised series of 71 patients , who underwent ACL reconstruction using BPTB or HS tendon autografts and interference screw fixation , were included in the study . Of these patients , 47/71 ( 66 % ) attended a clinical examination , including laxity measurements using the KT-1000 arthrometer , pre-operatively and on four post-operative occasions ; 6 months , 1 year , 2 years and 7 years after the reconstruction . The BPTB group consisted of 22 patients , while there were 25 patients in the HS group . There were no significant differences in the mean side-to-side knee laxity between the BPTB and the HS group pre-operatively or at the follow-up examinations . There was a tendency towards a reduction in side-to-side knee laxity over time in both groups , measured with the KT-1000 arthrometer . The decrease was significant when analysing the injured and uninjured knee separately ( injured side p < 0.001 ( BPTB ) and p = 0.005 ( HS ) , uninjured side p = 0.008 and p = 0.042 , respectively ) . Forty-four patients ( BPTB 21 , ST 23 ) underwent a radiographic assessment at the 7-year follow-up , which revealed no significant differences between the study groups in terms of osteoarthritic findings classified according to the Fairbank and Ahlbäck rating systems . In overall terms , osteoarthritis was identified in 16 % ( BPTB 19 % ; ST 13 % ; n.s . ) according to the Ahlbäck rating system and 68 % ( BPTB 67 % ; ST 70 % ; n.s . ) according to the Fairbank rating system . There were no significant differences in knee laxity measurements between the two study groups pre-operatively or at 7 years . A decrease in knee laxity over time was seen in both groups . There were no significant differences between the BPTB and ST groups in terms of osteoarthritic findings at 7 years Purpose The purpose of this study was to compare subjective , objective and radiographic outcome of the lateralized single-bundle bone-patellar tendon-bone autograft with a non-anatomical double-bundle hamstring tendons autograft anterior cruciate ligament ( ACL ) reconstruction technique at long-term follow-up . Methods Seventy-nine non-consecutive r and omized patients ( 42 men ; 37 women ) with unilateral ACL insufficiency were prospect ively evaluated , before and after ACL reconstruction by means of the above-mentioned techniques , with a minimum follow-up of 8 years ( range 8–10 years ; mean 8.6 years ) . In the double-bundle hamstrings technique , we used one tibial and one femoral tunnel combined with one “ over-the-top ” passage , cortical staple ’s fixation and we left intact hamstrings ’ tibial insertion . Patients were evaluated subjectively and objective ly , using IKDC score , Tegner level , manual maximum displacement test with KT-2000 ™ arthrometer . Radiographic evaluation was performed according to IKDC grading system , and re-intervention rate for meniscal lesions was also recorded . Results The subjective and objective IKDC were similar in both groups while double-bundle hamstrings group showed significantly higher Tegner level ( P = 0.0007 ) , higher passive range of motion recovery ( P = 0.0014 ) , faster sport resumption ( P = 0.0052 ) , lower glide pivot-shift phenomenon ( P = 0.0302 ) and lower re-intervention rate ( P = 0.0116 ) compared with patellar tendon group . Radiographic evaluation showed significant lower objective degenerative changes in double-bundle hamstrings group at final follow-up ( P = 0.0056 ) . Conclusion Although both techniques provide satisfactory results , double-bundle ACL reconstruction shows better functional results , with a faster return to sport activity , a lower re-operation rate and lower degenerative knee changes Purpose This study is to compare the clinical and radiographic results of anterior cruciate ligament ( ACL ) reconstruction with four-str and ed autogenous hamstring tendon and two-str and ed free tendon Achilles allograft fixed with EndoButton in the femoral tunnel and Intrafix in the tibial tunnel . Material s and methods 106 patients diagnosed with ACL rupture underwent ACL reconstruction . Autogenous hamstring tendon was used in 33 patients ( group I ) and free tendon Achilles allografts were used in 32 patients ( group II ) . Median age was 23 years old ( 20–51 ) in group I and 22 years old ( 20–55 ) in group II . Range of motion , Lachman test , Pivot shift test , IKDC score , Lysholm score and side-to-side difference ( SSD ) were evaluated preoperatively and at the last follow-up . Tegner activity scale was evaluated before injury and at the last follow-up . Results The mean follow-up periods were 28.1 months in group I and 31.6 months in group II . Range of motion of the knee was not different from that of the unaffected side in most cases except one flexion deficit in group I and three in group II ( n.s . ) . One in group I and three in group II showed grade two or three laxity on Lachman test at the last follow-up . One in group I and three in group II showed clear positive results on Pivot shift test at the last follow-up . Thirty in group I and 26 in group II were classified to IKDC A or B at the last follow-up ( n.s . ) . Median Lysholm scores were 98 ( 85–100 ) in group I and 99 ( 85–100 ) in group II at the last follow-up ( n.s . ) . Median Tegner activity scales were 6 ( 5–9 ) in group I and 6 ( 4–9 ) in group II at the last follow-up ( n.s . ) . The mean SSD at the last follow-up were 1.4 ± 2.0 mm in group I and 1.9 ± 2.4 mm in group II ( n.s . ) . Conclusion Clinical and radiological outcomes of ACL reconstruction with two-str and ed free tendon Achilles allograft were comparable to those of four-str and ed autogenous hamstring tendon . This technique is reasonable to accomplish good results without some weaknesses when using allograft with bone block . Level of evidence Therapeutic r and omized controlled prospect i ve study , Level Several investigators have reported the presence of biomechanical , kinematic , anatomic , fiber orientation patterns and biological differences between the anteromedial bundle and the posterolateral bundle of ACL . The purpose of this prospect i ve r and omized study was to compare the clinical , instrumental and X-ray outcome of two ACL reconstruction techniques with hamstring tendons : one with a single intra-articular bundle associated to an extra-articular sling , the second with a more anatomic double-bundle technique that reproduces better the native ACL function . From an initial group of 100 patients who underwent ACL reconstruction , 72 patients ( 35 single bundle plus lateral plasty and 37 double bundle ) were evaluated with IKDC , Tegner score , KT2000 arthrometer , Activity Rating Scale , Psychovitality Question naire and Ahlback radiographic score at a mean 3 years follow-up . Double-bundle group showed significantly better results regarding IKDC , ROM , Activity Rating Scale and time to return to sport . Also KT 2000 showed significant differences in objective stability . The double-bundle technique for ACL reconstruction described in this paper has demonstrated significantly better subjective , objective and functional results compared with a double-str and ed hamstrings plus extra-articular sling at a minimum 3-year follow-up BACKGROUND The optimal management of a torn anterior cruciate ligament ( ACL ) of the knee is unknown . METHODS We conducted a r and omized , controlled trial involving 121 young , active adults with acute ACL injury in which we compared two strategies : structured rehabilitation plus early ACL reconstruction and structured rehabilitation with the option of later ACL reconstruction if needed . The primary outcome was the change from baseline to 2 years in the average score on four subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS)--pain , symptoms , function in sports and recreation , and knee-related quality of life ( KOOS(4 ) ; range of scores , 0 [ worst ] to 100 [ best ] ) . Secondary outcomes included results on all five KOOS subscales , the Medical Outcomes Study 36-Item Short-Form Health Survey , and the score on the Tegner Activity Scale . RESULTS Of 62 subjects assigned to rehabilitation plus early ACL reconstruction , 1 did not undergo surgery . Of 59 assigned to rehabilitation plus optional delayed ACL reconstruction , 23 underwent delayed ACL reconstruction ; the other 36 underwent rehabilitation alone . The absolute change in the mean KOOS(4 ) score from baseline to 2 years was 39.2 points for those assigned to rehabilitation plus early ACL reconstruction and 39.4 for those assigned to rehabilitation plus optional delayed reconstruction ( absolute between-group difference , 0.2 points ; 95 % confidence interval , -6.5 to 6.8 ; P=0.96 after adjustment for the baseline score ) . There were no significant differences between the two treatment groups with respect to secondary outcomes . Adverse events were common in both groups . The results were similar when the data were analyzed according to the treatment actually received . CONCLUSIONS In young , active adults with acute ACL tears , a strategy of rehabilitation plus early ACL reconstruction was not superior to a strategy of rehabilitation plus optional delayed ACL reconstruction . The latter strategy substantially reduced the frequency of surgical reconstructions . ( Funded by the Swedish Research Council and the Medical Faculty of Lund University and others ; Current Controlled Trials number , IS RCT N84752559 . Double-bundle anterior cruciate ligament ( ACL ) reconstruction reproduces anteromedial and posterolateral bundles , and thus has theoretical advantages over conventional single-bundle reconstruction in controlling rotational torque in vitro . However , its superiority in clinical practice has not been proven . We analyzed rotational stability with three reconstruction techniques in 60 consecutive patients who were r and omly divided into three groups ( double-bundle , anteromedial single-bundle , posterolateral single-bundle ) . In the reconstructive procedure , the hamstring tendon was harvested and used as a free tendon graft . Followup examinations were performed 1 year after surgery . Anteroposterior laxity of the knee was examined with a KT-1000 arthrometer , whereas rotatory instability , as elicited by the pivot shift test , was assessed using a new measurement system incorporating three-dimensional electromagnetic sensors . Routine clinical evaluations , including KT examination , demonstrated no differences among the three groups . However , using the new measurement system , patients with double-bundle ACL reconstruction showed better pivot shift control of complex instability than patients with anteromedial and posterolateral single-bundle reconstruction . Level of Evidence : Level II , therapeutic study . See the Guideline for Authors for a complete description of levels of evidence ACL reconstruction with bone patellar tendon bone ( BPTB ) grafts has been shown to produce dependable results . Recently , reconstructions with double-looped semitendinosus gracilis ( DLSG ) grafts have become common . The prevailing opinion is that ACL reconstruction with patellar tendon graft produces a more stable knee with more anterior knee pain than DLSG grafts , while the functional results and knee scores are similar . The present study evaluates BPTB grafts fixed with metallic interference screws and DLSG grafts fixed with Bone Mulch Screw on the femur and WasherLoc fixation on the tibia . All else being the same , there is no difference in the outcome between the two grafts and fixation methods . This is a prospect i ve r and omized multicenter study . A total of 115 patients with isolated ACL ruptures were r and omized to either reconstruction with BPTB grafts fixed with metal interference screws ( 58 patients ) or DLSG grafts ( 57 patients ) fixed with Bone Mulch Screws and WasherLoc Screws . Follow-up was at one and two years ; the latter by an independent observer . At two years , one ACL revision had been performed in each group . Eight patients in the DLSG group and one in the BPTB group underwent meniscus surgery in the follow-up period ( P = 0.014 ) . Mean Lysholm score at the two year follow-up was 91 ( SD ± 10.3 ) in the DLSG group and also 91 ( SD ± 10.2 ) in the BPTB group . Mean KT-1000 at two years was 1.5 mm in the BPTB group and 1.8 mm in the DLSG group ( n.s . ) . At two years , four patients in the BPTB group and three in the DLSG group had a Lachman test grade 2 or 3 ( n.s . ) . More patients in the BPTB group had pain at the lower pole of the patella ( P = 0.04 ) . Peak flexion torque and total flexion work were lower in the DLSG group at one year ( P = 0.003 and P = 0.000 ) and total flexion work also at two years ( P = 0.05 ) . BPTB ACL reconstruction fixed with interference screws and DLSG fixed with Bone Mulch Screws on the femur and WasherLoc Screws on the tibia produce satisfactory and nearly identical outcomes . Among our patients in the DLSG group , flexion strength was lower , and more patients underwent meniscus surgery in the follow-up period . The BPTB group has more anterior knee pain Anatomical observation and biomechanical studies have shown that the anterior cruciate ligament ( ACL ) mainly consists of two distinct bundles , the anteromedial ( AM ) bundle and posterolateral ( PL ) bundle . Conventional single-bundle ACL reconstruction techniques have focused on the restoration of the AM bundle while giving limited attention to the PL bundle . The purpose of this prospect i ve , r and omized clinical study is to compare the outcomes of ACL reconstruction when using either double-bundle or single-bundle technique and bioabsorbable interference screw fixation , and similar rehabilitation with both techniques . Sixty-five patients were r and omized into either double-bundle ( n = 35 ) or single-bundle ( n = 30 ) ACL reconstruction with hamstring tendons and bioabsorbable screw ( Hexalon , Inion Company , Tampere , Finl and ) fixation in both groups . The evaluation methods were clinical examination , KT-1000 arthrometer measurements , radiographic evaluation , as well as International Knee Documentation Committee and Lysholm knee scores . There were no differences between the study groups preoperatively . For an average of 14 months of follow-up ( range 12–20 months ) , 30 patients of the double-bundle group and 29 patients of the single-bundle group were available ( 91 % ) . At the follow-up , the rotational stability , as evaluated by pivot shift test , was significantly better in the double-bundle group than in the single-bundle group . However , in anterior stability of the knee , there was no significant difference between the groups . None of the patients in the double-bundle group had graft failure , while four patients in the single-bundle group had . In addition , knee scores were equal at the follow-up , and all the results were significantly better at the follow-up than preoperatively , in both groups PURPOSE The purpose of this study was to obtain more than 2 years ' follow-up after surgery to investigate the effect of the difference in rotatory stability based on our previous data on the clinical outcome among 3 groups : double-bundle ( DB ) reconstruction group , anteromedial ( AM ) single-bundle reconstruction group , and posterolateral ( PL ) single-bundle reconstruction group . METHODS We r and omly separated 55 patients with anterior cruciate ligament rupture into 3 groups : 18 in DB group , 18 in AM group , and 19 in PL group . The mean follow-up period is 33.7 months for the DB group , 31.9 months for the AM group , and 33.2 months for the PL group . We evaluated the Lysholm score , Tegner score , anterior laxity with the KT-1000 arthrometer ( MEDmetric , San Diego , CA ) , rotator instability with the pivot-shift test , and muscle strength with knee extensor and flexor isokinetic peak torques at 60 ° /s . RESULTS There were no significant differences in postoperative Lysholm score and Tegner score . Anterior stability of the knee , as measured by the KT-1000 arthrometer , was significantly better in the DB group than the PL group ( P < .05 ) . The negative rate of the manual pivot-shift test in the DB group was significantly superior to the PL group ( P < .05 ) . Muscle strength of the extensor in the DB group was significantly superior to that in the AM group ( P < .05 ) , and muscle strength of the flexor in the PL group was significantly inferior to that in both the DB and AM groups ( P < .05 ) . Two patients in the PL group had rerupture ; however , there was no graft failure in the other groups . CONCLUSIONS At 2 years ' follow-up , patients undergoing DB anterior cruciate ligament reconstruction had greater extension strength than patients receiving an AM single-bundle reconstruction . The DB and AM groups had greater flexion strength than the PL group . The DB and AM groups had a similar rate of negative pivot-shift test results , whereas the PL group had fewer negative pivot-shift test results than the DB group . There were no KT-1000 side-to-side differences between the DB and AM groups , whereas the DB group had better results than the PL group . Overall , the clinical outcome as measured by Lysholm and Tegner scores was not different between groups . LEVEL OF EVIDENCE Level II , prospect i ve comparative study PURPOSE The purpose of this study was to test a new method of harvesting semitendinosus tendon during anterior cruciate ligament reconstruction that would allow an anatomic reinsertion of the regenerated tendon and minimize postoperative internal rotation strength loss . METHODS We prospect ively selected 35 patients surgically treated for anterior knee instability . The patients were r and omly assigned to either the study group ( group A ) ( 19 patients ) or the control group ( group B ) ( 16 patients ) . A modified harvesting technique of the semitendinosus , which reserves its distal insertion , was performed in group A , with the aim to allow a better postoperative recovery of flexion and internal rotation strength . Patients in group B underwent a " st and ard " harvesting technique . All patients were postoperatively evaluated by clinical examination , isokinetic tests , and magnetic resonance imaging . RESULTS At a follow-up of 25 months , all patients showed satisfactory postoperative knee stability . Isokinetic tests showed a significant deficit in internal rotation strength at 60 degrees /s in patients in group B ( 84.60 % v 97.37 % in patients in group A ) . No deficits were found in group A. Magnetic resonance imaging evaluations showed a higher percentage of regenerated semitendinosus in group A patients ( 100 % ) than that in group B patients ( 50 % ) at the joint line level . In group A , the site of reinsertion was found to be on the pes anserinus in 71 % of the patients and in the posteromedial corner of the tibial plateau in the other 29 % ; in group B , a distal signal was detected in 50 % of the patients , which was at the posteromedial corner of the tibia in every case . CONCLUSIONS This study seems to show that the proposed harvesting technique could minimize the postoperative loss of strength in internal rotation after anterior cruciate ligament reconstruction with hamstrings . LEVEL OF EVIDENCE Level I , high- quality therapeutic r and omized controlled trial Background Double-bundle ACL reconstruction popularity is increasing with the aim to reproduce native ACL anatomy and improve ACL reconstruction outcome . However , to date , only a few r and omized clinical studies have been published . Purpose The aim of this study was to prospect ively compare the clinical results of single- and double-bundle ACL reconstruction . Study Design R and omized controlled clinical trial ; Level of evidence , 1 . Methods Seventy patients with a chronic unilateral ACL rupture who underwent arthroscopically assisted ACL reconstruction using a hamstring graft were r and omized to receive a single- ( SB ) or double-bundle ( DB ) reconstruction . Both groups were comparable with regard to preoperative data . A double-incision surgical technique was adopted in both groups . The graft was fixed by looping the hamstring tendons around a bony ( DB ) or a metallic ( SB ) bridge on the tibial side and with interference screws reinforced with a staple on the femur . The same rehabilitation protocol was adopted . Outcome assessment was performed by a blinded , independent observer using the visual analog scale ( VAS ) score , the new International Knee Documentation Committee ( IKDC ) form , the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) , and KT-1000 arthrometer evaluation . Results All the patients reached a minimum follow-up of 2 years . No differences between the 2 groups were observed in terms of KOOS and IKDC subjective score . A statistically significant difference in favor of the DB group was found with the VAS ( P < .03 ) . The objective IKDC final scores showed statistically significantly more “ normal knees ” in the DB group than in the SB group ( P = .03 ) . There was 1 stability failure in the DB group and 3 in the SB group . The KT-1000 arthrometer data showed a statistically significant decrease in the average anterior tibial translation in the DB group ( 1.2 mm DB vs 2.1 mm SB ; P < .03 ) . The incidence of a residual pivot-shift glide was 14 % in DB and 26 % in SB ( P = .08 ) . Conclusion In the 2-year minimum follow-up , DB ACL reconstructions showed better VAS , anterior knee laxity , and final objective IKDC scores than SB . However , longer follow-up and accurate instrumented in vivo rotational stability assessment are needed PURPOSE The purpose of this study was to compare the clinical results of arthroscopic single-bundle and double-bundle anterior cruciate ligament ( ACL ) reconstruction . METHODS We design ed a prospect i ve study that included patients with an isolated ACL injury . From April 2004 to February 2007 , of 147 patients who underwent ACL reconstruction , 113 were included in this study . We serially obtained clinical and radiologic data preoperatively and postoperatively . We compared preoperative data and data at 2 years postoperatively in patients who had undergone single-bundle ACL reconstruction versus patients who had undergone double-bundle ACL reconstruction . There were 50 single-bundle reconstructions and 63 double-bundle reconstructions . Anteroposterior stability was assessed objective ly by anterior stress radiographs with the telos device ( telos , Marburg , Germany ) and the maximal manual test with the KT-2000 arthrometer ( MEDmetric , San Diego , CA ) . Rotational stability was determined by lateral pivot-shift test . The clinical results were assessed by International Knee Documentation Committee and Orthopadische Arbeitsgruppe Knie scores and Tegner activity scale . In addition , we evaluated postoperative thigh circumference and range of motion . RESULTS Residual anteroposterior laxity determined at 2 years postoperatively by telos and KT-2000 was 1.74 mm + /- 1.67 mm and 1.79 mm + /- 1.56 mm , respectively , in the single-bundle reconstruction group and 1.63 mm + /- 1.50 mm and 1.61 mm + /- 1.22 mm , respectively , in the double-bundle reconstruction group . There were no statistically significant differences . For the lateral pivot-shift test done at 2 years postoperatively , there was no statistically significant difference . In addition , clinical results such as International Knee Documentation Committee score , Orthopadische Arbeitsgruppe Knie score , Tegner activity scale , thigh circumference , and range of motion showed no significant differences between the 2 groups . CONCLUSIONS Double-bundle reconstruction of the ACL by a method using 2 femoral tunnel and 2 tibial tunnels showed no differences in stability results or any other clinical aspects or in terms of patient satisfaction . LEVEL OF EVIDENCE Level II , prospect i ve comparative study PURPOSE The purpose of this prospect i ve r and omized study was to assess biomechanical , radiographic , and functional results after single-bundle anterior cruciate ligament ( ACL ) reconstruction by use of a navigation system . METHODS ACL reconstruction was performed by use of the OrthoPilot navigation system ( B. Braun-Aesculap , Tuttlingen , Germany ) in 40 patients ( group 1 ) ; and in another 40 patients , surgery was done by the st and ard manual targeting technique ( group 2 ) . The anterior laxity was measured with a KT-1000 arthrometer ( MEDmetric , San Diego , CA ) . Femoral and tibial tunnel position was evaluated radiologically according to the method described by Bernard and Hertel and by Harner et al. , respectively . The question naire-based Lysholm and International Knee Documentation Committee scales were included to compare the functional state in both groups . RESULTS The knees in group 1 were as stable as those in group 2 during the arthrometer testing , with a lower value of dispersion . The postoperative Lysholm and International Knee Documentation Committee scores had the same value in both groups . Statistical differences existed with regard to anterior-posterior femoral tunnel placement when the navigated and st and ard techniques were compared ; in the navigated group , more exact results were found . No significant complications were observed . CONCLUSIONS The only difference that we found between the navigated and st and ard groups was in radiographic tunnel position measurement . The computer-assisted navigation technique in our study result ed in more accurate tunnel placement in the femur ( but not the tibia ) than the traditional arthroscopic technique . However , the performed st and ard radiographic measurements are of limited precision in principle . Functional scales and stability tests gave similar results in both groups . LEVEL OF EVIDENCE Level I , therapeutic study Anterior cruciate ligament ( ACL ) reconstruction in double-bundle technique is advocated to more closely restore the anatomy and function of the native ligament than conventional single-bundle technique . But up to now there are only a few clinical investigations comparing both techniques in a prospect i ve manner . We hypothesized that double-bundle ACL reconstruction reveals superior clinical and subjective results compared to single-bundle technique in a high-dem and collective . A total of 50 male patients ( mean age 29.4 years ) were prospect ively r and omized consecutively into one of the two reconstruction techniques . Group 1 ( SB ) underwent a 4-str and ed single-bundle reconstruction with a ST graft in femoral position at 10:00 and 02:00 o’clock , respectively . In group 2 ( DB ) , reconstruction was performed by using a 2-str and ed ST graft with double-bundle , four tunnel technique . Before surgery and at a 2 year follow-up ( range 23–25 months ) patients were evaluated by the same blinded observer . There was no significant difference in the side-to-side anterior laxity-measurement with the KT-1000 between both groups . As evaluated by the pivot shift , no significant correlation could be noted ( Fisher exact test P = 0.098 ) between rotational stability and any of the both reconstruction techniques . However , the anterior and rotational stability improved significantly at 2-year follow-up compared to preoperatively ( P = 0.003 ) in both groups . The statistical analysis showed a significant increase for the IKDC ( subjective , objective ) and the Lysholm Score at final follow-up among each single technique , while we found no significant difference between the two reconstruction methods . On the basis of our investigation , we conclude that reconstruction of the ACL by a double-bundle ST graft with an extracortical anchorage can achieve excellent clinical results . But in contrast to our initial hypothesis , we could not quote any significant advantages by creating two independent bundles . Reconstruction of the anterior cruciate ligament in conventional single-bundle technique with a more horizontal femoral tunnel placement obtains comparable clinical results in the present high-dem and collective We conducted a prospect i ve , r and omised controlled trial comparing anterior cruciate ligament reconstruction using middle third patellar tendon graft ( PT ) to synthetic Leeds-Keio ( LK ) ligament . The patients were r and omised ( 26 PT , 24 LK ) . Subjective knee function was classified ( Lysholm , Tegner activity , IKDC scores ) , laxity was measured ( Lachman test , Stryker laxometer ) , and functional ability was assessed ( one-hop test ) . There were no significant differences between Lysholm or IKDC scores at any stage by 5 years . Significant differences were found between the groups at 2 years for Tegner activity scores , laxity and one-hop testing . By 5 years there were no significant differences . Clinical equivalence was demonstrated between the two groups for the Lysholm score and one-hop test but not for the Tegner activity score at 5 years . The use of the LK ligament has been largely ab and oned due to reports of its insufficiency . Our results demonstrate that it is not as inferior as one might expect . We conclude that the results of LK ligament ACL reconstruction are as acceptable as those using PT . It may provide an additional means of reconstruction where no suitable alternative is present Background Several trials have been conducted to compare the clinical results between anatomic double-bundle and single-bundle anterior cruciate ligament ( ACL ) reconstruction procedures . In these studies , however , the number of patients was insufficient to compare the clinical results of the 2 procedures . Hypothesis The anatomic double-bundle procedure may be significantly better concerning the anterior laxity and the pivot-shift test than the single-bundle procedure , while there may be no significant differences in the other clinical evaluations and the intraoperative and postoperative complications between the 2 procedures . Study Design Cohort study ; Level of evidence , 2 . Methods Three hundred and twenty-eight patients with unilateral ACL reconstruction using hamstring autografts were divided into 2 groups . The first 157 consecutive patients underwent single-bundle reconstruction and the remaining 171 patients underwent anatomic double-bundle reconstruction . Concerning all background factors , there were no statistical differences between the 2 groups . Each patient was examined 2 years after surgery . Results No serious complications were experienced in either group . The anterior laxity was significantly less in the double-bundle reconstruction ( mean , 1.2 mm ) than in the single-bundle reconstruction ( mean , 2.5 mm ) . In the pivot-shift test , the double bundle ( + indication 16 % ; + + , 3 % ) was significantly better than the single bundle ( + result , 37 % ; + + , 12 % ) . The mean Lysholm score averaged 96.5 points ’ and 97.3 points in single-bundle and double-bundle reconstructions , respectively , while the International Knee Documentation Committee evaluation showed that 90 and 110 patients , respectively , were evaluated as rank A ( no significant difference between groups ) . There were no significant differences in the other clinical evaluations and the complications between the 2 procedures . Conclusions The postoperative anterior and rotational stability after the anatomic double-bundle ACL reconstruction was significantly better than that after the single-bundle reconstruction , although there were no significant differences between the 2 Procedures concerning the complications and the clinical evaluations BACKGROUND The aim of the study was to compare the results after arthroscopic anterior cruciate ligament ( ACL ) reconstruction using central -third bone-patellar tendon-bone ( BTB ) autografts and triple/quadruple semitendinosus ( ST ) autografts . HYPOTHESIS In the long-term , ACL reconstruction using BTB autografts will render more donor-site problems than ST autografts . STUDY DESIGN R and omized controlled trial ; Level of evidence , 1 . METHODS A r and omized series of 71 patients ( 22 women and 49 men ) with a unilateral ACL rupture who underwent reconstructive surgery were included in the study . The BTB graft was used in 34 patients ( BTB group ) and the ST-tendon graft was used in 37 patients ( ST group ) . The patients were examined a median of 86 months ( range , 68 to 114 months ) after the reconstruction . RESULTS Sixty-eight of 71 patients ( 96 % ) were examined at follow-up . The clinical assessment s at follow-up revealed no significant differences between the BTB group and the ST group in terms of the Lysholm score , Tegner activity level , International Knee Documentation Committee evaluation system , 1-legged hop test , KT-1000 arthrometer laxity measurements , manual Lachman test , and range of motion . A significant improvement was seen in both groups compared with the preoperative values in terms of most clinical assessment s. Donor-site morbidity in the form of knee-walking ability , kneeling ability , and area of disturbed anterior knee sensitivity revealed no significant differences between the groups . CONCLUSION Seven years after ACL reconstruction , the subjective and objective outcomes were similar after using the central -third BTB autograft and triple/quadruple ST autograft . Furthermore , no difference in terms of donor-site morbidity was found between the 2 groups Hamstring tendon autograft has become a popular graft choice for anterior cruciate ligament ( ACL ) reconstruction , but there is no consensus on the ideal technique of fixation . We performed a pilot r and omized controlled study to compare the clinical and mechanical outcome of two femoral fixation techniques for anterior cruciate ligament ( ACL ) reconstruction using hamstrings graft . We recruited 30 patients with a chronic unilateral tear of the anterior cruciate ligament . In all patients , quadrupled hamstring graft was used for ACL reconstruction . In 15 patients , femoral graft fixation was performed using Bio-interference Screws fixation ( Arthrex , Inc. Naples USA ) ( Group 1 ) . In the other 15 patients , femoral graft fixation was performed using BioTransFix femur extra cortical transverse fixation ( Arthrex , Inc. Naples USA ) ( Group 2 ) . In both groups , tibial fixation was achieved with a Delta bio-absorbable interference screw ( Arthrex ) . Both groups were comparable with regard to demographic data , pre-operative activity level , mechanism of injury , interval between the injury and the operation , and pre-operative knee laxity measurements . An independent observer , who was blinded with regard to the involved leg and the type of graft , performed the outcome assessment with the use of a Rolimeter arthrometer ( Aircast ) , and the International Knee Documentation Committee . At 13 months follow up , all patients except one had functionally normal or nearly normal IKDC objective scores . The mean IKDC subjective score was 83.38+/-9.4 in Group 1 and 79.92+/-11.01 in Group 2 ( P>.05 ) . The side to side laxity as measured with the Rolimeter arthrometer was 1.5 mm+/-1 ( range 0 - 3 ) for Group 1 , and 2 mm+/-1 ( range 0 - 3 ) for Group 2 ( P>.05 ) . Femoral Biotransfix fixation and Bio-interference Screws fixation provide comparable mechanical stability and clinical outcome at 13 months follow up . BiotransFix fixation is an effective alternative to other devices . Our preliminary study shows that there is no evidence to prefer femoral transfixation to the more traditional , technically less dem and ing , and more economical interference screw fixation . A full study requires 368 participants PURPOSE The aim of this study was to compare tunnel enlargement in patients with double-bundle and single-bundle anterior cruciate ligament ( ACL ) reconstruction . METHODS Sixty patients were r and omized by closed envelopes into 2 different groups of ACL reconstruction with hamstring tendons : double-bundle technique with bioabsorbable screw fixation ( n = 35 ) and single-bundle technique with bioabsorbable screw fixation ( n = 25 ) . Magnetic resonance imaging evaluation was performed in 53 patients ( 88 % ) ( 32 in double-bundle group and 21 in single-bundle group ) for a mean of 27 months ' follow-up ( range , 24 to 36 months ) . Tunnel enlargement was determined by digital measurement of the widths perpendicular to the long axis of the tunnels on an oblique coronal and sagittal plane . The magnetic resonance imaging measurements were compared with the intraoperative drill diameter . RESULTS No significant differences were found between the double-bundle group and the single-bundle group in tunnel enlargement on the femoral side . However , on the tibial side , tunnel enlargement was greater in the single-bundle group than in the double-bundle group in each tunnel ( P = .051 ) . In all knees , tunnel enlargement both on the tibial side and on the femoral side correlated significantly with the anterior and rotational laxity of the operated knee . In the double-bundle group , no tunnel communication between the anteromedial and posterolateral tunnels was seen in any of the patients on either the tibial side or femoral side . CONCLUSIONS This prospect i ve , r and omized study showed that our double-bundle ACL reconstruction technique results in less tunnel enlargement in each tunnel on the tibial side than the single-bundle technique with similar fixation methods , graft material , and rehabilitation . In addition , no tunnel communication was observed in the patients undergoing double-bundle ACL reconstruction . The clinical results were good in both groups . However , the patients who had more tunnel enlargement had significantly more anterior and rotational laxity of the operated knee as well . LEVEL OF EVIDENCE Level I , therapeutic r and omized controlled trial PURPOSE The purpose of this study was to analyze the clinical outcome of arthroscopic anterior cruciate ligament ( ACL ) reconstruction with bone-patellar tendon-bone autograft versus allograft . METHODS Between May 2000 and June 2004 , 172 patients undergoing arthroscopic bone-patellar tendon-bone ACL reconstruction were prospect ively r and omized into autograft ( n = 86 ) or allograft ( n = 86 ) groups . The senior surgeon performed all operations using the same surgical technique . Each fixation was performed by means of an interference screw . Patients were evaluated preoperatively and postoperatively at follow-up . Of the patients , 156 ( 76 in the autograft group and 80 in the allograft group ) were available for full evaluation . Evaluations included a detailed history , physical examination , functional knee ligament testing , KT-2000 arthrometer testing ( MEDmetric , San Diego , CA ) , Harner 's vertical jump and Daniel 's 1-leg hop tests , Lysholm score , Tegner score , International Knee Documentation Committee st and ard evaluation form , Cincinnati knee score , and radiograph . RESULTS Demographic data were comparable between groups . The mean follow-up was 5.6 years for both groups . There were no statistically significant differences according to evaluations of outcome between the 2 groups except that patients in the allograft group had a shorter operation time and longer fever time postoperatively compared with the autograft group . The postoperative infection rates were 0 % and 1.25 % for the autograft group and allograft group , respectively . There was a significant difference ( P < .05 ) in the development of osteoarthritis between the operated knee in comparison to the contralateral knee according to radiographs . However , no significant difference was found between the 2 groups at the final follow-up examination ( P > .05 ) . CONCLUSIONS Both groups of patients achieved almost the same satisfactory outcomes after a mean of 5.6 years of follow-up . Allograft is a reasonable alternative to autograft for ACL reconstruction . LEVEL OF EVIDENCE Level II , prospect i ve comparative study We investigated the long-term outcome of 100 patients 15 years after having been r and omly allocated to primary repair ( augmented or non-augmented ) or non-surgical treatment of an anterior cruciate ligament ( ACL ) rupture . The subjective outcome was similar between the groups , with no difference regarding activity level and knee-injury and osteoarthritis outcome score but with a slightly lower Lysholm score for the non-surgically treated group . This difference was attributed to more instability symptoms . The radiological osteoarthritis ( OA ) frequency did not differ between surgically or non-surgically treated patients , but if a meniscectomy was performed , two-thirds of the patients showed OA changes regardless of initial treatment of the ACL . There were significantly more meniscus injuries in patients initially treated non-surgically . One-third of the patients in the non-surgically treated group underwent secondary ACL reconstruction due to instability problems . In this study , ACL repair itself could not reduce the risk of OA nor increase the subjective outcome scores . However , one-third of the non-surgical treated patients were later ACL reconstructed due to instability . The status of the menisci was found to be the most important predictor of developing OA . Early ACL repair and also ACL reconstruction can reduce the risk of secondary meniscus tears . Indirectly this supports the hypothesis that early stabilization of the knee after ACL injury is advantageous for the long-term outcome We propose a new technique , with double bundle , double tibial tunnels with a bridge between them , using the hamstrings as auto-grafts , retaining either their central or peripheral attachment . A prospect i ve series of 41 patients underwent primary reconstruction of the anterior cruciate ligament by one surgeon , arthroscopically and electronically assisted ; 37 were men and 4 were women with a mean age of 24.7 years . The mean follow-up was19.05 ( 12–30 ) months . Normal function and joint stability was achieved . The patients returned to full occupational activities within 3–6 months after the operation . The function of hamstrings was not disturbed . Two patients have sustained a new injury without rupture of the grafts . The Noulis-Lachman test was negative in 35 knees . Positive Pivot shift , post-operatively , was present in 15.45 % of patients . The IKDC score was 84.55 . In the proposed ACL reconstruction technique , the two tendons are transferred and used as grafts , with gracillis and semitendinosus retaining their distal and central attachment , respectively ; the former superimposed upon the latter while entering the femoral tunnel . The tibial tunnels leave a bone bridge ranging between 12 and 15 mm within the footprints of ACL . The two bundles are tensioned , each at different angle . This configuration imitates both the anatomy and the function of ACL and controls not only the anterior translation , but also the rotatory stability . With this innovative technique , the final outcome is improved , thus being closer to normal , as evidence d from previous experiments and the present prospect i ve series Introduction : The goal of this study is to establish the influence of tensioning the graft during anterior cruciate ligament ( ACL ) reconstruction , with a semitendinosus tendon graft , on postoperative stability . Type of study : Prospect i ve controlled clinical trial . Material and methods : Forty-eight patients were r and omly allocated to three groups in which three different tensions , 8 , 12 , or 15 kg force , was applied on the reconstructed ACL during the operation . The patients were observed for 1 year or more after surgery ( min . 1 year , max . 2 years 8 months ) . Clinical outcome was evaluated using the visual analogue scale , anterior knee laxity ( using the KT2000 arthrometer ) and the torque of the knee extensor . Results : Postoperatively , the average side-to-side differences in anterior laxity were 1.3 mm in the 8 kg group , 2.1 mm in the 12 kg , and 2.4 mm in the 15 kg group . The visual analogue scale averaged 84 , 83 , and 79 mm , respectively . There were no significant differences among the three groups . There were also no significant differences between the groups for muscle strength recovery during isokinetic and isometric contraction at 1 year postoperatively . Conclusion : There were no significant differences among the groups in subjective clinical results , anterior laxity , and knee extensor strength in the ACL reconstructions that used the autogenous semitendinosus tendon graft Background Conventional anterior cruciate ligament reconstruction techniques have focused on restoration of the anterome-dial bundle only , which , however , may be insufficient in restoring the rotational stability of the knee . Hypothesis Rotational stability of the knee is better when using a double-bundle technique instead of a single-bundle technique for anterior cruciate ligament reconstruction . Study Design R and omized controlled clinical trial ; Level of evidence , 1 . Methods Seventy-seven patients were r and omized into 3 different groups for anterior cruciate ligament reconstruction with hamstring tendons : double-bundle with bioabsorbable screw fixation ( n = 25 ) , single-bundle with bioabsorbable screw fixation ( n = 27 ) , and single-bundle with metallic screw fixation ( n = 25 ) . The evaluation methods were clinical examination , KT-1000 arthrometric measurement , and the International Knee Documentation Committee and Lysholm knee scores . Results There were no differences between the study groups preoperatively . Seventy-three patients ( 95 % ) were available at a minimum 2-year follow-up ( range , 24–35 mo ) . The rotational stability of the knee , as evaluated by the pivot-shift test , was the best in the patients in the double-bundle group . In addition , the patients in the single-bundle groups had more graft failures than those in the double-bundle group . Concerning the anterior stability of the knee as measured with the KT-1000 arthrometer , the group differences were not statistically significant . No significant differences were found between the groups in knee scores . Conclusion Rotational stability of the knee is better when using the double-bundle technique instead of the single-bundle technique in anterior cruciate ligament reconstruction PURPOSE Biomechanical studies show increased anterior and rotational stability with double-bundle ( DB ) compared to single-bundle ( SB ) anterior cruciate ligament ( ACL ) reconstruction . The aim of this study was to evaluate the clinical results of four-tunnel DB ACL reconstruction . METHODS Seventy patients undergoing arthroscopic hamstring ACL reconstruction were prospect ively r and omized to DB ( n = 35 ) or SB ( n = 35 ) groups . Each bundle fixation was by means of a femoral EndoButton CL and a tibial biodegradable interference screw . Demographic data were comparable between groups , and the average age of all patients was 29 years . The average follow-up was 19 months for both groups and included a history , clinical evaluation with knee scores , and radiographs . RESULTS The subjective results were similar in groups . The subjective International Knee Documentation Committee ( IKDC ) 2000 score was 88 P for DB versus 90 P for SB ; the Lysholm score was 90 P for DB versus 93 P for SB ; and the Cincinnati knee score was 91 P for DB versus 92 P for SB . The objective IKDC was significantly higher for DB : 78 % " A " ( P < .000 ) and 19 % " B " compared to 24 % " A " and 68 % " B " for SB . The average KT-1000 side-to-side difference was 1.0 mm for DB and 1.6 mm for SB ( P = .054 ) and the pivot shift test was negative in 97 % for DB ( P = .01 ) and 71 % for SB . The range of motion was comparable for both groups . CONCLUSIONS Our study shows a significant advantage in anterior and rotational stability as well as objective IKDC for four-tunnel DB ACL reconstruction compared to SB ACL reconstruction . The subjective Cincinnati knee score , the Lysholm score , and the subjective IKDC 2000 did not show any statistical difference for one or the other technique . LEVEL OF EVIDENCE Level I , r and omized controlled trial Background Poor outcome in anterior cruciate ligament reconstruction is often related to tunnel position . Hypothesis Improving accuracy of the tunnel position will lead to improved outcome . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Sixty patients were r and omized to either st and ard instrumentation or computer-assisted guides to position the tibial and femoral tunnels . The results were evaluated on clinical outcome based on International Knee Documentation Committee form ( laxity ) and radiologic assessment : radiologic Lachman ( Telos at 150 and 200 N ) and analysis of the tunnel positions . Results International Knee Documentation Committee laxity was level A in 22 knees in the conventional group ( mean , 1.5 mm at 200 N ) compared with 26 navigated knees ( mean laxity , 1.3 mm ; P= .49 ) . Laxity was less than 2 mm in 96.7 % of the navigated group and 83 % of the conventional group ( P= .292 ) . The variability of laxity in the navigated group was significantly less than in the conventional group , with the st and ard deviation of the navigated group being smaller than that in the conventional group ( P= .0003 at 150 N and .0005 at 200 N Telos ) . A significant difference ( P= .03 ) was found between the groups in the ATB value ( distance between the projection of the Blumensaat line on the tibial plateau and the anterior edge of the tibial tunnel ) , characterizing the sagittal position of the tibial tunnel ( negative ATB values imply graft impingement in extension ) . In the conventional group , mean ATB was –0.2 ( –5 to + 4 ) , whereas it was 0.4 ( 0 to 3 ) in the navigated patients . There were no negative ATB values in the navigated group . Conclusion This study confirms that the accuracy and consistency of tibial tunnel position can be improved by the use of computer-assisted navigation and that the clinical result in terms of laxity is more reliable Background Next to graft fixation , correct positioning of the tibial and femoral tunnel is a deciding factor for the clinical result of anterior cruciate ligament reconstruction surgery . Computer-assisted navigation has been proposed as a method to improve tunnel positioning . Purpose To examine the differences in tibial tunnel placement between cruciate ligament operations using manual and computer-assisted navigation . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Between December 2003 and April 2004 , 53 athletes underwent anterior cruciate ligament reconstruction surgery with arthroscopic press-fit technique . The first group ( group N ; 24 athletes ) were operated on with the aid of a navigation system ( OrthoPilot , Aesculap AG & Co. KG , Braun ) , and the second group ( group M ; 29 athletes ) were “ manually ” operated on . A lateral radiograph of the knee at maximum extension was used to determine the exact position of the tibial tunnel four days postoperatively . In the measurements , the anterior and posterior boundaries of the tibial tunnel , as well as the center of the tibial tunnel in relation to the maximum tibia anteroposterior diameter were evaluated ( indicated in percent ) . An analysis of the tibial tunnel position proportional to the slope of the intercondylar roof was done to determine intercondylar impingement ( method according to Howell ) . The centers of the tibial tunnels were compared with the “ optimal ” position noted in previous studies . The st and ard deviation was determined for both groups to determine the variance of placement . Results The anterior tibial tunnel border was 19.4 mm in group M ( 29.7 % ) and 21.2 mm in group N ( 32.2 % ) ( P=.18 ) . The center of the tibial tunnel was located at 24.6 mm in group M ( 35.6 % ) and at 26.6 mm in group N ( 40.3 % ) ( P=.19 ) . In group M , the posterior tibial tunnel position was located at 30.2 mm ( 46.2 % ) , and in group N at 32.2 mm ( 49.1 % ) ( P=.21 ) . When comparing the centers of the tibial tunnels with the optimal 44 % found in previous studies , the value for group M ( 37.6 % ) varied significantly , while group N ( 40.5 % ) did not . However , there was no significant difference in the range variance for either group ; the st and ard deviation was 6.9 % ( 4.3 mm ) for group M and 5.9 % ( 3.5 mm ) for group N. One athlete showed moderate impingement in group N , and two athletes in group M. Conclusion Assisted navigation offers good support for correct placement of the tibial tunnel , although experienced surgeons can achieve essentially the same positioning as surgeons using computer-assisted navigation . Whether it is advisable to implement this procedure in daily surgical routine should be decided based on clinical results OBJECTIVE To study muscle strength and functional performance in patients with anterior cruciate ligament ( ACL ) injury with or without surgical reconstruction 2 to 5 years after injury . Good muscle function is important in preventing early-onset osteoarthritis ( OA ) , but the role of reconstructive surgery in restoring muscle function is unclear . METHODS Of 121 patients with ACL injury included in a r and omized controlled trial on training and surgical reconstruction versus training only ( the Knee , Anterior cruciate ligament , NON-surgical versus surgical treatment [ KANON ] study , IS RCT N : 84752559 ) , 54 ( mean age at followup 30 years , range 20 - 39 , 28 % women ) were assessed a mean + /- SD of 3 + /- 0.9 years after injury with reliable , valid , and responsive test batteries for strength ( knee extension , knee flexion , leg press ) and hop performance ( vertical jump , one-leg hop , side hop ) . The Limb Symmetry Index ( LSI ; injured leg divided by uninjured and multiplied by 100 ) value and absolute values were used for comparisons between groups ( analysis of variance ) . An LSI > or=90 % was considered normal . RESULTS There were no differences between the surgical and nonsurgical treatment groups in muscle strength or functional performance . Between 44 % and 89 % of subjects had normal muscle function in the single tests , and between 44 % and 56 % had normal function in the test batteries . CONCLUSION The lack of differences between patients treated with training and surgical reconstruction or training only indicates that reconstructive surgery is not a prerequisite for restoring muscle function . Abnormal muscle function , found in approximately one-third or more of the patients , may be a predictor of future knee OA Background : The purpose of this study was to identify the determinants of patient satisfaction with the outcome after reconstruction of the anterior cruciate ligament . Methods : A cohort of 201 patients undergoing primary reconstruction of the anterior cruciate ligament was studied prospect ively . All patients were followed for a minimum of two years ( mean , 35.9 months ) . The dependent variable was patient satisfaction with the outcome , grade d ordinally on a scale of 1 to 10 . Nonparametric univariate analysis and multivariable modeling were performed to identify determinants of satisfaction . Results : The demographic variables were not found to have a significant association ( p > 0.05 ) with patient satisfaction . The variables at surgery demonstrated a significant association ( p < 0.05 ) with patient satisfaction only with respect to the status of the lateral meniscus , the presence of osteophytes , and concurrent plica excision . The objective variables at follow-up revealed that patients were significantly less satisfied ( p < 0.05 ) if they had a flexion contracture , increased laxity of the involved leg on the manual maximum test as measured on a KT-1000 device , an abnormal result on the pivot-shift examination , effusion , or tenderness at the medial joint line or patella . With regard to the subjective symptoms at follow-up , patients were found to be significantly ( p < 0.05 ) less satisfied with the outcome if they had symptoms of pain , swelling , partial giving-way , full giving-way , locking , noise , stiffness , or a limp . Analysis of the subjective function at follow-up demonstrated that patients were significantly less satisfied ( p < 0.05 ) with the outcome if they had a lower level of activity , sports activity , strenuous work , activities of daily living , overall knee function , sports participation , or symptom-free activity ; if they were unemployed ; or if they had difficulty with walking , squatting , ascending or descending stairs , running , jumping , cutting , or twisting . Patient satisfaction was significantly associated ( p < 0.05 ) with the Lysholm knee score , overall International Knee Documentation Committee ( IKDC ) knee score , IKDC subjective subscore , IKDC symptoms subscore , and IKDC range-of-motion subscore . The seven independent multivariate determinants ( adjusted R 2 = 0.83 , p < 0.001 ) of patient satisfaction included the Lysholm score , overall subjective knee function , IKDC range-of-motion subscale , patellar tenderness , full giving-way , flexion contracture , and swelling . Conclusions : Univariate and multivariate determinants of patient satisfaction with the outcome after reconstruction of the anterior cruciate ligament were established . Although some specific surgical and objective variables were important , subjective variables of symptoms and function had the most robust associations with patient satisfaction . In assessing the outcome of reconstruction from the perspective of patient satisfaction with the outcome , we should emphasize patient-derived subjective assessment of symptoms and function , particularly those involving issues of stiffness , giving-way , swelling , and patellofemoral symptoms PURPOSE To compare the clinical outcome of anatomic double-bundle anterior cruciate ligament ( ACL ) reconstruction with that of nonanatomic single- and double-bundle reconstructions . TYPE OF STUDY Prospect i ve comparative cohort study . METHODS Seventy-two patients with unilateral ACL-deficient knees were r and omly divided into 3 groups . Concerning all background factors , there were no statistical differences among the 3 groups . In group S ( n = 24 ) , single-bundle ACL reconstruction was performed . In group N-AD ( n = 24 ) , nonanatomic double-bundle reconstruction was carried out . In group AD ( n = 24 ) , anatomic double-bundle reconstruction was performed . One surgeon performed all operations using hamstring tendon autografts . Each patient underwent clinical examinations , before surgery and at 2 years . RESULTS No intraoperative and postoperative complications were experienced in each group . There were no significant differences concerning the time for operation among the 3 groups . The statistical analysis showed a significant difference in the postoperative side-to-side anterior laxity among the 3 groups ( P = .006 ) . The laxity was significantly less ( P = .002 ) in group AD ( 1.1 mm ) than in group S ( 2.8 mm ) , while there was no significant difference ( P = .072 ) between groups AD and N-AD . Concerning the pivot-shift test , group AD was significantly superior to group S ( P = .025 ) . There were no significant differences in the range of knee motion , the muscle torque , and the International Knee Documentation Committee evaluation . CONCLUSIONS On the basis of the KT-2000 measurement , the side-to-side anterior laxity of our anatomic double-bundle ACL reconstruction was significantly better than that of the single-bundle reconstruction with the hamstring tendon graft , although there were no significant differences in the other clinical measures among any of the 3 procedures . LEVEL OF EVIDENCE Level II Background Biodegradable cross-pins have been shown to provide higher failure loads than do screws for fixation of hamstring tendons under laboratory conditions . Purpose To compare the clinical results of biodegradable pins ( RigidFix ) and interference screws ( BioCryl ) for fixation of hamstring grafts in arthroscopically assisted anterior cruciate ligament reconstruction . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods To test the hypothesis of a difference of 1.0 ± 1.2 mm in anterior knee laxity between the two fixation options , 54 patients were r and omly assigned to groups via a block r and omization scheme and sealed envelopes . All patients underwent st and ardized hamstring graft reconstruction and had similar postoperative aftercare by an accelerated rehabilitation protocol . Measures assessed at baseline and after 1 and 2 years of follow-up included ( 1 ) the side-to-side difference in anterior laxity ( KT-1000 arthrometer ) , ( 2 ) Short Form 36 physical and mental component scores , and ( 3 ) the International Knee Documentation Committee form scores . Results After 1 and 2 years , 26 and 21 patients in the BioCryl group and 28 and 24 patients in the RigidFix group were available for follow-up examination . No significant difference was noted in instrumented anterior translation between BioCryl and RigidFix fixation : 1 year , 0.11 ( 95 % CI , —0.60 to 0.82 ; P = .7537 ) ; 2 years , 0.33 ( 95 % CI , —0.43 to 1.08 mm ; P = .3849 ) . Also , there were no significant differences in the mean physical and mental component scores and International Knee Documentation Committee form scores and in overall complication and surgical revision rates . A pin dislocation was classified as the sole procedure-specific serious adverse event . Conclusion Bioresorbable pins do not provide better clinical results than do resorbable interference screws for hamstring graft fixation in anterior cruciate ligament reconstruction surgery A total of 218 patients with unilateral anterior cruciate ligament deficiency were r and omly assigned to one of four groups . In group A an anatomical double bundle anterior cruciate ligament reconstruction was performed ; group B were treated by a single bundle using an Endobutton for femoral fixation ; in group C by a single bundle using RigidFix cross pins for femoral fixation ; and in group D by a single bundle using a bioabsorbable TransFix II screw for femoral fixation . For tibial fixation a bioabsorbable Intrafix interference screw was used for all the groups and the graft was fashioned from the semitendinosus and gracilis tendons in all patients . In all , 18 patients were lost to follow-up . The remaining 200 were subjected to a clinical evaluation , with assessment of the anterior drawer , Lachman 's and the pivot-shift tests , and KT-1000 arthrometer measurement . They also completed the International Knee Documentation Committee , Lysholm knee and Tegner activity scores . At a mean of 29 months ( 25 to 38 ) follow-up there were no significant differences concerning time between injury and range of movement and Lysholm knee scores among the four groups . However , the double bundle method showed significantly better results for the pivot-shift test ( p = 0.002 ) . The KT 1000 measurements showed a mean difference between the reconstructed knee and the patients ' normal knee of 1.4 mm in the double bundle group and 2.4 mm in the single bundle group ; which was statistically significant . The Lachman and anterior drawer tests also showed superior results for the double bundle method . The International Knee Documentation Committee scale showed no significant difference among the groups ( p < 0.001 ) . On clinical evaluation the double bundle group showed less laxity than the single bundle groups . However , regardless of the technique , all knees were improved by anterior cruciate ligament reconstruction compared with their pre-operative status A prospect i ve , r and omised , 5-year follow-up study was design ed to compare the functional results between patellar tendon and hamstring tendon autografts after anterior cruciate ligament reconstruction . Primary reconstruction was performed in 32 patients using the central third of the patellar ligament and in 32 patients using double-looped semitendinosus and gracilis tendons . All reconstructions were performed by a single surgeon , with identical surgical technique and rehabilitation protocol . Of the total 64 patients in the study , 54 ( 85 % ) were available for the 5-year follow-up . No statistically significant differences were seen with respect to Lysholm score , International Knee Documentation Committee ( IKDC ) classification , clinical and KT-2000 arthrometer laxity testing , single-legged hop test and anterior knee pain . Graft rupture occurred in two patients ( 8 % ) in the patellar tendon group and in two patients ( 7 % ) in the hamstring tendon group ; 23 patients ( 88 % ) in the patellar tendon group and 23 patients ( 82 % ) in the hamstring tendon group returned to their pre-injury activity level . Good subjective outcome and stability can be obtained by using either graft ; no statistically significant differences were found in functional outcome between the grafts Background There are still controversies about graft selection for primary anterior cruciate ligament reconstruction . Prospect i ve r and omized long-term studies are needed to determine the differences between the material s. Hypothesis Five years after anterior cruciate ligament reconstruction , there is a difference between hamstring and patellar tendon grafts in development of degenerative knee joint disease . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods From June 1999 to March 2000 , 64 patients were included in this prospect i ve study . A single surgeon performed primary arthroscopically assisted anterior cruciate ligament reconstruction in an alternating sequence . In 32 patients , anterior cruciate ligament reconstruction was performed with hamstring tendon autograft , whereas in the other 32 patients , anterior cruciate ligament reconstruction was performed with patellar tendon autograft . Results At the 5-year follow-up , no statistically significant differences were seen with respect to the Lysholm score , clinical and KT-2000 arthrometer laxity testing , anterior knee pain , single-legged hop test , or International Knee Documentation Committee classification results ; 23 patients ( 82 % ) in the hamstring tendon group and 23 patients ( 88 % ) in the patellar tendon group returned to their preinjury activity levels . Graft rupture occurred in 2 patients from the hamstring tendon group ( 7 % ) and in 2 patients from the patellar tendon group ( 8 % ) . Grade B abnormal radiographic findings were seen in 50 % ( 13/26 ) of patients in the patellar tendon group and in 17 % ( 5/28 ) of patients in the hamstring tendon group ( P = . 012 ) . Conclusion Both hamstring and patellar tendon grafts provided good subjective outcomes and objective stability at 5 years . No significant differences in the rate of graft failure were identified . Patients with patellar tendon grafts had a greater prevalence of osteoarthritis at 5 years after surgery Background There is a common belief that surgical reconstruction of an acutely torn anterior cruciate ligament ( ACL ) should be delayed for at least 3 weeks because of the increased incidence of postoperative motion loss ( arthrofibrosis ) and suboptimal clinical results . Hypothesis There is no difference in postoperative range of motion or stability after ACL reconstructions performed either acutely or delayed . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Patients with an acute ACL tear were prospect ively r and omized to either early ( within 21 days ) or delayed ( beyond 6 weeks ) reconstruction using autograft hamstring tendon . Previous knee surgery on the index extremity and a multiligamentous injury were exclusionary criteria . Surgical technique and postoperative rehabilitation were identical for all patients . Postoperative assessment s included range of motion and KT-1000 arthrometer measurements compared with the contralateral knee . St and ardized outcome measures were used including single assessment numeric evaluation ( SANE ) , Lysholm , and Tegner Activity Score . Results Seventy consecutive patients were enrolled , and 1 patient was dropped after a postoperative infection . Sixty-nine patients ( 34 acute , 35 delayed ) with an average age of 27 years composed the study cohort . The mean time from injury to surgery was 9 days ( range , 2–17 days ) for patients in the early group and 85 days ( range , 42–192 ) for those in the delayed group . The average follow-up from surgery was 366 days ( range , 185–869 ) . Articular cartilage and meniscal injuries were comparable between the 2 groups . There were no significant differences between the 2 treatment groups in degrees of extension or flexion lost relative to the nonoperative side , operative time , KT-1000 arthrometer differences , or subjective knee evaluations . Conclusion Excellent clinical results can be achieved after ACL reconstructions performed soon after injury using autograft hamstrings . Although the authors do not advocate that all reconstructions should be performed acutely , they found that early ACL reconstructions do not result in loss of motion or suboptimal clinical results as long as a rehabilitation protocol emphasizing extension and early range of motion is employed Background Debate exists regarding the optimal graft for anterior cruciate ligament reconstruction . Few studies have compared the differences in outcome after reconstruction using similar fixation methods . Hypothesis Similar outcomes will be seen after anterior cruciate ligament reconstruction with bone-patellar tendon-bone or quadruple-str and semitendinosus/gracilis tendons fixed with bioabsorbable interference screws . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Ninety-nine patients were prospect ively r and omized to bone-patellar tendon-bone ( 46 patients ) or quadruple-str and semitendinosus/gracilis ( 53 patients ) reconstruction groups . The bone-patellar tendon-bone group had slightly lower preinjury Tegner scores ( 6.7 vs 7.1 , P = .03 ) ; otherwise , the groups were similar . All surgeries were performed by a single surgeon using an endoscopic technique with bioabsorbable interference screw fixation . Patients were evaluated at 3 , 6 , 12 , and 24 months . Results Forty-six bone-patellar tendon-bone and 50 quadruple-str and semitendinosus/gracilis patients were available at 24 months ( 97 % ) . No differences in International Knee Documentation Committee grade , Lysholm score , Tegner activity level , range of motion , single-legged hop test , KT-1000 arthrometer manual maximum difference , Short Form-36 , or patient knee rating were found . The bone-patellar tendon-bone group had better flexion strength in the operated leg than in the nonoperated leg ( 102 % vs 90 % , P = .0001 ) , fewer patients complaining of difficulty jumping ( 3 % vs 17 % , P = .03 ) , and a greater number of patients returning to preinjury Tegner level ( 51 % vs 26 % , P = .01 ) . The quadruple-str and semitendinosus/gracilis group had better extension strength in the operated leg than in the nonoperated leg ( 92 % vs 85 % , P = .04 ) , fewer patients with sensory deficits ( 14 % vs 83 % , P = .0001 ) , and fewer patients with difficulty kneeling ( 6 % vs 20 % , P = .04 ) . Both groups showed significant improvement in KT-1000 arthrometer manual maximum difference , Lysholm score , Tegner activity level , International Knee Documentation Committee grade , and patient knee rating score . Conclusions Good outcomes were seen in both the bone-patellar tendon-bone and quadruple-str and semitendinosus/gracilis groups . Subtle differences were noted between the groups , which may help guide optimal graft choice PURPOSE To compare the clinical efficacy of ACL reconstruction using the Mitek bone-tendon-bone cross pin ( RIGIDfix ) to the Linvatec Bioscrew ( control device ) . METHODS Forty subjects were r and omized into one of two groups : the RIGIDfix or control group . Eligible subjects were male and female , 18 years of age and older , with an ACL injury of at least 3 weeks duration and no evidence of ACL insufficiency on the contralateral side . Subjects were followed for 24-month post-operatively . Evaluations included the International Knee Documentation Committee ( IKDC ) Knee Ligament St and ard Evaluation , Mohtadi 's ACL Deficiency Quality of Life ( ACL-QOL ) question naire and the attainment of six rehabilitation milestones . Subjects and assessors were blinded to the surgical device used . RESULTS Four subjects in the RIGIDfix group and four controls were lost to follow-up . The change in final IKDC scores did not differ significantly between groups with the majority demonstrating an improvement of one to two grade s. The change in ACL-QOL scores did not differ significantly between the RIGIDfix subjects ( 40.0 + 4.4 ) and controls ( 46.0 + 3.6 ) . Furthermore , the number of weeks that the RIGIDfix subjects versus controls attained full active extension , functional range of motion , normal gait , stair climbing , running gait and sprinting did not differ significantly . CONCLUSIONS The RIGIDfix results in a similar post-operative course to the control device and is efficacious for the reconstruction of the ACL . No adverse events were associated with the use of the RIGIDfix . The results of this study should be considered preliminary due to the small sample size PURPOSE A r and omized clinical study was conducted to compare the outcome between double-bundle ( DB ) and single-bundle ( SB ) anterior cruciate ligament ( ACL ) reconstructions with 4-str and semitendinosus tendon ( ST ) . METHODS We divided 68 patients with unilateral ACL injury into 2 groups according to their birth date , and they were followed up in person for a mean of 25 months ( range , 18 to 41 months ) . Each group of 34 patients underwent either DB or SB ACL reconstruction using 4-str and ST with EndoButton femoral fixation ( Smith & Nephew Endoscopy , And over , MA ) and anchor staple tibial fixation . There was no difference between the 2 groups with regard to age at surgery , sex , follow-up period , period before surgery , combined meniscus injuries , and athletic activity level . All patients followed the same postoperative program . They were evaluated using manual knee laxity tests , instrumented anterior laxity measurements ( KT-1000 arthrometer [ MEDmetric , San Diego , CA ] ) , knee extension and flexion strength testing , and so on . General knee condition was evaluated by use of the Lysholm knee score and subjective rating scale . RESULTS There were no significant differences between the 2 groups with regard to range of motion , thigh girth , muscle strength , and Lysholm score . Manual knee laxity testing revealed that negative Lachman and pivot-shift test results were found in more patients in the DB group than in the SB group . KT measurements averaged 2.4 mm in the SB group and 1.4 mm in the DB group , which was statistically significantly different . Statistical analysis showed no significant difference regarding all of the modified International Knee Documentation Committee-categorized data between the 2 groups . CONCLUSIONS This r and omized controlled trial indicated that DB ACL reconstruction via 4-str and ST is superior to the SB technique with regard to anterior and rotational stability ; however , it fails to show any subjective difference . LEVEL OF EVIDENCE Level I , prospect i ve r and omized controlled clinical study BACKGROUND In clinical studies there is still a lot of controversy about the increased anterior and rotational stability between double-bundle ( DB ) and single-bundle ( SB ) anterior cruciate ligament ( ACL ) reconstruction . The aim of this study was to evaluate the clinical results of four-tunnel DB ACL reconstruction . METHODS Sixty-four consecutive patients with ACL ruptures from May 2005 to May 2006 were r and omly assigned into two groups : 32 cases for SB ACL reconstruction and 32 cases for DB ACL reconstruction . Clinical data , including KT 2000 , Biodex test , Lysholm score , Tegner score and IKDC score , were prospect ively collected until at least 10 months post-operative . RESULTS The average values of KT 2000 were ( 1.47 + /- 1.17 ) mm and ( 1.68 + /- 1.14 ) mm for the SB and DB ACL reconstruction groups at 30 degrees of knee flexion ( P > 0.05 ) , and were ( 1.04 + /- 0.98 ) mm and ( 1.13 + /- 0.98 ) mm at 90 degrees of knee flexion ( P > 0.05 ) . There were also no significant differences in Lysholm score , Tegner score , IKDC score and Biodex test scores between the two groups ( P > 0.05 ) . The operation time of DB ACL reconstruction was 20 minutes longer than the SB ACL reconstruction ( P < 0.05 ) . CONCLUSION Double bundle ACL reconstructions have no obvious clinical advantages over single bundle ACL reconstructions PURPOSE The purpose of this study was to prospect ively assess the outcome of hamstring autograft anterior cruciate ligament ( ACL ) reconstruction by use of identically shaped bioabsorbable and titanium interference screws in a r and omized trial . METHODS One hundred patients were r and omized to have either bioabsorbable or titanium interference screws used for graft tunnel fixation in hamstring autograft ACL reconstruction . Patients were objective ly and subjectively assessed preoperatively and 3 , 6 , 12 , and 24 months postoperatively . Radiographs at 12 months postoperatively were also assessed for tunnel width . RESULTS There were no differences in clinical outcome by use of Lysholm and International Knee Documentation Committee scores between the 2 groups at any stage of follow-up to 2 years . Tibial tunnel widths were the same between the 2 groups . There was slightly more tunnel widening in the femur when bioabsorbable interference screws were used . CONCLUSIONS Identically shaped bioabsorbable interference screws and titanium interference screws used for hamstring autograft ACL reconstruction are equally successful up to 2 years postoperatively . LEVEL OF EVIDENCE Level I , prospect i ve r and omized trial with more than 80 % follow-up Background Controversy remains over the most appropriate graft for anterior cruciate ligament reconstruction . Hypothesis There is no significant difference in outcomes after 4-str and hamstring and patellar tendon autograft anterior cruciate ligament reconstructions using similar fixation techniques . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Between August 2000 and May 2003 , 64 Keller Army Hospital patients with complete anterior cruciate ligament tears were r and omized to hamstring ( n = 32 ) or patellar tendon ( n = 32 ) autograft anterior cruciate ligament reconstruction . Operative graft fixation and rehabilitative techniques were the same for both groups . Follow-up assessment s included the Single Assessment Numeric Evaluation score , Lysholm score , International Knee Documentation Committee score , and Knee Injury and Osteoarthritis Outcome Score . Postoperative radiographs were analyzed for tunnel location and orientation . Results Eleven women and 53 men were r and omized . Eighty-three percent of the patients ( 53 of 64 ) had follow-up of greater than 2 years , or to the point of graft rupture or removal ( average follow-up , 36 months ) . Four hamstring grafts ( 12.5 % ) and three patellar tendon grafts ( 9.4 % ) ( P = .71 ) ruptured . One deep infection in a hamstring graft patient necessitated graft removal . Forty-five of the 56 patients with intact grafts had greater than 2-year follow-up . Patients with patellar tendon grafts had greater Tegner activity scores ( P = .04 ) . Single Assessment Numeric Evaluation scores were 88.5 ( 95 % confidence interval : 83.1 , 93.8 ) and 90.1 ( 95 % confidence interval : 85.2 , 96.1 ) for the hamstring and patellar tendon groups , respectively ( P = .53 ) . Lysholm scores were 90.3 ( 95 % confidence interval : 84.4 , 96.1 ) and 90.4 ( 95 % confidence interval : 84.5 , 96.3 ) for the hamstring and patellar tendon groups , respectively ( P = .97 ) . There were no significant differences in knee laxity , kneeling pain , isokinetic peak torque , International Knee Documentation Committee score , or Knee Injury and Osteoarthritis Outcome Scores . Postoperative graft rupture correlated with more horizontal tibial tunnel orientation . Conclusion Hamstring and patellar tendon autografts provide similar objective , subjective , and functional outcomes when assessed at least 2 years after anterior cruciate ligament reconstruction

Evidence of low or very low quality suggests that different techniques of posterior decompression and conventional laminectomy have similar effects on functional disability and leg pain . Only perceived recovery at final follow-up was better in patients that underwent bilateral laminotomy compared with conventional laminectomy . Unilateral laminotomy for bilateral decompression and bilateral laminotomy result ed in numerically fewer cases of iatrogenic instability , although in both cases , the incidence of instability was low . We found no evidence to show that the incidence of complications , length of the procedure , length of hospital stay and postoperative walking distance differed between techniques of posterior decompression .

Purpose To compare the effectiveness of techniques of posterior decompression that limit the extent of bony decompression or to avoid removal of posterior midline structures of the lumbar spine versus conventional facet-preserving laminectomy for the treatment of patients with degenerative lumbar stenosis .

Study Design . Prospect i ve , r and omized controlled study . Objective . To compare the functional outcomes and extent of paraspinal muscle damage between 2 decompressive techniques for lumbar canal stenosis . Summary of Background Data . Lumbar spinous process splitting decompression ( LSPSD ) preserves the muscular and liga-mentous attachments of the posterior elements of the spine . It can potentially avoid problems such as paraspinal muscle atrophy and trunk extensor weakness that can occur after conventional midline decompression . However , large series prospect i ve r and omized controlled studies are lacking . Methods . Patients with lumbar canal stenosis were r and omly allocated into 2 groups : LSPSD ( 28 patients ) and conventional midline decompression ( 23 patients ) . The differences in operative time , blood loss , time to comfortable mobilization , and hospital stay were studied . Paraspinal muscle damage was assessed by postoperative rise in creatine phosphokinase and C-reactive protein levels . Functional outcome was evaluated at 1 year by Japanese Orthopaedic Association score , neurogenic claudication outcome score , and visual analogue scale for back pain and neurogenic claudication . Results . Fifty-one patients of mean age 56 years were followed-up for a mean 14.2 ± 2.9 months . There were no significant differences in the operative time , blood loss , and hospital stay . Both the groups showed significant improvement in the functional outcome scores at 1 year . Between the 2 groups , the Japanese Orthopaedic Association score , neurogenic claudication outcome score improvement , visual analogue scale for back pain , neurogenic claudication visual analogue scale , and the postoperative changes in serum C-reactive protein and creatine phosphokinase levels did not show any statistically significant difference . On the basis of the Japanese Orthopaedic Association recovery rate , it was found that 73.9 % of conventional midline decompression group had good outcomes compared with only 60.7 % after LSPSD . Conclusion . The functional outcome scores , back pain , and claudication pain in the immediate period and at the end of 1 year are similar in both the techniques . More patients had better functional outcomes after conventional decompression than the LSPSD technique . On the basis of this study , the superiority of one technique compared with the other is not established , m and ating the need for further long-term studies . Level of Evidence : Study Design . A prospect i ve clinical study of M-ULBD of lumbar spinal stenosis ( LSS ) . Objective . In this article , the authors describe the technique of M-ULBD for lumbar spinal stenosis , and reported 2-year follow-up results . Summary of Background Data . Recent reports showed that atrophy of multifidus muscles and chronic low back pain after conventional laminectomy may relate to disturbance of the arterial supply caused by long duration of muscle retraction , extensive muscle stripping , and damage to the dorsal rami of the posterior branches . Methods . A total of 56 patients with LSS were r and omly divided into group A and B. The 27 patients in group A ( 15 males and 12 females ) underwent M-ULBD . The other 29 patients in group B ( 18 males and 11 females ) received conventional laminectomy . Japanese Orthopaedic Association score of low back pain , 10-cm visual analogue scale , creatine phosphokinase 3 days after operation , pre- and postoperative cross-sectional areas of multifidus were used to evaluate the clinical results . Results . There was no significant difference in preoperative data between both groups . A total of 54 patients ( 27 in each group A and B ) completed 2 years of follow-up . The postoperative Japanese Orthopaedic Association and visual analogue scale scores in both groups were improved significantly compared with the corresponding preoperative ones ( P < 0.05 ) . The postoperative creatine phosphokinase , visual analogue scale score of low back pain , and atrophy rate of multifidus CSA in group A are lower than those in group B ( P < 0.05 ) . Dural tear at the contralateral side occurred in 3 cases ( 11.1 % ) in group A and 1 case in group B ( 3.4 % ) . Conclusion . Our 2 years of follow-up shows that this method is efficient for lumbar spinal stenosis treatment ; however , it still needs long-term follow-up and needs to be compared with other modified methods . Level of Evidence : Abstract Study design Prospect i ve clinical observational study of low back pain ( LBP ) in patients undergoing laminectomy or laminotomy surgery for lumbar spinal stenosis ( LSS ) . Objectives To quantify any change in LBP following laminectomy or laminotomy spinal decompression surgery . Patients and methods 119 patients with LSS completed Oswestry Disability Index question naire ( ODI ) and Visual Analogue Scale for back and leg pain , preoperatively , 6 weeks and 1 year postoperatively . Results There was significant ( p < 0.0001 ) reduction in mean LBP from a baseline of 5.14/10 to 3.03/10 at 6 weeks . Similar results were seen at 1 year where mean LBP score was 3.07/10 . There was a significant ( p < 0.0001 ) reduction in the mean ODI at 6 weeks and 1 year postoperatively . Mean ODI fell from 44.82 to 25.13 at 6 weeks and 28.39 at 1 year . Conclusion The aim of surgery in patients with LSS is to improve the result ing symptoms that include radicular leg pain and claudication . This observational study reports statistically significant improvement of LBP after LSS surgery . This provides frequency distribution data , which can be used to inform prospect i ve patients of the expected outcomes of such surgery Study Design . A prospect i ve study to evaluate the outcomes of 2 different decompressive techniques for lumbar spinal stenosis . Objective . To explore a more effective and less invasive decompression technique without instrument and fusion for lumbar spinal stenosis . Summary of Background Data . The traditional surgical decompression of spinal stenosis involves laminectomy or unilateral laminotomy . Even in unilateral laminotomy cases , 85.3 % had an excellent-to-fair operative result , and the incidence of complications was 9.8 % . Although the addition of instrumentation does not increase the complication rate , but compared to the efficiency , the higher costs was controversial . Minimal invasion and destabilization are recommended . Methods . This prospect i ve study included 152 consecutive patients , sequentially divided into 2 groups , underwent Windows technique ( group A ) and decompressive laminectomy ( group B ) by 2 groups of surgeons . Results . The evaluation of the back pain , leg pain , walking tolerance , and neurologic recovery were performed before surgery and after surgery . In group A , at the final evaluation , the overall results were good to excellent in 89 % ( 68/76 ) of the patients , fair 11 % ( 8/76 ) , and poor 0 % . In group B , at the final evaluation , the overall results were good to excellent in 63 % ( 48/76 ) of the patients , fair 30 % ( 23/76 ) , and poor 7 % ( 5/76 ) . Conclusion . Degenerative spinal stenosis can be decompressed adequately with preserving the posterior elements . The “ Windows technique ” laminoforaminotomy , which obtained satisfactory long-term outcomes with few complications and low cost , can be a st and ard procedure for the surgical treatment of the degenerative spinal stenosis even with slight congenital spinal stenosis Introduction This observational study is design ed to test the equivalence between the clinical effectiveness of microdecompression and laminectomy in the surgical treatment of central lumbar spinal stenosis . Lumbar spinal stenosis is the most frequent indication for spinal surgery in the elderly , and as the oldest segment of the population continues to grow its prevalence is likely to increase . However , data on surgical outcomes are limited . Open or wide decompressive laminectomy , often combined with medial facetectomy and foraminotomy , was formerly the st and ard treatment . In recent years a growing tendency towards less invasive decompressive procedures has emerged . At present , many spine surgeons perform microdecompression for central lumbar spinal stenosis . Methods and analysis Prospect ively registered treatment and outcome data are obtained from the Norwegian Registry for Spine Surgery . The primary outcome measure is change in Oswestry disability index between baseline and 12-month follow-up . Secondary outcome measures are changes in health-related quality of life measured by the Euro-Qol-5D between baseline and 12-month follow-up , perioperative complications , and duration of surgical procedures and length of hospital stay . Ethics and dissemination The study has been evaluated and approved by the regional committee for medical research in central Norway and all participants provided written informed consent . The findings of this study will be disseminated through peer- review ed publications . Trial registration number Clinical trials.gov ( NCT02006901 ) Study Design The 2 groups of patients with severe lumbar spinal stenosis were prospect ively compared as a case control study . Objectives This prospect i ve case control study sought to evaluate bilateral microdecompressive laminatomy ( MDL ) for treatment of severe lumbar spinal stenosis . Summary of Background Data Total laminectomy is a general consensus on the therapy of severe spinal stenosis . The authors tried to investigate a new minimal invasive approach . Methods Patients were r and omly divided into 2 groups . In first group , 34 patients underwent total laminectomy ( TL ) for severe lumbar spinal stenosis . In the second group , 37 patients with the same diagnosis underwent bilateral MDL . The groups were compared for disability , walking distance , degree of postoperative back and leg pain , perioperative complications , and postoperative instability . Radiographic analyses were performed at regular intervals to demonstrate satisfactory decompression . Results Mean follow-up was 5 years . Postoperative computerized tomography and magnetic resonance imaging demonstrated adequate decompressions in both groups . The walking distance , pain control , and disability scores were slightly higher among patients in the MDL group , although these results did not achieve statistical significance . Perioperative complications and postoperative instability were significantly higher in the TL group ( P<0.05 ) . Conclusions Compared with classic approaches , bilateral MDL provides adequate and safe decompression in lumbar spinal stenosis . It significantly reduces clinical symptoms and disability . However , TL shows higher perioperative complications and postoperative instability . To the best of our knowledge , this is the first study to define a bilateral MDL approach to treat the stenotic lumbar spine without a herniated disc We assigned 67 patients with central lumbar stenosis alternately to either multiple laminotomy or total laminectomy . The protocol , however , allowed multiple laminotomy to be changed to total laminectomy if it was thought that the former procedure might not give adequate neural decompression . There were therefore three treatment groups : group I consisting of 26 patients su bmi tted to multiple laminotomy ; group II , 9 patients scheduled for laminotomy but su bmi tted to laminectomy ; and group III , 32 patients scheduled for , and su bmi tted to , laminectomy . The mean follow-up was 3.7 years . Bilateral laminotomy at two or three levels required a longer mean operating time than total laminectomy at an equal number of levels . The mean blood loss at surgery and the clinical results did not differ in the three groups . The mean subjective improvement score for low back pain was higher in group I but there was also a higher incidence of neural complications in this group . No patient in group I had postoperative vertebral instability , whereas this occurred in three patients in groups II and III , who had lumbar scoliosis or degenerative spondylolisthesis preoperatively . Multiple laminotomy is recommended for all patients with developmental stenosis and for those with mild to moderate degenerative stenosis or degenerative spondylolisthesis . Total laminectomy is to be preferred for patients with severe degenerative stenosis or marked degenerative spondylolisthesis STUDY DESIGN A cohort of 100 patients with symptomatic lumbar spinal stenosis , characterized in a previous article , were given surgical or conservative treatment and followed for 10 years . OBJECTIVES To identify the short- and long-term results after surgical and conservative treatment , and to determine whether clinical or radiologic predictors for the treatment result can be defined . SUMMARY OF BACKGROUND DATA Surgical decompression has been considered the rational treatment . However , clinical experience indicates that many patients do well with conservative treatment . METHODS In this study , 19 patients with severe symptoms were selected for surgical treatment and 50 patients with moderate symptoms for conservative treatment , whereas 31 patients were r and omized between the conservative ( n = 18 ) and surgical ( n = 13 ) treatment groups . Pain was decisive for the choice of treatment group . All patients were observed for 10 years by clinical evaluation and question naires . The results , evaluated by patient and physician , were rated as excellent , fair , unchanged , or worse . RESULTS After a period of 3 months , relief of pain had occurred in most patients . Some had relief earlier , whereas for others it took 1 year . After a period of 4 years , excellent or fair results were found in half of the patients selected for conservative treatment , and in four fifths of the patients selected for surgery . Patients with an unsatisfactory result from conservative treatment were offered delayed surgery after 3 to 27 months ( median , 3.5 months ) . The treatment result of delayed surgery was essentially similar to that of the initial group . The treatment result for the patients r and omized for surgical treatment was considerably better than for the patients r and omized for conservative treatment . Clinical ly significant deterioration of symptoms during the final 6 years of the follow-up period was not observed . Patients with multilevel afflictions , surgically treated or not , did not have a poorer outcome than those with single-level afflictions . Clinical or radiologic predictors for the final outcome were not found . There were no dropouts , except for 14 deaths . CONCLUSIONS The outcome was most favorable for surgical treatment . However , an initial conservative approach seems advisable for many patients because those with an unsatisfactory result can be treated surgically later with a good outcome OBJECT The object of this study was to assess the feasibility and efficacy of a novel , minimally invasive spinal surgery technique to correct degenerative lumbar spinal stenosis involving a modified unilateral-approach microendoscopic midline decompression . METHODS In this prospect i ve study , 41 patients with lumbar stenosis were r and omly assigned to undergo either a novel , median-approach microendoscopic laminectomy ( 20 patients ) or a conventional laminectomy ( 21 patients ) . Spinal anteroposterior diameter , cross-sectional area , lateral recess distance , spinal stability , postoperative back pain , functional outcomes , and muscle trauma were evaluated . Follow-up ranged from 16 to 24 months , with a mean of 17.8 months for the novel procedure group and 18.6 months for the conventional laminectomy group . RESULTS Compared with patients in the conventional laminectomy group , patients who received the novel procedure had a reduced mean duration of hospital stay , a lower mean creatine phosphokinase muscular-type isoenzyme level , a lower visual analog scale score for back pain at 1-year follow-up , and a faster recovery rate . These patients also had less mean blood loss compared with the conventionally treated group . Satisfactory neurological decompression and symptom relief were achieved in 90 % of these patients . There was no significant clinical difference compared with the conventional laminectomy group 's results . There was no evidence of spinal instability in any patient , and no patient required a follow-up conventional laminectomy . CONCLUSIONS This novel procedure provides effective spinal decompression . Although this method requires more operating time than a conventional method , it requires only minimal muscle trauma and spinal stability maintenance , and allows for early mobilization . This shortens the hospital stay , reduces postoperative back pain , and leads to satisfactory neurological and functional outcomes . Moreover , with the midline approach , decompression was accomplished without compromising the facet joints , even with a narrow width of lamina Study Design . A r and omized controlled trial . Objectives . To assess the effectiveness of decompressive surgery as compared with nonoperative measures in the treatment of patients with lumbar spinal stenosis . Summary of Background Data . No previous r and omized trial has assessed the effectiveness of surgery in comparison with conservative treatment for spinal stenosis . Methods . Four university hospitals agreed on the classification of the disease , inclusion and exclusion criteria , radiographic routines , surgical principles , nonoperative treatment options , and follow-up protocol s. A total of 94 patients were r and omized into a surgical or nonoperative treatment group : 50 and 44 patients , respectively . Surgery comprised undercutting laminectomy of the stenotic segments in 10 patients augmented with transpedicular fusion . The primary outcome was based on assessment of functional disability using the Oswestry Disability Index ( scale , 0–100 ) . Data on the intensity of leg and back pain ( scales , 0–10 ) , as well as self-reported and measured walking ability were compiled at r and omization and at follow-up examinations at 6 , 12 , and 24 months . Results . Both treatment groups showed improvement during follow-up . At 1 year , the mean difference in favor of surgery was 11.3 in disability ( 95 % confidence interval [ CI ] , 4.3–18.4 ) , 1.7 in leg pain ( 95 % CI , 0.4–3.0 ) , and 2.3(95 % CI , 1.1–3.6 ) in back pain . At the 2-year follow-up , the mean differences were slightly less : 7.8 in disability ( 95 % CI , 0.8–14.9 ) 1.5 in leg pain ( 95 % CI , 0.3–2.8 ) , and 2.1 in back pain ( 95 % CI , 1.0–3.3 ) . Walking ability , either reported or measured , did not differ between the two treatment groups . Conclusions . Although patients improved over the 2-year follow-up regardless of initial treatment , those undergoing decompressive surgery reported greater improvement regarding leg pain , back pain , and overall disability . The relative benefit of initial surgical treatment diminished over time , but outcomes of surgery remained favorable at 2 years . Longer follow-up is needed to determine if these differences persist OBJECT to reduce intraoperative damage to the posterior supporting structures of the lumbar spine during decompressive surgery for lumbar canal stenosis ( LCS ) , lumbar spinous process-splitting laminectomy ( LSPSL or split laminectomy ) was developed . This prospect i ve , r and omized , controlled study was conducted to clarify whether the split laminectomy decreases acute postoperative wound pain compared with conventional laminectomy . METHODS forty-one patients with LCS were enrolled in this study . The patients were r and omly assigned to either the LSPSL group ( 22 patients ) or the conventional laminectomy group ( 19 patients ) . Question naires regarding wound pain ( intensity , depth , and duration ) and activities of daily living ( ADL ) were administered at postoperative days ( PODs ) 3 and 7 . Additionally , the authors evaluated the pre- and postoperative serum levels of C-reactive protein and creatine phosphokinase , the amount of pain analgesics used during a 3-day postoperative period , and the muscle atrophy rate measured on 1-month postsurgical MR images . RESULTS data obtained in patients in the LSPSL group and in 16 patients in the conventional laminectomy group were analyzed . The mean visual analog scale for wound pain on POD 7 was significantly lower in the LSPSL group ( 16 ± 17 mm vs 34 ± 31 mm , respectively ; p = 0.04 ) . The mean depth-of-pain scores on POD 7 were significantly lower in the LSPSL group than in the conventional group ( 0.9 ± 0.6 vs 1.7 ± 0.8 , respectively ; p = 0.013 ) . On POD 3 , the mean serum creatine phosphokinase level was significantly lower in the LSPSL group ( 126 ± 93 U/L ) than in the other group ( 207 ± 150 U/L ) ( p = 0.02 ) ; on POD 7 , the mean serum C-reactive protein level was significantly lower in the LSPSL group ( 1.1 ± 0.6 mg/dl ) than in the conventional laminectomy group ( 1.9 ± 1.5 mg/dl ) ( p = 0.04 ) . The number of pain analgesics taken during the 3-day postoperative period was lower in the LSPSL group than in the conventional laminectomy group ( 1.7 ± 1.3 tablets vs 2.3 ± 2.4 tablets , respectively ; p = 0.22 ) . The mean muscle atrophy rate was also significantly lower in the LSPSL group ( 24 % ± 15 % vs 43 % ± 22 % ; p = 0.004 ) . CONCLUSIONS lumbar spinous process-splitting laminectomy for the treatment of LCS reduced acute postoperative wound pain and prevented postoperative muscle atrophy compared with conventional laminectomy , possibly because of minimized damage to the paraspinal muscles OBJECT The authors evaluated a new minimally invasive spinal surgery technique to correct degenerative lumbar spinal stenosis involving a split-spinous process laminotomy and discectomy ( also known as the " Marmot operation " ) . METHODS This prospect i ve study r and omized 70 patients with lumbar stenosis to undergo either a Marmot operation ( 40 patients ) , or a conventional laminectomy ( 30 patients ) , with or without discectomy . Spinal anteroposterior diameter , cross-sectional area , lateral recess distance , spinal stability , postoperative back pain , functional outcomes , and muscular trauma were evaluated . The follow up ranged from 10 to 18 months , with a mean of 15.1 months for the Marmot operation group and 14.8 months for the conventional laminectomy group . Compared with patients in the conventional laminectomy group , patients who received a Marmot operation had a shorter mean postoperative duration until ambulation without assistance , a reduced mean duration of hospital stay , a lower mean creatine phosphokinase-muscular-type isoenzyme level , a lower visual analog scale score for back pain at 1-year follow up , and a better recovery rate . These patients also had a longer mean duration of operative time and a greater mean blood loss compared with the conventional group . Satisfactory neurological decompression and symptom relief were achieved in 93 % of these patients . Most of the patients ( 66 % ) in this group needed discectomy for decompression . The postoperative mean lateral recess width , spinal anteroposterior diameter , and cross-sectional area were all significantly increased . There was no evidence of spinal instability in any patient . One patient with insufficient lateral recess decompression and recurrent disc herniation needed additional conventional laminectomy and discectomy , and one patient with mild superficial wound infection was successfully treated with antibiotics and frequent dressing changes . CONCLUSIONS A Marmot operation may provide effective spinal decompression . Although this method requires more operative time than a conventional method , it may involve only minimal muscular trauma , spinal stability maintenance , and early mobilization ; shorten the duration of hospital stay ; reduce postoperative back pain ; and provide satisfactory neurological and functional outcomes CONTEXT Conventional microdiskectomy is the most frequently performed surgery for patients with sciatica due to lumbar disk herniation . Transmuscular tubular diskectomy has been introduced to increase the rate of recovery , although evidence is lacking of its efficacy . OBJECTIVE To determine outcomes and time to recovery in patients treated with tubular diskectomy compared with conventional microdiskectomy . DESIGN , SETTING , AND PATIENTS The Sciatica Micro-Endoscopic Diskectomy r and omized controlled trial was conducted among 328 patients aged 18 to 70 years who had persistent leg pain ( > 8 weeks ) due to lumbar disk herniations at 7 general hospitals in The Netherl and s from January 2005 to October 2006 . Patients and observers were blinded during the follow-up , which ended 1 year after final enrollment . INTERVENTIONS Tubular diskectomy ( n = 167 ) vs conventional microdiskectomy ( n = 161 ) . MAIN OUTCOME MEASURES The primary outcome was functional assessment on the Rol and -Morris Disability Question naire ( RDQ ) for sciatica ( score range : 0 - 23 , with higher scores indicating worse functional status ) at 8 weeks and 1 year after r and omization . Secondary outcomes were scores on the visual analog scale for leg pain and back pain ( score range : 0 - 100 mm ) and patient 's self-report of recovery ( measured on a Likert 7-point scale ) . RESULTS Based on intention-to-treat analysis , the mean RDQ score during the first year after surgery was 6.2 ( 95 % confidence interval [ CI ] , 5.6 to 6.8 ) for tubular diskectomy and 5.4 ( 95 % CI , 4.6 to 6.2 ) for conventional microdiskectomy ( between-group mean difference , 0.8 ; 95 % CI , -0.2 to 1.7 ) . At 8 weeks after surgery , the RDQ mean ( SE ) score was 5.8 ( 0.4 ) for tubular diskectomy and 4.9 ( 0.5 ) for conventional microdiskectomy ( between-group mean difference , 0.8 ; 95 % CI , -0.4 to 2.1 ) . At 1 year , the RDQ mean ( SE ) score was 4.7 ( 0.5 ) for tubular diskectomy and 3.4 ( 0.5 ) for conventional microdiskectomy ( between-group mean difference , 1.3 ; 95 % CI , 0.03 to 2.6 ) in favor of conventional microdiskectomy . On the visual analog scale , the 1-year between-group mean difference in improvement was 4.2 mm ( 95 % CI , 0.9 to 7.5 mm ) for leg pain and 3.5 mm ( 95 % CI , 0.1 to 6.9 mm ) for back pain in favor of conventional microdiskectomy . At 1 year , 107 of 156 patients ( 69 % ) assigned to tubular diskectomy reported a good recovery vs 120 of 151 patients ( 79 % ) assigned to conventional microdiskectomy ( odds ratio , 0.59 [ 95 % CI , 0.35 to 0.99 ] ; P = .05 ) . CONCLUSIONS Use of tubular diskectomy compared with conventional microdiskectomy did not result in a statistically significant improvement in the Rol and -Morris Disability Question naire score . Tubular diskectomy result ed in less favorable results for patient self-reported leg pain , back pain , and recovery . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N51857546 Background Older patients undergo surgery for lumbar spinal stenosis in great numbers , but as a result of substantial diagnostic and surgical heterogeneity , the impact of age on results after surgery is poorly defined . Questions / purpose sWe compared groups of patients younger and older than 70 years with relative clinical and surgical homogeneity to determine differences in ( 1 ) interval improvement in Oswestry Disability Index ( ODI ) at 6 weeks , 6 months , and 12 months postoperatively and ( 2 ) perioperative adverse events . Methods We performed a subgroup analysis of an ongoing prospect i ve observational study . Patients were divided based primarily on age ( younger than 70 years [ n = 68 ] and 70 years or older [ n = 41 ] ) and secondarily on procedure ( minimally invasive decompression alone or decompression and instrumented fusion ) . With the exception of age and American Society of Anesthesiologists status , the two age groups were similar ( p > 0.3 ) in baseline demographics and ODI . Mean pre- and postoperative ODI were compared between groups at 6 weeks , 6 months , and 12 months . Perioperative adverse events were also compared . Results At all time intervals , both younger and older patients demonstrated ( p = 0.05 to < 0.001 ) improvements in ODI . At the 1-year mark , no differences in ODI were demonstrated between the younger and older patients for decompression only ( 21 versus 26 [ p = 0.29 ] ) or decompression and fusion ( 19 versus 18 [ p = 0.97 ] ) . Interval improvement in ODI was not different between younger and older patients at any time point for decompression only ( 6 weeks : −18 versus −20 [ p = 0.66 ] ; 6 months : −21 versus −17 [ p = 0.41 ] ; 12 months : −21 versus −15 [ p = 0.29 ] ) or decompression and fusion ( 6 weeks : −11 versus −12 [ p = 0.58 ] ; 6 months : −21 versus −22 [ p = 0.69 ] ; 12 months : −23 versus −27 [ p = 0.97 ] ) . There were no differences in perioperative adverse events between groups ( p = 0.67 ) . Conclusions When clinical and surgical heterogeneity is minimized , improvements in terms of disability as measured by the ODI and the frequency of adverse events after surgery in elderly patients with lumbar spinal stenosis are comparable to those of younger patients . For patients with focal lumbar spinal stenosis , age alone should not dissuade us from considering surgical intervention if otherwise indicated . Level of Evidence Level III , therapeutic study . See Instructions for Authors for a complete description of levels of evidence Study Design . A sub analysis study . Objective . The purpose of this study was to determine the impact of multilevel lumbar stenosis with or without degenerative spondylolisthesis compared to single level disease on patients ' baseline symptoms and clinical outcomes over time . Summary of Background Data . Previous studies have demonstrated better clinical outcomes with surgery than nonoperative treatment in patients with spinal stenosis with or without degenerative spondylolisthesis . However , the impact of multilevel stenosis has not been studied in these patients . Methods . The results from a multicenter r and omized and observational study , the Spine Patient Outcomes Research Trial ( SPORT ) comparing surgical versus nonoperative treatment for spinal stenosis with or without spondylolisthesis , were analyzed . The primary outcomes measures were the Bodily Pain and Physical Function scales of the Medical Outcomes Study 36-item Short-Form General Health Survey ( SF-36 ) and the modified Oswestry Disability Index at 6 weeks , 3 months , 6 months , 1 year , and 2 years . Secondary outcome measures included the stenosis bothersomeness index , leg pain bothersomeness , low back pain bothersomeness , and patient satisfaction . Results . In this sub analysis of SPORT data , multilevel spinal stenosis did not demonstrate worse baseline symptoms or worse treatment outcomes in isolated spinal stenosis ; however , if concomitant degenerative spondylolisthesis existed , patients with only single level stenosis tended to improve more than those with multilevel stenosis , particularly after surgery . Conclusion . Patients with spinal stenosis without associated degenerative spondylolisthesis or scoliosis can be managed nonoperatively irrespective of the number of levels involved . If surgery is performed , the number of levels treated does not predict outcome . In contrast , patients with concomitant degenerative spondylolisthesis and single level stenosis do better surgically than those with additional levels of stenosis . This study emphasizes the importance of shared decision-making between the physician and patient when considering treatment for spinal stenosis In conventional laminectomy for lumbar canal stenosis ( LCS ) , intraoperative damage of posterior supporting structures can lead to irreversible atrophy of paraspinal muscles . In 2001 , the authors developed a new procedure for lumbar laminectomy , the lumbar spinous process-splitting laminectomy ( LSPSL ) . In this new procedure , the spinous process is split longitudinally in the middle and then divided at its base from the posterior arch , leaving the bilateral paraspinal muscles attached to the lateral aspects . Ample working space for laminectomy is obtained by retracting the split spinous process laterally together with its attached paraspinal muscles . After successfully decompressing nerve tissues , each half of the split spinous process is reapproximated using a strong suture . Thus , the supra- and interspinous ligaments are preserved , as is the spinous process , and damage to the paraspinal muscles is minimal . Eighteen patients with LCS underwent surgery in which this new technique was used . Twenty patients in whom conventional laminectomy was undertaken were chosen as controls . At 2 years , the clinical outcomes ( as determined using the Japanese Orthopaedic Association [ JOA ] scores and recovery rate ) and the rate of measured magnetic resonance imaging-documented paravertebral muscle atrophy were evaluated and compared between the two groups . The mean JOA score recovery rates were 67.6 and 59.2 % , respectively , for patients treated with LSPSL and conventional laminectomy ; the mean rates of paravertebral muscle atrophy were 5.3 and 23.9 % , respectively ( p = 0.0005 ) . Preservation of posterior supporting structures and satisfactory recovery rate after 2 years indicated that this technique can be a useful alternative to conventional decompression surgery for lumbar canal stenosis OBJECT Recently , limited decompression procedures have been proposed in the treatment of lumbar stenosis . The authors undertook a prospect i ve study to compare the safety and outcome of unilateral and bilateral laminotomy with laminectomy . METHODS One hundred twenty consecutive patients with 207 levels of lumbar stenosis without herniated discs or instability were r and omized to three treatment groups ( bilateral laminotomy [ Group 1 ] , unilateral laminotomy [ Group 2 ] , and laminectomy [ Group 3 ] ) . Perioperative parameters and complications were documented . Symptoms and scores , such as visual analog scale ( VAS ) , Rol and -Morris Scale , Short Form-36 ( SF-36 ) , and patient satisfaction were assessed preoperatively and at 3 , 6 , and 12 months after surgery . Adequate decompression was achieved in all patients . The overall complication rate was lowest in patients who had undergone bilateral laminotomy ( Group 1 ) . The minimum follow up of 12 months was obtained in 94 % of patients . Residual pain was lowest in Group 1 ( VAS score 2.3 + /- 2.4 and 4 + /- 1 in Group 3 ; p < 0.05 and 3.6 + /- 2.7 in Group 2 ; p < 0.05 ) . The Rol and -Morris Scale score improved from 17 + /- 4.3 before surgery to 8.1 + /- 7 , 8.5 + /- 7.3 , and 10.9 + /- 7.5 ( Groups 1 - 3 , respectively ; p < 0.001 compared with preoperative ) corresponding to a dramatic increase in walking distance . Examination of SF-36 scores demonstrated marked improvement , most pronounced in Group 1 . The number of repeated operations did not differ among groups . Patient satisfaction was significantly superior in Group 1 , with 3 , 27 , and 26 % of patients unsatisfied ( in Groups 1 , 2 , and 3 , respectively ; p < 0.01 ) . CONCLUSIONS Bilateral and unilateral laminotomy allowed adequate and safe decompression of lumbar stenosis , result ed in a highly significant reduction of symptoms and disability , and improved health-related quality of life . Outcome after unilateral laminotomy was comparable with that after laminectomy . In most outcome parameters , bilateral laminotomy was associated with a significant benefit and thus constitutes a promising treatment alternative OBJECTIVE To assess the feasibility and efficacy of a novel , minimally invasive spinal surgery technique for the correction of lumbar spinal stenosis involving unilateral approach for bilateral decompression . STUDY DESIGN Cross-sectional observational study . PLACE AND DURATION OF STUDY Neurosurgery Department of PGMI , Lady Reading Hospital , Peshawar , from January to December 2010 . METHODOLOGY A total of 60 patients with lumbar stenosis were r and omly assigned to undergo either a conventional laminectomy ( 30 patients , Group A ) , or a unilateral approach ( 30 patients , Group B ) . Clinical outcomes was measured using the scale of Finneson and Cooper . All the data was collected by using a proforma and different parameters were assessed for a minimum follow-up period of three months . Data was analyzed by descriptive statistics using SPSS software version 17 . RESULTS Adequate decompression was achieved in all patients . Compared with patients in the conventional laminectomy group , patients who received the novel procedure ( unilateral approach ) had a reduced mean duration of hospital stay , a faster recovery rate and majority of the patients ( 88.33 % ) had an excellent to fair operative result according to the Finneson and Cooper scale . Five major complications occurred in all patient groups , 2 patients had unintended dural rent and 2 wound dehiscence each and fifth patient had worsening of symptoms . There was no mortality in the series . CONCLUSION The ultimate goal of the unilateral approach to treat lumbar spinal stenosis is to achieve adequate decompression of the neural elements . An additional benefit of a minimally invasive approach is adequate preservation of vertebral stability , as it requires only minimal muscle trauma , preservation of supraspinous/intraspinous ligament complex and spinous process , therefore , allows early mobilization . This also shortens the hospital stay , reduces postoperative back pain , and leads to satisfactory outcome The aim of the current study was to evaluate the clinical outcome after laminectomy or undercutting decompression in patients with lumbar spinal stenosis ( LSS ) without apparent signs of instability . In a prospect i ve controlled , nonr and omized trial 1 year after operation , two groups of patients were compared . Out of 85 consecutive patients , treated from 1998 to 1999 in an orthopedic university clinic for symptomatic LSS , decompression without simultaneous fusion was performed in 40 cases . In group I ( n=13 ) a laminectomy was done and in group II ( n=27 ) an undercutting of the vertebral arch and facet joints . The main outcome measure was the Oswestry Low Back Disability Score . Subjective complaints , visual analog scale ( VAS ) , claudication distance , analgesic dem and s , and radiomorphometric parameters following the procedure of Dupuis and Nash/Moe at 6 and at 12 months after the operation were secondary objective criteria . One year postoperatively the main outcome measure showed no significant difference between the two groups , although group II had shown better results ( p=0.0195 ) 6 months postoperatively . The required analgesics could be significantly lowered in group II compared with group I at 12 months ( p=0.0011 ) . The remaining secondary outcome measures showed no statistically significant differences . The extent of decompression in LSS without apparent instability did not influence the outcome . If there is any doubt intraoperatively about the adequate amount of decompression of the lumbar spinal canal , undercutting decompression should be extended to laminectomy without fear of consecutive segmental instability OBJECT Extensive decompression with laminectomy where appropriate is often still described as the method of choice in surgery for lateral recess stenosis . Nonetheless , tissue-sparing procedures are becoming more common . Endoscopic techniques have become the st and ard in many areas because of the advantages they offer in surgical technique and in rehabilitation . Transforaminal and interlaminar access provide 2 full-endoscopic ( FE ) techniques for lumbar spine surgery . The goal of this prospect i ve r and omized controlled study was to compare the surgical results for the FE technique via the interlaminar approach with those of the conventional microsurgical technique in patients with degenerative lateral recess stenosis . METHODS A total of 161 patients with FE or microsurgical decompression underwent follow-up for 2 years . In addition to general and specific parameters , the following measuring instruments were used : visual analog scale , German version of the North American Spine Society instrument , and the Oswestry low-back pain disability question naire . RESULTS The results show that 74.5 % of patients reported no longer having leg pain , and 20.5 % had only occasional pain . The clinical results were the same in both groups . The rate of complications and revisions was significantly reduced in the FE group . The FE techniques brought advantages in the following areas : operation , complications , traumatization , and rehabilitation . CONCLUSIONS The clinical results of the FE interlaminar technique are equal to those of the microsurgical technique . At the same time , there are advantages in the operation technique , such as reduced traumatization . The FE interlaminar spinal decompression procedure is a sufficient and safe supplement and alternative to microsurgical procedures Study Design . A prospect i ve comparative study . Objective . To compare prospect ively 2 different types of minimally invasive surgery for lumbar spinal canal stenosis ( LSCS ) : unilateral laminotomy for bilateral decompression ( ULBD ) , and muscle-preserving interlaminar decompression ( MILD ) . Summary of Background Data . Although previous studies have reported several procedures of minimally invasive surgery for the treatment of LSCS , no articles prospect ively compared 2 different procedures . Methods . From 2005 to 2009 , we prospect ively enrolled 50 patients with LSCS for the treatment with ULBD , and 50 patients for MILD . The patients ' symptoms were evaluated using Japanese Orthopedic Association ( JOA ) score , JOA Back Pain Evaluation Question naire , and visual analogue scale before and 2 years after operation . For radiological evaluation , changes in disc height , sagittal translation , and lateral wedging at the decompressed segment , as well as lumbar lordosis were investigated using plain radiographs . Results . Ninety-nine of 100 patients were followed for a minimum of 2 years . No significant differences were found in the recovery rate of JOA score , improvement of JOA Back Pain Evaluation Question naire , and changes of the visual analogue scale between the 2 groups . Radiologically , no significant differences were present in the postoperative degenerative changes in disc height , sagittal translation , and lateral wedging . In multilevel surgical procedures ; however , clinical scores in low back pain , and lumbar function were significantly greater in the ULBD group than those in the MILD group . The lateral wedging change at L2–L3 and L3–L4 more frequently occurred in the ULBD group than in the MILD group . On the contrary , the number of patients who demonstrated the postoperative sagittal translation at L4–L5 was significantly greater in the MILD group than in the ULBD group . Conclusion . Both MILD and ULBD were efficacious procedures for improving neurological symptoms in patients with LSCS . In multilevel decompression surgical procedures , ULBD was superior to MILD in terms of improvement of low back pain and lumbar function at the 2-year time point . Level of Evidence : Study Design : Prospect i ve radiographic cohort study . Objective : To study the extent of bony decompression and dural sac expansion after laminectomy ( including subtotal laminectomy and laminotomy with midline resection ) , bilateral fenestration , and unilateral fenestration with contralateral undercutting in lumbar spinal canal stenosis . Further , to investigate differences of incidence and extent of early postoperative epidural hematoma in these approaches . Summary of Background Data : There are different techniques of decompression in lumbar spinal stenosis . An overall good clinical outcome has been reported with different biomechanical consequences , but no morphometric comparative reports exist on these approaches . Methods : Using the data of a previous prospect i ve study of 30 patients , who underwent lumbar decompression for degenerative stenosis , 49 levels treated with 3 different kinds of surgical approaches were analyzed : ( 1 ) laminectomy ( including subtotal laminectomy , laminotomy with midline resection ) ; ( 2 ) bilateral fenestration ; and ( 3 ) unilateral fenestration with contralateral undercutting . In all 3 groups , the cross-sectional area of the maximum bony stenosis and dural sac compression ( bony margins and dural sac expansion ) were measured in each operated level before and after the operation . Occurrence of epidural hematoma and its size were noted in the 3 groups . Results : Median postoperative bony stenosis was not significantly different in the groups , being 330 mm2 , 333.5 mm2 , and 261.5 mm2 , respectively , in groups 1 , 2 , and 3 . There was no statistically significant difference between the median postoperative extension of dural sac areas in the 3 groups , measuring 125 mm2 , 123 mm2 , and 137 mm2 . The incidence of epidural hematoma was similar in the 3 groups . Levels where postoperative epidural hematoma was detected had larger bony decompression independent of the surgical approach compared with the whole group . Conclusions : Unilateral and bilateral approaches achieve a similar amount of dural sac extension by a lesser extent of bony resection in comparison with the laminectomy approach . There is a tendency of increased postoperative hematoma in approaches with greater bony decompression area

Findings suggest that more studies with rigorous research design s are needed to compare outcomes for interprofessional interventions and to determine the effectiveness of IPE on patient outcomes

The aim of this systematic review was to synthesize research in the last 5 years to report the current state of the science related to interprofessional education ( IPE ) in nursing .

Healthcare delivery is reliant on a team‐based approach , and interprofessional education ( IPE ) provides a means by which such collaboration skills can be fostered prior to entering the workplace . IPE within healthcare programs has been associated with improved collaborative behavior , patient care and satisfaction , reduced clinical error , and diminished negative professional stereotypes . An intensive interprofessional gross anatomy dissection course was created in 2009 to facilitate IPE at McMaster University . Data were collected from five cohorts over five years to determine the influence of this IPE format on the attitudes and perceptions of students towards other health professions . Each year , 28 students from the medicine , midwifery , nursing , physician 's assistant , physiotherapy , and occupational therapy programs were r and omly assigned into interprofessional teams for 10 weeks . Sessions involved an anatomy and scope‐of‐ practice presentation , a small‐group case‐based session , and a dissection . A before/after design measured changes in attitudes and perceptions , while focus group data elaborated on the student experience with the course . Pre‐ and postmatched data revealed significant improvements in positive professional identity , competency and autonomy , role clarity and attitudes toward other health professions . Qualitative analysis of intraprofessional focus group interviews revealed meaningful improvements in a number of areas including learning anatomy , role clarity , and attitudes towards other health professions . Anat Sci Educ 8 : 305–316 . © 2015 American Association of Anatomists Background The present study was design ed to implement an interprofessional simulation-based education program for nursing students and evaluate the influence of this program on nursing students ’ attitudes toward interprofessional education and knowledge about operating room nursing . Methods Nursing students were r and omly assigned to either the interprofessional simulation-based education or traditional course group . A before- and -after study of nursing students ’ attitudes toward the program was conducted using the Readiness for Interprofessional Learning Scale . Responses to an open-ended question were categorized using thematic content analysis . Nursing students ’ knowledge about operating room nursing was measured . Results Nursing students from the interprofessional simulation-based education group showed statistically different responses to four of the nineteen questions in the Readiness for Interprofessional Learning Scale , reflecting a more positive attitude toward interprofessional learning . This was also supported by thematic content analysis of the open-ended responses . Furthermore , nursing students in the simulation-based education group had a significant improvement in knowledge about operating room nursing . Conclusions The integrated course with interprofessional education and simulation provided a positive impact on undergraduate nursing students ’ perceptions toward interprofessional learning and knowledge about operating room nursing . Our study demonstrated that this course may be a valuable elective option for undergraduate nursing students in operating room nursing education EXECUTIVE SUMMARY Implementing interprofessional collaborative practice s in primary care is challenging , and research about its facilitating factors remains scarce . The goal of this participatory action research study was to better underst and the driving forces during the early stage of the implementation process of a community‐driven and patient‐focused program in primary care titled “ TRANSforming InTerprofessional cardiovascular disease prevention in primary care ” ( TRANSIT ) . Eight primary care clinics in Quebec , Canada , agreed to participate by creating and implementing an interprofessional facilitation team ( IFT ) . Sixty‐three participants volunteered to be part of an IFT , and 759 patients agreed to participate . We r and omized six clinics into a supported facilitation ( “ supported ” ) group , with an external facilitator ( EF ) and financial incentives for participants . We assigned two clinics to an unsupported facilitation ( “ unsupported ” ) group , with no EF or financial incentives . After 3 months , we held one interview for the two EFs . After 6 months , we held eight focus groups with IFT members and another interview with each EF . The analyses revealed three key forces : ( 1 ) opportunity for dialogue through the IFT , ( 2 ) active role of the EF , and ( 3 ) change implementation budgets . Decisionmakers design ing implementation plans for interprofessional programs should ensure that these driving forces are activated . Further research should examine how these forces affect interprofessional practice s and patient outcomes BACKGROUND Effective teamwork in the operating room ( OR ) is often undermined by the " silo mentality " of the differing professions . Such thinking is formed early in one 's professional experience and is fostered by undergraduate medical and nursing curricula lacking interprofessional education . We investigated the immediate impact of conducting interprofessional student OR team training using high-fidelity simulation ( HFS ) on students ' team-related attitudes and behaviors . STUDY DESIGN Ten HFS OR interprofessional student team training sessions were conducted involving 2 st and ardized HFS scenarios , each of which was followed by a structured debriefing that targeted team-based competencies . Pre- and post-session mean scores were calculated and analyzed for 15 Likert-type items measuring self-efficacy in teamwork competencies using the t-test . Additionally , mean scores of observer ratings of team performance after each scenario and participant ratings after the second scenario for an 11-item Likert-type teamwork scale were calculated and analyzed using one-way ANOVA and t-test . RESULTS Eighteen nursing students , 20 nurse anesthetist students , and 28 medical students participated in the training . Statistically significant gains from mean pre- to post-training scores occurred on 11 of the 15 self-efficacy items . Statistically significant gains in mean observer performance scores were present on all 3 subscales of the teamwork scale from the first scenario to the second . A statistically significant difference was found in comparisons of mean observer scores with mean participant scores for the team-based behaviors subscale . CONCLUSIONS High-fidelity simulation OR interprofessional student team training improves students ' team-based attitudes and behaviors . Students tend to overestimate their team-based behaviors Medical and nursing students organized a context ual interprofessional learning experience involving observation of surgical safety practice s according to the parameters of the World Health Organization ( WHO ) surgical safety checklist . Students were oriented to patient safety principles , operating room ( OR ) protocol , and the WHO surgical safety checklist . One hundred thirty students participated in interprofessional OR visitations . Selected students participated in focus groups , during which feedback regarding educational value and OR observations was obtained : Students thought that patient safety education was more meaningful in a clinical setting , and the degree of interprofessional collaboration appeared related to individual factors . Focus group data collected provides a foundation on which future research can build . Areas of inquiry may include development of teamwork within the context of interprofessional education , examination of the role of students in developing their own curricula , and r and omized comparisons of clinical -based and classroom-based approaches to surgical safety education

These quality indicators will help research ers and clinicians target quality improvement efforts .

OBJECTIVES Emergency departments ( EDs ) , similar to other health care environments , are concerned with improving the quality of patient care . Older patients comprise a large , growing , and particularly vulnerable subset of ED users . The project objective was to develop ED-specific quality indicators for older patients to help practitioners identify quality gaps and focus quality improvement efforts .

Context Quality -of-care evaluation often focuses on how often patients receive certain tests or treatments . Theoretically , the content of care should predict patient survival , but the evidence is inconclusive . Contribution This study used 207 criteria to assess good care in 372 vulnerable elderly patients . When care did not meet these st and ards , patients were more likely to die during the 3 years of follow-up . Implication s In vulnerable older patients , the content of care is associated with mortality . This finding supports the use of process measures in the evaluation of quality of care and shows that good care may prolong life . The Editors As clinicians , the public , and health systems become more aware that many Americans do not receive necessary care , the importance of measuring and improving quality of care has gained increasing attention ( 1 - 3 ) . Although quality of care can theoretically be measured by outcomes ( what happens to patients ) , process ( what providers do ) is often preferred ( 3 - 5 ) because process is under relatively greater control of providers , needs a shorter time frame , can directly inform improvement , and may not require statistical adjustment for severity of illness ( 6 , 7 ) . Typically , process measures evaluate the proportion of eligible patients who receive care as recommended ( for example , the proportion of patients 65 years of age receiving pneumococcal vaccine ) . To be a meaningful measure of quality , a process of care must be related to improved patient outcomes . For many quality indicators , this relationship is based on evidence of efficacy from r and omized , controlled trials , usually among a select patient population . However , the relationship between performance on process of care quality indicators and better health outcomes remains a largely untested assumption for general population s of patients receiving care in community setting s. The lack of a demonstrated relationship between performance on process quality measures and outcome advantage in a cohort of patients has hindered the acceptance of quality indicators as a way to measure and improve health outcomes ( 8) . The Assessing Care of Vulnerable Elders ( ACOVE ) project developed a set of process quality criteria that were judged by clinical experts to improve patient outcomes on the basis of clinical evidence and professional opinion ( 9 - 11 ) . Combined with mortality information available through the National Death Index , our study evaluated the process outcome relationship . While the development method conferred content validity on the process measures , we aim ed to assess the predictive validity of the quality measurement system by examining the relationship between the quality of care received by sample d participants and their subsequent survival . Methods The ACOVE Project The ACOVE project developed and implemented a set of quality indicators that focuses on process of care for clinical conditions important in the care of vulnerable older patients . Details of the methods of selecting conditions and developing quality indicators have been described in previous reports ( 9 , 10 ) 12 ) . We selected quality indicators by using systematic review s of the medical literature followed by deliberations by several panels of clinical experts using formal consensus methods to assess the validity of quality indicators . This process result ed in 236 quality indicators covering 22 clinical areas ( continuity of care , dementia , depression , diabetes mellitus , end-of-life care , falls and mobility problems , hearing loss , heart failure , hospital care , hypertension , ischemic heart disease , malnutrition , medication management , osteoarthritis , osteoporosis , pain management , pneumonia , pressure ulcer , screening and prevention , stroke and atrial fibrillation , urinary incontinence , and vision care ) across the continuum of care , including prevention , diagnosis , treatment , and follow-up . Each quality indicator contains an if clause that defines the patient who is eligible to receive it and a then clause that describes what care is recommended ( for example : If a vulnerable elder has had a myocardial infa rct ion , then he or she should be offered a -blocker ) . If the medical record describes a contraindication to the recommended care , the patient is not eligible for the quality indicator . Furthermore , we explicitly defined certain indicators as being not applicable , and therefore not included , when assessing the care of patients with advanced dementia or poor prognosis ( 13 ) . We applied the ACOVE quality indicators to a sample of vulnerable older patients in 2 large managed care organizations , 1 in the northeastern United States and the other in the southwestern United States ( 11 ) . Each managed care plan had more than 20000 senior members and contracted with a network of providers for delivery of care . Eligibility criteria included continuous enrollment in the managed care organization with no out-of-network care during the 13-month study period and no active treatment for malignant conditions except for nonmelanoma skin cancer . We identified vulnerable older persons by telephone interview using the Vulnerable Elders Survey-13 ( VES-13 ) ( 14 ) . The VES-13 is a 13-item question naire that produces a vulnerability score ranging from 0 to 10 based on age , self-reported health , and function . Patients with scores of 3 or higher are at 4 times the risk for death or functional decline over the next 2 years and are therefore defined as vulnerable . We excluded nonEnglish- language speakers because interviews were available only in English . Among 3207 community-dwelling patients 65 years of age and older who were r and omly selected from the 2 managed care plans , we conducted screening interviews with 2278 patients ( 9 % through proxies ) and identified 475 ( 21 % ) patients as vulnerable . Among them , 420 ( 88 % ) patients consented to participate in the study and 372 ( 78 % ) patients had medical records for the 13-month period from 1 July 1998 to 31 July 1999 that were able to be abstract ed . We collected all participants ' medical records , including those for inpatient care , outpatient care , nursing home care , home care , and mental health care . Trained nurses abstract ed charts to apply quality indicators . A senior nurse review er assessed completed abstract ions , and physician overreaders review ed them for clinical assessment . We evaluated inter-rater reliability by re abstract ion of 10 % of the medical records , which contained 698 quality indicators . Agreement was 97 % for quality indicator eligibility and 95 % for overall quality score . We collected patient characteristics , including age , sex , cognitive function measured by the Blessed OrientationMemoryConcentration test ( 15 ) , and mental health score derived from Medical Outcomes Study Short Form-36 items ( 16 ) , at the time of the recruitment telephone interview . The R AND institutional review board approved the study protocol . Among the 236 ACOVE quality indicators , 207 could be implemented in the field trial either by medical record ( 183 indicators ) or patient interview ( 24 indicators ) . Because some patients died before the interview was conducted , we used only quality indicators for which information was available in medical records . Among these , 160 quality indicators had at least 1 eligible patient ; 43 focused on prevention , 42 on diagnosis , 47 on treatment , and 28 on follow-up care . These 160 quality indicators covered all 22 conditions . The Appendix Table contains the list of quality indicators used in our report , the number of eligible patients , and the pass rate for each indicator . Appendix Table . Quality Indicators Using Medical Records as the Information Source , Eligible Patients , and Pass Rates Statistical Analysis We calculated quality scores for each patient on the basis of the percentage of ACOVE quality indicators for which an eligible patient received recommended care . We obtained death , date , and cause-of-death data for ACOVE participants from the National Death Index during 3 years after the quality measurement period ( from August 1999 to September 2002 ) . We used both unadjusted and adjusted analyses to examine the link between patient survival and quality score . For the unadjusted analysis , we first divided the sample in half on the basis of quality score ( that is , median and < median ) and examined the difference in survival curves between patients with higher quality and patients with lower quality by using the log-rank test . Second , we calculated survival for 10 equal intervals of quality score from the lowest quality score to the highest quality score in the sample and graphically assessed the grade d relationship between quality score and survival . We used the Cox proportional hazards survival model in adjusted analyses . Because the proportional hazards assumption for the multivariate survival analysis did not hold for the entire observation period , we used a piecewise model that allowed the coefficients for quality to vary between 500 days or less and more than 500 days , as suggested by the KaplanMeier survival curve in the unadjusted analysis . Covariates included sex , VES-13 score ( including age ) , mental health , number of hospitalizations and office visits during the quality measurement period , and number of conditions that patients had during the quality measurement period among 13 comorbid conditions ( dementia , depression , diabetes mellitus , heart failure , hypertension , ischemic heart disease , osteoarthritis , osteoporosis , pressure ulcer , atrial fibrillation , urinary incontinence , chronic obstructive pulmonary disease , and chronic renal failure ) . The mental health score ranged from 1 to 6 , and we created 3 categories on the basis of the score ( < 2 , very good ; 2 to 3 , good ; and > 3 , fair ) . An indicator variable design ated patients who were not interviewed for mental health items because of cognitive impairment . To further examine a plausible mechanism for the quality survival link , we examined the relationship between survival and OBJECTIVE To evaluate the pain experience of very old hospitalized patients during and up to 1 year after hospitalization . To underst and the relationship of level of pain to demographic , psychological , and illness-related variables . DESIGN Prospect i ve cohort study . SETTING Four teaching hospitals . PARTICIPANTS 1266 patients at least 80 years of age in the Hospitalized Elderly Longitudinal Project ( HELP ) . MEASUREMENTS Pain interviews during hospitalization and 2 and 6 months later . Ordinal logistic regression was used to study the association of variables with level of pain . RESULTS Interviews about symptoms were available for 806 ( 64.6 % of survivors ) patients during hospitalization , 614 ( 57.9 % of survivors ) at 2-months , and 416 ( 48.0 % of survivors ) at 12 months ; of these , 45.8 , 49.8 and 53.6 % , respectively , reported pain , and 12.9 % of those with pain during hospitalization were dissatisfied with its control . Multivariable analysis revealed that study hospital , admission diagnosis , depressed mood , alertness , and level of activity 2 weeks before admission were associated with pain during hospitalization , and pain reported during hospitalization , study site , patient level of activity 2 weeks before hospital admission , and patient education were associated with pain 2 months later . CONCLUSIONS Frequency of pain among very old hospitalized patients and at follow-up is similar to that reported for other hospitalized patients . Further studies of strategies to better control pain during and after hospitalization in very old patients are needed . These studies will have to adjust for other variables associated with pain in the oldest-old OBJECTIVE Long-term pain is a common sequela of thoracotomy , occurring in approximately 50 % of patients 2 years after thoracic surgery . Despite this alarming statistic , little is known about the factors responsible for the transition of acute to chronic pain . The aim of the present study is to identify predictors of long-term post-thoracotomy pain . DESIGN Follow-up was for 1.5 years for patients who had participated in a prospect i ve , r and omized , controlled trial of preemptive , multimodal analgesia . SETTING Subjects were recruited from a tertiary care center . PATIENTS Thirty patients who had undergone lateral thoracotomy were followed up by telephone , administered a structured interview , and classified according to long-term pain status . MAIN OUTCOME MEASURES Present pain status was measured by a verbal rating scale ( VAS ) . Measures obtained within the first 48 h after surgery were compared between patients with and without pain 1.5 years later . These include VAS pain scores at rest and after movement , McGill Pain Question naire data , patient-controlled morphine consumption ( mg ) , and pain thresholds to pressure applied to a rib contralateral to the thoracotomy incision . RESULTS Fifty-two percent of patients reported long-term pain . Early postoperative pain was the only factor that significantly predicted long-term pain . Pain intensity 24 h after surgery , at rest , and after movement was significantly greater among patients who developed long-term pain compared with pain-free patients . A significant predictive relationship was also found at 24 and 48 h using the McGill Pain Question naire . Cumulative morphine was comparable for the two groups . Pain thresholds to pressure applied to a rib contralateral to the incision did not differ significantly between the groups . CONCLUSION Aggressive management of early postoperative pain may reduce the likelihood of long-term post-thoracotomy pain OBJECTIVE To compare the experience of pain and treatment of pain in cognitively impaired and cognitively intact older adults after surgical repair of a hip fracture . DESIGN Prospect i ve comparative survey design . PARTICIPANTS A convenience sample of 88 hip fracture patients ( 53 cognitively impaired , 35 cognitively intact ) from three Midwestern urban hospital orthopedic units was interviewed between days 2 and 5 postoperatively . Subjects whose Folstein Mini-Mental State Exam ( MMSE ) score was less than or equal to 23 were categorized as impaired . RESULTS Pain report and intensity did not differ significantly between the two groups . One-third of the subjects in both groups rated pain as severe or worse . Cognitively impaired subjects scored significantly higher on the Checklist of Nonverbal Pain Indicators observed with movement ( CNPI-m ) than did cognitively intact subjects . Cognitively impaired subjects received significantly less opioid analgesics than cognitively intact subjects in the first and second 48 hours postoperatively . Both groups received less than 25 % of the mean prescribed amount of opioid analgesics . Age , MMSE , and CNPI-m score accounted for 27 % of the variance in the amount of opioid analgesic administered in the first 48 hours postoperatively . CONCLUSIONS Pain is treated poorly in older postoperative patients . Cognitive impairment and age strongly influence the amount of analgesic nurses administer to older patients after surgical repair of hip fracture . Provision for patient comfort is a fundamental ethical obligation of healthcare providers . Clinicians need to pursue this goal more aggressively , especially for cognitively impaired , postoperative older adults OBJECTIVES To evaluate the effect of emergency department ( ED ) crowding on assessment and treatment of pain in older adults . DESIGN Retrospective review of ED records from a prospect i ve cohort study . SETTING Urban , academically affiliated , tertiary medical center . PARTICIPANTS One hundred fifty-eight patients , aged 50 and older , evaluated and hospitalized from the ED with hip fracture . MEASUREMENTS Patient-related risk factors : age , sex , nursing home residence , ED triage status , dementia , Acute Physiology in Age and Chronic Health Evaluation II physiological score , and R AND comorbidity score . ED crowding risk factors : ED census and mean length of stay . OUTCOMES documentation of pain assessment , time to pain assessment , time to pain treatment , patients reporting pain receiving analgesia , and meperidine use . RESULTS Mean age was 83 ( range 52 - 101 ) , 81.0 % of patients complained of pain , mean time to pain assessment was 40 minutes ( range 0 - 600 ) , time to treatment was 141 minutes ( range 10 - 525 ) , and mean delay to treatment was 122 minutes ( range 0 - 526 ) . Of those with pain , 35.9 % received no analgesia , 7.0 % received nonopioids , and 57.0 % received opioids . Of those receiving opioids , 32.8 % received meperidine . ED crowding at census levels greater than 120 % bed capacity was significantly associated with a lower likelihood of documentation of pain assessment ( P = .05 ) and longer times to pain assessment ( P = .01 ) . CONCLUSION Older adults with hip fracture are at risk for under assessment of pain , considerable delays in analgesic administration after pain is identified , and treatment with inappropriate analgesics ( e.g. , meperidine ) in the ED . Higher levels of ED census are significantly associated with poorer pain management OBJECTIVES Screening for cognitive impairment in older emergency department ( ED ) patients is recommended to ensure quality care . The Mini-Mental State Examination ( MMSE ) may be too long for routine ED use . Briefer alternatives include the Six-Item Screener ( SIS ) and the Mini-Cog . The objective of this study was to describe the test characteristics of the SIS and the Mini-Cog compared with the MMSE when administered to older ED patients . METHODS This institutional review board-approved , prospect i ve , r and omized study was performed in a university-affiliated teaching hospital ED . Eligible patients were 65 years and older and able to communicate in English . Patients who were unable or unwilling to perform testing , who were medically unstable , or who received medications affecting their mental status were excluded . Patients were r and omized to receive the SIS or the Mini-Cog by the treating emergency physician . Investigators administered the MMSE 30 minutes later . An SIS score of < or=4 , the Mini-Cog 's scoring algorithm , and an MMSE score of < or=23 defined cognitive impairment . RESULTS A total of 149 of 188 approached patients were enrolled ; 74 received the SIS and 75 the Mini-Cog . Fifty-five percent were female , the average age was 75 years , and 23 % had an MMSE score of < or=23 . The SIS had a sensitivity of 94 % ( 95 % confidence interval [ CI ] = 73 % to 100 % ) and a specificity of 86 % ( 95 % CI = 74 % to 94 % ) . The Mini-Cog had a sensitivity of 75 % ( 95 % CI = 48 % to 93 % ) and a specificity of 85 % ( 95 % CI = 73 % to 93 % ) . CONCLUSIONS The SIS , using a cutoff of < or=4 as impaired , is a promising test for ED use . It is short , easy to administer , and unobtrusive , allowing it to be easily incorporated into the initial assessment of older ED patients STUDY OBJECTIVES We determine the effect of screening examinations for mental status impairment on the care of elderly patients in the emergency department and prospect ively assess recognition of mental status impairment by emergency physicians . METHODS We performed a prospect i ve cross-sectional study . Patients were 70 years of age or older and presented to an urban teaching hospital ED over a 17-month period . Mental status impairment screening comprised the Orientation Memory Concentration examination for cognitive impairment and the Confusion Assessment Method for delirium . Emergency physicians who were blinded to the patient 's screening results were interviewed to assess recognition of mental status impairment , dispositions , and referrals . Results of mental status impairment screens were then given to emergency physicians , and emergency physicians were reinterviewed regarding any change in care . RESULTS Two hundred seventy-one of the 327 eligible patients were enrolled . Seventy-four ( 27 % ; 95 % confidence interval [ CI ] 22 % to 33 % ) patients had impaired mental status . Nineteen ( 7 % ; 95 % CI 4 % to 11 % ) had delirium , and 55 ( 20 % ; 95 % CI 16 % to 25 % ) had cognitive impairment without delirium . Mental status impairment was recognized in only 28 ( 38 % ; 95 % CI 27 % to 50 % ) of 74 patients : 3 ( 16 % ; 95 % CI 3 % to 40 % ) of 19 with delirium and 25 ( 46 % ; 95 % CI 32 % to 59 % ) of 55 with cognitive impairment without delirium . Emergency physicians altered management in none of the study patients on the basis of survey results . Five ( 26 % ; 95 % CI 9 % to 51 % ) of the 19 patients with delirium were discharged to home . Of these 5 patients discharged to home with unrecognized delirium , 1 presented with fall , 2 returned 3 days later and required hospitalization , and 1 with a history of colon cancer was given a new diagnosis of metastatic disease 4 days after the initial ED visit . CONCLUSION Mental status impairment is highly prevalent in older ED patients . There is a lack of recognition by emergency physicians of mental status impairment in this group . Screening tools for mental status impairment in the ED did not substantially alter the care of elderly patients with mental status impairment OBJECTIVES To determine whether prevalent delirium is an independent predictor of mortality in older patients seen in emergency departments ( EDs ) and discharged home without admission . DESIGN Prospect i ve study with 18 months of follow-up . SETTING EDs in two Montreal hospitals . PARTICIPANTS From a cohort study of prognosis for delirium ( 107 delirious and 161 nondelirious subjects ) , 30 delirious and 77 nondelirious subjects aged 66 and older who were discharged home without admission were identified . MEASUREMENTS Detailed interviews with patients and their proxies and review of medical charts were performed at enrollment . Trained lay interviewers determined delirium status using the Confusion Assessment Method . Subjects were followed up at 6-month intervals for a total of 18 months . Date s of death were obtained from the Ministère de la Santé et des Service Sociaux ( Ministry of Health and Social Services ) . Survival analysis was performed using the Cox proportional hazards modeling adjusting for potential confounding variables . RESULTS The analysis revealed a statistically significant association between delirium and mortality after adjustments for age , sex , functional level , cognitive status , comorbidity , and number of medications for the first 6 months of follow-up ( hazard ratio = 7.24 ; 95 % confidence interval = 1.62 - 32.35 ) . The subjects whose delirium was not detected by the ED physician or nurse had the highest mortality over 6 months ( 30.8 % ) . The mortality of delirious subjects detected in the ED was similar to that of the nondelirious subjects ( 11.8 vs 14.3 % ) . CONCLUSION The results of this study suggests that nondetection of delirium in the ED may be associated with increased mortality within 6 months after discharge . Further research is necessary to examine the effectiveness of improving detection on subsequent prognosis of older patients with delirium STUDY OBJECTIVE We sought to determine the prevalence of mental status impairment in elderly emergency department patients and to assess documentation of and referrals by emergency physicians for mental status impairment after discharge from the ED . METHODS We performed a prospect i ve , observational study of a convenience sample of 297 patients 70 years or older presenting to an urban teaching hospital ED over a 12-month period . Patients were screened with the Orientation-Memory-Concentration examination for cognitive impairment and the Confusion Assessment Method for delirium . Documentation , dispositions , and referrals were abstract ed from chart review . RESULTS Two hundred ninety-seven of the 337 eligible patients were enrolled . Seventy-eight of the 297 ( 26 % ; 95 % confidence interval [ CI ] 21 % to 31 % ) patients had mental status impairment ; 30 ( 10 % ; 95 % CI 7 % to 14 % ) had delirium ; 48 ( 16 % ; 95 % CI 12 % to 20 % ) had cognitive impairment without delirium ; 17 ( 6 % ; 95 % CI 3 % to 9 % ) screened positive on both examinations . Only 22 ( 28 % ; 95 % CI 19 % to 40 % ) of the 78 patients had any documentation of mental status impairment by the emergency physician . Specific mention of delirium , cognitive impairment , or an acceptable synonym was noted in 13 ( 17 % ; 95 % CI 9 % to 27 % ) . Of 34 ( 44 % ; 95 % CI 32 % to 55 % ) patients with mental status impairment discharged home , only 6 ( 18 % ; 95 % CI 7 % to 35 % ) had plans documented by the emergency physician to address impairment . Eleven ( 37 % ; 95 % CI 20 % to 56 % ) of the 30 patients with delirium were discharged home . Sixteen ( 70 % ; 95 % CI 47 % to 87 % ) of the 23 patients with cognitive impairment who were discharged home had no prior history of dementia ; these patients were less likely to have specialized assistance with care ( 13 % ; 95 % CI 4 % to 27 % ) than those with known dementia ( 58 % ; 95 % CI 28 % to 85 % ) . CONCLUSION Impaired mental status is common among older ED patients . Lack of documentation , admission , or referral by emergency physicians suggests a lack of recognition of this important problem Context Many Americans 65 years of age and older are at risk for functional decline , yet we know little about the quality of care for geriatric conditions . Contribution This study used a 13-item survey about functional status to evaluate the care of 420 people 65 years of age and older whom the investigators identified as vulnerable to functional decline . Quality of care was highly variable from condition to condition but was generally better for general medical conditions , such as diabetes , than for geriatric conditions , such as incontinence . Implication s Efforts to improve care for vulnerable elders should focus on the geriatric conditions that profoundly influence functional status . The Editors The quality of care among patients 65 years of age and older has not been extensively investigated , and most existing studies have focused on general adult medical conditions . This is surprising , considering that more than 40 % of all medical expenditures are for persons 65 years of age and older ( 1 ) . The most comprehensive study to date of quality of care among older patients evaluated 24 process indicators among U.S. Medicare beneficiaries in all 50 states between 1997 and 1999 ( 2 ) . Care for acute myocardial infa rct ion , heart failure , stroke , and pneumonia was evaluated by using inpatient medical records . Pneumonia , breast cancer , and diabetes indicators were evaluated by using survey and Medicare cl aims data . The investigators found that the percentage of patients receiving appropriate care varied widely by measure and state . Several other studies of older patients evaluated cardiovascular conditions , diabetes , or aspects of preventive care and medication use ( 3 - 10 ) . No study , however , has assessed the quality of medical care provided for geriatric conditions that profoundly affect the lives of vulnerable older patients . Furthermore , surveys find that older persons often prioritize function and comfort over disease treatment and prolongation of life ( 11 ) . Quality -of-care measurement for older patients that examines only a few conditions and only indicators aim ed at prolonging life yields an incomplete assessment because it ignores other conditions and aspects of care that are of equal or even greater importance to older patients . For this reason , we developed a quality assessment system that assesses more conditions . Together , these conditions account for a majority of all of the care older patients receive ( 12 ) and include several geriatric syndromes . We used this quality assessment system to evaluate the care provided to a sample of vulnerable elders at increased risk for death or functional decline . Methods The Assessing Care of Vulnerable Elders ( ACOVE ) project developed and applied a quality assessment system for vulnerable older persons . The assessment system aim ed to develop quality indicators ( QIs ) that cover the spectrum of care for these patients . Indicators were implemented by using medical record abstract ion and patient interview . The ACOVE Quality -of-Care Assessment System The ACOVE investigators developed a system of QIs to cover the most important conditions vulnerable elders encounter in all care venues . This system focused on processes ( care behaviors ) rather than outcomes for 2 reasons . First , although most agree that outcomes should be adjusted for risk when quality is measured , there is little consensus regarding the best severity measurement system ( 13 ) . Second , measurement of processes of care is thought to be a more direct assessment of quality than measurement of outcomes ( 14 ) . The process measures were selected to represent the various domains of care : screening and prevention , diagnosis , treatment , and follow-up . The development of the assessment system was guided by a Policy Advisory Committee , which helped to direct the focus toward practical applications , and by a Clinical Committee , which provided clinical expertise for development and monitored the assembly of the QIs into a comprehensive system ( 15 ) . The methods for selecting conditions and developing the QIs have been described in detail elsewhere ( 12 , 16 ) . In brief , the Clinical Committee used the criteria of prevalence , impact , effectiveness of prevention or treatment , need for quality improvement , feasibility of measurement , and geriatric niche in a formal group rating process to identify 22 target conditions for quality improvement ( 12 ) . For each of the 22 conditions , we developed a set of evidence -based QIs for vulnerable elders using a combination of systematic review s and expert judgment ( 16 ) . Of 420 proposed QIs , the 2 expert panels , the Clinical Committee , and the American College of Physicians Task Force on Aging accepted 236 as valid indicators ; these were assembled into the ACOVE QI set ( 17 ) . The 236 QIs covered the domains of care as follows : Sixty-one ( 26 % ) focused on screening and prevention , 50 ( 21 % ) focused on diagnosis , 84 ( 36 % ) focused on treatment , and 41 ( 17 % ) focused on follow-up and continuity of care . Examples of ACOVE QIs for each condition are presented in Table 1 . Table 1 . Examples of Assessing Care of Vulnerable Elders Quality Indicators Patients and Data Collection Using the ACOVE QI set , we assessed care provided to seniors who were enrolled in 2 managed care organizations . These patients were defined as vulnerable on the basis of self-report or proxy report on a brief , 13-item screening survey ( Vulnerable Elders-13 [ VE-13 ] Survey [ 18 ] ) . Vulnerable elders , identified by this function-based survey , are community-dwelling persons 65 years of age and older who have 4 times the risk for functional decline or death over the next 2 years compared with individuals not identified as vulnerable ( 18 ) . Each managed care organization , 1 in the northeastern United States and the other in the southwestern United States , had more than 20 000 elderly enrollees and contracted with a network of providers to deliver care . Eligibility criteria included continuous enrollment in the managed care organization for at least 13 months and no out-of-plan care or active treatment for malignant conditions ( excluding nonmelanoma skin cancer ) during this period . A r and om sample of 3207 community-dwelling elderly adults was drawn from eligible persons in each managed care organization by using a r and om-number generator . Vulnerable elders were identified by using the VE-13 Survey as part of a telephone interview . Patients who did not speak English were not eligible to participate . The R AND Institutional Review Board approved the study protocol . Medical Record Review Using administrative data , we identified all inpatient and outpatient medical care received by study participants during the 13-month period of 1 July 1998 to 31 July 1999 . Medical records were requested from primary care and specialist providers ( including eye care and mental health providers ) , acute care hospitals , skilled-nursing facilities , home health agencies , and facilities providing outpatient services ( for example , physical therapy ) . Identifying information of patients and providers was removed from the medical records . Trained nurses with previous experience in quality assessment performed medical record abstract ion . Abstract ors were provided with written abstract ion guidelines and real-time consultation with a senior nurse review er . The abstract or considered all of a patient 's records when assessing whether he or she was eligible for and received the indicated care processes . In other words , information on eligibility for a QI could have been derived from 1 record ( such as an outpatient note ) while the care process was delivered and documented in another setting ( for example , inpatient medical record ) . If the care process was performed in the defined time interval , care was scored as complying with the QI . The senior nurse review er also assessed each completed medical record abstract ion . Physicians review ed QIs that required a more detailed level of clinical assessment . Examples include whether the elements of a delirium evaluation had been completed or whether an adequate intervention was performed for hyperlipidemia . An ophthalmologist evaluated selected data elements addressing vision care . Ten percent of all records were re abstract ed to evaluate reliability of the abstract ion process . Exact agreement on QI eligibility and score was 95 % . ( For details of abstract or preparation and abstract ion material s , see the Appendix . ) Quality -of-Care Interview A quality -of-care interview was conducted to ask study participants ( or , if participants were incapable of responding , their proxies ) about aspects of their care that might not be captured in the medical record ( for example , physicianpatient counseling ) . On the basis of conditions and medications reported during the interview , patients were asked about specific processes of care they had received . Patients were also asked about care preferences that might affect the applicability of QIs . In addition , the interview included demographic questions and functional status items . The quality -of-care interview was conducted by telephone between August and October 2000 and required , on average , 44 minutes to complete . Statistical Analysis Of the 236 QIs , we were able to evaluate 207 using chart abstract ion ( n = 185 [ 89 % ] ) or interview ( n = 22 [ 11 % ] ) . Interview was used to score QIs for data elements that we did not collect from the medical record . A QI was scored for a patient if he or she satisfied the IF statement of the QI and thus was eligible to receive the specified care process ( Table 1 ) . A score of 1 was awarded if the care process was carried out , and a score of 0 was assigned if it was not . For QIs that included several triggering events , a score between 0 and 1 was possible . If the medical record indicated that the patient declined the care process , the QI was considered to be passed ( the care was credited in both the numerator and the denominator of the indicator score ) . On the other h and , if the patient had a OBJECTIVE To describe the process and outcomes of nursing home ( NH ) residents transferred to hospital EDs . METHODS This was a prospect i ve , observational study conducted at 2 Midwestern community teaching hospitals during a 12-month period . All elder patients ( > 64 years of age ) transferred to hospital EDs from regional NHs were eligible for the study . Hospital records were used to abstract relevant descriptive and clinical data . Need for ambulance use was grade d prospect ively using 3 categories of urgency developed in other studies . Transfers were considered " appropriate " based on outcome measures or if the problem necessitated diagnostic and /or therapeutic procedures not available in the NH . Transfer documentation was evaluated using a st and ardized 18-item checklist . RESULTS A total of 709 consecutive NH patients made 1,012 ED visits . Their mean age was 83.4 years ( range 65 - 100 ) ; 76 % were female . The majority of patients ( 94 % ) were transferred by ambulance . Ambulance transfer was classified as emergent ( 16 % of patients ) , urgent ( 45 % ) , or routine ( 39 % ) . There were 319 ( 45 % ) patients subsequently admitted to the hospital . Approximately 77 % ( 546/709 ) of the NH transfers were considered appropriate by the emergency physician ( EP ) . Sixty-seven patients ( 10 % ) were transferred without any documentation . For those patients with transfer documentation , 6 common discrepancies were identified . CONCLUSION Although the majority of NH transfers in this population were appropriate , many patients were transferred without adequate documentation for the EP BACKGROUND Delirium and pain are common following hip fracture . Untreated pain has been shown to increase the risk of delirium in older adults undergoing elective surgery . This study was performed to examine the relationship among pain , analgesics , and other factors on delirium in hip fracture patients . METHODS We conducted a prospect i ve cohort study at four New York hospitals that enrolled 541 patients with hip fracture and without delirium . Delirium was identified prospect ively by patient interview supplemented by medical record review . Multiple logistic regression was used to identify risk factors . RESULTS Eighty-seven of 541 patients ( 16 % ) became delirious . Among all subjects , risk factors for delirium were cognitive impairment ( relative risk , or RR , 3.6 ; 95 % confidence interval , or CI , 1.8 - 7.2 ) , abnormal blood pressure ( RR 2.3 , 95 % CI 1.2 - 4.7 ) , and heart failure ( RR 2.9 , 95 % CI 1.6 - 5.3 ) . Patients who received less than 10 mg of parenteral morphine sulfate equivalents per day were more likely to develop delirium than patients who received more analgesia ( RR 5.4 , 95 % CI 2.4 - 12.3 ) . Patients who received meperidine were at increased risk of developing delirium as compared with patients who received other opioid analgesics ( RR 2.4 , 95 % CI 1.3 - 4.5 ) . In cognitively intact patients , severe pain significantly increased the risk of delirium ( RR 9.0 , 95 % CI 1.8 - 45.2 ) . CONCLUSIONS Using admission data , clinicians can identify patients at high risk for delirium following hip fracture . Avoiding opioids or using very low doses of opioids increased the risk of delirium . Cognitively intact patients with undertreated pain were nine times more likely to develop delirium than patients whose pain was adequately treated . Undertreated pain and inadequate analgesia appear to be risk factors for delirium in frail older adults A prospect i ve blinded observational study was carried out to document acute pain assessment and management in an academic emergency department . Over a 2-month period , 42 patients with a primary complaint of pain were studied . Physicians and nurses did not document levels of pain or changes in pain during patient stays . Eleven of 42 patients had severe pain upon arrival , 5 of whom received medications , only 1 obtaining good relief . No other patient received medication , although five others received some intervention for their pain . Eleven of 38 patients who were discharged home had severe pain on discharge . Despite minimal pain relief , patient satisfaction with pain management was relatively high . Pain assessment and treatment may be poorer than previous retrospective studies have indicated Quality of care can be measured by using either processes or outcomes . Each method has its strengths and limitations ( 1 ) . With the concurrence of the Assessing Care of Vulnerable Elders ( ACOVE ) Policy Advisory Committee [ 2 ] , we chose to assess the care of vulnerable elders by using processes rather than outcomes . We did so because 1 ) processes are a more efficient measure of quality ; 2 ) for most conditions there are insufficient information in the medical record and a paucity of vali date d models to adequately adjust outcomes for differences in case mix between providers ; and 3 ) ultimately , processes of care are amenable to direct action by providers . To be a valid measure of quality , a health care process must be strongly linked to an outcome that is important to patients . Ideally , high- quality published studies would link performance of all such processes to outcomes ; however , few health care processes are supported by high- quality evidence ( 3 ) . Even when a process is supported by strong evidence from r and omized clinical trials , the inclusion and exclusion criteria of the clinical trials leave the evidence directly applicable to only a narrow group of patients ( 4 , 5 ) . This is particularly true for vulnerable elders , who are typically excluded from clinical trials ( 6 ) . Therefore , as we developed the ACOVE quality indicators , we used expert opinion to interpret the available evidence for applicability to vulnerable elders . Our methods entailed a literature review and several levels of expert opinion ( Figure ) , which we explain in detail . Figure . Assessing Care of Vulnerable Elders ( ACOVE ) method for developing quality indicators for vulnerable elders . Methods Development of Draft Process Indicators For each ACOVE condition that we selected for quality improvement in vulnerable elders ( 2 ) , we identified a content expert , who worked as a team with another project member knowledgeable about systematic review s and quality indicator development . Together , the content expert and project member developed potential quality indicators from existing guidelines , review criteria , and expert opinion . Because practice guidelines and existing quality indicators are seldom referenced in the traditional scientific data bases , we used various search strategies to locate these material s. In addition to search ing MEDLINE , we search ed the following sources : CONQUEST 1.1 ( A Computerized Needs-Oriented Quality Measurement Evaluation System ) ( 7 ) ; DEMPAQ : A Project to Develop and Evaluate Methods to Promote Ambulatory Care Quality ( 8) ; Directory of Clinical Practice Guidelines ( 9 ) ; Guide to Clinical Preventive Services ( 10 ) ; HEDIS 3.0 : Health Plan Employer Data and Information Set ( 11 ) ; National Guideline Clearinghouse ( 12 ) ; National Library of Health Care Indicators ( 13 ) ; and The Medical Outcomes & Guidelines Source book ( 14 ) . We also h and search ed the tables of contents of all issues of The Journal of the American Medical Association and Medical Care published April through November 1998 for relevant practice guidelines and quality indicators . Furthermore , we requested practice guidelines and quality indicators from the following agencies and organizations : Administration on Aging ( AOA ) ; Agency for Health Care Policy and Research (AHCPR)now known as Agency for Healthcare Research and Quality ( AHRQ ) ; Centers for Disease Control and Prevention ( CDC ) ; Department of Health and Human Services ( DHHS ) ; Department of Veterans Affairs ; Foundation for Accountability ( FACCT ) ; Health Care Financing Administration ( HCFA ) ; HCFA/Connecticut Peer Review Organization ; Joint Commission on Accreditation of Healthcare Organizations ( JCAHO ) ; National Committee for Quality Assurance ( NCQA ) ; and National Institutes of Health ( NIH ) . By using the quality indicators identified through this process , as well as using expert opinion and existing guidelines , the content expert developed 20 to 30 preliminary quality indicators for further review . Potential indicators were constructed in an IFTHENBECAUSE format : IF refers to the clinical characteristics that describe persons eligible for the quality indicator ; THEN indicates the actual process that should or should not be performed ; and BECAUSE refers to the expected health impact if the indicator is performed . For example , IF a vulnerable elder has heart failure with an ejection fraction of 40 % or less , THEN an angiotensin-converting enzyme ( ACE ) inhibitor should be offered BECAUSE treatment with ACE inhibitors improves longevity . We circulated this initial set of potential quality indicators to other clinical experts for their review . On the basis of review ers ' comments , we narrowed down the initial set to the 10 to 25 most promising indicators for future development . Review of Scientific Literature Next , we assessed the published evidence supporting a link between the process specified in each quality indicator and patient outcomes . To do so , we performed a systematic review on each quality indicator by using the essence of the Cochrane Collaboration 's methods (15)except that we used a single review er to screen and assess studies . With the assistance of a reference librarian , we electronically search ed MEDLINE , EMBASE , The Cochrane Data base of Systematic Review s , HealthSTAR , Ageline , and other specialized data bases on a condition-specific basis by using keywords and free-text terms to identify potentially relevant studies . For most conditions , the search es were not restricted by language . The content expert review ed the retrieved citations by using a three-step process : First , the titles were review ed for possibly relevant studies ; the abstract s associated with the titles that passed the first round of screening were then review ed ; and , finally , the full articles of abstract s that passed the second round of screening were review ed . Abstract s and articles were not masked for review . To be accepted , titles and abstract s had to contain information indicating that the full article probably reported evidence on the potential relationship between the process in question and better outcomes in humans . We excluded animal studies , letters , review articles , and other articles that did not report original data . In review ing full articles , we gave priority to evidence from studies with the strongest design s that were relevant to the potential quality indicator being examined . In general , this meant that we chose r and omized clinical trials for questions about the efficacy or effectiveness of interventions and prospect i ve cohort studies to answer questions about risk or prognosis . We considered such evidence to be direct evidence , and we judged direct evidence in elderly persons to be the strongest level of evidence available . In the absence of direct evidence in elderly persons , we performed search es for direct evidence in other groups . Indirect evidence that from less rigorous design sin elderly or nonelderly persons was review ed if the available direct evidence was insufficient . When both direct evidence and indirect evidence were lacking , we included the statements of authoritative bodies ( for example , specialty societies , National Institutes of Health consensus development conferences , or Agency for Health Care Policy and Research practice guidelines ) . After review ing all of the relevant articles , the content expert prepared a monograph detailing each of the quality indicators and summaries of the evidence supporting them . This monograph was sent to one or more peer review ers , who were asked to assess the quality of the monograph according to the following guidelines : 1 ) Is the review complete in terms of both the proposed quality criteria and the evidence ? 2 ) Is the review fair ( that is , is the presentation of the evidence unbiased ) ? The authors subsequently revised the monographs on the basis of review ers ' comments in a manner analogous to the response to a critique of a journal article : Each comment was addressed in turn , and the author provided an appropriate revision or stated the reason why he or she believed that no revision was indicated . Expert Panels We convened two multidisciplinary groups , each composed of 12 clinical experts , to interpret the supporting evidence detailed in the monographs and to select quality indicators for further consideration . Each panel of experts considered a separate set of ACOVE conditions . Table 1 lists the members of the panels and the conditions they considered . Table 1 . ACOVE Expert Panels To assess the expert opinions of the panelists , we used a modified version of the R AND /UCLA Appropriateness Method ( 16 , 17 ) . In brief , the method entails two rounds of anonymous ratings on a riskbenefit scale ranging from 1 to 9 and a face-to-face group discussion between rounds . Each panelist has equal weight in determining the final ratings . The reproducibility of the R AND /UCLA Appropriateness Method is consistent with that of well-accepted diagnostic tests , such as the interpretation of coronary angiography and screening mammography ( 18 ) . It also has content , construct , and predictive validity ( 5 , 17 , 19 , 20 ) . In this application of the method , we sent each panelist the proposed quality indicators and the relevant condition-specific monographs . We asked the panelists to assess the validity of each proposed indicator on a scale of 1 to 9 , in which 1 was definitely not valid and 9 was definitely valid . We considered an indicator to be valid if 1 ) adequate scientific evidence or professional consensus supported a link between the process specified by the indicator and a health benefit to the patient ; 2 ) a physician or health plan with high rates of adherence to the indicator would be considered a higher- quality provider ; and 3 ) the physician or health plan influenced a majority of factors that determine adherence to the indicator ( such as smoking cessation ) . Each panelist was instructed to rate each potential quality indicator for validity and return the ratings to us before the face-to-face STUDY OBJECTIVE To determine the prevalence of delirium and other alterations in mental status in older adults in the emergency department setting . DESIGN Prospect i ve , cross-sectional study . SETTING Private , nonprofit , academic medical center in a densely populated urban area . PARTICIPANTS One hundred eighty-eight adults 70 years or older who presented to the ED . INTERVENTIONS None . RESULTS Delirium and other alterations in mental status were present in 39.9 % of the patients studied ; 24 % of these patients had delirium . Age and severity of illness were positively correlated with alteration in mental status . Patients with alterations in mental status were more likely to be admitted to an inpatient unit . Among those admitted from home , alterations in mental status in the ED were associated with a higher likelihood of institutionalization at discharge . CONCLUSION Alterations in mental status are prevalent in ED patients . Older adults with alterations in mental status , particularly alterations in consciousness and delirium , are at high risk for admission to an inpatient unit and institutionalization after discharge . St and ardized mental status testing identified high-risk older adults in the ED & NA ; Untreated pain is a major health care issue and very little is known about the treatment of pain and the effect of pain on post‐operative outcomes in older adults . This study was performed to identify the impact of pain on outcomes following hip fracture in older adults . Four hundred and eleven consecutive cognitively intact patients admitted with hip fracture to four New York hospitals were enrolled in a prospect i ve cohort study . Patients were interviewed daily using st and ardized pain assessment s. We used multiple logistic regression and ordinary least squares linear regression to examine the association of post‐operative pain on immediate post‐operative outcomes ( duration of stay , physical therapy sessions missed or shortened , ambulation following surgery , and post‐operative complications ) and outcomes 6 months following fracture ( locomotion , mortality , return to the community , residual pain ) . Patients with higher pain scores at rest had significantly longer hospital lengths of stay ( P=0.03 ) , were significantly more likely to have physical therapy sessions missed or shortened ( P=0.002 ) , were significantly less likely to be ambulating by post‐operative day 3 ( P<0.001 ) , took significantly longer to ambulate past a bedside chair ( P=0.01 ) , and had significantly lower locomotion scores at 6 months ( P=0.02 ) . Pain at rest was not significantly associated with post‐operative complications , nursing home placement , survival at 6 months , or residual pain at 6 months . Post‐operative pain is associated with increased hospital length of stay , delayed ambulation , and long‐term functional impairment . Whereas appropriate caution is warranted in administering opioid analgesics to older adults , these data suggest that improved pain control may decrease length of stay , enhance functional recovery , and improve long‐term functional outcomes OBJECTIVE To evaluate the effects of a program of case-finding and liaison service for older patients visiting the emergency department . DESIGN Nonr and omized controlled trial with systematic ally assembled intervention cohort and matched control group . SETTING An urban teaching hospital . PARTICIPANTS There were 385 intervention subjects aged 65 years and older and 385 control subjects matched by day of visit , gender , and age within 5 years . INTERVENTIONS Geriatric medical , dental and social problems were identified in intervention subjects by a geriatric nurse clinician using well vali date d assessment instruments during a 30-minute evaluation . Recommendations were made to the patient , family , and attending emergency department physician , and attempts were made to arrange appropriate follow-up services . MEASUREMENTS Frequency with which geriatric problems were identified in intervention subjects ; physician , patient , and family compliance with recommendations ; and mortality , institutionalization , health status , use of medical and social services , presence of an advanced directive , and quality of life at 3-month follow-up . RESULTS Sixty-seven percent of patients were dependent in at least one activity of daily living , 82 % had at least one geriatric problem identified , and 77 % reported at least one unmet dental or social support need . The cost of identifying geriatric and dental/social issues was $ 5 and $ 1 , respectively , for each problem . Physicians compiled with 61.6 % of suggestions , and patients and families complied with 36.6 % of recommendations . Mortality and nursing home residence proportions at 3 months were not significantly different ( 9.3 % vs 9.7 % and 5.0 % vs 2.5 % in intervention and control groups , respectively ) . Intervention subjects reported more difficulty communicating ( 21 % fair or poor ability vs 13 % , P = 0.2 ) than did control subjects . There were strong trends for fewer subsequent visits to emergency departments ( 0.26 intervention vs 0.39 control , P = .06 ) and more advance directives in the intervention group ( 6.7 % intervention vs 2.9 % control , P = .07 ) . There was no statistically or clinical ly significant difference in any other health outcome . The number of new dental or social services initiated per patient over the 3-month follow-up was nearly identical ( 1.7 in the intervention group vs 1.5 in the control ) . Results in subjects aged 75 years and older and those discharged home from the emergency department were essentially identical to those in the main group . CONCLUSIONS Numerous previously unrecognized geriatric medical and social problems can be detected in older persons visiting the emergency department . Despite this , an emergency department-based geriatric assessment and management program failed to produce improved outcomes . This suggests that either disease acuity is an overwhelming factor in subsequent outcome or , alternatively , more control over medical and social service delivery during and after the emergency department visit than was demonstrated in this program will be required before successful outcomes can be assured ABSTRACT During an episode of illness , older patients may receive care in multiple setting s ; often result ing in fragmented care and poorly-executed care transitions . The negative consequences of fragmented care include duplication of services ; inappropriate or conflicting care recommendations , medication errors , patient/caregiver distress , and higher costs of care . Despite the critical need to reduce fragmented care in this population , few interventions have been developed to assist older patients and their family members in making smooth transitions . This article introduces a patient-centered interdisciplinary team intervention design ed to improve transitions across sites of geriatric care Civilization and modern medicine now allow an unprecedented number of people to survive to old age . Not only has the definition of old evolved , but the aims of medical care for the elderly have progressed far beyond survival to maximizing functional and cognitive status , improving quality of life , and preserving productivity . Although many health problems in older age can be prevented or postponed by medical interventions , the quality of medical care for older persons remains largely unexamined . Previous work on quality -of-care measurement has focused on specific diseases or aspects of care , and in some cases targeted only a slice of the older population ( 16 ) . Such targeted approaches may not present a fair picture of overall quality and may lead to unintended incentives ( gaming the system ) ( 7 ) . Although broad systems of quality -of-care evaluation are less susceptible to gaming , they seldom include quality indicators focused on aspects of care important to older sick persons ( 8 , 9 ) . Substantial variation in preferences may make quality of care for older adults particularly difficult to measure . For example , older adults do not consistently prefer care that prolongs life , particularly if this care occurs at the expense of comfort . Furthermore , many ill , older adults can not advocate for themselves and may have no family members or friends to do so on their behalf . Thus , objective measures of the care they receive are particularly important . The Assessing Care of Vulnerable Elders ( ACOVE ) project endeavored to develop a comprehensive set of quality - assessment tools for ill older persons . Because ill older persons constitute a heterogeneous cohort that is not easily delineated , we created a system to identify high-risk , community-dwelling individuals and targeted the most important clinical conditions affecting them . Specifically , our goals for this project were the following : 1 . Develop a definition of vulnerable elders that delineates a group of community-living persons 65 years of age and older who are at high risk for death or functional decline , and develop a system to identify them . 2 . Identify important medical conditions that affect vulnerable elders and for which effective methods of prevention or management exist . 3 . Develop a set of evidence -based , quality -of-care indicators that are relevant to vulnerable elders using systematic literature review s , expert opinion , and the guidance of expert groups and stakeholders . 4 . Design a chart abstract ion tool , interview instrument , and administrative data analytic methods to implement the quality -of-care indicator system . Project Structure : Advisory Boards To make the ACOVE tools as clinical ly useful as possible and to enhance their value to those who may use them , two advisory committees oversaw the project . The Clinical Committee directed the definition of the target population and identified the target conditions . It also review ed the full set of quality indicators assembled by the expert panels ( see the Methods paper ) . The Policy Advisory Committee directed the structure of the quality indicator system and the measurement approach . This committee review ed the sampling system , considered the value of a community surveybased sample versus a sample drawn from administrative data , advised the project on methods of data collection , and advocated the use of process measures rather than outcomes .Project Overview The Appendix lists the members and institutional affiliations of the Clinical Committee and the Policy Advisory Committee and ACOVE investigators and staff . Definition and Selection of the Patient Sample We termed our target sample vulnerable elders . With the assistance of the Clinical Committee , we defined vulnerable elders as persons 65 years of age and older who are at increased risk for death or functional decline . We considered several methods of identifying a community-based sample for measurement , including use of administrative data and survey sampling . The Policy Advisory Committee advised against using a sampling method based solely on administrative data because , by definition , using utilization data to define health status and disease burden disproportionately sample s persons with higher utilization of health services and may not identify persons who are undertreated or underdiagnosed . We selected a survey method that would identify vulnerable elders regardless of the amount of health care they used and that would be versatile for use across venues and health insurance systems . Using the Medicare Current Beneficiary Survey , we determined that functional status is a more important predictor of death and functional decline than are specific clinical conditions . A parsimonious set of factors that could be asked about in a brief interview , including age , self-rated health , and functional disabilities and limitations , predicted functional decline and death . Using these factors , we developed a scoring system that identified 32 % of a nationally representative sample as vulnerable : This group had more than four times the risk for death or functional decline over a 2-year period compared to the lower-scoring majority of the sample ( 10 ) . When we applied this definition to a r and om sample of persons 65 years of age and older enrolled in managed care plans , 21 % of elders were classified as vulnerable . Target Conditions for Assessing Quality of Care We selected the target conditions for quality -of-care assessment using literature review s and a formal group-judgment process . Target conditions were conceptualized as prevalent , important to health status and quality of life , having outcomes affected by medical care , feasible to measure , and geriatric . The Clinical Committee used these criteria to select 21 diseases , geriatric syndromes , physiologic impairments , and clinical situations ( see the Methods article for a list of these 21 conditions ) . The Policy Advisory Committee added a 22nd condition , continuity and coordination of care . According to national survey estimates , the prevalence of the selected conditions ranged from 10 % to 50 % among community-dwelling elders . These conditions accounted for at least 43 % of acute hospital admissions and 33 % of office visits for persons 65 years of age and older . The process of selecting the conditions is discussed in detail elsewhere ( 11 ) . Developing Quality -of-Care Indicators for Vulnerable Elders Clinical experts developed potential quality indicators for each target condition using existing guidelines and clinical opinion . Indicators covered the domains of prevention , diagnosis , treatment , and follow-up . Structured literature review s were then performed to assess the evidence supporting a link between the proposed processes of care and improved outcomes in older adults . We subsequently presented the proposed quality indicators and the literature syntheses to panels of experts in geriatric care and medical specialists . These expert panels considered the indicators ' validity and feasibility . On the basis of the panels ' ratings and a comprehensive review of the set by the Clinical Committee , we developed a set of 236 quality indicators covering the 22 conditions . The Methods article describes this process in detail . This set of indicators was review ed and modified by the American College of PhysiciansAmerican Society of Internal Medicine ( ACPASIM ) Task Force on Aging . The full set of quality indicators with the literature substantiation for 11 of the conditions constitute the remainder of this supplement . A review of the accepted quality indicators reveals their decidedly geriatric nature . Many of them focus on the transfer of information between the health care provider and the patient or patient 's proxy . In addition to disease management , the indicators pay attention to detecting classically underidentified conditions , such as depression , dementia , and functional impairment . Consideration of proportionate care , informed consent , and end-of-life issues permeates the set . Implementing the Quality Indicators We developed instruments to implement the quality indicators using information collected from three sources : the medical record , a patient ( or , if necessary , proxy ) interview , and administrative data . Medical records include all inpatient and outpatient care over a 1-year period . The interview is design ed to be conducted by telephone with the patient to identify aspects of care that are not well captured in the medical record . The quality indicators presented here are currently undergoing feasibility testing in two managed care plans . Scoring the quality indicators accounts for clinical circumstances , patient preferences , and patient prognosis . The scoring of each quality indicator accounts for these factors at the following five levels : 1 . Any chart documentation indicating that a care process does not apply to the patient excludes application of this indicator to the patient . 2 . Any care process that is contraindicated because of comorbidity , allergy , or intolerance ( such as contraindications to medication ) excludes application of the indicator to the patient . 3 . If an indicator states that a care process should be offered to a patient , this indicator is satisfied if the care process occurs , if the medical record ( or patient interview ) indicates that the patient rejected the care process , or if the medical record ( or patient interview ) documents that the care process was offered to the patient . 4 . If the medical record contains documentation or if during an interview a patient states that he or she would not want , under any circumstances , to be hospitalized , then the 11 indicators that would require hospitalization do not apply . Similarly , a preference not to accept surgery would exclude from application to that patient the 9 indicators that prescribe surgery or procedures that would lead to surgery . 5 . If a patient has advanced dementia or a chart-documented poor prognosis ( expected survival < 6 months ) , then

The occurrence of side effects and young age were cited as the top reasons for poor adherence , followed by forgetfulness . Conclusions Overall , the values reflected a population adherent to both topical and oral medications , with no significant difference in adherence between the two . However , the method ologies used by many of the studies were weak , and the findings are not consistent with results of more objective measures of adherence .

Background Poor adherence of acne patients to treatment may equate to poor clinical efficacy , increased healthcare costs , and unnecessary treatments . Authors have investigated risk factors for poor medical adherence and how to improve this difficult problem in the context of acne . Objective This systematic review aims to describe what methods have been used to measure adherence , what is known about acne patients ’ adherence to treatment , and the factors affecting adherence .

Acne vulgaris can affect adolescents at a time of profound physical , social , and psychological change . The negative impact of acne on self-image and self-confidence can be severe , leading to potential psychiatric problems and limiting social interactions , even in adults . Adherence is necessary for successful treatment of acne , and patient satisfaction is crucial for adherence . The Measuring Acne Outcomes in a Real-World Experience ( MORE ) trial enrolled 1979 subjects who used combination acne treatments , all containing adapalene gel 0.1 % . Among other measures , subjects were surveyed regarding their satisfaction with treatment . Adherence to treatment protocol was high throughout the study ( 94.5 % and 88.0 % at weeks 6 and 12 , respectively , determined by self-report , and 93.7 % and 80.3 % , respectively , determined by filled prescriptions ) . Of the subjects who completed preference surveys , more than 70 % rated adapalene gel 0.1 % as much superior or superior to other acne treatments ; more than 85 % of subjects were very satisfied or satisfied with adapalene gel 0.1 % to treat their acne ; and more than 85 % of subjects reported feeling more confident or positive after using this treatment . About 75 % of subjects planned to continue using adapalene gel 0.1 % and /or use it in the future if they needed acne treatment , and close to 75 % of subjects indicated that they would recommend this treatment to a friend . The high level of patient satisfaction with adapalene gel 0.1 % as an acne treatment is likely to translate into a high level of adherence to treatment , including maintenance treatment , and a major improvement in quality of life ( QOL ) for patients with acne Background Patient adherence is an important component of the treatment of chronic disease . An underst and ing of patient adherence and its modulating factors is necessary to correctly interpret treatment efficacy and barriers to therapeutic success . Purpose This meta- analysis aims to systematic ally review published r and omized controlled trials of reminder interventions to assist patient adherence to prescribed medications . Methods A Medline search was performed for r and omized controlled trials published between 1968 and June 2011 , which studied the effect of reminder-based interventions on adherence to self-administered daily medications . Results Eleven published r and omized controlled trials were found between 1999 and 2009 which measured adherence to a daily medication in a group receiving reminder interventions compared to controls receiving no reminders . Medication adherence was measured as the number of doses taken compared to the number prescribed within a set period of time . Meta- analysis showed a statistically significant increase in adherence in groups receiving a reminder intervention compared to controls ( 66.61 % versus 54.71 % , 95 % CI for mean : 0.8 % to 22.4 % ) . Self-reported and electronically monitored adherence rates did not significantly differ ( 68.04 % versus 63.67 % , P = 1.0 ) . Eight of eleven studies showed a statistically significant increase in adherence for at least one of the reminder group arms compared to the control groups receiving no reminder intervention . Limitations The data are limited by imperfect measures of adherence due to variability in data collection methods . It is also likely that concomitant educational efforts in the study population s , such as instructions regarding proper administration and importance of correct dosing schedules , contributed to improved patient adherence , both in reminder and control arms . The search strategy could have missed relevant studies which were categorized by disease rather than adherence . Conclusions Reminder-based interventions may improve adherence to daily medications . However , the interventions used in these studies , which included reminder phone calls , text messages , pagers , interactive voice response systems , videotelephone calls , and programmed electronic audiovisual reminder devices , are impractical for widespread implementation , and their efficacy may be optimized when combined with alternative adherence-modifying strategies . More practical reminder-based interventions should be assessed to determine their value in improving patient adherence and treatment outcomes The US Food and Drug Administration has approved adapalene gel 0.1 % for use in the treatment of acne vulgaris . The objective of our study was to evaluate the efficacy and tolerability of adapalene gel 0.1 % in the treatment of acne vulgaris in a clinical practice . We used a 12-week , multicenter , open-label , noncomparative phase 4 study of adapalene gel 0.1 % . The study involved approximately 600 dermatologists in the United States and included 2,545 healthy men and nonpregnant women older than 14 years who had mild or moderate acne vulgaris . Of the patients enrolled , 75 % completed the study and most of them ( 89 % ) showed an improvement in their acne ( clear of acne or marked , definite , or minimal improvement ) from baseline . Most patients ( 69 % ) were satisfied or very satisfied with adapalene therapy , and most ( 80 % ) wished to continue treatment . Only 3.7 % of patients enrolled reported treatment-related adverse events ( n=94 ) , the most common being skin irritation ( 2.2 % ) . We conclude from this open-label trial in a dermatology practice setting that adapalene gel 0.1 % was effective and well tolerated and had a favorable safety profile . Furthermore , compliance with once-daily application of adapalene was rated as high by 92 % of patients who responded to a self- assessment question naire It is well known that the setting of clinical trials for registration studies do not necessarily represent efficacy seen in clinical practice , where physicians have the flexibility to select , combine , and change the acne treatment prescription . In this phase 4 , open-label , multicenter , community-based study , 544 patients who were dissatisfied with their current acne treatment received tretinoin gel microsphere ( TGM ) 0.04 % or 0.1 % in a pump dispenser for 12 weeks . Patients were allowed the use of up to 2 other concurrent acne therapies , not including other retinoids . A total of 361 patients received TGM 0.04 % and 183 received TGM 0.1 % . Compliance was high ( defined as 75 % to 100 % of prescribed doses taken ) for approximately 95 % of patients in both groups at every evaluation . At week 12 , the mean modified Global Acne Grade score ( mGAGs ) and the investigator global evaluation ( IGE ) demonstrated significant ( P<.0001 ) improvement from baseline for both concentrations , with 72 % having at least moderate improvement . In approximately 25 % of patients , acne was assessed as cleared or almost cleared . Most side effects were characteristic of topical retinoids . These results indicate TGM in a pump dispenser as an effective , well-tolerated acne treatment that is associated with a high rate of compliance Background : Adherence to treatment is a mayor issue in dermatology , and its relationship to quality of life has barely been studied . Objective : To evaluate the relationship between scores on the Skindex-29 skin disease assessment scale and adherence to treatment in patients with acne . Methods : An observational , prospect i ve study of 1,628 patients carried out by 252 clinicians in Spain . Results : Adherence was related to better objective and subjective severity index scores and better Skindex-29 scale scores at the end of the study . Young , male and unemployed patients had the worst adherence scores . Baseline and final Skindex-29 scale scores were significantly worse in non-adherent females , while non-adherent males scored better . Reasons for non-adherence were side effects for older patients and forgetfulness for younger ones . Conclusion : Dermatologists should explain that adherence to treatment is linked to better outcomes and better quality of life . Young females with high Skindex-29 scale scores and males with low Skindex scores are especially prone to non-adherence BACKGROUND : Topical retinoid therapy has been shown to be an effective means of treating both the inflammatory and non-inflammatory lesions of acne vulgaris . AIM : To assess the efficacy and safety of the test product , a gel containing isotretinoin 0.1 % w/w and erythromycin 4.0 % w/w , with a currently used and effective treatment for mild to moderate acne vulgaris , a gel containing benzoyl peroxide 5.0 % w/w and erythromycin 3.0 % w/w . METHODS : This multi-centre , single-blind ( investigator blind ) , parallel group study compared the efficacy and safety of isotretinoin/erythromycin gel ( Double Strength IsotrexinA ) once daily against benzoyl peroxide/erythromycin gel ( Benzamycin ® ) twice daily in the topical treatment of mild to moderate acne vulgaris . Patients ( n = 188 ) with a history ( mean duration 3.3 years ) of facial acne vulgaris and with 15 - 100 inflammatory lesions and /or 15 - 100 non-inflammatory lesions , but not more than three nodulocystic lesions , were included . At baseline and weeks 2 , 4 , 8 and 12 , the investigator assessed efficacy ( total number and severity of inflammatory and non-inflammatory lesions and acne grade ) while subjective global change assessment s of facial acne from baseline and symptom-specific skin tolerance were assessed by the patient . The investigator recorded an overall global assessment of skin tolerability at week 12 . Adverse events were recorded throughout . RESULTS : The treatments were comparable with regard to their effects on inflammatory and non-inflammatory lesions and acne grade . Few adverse events were considered to be treatment-related . Both the isotretinoin/erythromycin and benzoyl peroxide/erythromycin gels were generally well tolerated . Compliance was better with the isotretinoin/erythromycin gel , which had the advantages of not requiring mixing or storage in a refrigerator , and was applied once rather than twice daily . CONCLUSIONS : Isotretinoin/erythromycin gel given only once daily showed comparable efficacy with benzoyl peroxide/erythromycin given twice daily in the treatment of mild to moderate acne vulgaris of the face Introduction : A topical acne treatment in which clindamycin phosphate equivalent to 1 % clindamycin is presented in a gel formulation has received marketing authorizations in a number of EU and non‐EU countries . Clindamycin/zinc gel contains zinc acetate in a formulation that reduces systemic absorption of clindamycin through the skin . Objectives : To compare the efficacy and safety of a 1 % clindamycin/zinc gel when applied to the face once daily or twice daily with a 1 % clindamycin lotion applied twice daily for 16 weeks in patients with mild to moderate acne vulgaris . Methods : This was a r and omized , comparative , observer‐blind , parallel‐group , multicentre study involving 246 acne patients . Results : The study demonstrated therapeutic similarity between clindamycin/zinc gel applied once and twice daily with clindamycin lotion applied twice daily . All three regimens produced a gradual and time‐dependent reduction in inflamed lesions , non‐inflamed lesions and overall grade . Side effects were similar and minimal , consisting predominantly of mild irritant dermatitis . All regimes produced a time‐related significant reduction in skin surface and follicular Propionibacterium spp . and Micrococcaceae . The emergence of resistant strains was less than 5 % and was similar with all three regimes . Conclusion : The equivalent efficacy and safety of clindamycin/zinc gel either once or twice daily to clindamycin lotion twice daily has been demonstrated . It is suggested that a treatment regime of one application per day may significantly enhance compliance and thus treatment success in acne patients BACKGROUND The efficacy of topical medications is limited by non-adherence . Interventions to improve adherence to topical treatments are not well characterized . OBJECTIVE To assess the impact of office visits on patients ' adherence to topical treatment . METHODS Twenty-nine subjects enrolled in a clinical trial for psoriasis and were followed for up to 8 weeks . Subjects were told to apply 6 % salicylic acid gel twice daily . Electronic monitors were used to assess adherence . Results were compared to adherence in clinical trials of h and dermatitis and atopic dermatitis . RESULTS Adherence rates were significantly higher around the time of office visits ( P < .05 ) . LIMITATIONS This is a small study in a limited patient population . The study was observational and not a r and omized trial of the effect of increased office visits . CONCLUSION Frequent follow-up visits in clinical trials increase patients ' adherence to medications . The use of a follow-up visit shortly after initiating treatment may be an effective way to boost patients ' use of their medication and achieve better treatment outcomes

Results The performance of the search strategies varied widely according to the clinical question . This benefit was consistent for most clinical questions . Conclusions The Clinical Queries narrow filter , along with well-formulated queries based on the PICO framework , provided the greatest aid in retrieving relevant clinical trials within the 2 first PubMed pages .

Background Clinicians perform search es in PubMed daily , but retrieving relevant studies is challenging due to the rapid expansion of medical knowledge . Little is known about the performance of search strategies when they are applied to answer specific clinical questions . Objective To compare the performance of 15 PubMed search strategies in retrieving relevant clinical trials on therapeutic interventions .

Objective To evaluate the ability of international point of care information summaries to up date evidence relevant to medical practice . Design Prospect i ve cohort bibliometric analysis . Setting Top five point of care information summaries ( Clinical Evidence , EBM Guidelines , eMedicine , Dynamed , UpTo Date ) ranked for coverage of medical conditions , editorial quality , and evidence based methodology . Main outcome measures From June 2009 to May 2010 we measured the incidence of research findings relating to potentially eligible newsworthy evidence . As sample s , we chose systematic review s rated as relevant by international research networks ( such as , Evidence -Based Medicine , ACP Journal Club , and the Cochrane Collaboration ) . Every month we assessed whether each sample d review was cited in at least one chapter of the five summaries . The cumulative updating rate was analysed with Kaplan-Meier curves . Results From April to December 2009 , 128 review s were retrieved ; 53 % ( 68 ) from the literature surveillance journals and 47 % ( 60 ) from the Cochrane Library . At nine months , Dynamed had cited 87 % of the sample d review s , while the other summaries had cited less than 50 % . The updating speed of Dynamed clearly led the others . For instance , the hazard ratios for citations in EBM Guidelines and Clinical Evidence versus the top performer were 0.22 ( 95 % confidence interval 0.17 to 0.29 ) and 0.03 ( 0.01 to 0.05 ) . Conclusions Point of care information summaries include evidence relevant to practice at different speeds . A qualitative analysis of updating mechanisms is needed to determine whether greater speed corresponds to more appropriate incorporation of new information Background The use of PubMed to answer daily medical care questions is limited because it is challenging to retrieve a small set of relevant articles and time is restricted . Knowing what aspects of queries are likely to retrieve relevant articles can increase the effectiveness of PubMed search es . The objectives of our study were to identify queries that are likely to retrieve relevant articles by relating PubMed search techniques and tools to the number of articles retrieved and the selection of articles for further reading . Methods This was a prospect i ve observational study of queries regarding patient-related problems sent to PubMed by residents and internists in internal medicine working in an Academic Medical Centre . We analyzed queries , search results , query tools ( Mesh , Limits , wildcards , operators ) , selection of abstract and full-text for further reading , using a portal that mimics PubMed . Results PubMed was used to solve 1121 patient-related problems , result ing in 3205 distinct queries . Abstract s were viewed in 999 ( 31 % ) of these queries , and in 126 ( 39 % ) of 321 queries using query tools . The average term count per query was 2.5 . Abstract s were selected in more than 40 % of queries using four or five terms , increasing to 63 % if the use of four or five terms yielded 2–161 articles . Conclusion Queries sent to PubMed by physicians at our hospital during daily medical care contain fewer than three terms . Queries using four to five terms , retrieving less than 161 article titles , are most likely to result in abstract viewing . PubMed search tools are used infrequently by our population and are less effective than the use of four or five terms . Methods to facilitate the formulation of precise queries , using more relevant terms , should be the focus of education and research OBJECTIVES The research sought to determine the value of PubMed filters and combinations of filters in literature selected for systematic review s on therapy-related clinical questions . METHODS References to 35,281 included and 48,514 excluded articles were extracted from 2,629 review s published prior to January 2008 in the Cochrane Data base of Systematic Review s and sent to PubMed with and without filters . Sensitivity , specificity , and precision were calculated from the percentages of unfiltered and filtered references retrieved for each review and averaged over all review s. RESULTS Sensitivity of the Sensitive Clinical Queries filter was reasonable ( 92.7 % , 92.1 - 93.3 ) ; specificity ( 16.1 % , 15.1 - 17.1 ) and precision were low ( 49.5 % , 48.5 - 50.5 ) . The Specific Clinical Queries and the Single Term Medline Specific filters performed comparably ( sensitivity , 78.2 % , 77.2 - 79.2 vs. 78.0 % ; 77.0 - 79.0 ; specificity , 52.0 % , 50.8 - 53.2 vs. 52.3 % , 51.1 - 53.5 ; precision , 60.4 % , 59.4 - 61.4 vs. 60.6 % , 59.6 - 61.6 ) . Combining the Abridged Index Medicus ( AIM ) and Single Term Medline Specific ( 65.2 % , 63.8 - 66.6 ) , Two Terms Medline Optimized ( 64.2 % , 62.8 - 65.6 ) , or Specific Clinical Queries filters ( 65.0 % , 63.6 - 66.4 ) yielded the highest precision . CONCLUSIONS Sensitive and Specific Clinical Queries filters used to answer questions about therapy will result in a list of clinical trials but can not be expected to identify only method ologically sound trials . The Specific Clinical Queries filters are not suitable for questions regarding therapy that can not be answered with r and omized controlled trials . Combining AIM with specific PubMed filters yields the highest precision in the Cochrane data set Background Supporting 21st century health care and the practice of evidence -based medicine ( EBM ) requires ubiquitous access to clinical information and to knowledge-based re sources to answer clinical questions . Many questions go unanswered , however , due to lack of skills in formulating questions , crafting effective search strategies , and accessing data bases to identify best levels of evidence . Methods This r and omized trial was design ed as a pilot study to measure the relevancy of search results using three different interfaces for the PubMed search system . Two of the search interfaces utilized a specific framework called PICO , which was design ed to focus clinical questions and to prompt for publication type or type of question asked . The third interface was the st and ard PubMed interface readily available on the Web . Study subjects were recruited from interns and residents on an inpatient general medicine rotation at an academic medical center in the US . Thirty-one subjects were r and omized to one of the three interfaces , given 3 clinical questions , and asked to search PubMed for a set of relevant articles that would provide an answer for each question . The success of the search results was determined by a precision score , which compared the number of relevant or gold st and ard articles retrieved in a result set to the total number of articles retrieved in that set . Results Participants using the PICO templates ( Protocol A or Protocol B ) had higher precision scores for each question than the participants who used Protocol C , the st and ard PubMed Web interface . ( Question 1 : A = 35 % , B = 28 % , C = 20 % ; Question 2 : A = 5 % , B = 6 % , C = 4 % ; Question 3 : A = 1 % , B = 0 % , C = 0 % ) 95 % confidence intervals were calculated for the precision for each question using a lower boundary of zero . However , the 95 % confidence limits were overlapping , suggesting no statistical difference between the groups . Conclusion Due to the small number of search es for each arm , this pilot study could not demonstrate a statistically significant difference between the search protocol s. However there was a trend towards higher precision that needs to be investigated in a larger study to determine if PICO can improve the relevancy of search results Background Search filters or hedges play an important role in evidence -based medicine but their development depends on the availability of a " gold st and ard " – a reference st and ard against which to establish the performance of the filter . We demonstrate the feasibility of using relative recall of included studies from multiple systematic review s to vali date method ological search filters as an alternative to validation against a gold st and ard formed through h and search ing . Methods We identified 105 Cochrane review s that used the Highly Sensitive Search Strategy ( HSSS ) , included r and omized or quasi-r and omized controlled trials , and reported their included studies . We measured the ability of two published and one novel variant of the HSSS to retrieve the MEDLINE -index studies included in these review s. Results The systematic review s were comprehensive in their search es . 72 % of included primary studies were indexed in MEDLINE . Relative recall of the three strategies ranged from .98 to .91 across all review s and more comprehensive strategies showed higher recall . Conclusion An approach using relative recall instead of a h and search ing gold st and ard proved feasible and produced recall figures that were congruent with previously published figures for the HSSS . This technique would permit validation of a method ological filter using a collection of approximately 100 studies of the chosen design drawn from the included studies of multiple systematic review s that used comprehensive search strategies Background The explosion of biomedical information has led to an ‘ information paradox’—the volume of biomedical information available has made it increasingly difficult to find relevant information when needed . It is thus increasingly critical for physicians to acquire a working knowledge of biomedical informatics . Aim To evaluate four search tools commonly used to answer clinical questions , in terms of accuracy , speed , and user confidence . Methods From December 2008 to June 2009 , medical students , resident physicians , and attending physicians at the authors ' institution were asked to answer a set of four anaesthesia and /or critical care based clinical questions , within 5 min , using Google , Ovid , PubMed , or UpTo Date ( only one search tool per question ) . At the end of each search , participants rated their results on a four point confidence scale . One to 3 weeks after answering the initial four questions , users were r and omised to one of the four search tools , and asked to answer eight questions , four of which were repeated . The primary outcome was defined as a correct answer with the highest level of confidence . Results Google was the most popular search tool . Users of Google and UpTo Date were more likely than users of PubMed to answer questions correctly . Subjects had the most confidence in UpTo Date . Search es with Google and UpTo Date were faster than search es with PubMed or Ovid . Conclusion Non- Medline based search tools are not inferior to Medline based search tools for purpose s of answering evidence based anaesthesia and critical care questions Background Rather than search ing the entire MEDLINE data base , clinicians can perform search es on a filtered set of articles where relevant information is more likely to be found . Members of our team previously developed two types of MEDLINE filters . The ' methods ' filters help identify clinical research of high method ological merit . The ' content ' filters help identify articles in the discipline of renal medicine . We will now test the utility of these filters for physician MEDLINE search ing . HypothesisWhen a physician search es MEDLINE , we hypothesize the use of filters will increase the number of relevant articles retrieved ( increase ' recall , ' also called sensitivity ) and decrease the number of non-relevant articles retrieved ( increase ' precision , ' also called positive predictive value ) , compared to the performance of a physician 's search unaided by filters . Methods We will survey a r and om sample of 100 nephrologists in Canada to obtain the MEDLINE search that they would first perform themselves for a focused clinical question . Each question we provide to a nephrologist will be based on the topic of a recently published , well-conducted systematic review . We will examine the performance of a physician 's unaided MEDLINE search . We will then apply a total of eight filter combinations to the search ( filters used in isolation or in combination ) . We will calculate the recall and precision of each search . The filter combinations that most improve on unaided physician search es will be identified and characterized . Discussion If these filters improve search performance , physicians will be able to search MEDLINE for renal evidence more effectively , in less time , and with less frustration . Additionally , our methodology can be used as a proof of concept for the evaluation of search filters in other disciplines Purpose Many educational programs seek to develop skills in evidence -based medicine ( EBM ) . The authors examined the efficacy of teaching the EBM skill of efficiently search ing the research literature . They compared students who received brief training in EBM search ing skills with those who did not , and assessed the quality of literature search ing one month after that training . Method The authors used a nonr and omized control group study design to quantify the impact of a single , brief ( two-hour ) instructional intervention on EBM-based techniques for search ing Medline for evidence related to a clinical problem provided to the students . Ninety-two fourth-year medical students ( 34 intervention , 58 control ) at the University of Michigan participated in a four-week EBM elective between 2001 and 2003 . The authors conducted a preintervention assessment of search ing skills , followed by a repeat assessment one month after the intervention . Search quality was judged by medical librarians using a structured clinical scenario and scoring algorithm . Results Data for 30 intervention and 40 control students could be analyzed . Intervention students had fewer search errors and correspondingly higher quality search es than did control students . The educational intervention accounted for approximately 8 % of the variance in both of these outcomes . The most common search errors were a lack of Medical Subject Headings ( MeSH ) explosion , missing MeSH terms , lack of appropriate limits , failure to search for best evidence , and inappropriate combination of all search concepts . Conclusions This study provides evidence that a single , brief training session can have a marked beneficial effect on the quality of subsequent , short-term EBM literature search ing performance outcomes Background To practice Evidence -Based Medicine ( EBM ) , physicians must quickly retrieve evidence to inform medical decisions . Internal Medicine ( IM ) residents receive little formal education in electronic data base search ing , and have identified poor search ing skills as a barrier to practicing EBM . Objective To design and implement a data base search ing tutorial for IM residents on inpatient rotations and to evaluate its impact on residents ’ skill and comfort search ing MEDLINE and filtered EBM re sources . Design R and omized controlled trial . Residents r and omized to the search ing tutorial met for up to 6 1-hour small group sessions to search for answers to questions about current hospitalized patients . Participants Second- and 3rd-year IM residents . Measurements Residents in both groups completed an Objective Structured Search ing Evaluation ( OSSE ) , search ing for primary evidence to answer 5 clinical questions . OSSE outcomes were the number of successful search es , search times , and techniques utilized . Participants also completed self- assessment surveys measuring frequency and comfort using EBM data bases . Results During the OSSE , residents who participated in the intervention utilized more search ing techniques overall ( p < .01 ) and used PubMed ’s Clinical Queries more often ( p < .001 ) than control residents . Search ing “ success ” and time per completed search did not differ between groups . Compared with controls , intervention residents reported greater comfort using MEDLINE ( p < .05 ) and the Cochrane Library ( p < .05 ) on post-intervention surveys . The groups did not differ in comfort using ACP Journal Club , or in self-reported frequency of use of any data bases . Conclusions An inpatient EBM search ing tutorial improved search ing techniques of IM residents and result ed in increased comfort with MEDLINE and the Cochrane Library , but did not impact overall search ing success BACKGROUND Physicians often search for information to improve patient care . We evaluated how nephrologists use online information sources for this purpose . METHODS In this cross-sectional study ( 2008 to 2010 ) , a r and om sample of Canadian nephrologists completed a survey of their online search practice s. We queried respondents on their search ing preferences , practice s and use of 9 online information sources . RESULTS Respondents ( n=115 ; 75 % response rate ) comprised both academic ( 59 % ) and community-based ( 41 % ) nephrologists . Respondents were an average of 48 years old and were in practice for an average of 15 years . Nephrologists used a variety of online sources to retrieve information on patient treatment including UpTo Date ( 92 % ) , PubMed ( 89 % ) , Google ( 76 % ) and Ovid MEDLINE ( 55 % ) . Community-based nephrologists were more likely to consult UpTo Date first ( 91 % ) , while academic nephrologists were divided between UpTo Date ( 58 % ) and PubMed ( 41 % ) . When search ing bibliographic re sources such as PubMed , 80 % of nephrologists scan a maximum of 40 citations ( the equivalent of 2 search pages in PubMed ) . Search ing practice s did not differ by age , sex or years in practice . CONCLUSIONS Nephrologists routinely use a variety of online re sources to search for information for patient care . These include bibliographic data bases , general search engines and specialized medical re sources PURPOSE The aim of this study was to determine the information needs of primary care physicians in Spain and to describe their information-seeking patterns . METHODS This observational study took place in primary care practice s located in Madrid , Spain . Participants were a r and om stratified sample of 112 primary care physicians . Physicians ’ consultations were video recorded for 4 hours . Clinical questions arising during the patient visit and the sources of information used within the consultation to answer questions were identified . Physicians with unanswered questions were followed up by telephone 2 weeks later to determine whether their questions had since been answered and the sources of information used . Clinical questions were classified by topic and type of information . RESULTS A total of 3,511 patient consultations ( mean length , 7.8 minutes ) were recorded , leading to 635 clinical questions ( 0.18 questions per consultation ) . The most frequent questions were related to diagnosis ( 53 % ) and treatment ( 26 % ) . The most frequent generic type of questions was “ What is the cause of symptom x ? ” ( 20.5 % ) . Physicians search ed for answers to 22.8 % of the questions ( 9.6 % during consultations ) . The time taken and the success rate in finding an answer during a consultation and afterward were 2 minutes ( 100 % ) and 32 minutes ( 75 % ) , respectively . CONCLUSIONS Primary care physicians working in setting s where consultations are of short duration have time to answer only 1 in 5 of their questions . Better methods are needed to provide answers to questions that arise in office practice in setting s where average consultation time is less than 10 minutes OBJECTIVE The paper compares the speed , validity , and applicability of two different protocol s for search ing the primary medical literature . DESIGN A r and omized trial involving medicine residents was performed . SETTING An inpatient general medicine rotation was used . PARTICIPANTS Thirty-two internal medicine residents were block r and omized into four groups of eight . MAIN OUTCOME MEASURES Success rate of each search protocol was measured by perceived search time , number of questions answered , and proportion of articles that were applicable and valid . RESULTS Residents r and omized to the MEDLINE -first ( protocol A ) group search ed 120 questions , and residents r and omized to the MEDLINE -last ( protocol B ) search ed 133 questions . In protocol A , 104 answers ( 86.7 % ) and , in protocol B , 117 answers ( 88 % ) were found to clinical questions . In protocol A , residents reported that 26 ( 25.2 % ) of the answers were obtained quickly or rated as " fast " ( < 5 minutes ) as opposed to 55 ( 51.9 % ) in protocol B , ( P = 0.0004 ) . A subset of questions and articles ( n = 79 ) were review ed by faculty who found that both protocol s identified similar numbers of answer articles that addressed the questions and were felt to be valid using critical appraisal criteria . CONCLUSION For resident-generated clinical questions , both protocol s produced a similarly high percentage of applicable and valid articles . The MEDLINE -last search protocol was perceived to be faster . However , in the MEDLINE -last protocol , a significant portion of questions ( 23 % ) still required search ing MEDLINE to find an answer

Conclusions and Relevance Among patients with acute low back pain , spinal manipulative therapy was associated with modest improvements in pain and function at up to 6 weeks , with transient minor musculoskeletal harms .

Importance Acute low back pain is common and spinal manipulative therapy ( SMT ) is a treatment option . R and omized clinical trials ( RCTs ) and meta-analyses have reported different conclusions about the effectiveness of SMT . Objective To systematic ally review studies of the effectiveness and harms of SMT for acute ( ⩽6 weeks ) low back pain .

Summary A total of 101 out patients with acute or subacute low-back pain was r and omly allocated to one of two treatment groups . One group was given st and ardised conventional and optimised activating treatment by primary health care teams . The other group received , according to a pragmatic approach , another treatment programme including manipulation , specific mobilisation , muscle stretching , autotraction and cortisone injections . The treatment effect was evaluated by st and ardised telephone interviews 3 , 7 , 14 , 21 and 90 days after the start of treatment . The two groups were similar in most of the pretrial variables , including age , sex , occupation , education , previous low-back pain problems , previous treatment , sickleave , findings at the physical examination , quality -of-life score , presence of common symptoms , disability rating and pain score . In the early phase as well as at the 90 days ' follow-up , the group receiving manual therapy had significantly less pain , less disability , faster rate of recovery and lower drug consumption , indicating that this type of treatment is superior to conventional treatment A total of 132 infants and children with grade s III and IV primary vesicoureteral reflux was entered into a prospect i ve trial comparing medical to surgical management . Inclusion criteria were an age not exceeding 10 years and a glomerular filtration rate of at least 70 ml . per minute per 1.73 m.2 . Children with significant urinary tract malformations and clinical signs/symptoms of dysfunctional voiding were not accepted into the trial . Medical therapy consisted of continuous low dose antibiotic prophylaxis until vesicoureteral reflux resolved . The type of surgical procedure used for the correction of reflux was left to the discretion of the surgeon . Outcome variables included the appearance or progression of renal lesions , rate of renal growth , recurrence rate of urinary tract infection or pyelonephritis , changes in total kidney glomerular filtration rate , development of hypertension and resolution rate of vesicoureteral reflux . Followup at 6 , 18 , 36 and 54 months after entry included , in addition to history and physical examination , voiding cystourethrography , excretory urography and a urine culture . Of the patients 68 were allocated to the medical group and 64 to the surgical group . They were stratified for age , sex and preexisting renal scarring . Of the patients 10 % were boys , 47 % were between 2 and 6 years old at entry , 93 % had a history of pyelonephritis , 67 % had either scarring or thinning of the parenchyma at entry , 87 % had grade IV vesicoureteral reflux in at least 1 unit and 56 % had bilateral reflux . There were no significant differences in the frequency distribution of entry characteristics between the patients allocated to either group . New renal scarring developed in 22 % of medical and 31 % of surgical patients ( p < 0.4 ) . Growth of kidneys with grade IV vesicoureteral reflux was slightly less than normal in the medical ( -0.67 + /- 0.15 st and ard deviation ) and surgical ( -0.42 + /- 0.11 st and ard deviation ) groups ( p < 0.7 ) . Pyelonephritis occurred in 15 medical patients versus 5 surgical patients ( p < 0.05 ) . There was no significant change in glomerular filtration rate within each treatment group and no difference in glomerular filtration rate between groups . No patient had hypertension during the followup period . The disappearance rate of vesicoureteral reflux in patients with grade IV reflux was approximately 8 % per year . Of the medical patients 75 % still had vesicoureteral reflux after 3 years of observation . ( ABSTRACT TRUNCATED AT 400 WORDS Objective : To evaluate if a comprehensive manual therapy programme reduces sick leave due low back pain and facilitates return to work more than the conventional optimized activating care . Design : A r and omized controlled trial over a 10-week period with a two-year follow-up . Setting : Primary health care and Visby Hospital , Municipality of Gotl and , Sweden . Subjects : One hundred and sixty patients ( 70 women , 90 men , ages 20—55 years ) with acute or subacute low back pain with or without pain radiation into the legs . Interventions : St and ardized optimized activating care ( n = 71 ) versus a comprehensive pragmatic manual therapy programme including specific corticosteroid injections ( n = 89 ) . Main measures : Sick leave measured as net sick leave volume , point prevalence and return to work . Results : After 10 weeks , significantly more manual therapy patients than reference patients had returned to work ( hazards ratio 1.62 , 95 % confidence interval ( CI ) 1.006—2.60 , P<0.05 ) , and among those on sick leave at baseline , significantly fewer were still on sick leave ( 8/58 versus 13/40 , ratio 0.35 , 95 % CI 0.13—0.97 , P<0.05 ) . For all other measures there were inconclusive differences in favour of the manual therapy group . No significant differences remained after two years . Conclusions : The manual therapy programme used in this study decreased sick leave and increased return to work more than the st and ardized optimized activating care only up to 10 weeks but not up to two years Study Design . A prospect i ve clinic‐based survey . Objectives . To study the type , frequency , and characteristics of unpleasant side effects after spinal manipulative therapy . Summary of Background Data . Spinal manipulative therapy is a commonly used treatment , but there is little knowledge of its side effects . Methods . Information regarding unpleasant reactions after spinal manipulative therapy was collected after 4712 treatments on 1058 new patients by 102 Norwegian chiropractors ( response rate , 70 % ) through structured interviews . Results . At least one reaction was reported by 55 % of the patients some time during the course of a maximum of six treatments . Of the reported reactions , the most common were local discomfort ( 53 % ) , headache ( 12 % ) , tiredness ( 11 % ) , or radiating discomfort ( 10 % ) . Reactions were mild or moderate in 85 % of patients . Sixty‐four percent of reactions appeared within 4 hours of treatment , and 74 % had disappeared within 24 hours . Uncommon reactions were dizziness , nausea , hot skin , or " other " complaints , each accounting for 5 % or less of reactions . It was unusual that symptoms commenced later than on the day of or the day after treatment , were of long duration ( not gone at the latest on the day after onset ) , described as severe , or that they result ed in reduced activities of daily living . There were no reports of serious complications in this study . Conclusions . Profiles now are described of common and uncommon reactions to spinal manipulative therapy and their latency , duration , and severity Background The safety of the manual treatment techniques such as spinal manipulation has been discussed and there is a need for more information about potential adverse events after manual therapy . The aim of this r and omized controlled trial was to investigate differences in occurrence of adverse events between three different combinations of manual treatment techniques used by manual therapists ( i.e. chiropractors , naprapaths , osteopaths , physicians and physiotherapists ) for patients seeking care for back and /or neck pain . In addition women and men were compared regarding the occurrence of adverse events . Methods Participants were recruited among patients , ages 18–65 , seeking care at the educational clinic of the Sc and inavian College of Naprapathic Manual Medicine in Stockholm . The patients ( n = 767 ) were r and omized to one of three treatment arms 1 ) manual therapy ( i.e. spinal manipulation , spinal mobilization , stretching and massage ) ( n = 249 ) , 2 ) manual therapy excluding spinal manipulation ( n = 258 ) and 3 ) manual therapy excluding stretching ( n = 260 ) . Treatments were provided by students in the seventh semester of total eight . Adverse events were measured with a question naire after each return visit and categorized in to five levels ; 1 ) short minor , 2 ) long minor , 3 ) short moderate , 4 ) long moderate and 5 ) serious adverse events , based on the duration and /or severity of the event . Generalized estimating equations were used to examine the association between adverse event and treatments arms . Results The most common adverse events were soreness in muscles , increased pain and stiffness . No differences were found between the treatment arms concerning the occurrence of adverse event . Fifty-one percent of patients , who received at least three treatments , experienced at least one adverse event after one or more visits . Women more often had short moderate adverse events ( OR = 2.19 ( 95 % CI : 1.52 - 3.15 ) ) , and long moderate adverse events ( OR = 2.49 ( 95 % CI : 1.77 - 3.52 ) ) compared to men . Conclusion Adverse events after manual therapy are common and transient . Excluding spinal manipulation or stretching do not affect the occurrence of adverse events . The most common adverse event is soreness in the muscles . Women reports more adverse events than men . Trial registration This trial was registered in a public registry ( Current Controlled Trials ) ( IS RCT N92249294 ) Fifty-four subjects volunteered to participate in a controlled study contrasting spinal manipulation with spinal mobilization without the rotational forces and leverage required to move facet joints . All suffered from regional low-back pain for less than 1 month , were ages 18–40 , had never previously undergone any form of spinal manipulation , and denied a prior episode of backache within the previous 6 months . R and omization was stratified at outset into those who suffered for less than 2 weeks and those whose discomfort had persisted for 2–4 weeks . Outcome was monitored by a question naire assessing functional impairment . A treatment effect of manipulation was demonstrated only in the strata with more prolonged illness at entry . In the first week following manipulation , these patients improved to a greater degree ( P=.009 , t test ) and more rapidly ( P < .025 , Wilcoxon rank-sum test ) Spinal manipulative therapy ( SMT ) and exercise have demonstrated effectiveness for neck pain ( NP ) . Adverse events ( AE ) reporting in trials , particularly among elderly participants , is inconsistent and challenges informed clinical decision making . This paper provides a detailed report of AE experienced by elderly participants in a r and omized comparative effectiveness trial of SMT and exercise for chronic NP . AE data , consistent with CONSORT recommendations , were collected on elderly participants who received 12 weeks of SMT with home exercise , supervised plus home exercise , or home exercise alone . St and ardized questions were asked at each treatment ; participants were additionally encouraged to report AE as they occurred . Qualitative interviews documented participants ' experiences with AE . Descriptive statistics and content analysis were used to categorize and report these data . Compliance was high among the 241 r and omized participants . Non-serious AE were reported by 130/194 participants . AE were reported by three times as many participants in supervised plus home exercise , and nearly twice as many as in SMT with home exercise , as in home exercise alone . The majority of AE were musculoskeletal in nature ; several participants associated AE with specific exercises . One incapacitating AE occurred when a participant fell during supervised exercise session and fractured their arm . One serious adverse event of unknown relationship occurred to an individual who died from an aneurysm while at home . Eight serious , non-related AE also occurred . Musculoskeletal AE were common among elderly participants receiving SMT and exercise interventions for NP . As such , they should be expected and discussed when developing care plans IMPORTANCE Low back pain ( LBP ) is common in primary care . Guidelines recommend delaying referrals for physical therapy . OBJECTIVE To evaluate whether early physical therapy ( manipulation and exercise ) is more effective than usual care in improving disability for patients with LBP fitting a decision rule . DESIGN , SETTING , AND PARTICIPANTS R and omized clinical trial with 220 participants recruited between March 2011 and November 2013 . Participants with no LBP treatment in the past 6 months , aged 18 through 60 years ( mean age , 37.4 years [ SD , 10.3 ] ) , an Oswestry Disability Index ( ODI ) score of 20 or higher , symptom duration less than 16 days , and no symptoms distal to the knee in the past 72 hours were enrolled following a primary care visit . INTERVENTIONS All participants received education . Early physical therapy ( n = 108 ) consisted of 4 physical therapy sessions . Usual care ( n = 112 ) involved no additional interventions during the first 4 weeks . MAIN OUTCOMES AND MEASURES Primary outcome was change in the ODI score ( range : 0 - 100 ; higher scores indicate greater disability ; minimum clinical ly important difference , 6 points ) at 3 months . Secondary outcomes included changes in the ODI score at 4-week and 1-year follow-up , and change in pain intensity , Pain Catastrophizing Scale ( PCS ) score , fear-avoidance beliefs , quality of life , patient-reported success , and health care utilization at 4-week , 3-month , and 1-year follow-up . RESULTS One-year follow-up was completed by 207 participants ( 94.1 % ) . Using analysis of covariance , early physical therapy showed improvement relative to usual care in disability after 3 months ( mean ODI score : early physical therapy group , 41.3 [ 95 % CI , 38.7 to 44.0 ] at baseline to 6.6 [ 95 % CI , 4.7 to 8.5 ] at 3 months ; usual care group , 40.9 [ 95 % CI , 38.6 to 43.1 ] at baseline to 9.8 [ 95 % CI , 7.9 to 11.7 ] at 3 months ; between-group difference , -3.2 [ 95 % CI , -5.9 to -0.47 ] , P = .02 ) . A significant difference was found between groups for the ODI score after 4 weeks ( between-group difference , -3.5 [ 95 % CI , -6.8 to -0.08 ] , P = .045 ] ) , but not at 1-year follow-up ( between-group difference , -2.0 [ 95 % CI , -5.0 to 1.0 ] , P = .19 ) . There was no improvement in pain intensity at 4-week , 3-month , or 1-year follow-up ( between-group difference , -0.42 [ 95 % CI , -0.90 to 0.02 ] at 4-week follow-up ; -0.38 [ 95 % CI , -0.84 to 0.09 ] at 3-month follow-up ; and -0.17 [ 95 % CI , -0.62 to 0.27 ] at 1-year follow-up ) . The PCS scores improved at 4 weeks and 3 months but not at 1-year follow-up ( between-group difference , -2.7 [ 95 % CI , -4.6 to -0.85 ] at 4-week follow-up ; -2.2 [ 95 % CI , -3.9 to -0.49 ] at 3-month follow-up ; and -0.92 [ 95 % CI , -2.7 to 0.61 ] at 1-year follow-up ) . There were no differences in health care utilization at any point . CONCLUSIONS AND RELEVANCE Among adults with recent-onset LBP , early physical therapy result ed in statistically significant improvement in disability , but the improvement was modest and did not achieve the minimum clinical ly important difference compared with usual care . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01726803 Study Design . A r and omized , double-blinded , placebo-controlled , parallel trial with 3 arms . Objective . To investigate in acute nonspecific low back pain ( LBP ) the effectiveness of spinal high-velocity low-amplitude ( HVLA ) manipulation compared with the nonsteroidal anti-inflammatory drug diclofenac and with placebo . Summary of Background Data . LBP is an important economical factor in all industrialized countries . Few studies have evaluated the effectiveness of spinal manipulation in comparison to nonsteroidal anti-inflammatory drugs or placebo regarding satisfaction and function of the patient , off-work time , and rescue medication . Methods . A total of 101 patients with acute LBP ( for < 48 hr ) were recruited from 5 outpatient practice s , exclusion criteria were numerous and strict . The subjects were r and omized to 3 groups : ( 1 ) spinal manipulation and placebo-diclofenac ; ( 2 ) sham manipulation and diclofenac ; ( 3 ) sham manipulation and placebo-diclofenac . Outcomes registered by a second and blinded investigator included self-rated physical disability , function ( SF-12 ) , off-work time , and rescue medication between baseline and 12 weeks after r and omization . Results . Thirty-seven subjects received spinal manipulation , 38 diclofenac , and 25 no active treatment . The placebo group with a high number of dropouts for unsustainable pain was closed praecox . Comparing the 2 active arms with the placebo group the intervention groups were significantly superior to the control group . Ninety subjects were analyzed in the collective intention to treat . Comparing the 2 intervention groups , the manipulation group was significantly better than the diclofenac group ( Mann-Whitney test : P = 0.0134 ) . No adverse effects or harm was registered . Conclusion . In a subgroup of patients with acute nonspecific LBP , spinal manipulation was significantly better than nonsteroidal anti-inflammatory drug diclofenac and clinical ly superior to placebo Four treatment regimens for patients with specified combinations of low back pain and sciatica were evaluated . The largest group studied had low back pain with limited straight-leg raising ( SLR ) and in them the beneficial effect of manipulation in hastening pain relief was highly significant . In similar patients without limitation of SLR , the effect was of borderline significance . In all the other groups , treated patients also recovered more quickly than their controls . Traction , for patients with low back pain and sciatica , and epidural injections when a root palsy was present also produced some significant pain relief . The effect of sclerosants for back pain was less clear OBJECTIVE This study examines which variables may predict adverse events in subjects undergoing chiropractic treatment for neck pain . METHODS This was a prospect i ve , multi-center , cohort study . All new patients , 18 to 65 years of age with neck pain of any duration , who had not undergone chiropractic care or manual therapy in the prior 3 months , were eligible . Sources of data were question naires administered during the first 3 treatments . In all , 60 putative prognostic variables were examined , including descriptors of the patient , chiropractor , and type of treatment delivered . Adverse events were defined as either a new complaint , or the worsening of an existing complaint by more than 30 % on an 11-point numerical rating scale . Multivariate r and om coefficients logistic regression analyses were conducted to determine predictors for the following outcome variables : ( 1 ) any adverse event after any of the first 3 visits , ( 2 ) any type of adverse event after the first visit only , and ( 3 ) specific types of adverse events after the first visit only ( ie , headache , increased neck pain , pain and /or stiffness at the treated area ) . RESULTS In total , 579 patients were recruited , of whom 529 fulfilled the inclusion criteria . The reported use of a manipulative technique involving cervical rotation , and working status of the patient ( sick leave or workers ' compensation ) were moderately associated with an adverse event after any of the first 3 visits . Patients who had visited their general practitioner in the 6 months before treatment , however , were less likely to have an adverse event . A longer duration with neck pain in the preceding year was moderately associated with specific types of events after the first visit , namely , headache or worsening of the presenting neck pain . Increased neck pain after the first visit was the easiest outcome variable to predict ( area under the curve , 0.88 ; 95 % confidence interval , 0.84 - 0.91 ) . CONCLUSIONS Of the 60 independent variables examined , only 4 were found to be predictive of adverse events after chiropractic treatment for neck pain , one of which was found to be protective . The chiropractic practitioner can identify 3 of these variables before initiating treatment OBJECTIVE To compare prospect ively the effect of manual treatment such as manipulation , specific mobilization , muscle stretching , auto-traction , and cortisone injections with st and ardized conventional but optimized activating treatment by primary health care teams . DESIGN Prospect i ve controlled multicentre trial with four months ' follow-up . SETTING Kopparberg County , Sweden . Six primary health care or occupational health care centres , representing a catchment area of 56000 residents participated . PARTICIPANTS 101 out patients with acute or subacute low-back pain were , during the period February 1988 to April 1989 , r and omly allocated to one of two treatment groups . MAIN OUTCOME MEASURE Quality of life was assessed at baseline and at four months by means of visual analogue scales ( VAS ) . The occurrence of 27 different symptoms of a psychosomatic character was surveyed initially and at four months by questions answered by " yes " or " no " in a question naire . RESULTS There were significant differences concerning quality of life and presence of general symptoms in favour of the group receiving manual treatment with steroid injections . CONCLUSION Manual treatment with steroid injections was superior to conventional treatment in minimizing mental and somatic symptoms and increasing quality of life , in parallel with other measures of improvement BACKGROUND CONTEXT Acute back pain and sciatica are major sources of disability . Many medical interventions are available , including manipulations , with conflicting results . PURPOSE To assess the short- and long-term effects of spinal manipulations on acute back pain and sciatica with disc protrusion . STUDY DESIGN / SETTING R and omized double-blind trial comparing active and simulated manipulations in rehabilitation medical centers in Rome and suburbs . PATIENT SAMPLE 102 ambulatory patients with at least moderate pain on a visual analog scale for local pain ( VAS1 ) and /or radiating pain ( VAS2 ) . OUTCOME MEASURES Pain-free patients at end of treatment ; treatment failure ( proportion of patients stopping the assigned treatment for lack of effect on pain ) ; number of days with no , mild , moderate , or severe pain ; quality of life ; number of days on nonsteroidal anti-inflammatory drugs ; number of drug prescriptions ; VAS1 and VAS2 scores ; quality of life and psychosocial findings ; and reduction of disc protrusion on magnetic resonance imaging . METHODS Manipulations or simulated manipulations were done 5 days per week by experienced chiropractors , with a number of sessions which depended on pain relief or up to a maximum of 20 , using a rapid thrust technique . Patients were assessed at admission and at 15 , 30 , 45 , 90 , and 180 days . At each visit , all indicators of pain relief were used . RESULTS A total of 64 men and 38 women aged 19 - 63 years were r and omized to manipulations ( 53 ) or simulated manipulations ( 49 ) . Manipulations appeared more effective on the basis of the percentage of pain-free cases ( local pain 28 vs. 6 % ; p<.005 ; radiating pain 55 vs. 20 % ; p<.0001 ) , number of days with pain ( 23.6 vs. 27.4 ; p<.005 ) , and number of days with moderate or severe pain ( 13.9 vs. 17.9 ; p<.05 ) . Patients receiving manipulations had lower mean VAS1 ( p<.0001 ) and VAS2 scores ( p<.001 ) . A significant interaction was found between therapeutic arm and time . There were no significant differences in quality of life and psychosocial scores . There were only two treatment failures ( manipulation 1 ; simulated manipulation 1 ) and no adverse events . CONCLUSIONS Active manipulations have more effect than simulated manipulations on pain relief for acute back pain and sciatica with disc protrusion Objective : To determine whether treatment with spinal manipulative therapy ( SMT ) administered in addition to st and ard care is associated with clinical ly relevant early reductions in pain and analgesic consumption . Methods : 104 patients with acute low back pain were r and omly assigned to SMT in addition to st and ard care ( n = 52 ) or st and ard care alone ( n = 52 ) . St and ard care consisted of general advice and paracetamol , diclofenac or dihydrocodeine as required . Other analgesic drugs or non-pharmacological treatments were not allowed . Primary outcomes were pain intensity assessed on the 11-point box scale ( BS-11 ) and analgesic use based on diclofenac equivalence doses during days 1–14 . An extended follow-up was performed at 6 months . Results : Pain reductions were similar in experimental and control groups , with the lower limit of the 95 % CI excluding a relevant benefit of SMT ( difference 0.5 on the BS-11 , 95 % CI −0.2 to 1.2 , p = 0.13 ) . Analgesic consumptions were also similar ( difference −18 mg diclofenac equivalents , 95 % CI −43 mg to 7 mg , p = 0.17 ) , with small initial differences diminishing over time . There were no differences between groups in any of the secondary outcomes and stratified analyses provided no evidence for potential benefits of SMT in specific patient groups . The extended follow-up showed similar patterns . Conclusions : SMT is unlikely to result in relevant early pain reduction in patients with acute low back pain Study Design Low back pain patients seen in primary care were allocated r and omly to one of two educational interventions or to usual care . Objective To evaluate educational interventions design ed to improve the outcomes of primary care for low back pain . Summary of Background Data Patients with back pain are frequently dissatisfied with their medical care and identify lack of information as the most insufficient aspect . Methods In a large Health Maintenance Organization clinic , 293 subjects were allocated r and omly to receive usual care , an educational booklet , or a 15-minute session with a clinic nurse , including the booklet and a follow-up telephone call . Outcome measures included satisfaction with care , perceived knowledge , participation in exercise , functional status , symptom relief , and health care use . Outcomes were assessed 1 , 3 , 7 , and 52 weeks after the intervention . Results The nurse intervention result ed in higher patient satisfaction than usual care ( P < 0.001 ) and higher perceived knowledge ( P < 0.001 ) . Self-reported exercise participation was also higher in the nurse intervention group after a 1-week follow-up period ( 97 % vs. 65 % in the other groups ; P < 0.0001 ) . There were no significant differences among the three groups in worry , symptoms , functional status , or health care use at any follow-up interval . Differences in self-reported exercise and perceived knowledge were no longer significant after 7 weeks . Conclusions These findings challenge the value of purely educational approaches in reducing functional impact or health care use related to back pain and also challenge the value of fitness exercise in the most acute phase of back pain Fifty-three acute or subacute patients with low back pain were given st and ardized but optimized activating conventional treatment by primary health care teams . Forty-eight patients received an experimental treatment that included specific manual treatment , such as manipulation and specific mobilization , muscle stretching , auto-traction , and cortisone injections . After 4 months , the experimental group had a less restricted range of movement in extension , less restricted side-bending to the right and to the left , less local pain caused by extension and side-bending to the right , less pain radiating to the right leg caused by side-bending to the left , and a less positive straight leg raising test ( both sides ) than the conventionally treated group . Manual treatment was superior to the conventional activating treatment in normalizing pathologic findings on physical examination of the lower back . These results agree with the positive influence on pain , drug consumption , sick-leave , disability rating , and quality of life reported in other reports from the same study Study Design . R and omized clinical trial . Objective . Compare outcomes of patients with low back pain receiving treatments matched or unmatched to their subgrouping based on initial clinical presentation . Summary of Background Data . Patients with “ nonspecific ” low back pain are often viewed as a homogeneous group , equally likely to respond to any particular intervention . Others have proposed methods for subgrouping patients as a means for determining the treatment most likely to benefit patients with particular characteristics . Methods . Patients with low back pain of less than 90 days ’ duration referred to physical therapy were examined before treatment and classified into one of three subgroups based on the type of treatment believed most likely to benefit the patient ( manipulation , stabilization exercise , or specific exercise ) . Patients were r and omly assigned to receive manipulation , stabilization exercises , or specific exercise treatment during a 4-week treatment period . Disability was assessed in the short-term ( 4 weeks ) and long-term ( 1 year ) using the Oswestry . Comparisons were made between patients receiving treatment matched to their subgroup , versus those receiving unmatched treatment . Results . A total of 123 patients participated ( mean age , 37.7 ± 10.7 years ; 45 % female ) . Patients receiving matched treatments experienced greater short- and long-term reductions in disability than those receiving unmatched treatments . After 4 weeks , the difference favoring the matched treatment group was 6.6 Oswestry points ( 95 % CI , 0.70–12.5 ) , and at long-term follow-up the difference was 8.3 points ( 95 % CI , 2.5–14.1 ) . Compliers-only analysis of long-term outcomes yielded a similar result . Conclusions . Nonspecific low back pain should not be viewed as a homogenous condition . Outcomes can be improved when subgrouping is used to guide treatment decision-making Manipulative therapy as part of a multidimensional approach may be more effective than st and ard physical therapy in treating Acute Nonspecific Low Back Pain . 64 participants , 29 women and 35 men , with Acute Nonspecific Low Back Pain and a mean age of 40 yr . ( SD = 9.6 ) were r and omly assigned to two groups : an experimental group ( manipulative therapy plus physical therapy ) and a control group ( only physical therapy ) . A multicentre , nonblinded , r and omised clinical trial was conducted . Pain relief was the main performance criteria measured together with secondary criteria which included functional status and mobility of the lower back . Fritz , Childs , and Flynn 's clinical prediction rule — a duration of symptoms less than 16 days , no pain distal of the knee — was used to analyse the results . In combination with an age > 35 years , results showed a statistical significant effect for disability , but no statistically significant benefit of additional manipulative therapy over physical therapy found for pain and mobility within 4 treatments . Controlled for the applied clinical prediction rule , there were statistically significant interaction effects with low effect size for disability and sex , but no significant effects were found for pain of mobility OBJECTIVES To compare the effect of manual therapy in addition to the stay-active concept versus the stay-active concept only in low back pain patients . STUDY DESIGN A r and omized , controlled trial during 10 weeks . METHODS One hundred sixty out patients with acute or subacute low back pain were recruited from a geographically defined area . They were r and omly allocated to a reference group treated with the stay-active concept and , in some cases , muscle stretching and an experimental group receiving manual therapy and , in some cases , steroid injections in addition to the stay-active concept . Pain and disability rating index were used as outcome measures . RESULTS At baseline , the experimental group had somewhat more pain , a higher disability rating index , and more herniated disks than the reference group . After 5 and 10 weeks , the experimental group had less pain and a lower disability rating index than the reference group . CONCLUSIONS The manual treatment concept used in this study in low back pain patients appears to reduce pain and disability rating better than the traditional stay-active concept OBJECTIVE To evaluate the use of the Hmax/Mmax ( H/M ) ratio as an outcome measure for acute low back pain and to determine the change of this ratio in acute low back pain patients treated with spinal manipulation . DESIGN R and omized clinical trial . SETTING Chiropractic college teaching clinic . PATIENTS Thirty-six patients with acute low back pain ( pain of less than 2 wk duration ) were referred by clinicians of the teaching clinic . Eligibility criteria for inclusion into the study consisted of the following : a score of eight or more on the Oswestry question naire , 33 mm or greater on a 100-mm visual analog scale , no involvement in litigation related to the low back pain complaint , patient not pregnant and no physical or electrodiagnostic signs of nerve root entrapment . INTERVENTIONS The patients were r and omly assigned to either a treatment or control group . The treatment group ( n = 17 ) received treatment deemed appropriate by the clinician as long as it included a side-lying manipulation to the appropriate level . The control group ( n = 19 ) received detuned ultrasound , application of a cold pack and 15 - 30 sec of very gentle soft tissue massage . Patients were treated three to five times over a period of 10 days and were subsequently reevaluated . MEASUREMENTS The Hmax/Mmax ratio was calculated from the results of electrodiagnostic testing of the posterior tibial nerve . Extension/flexion ratio of the trunk musculature , Oswestry score and Visual Analog Scale score were also measured . MAIN RESULTS The mean difference between H/M ratios pre- and postintervention for the group treated by chiropractic methods was -0.101 on the left and -0.117 on the right . The mean difference for the control group was 0.038 on the left and 0.036 on the right . Although not statistically significant , trends suggest that at the time of final assessment , the group receiving chiropractic care had improved more than the control group . CONCLUSIONS The H/M ratio was found to be within normal limits in subjects with acute low back pain . The H/M ratio showed greater change in the group which received spinal manipulation , but the change was subtle . The results indicate that the H/M ratio may be of limited value in clinical practice Study Design . A prospect i ve , cohort study of patients with nonradicular low back pain referred to physical therapy . Objective . Develop a clinical prediction rule for identifying patients with low back pain who improve with spinal manipulation . Summary of Background Data . Development of clinical prediction rules for classifying patients with low back pain who are likely to respond to a particular intervention , such as manipulation , would improve clinical decision-making and research . Methods . Patients with nonradicular low back pain underwent a st and ardized examination and then underwent a st and ardized spinal manipulation treatment program . Success with treatment was determined using percent change in disability scores over three sessions and served as the reference st and ard for determining the accuracy of examination variables . Examination variables were first analyzed for univariate accuracy in predicting success and then combined into a multivariate clinical prediction rule . Results . Seventy-one patients participated . Thirty-two had success with the manipulation intervention . A clinical prediction rule with five variables ( symptom duration , fear – avoidance beliefs , lumbar hypomobility , hip internal rotation range of motion , and no symptoms distal to the knee ) was identified . The presence of four of five of these variables ( positive likelihood ratio = 24.38 ) increased the probability of success with manipulation from 45 % to 95 % . Conclusion . It appears that patients with low back pain likely to respond to manipulation can be accurately identified before treatment Glover , J. R. , Morris , Jean G. , and Khosla , T. (1974).British Journal of Industrial Medicine,31 , 59 - 64 . Back pain : a r and omized clinical trial of rotational manipulation of the trunk . A therapeutic trial was conducted in a medium-sized engineering works on patients suffering from back pain with its accompanying tenderness and hyperaesthesia . The patients were r and omly allocated to two treatment groups , ( a ) manipulation , and ( b ) de-tuned ( i.e. , simulated ) short-wave diathermy , the latter acting as a placebo . The manipulated group were given one lumbar rotational manipulation session of 15 minutes or less and this was followed by four daily detuned short-wave diathermy sessions of 15 minutes . The control group were given five 15-minute daily sessions of detuned short-wave diathermy only . The patients ' own subjective assessment of relief from pain was recorded in the range 0 % ( no relief ) to 100 % ( complete relief ) . The responses were measured at three stages , ( 1 ) within 15 minutes , ( 2 ) three days after treatment , and ( 3 ) seven days after treatment . Although each of the two treatment groups showed progressive and marked improvement in the percentage of relief from pain during the seven-day period , there was no demonstrable difference between the two , except that at the 15-minute stage the relief from pain in the manipulated group was always greater than in the controls Abstract We evaluated three different conservative treatment methods for acute low-back pain patients in groups following a manual therapy programme , an intensive training programme , or a general practitioner programme , the latter serving as the control group . Patients aged 19–64 years on sick leave for low-back pain with or without sciatica were included in a prospect i ve r and omised study evaluating outcomes such as impairment , pain , functional disability , socio-economic disability and satisfaction with the treatment or explanations . Evaluation by unbiased observers was performed at 1 , 3 and 12 months . The three treatment groups were comparable at baseline . With regard to satisfaction , the patients in the manual therapy programme and those in the intensive training programme were more satisfied with the treatment than those in the general practitioner programme at all follow-ups . With regard to the explanations of current low-back pain episodes , the patients in the manual therapy programme were more satisfied than those in the general practitioner programme at all follow-ups . The manual therapy programme group were also more satisfied with the explanations than those in the intensive training programme at the 1-month follow-up . However , no differences were revealed between the groups with respect to outcomes on measures of impairment , pain , functional disability or socio-economic disability . All three study groups showed rapid improvement . After 1 month a significant improvement was noted in all outcome values compared with the values on entry to the study . Within the limitations discussed in our study , it is concluded that ( 1 ) patients sick listed with acute low-back pain , with or without sciatica , will be significantly improved after 1 month regardless of conservative treatment programme ; ( 2 ) they will be more satisfied with the treatment if they are referred to a manual treatment programme or a training treatment programme ; ( 3 ) they will be more satisfied with the explanations of the acute low-back problem if they are referred to one of the above groups , especially the manual treatment group ; ( 4 ) they will not show any other differences with respect to subjective and objective variables , either at short-term or at long-term follow-ups Study Design . A r and omized trial was conducted in which patients with back and neck pain , visiting a general practitioner , were allocated to chiropractic or physiotherapy . Objectives . To compare outcome and costs of chiropractic and physiotherapy as primary treatment for patients with back and neck pain , with special reference to subgroups , recurrence rate , and additional health care use at follow‐up evaluation 12 months after treatment . Summary of Background Data . Earlier studies on the effect of spinal manipulation have shown inconsistent results . Mostly they include only short‐term follow‐up periods , and few cost‐effectiveness analyses have been made . Methods . A group of 323 patients aged 18‐60 years who had no contraindications to manipulation and who had not been treated within the previous month were included . Outcome measures were changes in Oswestry scores , pain intensity , and general health ; recurrence rate ; and direct and indirect costs . Results . No differences were detected in health improvement , costs , or recurrence rate between the two groups . According to Oswestry score , chiropractic was more favorable for patients with a current pain episode of less than 1 week ( 5 % ) and physiotherapy for patients with a current pain episode of greater than 1 month ( 6.8 % ) . Nearly 60 % of the patients reported two or more recurrences . More patients in the chiropractic group ( 59 % ) than in the physiotherapy group ( 41 % ) sought additional health care . Costs varied considerably among individuals and subgroups ; the direct costs were lower for physiotherapy in a few subgroups . Conclusions . Effectiveness and costs of chiropractic or physiotherapy as primary treatment were similar for the total population , but some differences were seen according to subgroups . Back problems often recurred , and additional health care was common . Implication s of the result are that treatment policy and clinical decision models must consider subgroups and that the problem often is recurrent . Models must be implemented and tested Objective : To evaluate the health-related quality of life effects of muscle stretching , manual therapy and steroid injections in addition to ‘ stay active ’ care in acute or subacute low back pain patients . Study design : A r and omized , controlled trial during 10 weeks with four treatment groups . Setting : Nine primary health care and one outpatient orthopaedic hospital department . Subjects : One hundred and sixty patients with acute or subacute low back pain . Interventions : Ten weeks of ‘ stay active ’ care only ( group 1 ) , or ‘ stay active ’ and muscle stretching ( group 2 ) , or ‘ stay active ’ , muscle stretching and manual therapy ( group 3 ) , or ‘ stay active ’ , muscle stretching , manual therapy and steroid injections ( group 4 ) . Main measures : The Gothenburg Quality of Life instrument subscales Well-being score and Complaint score . Results : In a multivariate analysis adjusted for possible outcome affecting variables other than the treatment given Well-being score was 68.4 ( 12.5 ) , 72.1 ( 12.4 ) , 72,3 ( 12.4 ) and 72.7 ( 12.5 ) in groups 1–4 , respectively ( P for trend < 0.05 ) . There were significant trends for the well-being components patience ( P < 0.005 ) , energy ( P < 0.05 ) , mood ( P < 0.05 ) and family situation ( P < 0.05 ) . The remaining two components and Complaint score showed a non-significant trend towards improvement . Conclusion : The effects on health-related quality of life were greater the larger the number of treatment modalities available . The ‘ stay active ’ treatment group , with the most restricted number of modalities , had the most modest health-related quality of life improvement , while group 4 with the most generous choice of treatment modalities , had the greatest improvement An open controlled pilot trial on nonspecific low-back pain sufferers demonstrated responsiveness to osteopathic manipulation of some patients presenting with pain duration s of 14 to 28 days . No response was demonstrated in those with shorter episodes at presentation . The advantage to manipulated patients was maximal between 1 and 2 weeks after commencing treatment , but was not discernable after 4 weeks . The demonstration of a similar responsive stratum by other investigators , with both teams totally unaware of each other 's work during data collection , suggests a high degree of reliability for this finding The authors carried out a single-blind , r and omized controlled clinical trial of rotational manipulation for low-back pain of recent onset in 81 adults . Control treatments were minimal massage and low-level electrostimulation . Initial status and outcome were measured on scales quantifying symptoms , activities of dally life , mobility , tenderness to palpation , aggravation of pain by coughing or sneezing , limitation of motion on testing , and forward flexion . Both treated and control patients improved rapidly in the 2 - 3-week observation period . On retest there was no statistically significant difference between the improvement scores of the treated or control groups on any of the scales One hundred and twelve patients with acute mechanical low back pain were r and omly divided into three treatment groups . All patients received ergonomic advice and then either a non-steroidal anti-inflammatory drug or conservative or manipulative types of physiotherapy . Serial assessment s of pain and spinal mobility showed similar response rates in all three treatment groups and no significant difference between therapies . The overall improvement ratings , time off work , and economic cost favoured the group treated with the nonsteroidal anti-inflammatory drug , but this group had a better range of spinal flexion at the onset so firm conclusions regarding the preferred management of these patients in general practice can not be drawn . Treatment failures occurred in all groups highlighting the need for a variety of therapeutic approaches in managing the patient with low back pain BACKGROUND The adult lifetime incidence for low back pain is 75 % to 85 % in the United States . Investigating appropriate care has proven difficult , since , in general , acute pain subsides spontaneously and chronic pain is resistant to intervention . Subacute back pain has been rarely studied . OBJECTIVE To compare the relative efficacy of chiropractic adjustments with muscle relaxants and placebo/sham for subacute low back pain . DESIGN A r and omized , double-blind clinical trial . METHODS Subjects ( N = 192 ) experiencing low back pain of 2 to 6 weeks ' duration were r and omly allocated to 3 groups with interventions applied over 2 weeks . Interventions were either chiropractic adjustments with placebo medicine , muscle relaxants with sham adjustments , or placebo medicine with sham adjustments . Visual Analog Scale for Pain , Oswestry Disability Question naire , and Modified Zung Depression Scale were assessed at baseline , 2 weeks , and 4 weeks . Schober 's flexibility test , acetaminophen usage , and Global Impression of Severity Scale ( GIS ) , a physician 's clinical impression used as a secondary outcome , were assessed at baseline and 2 weeks . RESULTS Baseline values , except GIS , were similar for all groups . When all subjects completing the protocol were combined ( N = 146 ) , the data revealed pain , disability , depression , and GIS decreased significantly ( P < .0001 ) ; lumbar flexibility did not change . Statistical differences across groups were seen for pain , a primary outcome , ( chiropractic group improved more than control group ) and GIS ( chiropractic group improved more than other groups ) . No significant differences were seen for disability , depression , flexibility , or acetaminophen usage across groups . CONCLUSION Chiropractic was more beneficial than placebo in reducing pain and more beneficial than either placebo or muscle relaxants in reducing GIS 101 out patients with acute or subacute low-back pain were r and omly allocated to one of two treatment groups . One group was given st and ardized conventional but optimal activating treatment by primary health care teams . The other group received manual treatment such as manipulation , specific mobilization , muscle stretching , auto-traction , and cortisone injections . The two groups were similar in most of the pretrial variables , including age , sex , previous low-back pain problems , sick-leave , previous treatment , findings at the physical examination , quality -of-life score , disability rating , and pain score . After one month in the study , the proportion of patients on sick-leave was six times larger in the conventionally treated group than in the group receiving the specific manual treatment . The difference diminished over time but was still significant after eight months . Two slightly different pain scores ( " pain at the moment " and " pain during the last weeks " ) , initially similar in the two groups , diminished in both groups but were significantly lower in the manual treatment group during the study . The group receiving specific manual treatment thus had a significantly better outcome than the group receiving conventional treatment as far as sick-leave and pain score are concerned OBJECTIVES The purpose of this paper is to describe the demographic and clinical characteristics of chiropractic patients and to document chiropractic visit rates in 6 sites in the United States and Canada . METHODS R and om sample s of chiropractors from 5 US sites and 1 Canadian site were selected . A record abstract ion system was developed to obtain demographic and clinical data from office charts . RESULTS Of the 185 eligible chiropractors sample d , 131 ( 71 % ) participated . Sixty-eight percent of the selected charts showed that care was sought for low back pain , while 32 % recorded care for other reasons . Spinal manipulative therapy was recorded in 83 % of all charts . There was a greater than 2-fold difference in the median number of visits related to low back pain per episode of care across sites . The chiropractic visit rates in the US sites and Ontario are estimated to be 101.2 and 140.9 visits per 100 person-years , respectively . CONCLUSIONS The chiropractic use rate in these sites is twice that of estimates made 15 years ago . The great majority of patients receive care for musculoskeletal conditions of the back and neck . The number of visits per episode varies appreciably by site BACKGROUND We aim ed to investigate whether the addition of non-steroidal anti-inflammatory drugs or spinal manipulative therapy , or both , would result in faster recovery for patients with acute low back pain receiving recommended first-line care . METHODS 240 patients with acute low back pain who had seen their general practitioner and had been given advice and paracetamol were r and omly allocated to one of four groups in our community-based study : diclofenac 50 mg twice daily and placebo manipulative therapy ( n=60 ) ; spinal manipulative therapy and placebo drug ( n=60 ) ; diclofenac 50 mg twice daily and spinal manipulative therapy ( n=60 ) ; or double placebo ( n=60 ) . The primary outcome was days to recovery from pain assessed by survival curves ( log-rank test ) in an intention-to-treat analysis . This trial was registered with the Australian Clinical Trials Registry , ACTRN012605000036617 . FINDINGS Neither diclofenac nor spinal manipulative therapy appreciably reduced the number of days until recovery compared with placebo drug or placebo manipulative therapy ( diclofenac hazard ratio 1.09 , 95 % CI 0.84 - 1.42 , p=0.516 ; spinal manipulative therapy hazard ratio 1.01 , 95 % CI 0.77 - 1.31 , p=0.955 ) . 237 patients ( 99 % ) either recovered or were censored 12 weeks after r and omisation . 22 patients had possible adverse reactions including gastrointestinal disturbances , dizziness , and heart palpitations . Half of these patients were in the active diclofenac group , the other half were taking placebo . One patient taking active diclofenac had a suspected hypersensitivity reaction and ceased treatment . INTERPRETATION Patients with acute low back pain receiving recommended first-line care do not recover more quickly with the addition of diclofenac or spinal manipulative therapy BACKGROUND AND PURPOSE The relative effectiveness of an extension program and a manipulation program with flexion and extension exercises was examined in patients with low back syndrome . SUBJECTS Forty-nine patients with less than a 3-month history of low back pain were seen at physical therapy clinics in western Pennsylvania , southern Mississippi , and eastern Missouri during a 6-month period . Twenty-seven of the 49 patients were classified a priori into a treatment-oriented category of extension/mobilization and were then r and omly assigned to participate in an extension program or a program of manipulation followed by h and -heel rocks ( flexion and extension ) . Two patients dropped out of the study ( 1 patient returned to work , and the other patient was unable to comply with the treatment schedule ) , and 1 patient was eliminated from the study because of magnified illness behavior . The remaining 24 patients ( 15 male , 9 female ; mean age = 44 years , SD = 15 , range = 14 - 73 ) were assigned r and omly and equally to the two groups . Eight physical therapists participated in the study . METHODS A r and omized clinical trial comparing the two regimens was conducted for a 1-week period . Outcome was assessed using an Oswestry Low Back Pain Question naire initially ( before treatment ) and at 3 and 5 days posttreatment , and data were analyzed using a 2 x 3 ( group x time ) analysis of variance . RESULTS A significant interaction of the group and time variables was demonstrated , indicating that the rate of positive response was greater in the manipulation/h and -heel rock group than in the extension group . CONCLUSION AND DISCUSSION In this category of patients with low back pain , the use of manipulation as an adjunct to an ongoing exercise program appears to be warranted Context In this r and omized , controlled trial , spinal manipulation plus exercise produced outcomes for low back pain similar to those produced by exercise alone . Yet , some patients did respond to spinal manipulation , and it would be helpful for doctors to be able to identify such patients . Contribution Patients were most likely to benefit from spinal manipulation if they met 4 of 5 of the following criteria : symptom duration less than 16 days , no symptoms distal to knee , score less than 19 on a fear-avoidance measure , at least 1 hypomobile lumbar segment , and at least 1 hip with more than 35 degrees of internal rotation . Implication s Clinicians may be able to use these criteria to identify patients with low back pain who are good c and i date s for spinal manipulation . The Editors Next to the common cold , low back pain is the most common reason that individuals visit a physician 's office ( 1 ) . Billions of dollars in medical expenditures and lost labor costs for this condition are incurred each year ( 2 , 3 ) . Attempts to identify effective interventions for individuals with low back pain have been largely unsuccessful ( 4 ) . In particular , conflicting evidence exists about the effectiveness of spinal manipulation ; some r and omized trials have shown a benefit , while other trials have not ( 5 - 7 ) . These conflicting conclusions are reflected in the various recommendations in national clinical practice guidelines , with some recommending manipulation and others not ( 8) . The variety of conclusions in trials of manipulation may be attributable to the failure of research ers to adequately consider the importance of classification . Using broad inclusion criteria results in a heterogeneous sample that may include many patients for whom no benefit is expected , thus masking the intervention 's true value ( 9 , 10 ) . Consequently , developing methods for matching patients with low back pain to treatments that are most likely to benefit them has become an important research priority ( 11 ) . Clinical prediction rules are tools design ed to assist clinicians in decision making when caring for patients ( 12 ) . Several clinical prediction rules have been developed and vali date d to improve clinical decision making for the use of imaging in patients with ankle , knee , cervical spine , or minor head injuries ( 13 - 16 ) . Few studies have attempted to develop rules that establish prognosis on the basis of outcome from a specific intervention , such as spinal manipulation . Recently , Flynn and colleagues ( 17 ) developed a clinical prediction rule for identifying patients with low back pain who are likely to benefit from manipulation . They examined a series of patients with low back pain who received a manipulation intervention . Five factors formed the most parsimonious set of predictors for identifying patients who achieved at least 50 % improvement in disability within 1 week with a maximum of 2 manipulation interventions ( Table 1 ) ( 17 ) . The positive likelihood ratio among patients who met at least 4 of 5 of the criteria was 24.4 ( 95 % CI , 4.6 to 139.4 ) . Table 1 . Five Criteria in the Spinal Manipulation Clinical Prediction Rule Clinical prediction rules must be vali date d in separate population s before being recommended for widespread implementation ( 18 ) . A clinical prediction rule for identifying which patients with low back pain are most likely to respond to manipulation could improve clinical efficiency and re source utilization . Thus , we aim ed to vali date the spinal manipulation clinical prediction rule in a multicenter trial . Methods We considered consecutive patients with a primary symptom of low back pain who were referred to physical therapy for participation . We used 14 physical therapists at 8 clinics in various U.S. regions and setting s ( 2 academic medical centers and smaller outpatient practice setting s ) . Most participating sites were health care facilities within the U.S. Air Force . Each site 's institutional review board approved the study before we began recruitment and data collection . Inclusion criteria were age 18 to 60 years ; a primary symptom of low back pain , with or without referral into the lower extremity ; and an Oswestry Disability Question naire ( ODQ ) score of at least 30 % . We excluded patients who had red flags for a serious spinal condition ( for example , tumor , compression fracture , or infection ) , those who had signs consistent with nerve root compression ( that is , positive straight-leg increase < 45 degrees or diminished reflexes , sensation , or lower-extremity strength ) , those who were pregnant , or those who had previous surgery to the lumbar spine or buttock . These criteria are consistent with those used in Flynn and colleagues ' study ( 17 ) and were design ed to include patients without a contraindication to manipulation . Once patients were admitted to the study , we used intention-to-treat principles , and no patient was removed for nonadherence . History and Physical Examination Before r and omization , patients completed several self-report measures and then received a st and ardized history and physical examination . We collected demographic information , including age and sex ; medical history ; and location and nature of symptoms . Self-report measures included a body diagram to assess the symptom distribution ( 19 ) . We used an 11-point pain-rating scale ranging from 0 ( no pain ) to 10 ( worst imaginable pain ) to assess current pain intensity and the best and worst level of pain during the last 24 hours ( 20 ) . We used the average of the 3 ratings . We used the Fear-Avoidance Beliefs Question naire ( FABQ ) to quantify the patient 's fear of pain and beliefs about avoiding activity ( 21 ) . Previous studies have found a high level of testretest reliability for both the FABQ physical activity and work subscales ( 22 ) . Fearavoidance beliefs have been associated with current and future disability and work loss in patients with acute ( 23 ) and chronic ( 24 ) low back pain . The modified ODQ is a region-specific disability scale for patients with low back pain ( 25 ) that has high levels of reliability , validity , and responsiveness ( 26 ) . Physical examination measures included lumbar active range of motion ( 27 ) and various tests purported to identify dysfunction in the lumbopelvic region ( 28 ) . Complete details of the physical examination are described elsewhere ( 26 ) . Specific components pertinent to validation of the rule were assessment s of segmental mobility and hip internal rotation range of motion , the performance of which is described in Appendix 1 and Appendix 3 video . Each physical therapist received a detailed manual that operationally defined each examination and treatment procedure and was trained in the study procedures by an investigator before data collection began . Supplement . Appendix 3 video : A Clinical Prediction Rule To Identify Patients with Low Back Pain Most Likely To Benefit from Spinal Manipulation Determining Status on the Clinical Prediction Rule A physical therapist who was blinded to the patients ' treatment group assignment assessed the 5 criteria in the rule ( Table 1 , Appendix 1 , and Appendix 3 video ) . To further minimize bias , examiners were not instructed in the rule 's criteria and were unaware of the patient 's status on the rule . After completion of the study , an examiner who was blinded to the patient 's treatment assignment determined the patient 's status on the rule by using the results of the baseline examination . As was done in the initial study ( 17 ) , we classified patients as positive if they met at least 4 of 5 criteria and were therefore likely to respond to manipulation . We classified patients with 3 or fewer criteria as negative . An examiner who was blinded to the patient 's status on the rule repeated the history and physical examination 1 and 4 weeks after r and omization . Patients also completed a 6-month follow-up postal question naire to assess disability , work status , and health care utilization . Treatment Groups We used a r and om-number generator to generate a r and omization list before the study began . We prepared individual , sequentially numbered index cards with the r and omization assignments . We folded the cards and placed them in sealed envelopes . After the baseline examination , the physical therapist who conducted the examination opened the next envelope , indicating the treatment group assignment . We r and omly assigned patients to 1 of 2 groups : 1 ) spinal manipulation plus an exercise program ( manipulation group ) or 2 ) an exervideocise program alone ( exercise group ) . Patients in both groups attended physical therapy twice during the first week and then once a week for the next 3 weeks , for a total of 5 sessions . We initiated treatment immediately after completion of the baseline examination , unless prohibited by time constraints ; in that case the first treatment session took place 24 to 48 hours after the baseline examination . All patients received an exercise instruction booklet that outlined the proper performance and frequency of each exercise and were instructed to perform their assigned exercise program once daily on the days that they did not attend therapy . On the basis of the benefits associated with remaining active ( 29 ) , patients in both groups were given advice to maintain usual activity within the limits of pain . Manipulation Group The treatment received by the manipulation group differed from that of the exercise group during the first 2 physical therapy sessions . During these 2 sessions , patients received high-velocity thrust spinal manipulation and a range-of-motion exercise only . First , the physical therapist performed the manipulation by using the same technique used by Flynn and colleagues ( 17 ) . Appendix 2 describes and Figure 1 and Appendix 3 video illustrate the procedures used to perform the manipulation technique . Figure 1 . Manipulative intervention used in developing and validating the spinal manipulation clinical prediction rule . Exercise Group We treated patients in the exercise group with a low-stress Study Design . R and omized controlled trial . Objective . To assess changes in pain levels and physical functioning in response to st and ard medical care ( SMC ) versus SMC plus chiropractic manipulative therapy ( CMT ) for the treatment of low back pain ( LBP ) among 18 to 35-year-old active-duty military personnel . Summary of Background Data . LBP is common , costly , and a significant cause of long-term sick leave and work loss . Many different interventions are available , but there exists no consensus on the best approach . One intervention often used is manipulative therapy . Current evidence from r and omized controlled trials demonstrates that manipulative therapy may be as effective as other conservative treatments of LBP , but its appropriate role in the healthcare delivery system has not been established . Methods . Prospect i ve , 2-arm r and omized controlled trial pilot study comparing SMC plus CMT with only SMC . The primary outcome measures were changes in back-related pain on the numerical rating scale and physical functioning at 4 weeks on the Rol and -Morris Disability Question naire and back pain functional scale ( BPFS ) . Results . Mean Rol and -Morris Disability Question naire scores decreased in both groups during the course of the study , but adjusted mean scores were significantly better in the SMC plus CMT group than in the SMC group at both week 2 ( P < 0.001 ) and week 4 ( P = 0.004 ) . Mean numerical rating scale pain scores were also significantly better in the group that received CMT . Adjusted mean back pain functional scale scores were significantly higher ( improved ) in the SMC plus CMT group than in the SMC group at both week 2 ( P < 0.001 ) and week 4 ( P = 0.004 ) . Conclusion . The results of this trial suggest that CMT in conjunction with SMC offers a significant advantage for decreasing pain and improving physical functioning when compared with only st and ard care , for men and women between 18 and 35 years of age with acute LBP The study evaluated the manual treatment of dysfunction of the pelvic joints . This is one of many condition causing low back pain . In 1987 - 1988 a general practitioner with special knowledge of physical examination and manual treatment of lumbar and pelvic dysfunctions made a survey of patients with acute or subacute low back pain as the main cause of the patient-to-doctor contact . Patients with defined criteria of pelvic joint dysfunction ( n = 46 ) were r and omized . After dropouts and exclusions , 18 patients with defined criteria of pelvic joint dysfunction received manual treatment , while 21 patients with similar dysfunction served as controls and received placebo treatment in a form of massage . Both groups were seen only once to evaluate whether a single treatment might be sufficient . After a period of three weeks , evaluation was made by an independent observer . Subjective pain measurement and a mobility test showed no significant difference . Sick-leave and consumption of analgesics ( both decided by patient ) were significantly less in the treatment group Abstract Objective Acute low back pain ( ALBP ) may limit mobility and impose functional limitations in active duty military personnel . Although some manual therapies have been reported effective for ALBP in military personnel , there have been no published r and omized controlled trials ( RCTs ) of osteopathic manipulative treatment ( OMT ) in the military . Furthermore , current military ALBP guidelines do not specifically include OMT . Methods This RCT examined the efficacy of OMT in relieving ALBP and improving functioning in military personnel at Fort Lewis , Washington . Sixty-three male and female soldiers ages 18 to 35 were r and omly assigned to a group receiving OMT plus usual care or a group receiving usual care only ( UCO ) . Results The primary outcome measures were pain on the quadruple visual analog scale , and functioning on the Rol and Morris Disability Question naire . Outcomes were measured immediately preceding each of four treatment sessions and at four weeks post-trial . Intention to treat analysis found significantly greater post-trial improvement in ‘ Pain Now ’ for OMT compared to UCO ( P = 0·026 ) . Furthermore , the OMT group reported less ‘ Pain Now ’ and ‘ Pain Typical ’ at all visits ( P = 0·025 and P = 0·020 respectively ) . Osteopathic manipulative treatment subjects also tended to achieve a clinical ly meaningful improvement from baseline on ‘ Pain at Best ’ sooner than the UCO subjects . With similar baseline expectations , OMT subjects reported significantly greater satisfaction with treatment and overall self-reported improvement ( P<0·01 ) . Conclusion This study supports the effectiveness of OMT in reducing ALBP pain in active duty military personnel BACKGROUND AND METHODS There are few data on the relative effectiveness and costs of treatments for low back pain . We r and omly assigned 321 adults with low back pain that persisted for seven days after a primary care visit to the McKenzie method of physical therapy , chiropractic manipulation , or a minimal intervention ( provision of an educational booklet ) . Patients with sciatica were excluded . Physical therapy or chiropractic manipulation was provided for one month ( the number of visits was determined by the practitioner but was limited to a maximum of nine ) ; patients were followed for a total of two years . The bothersomeness of symptoms was measured on an 11-point scale , and the level of dysfunction was measured on the 24-point Rol and Disability Scale . RESULTS After adjustment for base-line differences , the chiropractic group had less severe symptoms than the booklet group at four weeks ( P=0.02 ) , and there was a trend toward less severe symptoms in the physical therapy group ( P=0.06 ) . However , these differences were small and not significant after transformations of the data to adjust for their non-normal distribution . Differences in the extent of dysfunction among the groups were small and approached significance only at one year , with greater dysfunction in the booklet group than in the other two groups ( P=0.05 ) . For all outcomes , there were no significant differences between the physical-therapy and chiropractic groups and no significant differences among the groups in the numbers of days of reduced activity or missed work or in recurrences of back pain . About 75 percent of the subjects in the therapy groups rated their care as very good or excellent , as compared with about 30 percent of the subjects in the booklet group ( P<0.001 ) . Over a two-year period , the mean costs of care were $ 437 for the physical-therapy group , $ 429 for the chiropractic group , and $ 153 for the booklet group . CONCLUSIONS For patients with low back pain , the McKenzie method of physical therapy and chiropractic manipulation had similar effects and costs , and patients receiving these treatments had only marginally better outcomes than those receiving the minimal intervention of an educational booklet . Whether the limited benefits of these treatments are worth the additional costs is open to question Study Design . Blinded parallel-group r and omized controlled trial . Objective . Establish the frequency and severity of adverse effects from short-term usual chiropractic treatment of the spine when compared with a sham treatment group . Summary of Background Data . Previous studies have demonstrated that adverse events occur during chiropractic treatment . However , as a result of design limitations in previous studies , particularly the lack of sham-controlled r and omized trials , underst and ing of these adverse events and their relation with chiropractic treatment is suboptimal . Methods . We conducted a trial to examine the occurrence of adverse events result ing from chiropractic treatment . It was conducted across 12 chiropractic clinics in Perth , Western Australia . The participants comprised 183 adults , aged 20 to 85 years , with spinal pain . Ninety-two participants received individualized care consistent with the chiropractors ’ usual treatment approach ; 91 participants received a sham intervention . Each participant received 2 treatments . Results . Completed adverse question naires were returned by 94.5 % of the participants after appointment 1 and 91.3 % after appointment 2 . Thirty-three percent of the sham group and 42 % of the usual care group reported at least 1 adverse event . Common adverse events were increased pain ( sham 29 % ; usual care 36 % ) , muscle stiffness ( sham 29 % ; usual care 37 % ) , and headache ( sham 17 % ; usual care 9 % ) . The relative risk ( RR ) was not significant for adverse event occurrence ( RR = 1.24 ; 95 % CI : 0.85–1.81 ) , occurrence of severe adverse events ( RR = 1.9 ; 95 % CI : 0.98–3.99 ) , adverse event onset ( RR = 0.16 ; 95 % CI : 0.02–1.34 ) , or adverse event duration ( RR = 1.13 ; 95 % CI : 0.59–2.18 ) . No serious adverse events were reported . Conclusion . A substantial proportion of adverse events after chiropractic treatment may result from natural history variation and nonspecific effects . Level of Evidence :

No significant differences of coronary events were found .

Background : Patients undergoing percutaneous coronary intervention ( PCI ) who require anticoagulant therapy are at increased risk of bleeding . The optimal regimen for these patients is uncertain . This study aim ed to compare safety and efficacy of antithrombotic regimens used in patients undergoing PCI with concomitant anticoagulant therapy .

The PIONEER AF-PCI trial ( Open-Label , R and omized , Controlled , Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with AF who Undergo Percutaneous Coronary Intervention ) is an ambitious , open-label comparison of 3 regimens , almost exclusively in Caucasians , all of whom had coexisting atrial fibrillation and atherosclerotic coronary artery disease requiring stenting ( PCI-S ) . These 2 conditions when they coexist pose a clinical challenge , necessitating concurrent usage of dual antiplatelet and anticoagulation therapy , a cocktail which presents major bleeding risks . Because anticoagulation therapy is suboptimal in preventing stent thrombosis and dual anti platelet therapy is inadequate in averting embolic stroke in atrial fibrillation , neither treatment is sufficient and they must be combined . The study has a unique design and consists of 2 treatment arms and a control ( see Figure 1 for trial design ) , each with about 700 patients and a 20 % dropout rate in groups 1 and 2 but a statistically greater rate of 29 % in group 3 . Both treatment arms are modeled upon previous studies , which involved patients with the need for both antiplatelet therapy and anticoagulation ( see Figure 2 for derivation of trial from WOEST and ATLAS-TIMI 51 ) . The control arm , design ated group 3 in the trial , consists of the US st and ard of practice regimen , in this situation , called “ triple therapy , ” consisting of aspirin 100 mg/d , clopidogrel 75 mg/d , and warfarin maintaining the INR between 2 and 3 . About 7 % of patients in groups 1 and 2 received a different P2Y12 inhibitor , either prasugrel or ticagrelor , and about 4 % in group 3 . Prominent among the numerous exclusions were patients with a previous stroke and a creatinine clearance of under 30 mL/min . In arm 1 , patients with a creatinine clearance between 30 and 60 mL/min received a lower dose of 10 mg of rivaroxaban . The first treatment arm , called arm 1 , is a reprisal of the treatment arm of the Belgian 2013 WOEST trial which showed that clopidogrel 75 mg and warfarin , maintaining an INR of 2 to 3 , were associated with less combined TIMI major and minor bleeding as well as no increase in cardiac or neurological thrombotic complications when compared to the same control arm as is in this study . Despite having studied only 573 patients for just a year , WOEST was influential in generating the recommendation ( level B ) from the European Society of Cardiology to use this regimen in some people at high risk for bleeding with stents who also require anticoagulation . Furthermore in PIONEER , arm 1 , rivaroxaban 15 mg has been substituted for warfarin ; otherwise , the other trial drugs are identical to those in WOEST . A compelling question posed by this arm of the study , although not the primary end point of the study , is whether equivalent stent patency or prevention of atherosclerotic or thromboembolic complications can be achieved with only a single antiplatelet drug throughout the entire 12 months of treatment , including the vital first month poststent . Also addressed is whether the WOEST results can be replicated substituting rivaroxaban , a drug that offers several advantages over warfarin . In treatment group 1 , one would intuitively expect confirmation of the bleeding advantage observed in WOEST , since it contains 2 drugs versus the 3 in the control group , and therefore would be expected to be associated with less bleeding in group 1 versus group 3 . The second treatment group is based on the 2012 ATLAS ACS 2-TIMI 51 trial and consists of very-low-dose rivaroxaban 2.5 mg twice a day along with clopidogrel 75 mg/d and aspirin 100 mg/d . An interesting point of arm 2 versus 3 , although again not the primary end point , is if a dosage of rivaroxaban , which is only 25 % of the FDA -approved dose of that needed to treat atrial fibrillation , would be adequate in preventing embolic strokes . One would anticipate in group 2 that the dual antiplatelet therapy would be equally effective in preventing stent occlusion and recurrent coronary events as the BACKGROUND Patients receiving oral anticoagulation ( OAC ) who undergo drug-eluting stent ( DES ) implantation require additional dual antiplatelet therapy with aspirin and clopidogrel . Such triple therapy confers an elevated bleeding risk , and its optimal duration is not known . OBJECTIVES The goal of this study was to evaluate whether shortening the duration of clopidogrel therapy from 6 months to 6 weeks after DES implantation was associated with a superior net clinical outcome in patients receiving concomitant aspirin and OAC . METHODS In this r and omized , open-label trial , we enrolled patients receiving OAC who underwent DES implantation at 3 European centers between September 2008 and December 2013 . A total of 614 patients receiving concomitant aspirin and OAC were r and omized to either 6-week clopidogrel therapy ( n=307 ) or 6-month clopidogrel therapy ( n=307 ) . The primary endpoint was a composite of death , myocardial infa rct ion ( MI ) , definite stent thrombosis , stroke , or Thrombolysis In Myocardial Infa rct ion ( TIMI ) major bleeding at 9 months . RESULTS The primary endpoint occurred in 30 patients ( 9.8 % ) in the 6-week group compared with 27 patients ( 8.8 % ) in the 6-month group ( hazard ratio [ HR ] : 1.14 ; 95 % CI : 0.68 to 1.91 ; p=0.63 ) . There were no significant differences for the secondary combined ischemic endpoint of cardiac death , MI , definite stent thrombosis , and ischemic stroke ( 12 [ 4.0 % ] vs. 13 [ 4.3 % ] ; HR : 0.93 ; 95 % CI : 0.43 to 2.05 ; p=0.87 ) or the secondary bleeding endpoint of TIMI major bleeding ( 16 [ 5.3 % ] vs. 12 [ 4.0 % ] ; HR : 1.35 ; 95 % CI : 0.64 to 2.84 ; p=0.44 ) . CONCLUSIONS Six weeks of triple therapy was not superior to 6 months with respect to net clinical outcomes . These results suggest that physicians should weigh the trade-off between ischemic and bleeding risk when choosing the shorter or longer duration of triple therapy . ( Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation [ ISAR-TRIPLE ] ; NCT00776633 ) Background Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the st and ard of care after percutaneous coronary intervention ( PCI ) for patients with atrial fibrillation , but this therapy is associated with a high risk of bleeding . Methods In this multicenter trial , we r and omly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor ( clopidogrel or ticagrelor ) and aspirin ( for 1 to 3 months ) ( triple‐therapy group ) or dual therapy with dabigatran ( 110 mg or 150 mg twice daily ) plus a P2Y12 inhibitor ( clopidogrel or ticagrelor ) and no aspirin ( 110‐mg and 150‐mg dual‐therapy groups ) . Outside the United States , elderly patients ( ≥80 years of age ; ≥70 years of age in Japan ) were r and omly assigned to the 110‐mg dual‐therapy group or the triple‐therapy group . The primary end point was a major or clinical ly relevant nonmajor bleeding event during follow‐up ( mean follow‐up , 14 months ) . The trial also tested for the noninferiority of dual therapy with dabigatran ( both doses combined ) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events ( myocardial infa rct ion , stroke , or systemic embolism ) , death , or unplanned revascularization . Results The incidence of the primary end point was 15.4 % in the 110‐mg dual‐therapy group as compared with 26.9 % in the triple‐therapy group ( hazard ratio , 0.52 ; 95 % confidence interval [ CI ] , 0.42 to 0.63 ; P<0.001 for noninferiority ; P<0.001 for superiority ) and 20.2 % in the 150‐mg dual‐therapy group as compared with 25.7 % in the corresponding triple‐therapy group , which did not include elderly patients outside the United States ( hazard ratio , 0.72 ; 95 % CI , 0.58 to 0.88 ; P<0.001 for noninferiority ) . The incidence of the composite efficacy end point was 13.7 % in the two dual‐therapy groups combined as compared with 13.4 % in the triple‐therapy group ( hazard ratio , 1.04 ; 95 % CI , 0.84 to 1.29 ; P=0.005 for noninferiority ) . The rate of serious adverse events did not differ significantly among the groups . Conclusions Among patients with atrial fibrillation who had undergone PCI , the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin , a P2Y12 inhibitor , and aspirin . Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events . ( Funded by Boehringer Ingelheim ; RE‐DUAL PCI Clinical Trials.gov number , NCT02164864 . OBJECTIVES Optimal antithrombotic/anticoagulation therapy in patients on chronic oral anticoagulation ( OAC ) undergoing drug-eluting stent ( DES ) implantation is unknown . We investigated the efficacy and safety of two regimens of antithrombotic/anticoagulation therapy in patients who present for DES implantation whilst on OAC . METHODS We included a series of 515 patients on OAC who underwent DES implantation between 2002 and 2007 . Based on predefined clinical and echocardiographic criteria , 306 patients continued OAC ( triple therapy ) and 209 patients discontinued OAC ( dual therapy ) for the time they received antiplatelet therapy with clopidogrel and aspirin [ stent-related antithrombotic treatment ( SRAT ) ] . The primary end point was a composite of death , myocardial infa rct ion , stent thrombosis or stroke . RESULTS During SRAT the primary endpoint was observed in 13 patients in the group with triple therapy versus 15 patients in the group with dual therapy [ Kaplan-Meier estimates 4.2 % and 7.2 % , odds ratio ( OR ) = 0.61 , 95 % confidence interval ( CI ) 0.29 - 1.28 ; P = 0.19 ] . At 2 years of follow-up , the primary endpoint was observed in 35 patients in the group with triple therapy versus 36 patients in the group with dual therapy ( Kaplan-Meier estimates 14.1 % and 18.0 % , OR = 0.76 , 95 % CI : 0.48 - 1.21 ; P = 0.25 ) . Two-year incidence of major bleeding was 1.4 % ( n = 4 , triple therapy ) versus 3.1 % ( n = 6 , dual therapy ) ( P = 0.34 ) . CONCLUSIONS In patients on chronic OAC undergoing DES implantation , clinical and echocardiographic criteria help to define postprocedural antithrombotic/anticoagulation therapy . Based on these criteria , both a double antiplatelet therapy ( clopidogrel plus aspirin ) and a triple therapy ( OAC plus clopidogrel plus aspirin ) are associated with favourable safety and efficacy Most evidence regarding the efficacy and safety of the antithrombotic regimens for patients with atrial fibrillation ( AF ) undergoing percutaneous coronary intervention with stent ( PCI‐S ) derives from small , single‐center , retrospective data sets . To obtain further data on this issue , we carried out the prospect i ve , multicenter , observational Management of patients with Atrial Fibrillation undergoing Coronary Artery Stenting ( AFCAS ) registry ( Clinical trials.gov identifier NCT00596570 ) BACKGROUND If percutaneous coronary intervention ( PCI ) is required in patients taking oral anticoagulants , antiplatelet therapy with aspirin and clopidogrel is indicated , but such triple therapy increases the risk of serious bleeding . We investigated the safety and efficacy of clopidogrel alone compared with clopidogrel plus aspirin . METHODS We did an open-label , multicentre , r and omised , controlled trial in 15 centres in Belgium and the Netherl and s. From November , 2008 , to November , 2011 , adults receiving oral anticoagulants and undergoing PCI were assigned clopidogrel alone ( double therapy ) or clopidogrel plus aspirin ( triple therapy ) . The primary outcome was any bleeding episode within 1 year of PCI , assessed by intention to treat . This study is registered with Clinical Trials.gov , number NCT00769938 . FINDINGS 573 patients were enrolled and 1-year data were available for 279 ( 98·2 % ) patients assigned double therapy and 284 ( 98·3 % ) assigned triple therapy . Mean ages were 70·3 ( SD 7·0 ) years and 69·5 ( 8·0 ) years , respectively . Bleeding episodes were seen in 54 ( 19·4 % ) patients receiving double therapy and in 126 ( 44·4 % ) receiving triple therapy ( hazard ratio [ HR ] 0·36 , 95 % CI 0·26 - 0·50 , p<0·0001 ) . In the double-therapy group , six ( 2·2 % ) patients had multiple bleeding events , compared with 34 ( 12·0 % ) in the triple-therapy group . 11 ( 3·9 % ) patients receiving double therapy required at least one blood transfusion , compared with 27 ( 9·5 % ) patients in the triple-therapy group ( odds ratio from Kaplan-Meier curve 0·39 , 95 % CI 0·17 - 0·84 , p=0·011 ) . INTERPRETATION Use of clopiogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events . FUNDING Antonius Ziekenhuis Foundation , Strect Foundation We evaluated the safety and efficacy of dual antiplatelet therapy , in association with oral anticoagulant ( OAC ) therapy , in patients undergoing percutaneous coronary intervention ( PCI ) . The use of this triple therapy increases the rate of adverse outcomes , as shown by retrospective studies . In this first prospect i ve multicenter registry STENTIng and oral antiCOagulation ( STENTICO ) , all patients with OAC therapy undergoing PCI were included and followed up at 2 and 12 months . A total of 359 patients were included from 40 French centers . In 234 ( 65.2 % ; group 1 ) of these 359 patients , OAC therapy was discontinued ( 22 + /- 31 days ) . In 125 patients ( 34.8 % ; group 2 ) , triple therapy was continued . The baseline characteristics were similar in the 2 groups . In group 2 , a radial approach was more often used ( 65.6 % vs 43.8 % , p = 0.003 ) , fewer drug-eluting stents were implanted ( 33.3 % vs 24.8 % , p = 0.06 ) , and fewer anti-glycoprotein IIb/IIIa antagonists were prescribed ( 5.6 % vs 8.5 % , p = 0.02 ) . The stroke rate did not differ significantly , at 3.0 % ( 95 % confidence interval 0.8 % to 5.2 % ) for group 1 versus 0.8 % ( 95 % confidence interval -0.8 % to 2.4 % ) in group 2 . Severe and moderate bleeding , according to the Global Use of Strategies to Open Coronary Arteries ( GUSTO ) criteria , occurred in 2.1 % and 6.4 % of groups 1 and 2 , respectively ( p = 0.04 ) . A significant difference in bleeding risk was found between the femoral and radial approaches ( 10.3 % vs 3.8 % , respectively ; p = 0.01 ) . In conclusion , adding dual antiplatelet therapy to pre-existing OAC therapy increases the post-PCI bleeding risk . Temporary discontinuation decreased this bleeding risk but tended to increase the risk of stroke . A radial approach for PCI could be a good alternative to the conventional femoral route to avoid bleeding Introduction Atrial fibrillation ( AF ) has nowadays become a common disease as it comes along with medical procedures propagation in the ageing population with coexistent diseases . Hence a need for use of combined anticoagulant and antithrombotic therapy has arisen . According to the 2010 ESC guidelines on myocardial revascularization , short-term triple antithrombotic therapy after percutaneous coronary intervention ( PCI ) should be given if compelling indications exist . Aim To assess bleeding and thromboembolic events depending on the antithrombotic regimen in short- and long-term follow-up in patients with AF after PCI with stent implantation . Material and methods A 12-month prospect i ve , non-r and omized registry was conducted in the 3rd Department of Cardiology in the Upper Silesian Medical Center in Katowice from October 2008 to April 2011 . One hundred and four patients in two groups – on triple therapy ( TT ; aspirin + clopidogrel + vitamin K antagonists ( VKA ; warfarin or acenocoumarol ) n = 44 ) and on dual therapy ( DT ; aspirin + clopidogrel ; n = 60 ) – were assessed 30 days and 12 months after angioplasty . Results All bleeding events occurred more often in the triple anticoagulated group in 30 days ( TT 20.5 % vs. DT 6.7 % ; p = 0.03 ) and after 12 months ( TT 38.9 % vs. DT 17.2 % , p = 0.09 ) . The difference in major bleeding events was not significant after 30 days ( TT 9.1 % vs. DT 3.3 % ; p = NS ) or 12 months ( TT 11.1 % vs. DT 6.9 % ; p = NS ) . Thromboembolic events after 30 days ( DT 5.0 % vs. TT 2.3 % ) and 12 months ( TT 11.1 % vs. DT 3.4 % ) were comparable . The percentage of deaths after 30 days ( DT 1.7 % vs. TT 0.0 % , p = NS ) increased after 12 months ( DT 13.8 % vs. TT 0.0 % , p = 0.09 ) . Conclusions Significantly higher risk of bleeding on TT becomes blurred by a tendency to increased mortality in patients on DT Background Chronic atrial fibrillation ( AF ) , coexisting with a history of recent coronary angioplasty with stent ( PCI-S ) , represents an encoded indication for oral anticoagulation ( OAC ) with warfarin plus dual antiplatelet therapy ( DAPT ) . Methods Using a retrospective cohort study , we determined the respective impacts on cardiovascular outcomes of three different pharmacologic regimens , i.e. , triple therapy ( TT ) with warfarin + clopidogrel and aspirin , dual therapy ( DT ) with warfarin + clopidogrel or aspirin , and DAPT with clopidogrel + aspirin . Outcomes of interest were all-cause mortality , ischemic cardiac events , ischemic cerebral events , and bleeding events . The inclusion criterion was the coexistence of an indication for OAC ( e.g. , chronic AF ) with an indication for DAPT due to recent PCI-S. Results Among the 98 patients enrolled , 48 ( 49 % ) , 31 ( 31.6 % ) , and 19 ( 19.4 % ) patients were prescribed TT , DT , and DAPT , respectively . Throughout a mean follow-up of 378 ± 15.7 days , there were no significant differences between the three regimens for all abovementioned outcomes . In particular , the total frequency of major bleeding was similar in the three groups : five cases ( 10.4 % ) in TT , one case ( 3.22 % ) in DT and no case in DAPT groups ( Chi-square test , P = 0.1987 ) . Conclusions TT , DT and DAPT displayed similar efficacy and safety . Although the superiority of OAC vs. DAPT for stroke prevention in AF patients has been demonstrated by previous r and omized trials , a smaller frequency of high thromboembolic risks ’ features in DAPT group of the present study may have prevented the observation of a higher incidence of ischemic stroke in this group BACKGROUND Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention . METHODS To compare prasugrel , a new thienopyridine , with clopidogrel , we r and omly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel ( a 60-mg loading dose and a 10-mg daily maintenance dose ) or clopidogrel ( a 300-mg loading dose and a 75-mg daily maintenance dose ) , for 6 to 15 months . The primary efficacy end point was death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . The key safety end point was major bleeding . RESULTS The primary efficacy end point occurred in 12.1 % of patients receiving clopidogrel and 9.9 % of patients receiving prasugrel ( hazard ratio for prasugrel vs. clopidogrel , 0.81 ; 95 % confidence interval [ CI ] , 0.73 to 0.90 ; P<0.001 ) . We also found significant reductions in the prasugrel group in the rates of myocardial infa rct ion ( 9.7 % for clopidogrel vs. 7.4 % for prasugrel ; P<0.001 ) , urgent target-vessel revascularization ( 3.7 % vs. 2.5 % ; P<0.001 ) , and stent thrombosis ( 2.4 % vs. 1.1 % ; P<0.001 ) . Major bleeding was observed in 2.4 % of patients receiving prasugrel and in 1.8 % of patients receiving clopidogrel ( hazard ratio , 1.32 ; 95 % CI , 1.03 to 1.68 ; P=0.03 ) . Also greater in the prasugrel group was the rate of life-threatening bleeding ( 1.4 % vs. 0.9 % ; P=0.01 ) , including nonfatal bleeding ( 1.1 % vs. 0.9 % ; hazard ratio , 1.25 ; P=0.23 ) and fatal bleeding ( 0.4 % vs. 0.1 % ; P=0.002 ) . CONCLUSIONS In patients with acute coronary syndromes with scheduled percutaneous coronary intervention , prasugrel therapy was associated with significantly reduced rates of ischemic events , including stent thrombosis , but with an increased risk of major bleeding , including fatal bleeding . Overall mortality did not differ significantly between treatment groups . ( Clinical Trials.gov number , NCT00097591 [ Clinical Trials.gov ] . Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies BACKGROUND The effects of dual antiplatelet therapy ( DAPT ) and triple therapy ( TT : DAPT plus oral anticoagulation ) in patients with atrial fibrillation ( AF ) undergoing percutaneous coronary intervention ( PCI ) regarding to CHA2DS2-VASc score remain undefined . We compare the effect of TT vs. DAPT in this setting regarding the CHA2DS2-VASc score . METHODS AND RESULTS In a prospect i ve multicenter registry , 585 patients ( 75.2 % male , 73.2 ± 8.2 years ) with AF undergoing PCI were followed up during 1 year . Of them , 157 ( 26.8 % ) had a CHA2DS2-VASc=1 , and 428 ( 73.2 % ) had a CHA2DS2-VASc ≥2 . TT was prescribed in 51.6 % with CHA2DS2-VASc=1 and in 55.5 % with CHA2DS2-VASc ≥ 2 . Patients with CHA2DS2-VASc=1 receiving TT had a similar thromboembolism rate to those on DAPT ( 1.2 % vs. 1.3 % , P=0.73 ) , but more total ( 19.5 % vs. 6.9 % , P=0.01 ) and a tendency to more major ( 4.9 % vs. 0 % , P=0.06 ) bleeding . However , patients with CHA2DS2-VASc ≥ 2 receiving TT had a lower thromboembolism rate ( 1.7 % vs. 5.3 % , P=0.03 ) and a trend towards more bleeds ( 21.8 % vs. 15.6 % , P=0.06 ) , with an excess of major bleeding ( 8.4 % vs. 3.1 % , P=0.01 ) . Rates of major adverse cardiac events ( MACE ) in both CHA2DS2-VASc subgroups were similar , irrespective of treatment . In a Cox multivariate analysis , TT was associated to major bleeding , but not with MACE . CONCLUSIONS In patients with AF and CHA2DS2-VASc=1 undergoing PCI , the use of TT involves a high risk of bleeding without a significant benefit in preventing thromboembolism BACKGROUND Delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity secondary to systemic disturbances . OBJECTIVE The authors investigated the effects of postoperative sedation on the development of delirium in patients undergoing cardiac-valve procedures . METHODS Patients underwent elective cardiac surgery with a st and ardized intraoperative anesthesia protocol , followed by r and om assignment to one of three postoperative sedation protocol s : dexmedetomidine , propofol , or midazolam . RESULTS The incidence of delirium for patients receiving dexmedetomidine was 3 % , for those receiving propofol was 50 % , and for patients receiving midazolam , 50 % . Patients who developed postoperative delirium experienced significantly longer intensive-care stays and longer total hospitalization . CONCLUSION The findings of this open-label , r and omized clinical investigation suggest that postoperative sedation with dexmedetomidine was associated with significantly lower rates of postoperative delirium and lower care costs OBJECTIVES The purpose of this study was to determine the predictors of major bleeding and the impact of major bleeding on outcomes , including mortality , in acute coronary syndromes ( ACS ) . BACKGROUND Whether major bleeding independently predicts mortality in patients with ACS undergoing an early invasive strategy is undefined . METHODS Patients ( n = 13,819 ) with moderate- and high-risk ACS were r and omized to heparin ( unfractionated or enoxaparin ) plus glycoprotein IIb/IIIa inhibition ( GPI ) , bivalirudin plus GPI , or bivalirudin monotherapy ( plus provisional GPI ) . Logistic regression was used to determine predictors of 30-day major bleeding and mortality . RESULTS Major bleeding rates in patients treated with heparin plus GPI were higher versus bivalirudin monotherapy ( 5.7 % vs. 3.0 % , p < 0.001 ) and similar versus bivalirudin plus GPI ( 5.7 % vs. 5.3 % , p = 0.38 ) . Independent predictors of major bleeding were advanced age , female gender , diabetes , hypertension , renal insufficiency , anemia , no prior percutaneous coronary intervention , cardiac biomarker elevation , ST-segment deviation > /=1 mm , and treatment with heparin plus GPI versus bivalirudin monotherapy . Patients with major bleeding had higher 30-day rates of mortality ( 7.3 % vs. 1.2 % , p < 0.0001 ) , composite ischemia ( 23.1 % vs. 6.8 % , p < 0.0001 ) , and stent thrombosis ( 3.4 % vs. 0.6 % , p < 0.0001 ) versus those without major bleeding . Major bleeding was an independent predictor of 30-day mortality ( odds ratio 7.55 , 95 % confidence interval 4.68 to 12.18 , p < 0.0001 ) . CONCLUSIONS Major bleeding is a powerful independent predictor of 30-day mortality in patients with ACS managed invasively . Several factors independently predict major bleeding , including treatment with heparin plus GPI compared with bivalirudin monotherapy . Knowledge of these findings might be useful to reduce bleeding risk and improve outcomes in ACS BACKGROUND Long-term oral anticoagulant treatment is obligatory in patients with atrial fibrillation ( AF , score of CHA₂DS₂VASc≥2 ) . When these patients undergo percutaneous coronary intervention with a drug-eluting stent ( PCI-eS ) , there is also an indication for aspirin and clopidogrel treatment , according to the ESC Guidelines . However , triple therapy has been known to increase the risk of bleeding complications . Unfortunately , there is little prospect i ve data available to resolve this issue . Therefore , it is imperative that an optimal therapy for AF patients with indications of both anticoagulation and antiplatelet intervention to prevent thrombotic complications without increasing the risk of bleeding is found . OBJECTIVES This prospect i ve , r and omized , multicenter study is going to assess the hypothesis that in persistent or permanent AF patients ( score of CHA₂DS₂VASc≥2 ) after PCI-eS , the combination therapy of oral anticoagulation ( warfarin ) and ticagrelor ( 90 mg/bid ) could reduce the risk of bleeding events . DESIGN A multicenter , active-controlled , open-label , r and omized trial is to be performed to evaluate dual antithrombotic therapy ( ticagrelor+warfarin ) in persistent or permanent AF patients ( score of CHA₂DS₂VASc≥2 ) after PCI-eS versus the combination of triple antithrombosis ( clopidogrel+aspirin+warfarin ) . The primary endpoint is the overall bleeding up to 6 months , according to TIMI criteria and classifications . The secondary endpoints are the major bleeding events up to 6 months , according to TIMI criteria . The sample size is estimated at 296 . CONCLUSION This study is intended to provide information about the safety characteristics of warfarin and ticagrelor in persistent or permanent AF patients after PCI-eS. No prospect i ve r and omized study has been conducted on the issue of antithrombotic therapy using warfarin and ticagrelor in these patients . Therefore , the MANJUSRI trial will help to explore and determine a new potential therapeutic regimen for AF patients after PCI-eS. TRIAL REGISTRATION Clinical Trials.gov # NCT02206815 , registered July 30 , 2014 Objectives : To identify the therapeutic regimens used at discharge in patients receiving oral anticoagulant therapy ( OAT ) who undergo stenting percutaneous coronary intervention and stent implantation ( PCI-S ) , and to assess the safety and efficacy associated with different therapeutic regimens according to thromboembolic risk . Design : A prospect i ve multicentre registry . Setting : In hospital , after discharge and follow-up by telephone call . Patients and methods : 405 patients ( 328 male/77 female ; mean ( SD ) age 71 ( 9 ) years ) receiving OAT who underwent PCI-S between November 2003 and June 2006 from nine catheterisation laboratories of tertiary care teaching hospitals in Spain and one in the United Kingdom were included . Results : Three therapeutic regimens were identified at discharge : triple therapy (TT)—that is , any anticoagulant ( AC ) plus double antiplatelet therapy ( DAT ; 278 patients ( 68.6 % ) ; AC and a single antiplatelet ( AC+AT ; 46 ( 11.4 % ) ) and DAT only ( 81 ( 20 % ) ) . At 6 months , patients receiving TT showed the greatest rate of bleeding events . No patients receiving DAT at low thromboembolic risk presented a bleeding event ( 14.8 % receiving TT , 11.8 % receiving AC+AT and 0 % receiving DAT , p = 0.033 ) or cardiovascular event ( 6.7 % receiving TT , 0 % receiving AC+AT and 0 % receiving DAT , p = 0.126 ) . The combination of AC+AT showed the worst rate of adverse events in the whole cohort , especially in patients at moderate – high thromboembolic risk . Conclusions : In patients receiving OAT , TT was the most commonly used regimen after PCI-S. DAT was associated with the lowest rate of bleeding events and a similar efficacy to TT in patients at low thromboembolic risk . TT should probably be restricted to patients at moderate – high thromboembolic risk BACKGROUND The optimal antithrombotic strategy for patients with atrial fibrillation ( AF ) undergoing drug-eluting stent ( DES ) implantation is unknown . METHODS AND RESULTS The 622 consecutive AF patients undergoing DES implantation were prospect ively enrolled . Among them , 142 patients ( TT group ) continued triple antithrombotic therapy comprising aspirin , clopidogrel and warfarin after discharge ; 355 patients ( DT group ) had dual antiplatelet therapy ; 125 patients ( WS group ) were discharged with warfarin and a single antiplatelet agent . Target INR was set as 1.8 - 2.5 and was regularly monitored after discharge . The TT group had a significant reduction in stroke and major adverse cardiac and cerebral events ( MACCE ) ( 8.8 % vs 20.1 % vs 14.9 % , P=0.010 ) as compared with either the DT or WS group . In the Cox regression analysis , administration with warfarin ( hazard ratio ( HR ) 0.49 ; 95 % confidence interval ( CI ) 0.31 - 0.77 ; P=0.002 ) and baseline CHADS(2 ) score > or=2 ( HR 2.09 ; 95%CI 1.27 - 3.45 ; P=0.004 ) were independent predictors of MACCE . Importantly , the incidence of major bleeding was comparable among 3 groups ( 2.9 % vs 1.8 % vs 2.5 % , P=0.725 ) , although the overall bleeding rate was increased in the TT group . Kaplan-Meier analysis indicated that the TT group was associated with the best net clinical outcome . CONCLUSIONS The cardiovascular benefits of triple antithrombotic therapy were confirmed by reducing the MACCE rate , and its major bleeding risk might be acceptable if the INR is closely monitored Current recommendations for the antithrombotic management of patients receiving oral anticoagulation ( OAC ) who undergo percutaneous coronary intervention with stent implantation ( PCI-S ) are based on limited and relatively weak data . To broaden and strengthen available evidence , the management and 1-year outcomes of OAC patients who underwent PCI-S and were included in a prospect i ve , multicenter registry from 2003 to 2007 were evaluated . Among the 632 patients receiving OAC , mostly because of atrial fibrillation ( 58 % ) , who underwent PCI-S , mostly because of acute coronary syndromes ( 63 % ) , dual-antiplatelet therapy with aspirin and clopidogrel was the most frequently prescribed at discharge ( 48 % ) , followed by triple therapy with OAC , aspirin , and clopidogrel ( 32 % ) and OAC plus aspirin ( 18 % ) . The choice of antithrombotic therapy largely matched the thromboembolic risk profiles of patients , with the prescription of regimens including OAC predicted by the presence of non-low-risk features . The cumulative 1-year occurrence of major adverse cardiovascular events was as high as 27 % and was not significantly different among the 3 treatment groups . Stroke and stent thrombosis were limited to 2 % and 3 % , respectively , and although no significant differences were found among the 3 groups , stroke was 4 times less frequent when OAC , with either 1 or 2 antiplatelet agents , was administered . Major bleeding was also limited to 3 % , with no significant differences among the 3 groups . In conclusion , these findings suggest overall real-world management of OAC patients who undergo PCI-S that is in accordance with their clinical risk profiles and give further support to the reported efficacy and safety of triple therapy for the optimal treatment of these patients Bleeding is a complication of current therapies for acute coronary syndrome ( ACS ) . No studies have examined the effect of bleeding events on clinical outcomes . We analyzed pooled data from 4 multicenter , r and omized clinical trials of patients who had ACS ( n = 26,452 ) to determine an association between bleeding severity as measured by the GUSTO scale and 30-day and 6-month mortality rates using Cox proportional hazards modeling that incorporated bleeding as a time-dependent covariate . The analysis was repeated to examine procedure- and non-procedure-related bleeding and after censoring at the time of coronary artery bypass grafting . Of all the patients included , 27.6 % had > or = 1 bleeding episode . Patients who bled were older and sicker at presentation than were those who did not bleed . Unadjusted rates of 30-day and 6-month mortality increased as bleeding severity increased . There were stepwise increases in the adjusted hazards of 30-day mortality ( mild bleeding , hazard ratio [ HR ] 1.6 , 95 % confidence interval [ CI ] 1.3 to 1.9 ; moderate bleeding , HR 2.7 , 95 % CI l 2.3 to 3.4 ; severe bleeding , HR 10.6 , 95 % CI 8.3 to 13.6 ) and 6-month mortality ( mild bleeding , HR 1.4 , 95 % CI 1.2 to 1.6 ; moderate bleeding , HR 2.1 , 95 % CI 1.8 to 2.4 ; severe bleeding , HR 7.5 , 95 % CI 6.1 to 9.3 ) as bleeding severity increased . Results were consistent after censoring for coronary artery bypass grafting and for procedure- and non-procedure-related bleeds . In conclusion , the GUSTO bleeding classification identifies patients who are at risk for short- and long-term adverse events . Therapies that minimize bleeding risk and maintain an anticoagulant effect may improve outcomes among patients who have ACS Background : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia sustained and frequently occurs in patients with coronary heart disease . Thus , a large number of patients requiring percutaneous coronary intervention ( PCI ) also suffer from AF . An anticoagulant regimen has not been st and ardized for patients with AF after coronary stent implantation . Patients and Methods : The authors investigated data from 159 patients with AF who underwent PCI in their department . Baseline variables and incidence of a combined endpoint ( stroke , myocardial infa rct ion , cardiovascular death , severe bleeding ) were compared in patients receiving clopidogrel and acetylsalicylic acid ( ASA ; group 1 ) versus patients receiving the combination of clopidogrel and ASA with low-molecular-weight heparin ( LMWH ; group 2 ) versus patients receiving the combination of clopidogrel and ASA with oral anticoagulation ( OAC ; group 3 ) at discharge . Results : Patients discharged with triple therapy including OAC seemed to be at higher risk : patients in group 3 had decreased left ventricular ejection fraction and increased inflammatory state as measured by plasma fibrinogen and C-reactive protein . Moreover , previous OAC treatment and strokes were found more often in this subgroup of patients . In a median follow-up of 1.4 years , two severe bleeding events ( both in group 1 ) , four myocardial infa rct ions ( all in group 1 ) , 13 strokes ( nine in group 1 , four in group 2 ) , and nine cardiovascular deaths ( three in group 1 , five in group 2 , one in group 3 ) occurred . Conclusion : In this analysis , no treatment regimen seemed to be clearly superior . It underlines the importance of prospect i ve , r and omized trials to investigate the optimal antithrombotic/antiplatelet treatment for patients with AF after PCI.ZusammenfassungHintergrund : Vorhofflimmern ( VHF ) ist die häufigste Herzrhythmusstörung und wichtige Komorbidität bei Patienten mit koronarer Herzkrankheit . Welche antithrombotische/antithrombozytäre Therapiestrategie bei Patienten mit Vorhofflimmern nach perkutaner Koronarintervention ( PCI ) verfolgt werden sollte , ist aktuell nicht eindeutig zu beantworten . Patienten und Method ik : Die Autoren identifizierten retrospektiv 159 Patienten mit VHF , die in ihrer Abteilung in den Jahren 1999–2004 eine PCI erhalten hatten . Die Grunderkrankungen und die Inzidenz eines kombinierten Endpunkts ( Schlaganfall , Myokardinfarkt , kardiovaskulär bedingter Tod , schwere Blutung ) wurden bei Patienten verglichen , die Clopidogrel und Acetylsalicylsäure ( ASS ; Gruppe 1 ) , Clopidogrel und ASS in Kombination mit niedermolekularem Heparin ( Gruppe 2 ) sowie Clopidogrel und ASS und zusätzlich orale Antikoagulation erhalten hatten ( Gruppe 3).Ergebnisse : Die Grunderkrankungen der Patienten in den drei Gruppen waren nicht signifikant unterschiedlich . In einem medianen Beobachtungszeitraum von 1,4 Jahren konnten zwei schwere Blutungen ( in Gruppe 1 ) , vier Myokardinfarkte ( in Gruppe 1 ) , 13 Schlaganfälle ( neun in Gruppe 1 , vier in Gruppe 2 ) und neun kardiovaskulär bedingte Todesfälle ( drei in Gruppe 1 , fünf in Gruppe 2 , einer in Gruppe 3 ) nachgewiesen werden . Schlussfolgerung : In dieser Untersuchung erwies sich keine Therapiestrategie einer and eren gegenüber als eindeutig überlegen . Die erhobenen Date n zeigen , wie wichtig es ist , prospektive , r and omisierte Studien bezüglich der antithrombotischen/antithrombozytären Therapie durchzuführen , um Patienten mit AF nach PCI optimal beh and eln zu können Advances in antithrombotic therapy , along with an early invasive strategy , have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes ( ACS ; unstable angina , non – ST-segment – elevation myocardial infa rct ion [ MI ] , and ST-segment – elevation MI).1,–,4 However , the combination of multiple pharmacotherapies , including aspirin , platelet P2Y12 inhibitors , heparin plus glycoprotein IIb/IIIa inhibitors , direct thrombin inhibitors , and the increasing use of invasive procedures , has also been associated with an increased risk of bleeding . Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes , including MI , stroke , stent thrombosis , and death , in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting .11,12 Thus , balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients . Prior r and omized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS , bleeding events have been systematic ally identified as a crucial end point for the assessment of the safety of drugs during the course of r and omized clinical trials , and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events ( eg , cardiac death , MI , stent thrombosis ) , for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use . Lack of st and ardization makes it difficult to optimally organize key clinical trial processes such as adjudication , and even more difficult to interpret relative OBJECTIVES To obtain further , and more focused , information on the efficacy and safety of the antithrombotic regimens , including triple therapy ( TT ) of warfarin , aspirin , and clopidogrel ; dual therapy ( DT ) of warfarin and single antiplatelet agent ( aspirin or clopidogrel ) ; and dual-antiplatelet therapy ( DAPT ) of aspirin and clopidogrel , prescribed to patients on oral anticoagulation ( OAC ) undergoing percutaneous coronary intervention with stent ( PCI-S ) . BACKGROUND The true efficacy and safety of TT , DT , and DAPT in OAC patients undergoing PCI-S is largely undefined . METHODS We analyzed the data base of the prospect i ve , multicenter WARfarin and coronary STENTing ( WAR-STENT ) registry ( Clinical Trials.gov identifier NCT00722319 ) , only including the post-discharge period . RESULTS Of the 401 patients discharged alive from index hospitalization , 339 ( 85 % ) , 20 ( 5 % ) , and 42 ( 10 % ) were prescribed TT , DT , and DAPT , respectively . Throughout a mean follow-up of 368.3 ± 22.8 days , major adverse cardiovascular events ( MACE ) ( including cardiovascular death , myocardial infa rct ion , repeat revascularization , stent thrombosis , and thromboembolism ) , total bleeding , major bleeding , and combination of MACE plus total bleeding were comparable across the three treatment groups . The absolute rate of major bleeding with TT was 4 % . The antithrombotic treatment actually ongoing at major bleeding was TT in 44 % , DT in 50 % , and DAPT in 6 % of cases . CONCLUSION In the real-world population of OAC patients undergoing PCI-S in the WAR-STENT registry , the three antithrombotic regimens of TT , DT , and DAPT showed comparable efficacy and safety . Due to several limitations , our data can not be considered conclusive in confuting the current recommendations to prescribe TT . Further properly design ed and sized studies are warranted BACKGROUND Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation . However , long-term monitoring is necessary and many patients can not achieve optimum anticoagulation . We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events . METHODS Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke , and were r and omly allocated to receive oral anticoagulation therapy ( target international normalised ratio of 2.0 - 3.0 ; n=3371 ) or clopidogrel ( 75 mg per day ) plus aspirin ( 75 - 100 mg per day recommended ; n=3335 ) . Outcome events were adjudicated by a blinded committee . Primary outcome was first occurrence of stroke , non-CNS systemic embolus , myocardial infa rct ion , or vascular death . Analyses were by intention-to-treat . This study is registered with Clinical Trials.gov , number NCT00243178 . RESULTS The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy . There were 165 primary events in patients on oral anticoagulation therapy ( annual risk 3.93 % ) and 234 in those on clopidogrel plus aspirin ( annual risk 5.60 % ; relative risk 1.44 ( 1.18 - 1.76 ; p=0.0003 ) . Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events ( relative risk 1.50 , 95 % CI 1.19 - 1.89 ) and a significantly ( p=0.03 for interaction ) lower risk of major bleeding with oral anticoagulation therapy ( 1.30 ; 0.94 - 1.79 ) than patients not on this treatment at study entry ( 1.27 , 0.85 - 1.89 and 0.59 , 0.32 - 1.08 , respectively ) . CONCLUSION Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke , especially in those already taking oral anticoagulation therapy Background The optimal antithrombotic treatment after percutaneous coronary intervention ( PCI ) with stenting in patients with atrial fibrillation ( AF ) is unknown . In the ENGAGE AF‐TIMI 48 trial , edoxaban was noninferior to a vitamin K antagonist ( VKA ) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF . The effects of edoxaban in combination with single‐ or dual‐antiplatelet therapy in the setting of PCI are unexplored . Design The ENTRUST‐AF PCI trial is a multinational , multicenter , r and omized , open‐label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF . Patients are r and omized between 4 hours and 5 days after successful PCI to either an edoxaban‐based strategy ( experimental arm ; 60 mg [ or 30 mg according to dose reduction criteria ] once daily plus a P2Y12 antagonist [ default clopidogrel , 75 mg once daily ] for 12 months ) or a VKA‐based strategy ( control arm ; VKA plus a P2Y12 antagonist [ as above ] plus acetylsalicylic acid [ 100 mg once daily ] for 30 days to 12 months ) . The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis – defined major or clinical ly relevant nonmajor bleeding . The main efficacy end point is the composite of cardiovascular death , stroke , systemic embolic events , spontaneous myocardial infa rct ion , and definite stent thrombosis . Summary The ENTRUST‐AF PCI trial tests the hypothesis that an edoxaban‐based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual‐antiplatelet therapy in patients with AF in need of oral anticoagulation . The relative risk of ischemic events between groups will be compared BACKGROUND In patients with atrial fibrillation undergoing percutaneous coronary intervention ( PCI ) with placement of stents , st and ard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy ( DAPT ) with a P2Y12 inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding . The effectiveness and safety of anticoagulation with rivaroxaban plus either one or two antiplatelet agents are uncertain . METHODS We r and omly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive , in a 1:1:1 ratio , low-dose rivaroxaban ( 15 mg once daily ) plus a P2Y12 inhibitor for 12 months ( group 1 ) , very-low-dose rivaroxaban ( 2.5 mg twice daily ) plus DAPT for 1 , 6 , or 12 months ( group 2 ) , or st and ard therapy with a dose-adjusted vitamin K antagonist ( once daily ) plus DAPT for 1 , 6 , or 12 months ( group 3 ) . The primary safety outcome was clinical ly significant bleeding ( a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infa rct ion [ TIMI ] criteria or bleeding requiring medical attention ) . RESULTS The rates of clinical ly significant bleeding were lower in the two groups receiving rivaroxaban than in the group receiving st and ard therapy ( 16.8 % in group 1 , 18.0 % in group 2 , and 26.7 % in group 3 ; hazard ratio for group 1 vs. group 3 , 0.59 ; 95 % confidence interval [ CI ] , 0.47 to 0.76 ; P<0.001 ; hazard ratio for group 2 vs. group 3 , 0.63 ; 95 % CI , 0.50 to 0.80 ; P<0.001 ) . The rates of death from cardiovascular causes , myocardial infa rct ion , or stroke were similar in the three groups ( Kaplan-Meier estimates , 6.5 % in group 1 , 5.6 % in group 2 , and 6.0 % in group 3 ; P values for all comparisons were nonsignificant ) . CONCLUSIONS In participants with atrial fibrillation undergoing PCI with placement of stents , the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1 , 6 , or 12 months was associated with a lower rate of clinical ly significant bleeding than was st and ard therapy with a vitamin K antagonist plus DAPT for 1 , 6 , or 12 months . The three groups had similar efficacy rates , although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy . ( Funded by Janssen Scientific Affairs and Bayer Pharmaceuticals ; PIONEER AF-PCI Clinical Trials.gov number , NCT01830543 . ) OBJECTIVES This study sought to evaluate whether prasugrel may serve as an alternative to clopidogrel in patients with triple therapy . BACKGROUND Approximately 10 % of patients who receive dual antiplatelet therapy after percutaneous coronary intervention have an indication for oral anticoagulation and are thus treated with triple therapy . The st and ard adenosine diphosphate receptor blocker in this setting is clopidogrel . Data regarding prasugrel as part of triple therapy are not available . METHODS We analyzed a consecutive series of 377 patients who underwent drug-eluting stent implantation and had an indication for oral anticoagulation between February 2009 and December 2011 and were treated with a 6-month regimen of aspirin and oral anticoagulation with either prasugrel or clopidogrel . The primary endpoint was a composite of Thrombolysis In Myocardial Infa rct ion ( TIMI ) major and minor bleeding at 6 months . The secondary endpoint was a composite of death , myocardial infa rct ion , ischemic stroke , or definite stent thrombosis . RESULTS Twenty-one patients ( 5.6 % ) received prasugrel instead of clopidogrel . These patients had a higher-risk profile at baseline , and the majority had high platelet reactivity to clopidogrel . TIMI major and minor bleeding occurred significantly more often in the prasugrel compared with the clopidogrel group ( 6 [ 28.6 % ) vs. 24 [ 6.7 % ] ; unadjusted hazard ratio ( HR ) : 4.6 , 95 % confidence interval [ CI ] : 1.9 to 11.4 ] , p < 0.001 ; adjusted HR : 3.2 , 95 % CI : 1.1 to 9.1 ] , p = 0.03 ) . There was no significant difference regarding the combined ischemic secondary endpoint ( 2 [ 9.5 % ] vs. 25 [ 7.0 % ] ; unadjusted HR : 1.4 , 95 % CI : 0.3 to 6.1 ] , p = 0.61 ) . CONCLUSIONS These findings suggest that substitution of prasugrel for clopidogrel in patients needing triple therapy increases the risk of bleeding . However , specific r and omized trials are needed to define the role of newer adenosine diphosphate receptor antagonists in this setting

Conclusions There is still insufficient evidence to confirm that cognitive behavioural group therapy for perpetrators of intimate partner violence has a positive effect .

Background Violence against intimate partners is a worldwide public health problem . Cognitive behavioural therapy delivered in a group format is widely used for the treatment of men ’s violent behaviour towards their female partners . A Cochrane review about the effectiveness of this therapy from 2011 revealed a lack of controlled studies . Our aim is to up date the current evidence on the effectiveness of cognitive behavioural group therapy on men ’s violent behaviour towards their female partner .

Background Research has shown that treatments that solely addressed intimate partner violence ( IPV ) perpetration were not very effective in reducing IPV , possibly due to neglecting individual differences between IPV perpetrators . A large proportion of IPV perpetrators is diagnosed with co-occurring substance use disorders and it has been demonstrated that successful treatment of alcohol dependence among alcohol dependent IPV perpetrators also led to less IPV . The current study investigated the relative effectiveness of Integrated treatment for Substance abuse and Partner violence ( I-StoP ) to cognitive behavioral treatment addressing substance use disorders including only one session addressing partner violence ( CBT-SUD+ ) among patients in substance abuse treatment who repeatedly committed IPV . Substance use and IPV perpetration were primary outcome measures . Method Patients who entered substance abuse treatment were screened for IPV . Patients who disclosed at least 7 acts of physical IPV in the past year ( N = 52 ) were r and omly assigned to either I-StoP or CBT-SUD+ . Patients in both conditions received 16 treatment sessions . Substance use and IPV perpetration were assessed at pretreatment , halfway treatment and posttreatment in blocks of 8 weeks . Both completers and intention-to-treat ( ITT ) analyses were performed . Results Patients ( completers and ITT ) in both conditions significantly improved regarding substance use and IPV perpetration at posttreatment compared with pretreatment . There were no differences in outcome between conditions . Completers in both conditions almost fully abstained from IPV in 8 weeks before the end of treatment . Conclusions Both I-StoP and CBT-SUD+ were effective in reducing substance use and IPV perpetration among patients in substance abuse treatment who repeatedly committed IPV and self-disclosed IPV perpetration . Since it is more cost and time-effective to implement CBT-SUD+ than I-StoP , it is suggested to treat IPV perpetrators in substance abuse treatment with CBT-SUD+.Trial registration Clinical Trials.gov : Background : Domestic violence is a major problem in society . In spite of this , there are few studies on the treatment of men who voluntarily seek help to stop their violent behaviour towards intimate partners . Most studies are performed on court-ordered individuals . Aim : The objective of this study was to evaluate results of a manualized cognitive – behaviour group therapy for voluntarily treatment-seeking men , aware of and willing to change their abusive behaviour . Methods : Thirty-six men recruited on a voluntary basis were offered a 15-week manualized group therapy . After initial assessment but before group therapy sessions they were r and omly selected for immediate treatment or treatment after 4 months on a “ waiting list ” . All 26 who started group therapy treatment fulfilled the programme . Changes in violent behaviour , before and after treatment , were assessed by self-reports using the Conflict Tactic Scales . Also , the men on the waiting list were compared after 4 months without treatment with the men receiving treatment immediately . Results : All kinds of self-reported partner related violence were significantly reduced by treatment , but being on a waiting list for 4 months did not reduce violent behaviour compared with those immediately receiving treatment . The results indicate that that the group treatment had an effect in itself beyond the wish and intention from the men to reduce their partner violence OBJECTIVE We evaluated the efficacy of the Strength at Home Men 's Program ( SAH-M ) , a trauma-informed group intervention based on a social information processing model to end intimate partner violence ( IPV ) use in a sample of veterans/service members and their partners . To date , no r and omized controlled trial has supported the efficacy of an IPV intervention in this population . METHOD Participants included 135 male veterans/service members and 111 female partners . Recruitment was conducted from February 2010 through August 2013 , and participation occurred within 2 Department of Veterans Affairs hospitals . Male participants completed an initial assessment that included diagnostic interviews and measures of physical and psychological IPV using the Revised Conflict Tactics Scales and were r and omly assigned to an enhanced treatment as usual ( ETAU ) condition or SAH-M. Those r and omized to SAH-M were enrolled in this 12-week group immediately after baseline . Those r and omized to ETAU received clinical referrals and re sources for mental health treatment and IPV services . All male participants were reassessed 3 and 6 months after baseline . Female partners completed phone assessment s at the same intervals that were focused both on IPV and on the provision of safety information and clinical referrals . RESULTS Primary analyses using hierarchical linear modeling indicated significant time-by-condition effects such that SAH-M participants compared with ETAU participants evidence d greater reductions in physical and psychological IPV use ( β = -0.135 [ SE = 0.061 ] , P = .029 ; β = -0.304 [ SE = 0.135 ] , P = .026 ; respectively ) . Additional analyses of a measure that disaggregated forms of psychological IPV showed that SAH-M , relative to ETAU , reduced controlling behaviors involving isolation and monitoring of the partner ( β = -0.072 [ SE = 0.027 ] , P = .010 ) . CONCLUSIONS Results provide support for the efficacy of SAH-M in reducing and ending IPV in male veterans and service members . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT01435512 Men who are violent toward their partners tend to have a dual problem with alcohol and drug use , yet little is known about differences between men with single rather than dual problems . This study was one of the first to evaluate differences between alcohol dependent men who were arrested for Intimate Partner Violence ( IPV ) with and without concurrent illicit drug use . Seventy-eight participants were r and omly assigned to manual-guided group behavioral therapies ( Cognitive Behavioral Therapy or Twelve Step Facilitation ) and assessed across 12 weeks of treatment . Despite denying drug use at baseline , thirty-two clients ( 43 % ) tested positive for illicit drug use ( cocaine and marijuana ) during the 12 weeks of treatment . The study specifically addressed whether there were differences between clients using alcohol only versus individuals using both alcohol + drugs in terms of 1 ) baseline characteristics ; 2 ) treatment compliance ( e.g. , attendance and substance use during treatment ; and 3 ) treatment outcomes ( alcohol , drug use , anger management , and aggression at the completion of treatment ) . The results showed that there were comparatively few differences between the alcohol versus the alcohol + drug using groups at baseline . Regarding treatment compliance and retention , alcohol + drug using participants attended significantly fewer sessions , had significantly fewer percent days abstinence from alcohol use , significantly more total days of positive breathalyzer results . Regarding treatment outcomes across anger management and aggression scores , the alcohol + drug using participants had significantly more impairments in anger management styles from pre- to post-treatment . However , there were no differences between the groups across verbal or physical aggression . Both groups improved in their verbal aggression from pre- to post-treatment . The findings suggest that alcohol dependent men who continue to use illicit drugs may require additional interventions to effectively control their drug use and , their anger management styles Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Adequate reporting of r and omized , controlled trials ( RCTs ) is necessary to allow accurate critical appraisal of the validity and applicability of the results . The CONSORT ( Consoli date d St and ards of Reporting Trials ) Statement , a 22-item checklist and flow diagram , is intended to address this problem by improving the reporting of RCTs . However , some specific issues that apply to trials of nonpharmacologic treatments ( for example , surgery , technical interventions , devices , rehabilitation , psychotherapy , and behavioral intervention ) are not specifically addressed in the CONSORT Statement . Furthermore , considerable evidence suggests that the reporting of nonpharmacologic trials still needs improvement . Therefore , the CONSORT group developed an extension of the CONSORT Statement for trials assessing nonpharmacologic treatments . A consensus meeting of 33 experts was organized in Paris , France , in February 2006 , to develop an extension of the CONSORT Statement for trials of nonpharmacologic treatments . The participants extended 11 items from the CONSORT Statement , added 1 item , and developed a modified flow diagram . To allow adequate underst and ing and implementation of the CONSORT extension , the CONSORT group developed this elaboration and explanation document from a review of the literature to provide examples of adequate reporting . This extension , in conjunction with the main CONSORT Statement and other CONSORT extensions , should help to improve the reporting of RCTs performed in this field OBJECTIVE Behaviorally based therapies for the treatment of perpetrators who initiate intimate partner violence ( IPV ) have generally shown minimal therapeutic efficacy . To explore a new treatment approach for IPV , we examined the effects of a selective serotonin reuptake inhibitor on the irritability subscale score of the Modified Overt Aggression Scale . This score served as a surrogate marker for the anger and physical aggression that characterize perpetrators of IPV . METHOD A 12-week , double-blind , r and omized , placebo-controlled intervention study employing fluoxetine , alcohol treatment , and cognitive-behavioral therapy was performed . Sixty ( 46 men ) non-court-m and ated , DSM-IV-diagnosed alcoholic perpetrators of IPV with a history of at least 2 episodes of IPV in the year prior to participation in the study were evaluated . The primary outcome measure was the score on the irritability subscale of the Modified Overt Aggression Scale . Secondary measures included anxiety , depression , and ratings by the perpetrator 's spouse/significant other . The study was conducted from January 2002 through December 2007 . RESULTS A repeated- measures analysis of variance using the irritability subscale scores obtained from perpetrators who completed the 12-week study ( n = 24 ) showed a significant drug effect ( F(1,21 ) = 12.09 , P = .002 ) . Last observation carried forward ( F(1,32 ) = 4.24 , P = .048 ) as well as intent-to-treat analysis ( F(1,54 ) = 5.0 , P = .034 ) also showed a significant drug effect . Spouses'/significant others ' physical and nonphysical Partner Abuse Scale ratings showed a significant reduction of abuse over time ( F(1,11 ) = 10.2 , P = .009 and F(1,11 ) = 24.2 , P = .0005 , respectively ) . CONCLUSION This is the first controlled study to show that a pharmacologic intervention employing a selective serotonin reuptake inhibitor , in conjunction with alcohol treatment and cognitive-behavioral therapy , can reduce measures of anger and physical aggression in alcoholic perpetrators of IPV Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies A r and omized clinical trial tested the hypothesis that a flexible , case formulation – based , individual treatment approach integrating motivational interviewing strategies with cognitive-behavioral therapy ( ICBT ) is more efficacious than a st and ardized group cognitive-behavioral approach ( GCBT ) for perpetrators of intimate partner violence ( IPV ) . Forty-two men presenting for services at a community domestic violence agency were r and omized to receive 20 sessions of ICBT or a 20-week group cognitive-behavioral therapy ( CBT ) program . Participants and their relationship partners completed assessment s of relationship abuse and relationship functioning at baseline and quarterly follow-ups for 1 year . Treatment uptake and session attendance were significantly higher in ICBT than GCBT . However , contrary to the study hypothesis , GCBT produced consistently equivalent or greater benefits than ICBT . Participant self-reports revealed significant reductions in abusive behavior and injuries across conditions with no differential benefits between conditions . Victim partner reports revealed more favorable outcomes for group treatment , including a statistically significant difference in psychological aggression , and differences exceeding a medium effect size for physical assault , emotional abuse , and partner relationship adjustment . In response to hypothetical relationship scenarios , GCBT was associated with greater reductions than ICBT ( exceeding a medium effect ) in articulated cognitive distortions and aggressive intentions . Treatment competence ratings suggest that flexible , individualized administration of CBT creates challenges in session agenda setting , homework implementation , and formal aspects of relationship skills training . Although caution is needed in generalizing findings from this small-scale trial , the results suggest that the mutual support and positive social influence available in group intervention may be particularly helpful for IPV perpetrators Three different 12-month interventions for servicemen who had been substantiated as having physically assaulted their wives were used and the outcomes examined . The 861 couples of the study were r and omly assigned to 4 groups : a men 's group , a conjoint group , a rigorously monitored group , and a control group . Cognitive-behavioral interventions were implemented for the men 's and conjoint groups , and outcome data were gathered from male perpetrators and female victims at roughly 6-month intervals over the approximately 18-month experimental period . Data analyses revealed nonsignificant differences between the experimental groups over a variety of outcome measures A stages-of-change motivational interviewing ( SOCMI ) treatment approach was compared with a st and ard cognitive behavioral therapy gender reeducation ( CBTGR ) approach in a sample of 528 English-speaking and Spanish-speaking male batterers who were r and omly assigned to 49 26-week groups in either condition . Blind ratings of therapist adherence differentiated the two conditions . Language spoken neither predicted outcome nor interacted with treatment . The SOCMI curriculum led to significant reductions in female partners ’ reports of physical aggression at follow-up , but not to changes in self-reported aggression . Men who were initially less ready to change benefited more from the SOCMI approach while men who were more ready to change benefited more from the CBTGR approach . Results suggest the importance of tailoring abuser intervention programs to individuals ’ initial readiness to change R and omised controlled trials , when appropriately design ed , conducted , and reported , represent the gold st and ard in evaluating healthcare interventions . However , r and omised trials can yield biased results if they lack method ological rigour [ 1 ] . To assess a trial accurately , readers of a published report need complete , clear , and transparent information on its methodology and findings . Unfortunately , attempted assessment s frequently fail because authors of many trial reports neglect to provide lucid and complete descriptions of that critical information [ 2,3,4 ] . That lack of adequate reporting fuelled the development of the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement in 1996 [ 5 ] and its revision five years later [ 6,7,8 ] . While those statements improved the reporting quality for some r and omised controlled trials [ 9,10 ] , many trial reports still remain inadequate [ 2 ] . Furthermore , new method ological evidence and additional experience has accumulated since the last revision in 2001 . Consequently , we organised a CONSORT Group meeting to up date the 2001 statement [ 6,7,8 ] . We introduce here the result of that process , CONSORT 2010 . At a community-based domestic violence program , 218 men with a history of partner abuse were r and omly assigned to either feminist-cognitive-behavioral or process-psychodynamic group treatments . The treatments were not hypothesized to differ in outcome . However , men with particular characteristics were expected to have lower recidivism rates depending on the type of treatment received . Treatment integrity was verified through audio-taped codings of each session . The partners of 79 % of the 136 treatment completers gave reports of the men ’s behavior an average of 2 years post-treatment . These reports were supplemented with arrest records and self-reports . Rates of violence did not differ significantly between the two types of treatment nor did reports from the women of their fear level , general changes perceived in the men , and conflict resolution methods . However , interaction effects were found between some offender traits and the two treatments . As predicted , men with dependent personalities had better outcomes in the process-psychodynamic groups and those with antisocial traits had better outcomes in the cognitive-behavioral groups . The results suggest that more effective treatment may occur if it is tailored to specific characteristics of offenders

A CMA-COC group had more ' responders , ' those with 50 % or greater decrease in facial papules and pustules ( OR 2.31 ; 95 % CI 1.50 to 3.55)Differences in the comparative effectiveness of COCs containing varying progestin types and dosages were less clear , and data were limited for any particular comparison . COCs that contained chlormadinone acetate or cyproterone acetate improved acne better than levonorgestrel . Likewise , levonorgestrel showed a slight improvement over desogestrel in acne outcomes , but results were not consistent . A drospirenone COC appeared to be more effective than norgestimate or nomegestrol acetate plus 17β-estradiol but less effective than cyproterone acetate . The six COCs evaluated in placebo-controlled trials are effective in reducing inflammatory and non-inflammatory facial acne lesions . Few important and consistent differences were found between COC types in their effectiveness for treating acne .

BACKGROUND Acne is a common skin disorder among women . Although no uniform approach to the management of acne exists , combination oral contraceptives ( COCs ) , which contain an estrogen and a progestin , often are prescribed for women . OBJECTIVES To determine the effectiveness of combined oral contraceptives ( COCs ) for the treatment of facial acne compared to placebo or other active therapies .

Objective : To investigate the effect of a combiphasic oral contraceptive containing ethinylestradiol and desogestrel ( combiphasic EE/DSG ) on acne , compared with a preparation containing ethinylestradiol and cyproterone acetate ( EE35/CPA ) . Methods : An open , r and omized , group-comparative , multicenter study was carried out , with 172 women r and omized to treatment with either combiphasic EE/DSG ( 25 μg desogestrel and 40 μg ethinylestradiol for 7 days followed by 125 μg desogestrel and 30 μg ethinylestradiol for 15 days ) or EE35/CPA ( 2.0 mg cyproterone acetate and 35 μg ethinylestradiol for 21 days ) . Assessment s were performed at pretreatment and after cycles 3 and 6 . Results : The number of comedones , papules , pustules and nodules significantly decreased in both groups over the 6-month study . Compared with pretreatment (= 100 % ) , the relative numbers of comedones , papules , pustules and nodules at cycle 6 significantly decreased to 37 % , 38 % , 19 % and 12.5 % in the combiphasic EE/DSG group and to 24 % , 36 % , 17 % and 1 % in the EE35/CPA group , respectively . All reductions were statistically significant ( p ≤ 0.003 ) at both cycles 3 and 6 , except for nodules at cycle 6 with combiphasic EE/DSG , which probably result ed from differences between the treatment groups at baseline . There were no statistically significant differences between the two treatments . In both groups , the majority of women with severe acne shifted to a less severe acne category . Conclusions : Combiphasic EE/DSG progressively reduced the number and severity of acne lesions during the six cycles of treatment . The reduction in acne with the combiphasic oral contraceptive was comparable to a preparation containing the anti and rogen cyproterone acetate Abstract ▴ Ethinylestradiol/chlormadinone acetate 0.03/2 mg ( EE/CMA ) is a combined monophasic contraceptive pill with anti and rogenic properties . ▴ In a large , noncomparative , multicentre trial ( ≤24 cycles of treatment per woman ) and two ( 6- and 12-cycle ) postmarketing surveillance studies , EE/ CMA was effective in preventing pregnancy . ▴ EE/CMA was significantly more effective than EE/ levonorgestrel 0.03/0.15 mg/day in treating women with mild-to-moderate papulopustular acne of the face and related disorders in a r and omised , single-blind , multicentre trial . ▴ EE/CMA was well tolerated in clinical trials and the postmarketing surveillance studies . Adverse events were those commonly reported with oral contraceptives . As expected , the most common menstrual disturbances were breakthrough bleeding , spotting and amenorrhoea To study the question of whether one br and of oral contraceptives may be as acceptable as another for use of publicly-assisted family planning programs , a double blind study of two well-known br and s , Ovral and Norinyl , was undertaken in Costa Rica and Trinidad . The pills were r and omly assigned to 1,200 women . Common side effects - nausea , dizziness , vomiting , headaches - were associated with both Norinyl and Ovral . Differences in event rates for these conditions were much more marked by country than by the pill used . Ovral was associated with increases in skin problems , notably chloasma , in Cost Rica . A higher percentage of women using Norinyl reported intermenstrual bleeding and spotting in both countries . In Costa Rica continuation rates for Norinyl were adversely affected by this . With these exceptions there appear to be no important differences between the br and s that would affect their use in family planning programs OBJECTIVE To investigate the effects of an ethinylestradiol ( EE ) 20 μg/drospirenone ( drsp ) 3 mg combined oral contraceptive ( COC ) administered in a 24/4 regimen ( 24 active tablets/4 inert tablets per cycle ) for the treatment of moderate acne vulgaris , based on a pooled analysis of two identically design ed US studies . STUDY DESIGN Healthy females ( n=893 ) aged 14 - 45 years with moderate facial acne were r and omised to EE 20 μg/drsp 3 mg COC ( n=451 ) or placebo ( n=442 ) for six cycles . Primary outcome measures were mean percent change in acne lesion counts and the investigators ' assessment of acne from baseline to endpoint . RESULTS There were significantly greater reductions in the mean percent change from baseline to endpoint in inflammatory , non-inflammatory and total lesion counts in the EE 20 μg/drsp 3 mg 24/4 COC group compared with the placebo group ( P<0.0001 ) . The odds of women in the EE 20 μg/drsp 3 mg 24/4 COC group having ' clear ' or ' almost clear ' skin as rated by the investigators at endpoint were around three-fold greater than in the placebo group ( odds ratio 3.41 ; 95 % CI : 2.15 - 5.43 ; P<0.0001 ) . CONCLUSIONS A low-dose COC containing EE 20 μg/drsp 3 mg ( 24/4 ) more effectively reduced acne lesions than placebo and demonstrated greater improvement in the investigator global assessment of acne OBJECTIVE To compare the effects of a low-dose oral contraceptive containing desogestrel ( Marvelon ) and an anti- and rogenic preparation containing cyproterone acetate ( Diane ) in Oriental women suffering from acne . METHODS In an open-label , bi-center , r and omized study , 32 women using Marvelon and 34 using Diane were followed for 6 treatment cycles . The measured variables were objective and subjective severity of acne , and related biochemical variables such as sex hormone-binding globulin and free and total testosterone . RESULTS In Center A , with both preparations a decrease in mean objective acne score was observed , reaching statistical significance with Diane ( P < .05 ) . In addition , there was a significant between group difference at cycle 6 ( P < .05 ) . In Center B , a consistent and significant decrease in mean acne score was observed with Marvelon after three and six treatment cycles ( P < .05 and P < .01 ) and with Diane after six treatment cycles ( P < .001 ) . There were no significant between-group differences . The decrease in percentage of severe/moderate acne was statistically significant with Marvelon in Center B ( P = 0.002 ) and with Diane in Centers A ( P = 0.014 ) and B ( P = 0.004 ) . Both preparations increased plasma levels of sex hormone binding globulin and seemed to decrease those of total and free testosterone , but no statistically significant relationships between acne severity and biochemical variables could be detected . CONCLUSION Both Marvelon and Diane are effective in the treatment of acne in Oriental women who also need reliable contraception , without marked differences between the preparations A multicenter r and omized study was carried out to compare the efficacy of combined therapy with a GnRH analog ( goserelin ) + an oral contraceptive ( OC ) containing ethinyl estradiol and cyproterone acetate and same OC alone in the treatment of severe hirsutism . The effect of these two therapies was assessed in a subjective and an objective evaluation of hair growth . According to the subjective evaluation , judged by physician and patient . 95 % of patients obtained a partial response . The objective response was assessed by measuring the mean diameter of hair from 3 different areas and 1 control area . The decrease in hair diameter compared to pretreatment was statistically significant for both treatments , mainly for the abdomen and face . The difference between the two groups did not reach statistical significance . Therefore , we assume that OC alone remains the treatment of choice for hirsutism . However , the addition of the GnRH analog to OC needs further investigation and could be justified for patients with no response to st and ard monotherapy BACKGROUND An excess of and rogen is believed to contribute to development of acne in some patients . Because oral contraceptives ( OCs ) may reduce the active and rogen level , hormonal therapy with OCs has been used successfully to treat patients with acne , although this treatment has previously not been studied in placebo-controlled trials . OBJECTIVE Our purpose was to evaluate the efficacy of a triphasic , combination OC ( ORTHO TRI-CYCLEN [ Ortho-McNeil Pharmaceutical , Raritan , N.J. ] , norgestimate/ethinyl estradiol ) compared with placebo in the treatment of moderate acne vulgaris . METHODS Two hundred fifty-seven healthy female subjects , 15 to 49 years of age with moderate acne vulgaris , were enrolled in a multicenter , r and omized , double-blind , placebo-controlled clinical trial . Each month for 6 months , subjects received either 3 consecutive weeks of the OC ( i.e. , tablets containing a fixed dose of ethinyl estradiol [ 0.035 mg ] and increasing doses of norgestimate [ 0.180 mg , 0.215 mg , 0.250 mg ] ) followed by 7 days of inactive drug or placebo ( color-matched tablets ) . Efficacy was assessed by facial acne lesion counts , an investigator 's global assessment , a subject 's self- assessment , and an analysis of within-cycle variation ( cycle 6 ) in lesion counts . RESULTS Of the 160 subjects in whom efficacy could be evaluated , the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures . The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 ( 62.0 % ) versus 7.6 ( 38.6 % ) ( p = 0.0001 ) , and the mean decrease in total lesion count was 29.1 ( 53.1 % ) versus 14.1 ( 26.8 % ) ( p = 0.0001 ) in the OC and placebo groups , respectively . In the investigator 's global assessment , 93.7 % of the active treatment group versus 65.4 % of the placebo group were rated as improved at the end of the study ( p < 0.001 ) . Six of the seven secondary efficacy measures ( total comedones , open comedones , closed comedones , papules , pustules , and the subject 's self- assessment of study treatment ) were also significantly more favorable in the OC group compared with the placebo group . CONCLUSION An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy The early days of oral contraceptives showed some evidence that these medications may have caused undesirable side effects on the voice , mainly in terms of virilization . In a r and om study carried out at the university hospitals of Jena and Berlin ( Charité ) , two more recent drugs were tested in this regard , one containing cyproterone acetate ( Diane-35 ) and the other one levonorgestrel ( Microgynon ) , both from Schering . Ninety-one patients took part in extensive clinical and instrumental phoniatric investigations of voice function over a period of one year . No significant side effects on the voice could be proven for the two preparations . Gynecological and clinical effects of both Diane-35 and Microgynon were similar during the one-year study period . Women taking Diane-35 had less intracyclic bleedings and amenorrhea . Also , acne was more favorably influenced by Diane-35 The aim for improving the progestogen component of oral contraceptives is both to increase their selectivity by obtaining a highly effective contraceptive action and to decrease the side effects related to the existing progestogens . The and rogenic activity of the existing progestogens modifies the lipid metabolism , particularly a decrease in the high density lipoprotein ( HDL ) level , which increases the risks of cardiovascular diseases . Thus , the discovery of a progestogen with good anti-ovulatory and minimal and rogenic properties would constitute an important progress in the field of oral contraception . Norgestimate ( NGM ) is a new progestogen presenting an exceptional profile of biological activity , and has proved to be extremely selective , as observed during the clinical trials . The studies described below have been carried out in order to confirm clinical ly the low and rogenic activity of NGM . In two clinical trials , Norgestimate ( 0.25 mg ) associated with 0.035 mg of ethinyloestradiol ( NGM 0.25/35 ) was compared to norgestrel ( 0.30 mg ) associated with 0.030 mg of ethinyloestradiol ( Lo/Ovral ) . In the first trial ( 1,261 women ) , the following observations were made : an important increase in the HDL level compared to the base levels in the subjects taking NGM 0.25/35 , and an important decrease in the HDL level in those taking Lo/Ovral . The low density lipoprotein ( LDL ) level increased slightly in the NGM 0.25/35 group , while a higher increase was observed in the Lo/Ovral group . Moreover , the LDL/HDL ratio translates a more favourable lipid profile in the NGM 0.25/35 group , since the values are lower than those observed for the Lo/Ovral group . ( ABSTRACT TRUNCATED AT 250 WORDS The objective of this study was to assess the influence of oral contraceptives ( OCs ) on the risk of venous thromboembolism ( VTE ) in young women . A 5-year case-control study including all Danish hospitals was conducted . All women 15 - 44 years old , suffering a first ever deep venous thrombosis or a first pulmonary embolism ( PE ) during the period January 1 , 1994 , to December 30 , 1998 , were included . Controls were selected annually , 600 per year in 1994 - 1995 and 1200 per year 1996 - 1998 . Response rates for cases and controls were 87.2 % and 89.7 % , respectively . After exclusion of nonvalid diagnoses , pregnant women , and women with previous thrombotic disease , 987 cases and 4054 controls were available for analysis . A multivariate , matched analysis was performed . Controls were matched to cases within 1-year age b and s. Adjustment was made for confounding influence ( if any ) from the following variables : age , year , body mass index , length of OC use , family history of VTE , cerebral thrombosis or myocardial infa rct ion , coagulopathies , diabetes , years of schooling , and previous birth . The risk of VTE among current users of OCs was primarily influenced by duration of use , with significantly decreasing odds ratios ( OR ) over time : < 1 year , 7.0 ( 5.1 - 9.6 ) ; 1 - 5 years , 3.6 ( 2.7 - 4.8 ) ; and > 5 years , 3.1 ( 2.5 - 3.8 ) , all compared with nonusers of OCs . After adjustment for confounders , current use of OCs with second- ( levonorgestrel or norgestimate ) and third- ( desogestrel or gestodene ) generation progestins when compared with nonuse result ed in ORs for VTE of 2.9 ( 2.2 - 3.8 ) and 4.0 ( 3.2 - 4.9 ) , respectively . After adjusting for progestin types and length of use , the risk decreased significantly with decreasing estrogen dose . With 30 - 40 microg as reference , 20 and 50 microg products implied ORs of 0.6 ( 0.4 - 0.9 ) and 1.6 ( 0.9 - 2.8 ) , respectively ( p(trend ) = 0.02 ) . After correction for duration of use and differences in estrogen dose , the third/second-generation risk ratio was 1.3 ( 1.0 - 1.8 ; p < 0.05 ) . In conclusion , use of OCs was associated significantly to the risk of VTE . The risk among current users was reduced by more than 50 % during the first years of use . The risk increased more than 100 % with increasing estrogen dose , and the difference in risk between users of third- and second-generation OCs , after correction for length of use and estrogen dose , was 33 % A multi‐centre controlled trial of low‐dose cyproterone acetate ( Diane ® , Schering Health t are Ltd ) compared with minocycline hydrochloride ( Minocin ® , Lederle Laboratories Ltd ) in female patients with acne vulgaris has been undertaken . Seventy‐eight patients completed the study . Over a 24‐week treatment period , Diane and Minocin were found to be equally effective in reducing the lesion count for comedones , papules and pustules , and in the patients ' subjective assessment of their skin . No significant changes in weight or blood pressure were found in either treatment group , and the number of patients reporting ; side‐effects was similar Abstract . The combination of 2 mg cyproterone acetate , a pronounced anti and rogenic substance , in combination with 0.05 mg ethinyl estradiol has undergone intensive multiphasic clinical evaluation . the preparation with the trade name Diane ® has proven to be not only a reliable contraceptive , but also a very potent drug for the treatment of both acne and seborrhea , and of milder cases of hirsutism . the effect of Diane ® on markedly increased hair growth was not so pronounced . in addition to the presentation of the most pertinent steps of the clinical investigation of Diane ® , the possible mode of actions of anti and rogens alone and in combination with an estrogen is discussed The efficacy and acceptability of two third generation oral contraceptives in Thai women were evaluated in a prospect i ve , open , group-comparative , r and omized , multicenter trial of women asking for contraception . In six Family Planning Centers and Outpatient Gynaecological Clinics in urban areas in Thail and , 783 healthy women who were at risk for pregnancy and did not have contraindications to oral contraceptive use were r and omly allocated to one of the two study groups . An oral contraceptive containing 30 mcg ethinylestradiol and 150 mcg desogestrel was given to 394 women and an oral contraceptive with the same amount of ethinylestradiol and 75 mcg gestodene to 389 women during 6 cycles . Criteria of cycle control , side effects and the presence and severity of acne vulgaris were assessed and blood pressure and body weight measured at pretreatment and after cycles 1 , 3 and 6 . Furthermore , the efficacy was evaluated after the last cycle . No pregnancies occurred with either of the contraceptives . The incidences of irregular bleeding and minor side effects in both groups were very low and decreased after an initial increase in the first cycle . Acne improved in both groups . Blood pressure and body weight remained unchanged . The two oral contraceptives were found to be effective and acceptable in Thai women . Compared to Caucasian women , the incidences of irregular bleeding and side effects were apparently lower in these Asian women . Furthermore , the effects of both oral contraceptives were comparable Oral contraceptives ( OC ) suppress excess and rogen production ; however , different progestins in combination with low-dose estrogens produce divergent effects on sex hormone-binding globulin ( SHBG ) and testosterone that may influence clinical outcomes . This multicenter , open-label , r and omized study compared biochemical and rogen profiles and clinical outcomes associated with two OC containing the same amounts of ethinyl estradiol ( EE , 20 micrograms ) but different progestins , levonorgestrel ( LNG , 100 micrograms ) , and norethindrone acetate ( NETA , 1000 micrograms ) . Fifty-eight healthy women ( 18 - 28 years old ) received three cycles of treatment with LNG/EE ( n = 30 ) or NETA/EE ( n = 28 ) . The results showed that LNG reduced and rogen levels in three compartments -- adrenal , ovarian , and peripheral . NETA reduced only adrenal and peripheral and rogens . Despite a 2.2-fold greater relative increase in SHBG with NETA than LNG , bioavailable testosterone ( T ) was reduced by the same amount with LNG and NETA . Both treatments improved acne and were well tolerated . Low-dose OC ( EE , 20 micrograms ) are effective in reducing circulating and rogens and acne lesions without causing weight gain . Although LNG and NETA affected secondary markers differently , both OC formulations produced an equivalent decrease in bioavailable Blinding embodies a rich history spanning over two centuries . Most research ers worldwide underst and blinding terminology , but confusion lurks beyond a general comprehension . Terms such as single blind , double blind , and triple blind mean different things to different people . Moreover , many medical research ers confuse blinding with allocation concealment . Such confusion indicates misunderst and ings of both . The term blinding refers to keeping trial participants , investigators ( usually health-care providers ) , or assessors ( those collecting outcome data ) unaware of the assigned intervention , so that they will not be influenced by that knowledge . Blinding usually reduces differential assessment of outcomes ( information bias ) , but can also improve compliance and retention of trial participants while reducing biased supplemental care or treatment ( sometimes called co-intervention ) . Many investigators and readers naïvely consider a r and omised trial as high quality simply because it is double blind , as if double-blinding is the sine qua non of a r and omised controlled trial . Although double blinding ( blinding investigators , participants , and outcome assessors ) indicates a strong design , trials that are not double blinded should not automatically be deemed inferior . Rather than solely relying on terminology like double blinding , research ers should explicitly state who was blinded , and how . We recommend placing greater credence in results when investigators at least blind outcome assessment s , except with objective outcomes , such as death , which leave little room for bias . If investigators properly report their blinding efforts , readers can judge them . Unfortunately , many articles do not contain proper reporting . If an article cl aims blinding without any accompanying clarification , readers should remain sceptical about its effect on bias reduction An open , r and omized , multicenter study was carried out to compare two oral contraceptives as regards their therapeutic efficacy in and rogenization symptoms such as acne , seborrhea and hirsutism in women . The preparations used were the combination of 2 mg cyproterone acetate ( CPA ) with 0.035 mg ethinyl estradiol ( EE ) ( Diane35 ® , Schering AG , Berlin‐West ) and 0.150 mg desogestrel ( DG ) with 0.03 mg ethinyl estradiol ( Marvelon ® , Organon , Oss , The Netherl and s ) ABSTRACT Objectives The primary objective was to assess the efficacy , cycle control and tolerability of a monophasic combined oral contraceptive ( COC ) containing nomegestrol acetate ( NOMAC ) and 17β-oestradiol ( E2 ) . Effects on acne were evaluated as a secondary objective . Results were compared to those of a COC containing drospirenone ( DRSP ) and ethinylestradiol ( EE ) . Methods Women ( aged 18–50 years ) were r and omised to receive NOMAC/E2 ( 2.5 mg/1.5 mg ) in a 24/4-day regimen ( n = 1591 ) or DRSP/EE ( 3 mg/30 μg ) in a 21/7-day regimen ( n = 535 ) for 13 cycles . Results Estimated Pearl Indices for NOMAC/E2 and DRSP/EE were 0.38 and 0.81 in women aged ≤ 35 years and 0.31 and 0.66 for all women ( 18–50 years ) , respectively . Scheduled withdrawal bleedings were shorter and lighter among users of NOMAC/E2 and were sometimes absent altogether . Intracyclic bleeding/spotting was infrequent in both groups , and decreased over time . Type and frequency of adverse events were similar to those typically reported for COCs . Conclusions These data show that NOMAC/E2 provides high contraceptive efficacy with acceptable cycle control as well as an overall adverse event profile similar to that of DRSP/EE Background and Objective : Acne in women can often be successfully treated by the intake of oral contraceptives containing gestagens with anti- and rogenic properties . This study aim ed to evaluate the efficacy of the monophasic oral contraceptive ethinylestradiol/chlormadinone acetate ( EE/CMA ; Belara ® ) for the treatment of mild to moderate papulopustular acne of the face and acne-related disorders in comparison to EE/levonorgestrel ( LNG ; Microgynon ® ) . Methods : 199 female acne patients were enrolled in a single-blind , r and omized , multicentre phase III study and divided into two groups who received either EE/CMA or EE/LNG . The primary end point was fulfilled if the number of papules/pustules per half of the face present on admission had decreased by at least 50 % in the 12th medication cycle . Results : 59.4 % of the women under EE/CMA and 45.9 % under EE/LNG were responders . The relative frequency of women with complete resolution was 16.5 % under EE/CMA and 4.3 % under EE/LNG at cycle 12 . Conclusion : EE/CMAis an efficient treatment for women with mild and moderate papulopustular acne of the face and related disorders , reflecting the well-known anti- and rogenic properties of the progestogen CMA OBJECTIVE This study was undertaken to compare the clinical efficacy of second- versus third-generation oral contraceptives in the treatment of acne . STUDY DESIGN Thirty-four women with acne were r and omly selected to receive an oral contraceptive containing 0.3 mg of ethinyl estradiol (EE)/0.15 mg of desogestrel or 0.3 mg of EE/0.15 mg of levonorgestrel for 9 months . Acne was scored by lesion counting by a single examiner , and serum was analyzed for sex hormone-binding globulin ( SHBG ) , dehydroepi and rosterone sulfate ( DHEAS ) , and free and total testosterone at baseline and 3-month intervals . RESULTS At baseline , the two treatment groups did not differ in the mean age , body mass index , acne lesion counts , SHBG , DHEAS , or free and total testosterone . Mean acne lesion counts decreased significantly in both groups from baseline ( P < .02 ) . In subjects completing 9 months of therapy , acne decreased by 52.8 % in the EE/levonorgestrel group ( n = 9 ) and by 58.5 % in the EE/desogestrel group ( n = 7 ) ( between groups : P not significant ) . Mean SHBG increased by 46.3 nmol/L in the EE/desogestrel group ( P not significant ) , and 20.0 nmol/L in the EE/levonorgestrel group ( P < .05 ) . Decreases in free testosterone from baseline occurred in each group , but these differences did not reach statistical significance . CONCLUSION Oral contraceptives containing EE/desogestrel and EE/levonorgestrel were both effective in treating acne Pituitary function ( TRH-LHRH stimulation test ) was investigated in male acne patients and serum levels of dehydroepi and rosterone sulphate ( DHEA-S ) , sex hormone binding globulin ( SHBG ) and other biochemical parameters were investigated in male acne patients and in female acne patients before and after treatment with an oral contraceptive . The TRH-LHRH stimulation test was performed with 15 male patients suffering from severe cystic acne and 7 healthy volunteers . Basal and stimulated prolactin , LH and FSH levels were statistically similar in the patients and control groups . However , the stimulated LH levels of the patients were 60 % higher than those in controls . SHBG levels were significantly ) higher in the patient group compared to those in the control group . Thirty-three female acne patients were r and omly divided into two groups and treated for six months with an oral contraceptive containing 0.030 mg ethinylestradiol ( EE ) plus 0.150 mg levonorgestrel or 0.150 mg levonorgestrel . After six months ' treatment a 30 % decrease in DHEA-S levels were observed in the desogestrel/EE group and a 15 % decrease in the levonorgestrel/EE group ; the difference was not statistically significant . At the same time serum total cortisol increased by 75 - 100 % and free testosterone fell by 30 - 40 % in both groups , whereas SHBG elevated 250 % in the desogestrel/EE group and 30 % in the levonorgestrel/EE group . Acne improved significantly in both groups , desogestrel/EE showing greater improvement . A decrease in SHBG and increase in DHEA-S levels appear to be the most common hormonal changes in acne . Oral contraceptive treatment induces an increase in SHBG and decrease in DHEA-S and also improves acne The effect of gestodene 75 micrograms ( GTD ) versus desogestrel 150 micrograms ( DSG ) combined with 30 micrograms of ethinylestradiol ( EE ) on acne lesions and plasma and rostenedione ( A ) , total testosterone ( T ) , sex hormone binding globulin ( SHBG ) and " free and rogen index " ( FAI ) was evaluated in an open study on 19 patients aged 18 - 35 years affected with postpubertal or persistent non-severe acne vulgaris . The patients were r and omly allocated into two groups receiving EE-GTD ( n = 8) and EE-DSG ( n = 11 ) , 21 tablets per cycle for 9 consecutive cycles . Clinical and hormonal evaluations were made between days 17 - 21 in the cycle before treatment and between days 17 - 21 of the cycle 3 , 6 and 9 of treatment . During treatment , acne improved in most patients , reaching at cycle 9 a low score ( absent or minimal ) in 62 % of the cases in the GTD group ( mean acne score = 1.25 ) and in 90 % of the cases in the DSG group ( mean acne score = 0.90 ) . Before treatment , about 75 % of the patients showed one or more signs of biochemical hyper and rogenism , including elevated FAI ( 57 % ) , elevated A ( 15 % ) , elevated total T ( 15 % ) and decreased SHBG ( 21 % ) , and there was evidence of inverse correlation between SHBG and acne scores ( p < 0.05 ) . The echogenic texture of the ovaries was multifollicular in 55 % of the cases . By the end of the third cycle of treatment , the hormonal changes observed in both groups included significant decreases , with normalization of individual elevated levels of T , and a 3-fold rise of the initial values of plasma SHBG , which showed a further gradual increase at cycle 9 of EE-DSG administration . At cycle 9 , normalization of the echogenic ovarian texture was observed . Acne improvement under treatments with estrogen and progestin ( EP ) could be significantly correlated with the normalization of biochemical hyper and rogenism . In conclusion , the biochemical and clinical efficacy of EE-GTD and EE-DSG indicate that both these preparations can be a good choice in the therapy of acne vulgaris , with a non-significant better clinical result with EE-DSG Since the recent introduction of a drug regimen containing 2 mg of the anti and rogen cyproterone acetate and 50 micrograms ethinyl-oestradiol ( Diane ; oestrogen-cyproterone acetate ) several uncontrolled reports have extolled the benefits of this drug . Double blind studies , however , are lacking . Sixty two patients with moderate or moderately severe acne were therefore included in a double blind trial of treatment for six months comparing tetracycline alone , oestrogen-cyproterone acetate alone , and a combination of these agents . Sebum excretion rates and bacterial counts were measured before , during , and after treatment , at the same time as a clinical assessment was made . At six months the acne ( as assessed by overall grade ) had improved by 68 % in the antibiotic treated group and by 74 % in the oestrogen-cyproterone treated group . The group given a combination of both agents improved by 82 % , which was significantly better ( p less than 0.025 ) than the improvement in the tetracycline treated patients . No significant difference was found between the groups given oestrogen-cyproterone alone and the combined treatment . The sebum excretion rate was suppressed by 25 % in the patients in both groups receiving oestrogen-cyproterone but not in the group given antibiotics alone . Oestrogen-cyproterone acetate is as effective as antibiotics in treating acne in women , and adding antibiotics offers no advantage over using oestrogen-cyproterone on its own , although in this study the combination was more effective than tetracycline alone at six months Background : The prevalence of acne among adolescents appears to vary geographically . This study was therefore undertaken to describe the prevalence rate of acne among Danish adolescents and to study the possible influence of oral contraceptives ( OC ) and tobacco smoking on disease prevalence and severity . Both have been suggested to influence acne and are therefore potential confounders in studies of acne prevalence . Methods : A r and om sample of 186 15- to 22-year-old subjects participating in a population -based study of allergic diseases in Copenhagen County were also examined for acne . Question naire data on demographic variables , acne problems , smoking status and use of OC were recorded , and acne was grade d according to the Leeds scale . Results : The prevalence of clinical acne ( Leeds score > 1 ) was 40.7 % for men and 23.8 % for women ( odds ratio , OR , acne vs. no acne : 0.46 , 95 % confidence interval , CI : 0.24–0.85 ) . Acne was perceived as a personal problem by 37.6 % of all subjects , and this was associated with clinical acne ( OR : 5.5 , 95 % CI : 2.7–10.9 ) . The use of OC was associated with a significantly lower prevalence of acne ( OR : 0.32 , 95 % CI : 0.11–0.86 ) , while the use of tobacco smoking was not significantly associated with acne ( OR : 0.54 , 95 % CI : 0.17–1.78 ) . Conclusion : In congruence with recent reports from other countries , the prevalence rate of acne among adolescents was found to be lower than previously described in older reports . In this population , the use of OC was associated with a lower prevalence of acne OBJECTIVE To evaluate the clinical and hormonal response of topically applied cyproterone acetate , oral cyproterone acetate , and placebo lotion in women with acne . DESIGN Placebo-controlled , r and omized study . SETTING Patients were recruited from the Institute of Endocrine Cosmetics , Vienna , Austria . PATIENTS Forty women with acne . INTERVENTIONS Treatment with oral medication consisting of 0.035 mg of ethinyl estradiol and 2 mg of cyproterone acetate ( n=12 ) , 20 mg of topical cyproterone acetate lotion ( n=12 ) , and placebo lotion ( n=16 ) was offered . Patients were assessed monthly for 3 months . MAIN OUTCOME MEASURES Clinical grading according to acne severity and lesion counts as well as determinations of serum cyproterone acetate concentrations . RESULTS After 3 months of therapy with topical cyproterone acetate , the decrease of mean facial acne grade from 1.57 to 0.67 was significantly better ( P<.05 ) compared with placebo ( which showed a change from 1.57 to 1.25 ) , but not compared with oral medication ( 1.56 to 0.75 ) ( P>.05 ) . Lesion counts also decreased from 35.9 to 9.1 in the topical cyproterone acetate group compared with oral medication ( 45.4 to 15.5 ) ( P>.05 ) and placebo ( 38.2 to 23.1 ) ( P<.05 ) . After topical cyproterone acetate treatment , serum cyproterone acetate concentrations were 10 times lower than those found after oral cyproterone acetate intake . CONCLUSIONS The therapeutic effect of topically applied cyproterone acetate for acne treatment was clearly demonstrated . Topically applied sexual steroids in combination with liposomes are as effective as oral anti and rogen medication in acne treatment , while reducing the risk of adverse effects and avoiding high serum cyproterone acetate concentrations Serum and rosterone glucuronide ( AoG ) is a metabolite of circulating and rogens under the influence of 5α-reductase activity and has been shown to be particularly elevated in women with acne . In this study , we wanted to evaluate changes in AoG before and after treatment with an oral contraceptive or placebo , and to assess whether changes correlated with the number and type of acne lesions . In order to accomplish these aims , we obtained sera from a completed prospect i ve r and omized trial , which was design ed to assess the effectiveness of an oral contraceptive compared to placebo . Assessment s were carried out in 56 women with moderate acne who were treated with Ortho Tri-Cyclen ( norgestimate and ethinylestradiol ) ( 30 patients ) or placebo ( 26 patients ) for 6 months . Before and after treatment , the number and type of skin lesions , serum levels of total T , free-T , DHEAS and AoG were determined . Serum AoG increased significantly in women with moderate acne , although T , free-T and DHEAS were normal . 75 % of acne patients had elevated levels of serum AoG. Ratios of serum AoG to and rogen precursors were also elevated . Oral contraceptive ( OC ) treatment significantly reduced levels of free-T and AoG , both of which were unaffected by placebo . While both OC and placebo treatment result ed in improvement of comedones and inflammatory lesions , OC treatment decreased inflammatory lesions to a greater extent ( p<0.05 ) . After treatment , serum AoG correlated with the number of inflammatory lesions . Results showed that serum AoG is a sensitive marker of acne in women , even in those with normal circulating precursor and rogens ; and is lowered by OC treatment , correlating with the reduction of inflammatory lesions . We hypothesize that the increase of serum AoG in normo and rogenic acne may be related to inflammation , and serum AoG may serve as a marker of this process OBJECTIVE : To assess the efficacy of the combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol ( 3-mg drospirenone/20-microgram ethinyl estradiol ) administered as 24 consecutive days of active treatment after a 4-day hormone-free interval ( 24/4 regimen ) compared with placebo for the treatment of moderate acne vulgaris . METHODS : Healthy females aged 14–45 years with moderate acne were r and omized in this double-blind study to 3-mg drospirenone/20-microgram ethinyl estradiol ( n=270 ) or placebo ( n=268 ) for six cycles of 28 days . The primary outcome measures of acne lesion counts and Investigator Static Global Assessment scale ratings were assessed at baseline and during cycles 1 , 3 , and 6 . RESULTS : The percentage reduction from baseline to endpoint for total lesions is 46.3 % for 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 combination oral contraceptive group and 30.6 % for placebo group ( P<.001 ) . The likelihood of participants in the 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen group having “ clear ” or “ almost clear ” skin as rated by the investigators at endpoint was about threefold ( odds ratio 3.13 , 95 % confidence interval 1.69–5.81 ; P=.001 ) greater than in the placebo group . The 3-mg drospirenone/20-microgram ethinyl estradiol 24/4 regimen was well tolerated . CONCLUSION : The low-dose combined oral contraceptive containing 3-mg drospirenone/20-microgram ethinyl estradiol administered in a 24/4 regimen significantly reduced acne lesion counts more effectively than placebo and demonstrated greater improvement in the Investigator Static Global Assessment rating of acne . The safety profile was consistent with low-dose combined oral contraceptive use . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00651469 LEVEL OF EVIDENCE : Serum total an unbound testosterone ( T ) and sex hormone binding globulin ( SHBG ) levels were studied in fifty-four female acne patients before treatment and during the treatment by two different oral contraceptives , the other containing 0.150 mg desogestrel plus 0.03 mg EE and the other 0.150 mg levonorgestrel plus 0.03 mg EE . Pretreatment values were abnormal in 57 % of the patients . A borderline significant correlation between the severity of acne and SHBG was found . Ater six months ' treatment a 250 % increase in SHBG was seen in desogestrel/EE group and no significant change in SHBG in levonorgestrel/EE group . However , at the same time serum free testosterone fell 60 % in both treatment groups . SHBG can not be the only regulator of serum free testosterone . Acne improved significantly in both treatment groups . It is likely that the improvement was in connection with the free testosterone decrease and the improvement was better in the desogestrel/EE group where also SHBG elevation was seen In spite of an abundant literature on anti and rogen treatment with cyproterone acetate ( CA ) there have been no objective ly measured results to prove statistically the possible superiority of CA over combined oral contraceptive pills in the treatment of acne vulgaris . A multicenter study was therefore done , in which two preparations containing CA in combination with ethinylestradiol ( EE ) were compared with a marketed combined oral contraceptive pill . The preparations studied were : 1 ) CA 2 mg + EE 50μg ( DianeR ) , 2 ) CA 2 mg + EE 35 μg ( DianeR mite ) , 3 ) Levonorgestrel 150 μg + EE 30 μg ( NeovlettaR ) . A woman was eligible for the study if she was found by a dermatologist to have at least eight acne lesions ( sum of papules , pustules , cysts and nodules ) on her face , was otherwise healthy and without medication . After a primary assessment of the number of acne lesions by the dermatologist the woman was referred to a gynecologist and given one of the three test preparations double‐blind and at r and om . The treatment was to continue for 6 months . 133 women were recruited at eight different centers . The groups thus constituted were of similar size and comparable with regard to age , degree of acne , and menstrual and contraceptive histories . As the number of acne lesions varied considerably between patients all data were converted into percentage change during treatment before they were processed in a computer . After only 4 months of treatment the patients on DianeR and DianeR mite had a significantly greater reduction in the number of acne lesions compared with those on NeovlettaR. This difference was more pronounced at the end of the sixth treatment cycle , where there was an average reduction of acne lesions by 70 % in the DianeR and DianeR mite groups , compared with 35 % in the NeovlettaR group . Furthermore , the data scatter was less for the two DianeR groups . Among women taking DianeR or DianeR mite , only 4 % were found to have deteriorated , as compared with 18 % for NeovlettaR. The data support the previously unproven concept that regular oral contraceptive pills may improve acne in some women , whereas in others the condition was exacerbated . Bleeding patterns and contraceptive efficacy were excellent for all three preparations . Side effects were few and comparable to reports on other low‐dose oral contraceptives . DianeR mite had a tendency towards less pronounced “ estrogenic ” side effects and was equally effective in the treatment of acne as DianeR. DianeR mite is therefore suggested as the treatment of choice in women with acne who are otherwise willing to use an oral contraceptive Ninety female patients with acne were allocated r and omly to one of three groups and treated either with Diane , a high dose cyproterone acetate ( CPA ) regime with ethinyloestradiol , or Minovlar . The same dose of oestrogen was common to all three treatment groups BACKGROUND Acne is a multifactorial disease characterized by and rogenic stimulation of sebaceous gl and s. Therefore , combined oral contraceptives ( COCs ) containing anti- and rogenic progestogens are suitable c and i date s for acne treatment . This study aim ed to show that a COC containing the anti- and rogen dienogest ( DNG ) is superior to placebo and not inferior to a COC containing the potent anti- and rogen cyproterone acetate ( CPA ) in improving mild to moderate acne . STUDY DESIGN Healthy women between 16 and 45 years old with mild to moderate facial acne were r and omly assigned to receive ethinylestradiol (EE)/DNG ( n=525 ) , EE/CPA ( n=537 ) or placebo ( n=264 ) for six cycles in a multinational , multicenter , three-arm , double-blind and r and omized trial . The primary efficacy variables were the percentages of change ( from baseline to cycle 6 ) in inflammatory and total lesion count and the percentage of patients with acne improvement according to the Investigator Global Assessment . RESULTS All primary analyses proved that EE/DNG was superior to placebo and non-inferior to EE/CPA ( p<.05 ) . For inflammatory lesions , the reduction ( + /-SD ) rates were -65.6+/-29.9 % for EE/DNG , -64.6+/-31.2 % for EE/CPA and -49.4+/-41.0 % for placebo . For total lesions , the reduction rates were -54.7+/-26.3 % for EE/DNG , -53.6+/-27.5 % for EE/CPA and -39.4+/-33.6 % for placebo . The percentages of patients with improvement of facial acne were 91.9 % for EE/DNG , 90.2 % for EE/CPA and 76.2 % for placebo . CONCLUSION EE/DNG was superior to placebo , in spite of the prominent placebo effects , and as effective as EE/CPA in the treatment of mild to moderate acne , thus proving a valid option for the treatment of acne in women seeking oral contraception OBJECTIVE To assess the contraceptive efficacy , cycle control and acceptability of two monophasic oral contraceptives containing either 30 micrograms ethinylestradiol plus 150 micrograms desogestrel or 30 micrograms ethinylestradiol plus 75 micrograms gestodene . METHODS In a r and omized , open-label , six-cycle , group-comparative , multicenter study performed in Brazil , pregnancies , cycle-control parameters , incidence of side-effects and the presence and severity of acne vulgaris were assessed , and blood pressure and body weight were measured at pretreatment and after one , three and six cycles of oral contraceptive use . RESULTS Of the 595 women enrolled , 274 ( 86.7 % ) in the desogestrel/ethinylestradiol group and 227 ( 81.4 % ) in the gestodene/ethinylestradiol group completed the six cycles , providing data for 1753 and 1487 treatment cycles , respectively . Two pregnancies occurred , one of which ( in the desogestrel/ethinylestradiol group ) was attributed to user failure , whilst the other ( in the gestodene/ethinylestradiol group ) was thought to result from method failure . Cycle control was observed to be excellent ; the incidences of irregular bleeding and minor side-effects were low in both groups and decreased after an initial increase in the first cycle . Pre-existing acne improved in both groups , whereas blood pressure and body weight remained essentially unchanged . CONCLUSIONS Both desogestrel/ethinylestradiol and gestodene/ethinylestradiol provide effective oral contraception with comparable cycle control and acceptability Objective This pilot study evaluated the effects of a desogestrel-containing oral contraceptive ( DSG-OC ) on facial seborrhea ( oiliness ) , acne and related factors in otherwise healthy women with moderate facial acne vulgaris . Methods In this double-blind , placebo-controlled study , 41 women received DSG-OC ( 50/100/150 μg desogestrel plus 35/30/30 μg ethinylestradiol given in a 7/7/7 day regimen ) and 41 received placebo for six cycles . Seborrhea and skin assessment s , and hormone analyses were performed regularly . Results Analyses of sebum output ( measured using Sebutape ® ) indicated that the effect of DSG-OC on the skin varied with facial area . Compared with placebo , DSG-OC had a statistically significant effect on the cheeks ( 60 % relative reduction in sebum output ; p = 0.02 ) , and a non-significant effect on the forehead ( 30 % relative reduction in sebum output ) . Acne lesion counts did not differ significantly between groups . Both patient and investigator assessment s of skin condition ( visual analog scale ) indicated significant improvements with DSG-OC compared with placebo . The reduced sebum output with DSG-OC is associated with a three-fold increase in sex hormone binding globulin , as well as an expected decrease in free testosterone and other and rogens that were found in this group . Conclusion These results suggest that DSG-OC reduces facial oiliness and may be a useful contraceptive choice for women with this problem The purpose of this study was to compare , by a r and omized double-blind study , involving 30 women with either acne or mild hirsutism , the effects on plasma and rogens and lipoproteins , of two hormonal preparations used in acne and ensuring reliable contraception , namely DianeR ( cyproterone acetate 2 mg and ethinylestradiol 50 micrograms per pill - D-50 ) and Diane 35 ( cyproterone acetate 2 mg and ethinylestradiol 35 micrograms per pill - D-35 ) . Both drugs , used over a 6-month period ( treatment cycle of 21 days with a pill-free interval of 7 days ) , induced an impressive decrease of free testosterone levels and of 5 alpha- and rostane-3 alpha , 17 beta-diol-glucuronide , a parameter of peripheral and rogen formation ; also dehydroepi and rosterone sulfate levels decreased significantly . Except for an increase of both total T and dihydrotestosterone and as well as for a more important increase in SHBG levels during treatment with D-50 , consequences of its more pronounced estrogen dominance in comparison to D-35 , the effects of both drugs on and rogen levels were similar . The effects on lipids were characterized by a non-significant increase of total cholesterol and a significant increase of HDL-C , HDL2-C and Apo-Al lipoproteins , which were somewhat more pronounced during D-50 treatment . Triglycerides increased significantly during D-50 but hardly during D-35 treatment , whereas HDL-C/LDL-C increased similarly during treatment with either drug . It is concluded that , being as efficient as D-50 in treatment of acne and hirsutism and taking into account its reliable contraceptive effects , without unfavourable effects , as far as atherogenesis is concerned , on plasma lipids , D-35 is to be preferred over D-50 Objective To assess the contraceptive reliability , cycle control and tolerability of a new monophasic oral contraceptive containing 30 g ethinylestradiol plus 3 mg drospirenone ( Yasmin , Schering AG , Berlin , Germany ) , it was compared with an established oral contraceptive containing 30 g ethinylestradiol plus 150 g desogestrel ( Marvelon , NV Organon , Oss , The Netherl and s ) . Methods A r and omized , open-label , 13–cycle study was performed at 80 European centers . Contraceptive reliability , cycle control , blood pressure , body weight , the incidence of adverse events and skin condition were assessed during 13 cycles of oral contraceptive use , and at follow-up . Subjects recorded body weight on three consecutive days pretreatment and weekly thereafter . Results Of 2069 women who started the study and received the trial preparations in a ratio of 4:1 ( ethinylestradiol/drospirenone , n = 1657 ; ethinylestradiol/desogestrel , n = 412 ) , 1615 completed the 13 cycles plus follow-up , providing data for over 23 000 evaluable cycles . Eleven pregnancies occurred during treatment , only one of which ( in the ethinylestradiol/ drospirenone group ) could not be ascribed to user failure or interaction with other factors . Both preparations provided effective contraception and cycle control . Pre-existing acne and seborrhea were improved and blood pressure was essentially unchanged . The two treatments differed in their effect on body weight , the difference being statistically significant . In the ethinylestradiol/drospirenone group , there was a distinct decrease over the whole treatment phase , while a subtle and less distinct decrease was documented in the ethinylestradiol/desogestrel group . Conclusions The combination of 30 g ethinylestradiol/3 mg drospirenone provides effective oral contraception , excellent cycle control , good tolerability and a level of weight loss that may have a significant beneficial effect on compliance in women with a tendency to weight gain due to water retention Abstract Objective : To compare the cycle control , efficacy , and safety of a new low-dose combined oral contraceptive containing ethinylestradiol 20μg and drospirenone 3 mg with an established formulation containing ethinylestradiol 20μg and desogestrel 150μg . Methods : This was a r and omized , open-label , parallel-group , multicenter study of healthy women ( aged 18–35 years ) over seven treatment cycles . Both combined oral contraceptives were administered once daily for 21 consecutive days followed by a 7-day hormone-free interval . Results : A total of 445 women were r and omized to treatment ; of these , 441 ( ethinylestradiol 20μg/drospirenone 3 mg , n = 220 ; ethinylestradiol 20μg/desogestrel 150μg , n = 221 ) went on to receive study medication . There was a trend towards reduced intracyclic bleeding with continued treatment in both treatment groups , consistent with clinical experience . Intracyclic bleeding was highest during the first treatment cycle in both treatment groups , but was generally much lower in subsequent cycles . More than 90 % of women in each of the groups experienced withdrawal bleeding during the study . The duration of withdrawal bleeding remained fairly constant throughout the study . The maximum intensity was mainly bleeding , rather than spotting . Overall , cycle control , efficacy , and safety profiles were comparable between both groups . Adverse events were generally of mild-to-moderate intensity and were those typical of hormonal contraceptive use . Conclusion : In conclusion , both ethinylestradiol 20μg/drospirenone 3 mg and ethinylestradiol 20μg/desogestrel 150μg are effective and well tolerated contraceptives that provide good cycle control Changes in body weight and the incidence of estrogen-related side effects with low-dose oral contraceptives ( OCs ) containing 20 microg ethinyl estradiol ( EE ) have not been demonstrated in placebo-controlled trials . Two placebo-controlled , r and omized trials demonstrated the efficacy of a low-dose OC for the treatment of acne in healthy females ( n = 704 ; > or=14 years old ) with regular menstrual cycles and moderate facial acne . Patients were r and omized to receive 20 microg EE/100 microg levonorgestrel ( LNG ) or placebo for six cycles . Body weight was measured at baseline and during Cycles 1 , 3 , and 6 . The occurrence of adverse events was recorded at each visit . Mean changes in weight from baseline were similar with 20 microg EE/100 microg LNG [ 0.72 kg + /- 2.64 ( SD ; n = 349 ) ] and placebo [ 0.56 kg + /- 2.64 ( SD ; n = 355 ; p > 0.05 ) ] for the last measured weight of each patient . Rates of headache , nausea , weight gain , and breast pain , side effects commonly attributed to OCs , were also similar between groups ( p > 0.05 ) . No serious , unexpected , drug-related adverse events occurred during the study . The low-dose OC containing 20 microg EE/100 microg LNG is safe , well tolerated , and does not cause weight gain Levonorgestrel , as used in oral contraceptives , has antiovulatory activity at doses far lower than those producing and rogenic effects . Triphasil ® , containing levonorgestrel was compared with Diane ® , containing cyproterone acetate in a trial of acne treatment . Twenty closely matched patients were alternatively allocated to 6 months of Triphasil or Diane treatment . Both groups had a 72 % reduction in acne counts . Assays of total testosterone , and rogen index , free testosterone , dehydroepi and rosterone sulphate and and rostenedione showed significant reduction on treatment and sex hormone binding globulin was raised . All hormonal changes were more marked in the Diane group . Side effects caused only one withdrawal from the trial The basic characteristic of acne is seborrhea accompanied by increased keratinization and especially the irritation caused by the microorganism Propionibacterium acnes . About 90 % reduction in seborrhea can be accomplished by administration of Isotretonin but this substance has several side effects notably teratogenic activity . Since the production of sebum is controlled by and rogen the combination of cyproterone acetate and ethinyl estradiol has reduced seborrhea by 30- 50 % . For longterm therapy of acne in young women who desire a contraceptive an anti and rogen ovulation inhibiter has the " free " side effect of promoting skin efflorescence . A double blind r and omized clinical study of a combination of cyproterone acetate 2 mg and .035 mg ethinyl estradiol with 218 women over a total of 1695 cycles showed therapeutic results by the 3rd cycle in 51.9 % of the subjects and 91.5 % by the 9th cycle . Cycle control was stable and no pregnancies result ed during the study . In another comparable test slightly better results were obtained with a combination of ethinyl estradiol with chloramidinon acetate . There are no known cases of teratogenic effects from cyproterone acetate The objective of the study was to determine the suppressive effect on ovarian activity of 20 micrograms ethinylestradiol plus 75 micrograms gestodene administered for 21 or 23 days . The study was design ed as a double-blind , r and omized , multicenter trial in 60 women . A pre-treatment cycle , three treatment cycles and a post-treatment period were monitored by ovarian ultrasound and by LH , FSH , 17 beta-estradiol and progesterone measurements every other day . No ovulation and no luteinized , unruptured follicle were observed . Suppression of ovarian activity was more pronounced by the 23-day regimen . 17 beta-Estradiol serum levels during the last six days of a cycle and during the first six days of the next cycle were significantly less ( p < 0.05 ) in the 23-day regimen . The superiority of the 23-day regimen in comparison to the 21-day regimen with regard to the suppression of ovarian activity was shown in this study . The observed differences in the 17 beta-estradiol levels and follicular development between a 21-day and 23-day preparation combine to suggest that shortening the pill-free interval in combined oral contraceptives may increase the contraceptive safety margin in women on low-dose formulations BACKGROUND The study was conducted to assess the effects of the monophasic combined oral contraceptive containing ethinyl estradiol ( EE ) 0.03 mg and chlormadinone acetate ( CMA ) 2 mg ( EE/CMA ) on papulopustular acne of the face , décolleté ( low neck ) and back ; on moderate comedonal acne of the face ; and on seborrhea , alopecia and hirsutism . STUDY DESIGN Three hundred seventy-seven women were r and omized ( 2:1 ) to receive EE/CMA ( n=251 ) or placebo ( n=126 ) for six medication cycles . Due to the placebo-controlled , double-blind design of the trial , condoms were supplied for contraception . The primary efficacy end point was defined as a reduction of at least 50 % in the number of papules and /or pustules of the face from admission to Medication Cycle 6 . RESULTS In total , 64.1 % ( 161/251 ) of subjects treated with EE/CMA responded compared with 43.7 % ( 55/126 ) of those taking placebo ( p=.0001 ) . The median reduction in papules/pustules on the face at Cycle 6 compared with admission was 63.6 % ( EE/CMA ) compared with 45.3 % ( placebo group ) . For comedonal lesions of the face , the reduction in lesion numbers was 54.8 % ( EE/CMA ) compared with 32.4 % ( placebo ) . Moderate papulopustular acne of the décolleté decreased by 92.9 % ( EE/CMA ) vs. 50 % ( placebo group ) and of the back by 86.0 % and 58.3 % , respectively . For these skin conditions , the p values for the relative difference between groups vs. baseline were < .05 at Cycles 3 and 6 , in favor of EE/CMA . As part of a self- assessment rating , at least 70.5 % ( EE/CMA ) vs. 41.3 % ( placebo ) reported an at least satisfactory improvement of their moderate acne . Even 39.8 % of women taking EE/CMA reported an " excellent improvement " or " complete resolution " of moderate acne compared with 12.7 % taking placebo . CONCLUSION In addition to its contraceptive efficacy described elsewhere , EE/CMA is an effective treatment for moderate papulopustular acne and other and rogen-related skin disorders Abstract Background : The combined oral contraceptive Yasmin ® ( drospirenone 3 mg plus ethinylestradiol 30 μg [ DRSP 3 mg/EE 30 μg ] ) has been shown to be a well tolerated and effective combination that provides high contraceptive reliability and good cycle control . Furthermore , DRSP 3 mg/EE 30 μg has been shown to have a positive effect on premenstrual symptoms and well-being/health-related quality of life , and to improve the skin condition of women with acne . To date , however , there have been relatively few studies that have compared the effects of DRSP 3 mg/EE 30 μg on the general well-being of women with those of other oral contraceptives . Objectives : To compare the impact of DRSP 3 mg/EE 30 μg with that of levonorgestrel 150 mg/EE 30 μg ( LNG 150 μg/EE 30 μg ; Microgynon ® 30 ) on various parameters associated with well-being in healthy female subjects . Methods : This was a r and omized , single-blind , parallel-group , multicentre study conducted using 21/7-day regimens of DRSP 3 mg/EE 30 μg and LNG 150 μg/EE 30 μg over seven cycles . Efficacy parameters included : changes in Menstrual Distress Question naire ( MDQ ) normative T scores ; the proportion of subjects with acne ; and menstrual symptoms . Cycle control and subjective well-being parameters were also assessed . Results : Treatment with DRSP 3 mg/EE 30 μg had similar beneficial effects on symptoms of water retention and impaired concentration to LNG 150 μg/EE 30 μg , but was significantly better in alleviating negative affect symptoms during the menstrual phase ( median difference in MDQ T score −3 ; p = 0.027 ; Wilcoxon rank sum test ) . The proportion of subjects with acne decreased from approximately 55 % to approximately 45 % in the DRSP 3 mg/EE 30 μg group , but remained static at approximately 60 % in the LNG 150 μg/EE 30 μg group . Somatic and psychological symptoms occurred at the greatest intensity and for most subjects during the menstrual phase of the cycle in both groups . Both drugs had similar cycle control parameters with a tendency towards reduced bleeding with continued use . More subjects in the DRSP 3 mg/EE 30 μg group reported improved physical well-being ( 60 % vs 46 % ; p = 0.035 ; chi-squared [ χ2 ] test ) . Emotional well-being was reported improved in 61 % and 51 % of DRSP 3 mg/EE 30 μg and LNG 150 μg/EE 30 μg users , respectively ( p = 0.1190 ; χ2 test ) . Adverse events were typical of oral contraceptive use and did not give rise to any safety concerns . Conclusion : Both products had similar beneficial effects on symptoms of water retention and impaired concentration , but DRSP 3 mg/EE 30 μg was significantly better in alleviating negative affect symptoms during the menstrual phase . The proportion of subjects with acne decreased in the DRSP 3 mg/EE 30 μg group but not in the LNG 150 μg/EE 30 μg group . More subjects in the DRSP 3 mg/EE 30 μg group reported improved physical well-being compared with the LNG 150 μg/EE 30 μg group BACKGROUND A r and omized , double-blind , parallel-group study to investigate the efficacy and safety of the 3 mg drospirenone (drsp)/20 mcg ethinylestradiol ( EE ) combined oral contraceptive ( COC ) administered in a 24/4 regimen ( 24 active tablets and 4 inert tablets per cycle ) for the treatment of moderate acne vulgaris . STUDY DESIGN Healthy females ( aged 14 - 45 years old ) with moderate facial acne were r and omized to 3 mg drsp/20 mcg ( n=266 ) or placebo ( n=268 ) for six cycles of 28 days . RESULTS Women who received the 3 mg drsp/20 mcg EE 24/4 COC had greater reductions from baseline in inflammatory , noninflammatory and total lesion counts . The odds of women in the 3 mg drsp/20 mcg EE 24/4 regimen COC group having ' clear ' or ' almost clear ' skin as rated by the investigators at end point was about fourfold greater than that in the placebo group ( odds ratio 4.31 ; 95 % CI : 2.11 - 9.60 ; p=.001 ) . The 3 mg drsp/20 mcg EE 24/4 regimen COC was well tolerated and had a safety profile consistent with low-dose COC use . CONCLUSION The 3 mg drsp/20 mcg EE 24/4 regimen COC was significantly more effective than placebo in treating moderate acne vulgaris Premenstrual dysphoric disorder ( PMDD ) is a severe form of premenstrual syndrome ( PMS ) . This is the first trial of a unique oral contraceptive containing a combination of drospirenone ( DRSP , 3 mg ) and ethinyl estradiol ( EE , 30 microg ) for the treatment of PMDD . DRSP is a spironolactone-like progestin with anti and rogenic and antimineralocorticoid activity . Spironolactone has been shown to be beneficial in PMS , whereas oral contraceptives have shown conflicting results . In this double-blind , placebo-controlled trial , 82 women with PMDD ( Diagnostic and Statistical Manual of Mental Disorders , 4th ed . [ DSM IV ] ) were r and omized to receive DRSP/EE or placebo for three treatment cycles . The primary end point was change from baseline in luteal phase symptom scores as assessed on the Calendar of Premenstrual Experiences ( COPE ) scale . Patients treated with DRSP/EE showed a numerically greater change from baseline compared with those treated with placebo on each of the 22 COPE items and each of the 4 symptom factors . Between-group differences in symptom improvement reached statistical significance in factor 3 only ( appetite , acne , and food cravings , p = 0.027 ) . The secondary end points , Beck Depression Inventory ( BDI ) and Profile of Mood States ( PMS ) , were consistent with the primary end point in that patients treated with the oral contraceptive showed a numerically greater improvement from baseline compared with those treated with placebo . The results of this study show a consistent trend in the reduction of symptoms that suggested a beneficial effect of DRSP/EE for the treatment of PMDD , despite limitations of the study design OBJECTIVES Poor cycle control and tolerability can be reasons for irregular pill intake . This study compared the tolerability of two low-dose oral contraceptives and their effect on cycle control . METHODS In this open , group-comparative , r and omized multicenter trial in Germany and the Netherl and s , women received either 20 microg ethinylestradiol plus 150 microg desogestrel ( 20EE/DSG ; n = 500 ) or 20 microg ethinylestradiol plus 100 microg levonorgestrel ( 20EE/LNG ; n = 498 ) for six treatment cycles . Cycle control , dysmenorrhea and premenstrual syndrome ( PMS ) were assessed using diary cards . Tolerability was assessed using the self-administered question naires Psychological General Well-Being Index ( PGWBI ) and the Profile of Mood States ( POMS ) . Acne was assessed by objective ( acne counts ) and subjective ( no , moderate , mild , severe ) acne scoring of the facial area at baseline and treatment cycles 1 , 3 and 6 . RESULTS A total of 404 ( 78.1 % ) and 384 ( 75.3 % ) women in the 20EE/DSG and 20EE/LNG groups , respectively , completed the trial . The occurrence rate of irregular bleeding and spotting was statistically significantly higher with 20EE/LNG than with 20EE/DSG ( 0.18 vs. 0.13 ; p < 0.05 ) . The mean number of bleeding-spotting days per cycle was statistically significantly higher with 20EE/LNG than with 20EE/DSG ( 0.63 vs. 0.48 ; p < 0.05 ) . Early withdrawal bleeding was more frequent with 20EE/LNG ( 0.15 vs. 0.08 ; p < 0.005 ) , whereas continued withdrawal bleeding was more frequent with 20EE/DSG ( 0.32 vs. 0.45 ; p < 0.001 ) ; absence of withdrawal bleeding was comparable ( 0.06 vs. 0.04 , respectively ) . Thirteen subjects in the 20EE/LNG group and three in the 20EE/DSG group discontinued due to unacceptable bleeding ( p < 0.05 ) . Dysmenorrhea and PMS decreased comparably in both groups . There were no differences between groups for the mean total scores of PGWBI or POMS at all time-points . Fewer acne lesions were counted with 20EE/DSG vs. 20EE/LNG after six cycles ( p < 0.05 ) . The subjective acne scores supported this finding . CONCLUSIONS 20EE/DSG provided better cycle control than 20EE/LNG with less treatment discontinuation due to unacceptable bleeding . There were no apparent differences between the two groups regarding tolerability and quality of life . There was less acne with 20EE/DSG Treatment of virilization symptoms in 230 patients is reported . 68 patients were treated with Planovin ( 4 mg megestrol acetate and .05 mg ethinyl estradiol ) , 77 with SH81041 ( 100 mg Cyproterone acetate for 10 days and .05 mg ethinyl estradiol for 21 days ) , and 85 were treated first and Planovin and then with SH81041 . Acne , seborrhea , hirsutism , and alopecia improved under treatment with each preparation ; results were similar with acne and alopecia , while SH81041 was somewhat more effective than Planovin in treating seborrhea and hirsutism . Therapeutic results obtained during treatment with SH81041 in acne and alopecia are retained during Planovin treatment , but seborrhea and hirsutism become worse again . Successful treatment was independent of the severity of hirsutism and the duration of of treatment . Side effects included breakthrough bleeding and sweating One-hundred- and -eighty-three women were enrolled in an open , r and omized , multicentre study in which the effects on acne of a low-dose biphasic oral contraceptive containing a daily dosage of 25 micrograms desogestrel and 40 micrograms ethinylestradiol ( 7 days ) and a daily dosage of 125 micrograms desogestrel and 30 micrograms ethinylestradiol ( 15 days ) were compared to Diane-35 containing a daily dosage of 2.0 mg cyproterone acetate and 30 micrograms ethinylestradiol ( 21 days ) during four cycles of treatment . Clinical and photographic evaluation of acne plus laboratory assessment s were done before treatment and at the end of cycle 4 . A reduction with regard to the number of lesions and the degree of severity was observed in both groups . No differences were found between the two treatments in the clinical and photographic evaluation . In both treatment groups , a decrease in total testosterone and 3 alpha-17 beta- and rostanediol glucuronide was observed and an increase in SHBG . The decrease in 3 alpha-17 beta- and rostanediol was statistically significantly more pronounced in the Diane-35 group Two triphasic oral contraceptives containing either gestodene or norethindrone as the progestogenic compound combined with ethinyl estradiol were compared in a r and omized clinical trial to assess their contraceptive reliability , clinical tolerance and cycle control . Both preparations were effective in preventing pregnancy . The gestodene preparation proved significantly superior regarding cycle control and general tolerance The anti and rogen-containing preparation SH B 209 AB was tested in comparison with an ovulation inhibitor with no anti and rogenic effect ( Neogynon ) in a r and omized , double blind study conducted to determine the effects of both on and rogenization symptoms . 88 patients took part in the study . In the majority of cases the duration of the treatment period was more than 6 months . It was shown that the therapy with the combination preparation containing cyproterone acetate was distinctly more successful in cases of acne and seborrhoea : not only acne in its various locations but also all forms of seborrhoea were more favourably influenced by the trial preparation . This difference was statistically significant ( p less than 0.05 ) . It was not possible to establish a significant difference between the two preparations in the case of hirsutism in its various locations from the limited number of cases observed . There were also no differences detected in hepatic tolerance . During treatment with both preparations all values measured were within the normal range Summary Background Hormone studies have demonstrated the and rogen‐dependent character of female and rogenetic alopecia , but there have been few controlled studies of therapies for alopecia in women The investigators compared 2 mg cyproterone acetate ( CPA ) in combination with either 0.035 mg or 0.050 mg ethinyl estradiol ( EE2 ) ( Diane -35 versus Diane -50 ) in the treatment of acne . Both formulations of Diane were highly effective in improving acne , even in women who had been refractory to other types of medication . Cycle control with both formulations was excellent and adverse effects were generally mild and confined to the first two cycles of treatment . Mean plasma lipid levels increased with both treatments , yet most individual values remained within normal limits after one year of therapy while the LDL-cholesterol/HDL-cholesterol ratio was stable throughout the study period . Plasma testosterone and DHEA-S levels paralleled the decline in the clinical severity of the acne . There was no loss of clinical effectiveness with Diane -35 and it provided the advantage of a 30 % decrease in the amount of estrogen To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results

There was no overall effect on artificial airway occlusion , mortality , pneumonia , or respiratory complications ; however , the PaCO(2 ) and minute ventilation were increased when HMEs were compared to HHs and body temperature was lower . The cost of HMEs was lower in all studies that reported this outcome . There was some evidence that hydrophobic HMEs may reduce the risk of pneumonia and that blockages of artificial airways may be increased with the use of HMEs in certain subgroups of patients . There is little evidence of an overall difference between HMEs and HHs . However , hydrophobic HMEs may reduce the risk of pneumonia and the use of an HME may increase artificial airway occlusion in certain subgroups of patients . Therefore , HMEs may not be suitable for patients with limited respiratory reserve or prone to airway blockage .

BACKGROUND Humidification by artificial means must be provided when the upper airway is bypassed during mechanical ventilation . Heated humidification ( HH ) and heat and moisture exchangers ( HME ) are the most commonly used types of artificial humidification in this situation . OBJECTIVES To determine whether HHs or HMEs are more effective in preventing mortality and other complications in people who are mechanically ventilated .

We tested the hypothesis that active and passive airway humidification minimize hypothermia in infants , but that maintaining normothermia does not decrease the duration of postoperative recovery . A circle system was used to ventilate the lungs of anesthetized , intubated infants who were r and omly assigned to active airway humidification and warming with use of an MR450 Servo airway heater and humidifier set at 37 ° C ( n = 10 ) , passive airway humidification with use of the Humid-Vent Mini heat and moisture exchanger placed between the Y-piece of the circle and the endotracheal tube ( n = 10 ) , or no airway humidification and heating ( control , n = 10 ) . Anesthesia was induced with thiopental and maintained with isoflurane and nitrous oxide in oxygen . The relative humidity of inspired respiratory gases was ∼35 % in the control group and ∼90 % in the group undergoing active airway humidification . Initial inspired humidity in the passive humidification group ( 45 % ) increased to ∼80 % after 1 h of anesthesia . Humidity differed significantly across groups at all times ( P ≤ 0.05 ) . Steady-state rectal temperatures ( 100 - -120 min after induction ) were 36.2 ± 0.7 ° C in patients given active humidification and heating , 35.7 ± 0.9 ° C in the passively humidified group , and 35.2 ± 0.4 ° C in the control group ( P ≤ 0.05 between each group ) . Recovery from general anesthesia was rapid in all patients and did not correlate with central temperature changes or type of humidification ( P = NS ) . We conclude that heat and moisture exchangers are less effective than active heating and humidification , but significantly better than no humidification BACKGROUND The purpose of this study was to compare the performance of heat and moisture exchanger filters with heated humidifying systems in the mechanical ventilator circuit on the incidence of ventilator-associated pneumonia ( VAP ) and bacterial colonization . METHOD Two hundred and forty-three consecutive patients who required mechanical ventilation for 48 hours or more in the adult intensive care unit were r and omized to either a heat and moisture exchanger ( HME ) or a heated humidifying breathing circuit . RESULTS The VAP rate among the group with HME was 11.4 % ; the rate among the group with heated humidifying system ( HHS ) was 15.8 % . The difference was not statistically significant . Approximately 68 % of the patients in the HME group had no pathogen isolated compared with 50 % of the patients in the HHS group . This difference was statistically significant ( P = .006 ) . However , the distribution of the pathogens among those patients who had the isolated pathogens was mostly identical in the 2 groups . CONCLUSION Even though the study did not find HME to be significantly advantageous over the HHS , in as much as VAP rate is concerned , other advantages such as reduced nurses workload , reduced financial cost , and better safety made HME a more favorable device for use in our adult intensive care unit STUDY OBJECTIVE Determine the utility of a proposed algorithm in allowing safe , efficient humidification in mechanically ventilated patients using both a hygroscopic condenser humidifier ( HCH ) and heated humidifier ( HH ) . DESIGN A prospect i ve study using an algorithm to chose humidification devices based on physical examination and sputum characteristics . SETTING All patients admitted to the surgical ICU . PATIENTS One hundred twenty consecutive patients requiring mechanical ventilation ( MV ) were studied . INTERVENTIONS Patients were examined by the attending respiratory care practitioner and given either an HCH or HH . If patients demonstrated any of the following -- thick or tenacious secretions , core temperature < 32 degrees C , or bloody secretions -- they were given an HH . All others used an HCH . If any of the above conditions occurred during HCH use , the patient was given an HH . MEASUREMENTS AND RESULTS Duration of ventilation , incidence of nosocomial pneumonia , ventilator circuit colonization , and mortality were determined for patients in each group . Cost of humidification devices , number of suctioning procedures per day , and volume of saline solution instilled were also recorded . Initially , 27 percent ( 32/120 ) of patients used an HH and 73 percent ( 88/120 ) used an HCH . During the study , ten patients required changing to an HH during HCH use . Patients in the HH group were more likely to have preexisting lung disease and had a longer duration of ventilation ( 83 + /- 21 h ) and higher mortality ( 21 percent ) . Patients in the HCH group were more likely to be postoperative , had shorter duration s of ventilation ( 38 + /- 14 h ) , and lower mortality ( 9 percent ) . There was no difference in the incidence of nosocomial pneumonia between the two groups ( 9 percent vs 6 percent ) and endotracheal tube occlusion did not occur in either group . Circuit colonization was common in the HH group ( 64 percent ) but rate in the HCH group ( 5 percent ) . Cost per day was significantly less for the HCH group ( $ 4 vs $ 19.80 ) . Patients who required a change from HCH to HH did so at a mean of 5 days . CONCLUSION The proposed algorithm result ed in cost-efficient and safe application of humidification devices in patients in the surgical ICU Critically ill patients in the intensive care unit ( ICU ) are at high risk for infections associated with increased morbidity , mortality , and health care costs ( 1 - 3 ) . The overall infection rate in critically ill patients approaches 40 % and may be as high as 50 % or 60 % in patients who remain in the ICU for more than 5 days ( 4 , 5 ) . Respiratory tract infections account for 30 % to 60 % of all such infections . The incidence of pneumonia acquired in the ICU ranges from 10 % to 65 % ( 6 - 11 ) . Among patients at high risk for ventilator-associated pneumonia ( VAP ) are those who have chronic obstructive pulmonary disease , burns , neurosurgical conditions , the acute respiratory distress syndrome , and witnessed aspiration ; those who are reintubated ; and those who receive paralytic agents or enteral nutrition ( 12 , 13 ) . The attributable morbidity and mortality of VAP are clinical ly important . In a prospect i ve , matched cohort study , patients with VAP remained in the ICU 4.3 days ( 95 % CI , 1.5 to 7.0 days ) longer than patients who did not have VAP and had a trend toward an increased risk for death ( absolute risk increase , 5.8 % [ CI , 2.4 % to 14.0 % ] ) ( 14 ) . Six other studies using a matching strategy found a prolonged length of ICU stay associated with VAP ( range , 5 to 13 days ) and attributable mortality ranging from an absolute risk increase of 0 % to 50 % ( 15 - 20 ) . Therefore , strategies to decrease the incidence of VAP could decrease morbidity , mortality , and health care costs and improve patient safety . A survey of the use of VAP prevention strategies identified differences across countries ( 21 ) . For example , changing the ventilator circuit for each new patient was reported more frequently by French ICU directors than those in Canada ( 21 ) . This survey also showed that some effective strategies were used infrequently , suggesting inadequate translation of r and omized trial results into practice . One potential catalyst for knowledge translation is an evidence -based clinical practice guideline . Therefore , a Joint Planning Group of the Canadian Critical Care Society and Canadian Critical Care Trials Group commissioned the development of an evidence -based clinical practice guideline for the prevention of VAP . In this paper , we describe the methods used to create the guideline and the recommendations generated . Methods The Joint Planning Group selected an 11-member VAP Prevention Guideline Panel made up of 9 intensivists from university-affiliated and community hospitals , an ICU nurse , and an ICU respiratory therapist . Panel members were experts in critical care medicine ( n= 9 ) , VAP ( n= 4 ) , evidence -based medicine ( n= 4 ) , and guideline development ( n= 3 ) . The context was mechanically ventilated adult patients cared for in the ICU . The target audience was ICU clinicians in university-affiliated and community hospitals . To identify potentially relevant evidence , we search ed 3 bibliographic data bases ( MEDLINE , EMBASE , and the Cochrane Data base of Systematic Review s ) to 1 April 2003 for r and omized trials that evaluated interventions influencing VAP ( Appendix ) . We had no language restrictions . We also review ed personal files and practice guidelines on this subject previously published by the Centers for Disease Control and Prevention ( 22 ) and the American Thoracic Society ( 23 ) . We included r and omized trials and systematic review s of r and omized trials that 1 ) studied adult critically ill patients ; 2 ) had VAP as an outcome ; and 3 ) evaluated any of the following interventions : physical strategies ( route of endotracheal intubation , systematic search for maxillary sinusitis , frequency of ventilator circuit changes , type of airway humidification , frequency of humidifier changes , endotracheal suctioning system , subglottic secretion drainage , chest physiotherapy , and tracheostomy timing ) , positional strategies ( kinetic beds , semi-recumbent positioning , and prone positioning ) , and pharmacologic strategies ( stress ulcer prophylaxis and prophylactic antibiotics , including selective decontamination of the digestive tract ) . Since study authors used various definitions of VAP , we used the definitions they provided . The most common definition was a new or persistent radiographic infiltrate plus fever , leukocytosis , change in the volume or color of sputum , or isolation of a pathogen . If available , histologic evidence of pneumonia was also used . A priori , we decided to review only systematic review s of r and omized clinical trials for antibiotic prophylaxis and only r and omized clinical trials for all other topics . We excluded crossover and beforeafter studies . We also excluded r and omized trials of ventilator weaning , including noninvasive mechanical ventilation , and nutritional interventions evaluating VAP because guidelines addressing these topics have recently been published ( 24 , 25 ) . In duplicate and independently , 3 pairs of panel members critically appraised each trial ( 26 , 27 ) and systematic review ( 28 ) . Each member of a pair compared his or her independent appraisal of a given trial or systematic review with that of the other member of the pair . For each r and omized trial , we abstract ed sample , allocation , intervention , co- interventions , exclusions after r and omization , blinding of outcome assessment , definition of VAP , crude VAP events , relative risk for VAP , and other outcomes . For each intervention , we summarized the risk differences and calculated a pooled risk difference . For each systematic review , we abstract ed number of trials , population , intervention , selection criteria , search strategy , validity assessment , method of pooling results , homogeneity assessment , VAP definition , pooled event rates , and other outcomes . Before the panel meeting , each pair of appraisers achieved consensus on the validity and results of the trials they review ed . One month before the panel meeting , panel members received the evidence tables for review prepared by the 3 pairs of appraisers . A priori , panel members agreed to read all circulated documents and evidence tables in advance , to use levels of evidence to generate a status statement for each item , and to abide by the group process and consensus methods . The Canadian Critical Care Society appointed a chair to ensure that the panel achieved its objectives through group process ( 29 ) . At the panel meeting , each member recorded any potential conflicts of interest ( 30 ) . The pair of panel members responsible for critical appraisal of each intervention provided a structured written and oral presentation of the evidence . After the panel discussion , the initial evidence summary was revised if necessary . The panel members assigned levels of evidence , semi-quantitative scores to summarize the evidence and describe the intervention , and a status statement . We classified trials as level 1 if they had all of the following : concealed r and omization , blinded outcome adjudication , an intention-to-treat analysis , and an explicit definition of VAP . Trials were classified as level 2 if any one of these characteristics was unfulfilled and as level 3 if allocation was not strictly r and omized . We used a semi-quantitative score ( 0 , 1 , 2 , or 3 ) to evaluate each intervention with respect to the validity of the r and omized trials ; the effect size of each intervention ; the confidence intervals around the estimate of effect ; the homogeneity of the trial results ; and the safety , feasibility , and economic consequences of the intervention . The language of the status statement for each item was keyed to the levels of evidence and the semi-quantitative scores . We used the term recommended if there were no reservations about endorsing an intervention and the term considered if the evidence supported an intervention but there were minor uncertainties about the benefits , harms , or costs . No recommendation was made if evidence regarding an intervention was inadequate or if there were major uncertainties about the benefits , harms , or costs . After the panel meeting , the chair compiled the summaries and status statements and sent them to all panel members to check accuracy and clarity . In addition , the pairs of evidence appraisers wrote background documents for the interventions they appraised , including the rationale for each intervention , appraisal of r and omized trials and systematic review s , and harms and costs of the interventions . The chair and the writing committee organized the background documents , the evidence summaries , a table of the semi-quantitative scores , and the status statement for each item . We formatted the document with a structured abstract ( 31 ) , a summary of the evidentiary basis for each recommendation , and a status statement for each item . We also created a quick reference guide . The draft guideline document was su bmi tted for structured external review by the executives of the Canadian Critical Care Society and the Canadian Critical Care Trials Group and the respective executives of the Canadian Association of Critical Care Nurses , Canadian Society of Respiratory Therapists , Canadian Infectious Disease Society , and Canadian Thoracic Society . External review ers were asked to critique whether the guideline was logical , clear , and practical and to critique the guideline development process . The panel revised the document on the basis of this feedback . The final guideline was returned to the external review ers for further comments and official endorsement by their respective organizations . The final guideline was then piloted in 2 institutions . To record the agreement of each panel member with the final status statement for each item , we sent the final document to all panel members . Independently , blinded to each other 's ratings , panel members used a Likert scale from 1 to 9 that was anchored by disagree completely at the low end and agree completely at the high end . The panel will formally review and up date this guideline every 2 years ( 32 ) . The funding source played no role in study selection for this guideline and had no role in its Background Minimizing total respiratory heat loss is an important goal during mechanical ventilation . The aim of the present study was to evaluate whether changes in tracheal temperature ( a clinical parameter that is easy to measure ) are reliable indices of total respiratory heat loss in mechanically ventilated patients . Method Total respiratory heat loss was measured , with three different methods of inspired gas conditioning , in 10 se date d patients . The study was r and omized and of a crossover design . Each patient was ventilated for three consecutive 24-h periods with a heated humidifier ( HH ) , a hydrophobic heat-moisture exchanger ( HME ) and a hygroscopic HME . Total respiratory heat loss and tracheal temperature were simultaneously obtained in each patient . Measurements were obtained during each 24-h study period after 45 min , and 6 and 24 h. Results Total respiratory heat loss varied from 51 to 52 cal/min with the HH , from 100 to 108 cal/min with the hydrophobic HME , and from 92 to 102 cal/min with the hygroscopic HME ( P < 0.01 ) . Simultaneous measurements of maximal tracheal temperatures revealed no significant differences between the HH ( 35.7 - 35.9 ° C ) and either HME ( hydrophobic 35.3 - 35.4 ° C , hygroscopic 36.2 - 36.3 ° C ) . Conclusion In intensive care unit ( ICU ) mechanically ventilated patients , total respiratory heat loss was twice as much with either hydrophobic or hydroscopic HME than with the HH . This suggests that a much greater amount of heat was extracted from the respiratory tract by the HMEs than by the HH . Tracheal temperature , although simple to measure in ICU patients , does not appear to be a reliable estimate of total respiratory heat loss OBJECTIVE To compare the degree of bacterial circuit colonization , frequency of ventilator-associated pneumonia ( VAP ) , character of respiratory secretions , rewarming of hypothermic patients , disposable costs , and air flow resistance in intensive care patients ventilated using either a heat and moisture exchanger ( HME ) or hot water ( HW ) humidifier circuit . DESIGN A prospect i ve , r and omized blinded trial of patients in the intensive care unit undergoing mechanical ventilation . SETTING A metropolitan teaching hospital . PATIENTS One hundred sixteen patients undergoing mechanical ventilation for a minimum period of 48 hrs were enrolled . INTERVENTIONS Patients were r and omized to three ventilation groups using a ) an HW circuit with a 2-day circuit change ( n = 41 ) ; or b ) a bacterial-viral filtering HME in the circuit , with either a 2-day ( n = 42 ) ; or c ) a 4-day circuit change ( n = 33 ) . MEASUREMENTS AND MAIN RESULTS Circuit colonization was assessed using quantitative culture of washings taken from the circuit tubing and semiquantitative culture of swabs from the Y connectors . Sixty-seven percent of HW circuits became contaminated compared with 12 % in the two HME groups ( p < .0001 ) . Median colony counts were lower in the HME groups ( p < .0001 ) . If circuits at first circuit change were contaminated in the HW group , 89 % of subsequent circuit changes became contaminated compared with 0 % and 25 % for the 2- and 4-day HME groups , respectively . The frequency of VAP , the time to resolution of admission hypothermia , and the volume and fluidity of secretions were similar for all groups . The resistance of the HME after 24 hrs of use was < 0.025 cm H2O/L at gas flows of 40 L/min . HME use result ed in a cost reduction of $ 1.48 (Australian)/day . CONCLUSIONS Circuits with a bacterial-viral filtering HME are less readily colonized by bacteria . Contamination is a r and om event . Humidification technique has no influence on the frequency rate of VAP , the effectiveness of rewarming , nor the character of the respiratory secretions . Breathing resistance is generally low and disposable costs are reduced when an HME is used Abstract Objective In mechanically ventilated patients with induced hypothermia , the efficacy of heat and moisture exchangers and heated humidifiers to adequately humidify the airway is poorly known . The aim of the study was to assess the efficacy of different humidification devices during moderate hypothermia . Design Prospect i ve , cross-over r and omized study . Setting sMedical Intensive Care Unit in a University Hospital . Patients and participants Nine adult patients hospitalized after cardiac arrest in whom moderate hypothermia was induced ( 33 ° C for 24 h ) . Interventions Patients were ventilated at admission ( period design ated “ normothermia ” ) with a heat and moisture exchanger , and were r and omly ventilated during hypothermia with a heat and moisture exchanger , a heated humidifier , and an active heat and moisture exchanger . Measurements and results Core temperature , inspired and expired gas absolute and relative humidity were measured . Each system demonstrated limitations in its ability to humidify gases in the specific situation of hypothermia . Performances of heat and moisture exchangers were closely correlated to core temperature ( r2 = 0.84 ) . During hypothermia , heat and moisture exchangers led to major under-humidification , with absolute humidity below 25 mgH2O/l . The active heat and moisture exchanger slightly improved humidification . Heated humidifiers were mostly adequate but led to over-humidification in some patients , with inspiratory absolute humidity higher than maximal water content at 33 ° C with a positive balance between inspiratory and expiratory water content . Conclusions These results suggest that in the case of moderate hypothermia , heat and moisture exchangers should be used cautiously and that heated humidifiers may lead to over-humidification with the currently recommended setting Heat and moisture exchangers ( HME ) are increasingly used to warm and humidify inspired gases in intubated ventilated patients . But these devices add dead space that may alter the alveolar ventilation . This could impair the efficiency of spontaneous ventilation ( SV ) during weaning trials from mechanical ventilation . Fifteen patients were tested with an HME ( Hygrobac-DAR ) and a heated humidifier ( HH ) ( Fischer-Paykel MR 450 ) in a r and om order during weaning trials in SV with inspiratory pressure support . Minute ventilation VE , tidal volume ) , and respiratory rate were recorded and arterial blood was sample d for blood gas analysis with each device . The HME gave a significantly greater VE than the HH ( 9.3 + /- 0.8 L/min vs 8.1 + /- 0.8 L/min ; p < 0.005 ) , because of increased respiratory rate ( 21 + /- 2/min vs 19 + /- 2/min ; p < 0.05 ) . Tidal volume was unchanged for HME and HH ( 470 + /- 32 mL vs 458 + /- 39 mL ) . The higher PaCO2 with HME than with HH ( 44 + /- 2 mm Hg vs 42 + /- 2 mm Hg ; p < 0.005 ) revealed an insufficient alveolar ventilation response to the increase in dead space . Arterial Po2 rose with the HME , but not significantly above the HH values ( 103 + /- 6 mm Hg vs 97 + /- 6 mm Hg ; p = 0.055 ) , possibly because of a positive end-expiratory pressure effect of the HME . The need to increase VE in SV when an HME is used should be taken into account during difficult weaning from mechanical ventilation Objective : Complications following ventilation with dry and cold gases may be prevented by the use of artificial noses or heat and moisture exchangers , which are a solution to both the problems of humidification and heat preservation . The aim of the present study was to determine whether changing hydrophobic heat and moisture exchangers ( HMEs ) every 48 h rather than 24 h would affect their efficacy to preserve the heat and moisture of inspiratory gases . The impact of a prolonged use of the HME on its microbial colonization was also assessed.¶ Design : Prospect i ve observational study .¶ Setting : ICU of a university hospital.¶ Patients : Twelve patients requiring controlled mechanical ventilation for more than 2 days were evaluated.¶ Interventions : The patients were ventilated with a heat and moisture exchanger ( HME ) ( Maxipleat Filter , Europe Medical , France ) . The hydrophobic HME was placed between the Y-piece and the connecting tube and changed after 48 h of continuous use . Temperature ( ° C ) , relative humidity ( % ) and absolute humidity ( mgH2O/l ) were obtained using the capacitive sensor principle . Bacterial colonization ( tracheal secretions and ventilator side of the HME ) were obtained on days 1 and 2.¶ Measurements and results : After 48 h of ventilation with the same HME , tracheal tube occlusion was never observed . Using the same hydrophobic HME for 48 h rather than 24 h did not affect its technical performance : temperature at 24 h : 32.5 ± 1.3 ° C , at 48 h : 32.7 ± 1.8 ° C ; relative humidity(RH ) at 24 h : 99.0 ± 1.4 % , at 48 h : 99.0 ± 1.4 % ; absolute humidity(AH ) at 24 h : 34.0 ± 2.4 mgH2O/l , at 48 h : 34.4 ± 3.5 mgH2O/l . Peak and mean airway pressures did not change over the 48-h study period , with identical tidal and minute volumes in the study patients . Total respiratory heat losses were not modified during the 48-h study period ( at 24 h : 152 ± 47 cal/min , at 48 h : 149 ± 65 cal/min ) . Evaporative and convective heat losses were not modified either . On day 1 , eight patients had positive cultures of their tracheal secretions at a colony count of 103 or higher cfu/ml . After 48 h of use of the same HME , only six patients had a positive culture of their tracheal secretions . Cultures from the ventilator sides of the HMEs were all sterile ( 12/12 ) after 48 h of use.¶ Conclusions : Changing the hydrophobic HME after 48 h rather than 24 h did not affect its technical performance in terms of heat and water preservation of ventilatory gases . There is also some indirect evidence of very little , if any , change in HME resistance . No bacterial colonization of the ventilator sides of the HMEs was observed after 48 h of use . However , other large clinical trials should be undertaken to confirm the safety of extending the time between HME changes Objective : To investigate the mechanical effects of artificial noses . Setting : A general intensive care unit of a university hospital . Patients : 10 patients in pressure support ventilation for acute Abstract Objective : To document the changes in patterns of airway accidents in intubated patients . Design : Prospect i ve recording of all airway accidents over two periods:1994–1997 and 1998–1999 . Patients : Ventilated patients ( 5,046 ) intubated for 9,289 days over 4 years ( 1994–1997 ) and 2,932 ventilated patients intubated for 6,339 days over 2 years ( 1998–1999 ) . Measurements : The incidence and pattern of airway accidents over a 2-year period were compared to an earlier similar analysis done in the previous 4 years . Results : The total accident rate in the 1994–1997 period was 36 in 5,046 patients over 9,289 intubated-patient days . The total accident rate in the period 1998–1999 was 20 in 2,932 patients over 6,339 intubated-patient days . The frequency of blocked tracheal tube increased to equal that of unplanned extubation ( UE ) of endotracheal tube ( ETT ) as the commonest airway accident . There were nine episodes of blocked tracheal tube in the two current years compared to four in the previous 4 years and there were nine episodes of UE in the two current years compared to 15 in the previous 4 years . There were a total of 18 ETT accidents in 2,930 patients over 5,309 ETT days compared to a total of two tracheostomy accidents in 67 patients over 1,030 tracheostomy days . Conclusions : We noted a change of the pattern of airway accidents . We noted an increasing trend in the incidence of blocked tracheal tubes , associated with an increased duration of heat and moisture exchanger-filters use . We also noted that the incidence of tracheostomy tube accidents was similar to that of ETT accidents in the current study , unlike the earlier study where tracheostomy tube accidents were more frequent than ETT accidents . This was due to the elimination of tracheostomy tube displacements during the later study period . We associated this with the use of adjustable tracheostomy length tubes Introduction Some guidelines to prevent ventilator-associated pneumonia ( VAP ) do not establish a recommendation for the preferential use of either heat and moisture exchangers ( HMEs ) or heated humidifiers ( HHs ) , while other guidelines clearly advocate the use of HMEs . The aim of this study was to determine the incidence of VAP associated with HHs or HMEs . Methods A r and omized study was conducted in the intensive care unit of a university hospital involving patients expected to require mechanical ventilation for > 5 days . Patients were assigned to two groups ; one group received HH and the other group received HME . Tracheal aspirate sample s were obtained on endotracheal intubation , then twice a week , and finally on extubation , in order to diagnose VAP . Throat swabs were taken on admission to the intensive care unit , then twice a week , and finally at discharge from the intensive care unit in order to classify VAP as primary endogenous , secondary endogenous , or exogenous . Results A total of 120 patients were assigned to HMEs ( 60 patients ) and HHs ( 60 patients ) ; 16 patients received mechanical ventilation for less than five days and were excluded from the analysis . Data analysis of the remaining 104 patients ( 53 HMEs and 51 HHs ) showed no significant differences between groups regarding sex , age , Acute Physiology and Chronic Health Evaluation II score , pre-VAP use of antibiotics , days on mechanical ventilation , and diagnosis group . VAP was found in eight of 51 ( 15.69 % ) patients in the HH group and in 21 of 53 ( 39.62 % ) patients in the HME group ( P = 0.006 ) . The median time free of VAP was 20 days ( 95 % confidence interval , 13.34–26.66 ) for the HH group and was 42 days ( 95 % confidence interval , 35.62–48.37 ) for the HME group ( P < 0.001 ) . Cox regression analysis showed the HME as a risk factor for VAP ( hazard rate , 16.2 ; 95 % confidence interval , 4.54–58.04 ; P < 0.001 ) . Conclusion The patients mechanically ventilated for more than five days developed a lower incidence of VAP with a HH than with a HME There is no consensus concerning the best system of humidification during long-term noninvasive mechanical ventilation ( NIMV ) . In a technical pilot r and omised crossover 12-month study , 16 patients with stable chronic hypercapnic respiratory failure received either heated humidification or heat and moisture exchanger . Compliance with long-term NIMV , airway symptoms , side-effects and number of severe acute pulmonary exacerbations requiring hospitalisation were recorded . Two patients died . Intention-to-treat statistical analysis was performed on 14 patients . No significant differences were observed in compliance with long-term NIMV , but 10 out of 14 patients decided to continue long-term NIMV with heated humidification at the end of the trial . The incidence of side-effects , except for dry throat ( significantly more often present using heat and moisture exchanger ) , hospitalisations and pneumonia were not significantly different . In the present pilot study , the use heated humidification and heat and moisture exchanger showed similar tolerance and side-effects , but a higher number of patients decided to continue long-term noninvasive mechanical ventilation with heated humidification . Further larger studies are required in order to confirm these findings Background : Ventilation with endotracheal intubation bypasses the upper airway and the normal heat and moisture exchanging process of inspired gases . A continuous loss of moisture and heat occurs and predisposes patients to serious airway damage . We therefore prospect ively studied one heated humidifier system , one cold humidifier system and one heat and moisture exchanger in spontaneously breathing , tracheostomized intensive care unit patients to determine the ability to preserve patients ' heat and water Objective To determine whether use of a hygroscopic heat and moisture exchanger ( HME ) for 48 hrs without change affects its efficiency and the level of bacterial colonization in long-term mechanically ventilated medical intensive care unit patients . Design Prospect i ve , r and omized clinical study evaluating two hygroscopic HMEs . Setting Medical intensive care unit at a university teaching hospital . Patients Long-term mechanically ventilated medical intensive care unit patients , including chronic obstructive pulmonary disease patients . Interventions Patients were r and omly allocated to one of the two HMEs studied ( Hygrolife and EdithFlex ) and changed every 48 hrs . Devices in both groups could be changed if hygrometric measurements indicated insufficient humidity delivery . Measurements and Main Results Daily measurements of inspired gas temperature and relative and absolute humidity . In addition , cultures of tracheal aspirations and both patient and ventilator sides of the device were performed after 48 hrs of use . Ventilatory variables and clinical indicators of efficient humidification were also recorded . Prolonged use of both HMEs was safe and efficient ( no tracheal tube occlusion occurred ) . Mean duration of mechanical ventilation was 20 days . Both clinical indicators and hygrometric measurements showed that both devices performed well during 48 hrs . Absolute humidity with EdithFlex was significantly higher on day 0 and day 1 than with Hygrolife . Absolute humidity measured in chronic obstructive pulmonary disease patients was identical to that measured in the rest of the study population . Tracheal colonization and HME colonization were similar with both HMEs . Bacterial contamination of the ventilator side of both devices was markedly low . Conclusions These two purely hygroscopic HMEs provided safe and efficient humidification during a 48-hr period of use in long-term mechanically ventilated medical intensive care unit patients , including chronic obstructive pulmonary disease patients . In addition , they maintained ventilatory circuits clean , despite the absence of filtering media . The cost of mechanical ventilation is consequently reduced Heat and moisture exchangers ( HME ) ( Dar-Hygrobac II , Peters ) can safely be used every 24 h for long-term mechanical ventilation and provide a cost-saving alternative to heated humidifiers . We have prospect ively determined whether changing HMEs every 48 h only affects their clinical and bacteriological efficiency in a series of consecutive nonselected ICU patients requiring long-term mechanical ventilation . Two consecutive periods were compared . During period 1 , HMEs were replaced every day ; during period 2 , they were changed every 48 h. Patients from the two periods were similar in terms of age and indication for and overall duration of MV ( 10 + /- 8.6 versus 10 + /- 9 d , p = 0.9 ) . Minute ventilation and maximum values for peak airway pressure were identical during the two periods . These values were also identical after 1 and 2 d of HME use during period 2 , indicating that HME resistance was not increased by prolonged use . Obstruction of the tracheal tube occurred only once in a period 1 patient . The results of quantitative cultures indicate that the maximum and mean levels of bacterial colonization during the two periods were similar for the pharynx , trachea , Y-connector , patient , and ventilator side of the HME . More importantly , the incidence of nosocomial pneumonia was similar during the two periods ( 6/61 versus 8/68 , p = 0.7 ) . Thus , prolonged HME use is safe and provides a substantial reduction in the cost of mechanical ventilation Objective : To determine whether three hydrophobic and hygroscopic heat and moisture exchangers ( HMEs ) retain their heating and humidifying properties ( assessed by psychrometric measurements of absolute humidity , relative humidity , and tracheal temperature ) for 48 hrs without any drop in their bacteriologic efficiency . Design : Prospect i ve r and omized clinical trial . Patients : Sixty‐one consecutive unselected mechanically ventilated intensive care unit patients . Interventions : Patients were r and omly allocated to one of the three HMEs studied ( Hygrobac‐Dar from Mallinckrodt , n = 21 ; Humid‐Vent from Gibeck , n = 20 ; and Clear‐Thermal from Intersurgical , n = 20 ) . Measurements and Main Results : Hygrometric parameters were measured by psychrometry after 3 , 24 , and 48 hrs of use . Peak airway pressure was recorded every 6 hrs and averaged over 24 hrs . Bacterial colonization of both patients and circuits was studied . Patients in all three groups were similar in terms of age , indications for , and overall duration of mechanical ventilation . Tracheal tube occlusion never occurred . Hygrometric data included 371 measurements whereas bacteriologic data included > 700 sample s and cultures . The Hygrobac‐Dar HMEs gave a significantly higher absolute humidity whatever the time of measurement ( 3 , 24 , or 48 hrs ) than the other two HMEs ( p < .001 ) . The Clear‐Thermal HMEs gave the poorest hygrometric parameters ( p < .01 ) ; five of them were replaced prematurely ( 24 hrs ) because the absolute humidity was < 25 mg H2O/L. This did not occur for the other HMEs . Mean peak airway pressures were identical in the three groups . The bacterial colonizations of both patient and circuit were similar ( and negligible for circuits ) for all three groups . Conclusion : Some HMEs may be used safely for 48 hrs without change . However , this does not pertain to every br and of HME . Objective in vivo evaluation of their humidifying performances is decisive before extending their duration of use Purpose We hypothesized that expiratory tidal volume was underestimated , because a heat-moisture exchanger traps the expired vapor . We , therefore , design ed patient and bench studies to investigate the accuracy of tidal volume monitoring . Methods In a patient study , applying two humidifying systems ( a heat-moisture exchanger and a heated humidifier ) and two tidal volumes ( 12 and 6 ml·kg−1 ) with a Servo ventilator 300 , we recorded the displayed expiratory tidal volume and thoracic volume displacement , measured by respiratory inductive plethysmography . Temperature , relative humidity , and absolute humidity were measured at the airway opening and at the end of the expiratory limb . Using a model lung , we also tested three different ventilators ( Puritan-Bennett 7200ae , Evita 4 , and Servo ventilator 300 ) to investigate whether the effects of the heat-moisture exchanger and the heated humidifier on monitored tidal volume varied according to the br and of ventilator . Results With the use of the heat-moisture exchanger , the displayed expiratory tidal volume was significantly smaller , by 12%–14 % , than that with the heated humidifier , although thoracic volume displacement was identical in the two systems . The temperature and absolute humidity at the end of the expiratory limb were significantly lower with the heat-moisture exchanger than with the heated humidifier . In the model lung study , we investigated the effects of different br and s of ventilator on the expiratory tidal volume . A similar degree ( 8%–14 % ) of underestimation of tidal volume was observed with the heat-moisture exchanger , regardless of ventilator br and . Conclusion Monitored expiratory tidal volume was underestimated by approximately 10 % , when using a heat-moisture exchanger STUDY OBJECTIVE To determine the safety and cost-effectiveness of mechanical ventilation with an extended-use hygroscopic condenser humidifier ( Duration ; Nellcor Puritan-Bennett ; Eden Prairie , Minn ) compared with mechanical ventilation with heated-water humidification . DESIGN Prospect i ve r and omized clinical trial . SETTING Medical and surgical ICUs of Barnes-Jewish Hospital , St. Louis , a university-affiliated teaching hospital . PATIENTS Three hundred ten consecutive qualified patients undergoing mechanical ventilation . INTERVENTIONS Patients requiring mechanical ventilation were r and omly assigned to receive humidification with either an extended-use hygroscopic condenser humidifier ( for up to the first 7 days of mechanical ventilation ) or heated-water humidification . MEASUREMENTS Occurrence of ventilator-associated pneumonia , endotracheal tube occlusion , duration of mechanical ventilation , lengths of intensive care and hospitalization , acquired multiorgan dysfunction , and hospital mortality . RESULTS One hundred sixty-three patients were r and omly assigned to receive humidification with an extended-use hygroscopic condenser humidifier , and 147 patients were r and omly assigned to receive heated-water humidification . The two groups were similar at the time of r and omization with regard to demographic characteristics , ICU admission diagnoses , and severity of illness . Risk factors for the development of ventilator-associated pneumonia were also similar during the study period for both treatment groups . Ventilator-associated pneumonia was seen in 15 ( 9.2 % ) patients receiving humidification with an extended-use hygroscopic condenser humidifier and in 15 ( 10.2 % ) patients receiving heated-water humidification ( relative risk , 0.90 ; 95 % confidence interval=0.46 to 1.78 ; p=0.766 ) . No statistically significant differences for hospital mortality , duration of mechanical ventilation , lengths of stay in the hospital ICU , or acquired organ system derangements were found between the two treatment groups . No episode of endotracheal tube occlusion occurred during the study period in either treatment group . The total cost of providing humidification was $ 2,605 for patients receiving a hygroscopic condenser humidifier compared with $ 5,625 for patients receiving heated-water humidification . CONCLUSION Our findings suggest that the initial application of an extended-use hygroscopic condenser humidifier is a safe and more cost-effective method of providing humidification to patients requiring mechanical ventilation compared with heated-water humidification The hypothesis that both active and passive airway humidification prevents hypothermia in infants and children , but that neither decreases the duration of postoperative recovery was tested . Twenty-seven ASA physical status 1 or 2 patients were studied who weighed between 5 and 30 kg , underwent superficial operations , were anesthetized with halothane and 70 % N2O , and whose lungs were ventilated via a Rees modification of an Ayre 's t-piece . The children were r and omly assigned to receive active airway humidification and warming using an MR450 Servo airway heater and humidifier set at 37 degrees C ( n = 10 ) , passive airway humidification using the Humid-Vent 1 heat and moisture exchanger placed between the Ayre 's t-piece and the endotracheal tube ( n = 8) , or no airway humidification and heating ( control , n = 9 ) . Distal tracheal and tympanic membrane temperatures and airway humidity were recorded during the first 90 min of surgery . Rectal temperature was measured during the postanesthetic recovery period . Relative humidity of inspired respiratory gases was approximately 30 % in the control group and approximately 90 % in the group given active airway humidification . Initial inspired humidity in the passive humidification group ( 50 % ) increased to approximately 80 % , a level not significantly different from that in the active group after 80 min of anesthesia . Central body temperature increased 0.25 degrees C during active active airway humidification and heating , whereas temperature decreased 0.25 degrees C during passive humidification and 0.75 degrees C without airway humidification . Distal tracheal temperature was significantly higher in the groups given passive and active humidification than in the control group . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To study the efficiency of a heated humidifier and a heat and moisture exchanger in mechanically ventilated neonates and infants . DESIGN Prospect i ve , controlled , clinical study . SETTING University pediatric intensive care unit . PATIENTS Forty neonates and infants who needed mechanical ventilation were enrolled in the study . INTERVENTIONS None . MEASUREMENTS AND MAIN RESULTS A heat and moisture exchanger and active airway humidification were alternately used in the same patients to exclude interindividual differences in airway humidification . Airway humidity was measured by a new fast-response capacitive humidity sensor which measures airway humidity with an acquisition rate of 20 Hz throughout the respiratory cycle . The humidity sensor was placed at the endotracheal tube adapter . Measurements were done at the beginning and at the end of three consecutive sessions of passive , active , and again passive airway humidification , each session lasting 6 hrs . There was no significant difference between mean inspiratory airway humidity with the heated humidifier ( 33.8 + /- 2.9 mg/L ) and with the heat and moisture exchanger ( 34.0 + /- 2.6 mg/L ) . Moreover , the mode of airway humidification did not significantly influence body temperature or PCO2 . No serious side effects such as endotracheal tube occlusion were observed . CONCLUSIONS Passive airway humidification by a heat and moisture exchanger is effective in mechanically ventilated neonates and infants over a 6-hr period . However , the performance and safety of a heat and moisture exchanger in prolonged mechanical ventilation remain to be proven Inspired gases must be warmed and humidified during mechanical ventilation . In a prospect i ve r and omized study we compared the performance of a heated humidifier ( HH ) ( Draegger Aquaport ) and a heat and moisture exchanger ( HME ) ( Pall Filter BB 2215 ) . A total of 116 patients requiring mechanical ventilation ( Servo 900C Siemens ) were enrolled into the study and were r and omly assigned to 2 groups . Patients in group I were ventilated with a traditional breathing circuit with HH and patients in group II using a simplified circuit with HME . Pre-existing and hospital acquired atelectasis and pneumonia , occurrence of endotracheal tube ( ET ) occlusion and ventilatory parameters ( respiratory rate , tidal volume ) were studied . No statistical difference was found between groups for each parameter except the greater frequency of ET occlusions in the II group ( 0/61 vs 9/55 ) ( p=0.0008 ) . Pall Filter ( PF ) , a hydrophobic filter , humidifies the dry gases from the condensed water which is put down on the HME surfaces during cooling of saturated expired gases . This purely physical property is linked to the magnitude of the thermic gradient between the expired pried gase and the ambiant temperture . Performance impairment of PF in our study might be due to high ambiant temperature in the intensive care unit ( usually around 28 ° C ) which reduces thermic gradient and water exchanges . We conclude that efficiency of PF may be weak in some conditions of ambiant temperature OBJECTIVE To determine whether changing heat and moisture exchangers every 48 hrs rather than 24 hrs would affect their efficacy to preserve heat and moisture of expiratory gases . DESIGN Prospect i ve , controlled , r and omized , not blinded , study . SETTING Intensive care unit of a university hospital . PATIENTS Twenty-nine patients requiring controlled mechanical ventilation and paralysis for > 2 days . INTERVENTIONS After r and omization , the patients were allocated to one of the three following groups : a ) group 1 , ventilated for 24 hrs with a heat and moisture exchanger ; b ) group 2 , ventilated for 48 hrs with the same heat and moisture exchanger ; and c ) group 3 , ventilated for 48 hrs with a heated humidifier system . MEASUREMENTS AND MAIN RESULTS In each patient , during the inspiration phase , the following measurements were performed : a ) peak and mean airway pressures ; b ) mean values of temperature ; c ) relative and absolute humidity of inspired gases . In each patient , measurements were performed after 24 hrs and after 48 hrs , where appropriate . After 24 hrs , patients in groups 1 and 2 had similar levels of temperature ( 30.1 + /- 2.7 degrees C and 29.2 + /- 2.3 degrees C ) , relative humidity ( 98.3 + /- 3.6 % and 99.3 + /- 3.4 % ) , and absolute humidity ( 29.1 + /- 2.1 and 29.3 + /- 2.4 mg H2O/L ) . Using the same heat and moisture exchanger for 48 hrs rather than 24 hrs did not affect its technical performance . Results showed the following : a ) temperature , 24 hrs , 29.2 + /- 2.3 degrees C , 48 hrs , 28.7 + /- 1.9 degrees C ; b ) relative humidity , 24 hrs , 99.3 + /- 3.4 % , 48 hrs , 99.2 + /- 1.7 % ; and c ) absolute humidity , 24 hrs , 29.3 + /- 2.4 mg H2O/L , 48 hrs , 28.7 + /- 3.1 mg H2O/L. Peak and mean airway pressures did not change over the 48-hr study period , with identical tidal and minute volumes in the study patients . Higher levels of temperature and absolute humidity of inspired gases were observed in group 3 , compared with groups 1 and 2 ( p < .02 ) . CONCLUSIONS Changing the heat and moisture exchanger after 48 hrs rather than 24 hrs did not affect its technical performance in terms of heat and water preservation of ventilatory gases . There is also some indirect evidence of very few , if any , changes in heat and moisture exchanger resistance . However , other large clinical trials should be undertaken to confirm the safety of extending the time between heat and moisture exchanger change . The heated humidifier , supplied with electric energy maintained high levels of humidification and temperature over the 48-hr study period Background Limited data suggest that increased resistance to flow within endotracheal tubes ( ETT ) may occur in patients whose lungs are mechanically ventilated for more than 48 h , especially when airway humidification is inadequate . This could lead to sudden ETT obstruction or induce excessive loading during spontaneous breathing . Methods Twenty-three such patients were r and omly assigned to three types of airway humidifier based on three different working principles : a Fisher Paykell hot water system ( n = 7 ) , a Pall BB2215 heat and moisture exchanger ( HME ) hydrophobic filter ( n = 8) , and a Dar Hygrobac 35254111 HME hygroscopic filter ( n = 8) . The decrease in internal pressure along the ETT and the flow rate were measured in each patient every 2 days . An " effective inner diameter " was derived from these measurements and allowed the inner ETT configuration to be monitored . Results On the first day of intubation , the mean diameter was similar in the three groups , and was slightly smaller than the in vitro diameter ( mean + /- SD : 7.6 + /- 0.6 mm for Fisher-Paykell , 7.7 + /- 0.4 for Pall , and 7.5 + /- 0.4 for Dar ) . The mean diameter tended to decrease from day to day . At the end of the study , the overall reduction in mean diameter was significantly greater with the hydrophobic HME ( Pall ) than with the two other systems ( Pall : -6.5 + /- 4 % vs. -2.5 + /- 2.5 % for Dar and -1.5 + /- 3 % for Fisher-Paykell ; P < 0.01 with analysis of variance ) . The same was true of the mean reduction in effective inner ETT diameter expressed per day of ventilation ( -1.6 + /- 1.5 % per day for Pall vs. -0.5 + /- 0.4 % for Dar and -0.2 + /- 0.4 % for Fisher-Paykell ; P < 0.01 ) . In four patients , the ETT became obstructed and emergency repeated tracheal intubation was required . The Pall HME and the Fisher-Paykell system were being used in three and one patient , respectively . Before obstruction , the reduction in ETT diameter was significantly greater for these four patients than for the remaining 23 patients ( 7.8 + /- 1.4 % vs. 3.1 + /- 4.1 % ; P < 0.01 ) . Conclusions During prolonged mechanical ventilation , significant alterations in inner ETT configuration occur frequently and are influenced by the type of humidification device used . In vivo monitoring of ETT mechanical properties might be clinical ly useful STUDY OBJECTIVE To compare the thermal and humidification capacity of three heated hot water systems ( HHWSs ) and two heat and moisture exchangers ( HMEs ) in ICU patients su bmi tted to minute ventilation > 10 L/min . DESIGN Prospect i ve , controlled , r and omized , not blinded study . SETTING ICU of a university hospital . PATIENTS ICU patients requiring controlled mechanical ventilation with minute ventilation > 10 L/min . Patients had to be se date d and paralyzed and had to require ventilation for more than four days . INTERVENTIONS Following a r and omized order , the patients were ventilated for 24-h periods with three HHWSs ( Bennett Cascade 2 humidifier , Fisher-Paykel MR 460 and MR 600 ) and two HMEs ( Pall Ultipor and Hygrobac filter ) . MEASUREMENTS AND RESULTS In each patient and for each 24-h period , absolute humidity , ( AH ) , relative humidity ( RH ) of inspired gases , and tracheal temperature were obtained . Two HHWSs ( Bennett and Fisher-Paykel MR 460 ) had a better thermal and humidification capacity than any other systems ( p < 0.001 ) . The hydrophobic HME ( Pall filter ) had a poor thermal and humidification capacity ( RH : 79 + /- 8.7 percent ; AH : 20.6 + /- 2.3 mg H2O/L ) . The hygroscopic filter ( Hygrobac filter ) had better thermal and humidification capacity than the Pall filter ( RH : 92.5 + /- 3.6 percent ; AH : 29.1 + /- 1.8 mg H2O/L ; p < 0.001 ) . Tracheal temperature was well preserved by all systems . The thermic and humidification capability of the Hygrobac filter declined over 24 h. Since the Pall filter could not achieve an AH > 25 mg H2O/L in any patient , it was not studied beyond the first measurement . CONCLUSIONS The Hygrobac filter had a thermal and humidification capability closed to the two HHWSs ( 81 to 97 percent ) but the capability declines over 24 h. The Pall filter had a poor capability ( 54 to 74 percent of that of HHWSs ) PURPOSE To compare the performance of an in-line heat moisture exchanging filter ( HMEF ) ( Pall BB-100 ; Pall Corporation ; East Hills , NY ) to a conventional heated wire humidifier ( H-wH ) ( Marquest Medical Products Inc. , Englewood , Colo ) in the mechanical ventilator circuit on the incidence of ventilator-associated pneumonia ( VAP ) and the rate of endotracheal tube occlusion . METHODS This report describes a prospect i ve , r and omized trial of 280 consecutive trauma patients in a 20-bed trauma ICU ( TICU ) . All intubated patients not ventilated elsewhere in the medical center prior to their TICU admission were r and omized to either an in-line HMEF or a H-wH in the breathing circuit . Ventilator circuits were changed routinely every 7 days , and closed system suction catheters were changed every 3 days . HMEFs were changed every 24 h , or more frequently if necessary . A specific endotracheal tube suction and lavage protocol was not employed . Patients were dropped from the HMEF group if the filter was changed more than three times a day or the patient was placed on a regimen of ultra high-frequency ventilation . The Centers for Disease Control and Prevention ( CDC ) criteria for diagnosis of pneumonia were used ; early-onset , community-acquired pneumonia was defined if CDC criteria were met in < or =3 days , and late-onset , hospital-acquired pneumonia was defined if criteria were met in > 3 days . Laboratory and chest radiograph interpretation were blinded . RESULTS The patient ages ranged from 15 to 95 years in the HMEF group and 16 to 87 years in the H-wH group ( p = not significant ) , with a mean age of 46 years and 48 years , respectively . The male to female ratio ranged between 78 to 82%/22 to 18 % , respectively , and 55 % of all admissions were related to blunt trauma , 40 % secondary to penetrating trauma , and 5 % to major burns . There was no difference in Injury Severity Score ( ISS ) between the two groups . Moreover , there was no significant difference in mean ISS among those who did not develop pneumonia and those patients who developed either early-onset , community-acquired or late-onset , hospital-acquired pneumonia . The HMEF nosocomial VAP rate was 6 % compared to 16 % for the H-wH group ( p<0.05 ) , and total ventilator circuit costs ( per group ) were reduced . There were no differences in duration of ventilation ( mean+/-SD ) if the patient did not develop pneumonia or if the patient developed an early-onset , community-acquired or a late-onset , hospital-acquired pneumonia . Moreover , total TICU days were reduced in the HMEF group . In addition , the incidence of partial endotracheal tube occlusion was not significantly different between the H-wH and the HMEF groups . CONCLUSIONS The HMEF used in this study reduced the incidence of late-onset , hospital-acquired VAP , but not early-onset , community-acquired VAP , compared to the conventional H-wH circuit . This was associated with a significant reduction in total ICU stay . Disposable ventilator circuit costs in the HMEF group were reduced compared to the H-wH group in whom circuit changes occurred at 7-day intervals . CLINICAL IMPLICATION S The use of the HMEF is a cost-effective clinical practice associated with fewer late-onset , hospital-acquired VAPs , and should result in improved re source allocation and utilization Abstract Objective . To assess the ability of a heated humidifier to improve CO2 clearance in ARDS patients su bmi tted to protective ventilation . Design . Prospect i ve clinical study . Setting . University hospital intensive care unit . Patients . During a 12-month period , we studied 11 ARDS patients under protective mechanical ventilation with severe hypercapnia . Intervention . When PaCO2 was above 55 mmHg , the heat and moisture exchanger ( HME ) was removed and patients were ventilated using a heated humidifier ( HH ) until their recovery or death . The heated humidifier was inserted on the inspiratory limb of the respirator and the inspirated air was saturated to achieve a temperature of 40 ° C at the Y connector of ventilator tubing and of 37 ° C at the outlet of the endotracheal tube . Measurements and results . Mechanical measurements and blood gas analysis were performed just before removal of the HME , and 30 min after mechanical ventilation using HH . Ventilator parameters were kept constant in the two conditions . Using HH instead of HME , PaCO2 was safely decreased by 11±5 mmHg , without any need to change respiratory rate . No significant difference was noted in intrinsic PEEP or airway plateau pressure . Decrease in PaCO2 after HME removal was strongly correlated with the initial value of PaCO2 . Conclusion . Supposing there is an interest in correcting or limiting hypercapnic acidosis in ARDS patients su bmi tted to protective ventilation , HME removal and use of HH appears to be an efficient and safe way of increasing CO2 clearance Objective : To evaluate the effects of a heat and moisture exchanger and a heated humidifier on respiratory mucus and transportability by cilia and cough in patients undergoing invasive mechanical ventilation ( up to 72 hrs ) . Design : Prospect i ve , r and omized , clinical study . Setting : General intensive care unit and university research laboratory . Patients : A total of 32 consecutive patients with acute respiratory failure , who were intubated and mechanically ventilated in the intensive care unit setting , were enrolled in the study . Interventions : Patients were r and omly assigned to receive as a humidifying system a heat and moisture exchanger ( HME ) or heated humidified water ( HHW ) at the onset of mechanical ventilation ( time 0 ) . Respiratory mucus sample s were collected by suction using a sterile technique at time 0 , 24 , 48 , and 72 hrs of mechanical ventilation . Measurements and Main Results : Eleven patients were excluded from this study because of either extubation or death before 72 hrs of mechanical ventilation , leaving 12 patients in the HME group and nine patients in the HHW group . Ventilatory variables including minute volume , mean airway pressure , positive end‐expiratory pressure , FIO2 , as well as PaO2/FIO2 ratio , fluid balance ( last 6 hrs ) , furosemide , and inotrope administration ( last 4 hrs ) were recorded . In vitro mucus transportability by cilia was evaluated on the mucus‐depleted frog palate model , and the results were expressed as the mucus transport rate . Cough clearance ( an estimation of the interaction between the flow of air and the mucus lining the bronchial walls ) was measured using a simulated cough machine , the results being expressed in millimeters . Mucus wettability was measured by the contact angle between a mucus sample drop and a flat glass surface . Mucus rheologic properties ( mechanical impedance [ log G * ] and the ratio between viscosity and elasticity [ tan δ ] ) were measured using a magnetic microrheometer at 1 and 100 cGy/sec deformation frequency . The two humidification groups were comparable in terms of the Acute Physiology and Chronic Health Evaluation II score , age , gender , ventilatory variables , fluid balance , use of inotropes , and furosemide . Conclusion : Ours results indicate that air humidification with either HME or HHW at 32 ° C ( 89.6 ° F ) has similar effects on mucus rheologic properties , contact angle , and transportability by cilia in patients undergoing mechanical ventilation , except for transportability by cough , which diminished after 72 hrs of mechanical ventilation in the HME group ( p = .0441 ) The objective of this study was to compare the safety and efficacy of the Heat Moisture Exchange ( HME ) device with conventional humidification in neonates . Sixty-four neonates were r and omized at intubation to receive conventional humidification ( CH ) ( n = 34 ) or HME , via a Neoaid device ( n = 30 ) . Groups were compared for intrinsic characteristics and outcome variables . Data were assumed nonparametric and analyzed by Mann-Whitney and Fisher 's Exact test . No significant differences were found in group characteristics or outcome variables . Trends were noted for documented patent ductus arteriosus ( PDA ) , endotracheal tube blockage , and positive endotracheal aspirate culture . Rate of pneumothorax 2/34 ( CH ) versus 4/30 ( HME ) ( p = 0.4 ) ; rate of tube blockage 3/34 ( CH ) versus 2/30 ( HME ) ( p = 1.0 ) ; rate of PDA 8/34 ( CH ) versus 14/30 ( HME ) ( p = 0.093 ) and rate of endotracheal colonisation 1 7/34 ( CH ) versus 9/30 ( HME ) ( p = 0.17 ) . No significant difference was found for duration of ventilation or period in greater than 40 % oxygen between the two groups . There were no significant outcome differences between CH and HME . The HME device was cost-effective and simple to use . A larger multicenter trial is warranted to confirm the efficacy of HME A prospect i ve , r and omized , controlled study was undertaken to compare the Pall Ultipor breathing circuit filter ( PUBCF ) , a heat- and -moisture exchanger , and heated hot water systems ( HHWSs ) in ICU patients su bmi tted to controlled mechanical ventilation . Humidification of inspired gas and bacterial contamination of breathing circuits were evaluated . During the study , there were six episodes of tracheostomy tube ( TT ) occlusion in six patients included in the PUBCF group . No patient out of 42 included in the HHWS group experienced this complication ( p less than 0.01 ) . There were 4 percent of days with thick and tenacious bronchial secretions in the PUBCF group and no case in the HHWS group ( p less than 0.02 ) . In the PUBCF group , 23 percent of days with hypothermia were noted as opposed to 12 percent in the HHWS group ( p less than 0.01 ) . Fewer breathing circuits were found to be contaminated in the PUBCF group ( 11 percent ) than in the HHWS group ( 54 percent , p less than 0.01 ) . In patients with an organism growing in bronchial specimens , the same organism was found to contaminate the breathing circuit in 10 percent of cases in the PUBCF group and 77 percent of cases in the HHWS ( p less than 0.01 ) . We conclude that , in the conditions of this study , the PUBCF did not provide sufficient humidification of inspired gas in ICU patients . Protection against contamination of breathing circuits was effective , but 10 percent of patients remained at risk for this complication RATIONALE AND OBJECTIVES The respective influence on the incidence of ventilator-associated pneumonia of currently available systems used for warming and humidifying the gases delivered to mechanically ventilated patients , that is , heated humidifiers and heat and moisture exchanger filters , remains controversial . METHODS We addressed this question in a multicenter r and omized study comparing heated humidifiers ( with heated circuits ) and filters in an unselected population of 369 intensive care patients receiving mechanical ventilation for more than 48 h. MAIN MEASUREMENTS AND RESULTS The diagnosis of pneumonia was confirmed according to strict microbiologic criteria . There was no difference in pneumonia rate between the two groups ( 53 of 184 [ 28.8 % ] versus 47 of 185 [ 25.4 % ] for humidifiers versus filters ; p = 0.48 ) , or in the incidence density of pneumonia ( 27.4/1,000 ventilatory days versus 25.3/1,000 ventilatory days for humidifiers versus filters ; p = 0.76 ) . The mean duration of mechanical ventilation did not differ between the two groups ( 14.9 + /- 15.1 versus 13.5 + /- 16.3 days for humidifiers versus filters , p = 0.36 ) . Endotracheal tube occlusion occurred , respectively , in five patients and one patient in the humidifier and filter groups ( p = 0.12 ) . Intensive care mortality was identical in the two groups ( about 33 % ) . CONCLUSION These results suggest that both heated humidifiers and heat and moisture exchanger filters can be used with no significant impact on the incidence of ventilator-associated pneumonia and that other criteria may justify their choice Objective To evaluate the influence of airway humidification devices on the efficacy of ventilation in difficult to wean patients . Design A prospect i ve , r and omized , controlled physiologic study . Setting A 22-bed medical intensive care unit in a university hospital . Patients Chronic respiratory failure patients . Interventions Performances of a heated humidifier and a heat and moisture exchanger were evaluated on diaphragmatic muscle activity , breathing pattern , gas exchange , and respiratory comfort during weaning from mechanical ventilation by using pressure support ventilation . Eleven patients with chronic respiratory failure were su bmi tted to four pressure support ventilation sequences by using the heated humidifier and the heat and moisture exchanger at two different levels of pressure support ventilation ( 7 and 15 cm H2O ) . Measurement and Main Results Compared with the heated humidifier and regardless of the pressure support ventilation level used , the heat and moisture exchanger significantly increased all of the inspiratory effort variables ( inspiratory work of breathing expressed in J/L and J/min , pressure time product , changes in esophageal pressure , and transdiaphragmatic pressure;p < .05 ) and dynamic intrinsic positive end-expiratory pressure ( p < .05 ) . Similarly , the heat and moisture exchanger produced a significant increase in Paco2 ( p < .01 ) responsible for severe respiratory acidosis ( p < .05 ) , which was insufficiently compensated for despite a significant increase in minute ventilation ( p < .05 ) . This result ed in respiratory discomfort for all patients with the heat and moisture exchanger ( p < .01 ) . Adverse effects were partially counterbalanced by increasing the pressure support ventilation level with the heat and moisture exchanger by ≥8 cm H2O . Conclusions The type of airway humidification device used may negatively influence the mechanical efficacy of ventilation and , unless the pressure support ventilation level is considerably increased , the use of a heat and moisture exchanger should not be recommended in difficult or potentially difficult to wean patients with chronic respiratory failure Objective : To compare the temperature and humidification output of one heated humidifier system ( Bennett Cascade 2 Humidifier ) and two heat and moisture exchangers ( Pall Ultipor , BB 50 , and Humid‐Vent Filter ) in intensive care unit ( ICU ) patients su bmi tted to a minute ventilation of > 10 L/min . Design : Prospect i ve , controlled , r and omized , unblinded study . Setting : ICU of a university hospital . Patients : Eleven se date d and paralyzed patients who required controlled mechanical ventilation with a minute ventilation of > 10 L/min for > 3 days . Interventions : After a r and omized selection process , the patients were ventilated for 24‐hr periods with the humidifier and one of the heat and moisture exchangers . Both heat and moisture exchangers were first tested for 45 mins ; then , the heat and moisture exchanger that demonstrated the best performance in terms of temperature and water preservation was tested for 24 hrs . Measurements and Main Results : During the inspiration phase for each patient , the following measurements were performed : mean and minimum values of temperature , relative and absolute humidity of inspired gases . During the 45‐min test period , the Humid‐Vent Filter had a better temperature and humidification output than the Pall Ultipor Filter and thus was tested for 24 hrs . The Bennett Cascade 2 Humidifier and the Humid‐Vent Filter had a better thermic capacity than the Pall Ultipor Filter ( p < .001 ) . No difference was ever observed between the Bennett Cascade 2 Humidifier and the Humid‐Vent Filter regarding relative humidity . The Pall Ultipor Filter had a lower temperature and humidification output when compared with the other two systems ( p < .007 ) . Concerning absolute humidity of inspired gases , the Pall Ultipor Filter achieved a lower performance than any other tested systems ( p < .02 ) . A small but significant decrease in temperature and absolute humidity , but not in relative humidity , was seen after 24 hrs of use with the Humid‐Vent Filter . However , with this heat and moisture exchanger , all patients had an absolute humidity of > 28 mg H2O/L and a relative humidity of > 93 % after 24 hrs of use . Conclusions : In patients with a minute ventilation of > 10 L/min ( > 10.5 to 16.0 L/min ) , the Humid‐Vent Filter had a temperature and humidification output close to the reference system ( the Bennett Cascade 2 Humidifier ) . The Pall Ultipor Filter had a significantly lower temperature and humidification output in these patients . ( Crit Care Med 1994 ; 22:1871–1876 This prospect i ve study was conducted to evaluate the risk of nosocomial pneumonia when changing heat and moisture exchangers every 48 hours in 1996 instead of every 24 hours in 1995 for patients needing continuous mechanical ventilation . Medical and surgical patients in the two periods did not differ in terms of demographic characteristics and markers of acute or underlying illnesses . The incidence density of nosocomial pneumonia was not different in the two groups . Extended heat and moisture exchanger use reduces circuit manipulation and cost Objective : To compare the incidence of ventilator-associated pneumonia ( VAP ) in patients ventilated in intensive care by means of circuits humidified with a hygroscopic heat- and -moisture exchanger with a bacterial viral filter ( HME ) or hot-water humidification with a heater wire in both inspiratory and expiratory circuit limbs ( DHW ) or the inspiratory limb only ( SHW ) . Design : A prospect i ve , r and omized trial . Setting : A metropolitan teaching hospital 's general intensive care unit . Patients : Three hundred eighty-one patients requiring a minimum period of mechanical ventilation of 48 hrs . Interventions : Patients were r and omized to humidification with use of an HME ( n = 190 ) , SHW ( n = 94 ) , or DHW ( n = 97 ) . Measurements and Main Results : Study end points were VAP diagnosed on the basis of Clinical Pulmonary Infection Score ( CPIS ) ( 1 ) , HME resistance after 24 hrs of use , endotracheal tube resistance , and HME use per patient . VAP occurred with similar frequency in all groups ( 13 % , HME ; 14 % , DHW ; 10 % , SHW ; p = 0.61 ) and was predicted only by current smoking ( adjusted odds ratio [ AOR ] , 2.1 ; 95 % confidence interval [ CI ] , 1.1–3.9 ; p = .03 ) and ventilation days ( AOR , 1.05 ; 95 % CI , 1.0–1.2 ; p = .001 ) ; VAP was less likely for patients with an admission diagnosis of pneumonia ( AOR , 0.40 ; 95 % CI , 0.4–0.2 ; p = .04 ) . HME resistance after 24 hrs of use measured at a gas flow of 50 L/min was 0.9 cm H2O ( 0.4–2.9 ) . Endotracheal tube resistance was similar for all three groups ( 16–19 cm H2O min/L ; p = .2 ) , as were suction frequency , secretion thickness , and blood on suctioning ( p = .32 , p = .06 , and p = .34 , respectively ) . The HME use per patient per day was 1.13 . Conclusions : Humidification technique does not influence either VAP incidence or secretion characteristics , but HMEs may have air-flow resistance higher than manufacturer specifications after 24 hrs of use In recent years the use of devices called Heat and Moisture Exchangers ( HME ) has become widespread as gas conditioners for ICU patients requiring mechanical ventilation . As an important variation of the resistive properties of the HME , related to flow and duration of use , has recently been pointed out during “ in vitro ” studies , the use of these devices in COPD patients could increase the levels of auto PEEP and dynamic hyperinflation . In this study we have compared the levels of auto PEEP and difference in functional residual capacity ( Δ FRC ) in a group of COPD patients , requiring controlled mechanical ventilation ( CMV ) , at basal conditions and after the insertion into the circuit of three HMEs ( Dar Hygrobac , Pall Ultipor , Engstrom Edith ) at r and om : the results obtained excluded a significant increase of auto PEEP and Δ ( FRC ) both with “ new ” HMEs and after 12 h of continuous use STUDY OBJECTIVE To evaluate the safety of a combined heat and moisture exchanger filter ( HMEF ) for the conditioning of inspired gas in long-term mechanical ventilation ( MV ) . DESIGN R and omized controlled trial . SETTING Medical ICU in a large teaching hospital . PATIENTS One hundred fifteen consecutive patients who required > or = 48 h of MV . INTERVENTIONS Patients were r and omized at intubation time ( day 1 ) to receive inspired gas conditioned either by a water-bath humidifier heated at 32 degrees C ( HWBH ) or by an HMEF ( Hygroster ; DAR ; Mir and ola , Italy ) . MEASUREMENTS AND MAIN RESULTS The two study groups were comparable in terms of primary pathologic condition at the time of hospital admission , disease severity as measured by the Simplified Acute Physiology Score , and ICU mortality . They did not differ with respect to ventilator days per patient ( mean + /- SD : HMEF , 7.6 + /- 6.5 ; HWBH , 7.8 + /- 5.8 ) , incidence of endotracheal tube obstruction ( HMEF , 0/59 ; HWBH , 1/56 ) , and incidence of hypothermic episodes ( HMEF , five ; HWBH , two ) . In 41 patients receiving MV for > or = 5 days , the morphologic integrity of respiratory epithelium was evaluated on day 1 and day 5 , using a cytologic examination of tracheal aspirate smears . The state of ciliated epithelium was scored on a scale from 0 ( poorest integrity ) to 1,200 ( maximum integrity ) , according to a well-described method . In both patient groups , the scores slightly but significantly decreased from day 1 to day 5 ( mean + /- SD : HWBH , from 787 + /- 104 to 745 + /- 88 ; HMEF , from 813 + /- 79 to 739 + /- 62 ; p < 0.01 for both groups ) ; there were no statistically significant differences between groups . CONCLUSIONS These data indicate acceptable safety of HMEFs of the type used in the present study for long-term mechanical ventilation OBJECTIVES To evaluate the effect of two commonly used heat and moisture exchangers on respiratory function and gas exchange in patients with acute respiratory failure during pressure-support ventilation . DESIGN Prospect i ve , r and omized trial . SETTING Intensive care unit of a university hospital . PATIENTS Fourteen patients with moderate acute respiratory failure , receiving pressure-support ventilation . INTERVENTIONS Patients were assigned r and omly to two treatment groups , in which two different heat and moisture exchangers were used : Hygroster ( DAR S.p . A. , Mir and ola , Italy ) with higher deadspace and lower resistance ( group 1 , n = 7 ) , and Hygrobac-S ( DAR S.p . A. ) with lower deadspace and higher resistance ( group 2 , n = 7 ) . Patients were assessed at three pressure-support levels : a ) baseline ( 10.3 + /- 2.4 cm H2O for group 1 , 9.3 + /- 1.3 cm H2O for group 2 ) ; b ) 5 cm H2O above baseline ; and c ) 5 cm H2O below baseline . Measurements obtained with the heat and moisture exchangers were compared with those values obtained using the st and ard heated hot water humidifier . MEASUREMENTS AND MAIN RESULTS At baseline pressure-support ventilation , the insertion of both heat and moisture exchangers induced in all patients a significant increase in the following parameters : minute ventilation ( 12.4 + /- 3.2 to 15.0 + /- 2.6 L/min for group 1 , and 11.8 + /- 3.6 to 14.2 + /- 3.5 L/min for group 2 ) ; static intrinsic positive end-expiratory pressure ( 2.9 + /- 2.0 to 5.1 + /- 3.2 cm H2O for group 1 , and 2.9 + /- 1.7 to 5.5 + /- 3.0 cm H2O for group 2 ) ; ventilatory drive , expressed as P41 ( 2.7 + /- 2.0 to 5.2 + /- 4.0 cm H2O for group 1 , and 3.3 + /- 2.0 to 5.3 + /- 3.0 cm H2O for group 2 ) ; and work of breathing , expressed as either power ( 8.8 + /- 9.4 to 14.5 + /- 10.3 joule/ min for group 1 , and 10.5 + /- 7.4 to 16.6 + /- 11.0 joule/min for group 2 ) or work per liter of ventilation ( 0.6 + /- 0.6 to 1.0 + /- 0.7 joule/L for group 1 , and 0.8 + /- 0.4 to 1.1 + /- 0.5 joule/L. for group 2 ) . These increases also occurred when pressure-support ventilation was both above and below the baseline level , although at high pressure support the increase in work of breathing with heat and moisture exchangers was less evident . Gas exchange was unaffected by heat and moisture exchangers , as minute ventilation increased to compensate for the higher deadspace produced in the circuit by the insertion of heat and moisture exchangers . CONCLUSIONS The tested heat and moisture exchangers should be used carefully in patients with acute respiratory failure during pressure-support ventilation , since these devices substantially increase minute ventilation , ventilatory drive , and work of breathing . However , an increase in pressure-support ventilation ( 5 to 10 cm H2O ) may compensate for the increased work of breathing Adequate humidification of inspired gases with HMEs during long-term MV remains controversial . In this study , a comparison is made between tracheal secretions during long-term MV either with HME or conventional HH . Both the HME and HH groups were similar with respect to age , sex , diagnosis , duration of MV , SAPS and mortality . Temperature of gases in the tracheal tube was lower and the amount of tracheal instillations was greater in the HME group than in the HH group . Tracheal secretions became thicker between day 1 ( control ) and day 5 , in the HME group than in the HH group . Four and two tube occlusions occurred in HME and HH groups , respectively . Tracheal bacterial colonization was similar in the two groups . Given the advantages of HME ( reduced nurses ' work and financial cost ) , HME could be routinely used under cautious surveillance and replaced by HH if difficulty in suctioning occurs STUDY OBJECTIVE To compare the effects of using a heated humidifier ( HH ) , a heat and moisture exchanger ( HME ) , or no warming device in maintaining body temperature during surgical procedures of 1 to 4 hours ' duration . DESIGN A r and omized , controlled study . SETTING Operating room , Thomas Jefferson University Hospital , Philadelphia , PA . PATIENTS 51 ASA physical status I , II , and III patients , age 16 to 69 years , scheduled for a variety of lower abdominal procedures under general endotracheal anesthesia anticipated to last 1 to 4 hours . INTERVENTIONS We r and omly assigned patients to receiving an HH , an HME , or no warming device during the procedure . We then measured the patient 's sublingual temperature every 5 minutes prior to induction , every 15 minutes intraoperatively , and every 15 minutes postoperatively until he or she was discharged from the postanesthesia care unit , ( PACU ) . We also measured the esophageal temperature every 15 minutes intraoperatively . MEASUREMENTS AND MAIN RESULTS Sublingual temperature or esophageal temperature probes placed at the site of maximal heart tones indicated that the patients ' temperatures dropped significantly from baseline values in all three groups during the first 60 minutes of surgery , then remained constant during the next 120 minutes of surgery . Patients who had no warming device shivered and felt cold significantly more often than patients in the HH group but not more often than patients in the HME group . There was no difference in shivering between the HH and HME groups . The patients who received an HH tended to have a higher temperature ( a mean of 0.5 degrees C ) throughout the study , but this did not reach statistical significance . CONCLUSIONS Results indicate that these warming devices provide little benefit in preventing a temperature drop during procedures of 1 to 4 hours ' duration , although patients with an HH tended to have a higher temperature than those with an HME or no device STUDY OBJECTIVE To evaluate in patients su bmi tted to minute ventilation > 10 L/min the ability to preserve patients ' heat and humidity of two heat and moisture exchangers ( HMEs ) and one vaporizing humidifier ( VH ) . DESIGN Prospect i ve , r and omized , comparative , non-blinded study . SETTING Intensive care unit of a university hospital . PATIENTS Nine tracheally intubated , mechanically ventilated patients , se date d and su bmi tted to mechanical ventilation with minute ventilation > 10 L/min . INTERVENTIONS Using the psychrometric method , relative humidity ( RH ) and absolute humidity ( AH ) of inspired gas were obtained as well as temperature of inspired gas and tracheal temperatures ( maximal and minimal ) . Following a r and omized order , each patient was ventilated for two 24-h periods with a vaporizing humidifier ( Bennett Cascade 2 , Bennett ; France ) and one of two HMEs : Pall Ultipor filter BB50 ( Pall Biomedical ; France ) or DAR Hygroster filter ( Peters ; France ) . Both were first tested for a 45-min period and then the HME that achieved the best performance in terms of temperature and water preservation was tested for 24 h. MEASUREMENTS AND RESULTS During the 45-min test period , the Pall Ultipor HME achieved a lower performance than the other two systems for any of the studied parameters ( p < 0.05 to p < 0.0001 ) . The DAR Hygroster HME achieved lower temperature of inspired gas ( 29.9 vs 32.0 degrees C , p < 0.005 ) and lower absolute humidity ( 29.3 vs 33.2 mg H2O/L , p < 0.005 ) than the Bennett Cascade 2 . After 24 h of use , lower values of temperature of inspired gas ( 28.5 vs 32.0 degrees C , p < 0.002 ) and of AH ( 28.0 vs 33.6 mg H2O/L , p < 0.001 ) were obtained with the DAR Hygroster HME than with the Bennett Cascade 2 . No differences were found between the two systems for the other tested parameters . At that time , no patients had RH lower than 97 % and absolute humidity lower than 23 mg H2O/L with the use of the DAR Hygroster HME . CONCLUSIONS In patients with minute ventilation > 10 L/min , the DAR Hygroster HME showed a thermic and humidification capability similar to the reference system , the Bennett Cascade 2 VH . In these patients , the Pall Ultipor HME had a significantly lower capability STUDY OBJECTIVE To determine the correlation between simple rating of condensation seen in the flex-tube connecting the heating and humidifying device used with the endotracheal tube and hygrometric parameters ( absolute and relative humidity and tracheal temperature ) measured by psychrometry . DESIGN Prospect i ve r and omized clinical trial . SETTING Medical ICU of Louis Mourier Hospital , Colombes , France , a university-affiliated teaching hospital . PATIENTS Forty-five consecutive mechanically ventilated critically ill patients . INTERVENTIONS Patients undergoing mechanical ventilation were r and omly assigned to receive humidification with one of the four heat and moisture exchangers ( HMEs ) tested or with a conventional heated humidifier . MEASUREMENTS The hygrometric performances of four HMEs ( BB2215 , BB50 , and BB100 from Pall Biomedical , Saint-Germaine-en-Laye , France ; and Hygrobac-Dar from Mallinckrodt , Mir and ola , Italy ) and a heated humidifier ( Fisher & Paykel ; Auckl and , New Zeal and ) were studied after 3 h and also after 48 h of use for the Hygrobac-Dar and correlated to a clinical visual inspection rating the amount of condensation in the flex-tube of the endotracheal tube . RESULTS A total of 95 measurements in 45 patients were performed . The best hygrometric parameters were obtained with the heated humidifier ( p < 0.001 ) . The Hygrobac-Dar yielded significantly higher values for both humidities and tracheal temperature than the other three HMEs ( p < 0.001 ) . The performance of Hygrobac-Dar was unchanged after 48 h of use . There was a significant correlation between the condensation seen in the flex-tube and the hygrometric parameters measured by psychrometry ( absolute humidity , rho = 0.7 ; relative humidity , rho = 0.7 ; tracheal temperature , rho = 0.5 , p < 0.0001 ) . CONCLUSION In mechanically ventilated ICU patients , visual evaluation of the condensation in the flex-tube provides an estimation of the heating and humidifying efficacy of the heating and humidifying device used , thus allowing the clinician bedside monitoring of airway humidification Objective To evaluate the effects of the humidification device on respiratory , hemodynamic and gas exchange parameters in acute respiratory distress syndrome ( ARDS ) patients . Design A prospect i ve open study . Setting A medical intensive care unit of a university hospital . Patients Acute respiratory distress syndrome patients , with hypercapnia ( PaCO2>60 mmHg).InterventionA progressive reduction of the humidification system dead space ( DSh ) . The following five conditions were tested sequentially : ( 1 ) heat and moisture exchanger ( internal volume=95 ml ) with a tracheal closed-suction system ( internal volume=25 ml ; total DSh=120 ml ) , ( 2 ) heat and moisture exchanger ( internal volume=45 ml ) with the closed-suction system ( DSh=70 ml ) , ( 3 ) heat and moisture exchanger ( internal volume=25 ml ) with the closed-suction system ( DSh=50 ml ) , ( 4 ) heated humidifier with the closed-suction system ( DSh=25 ml ) and ( 5 ) heated humidifier alone ( DSh=0 ml ) . Recordings were performed at baseline and every 30 min after each artificial dead-space reduction . All ventilatory setting s remained constant during the measurement periods . Results Ten ARDS patients were included . A significant PaCO2 decrease was observed at each humidification system dead-space reduction , compared to baseline : PaCO2 = 80.3±20 mmHg at DSh120 compared to PaCO2 = 63.6±13 mmHg at DSh0 ( p<0.05 ) . No changes were observed for hemodynamic and ventilatory parameters between the different humidification devices . Conclusion Artificial airway dead-space reduction allows a significant PaCO2 reduction . Independently of any respiratory mechanical changes , this very simple maneuver may be of importance when low tidal volume ventilation is used in ARDS patients , and when PaCO2 lowering is warranted

They did not report tophi regression , pain and function . There was moderate- quality evidence of little or no difference in the proportion of participants achieving target serum urate when allopurinol was compared with benzbromarone .

BACKGROUND Allopurinol , a xanthine oxidase inhibitor , is considered one of the most effective urate-lowering drugs and is frequently used in the treatment of chronic gout . OBJECTIVES To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout .

BACKGROUND Febuxostat , a novel nonpurine selective inhibitor of xanthine oxidase , is a potential alternative to allopurinol for patients with hyperuricemia and gout . METHODS We r and omly assigned 762 patients with gout and with serum urate concentrations of at least 8.0 mg per deciliter ( 480 micromol per liter ) to receive either febuxostat ( 80 mg or 120 mg ) or allopurinol ( 300 mg ) once daily for 52 weeks ; 760 received the study drug . Prophylaxis against gout flares with naproxen or colchicine was provided during weeks 1 through 8 . The primary end point was a serum urate concentration of less than 6.0 mg per deciliter ( 360 micromol per liter ) at the last three monthly measurements . The secondary end points included reduction in the incidence of gout flares and in tophus area . RESULTS The primary end point was reached in 53 percent of patients receiving 80 mg of febuxostat , 62 percent of those receiving 120 mg of febuxostat , and 21 percent of those receiving allopurinol ( P<0.001 for the comparison of each febuxostat group with the allopurinol group ) . Although the incidence of gout flares diminished with continued treatment , the overall incidence during weeks 9 through 52 was similar in all groups : 64 percent of patients receiving 80 mg of febuxostat , 70 percent of those receiving 120 mg of febuxostat , and 64 percent of those receiving allopurinol ( P=0.99 for 80 mg of febuxostat vs. allopurinol ; P=0.23 for 120 mg of febuxostat vs. allopurinol ) . The median reduction in tophus area was 83 percent in patients receiving 80 mg of febuxostat and 66 percent in those receiving 120 mg of febuxostat , as compared with 50 percent in those receiving allopurinol ( P=0.08 for 80 mg of febuxostat vs. allopurinol ; P=0.16 for 120 mg of febuxostat vs. allopurinol ) . More patients in the high-dose febuxostat group than in the allopurinol group ( P=0.003 ) or the low-dose febuxostat group discontinued the study . Four of the 507 patients in the two febuxostat groups ( 0.8 percent ) and none of the 253 patients in the allopurinol group died ; all deaths were from causes that the investigators ( while still blinded to treatment ) judged to be unrelated to the study drugs ( P=0.31 for the comparison between the combined febuxostat groups and the allopurinol group ) . CONCLUSIONS Febuxostat , at a daily dose of 80 mg or 120 mg , was more effective than allopurinol at the commonly used fixed daily dose of 300 mg in lowering serum urate . Similar reductions in gout flares and tophus area occurred in all treatment groups Objectives : To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout , and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment . Methods : Prospect i ve , multicentre , open-label , two-stage r and omised controlled trial in gout patients with normal renal function . Enrolled patients were given 300 mg allopurinol for 2 months ( stage 1 ) . Those patients who could not tolerate allopurinol or who did not attain the target serum urate concentration ( sUr ) ⩽0.30 mmol/l ( 5.0 mg/dl ) , which was defined as successful , were r and omised to benzbromarone 200 mg/day or probenecid 2 g/day for another 2 months ( stage 2 ) . Results : 96 patients were enrolled in stage 1 . 82 patients ( 85 % ) were eligible for the analysis at the end of stage 1 : there was a mean ( SD ) decrease in sUr concentration of 35 (11)% from baseline ; 20 patients ( 24 % ) attained target sUr ⩽0.30 mmol/l ; and 9 patients ( 11 % ) stopped allopurinol because of adverse drug reactions . 62 patients were enrolled in stage 2 . 27 patients received benzbromarone ( 3 patients not eligible for analysis ) and 35 received probenecid ( 4 patients not eligible for analysis ) . Treatment with benzbromarone was successful in 22/24 patients ( 92 % ) and with probenecid in 20/31 patients ( 65 % ) ( p = 0.03 compared with benzbromarone ) . Compared with baseline values , there was a mean ( SD ) decrease of sUr concentration of 64 (9)% with benzbromarone and 50 (7)% with probenecid ( p<0.001 ) . Conclusion : This study showed that allopurinol 300 mg/day has a poor efficacy and tolerability profile when used to attain a biochemical predefined target level of sUr ⩽0.30 mmol/l , following 2 months of treatment . In stage 2 , benzbromarone 200 mg/day was more effective and better tolerated than probenecid 2 g/day . Trial registration number : IS RCT N21473387 Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone . Assessment s of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine . The renal function of patients given allopurinol did not change . Treatment with allopurinol result ed ina significant reduction of ammonium excretion , a phenomenon which could not be readily explained . Urate clearance also declined during allopurinol treatment , and the impaired urate clearance associated with gout became more evident . The most important observation was that allopurinol retarded an apparent decline of renal function . Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys Introduction The purpose of this study was to compare urate-lowering ( UL ) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate ( sUA ) ≥ 8.0 mg/dL in a six-month trial . Methods Subjects ( n = 2,269 ) were r and omized to febuxostat 40 mg or 80 mg , or allopurinol 300 mg ( 200 mg in moderate renal impairment ) . Endpoints included the proportion of all subjects with sUA < 6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA < 6.0 mg/dL. Safety assessment s included blinded adjudication of each cardiovascular ( CV ) adverse event ( AE ) and death . Results Comorbidities included : renal impairment ( 65 % ) ; obesity ( 64 % ) ; hyperlipidemia ( 42 % ) ; and hypertension ( 53 % ) . In febuxostat 40 mg , febuxostat 80 mg , and allopurinol groups , primary endpoint was achieved in 45 % , 67 % , and 42 % , respectively . Febuxostat 40 mg UL was statistically non-inferior to allopurinol , but febuxostat 80 mg was superior to both ( P < 0.001 ) . Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg ( 72 % ; P < 0.001 ) compared with febuxostat 40 mg ( 50 % ) or allopurinol ( 42 % ) , but febuxostat 40 mg showed greater efficacy than allopurinol ( P = 0.021 ) . Rates of AEs did not differ across treatment groups . Adjudicated ( APTC ) CV event rates were 0.0 % for febuxostat 40 mg and 0.4 % for both febuxostat 80 mg and allopurinol . One death occurred in each febuxostat group and three in the allopurinol group . Conclusions Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol ( 300/200 mg ) , which were comparable . In subjects with mild/moderate renal impairment , both febuxostat doses were more efficacious than allopurinol and equally safe . At the doses tested , safety of febuxostat and allopurinol was comparable . Clinical Trial Registration This study was aim ed to evaluate the efficacy of benzbromarone compared to allopurinol in lowering serum uric acid level in hyperuricemic patients with normal renal function ( serum creatinine < or = 1.5 ) . The authors conducted a crossover study consisting of two four-week treatment periods of allopurinol 300 mg/day and benzbromarone 100 mg/day separated by a four-week washout period . Fourteen patients with mean age and duration of hyperuricemia of 60.78 + /- 8.62 and 6.93 + /- 3.69 years , respectively , were recruited and all completed our study protocol . This study was a crossover design consisting of two four-week treatments of allopurinol and benzbromarone separated by a four-week washout period . The serum uric acid level was reduced from 9.89 + /- 1.43 mg/dl to 5.52 + /- 0.83 mg/dl and from 9.53 + /- 1.48 to 4.05 + /- 0.87 mg/dl by allopurinol and benzbromarone , respectively . The efficacy of benzbromarone in lowering serum uric acid level was significantly superior to allopurinol ( p=0.005 ) . No patient reported clinical side effects during treatment with either drug . In conclusion , the authors have shown that benzbromarone is more effective than allopurinol in the reduction of serum uric acid levels in hyperuricemic patients with normal renal function OBJECTIVE To observe the clinical effect of a modified Simiao Tang ( Modified Decoction of Four Wonderful Drugs ) for gouty arthritis and its influence on uric acid in blood . METHODS 120 cases of gouty arthritis were r and omly divided into the treatment group and control group with 60 cases in each group . Modified Simiao Tang ( MST ) was orally administered to the patients in the treatment group and allopurinol tablet was orally administered to the patients in the control group . The clinical effects of two groups were evaluated after one-week treatment and uric acid ( UA ) and C-reactive protein ( CRP ) levels in blood were determined after 1-month treatment . RESULTS The total effective rate in the treatment group was significantly higher than in the control group , 86.7 % vs. 68.3 % ( P < 0.01 ) . And the treatment group was also significantly better than the control group in decreasing UA and CRP ( P < 0.05 or P < 0.01 ) . CONCLUSIONS MST can significantly improve the symptoms and signs of gouty arthritis and decrease the levels of UA and CRP . It is good for gouty arthritis Objectives : To compare the efficacy and tolerability of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day used to attain a target serum urate concentration ( sUr ) ⩽0.30 mmol/l ( 5 mg/dl ) . Methods : A r and omised , controlled , open-label , multicentre trial in gout patients with renal function defined as a calculated creatinine clearance ⩾50 ml/min . Patients were treated with 300 mg allopurinol or 100 mg benzbromarone once a day ( stage 1 ) . If sUr ⩽0.30 mmol/l was not attained after 2 months , the dose was doubled to allopurinol 300 mg twice a day or benzbromarone 200 mg once a day ( stage 2 ) . The primary end point was treatment success in either of the two stages , defined as clinical tolerability and attainment of biochemical target sUr . Results : Sixty-five patients were enrolled in stage 1 ; 36 received allopurinol and 29 received benzbromarone . Fifty-five patients ( 85 % ) were analysed at stage 1 : the success rates were 8/31 ( 26 % ) and 13/25 ( 52 % ) , respectively , and the difference was −0.26 ( 95 % CI from −0.486 to −0.005 ) , p = 0.049 . At stage 2 , the success rates were 21/27 ( 78 % ) and 18/23 ( 78 % ) , respectively , and the difference was −0.005 ( 95 % CI from −0.223 to 0.220 ) , p = 1.00 . Two patients stopped receiving allopurinol and three stopped receiving benzbromarone because of adverse drug reactions . Conclusions : Increasing the allopurinol dose from 300 to 600 mg/day and the benzbromarone dose from 100 to 200 mg/day according to the target sUr produced significantly higher success rates ( both 78 % successful in attaining sUr ⩽0.30 mmol/l ) . No significant differences in treatment success between benzbromarone and allopurinol were found after dose escalation . Trial registration number : IS RCT N49563848 ) Abstract Background and objective : Combination therapy with allopurinol and probenecid is used to treat tophaceous gout in patients who do not respond sufficiently to allopurinol alone . However , the potential interaction between these drugs has not been systematic ally investigated . The objective of this study was to investigate the pharmacokinetics and hypouricaemic effect of oxypurinol ( the active metabolite of allopurinol ) and probenecid when administered alone and in combination in healthy subjects . Methods : An open-label , r and omized , three-way crossover clinical trial was conducted in 12 healthy adults . Subjects were r and omized to receive treatment for 7 days with allopurinol ( 150 mg twice daily ) , probenecid ( 500 mg twice daily ) or combination therapy with both drugs , with a 7-day washout period between treatments . Venous blood sample s were collected predose ( at 0 hours ) and 1 , 2 , 3 , 4 , 6 , 8 , 10 and 12 hours after dosage for determination of oxypurinol and /or probenecid concentrations . Plasma and urinary urate concentrations were determined on each study day and at the end of each washout period . Pharmacokinetic and pharmacodynamic parameters were analysed using two-way ANOVA . Results : Coadministration of allopurinol and probenecid significantly reduced average steady-state plasma oxypurinol concentrations ( mean ± SD : allopurinol alone 9.7 ± 2.1 mg/L vs combination 5.1 ± 1.0 mg/L , p < 0.001 ) . Probenecid concentrations were unaffected . Plasma urate concentrations decreased ( p < 0.01 ) during allopurinol therapy ( 0.16 ± 0.05 mmol/L ) , probenecid therapy ( 0.13 ± 0.02 mmol/L ) and combination therapy ( 0.09 ± 0.02 mmol/L ) compared with baseline ( 0.30 ± 0.05 mmol/L ) . Conclusion : Coadministration of allopurinol and probenecid to healthy subjects had a greater hypouricaemic effect than either allopurinol or probenecid alone , despite a reduction in plasma oxypurinol concentrations when the drugs were taken concomitantly In an open-controlled , r and omized trial over 24 weeks , the serum uric acid lowering effect of a daily dose of 100 mg allopurinol in combination with 20 mg benzbromarone compared to 300 mg allopurinol only was investigated on a total of 60 patients suffering from hyperuricemia . Both preparations led to a decrease of the serum uric acid value to normal . In those patients however , who had received the combination the reduction of the serum uric acid level was more pronounced . Tolerance was generally good . Side-effects were not reported Background : Lower dosages of allopurinol are recommended to avoid toxicity in gout patients with impaired renal function . This often has result ed in inadequate control of hyperuricemia . The optimum therapeutic range of plasma oxypurinol concentrations in gout patients with chronic kidney disease has never been investigated . This study was performed to examine the relationships between plasma oxypurinol concentrations and the changes in serum urate level and renal function after taking a st and ard dose of allopurinol , 300 mg daily , in gout patients with renal insufficiency . Patients and Methods : The study was conducted in 27 gout patients with renal insufficiency in a rheumatology clinic at the Rajvithi Hospital , Bangkok . Both new and current patients , after they discontinued allopurinol completely for 4 weeks , were treated with allopurinol 300 mg daily for 6 weeks . Blood sample s were collected immediately before and 5 hours after the studied dose had been taken . Serum urate levels and renal function were recorded before and after the 6 weeks of allopurinol treatments . Results : Most patients receiving allopurinol 300 mg/d had their plasma oxypurinol concentrations higher than the proposed therapeutic range for patients with normal renal function . There were significant relationships between changes in serum urate level with both trough and fifth-hour oxypurinol concentrations ( R2 = 0.42 , P = 0.002 and R2 = 0.27 , P = 0.007 , respectively ) . Higher plasma oxypurinol concentrations result ed in a higher percentage of patients who could meet the therapeutic treatment goal . No serious side effect and no significantly change in creatinine clearance were observed indicating that high levels of oxypurinol did not appear to relate to higher prevalence of adverse reaction . Conclusions : Higher percentages of patients could meet the treatment goal when their plasma oxypurinol concentrations were higher than the proposed therapeutic range for patients with normal renal function Successful long-term management of primary gout in the presence of normal renal function may be achieved in most instances by agents which diminish tubular reabsorption of urates , thus permitting increased urinary urate excretion . In recent years the two most widely used uricosuric agents have been probenecid and sulphinpyrazone . The easiest longterm control of gout with the fewest untoward sideeffects has been achieved with sulphinpyrazone ( Gutman and Yui , 1957a ; Kersley , Cook , and Tovey , 1958 ; Ogryzlo and Harrison , 1957 ; Kuzell , Glover , Gibbs , and Blau , 1964 ) . In spite of the relative ease in controlling gout with sulphinpyrazone , any large group of gouty patients will include some in whom the use of uricosuric agents may be impossible or inadvisable because of impairment of renal function or drug intolerance . Some patients , for reasons not yet understood , form tophi much more readily than others , and quite large dosages of uricosuric agents may arrest the formation of tophi without rapidly diminishing those already present . Some form urate stones in the urinary tract so readily that increasing the urinary output of urates may be hazardous . Finally , in secondary gout attended by excessive uric acid formation , the employment of uricosuric agents may be inadvisable because any increase in the already high excretion rate may lead to obstruction of the lower urinary tract by concretions of uric acid . A novel approach in the control of gout is offered by allopurinol , 4-hydroxypyrazolo ( 3 , 4-d ) pyrimidine ( 4-HPP ) , an inhibitor of xanthine oxidase which prevents conversion of hypoxanthine to xanthine and of xanthine to uric acid ( Rundles , Wyngaarden , Hitchings , Elion , and Silberman , 1963 ; Yu and Gutman , 1964 ; Rundles , Metz , and Silberman , 1966b ) . Uric acid available for excretion is diminished , and the relatively more soluble xanthines are readily excreted , thus permitting the use In 2003 , the uricosuric drug benzbromarone was withdrawn from the market . The first alternative drug of choice was the xanthine oxidase inhibitor allopurinol . The purpose was to ( 1 ) investigate the efficacy of allopurinol ( st and ard dosage ) compared with previous treatment with benzbromarone ; and ( 2 ) investigate the combination therapy allopurinol – probenecid as an effective alternative treatment compared with previous benzbromarone treatment . A prospect i ve , open study was carried out in a cohort of 51 gout patients who discontinued benzbromarone therapy because of market withdrawal . Patients were given 200–300 mg allopurinol ( stage 1 ) . When allopurinol failed to attain the target serum urate ( sUr ) levels ≤0.30 mmol/l , probenecid 1,000 mg/day was added ( stage 2 ) . Treatment with benzbromarone monotherapy ( range : 100–200 mg/day ; mean 138 mg/day ) result ed in 92 % of patients reaching target levels sUr ≤ 0.30 mmol/l with a decrease of 61[11]% compared to baseline . In stage 1 , 32 patients completed treatment with allopurinol monotherapy ( range 200–300 mg/day ; mean 256 mg/day ) , which result ed in 25 % of patients attaining sUr target levels . Decrease in sUr levels was 36[11]% , which was significantly less compared to treatment with benzbromarone ( p < 0.001 ) . In stage 2 , 14 patients received allopurinol – probenecid combination therapy , which result ed in 86 % of patients attaining target sUr levels ( after failure on allopurinol monotherapy ) , which was comparable to previous treatment with benzbromarone ( p = 0.81 ) . Decrease in sUr levels was 53[9]% ( CI 95 % : 48–58 % ) , which was a non-significant difference compared to previous treatment with benzbromarone ( p = 0.23 ) . Benzbromarone is a very effective antihyperuricemic drug with 91 % success in attainment of target sUr levels ≤0.30 mmol/l . Allopurinol 200–300 mg/day was shown to be a less potent alternative for most selected patients to attain target sUr levels ( 13 % success ) . In patients failing on allopurinol monotherapy , the addition of probenecid proves to be an effective treatment strategy for attaining sUr target levels ( 86 % success ) Summary The objectives of this study were to establish if , and to what extent , benzbromarone affects allopurinol/oxypurinol kinetics , and to compare the uric acid lowering capabilities of Allomaron ® ( allopurinol 100 mg plus benzbromarone 20 mg ) with the effects of allopurinol alone in patients with confirmed gout . We studied 14 adult men in an open r and omized cross-over study . After a 14 day run-in period with Zyloprim ® ( 2 × 100 mg allopurinol tablets in the morning ) , the patients were r and omly allocated to morning doses of either Allomaron ® ( 2 tablets ) or Zyloprim ® ( 2 tablets ) . Seven days later cross-over was effected and the alternative treatment was taken for a further 7 days . On days 7 and 14 the patients came into hospital and venous blood sample s were taken over 24 h for allopurinol and oxypurinol assays by HPLC . Serum uric acid was determined on days -14 , 1 , 7 , and 14.Benzbromarone lowered plasma oxypurinol concentrations ( Allomaron ® /Zyloprim ® mean ratio of AUC0→24 was 59 % ; 95 % confidence interval 54–64 % ) , but did not affect plasma allopurinol concentrations . Despite this pharmacokinetic interaction of benzbromarone with allopurinol , result ing in lower plasma concentrations of oxypurinol , Allomaron ® was superior to allopurinol alone in lowering serum uric acid , probably because of the added uricosuric effect of benzbromarone OBJECTIVES To study the efficacy of allopurinol and benzbromarone to reduce serum urate concentrations in patients with primary chronic gout . METHODS Prospect i ve , parallel , open study of 86 consecutive male patients with primary chronic gout . Forty nine patients ( 26 normal excretors and 23 under excretors ) were given allopurinol 300 mg/day and 37 under excretors benzbromarone 100 mg/day . After achieving steady plasma urate concentrations with such doses , treatment was then adjusted to obtain optimal plasmatic urate concentrations ( under 6 mg/dl ) . RESULTS Patients receiving allopurinol 300 mg/day showed a mean reduction of plasmatic urate of 2.75 mg/dl ( from 8.60 to 5.85 mg/dl ) and 3.34 mg/dl ( from 9.10 to 5.76 mg/dl ) in normal excretors and under excretors respectively . Patients receiving benzbromarone 100 mg/day achieved a reduction of plasmatic urate of 5.04 mg/dl ( from 8.58 to 3.54 mg/dl ) . Fifty three per cent of patients receiving allopurinol and 100 % receiving benzbromarone achieved optimal plasma urate concentrations at such doses . The patients with poor results with allopurinol 300 mg/day achieved a proper plasma urate concentration with allopurinol 450 to 600 mg/day , the mean final dose being 372 mg/day . Renal fuction improved and no case of renal lithiasis was observed among benzbromarone treated patients , whose mean final dose was 76 mg/day . CONCLUSION Benzbromarone is very effective to control plasma urate concentrations at doses ranging from 50 to 100 mg/day . Uricosuric treatment is a suitable approach to the treatment of patients with gout who show underexcretion of urate Treatment of gout and hyperuricemia can be difficult in patients with chronic renal failure . At present , there is no study available comparing the efficacy of the most widely used agent , allopurinol , and the uricosuric benzbromarone for the control of hyperuricemia in patients with renal insufficiency . We describe an open , r and omized , actively controlled , comparative trial in patients with clearance of creatinine from 20 to 80 mL/ min/1.73 m(2 ) . Patients were r and omized to take benzbromarone ( 100 - 200 mg/day ) or allopurinol ( 100 - 300 mg/day ) . Outcome variables were the following : reduction of serum urate ( Sur ) , Sur & tl ; 6 mg/dL ( 357 micromol/L ) , reduction of gouty bouts and reduction of tophi . During 9 - 24 months of follow-up 36 patients were studied . The reduction of Sur was higher with benzbromarone , and only 1 of 17 patients taking benzbromarone did not achieve Sur < 6 mg/dL versus 7 of 19 taking allopurinol . Patients who did not reach optimal Sur levels with allopurinol were more frequently taking diuretics and showed lower fractional excretion of urate and higher initial Sur levels than patients with proper control of Sur . Seven patients with suboptimal control of serum urate were changed to benzbromarone 100 mg/day , which showed efficacy similar in those who were initially r and omized to benzbromarone . A reduction of gouty bouts and size of tophi was observed after proper control of Sur . Allopurinol is effective in controlling hyperuricemia , but patients with higher initial Sur levels or taking concomitant diuretic therapy are less prone to reach therapeutic goals .Benzbromarone is useful for the control of hyperuricemia in patients with renal insufficiency even with concomitant diuretic administration ; patients benefited include those who previously had no improvement by taking allopurinol This study compared the effects of azapropazone and indomethacin plus allopurinol in the management of acute gout and hyperuricaemia . A group of 93 patients predominantly based in general practice were r and omly allocated to the two treatment regimens ( azapropazone ( days 1 - 225 ) or indomethacin ( 1 - 28 ) followed by allopurinol ( 29 - 225 ) ) on a double-blind double dummy basis . Azapropazone produced a substantial reduction in serum uric acid levels by day 4 compared with day 1 ( P<0.002 ) and was superior to indomethacin with regard to recorded levels of serum uric acid at day 4 ( P<0.01 ) and day 28 ( P<0.05 ) . From day 28 onwards allopurinol produced and azapropazone maintained similar reductions in serum uric acid . Both treatments rapidly controlled the initial acute attacks of gout and both produced side effects similar in frequency and nature . Fewer breakthrough attacks of gout occurred in the azapropazone group ( 12 ) than the indomethacin/allopurinol group (21).Although the results achieved in both treatment groups were similar it has been shown that azapropazone is effective monotherapy for controlling both acute attacks of gout and hyperuricaemia OBJECTIVE The Gout Impact Scale ( GIS ) is a gout-specific quality of life instrument that assesses impact of gout during an attack and impact of overall gout . The GIS has five scales and each is scored from 0 to 100 ( worse health ) . Our objective was to assess minimally important differences ( MIDs ) for the GIS administered in a r and omized controlled trial ( RCT ) assessing rilonacept vs placebo for prevention of gout flares during initiation of allopurinol therapy . METHODS Trial subjects ( n = 83 ) included those with two or more gout flares ( self-reported ) in the past year . Of these , 73 had data for Weeks 8 vs 4 and formed the MID analysis group and were analysed irrespective of the treatment assignment . Subjects completed the GIS and seven patient-reported anchors . Subjects with a one-step change ( e.g. from very poor to poor ) were considered as the MID group for each anchor . The mean change in GIS scores and effect size ( ES ) was calculated for each anchor 's MID group . The average of these created the overall summary MID statistics for each GIS . An ES of 0.2 - 0.5 was considered to represent MID estimates . Results . Trial subjects ( n = 73 ) were males ( 96.0 % ) , White ( 90.4 % ) , with mean age of 50.5 years and serum uric acid of 9.0 mg/dl . The mean change score for the MID improvement group for scales ranged from -5.24 to -7.61 ( 0 - 100 scale ) . The ES for the MID improvement group for the four scales ranged from 0.22 to 0.38 . CONCLUSION The MID estimates for GIS scales are between 5 and 8 points ( 0 - 100 scale ) . This information can aid in interpreting the GIS results in future gout RCTs . Trial Registration . Clinical trials.gov , www . clinical trials.gov , NCT00610363 OBJECTIVE To determine the efficacy and safety of increasing the allopurinol dose above the proposed creatinine clearance-based dose in patients with gout . METHODS Patients with gout who had been receiving a stable dose of allopurinol for ≥ 1 month were recruited . The dose of allopurinol was increased to obtain the target serum urate level of < 0.36 mmoles/liter ( < 6 mg/dl ) . Patients were seen monthly until the serum urate concentration was < 0.36 mmoles/liter for 3 consecutive months and then were seen every 3 months for at least 12 months . Data were analyzed using the dosage of allopurinol ( mg/day ) greater than the recommended dosage , as defined by the H and e criteria . RESULTS Ninety patients were enrolled . The mean age of the patients was 58.7 years ( range 27 - 83 years ) , 87.9 % were male , and 81.9 % were of European ancestry . Forty-five patients had a serum urate concentration of ≥ 0.36 mmoles/liter , and the dose of allopurinol was increased in these patients . Rashes developed in 3 patients , and either allopurinol was discontinued or dose escalation was ceased in these patients . Seven patients were lost to followup or developed intervening medical problems that precluded dose escalation . In 31 ( 88.8 % ) of 35 patients who completed the study , the serum urate level was < 0.36 mmoles/liter at 12 months . Two of the 5 patients who had a serum urate level ≥ 0.36 mmoles/liter had undetectable levels of plasma oxypurinol , indicating noncompliance with allopurinol treatment . A significant reduction in the serum urate concentration was observed for all allopurinol doses above the recommended dose . Eighteen of 45 patients were receiving furosemide ; those receiving furosemide were just as likely as those not receiving furosemide to achieve a serum urate concentration of < 0.36 mmoles/liter ( 72 % versus 88.5 % ; P = 0.24 ) . Patients receiving furosemide required a higher dose of allopurinol to achieve the target serum urate concentration . No serious adverse events were observed . CONCLUSION Increasing the dose of allopurinol above the proposed creatinine clearance-based dose led to a significant reduction in the serum urate concentration . Approximately 89 % of patients achieved a serum urate concentration of < 0.36 mmoles/liter . In this cohort , toxicity was not increased in patients receiving higher doses of allopurinol , including those with renal impairment OBJECTIVE To compare the efficacy of combined low dose of hypouricemic drugs ( Allopurinol 100 mg and benzbromarone 20 mg ; Allomaron ) and st and ard dose 300 mg of allopurinol in hyperuricemia . MATERIAL AND METHOD A prospect i ve , open study of 94 hyperuricemic patients was done at King Chulalongkorn Memorial Hospital . Each group of 47 patients was given a combined low dose of hypouricemic drugs ( Allopurinol 100 mg and benzbromarone 20 mg ; Allomaron ) and a st and ard dose 300 mg of allopurinol . Serum uric acid was measured before and 4 weeks after receiving the drugs . The efficacy was measured from the difference of the level of serum uric acid before and after receiving the drugs . RESULTS The patients receiving the combined low dose of hypouricemic drugs and st and ard dose of allopurinol showed a mean reduction of serum uric acid of 2.5+/-3.4 mg/dl and 4.1+/-2.7 mg/dl consecutively . There was a statistically significant difference between the 2 groups ( P = 0.010 ) . CONCLUSION This study demonstrates that the efficacy of st and ard dose 300 mg of allopurinol is superior to a combined low dose of allopurinol and benzbromarone in lowering the level of serum uric acid level Objective . To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout . Methods . Subjects ( n = 1086 ) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment ( ULT ) with febuxostat ( 80 mg or 120 mg ) or allopurinol ( 300 mg ) . ULT reassignment was permitted during months 1 to 6 to achieve serum urate ( SUA ) concentrations between 3.0 and < 6.0 mg/dl . Flares requiring treatment , tophus size , safety , and SUA levels were monitored during up to 40 months of ULT maintenance . Results . After 1 month initial treatment , > 80 % of subjects receiving either febuxostat dose , but only 46 % of subjects receiving allopurinol , achieved SUA < 6.0 mg/dl . After ULT reassignment , > 80 % of all remaining subjects maintained the primary efficacy endpoint of SUA < 6.0 mg/dl at each visit . More subjects initially r and omized to allopurinol required ULT reassignment to achieve SUA < 6.0 mg/dl compared with subjects receiving febuxostat . Maintenance of SUA < 6.0 mg/dl result ed in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment . Baseline tophus resolution was achieved by 46 % , 36 % , and 29 % of subjects maintained on febuxostat 80 mg , febuxostat 120 mg , and allopurinol , respectively . Overall adverse event rates ( including cardiovascular adverse event rates ) , adjusted for 10-fold greater febuxostat than allopurinol exposure , did not differ significantly among treatment groups . Conclusion . Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol result ed in near elimination of gout flares and improved tophus status over time . Registered as NCT00175019 An association between gout and kidney dysfunction has been long recognised . It is a reasonable presumption that gout might be the cause of the renal disease.1 Hypertension , urolithiasis and urinary infection may contribute to this association but it is far from certain whether hyperuricaemia itself may exert a deleterious effect . The available data have been variously interpreted as showing that hyperuricaemia is detrimental2 or of no The effect of daily administration of a single 300-mg tablet of allopurinol on serum urate levels was compared with the effect of divided doses of the drug ( 100 mg three times a day ) in an open-labeled crossover trial of 20 patients with hyperuricemia and gout . Under both regimens of treatment there was a prompt fall in serum urate levels , and analysis of variance indicated no significant difference between the two modes of administration of allopurinol . Nor was there any significant difference in the minimum serum levels of oxypurinol . On the basis of this short-term study , the use of a single 300-mg tablet of allopurinol per day appears to be an effective means of lowering the elevated serum urate levels of individuals with gouty hyperuricemia and compares favorably with the results obtained by allopurinol in divided doses Allopurinol was administered to seven patients with gout to compare the effects of three different methods of administration . Allopurinol 100 mg given three times daily . Allopurinol given once daily as three 100 mg tablets . Allopurinol given once daily as a single 300 mg tablet . Allopurinol as a single dose in the morning gave as sustained control of plasma levels as did divided administration OBJECTIVE Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved . Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack . METHODS A total of 57 men with crystal-proven gout were r and omized to allopurinol 300 mg daily or matching placebo for 10 days . All subjects received indomethacin 50 mg 3 times per day for 10 days , a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days , and open-label allopurinol starting at day 11 . Primary outcome measures were pain on visual analogue scale ( VAS ) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30 . RESULTS On the basis of 51 evaluable subjects ( allopurinol in 26 , placebo in 25 ) , mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10 . Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 ( P=.37 ) , declining to 0.18 versus 0.27 ( P=.54 ) at day 10 , with neither group consistently having more daily pain . Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo ( P=.60 ) . Although urate levels decreased rapidly in the allopurinol group ( from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3 ) , sedimentation rates and C-reactive protein levels did not differ between groups at any point . CONCLUSIONS Allopurinol initiation during an acute gout attack caused no significant difference in daily pain , recurrent flares , or inflammatory markers OBJECTIVE The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial . This observational , prospect i ve study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout . METHOD Sixty-three patients with crystal-confirmed tophaceous gout were treated with allopurinol , benzbromarone , or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues . The tophi targeted for evaluation during followup were the largest in diameter found during physical examination . RESULTS Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone . The velocity of tophi reduction was linearly related to the mean serum urate level during therapy . The lower the serum urate levels , the faster the velocity of tophi reduction . CONCLUSION Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout . Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy . Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single-drug therapy Objective . To investigate the pharmacokinetic and pharmacodynamic interaction between probenecid and oxypurinol ( the active metabolite of allopurinol ) in patients with gout . Methods . This was an open-label observational clinical study . Blood and urine sample s were collected to measure oxypurinol and urate concentrations . We examined the effects of adding probenecid to allopurinol therapy upon plasma concentrations and renal clearances of urate and oxypurinol . Results . Twenty patients taking allopurinol 100–400 mg daily completed the study . Maximum coadministered doses of probenecid were 250 mg/day ( n = 1 ) , 500 mg/day ( n = 19 ) , 1000 mg/day ( n = 7 ) , 1500 mg/day ( n = 3 ) , and 2000 mg/day ( n = 1 ) . All doses except the 250 mg daily dose were divided and dosing was twice daily . Estimated creatinine clearances ranged from 28 to 113 ml/min . Addition of probenecid 500 mg/day to allopurinol therapy decreased plasma urate concentrations by 25 % , from mean 0.37 mmol/l ( 95 % CI 0.33–0.41 ) to mean 0.28 mmol/l ( 95 % CI 0.24–0.32 ) ( p < 0.001 ) ; and increased renal urate clearance by 62 % , from mean 6.0 ml/min ( 95 % CI 4.5–7.5 ) to mean 9.6 ml/min ( 95 % CI 6.9–12.3 ) ( p < 0.001 ) . Average steady-state plasma oxypurinol concentrations decreased by 26 % , from mean 11.1 mg/l ( 95 % CI 5.0–17.3 ) to mean 8.2 mg/l ( 95 % CI 4.0–12.4 ) ( p < 0.001 ) ; and renal oxypurinol clearance increased by 24 % , from mean 12.7 ml/min ( 95 % CI 9.6–15.8 ) to mean 16.1 ml/min ( 95 % CI 12.0–20.2 ) ( p < 0.05 ) . The additional hypouricemic effect of probenecid 500 mg/day appeared to be lower in patients with renal impairment . Conclusion . Coadministration of allopurinol with probenecid had a significantly greater hypouricemic effect than allopurinol alone despite an associated reduction of plasma oxypurinol concentrations . Australian Clinical Trials Registry ACTRN012606000276550 OBJECTIVE To compare the urate-lowering efficacy and safety of febuxostat , allopurinol , and placebo in a large group of subjects with hyperuricemia and gout , including persons with impaired renal function . METHODS Subjects ( n = 1,072 ) with hyperuricemia ( serum urate level > or = 8.0 mg/dl ) and gout with normal or impaired ( serum creatinine level > 1.5 to < or = 2.0 mg/dl ) renal function were r and omized to receive once-daily febuxostat ( 80 mg , 120 mg , or 240 mg ) , allopurinol ( 300 or 100 mg , based on renal function ) , or placebo for 28 weeks . RESULTS Significantly ( P < or = 0.05 ) higher percentages of subjects treated with febuxostat 80 mg ( 48 % ) , 120 mg ( 65 % ) , and 240 mg ( 69 % ) attained the primary end point of last 3 monthly serum urate levels < 6.0 mg/dl compared with allopurinol ( 22 % ) and placebo ( 0 % ) . A significantly ( P < 0.05 ) higher percentage of subjects with impaired renal function treated with febuxostat 80 mg ( 4 [ 44 % ] of 9 ) , 120 mg ( 5 [ 45 % ] of 11 ) , and 240 mg ( 3 [ 60 % ] of 5 ) achieved the primary end point compared with those treated with 100 mg of allopurinol ( 0 [ 0 % ] of 10 ) . Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups , although diarrhea and dizziness were more frequent in the febuxostat 240 mg group . The primary reasons for withdrawal were similar across groups except for gout flares , which were more frequent with febuxostat than with allopurinol . CONCLUSION At all doses studied , febuxostat more effectively lowered and maintained serum urate levels < 6.0 mg/dl than did allopurinol ( 300 or 100 mg ) or placebo in subjects with hyperuricemia and gout , including those with mild to moderately impaired renal function

Our review found that even among studies with objective ly measured physical activity , the association between access to parks and physical activity varied between studies , possibly due to heterogeneity of exposure measurement . Self-reported ( vs. independently-measured ) neighborhood park environment characteristics and smaller ( vs. larger ) buffer sizes were more predictive of physical activity .

One strategy for increasing physical activity is to create and enhance access to park space . We assessed the literature on the relationship of parks and objective ly measured physical activity in population -based studies in the United States ( US ) and identified limitations in current built environment and physical activity measurement and reporting .

Background Few studies have investigated both the self-perceived and measured environment with objective ly determined physical activity in older adults . Accordingly , the aim of this study was to examine measured and perceived environmental associations with physical activity of older adults residing across different neighborhood types . Methods One-hundred and forty-eight older individuals , mean age 64.3 ± 8.4 , were r and omly recruited from one of four neighborhoods that were pre-determined as either having high- or low walkable characteristics . Individual residences were geocoded and 200 m network buffers established . Both objective environment audit , and self-perceived environmental measures were collected , in conjunction with accelerometer derived physical activity behavior . Using both perceived and objective environment data , analysis consisted of a macro-level comparison of physical activity levels across neighborhood , and a micro-level analysis of individual environmental predictors of physical activity levels . Results Individuals residing in high-walkable neighborhoods on average engaged in 11 min of moderate to vigorous physical activity per day more than individuals residing in low-walkable neighborhoods . Both measured access to non-residential destinations ( b = .11 , p < .001 ) and self-perceived access to non-residential uses ( b = 2.89 , p = .031 ) were significant predictors of time spent in moderate to vigorous physical activity . Other environmental variables significantly predicting components of physical activity behavior included presence of measured neighborhood crime signage ( b = .4785 , p = .031 ) , measured street safety ( b = 26.8 , p = .006 ) , and perceived neighborhood satisfaction ( b = .5.8 , p = .003 ) . Conclusions Older adult residents who live in high-walkable neighborhoods , who have easy and close access to nonresidential destinations , have lower social dysfunction pertinent to crime , and generally perceive the neighborhood to a higher overall satisfaction are likely to engage in higher levels of physical activity behavior . Efforts aim ed at promoting more walkable neighborhoods could influence activity levels in older adults OBJECTIVES . Physical activity may be constrained or facilitated by local environments . The availability of neighborhood facilities for physical activity may be particularly relevant for youth , who are unable to drive and whose activity is often limited to the immediate distance they are able to walk or bicycle . Several studies have shown that proximity to recreational facilities and parks is one of the most important predictors of physical activity . Because the United States already has an extensive infrastructure of parks , with 70 % of adults indicating that they live within walking distance of a park or playground , parks may be a potential venue for increasing physical activity . This might be particularly important for adolescent girls , whose physical activity levels decline substantially as they go through puberty . The goal of this study was to examine the association between park proximity , park type , and park features and physical activity in adolescent girls . PATIENTS AND METHODS . This was a cross-sectional study using baseline data from the Trial of Activity for Adolescent Girls . It included 1556 grade 6 girls who were r and omly selected from 6 middle schools in each of the following 6 field site areas : Washington , DC , and Baltimore , Maryl and ; Columbia , South Carolina ; Minneapolis , Minnesota ; New Orleans , Louisiana ; Tucson , Arizona ; and San Diego , California . Girls wore accelerometers for 6 days to measure metabolic equivalent – weighted moderate-to-vigorous physical activity , a measure accounting for the volume and intensity of activity . Metabolic equivalent – weighted moderate-to-vigorous physical activity was calculated for the hours outside of school time using 2 different cutpoints , activity levels ≥3.0 metabolic equivalents and ≥4.6 metabolic equivalents , the latter indicating activity at the intensity of a brisk walk or higher . We mapped all of the parks within 1 mile of each girl 's home . Trained staff used a checklist to document the presence of facilities and amenities at each park , including passive amenities , such as drinking fountains , restrooms , and areas with shade , as well as active amenities like basketball courts , multi purpose fields , playgrounds , and tennis courts . RESULTS . Mean nonschool metabolic equivalent – weighted moderate/vigorous physical activity , using the 4.6 metabolic equivalent cutoff , was 611.1 minutes ( range : 49.7–4718.6 metabolic equivalent minutes per 6 days ) and 1704.8 metabolic equivalent minutes per 6 days ( range : 276.2–5792.6 metabolic equivalent minutes per 6 days ) when using the 3.0 metabolic equivalent cutpoint . Many girls had multiple parks within a 1-mile radius of their homes : 57 % had ≥1 type of park , the majority being neighborhood or community parks ; 42 % had between 1 and 3 parks , 37 % had ≥4 parks , and 14 % had ≥8 parks . The type , number , and specific parks features were associated with girls ' nonschool metabolic equivalent – weighted moderate/vigorous physical activity . At the 4.6 metabolic equivalent cutpoint , higher levels of nonschool metabolic equivalent – weighted moderate/vigorous physical activity were associated with both neighborhood and community parks ( 22 metabolic equivalent minutes ) and miniparks ( 40 metabolic equivalent minutes ) . Each park , regardless of type , in the half-mile around each girl 's home was associated with an increase in nonschool metabolic equivalent – weighted moderate/vigorous physical activity by 2.8 % or 17.2 nonschool minutes of metabolic equivalent – weighted moderate/vigorous physical activity per 6 days . Beyond a half-mile , each park increased nonschool metabolic equivalent – weighted moderate/vigorous physical activity by 1.1 % or 6.7 metabolic equivalent minutes per 6 days . For the average girl with 3.5 parks within a 1-mile radius of home , the presence of parks accounted for 36.5 extra nonschool metabolic equivalent minutes per 6 days , ∼6 % of total nonschool metabolic equivalent – weighted moderate/vigorous physical activity . Using the 3.0 metabolic equivalent cutpoint , this sums to an additional 68 metabolic equivalent minutes of nonschool metabolic equivalent – weighted moderate/vigorous physical activity over 6 days , or 4 % of the total . The most common amenities in the parks were playgrounds , multi purpose fields , and picnic areas . Slightly more than one third of girls lived within a half-mile of a park with a basketball court , and > 20 % had access to walking paths and tennis courts in their local park . Higher levels of nonschool metabolic equivalent – weighted moderate/vigorous physical activity per 6 days were associated with walking paths ( 13 metabolic equivalent minutes ) , running tracks ( 82 metabolic equivalent minutes ) , playgrounds ( 28 metabolic equivalent minutes ) , and basketball courts ( 30 metabolic equivalent minutes ) . Parks with streetlights and floodlights were also associated with an increase of 18 and 22 minutes of nonschool metabolic equivalent – weighted moderate/vigorous physical activity , respectively . With the 3.0 metabolic equivalent cutoff for metabolic equivalent – weighted moderate/vigorous physical activity , additional nonschool metabolic equivalent minutes more than doubled when girls had miniparks ( 92 metabolic equivalent minutes ) , natural re source areas ( 36 metabolic equivalent minutes ) , walking paths ( 59 metabolic equivalent minutes ) , and running tracks ( 208 metabolic equivalent minutes ) within a half-mile of their homes . Skateboard areas and special-use parks were negatively associated with nonschool metabolic equivalent – weighted moderate/vigorous physical activity in adolescent girls . CONCLUSIONS . Adolescent girls who live near more parks , particularly near those with amenities that are conducive to walking and with active features , engage in more nonschool metabolic equivalent – weighted moderate/vigorous physical activity than those with fewer parks . Whether this is because of actual use of the parks or neighborhood choice could not be determined . Although the magnitude of the association between parks and additional minutes of metabolic equivalent – weighted moderate/vigorous physical activity was small for an individual , amounting to an average of 4%–6 % of a girl 's total nonschool metabolic equivalent – weighted moderate/vigorous physical activity , it is likely to have a large population -level association . Because of the potential population level impact , the use of parks to promote physical activity should be further studied BACKGROUND Regular physical activity is known to help prevent chronic disease and promote healthy aging . Yet , most older women are not regularly active . This study attempts to identify objective ly measured attributes of the neighborhood environment that may be associated with physical activity levels in older women . METHODS Sociodemographics and physical activity level , as measured by pedometer , were assessed in 158 overweight Caucasian and African-American postmenopausal women from southwestern Pennsylvania at the baseline evaluation of a r and omized clinical trial in 2002 - 2003 . Geographic information systems technology was used to obtain neighborhood-level data , including neighborhood socioeconomic status ( SES ) indicators , the median year that homes were built ( as a proxy measure for urban form ) , and proximity to businesses and facilities . Multiple linear regression was used to test associations between individuals ' physical activity level and neighborhood characteristics . RESULTS After controlling for individual age , race/ethnicity , education , smoking status , and body mass index , indicators of low neighborhood SES , living in a neighborhood with homes built between 1950 and 1969 ( representing an urban form that is more pedestrian-friendly than after 1969 ) , and living within walking distance ( 1500 m ) of specific types of businesses and facilities were positively associated with individuals ' physical activity level measured by pedometer ( p < 0.05 ) . CONCLUSIONS Results suggest that certain aspects of the neighborhood environment may have an important influence on the physical activity levels of postmenopausal women . Results warrant future research to clarify the role of these environmental attributes in other population Locational data , logged on portable GPS units and matched with accelerometer data , was used to examine associations of the built environment with physical activity and sedentary behaviors of adolescent females . In a sample of 293 adolescent females aged 15 to 18 years old in Minneapolis and San Diego , the built environment around each GPS point and its corresponding sedentary , light , and moderate-to-vigorous intensity physical activity was examined using r and om intercept multinomial logistic regression models . The odds of higher physical activity intensity ( 3-level outcome : sedentary , light , MVPA ) were higher in places with parks , schools , and high population density , during weekdays , and lower in places with more roads and food outlets . Underst and ing the places where physical activity and sedentary behaviors occur appears to be a promising strategy to clarify relationships and inform policy aim ed at increasing physical activity and reducing sedentary behaviors BACKGROUND This study examined predictors of adoption and maintenance of vigorous physical activity over time in a sample of 1,719 r and omly selected women and men . METHODS Based on reported frequency of vigorous exercise in a mail survey at baseline , subjects were classified as sedentary ( zero sessions per week ) , intermediate ( one to two sessions per week ) , or active ( three or more sessions per week ) . RESULTS On the same survey subjects reported on 25 potential determinants of physical activity based on a comprehensive learning model . Twenty-four months later , 85 % of subjects were resurveyed , and their physical activity levels were classified . Within each baseline category and gender subgroup , predictors of follow-up physical activity were identified . In multivariate analyses , adoption of vigorous exercise by sedentary men was predicted by self-efficacy , age ( inverse ) , and neighborhood environment ( inverse ) . Adoption by sedentary women was predicted by education , self-efficacy , and friend and family support for exercise . Maintenance of vigorous physical activity was predicted by self-efficacy and age ( inverse ) for initially active men and by education for initially active women . CONCLUSION These results suggest that factors influencing adoption are different for men and women , and there may be different factors influencing adoption versus maintenance of vigorous physical activity

We identified a benefit in the role of magnesium to reduce the incidence of cerebral vasospasm in patients with an aneurysmal SAH . However no benefit was found regarding improved favourable functional outcome or a reduction of mortality

BACKGROUND The value of magnesium for the prevention of cerebral arterial vasospasm in patients with aneurysmal subarachnoid haemorrhage ( SAH ) is debatable . We performed a systematic review to collate the available evidence to evaluate the effects of intravenous magnesium for the prevention of cerebral arterial vasospasm .

BACKGROUND Recent studies suggest that high-dose MgSO4 therapy is safe and reduces the incidence of DIND and subsequent poor outcome after SAH . We intended to assess the safety and efficacy of high-dose MgSO4 therapy after SAH as means to prevent DIND and to evaluate the impact on clinical outcome . METHODS This was a prospect i ve , r and omized , single-blind , placebo-controlled study . The MgSO4 infusion was adjusted every 12 hours until day 12 according to the target serum Mg2 + level . The occurrence of DIND , secondary infa rct ion , side effects , and the outcome after 3 and 12 months were assessed . RESULTS Fifty-eight patients were r and omized ; 27 received placebo and 31 MgSO4 . The difference in occurrence of DIND and secondary infa rct ion was not significant . The intention-to-treat analysis revealed a trend toward better outcome ( P = .083 ) after 3 months . On-treatment analysis showed a significantly better outcome after 3 months ( P = .017 ) and a trend toward better outcome after 1 year ( P = .083 ) . Significantly more often hypotension ( P = .040 ) and hypocalcemia ( P = .005 ) occurred as side effects in the treatment group . In 16 patients ( 52 % ) , the MgSO4 therapy had to be stopped before day 12 because of side effects . No predictive factor leading to termination was found in a postr and omization analysis . CONCLUSIONS High-dose MgSO4 therapy might be efficient as a prophylactic adjacent therapy after SAH to reduce the risk for poor outcome . Nevertheless , because of the high frequency of the side effects , patients should be observed in an intensive or intermediate care setting Background and Purpose — Pilot clinical trials using magnesium sulfate in patients with acute aneurysmal subarachnoid hemorrhage have reported trends toward improvement in clinical outcomes . This Phase III study aim ed to compare intravenous magnesium sulfate infusion with saline placebo among such patients . Methods — We recruited patients with aneurysmal subarachnoid hemorrhage within 48 hours of onset from 10 participating centers . The patients were r and omly assigned to magnesium sulfate infusion titrated to a serum magnesium concentration twice the baseline concentration or saline placebo for 10 to 14 days . Patients and assessors were blinded to treatment allocation . The study is registered at www.strokecenter.org/trials ( as Intravenous Magnesium Sulphate for Aneurysmal Subarachnoid Hemorrhage [ IMASH ] ) and www . Clinical Trials.gov ( NCT00124150 ) . Results — Of the 327 patients recruited , 169 were r and omized to receive treatment with intravenous magnesium sulfate and 158 to receive saline ( placebo ) . The proportions of patients with a favorable outcome at 6 months ( Extended Glasgow Outcome Scale 5 to 8) were similar , 64 % in the magnesium sulfate group and 63 % in the saline group ( OR , 1.0 ; 95 % CI , 0.7 to 1.6 ) . Secondary outcome analyses ( modified Rankin Scale , Barthel Index , Short Form 36 , and clinical vasospasm ) also showed no significant differences between the 2 groups . Predefined subgroups included age , admission World Federation of Neurological Surgeons grade , pre-existing hypertension , intracerebral hematoma , intraventricular hemorrhage , location of aneurysm , size of aneurysm , and mode of aneurysm treatment . In none of the subgroups did the magnesium sulfate group show a better outcome at 6 months . Conclusions — The results do not support a clinical benefit of intravenous magnesium sulfate infusion over placebo infusion in patients with acute aneurysmal subarachnoid hemorrhage OBJECT Despite the application of current st and ard therapies , vasospasm continues to result in death or major disability in patients treated for ruptured aneurysms . The authors investigated the effectiveness of continous MgSO4 infusion for vasospasm prophylaxis . METHODS Seventy-six adults ( mean age 54.6 years ; 71 % women ; 92 % Caucasian ) were included in this comparative matched-cohort study of patients with aneurysmal subarachnoid hemorrhage on the basis of computed tomography ( CT ) findings . Thirty-eight patients who received continuous MgSO4 infusion were matched for age , race , sex , treatment option , Fisher grade , and Hunt and Hess grade to 38 historical control individuals who did not receive MgSO4infusion . Twelve grams of MgSO4 in 500 ml normal saline was given intravenously daily for 12 days if the patient presented within 48 hours of aneurysm rupture . Vasospasm was diagnosed on the basis of digital substraction angiography , CT angiography , and transcranial Doppler ultrasonography , and evidence of neurological deterioration . Symptomatic vasospasm was present at a significantly lower frequency in patients who received MgSO4 infusion ( 18 % ) compared with patients who did not receive MgSO4 ( 42 % ) ( p = 0.025 ) . There was no significant difference in mortality rate at discharge ( p = 0.328 ) . A trend toward improved outcome as measured by the modifed Rankin Scale ( p = 0.084 ) , but not the Glasgow Outcome Scale ( p = 1.0 ) , was seen in the MgSO4 treated group . CONCLUSIONS Analysis of the results suggests that MgSO4 infusion may have a role in cerebral vasospasm prophylaxis if therapy is initiated within 48 hours of aneurysm rupture Objective : To examine whether the maintenance of elevated magnesium serum concentrations by intravenous administration of magnesium sulfate can reduce the occurrence of cerebral ischemic events after aneurysmal subarachnoid hemorrhage . Design : Prospect i ve , r and omized , placebo-controlled study . Setting : Neurosurgical intensive care unit of a University hospital . Interventions : One hundred ten patients were r and omized to receive intravenous magnesium sulfate or to serve as controls . Magnesium treatment was started with a bolus of 16 mmol , followed by continuous infusion of 8 mmol/hr . Serum concentrations were measured every 8 hrs , and infusion rates were adjusted to maintain target levels of 2.0–2.5 mmol/L. Intravenous administration was continued for 10 days or until signs of vasospasm had resolved . Thereafter , magnesium was administered orally and tapered over 12 days . Measurements and Main Results : Delayed ischemic infa rct ion ( primary end point ) was assessed by analyzing serial computed tomography scans . Transcranial Doppler sonography and digital subtraction angiography were used to detect vasospasm . Delayed ischemic neurologic deficit was determined by continuous detailed neurologic examinations ; clinical outcome after 6 months was assessed using the Glasgow outcome scale . Good outcome was defined as Glasgow outcome scale score 4 and 5 . The incidence of delayed ischemic infa rct ion was significantly lower in magnesium-treated patients ( 22 % vs. 51 % ; p = .002 ) ; 34 of 54 magnesium patients and 27 of 53 control patients reached good outcome ( p = .209 ) . Delayed ischemic neurologic deficit was nonsignificantly reduced ( 9 of 54 vs. 15 of 53 patients ; p = .149 ) and transcranial Doppler-detected/angiographic vasospasm was significantly reduced in the magnesium group ( 36 of 54 vs. 45 of 53 patients ; p = .028 ) . Fewer patients with signs of vasospasm had delayed cerebral infa rct ion . Conclusion : These data indicate that high-dose intravenous magnesium can reduce cerebral ischemic events after aneurysmal subarachnoid hemorrhage by attenuating vasospasm and increasing the ischemic tolerance during critical hypoperfusion We performed a r and omized , double-blind , pilot study on magnesium sulfate ( MgSO4 ) infusion for aneurysmal subarachnoid hemorrhage ( SAH ) . Sixty patients with SAH were r and omly allocated to receive either MgSO4 80 mmol/day or saline infusion for 14 days . Patients also received intravenous nimodipine . Episodes of vasospasm were treated with hypertensive and hypervolemic therapy . Neurologic status was assessed 6 months after hemorrhage using the Barthel index and Glasgow Outcome Scale . Incidences of cardiac and pulmonary complications were also recorded . Patient characteristics , severity of SAH , and surgical treatment did not differ between groups . The incidence of symptomatic vasospasm decreased from 43 % in the saline group to 23 % in patients receiving MgSO4 infusion , but it did not reach statistical significance , P=0.06 . For patients who had transcranial Doppler-detected vasospasm , defined as mean flow velocity > 120 cm/s and a Lindegaard index > 3 , the duration was shorter in the magnesium group compared with controls ( P<0.01 ) . There was , however , no difference between groups in functional recovery or Glasgow Outcome Scale score . The incidence of adverse events such as brain swelling , hydrocephalus , and nosocomial infection was also similar in patients receiving MgSO4 or saline . In this small pilot study , MgSO4 infusion for aneurysmal SAH is feasible . On the basis of the preliminary data , a larger study recruiting approximately 800 patients is required to test for a possible neuroprotective effect of magnesium after SAH Summary Background Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia . We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage . Methods We did this phase 3 r and omised , placebo-controlled trial in eight centres in Europe and South America . We r and omly assigned ( with computer-generated r and om numbers , with permuted blocks of four , stratified by centre ) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage , to receive intravenous magnesium sulphate , 64 mmol/day , or placebo . We excluded patients with renal failure or bodyweight lower than 50 kg . Patients , treating physicians , and investigators assessing outcomes and analysing data were masked to the allocation . The primary outcome was poor outcome —defined as a score of 4–5 on the modified Rankin Scale—3 months after subarachnoid haemorrhage , or death . We analysed results by intention to treat . We also up date d a previous meta- analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage . This study is registered with controlled-trials.com ( IS RCT N 68742385 ) and the EU Clinical Trials Register ( EudraCT 2006 - 003523 - 36 ) . Findings 1204 patients were enrolled , one of whom had his treatment allocation lost . 606 patients were assigned to the magnesium group ( two lost to follow-up ) , 597 to the placebo ( one lost to follow-up ) . 158 patients ( 26·2 % ) had poor outcome in the magnesium group compared with 151 ( 25·3 % ) in the placebo group ( risk ratio [ RR ] 1·03 , 95 % CI 0·85–1·25 ) . Our up date d meta- analysis of seven r and omised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage ( RR 0·96 , 95 % CI 0·86–1·08 ) . Interpretation Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage , therefore routine administration of magnesium can not be recommended . Funding Netherl and s Heart Foundation , UK Medical Research Council Background : There is limited information about the long-term consequences of subarachnoid hemorrhage ( SAH ) . Methods : Data were obtained from a population -based study of aneurysmal SAH conducted in Australia and New Zeal and between 1995 and 1998 . The authors report health outcomes for survivors 1 year after the onset of SAH . Results : From a total of 432 first-ever cases of SAH ( 76 % due to confirmed cerebral aneurysm rupture ) registered in four cities in Australia and New Zeal and , 242 ( 56 % ) were alive approximately 1 year later ( mean time 1.2 years ) , with 230 ( 95 % ) available for interview . Of those interviewed , 105 ( 46 % ) reported an incomplete recovery , with ongoing problems with memory ( 50 % ) , mood ( 39 % ) , speech ( 14 % ) , and self-care ( 10 % ) . Compared with age- and sex-adjusted Australian population norms , health-related quality of life , as determined by Short Form–36 , was significantly lower for cases in the domains of role limitations that result from physical problems . However , there were no patient or disease characteristics that predicted complete recovery from SAH . Conclusions : A high proportion of long-term survivors of SAH experience ongoing deficits in high level ( neuropsychological ) functioning . These deficits result in impairment in social roles BACKGROUND Among the many complications of SAH , one of the most important is vasospasm . Several treatment alternatives have been proposed for this condition , with far-from-ideal results being obtained . Magnesium sulfate recently returned to the scene ( with still unproven benefit ) as an adjuvant in the treatment of vasospasm . METHODS Seventy-two patients diagnosed with SAH by aneurysm rupture were su bmi tted to microsurgery craniotomy and subdivided in 2 groups . Group 1 , formed by 48 patients , received prophylactic hypervolemic and hemodilution therapy in addition to nimodipine . Group 2 , composed of 24 patients , received the same treatment of group 1 with the addition of magnesium sulfate in continuous infusion from 120 to 150 mg a day , keeping serum magnesium levels close to double normal values . RESULTS Age was 49 + /- 12.6 years . Ratio of female to male was 3.16:1 . Most patients were admitted in a Hunt-Hess grade 2 ( 46.4 % ) and Fisher grade 3 ( 52.8 % ) . Anterior communicating artery aneurysms were the most common in location ( 38.8 % ) . Both groups were compared , and there was no statistical difference related to age , sex , and Glasgow , Fisher , or Hunt-Hess admission grade s. No statistical difference in vasospasm incidence was found between the two groups . However , in group 1 , vasospasm was correlated with a longer hospitalization time ( P = .0003 ) , different from group 2 , in which patients with vasospasm receiving magnesium sulfate required less hospitalization time . CONCLUSION Magnesium did not seem to interfere in vasospasm frequency but apparently acted favorably in decreasing morbidity and length of hospital stay BACKGROUND Magnesium is a neuroprotective agent that might prevent or reverse delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage ( SAH ) . We are presently running a r and omized , placebo-controlled , double blind trial with magnesium sulphate ( 64 mmol/day intravenously ) . We studied whether this treatment regime result ed in our target serum magnesium levels of 1.0 - 2.0 mmol/L. METHODS Magnesium sulphate was administered intravenously as soon as possible after admission and continued until 14 days after occlusion of the aneurysm . Serum magnesium measurements were done at baseline and at least every 2 days during administration of trial medication . For comparison we used the serum magnesium levels of the placebo-treated patients . RESULTS Magnesium therapy was begun in 94 patients . The mean magnesium level in the treatment period was 1.47 + /- 0.32 mmol/L. In 81 patients serum magnesium stayed within target levels during the entire treatment period . One patient had a serum magnesium level below 1.0 mmol/L ( 0.91 mmol/L ) in a single measurement and 10 patients had serum magnesium levels above 2.0 mmol/L at one or more measurements . In six patients magnesium therapy was discontinued : in three because of nausea , headache , or both in combination with serum magnesium levels above 2.0 mmol/L and in the other three because of hypotension , phlebitis and renal failure . CONCLUSIONS With an intravenous dosage schedule of 64 mmol magnesium sulphate a day , serum magnesium levels of 1.0 - 2.0 mmol/L can easily be maintained without severe side effects for an extended period in a vast majority of patients with SAH

Conclusions Among 65 septic shock trials , there was a clinical ly relevant amount of heterogeneity in control group mortality rates which was explained only partly by differences in inclusion criteria and reported baseline characteristics

Purpose Although the definition of septic shock has been st and ardized , some variation in mortality rates among clinical trials is expected . Insights into the sources of heterogeneity may influence the design and interpretation of septic shock studies . We set out to identify inclusion criteria and baseline characteristics associated with between-trial differences in control group mortality rates .

Introduction The rate of weaning of vasopressors drugs is usually an empirical choice made by the treating in critically ill patients . We applied fuzzy logic principles to modify intravenous norepinephrine ( noradrenaline ) infusion rates during norepinephrine infusion in septic patients in order to reduce the duration of shock . Methods Septic patients were r and omly assigned to norepinephrine infused either at the clinician 's discretion ( control group ) or under closed-loop control based on fuzzy logic ( fuzzy group ) . The infusion rate changed automatically after analysis of mean arterial pressure in the fuzzy group . The primary end-point was time to cessation of norepinephrine . The secondary end-points were 28-day survival , total amount of norepinephine infused and duration of mechanical ventilation . Results Nineteen patients were r and omly assigned to fuzzy group and 20 to control group . Weaning of norepinephrine was achieved in 18 of the 20 control patients and in all 19 fuzzy group patients . Median ( interquartile range ) duration of shock was significantly shorter in the fuzzy group than in the control group ( 28.5 [ 20.5 to 42 ] hours versus 57.5 [ 43.7 to 117.5 ] hours ; P < 0.0001 ) . There was no significant difference in duration of mechanical ventilation or survival at 28 days between the two groups . The median ( interquartile range ) total amount of norepinephrine infused during shock was significantly lower in the fuzzy group than in the control group ( 0.6 [ 0.2 to 1.0 ] μg/kg versus 1.4 [ 0.6 to 2.7 ] μg/kg ; P < 0.01 ) . Conclusions Our study has shown a reduction in norepinephrine weaning duration in septic patients enrolled in the fuzzy group . We attribute this reduction to fuzzy control of norepinephrine infusion . Trial registration Trial registration : Clinical trials.gov NCT00763906 The effect of Shenfu on biochemical parameters and survival during resuscitation in patients with septic shock was examined . This was a multicenter , controlled , r and omized , open-label trial carried out in 210 patients with septic shock from seven medical centers in China . They were r and omized to Shenfu or saline . The primary outcome was lactate clearance . The secondary outcomes were shock index normalization , dose of vasopressors , ICU stay , hospital stay , and mortality . A total of 199 patients completed the trial . Blood pressure , heart rate , and other routine lab tests showed no difference between the groups . Lactate levels and lactate clearance were similar between the two groups . Hospital and ICU stay were similar between the two groups . When considering all patients , the 7- and 28-day mortality were similar between the two groups , but when considering only patients with lactate levels ≥4.5 mmol/L , the Shenfu group showed a better 7-day survival than the control group ( 7 days : 83.3 % versus 54.5 % , P = 0.034 ; 28 days : 72.7 % versus 47.6 % , P = 0.092 ) . Shenfu may improve the 7-day survival in patients with impaired lactate clearance ( ≥4.5 mmol/L ) , but the mechanism for this effect is unclear . Additional studies are necessary to characterize the hemodynamic changes after Shenfu infusion . This trial is registered with ChiCTR-TRC-11001369 CONTEXT AND OBJECTIVE Sepsis and septic shock are very common conditions among critically ill patients that lead to multiple organ dysfunction syndrome ( MODS ) and death . Our purpose was to investigate the efficacy of early administration of dexamethasone for patients with septic shock , with the aim of halting the progression towards MODS and death . DESIGN AND SETTING Prospect i ve , r and omized , double-blind , single-center study , developed in a surgical intensive care unit at Hospital das Clínicas , Faculdade de Medicina da Universidade de São Paulo . METHODS The study involved 29 patients with septic shock . All eligible patients were prospect ively r and omized to receive either a dose of 0.2 mg/kg of dexamethasone ( group D ) or placebo ( group P ) , given three times at intervals of 36 hours . The patients were monitored over a seven-day period by means of the sequential organ failure assessment score . RESULTS Patients treated with dexamethasone did not require vasopressor therapy for as much time over the seven-day period as did the placebo group ( p = 0.043 ) . Seven-day mortality was 67 % in group P ( 10 out of 15 ) and 21 % in group D ( 3 out of 14 ) ( relative risk = 0.31 , 95 % confidence interval 0.11 to 0.88 ) . Dexamethasone enhanced the effects of vasopressor drugs . CONCLUSIONS Early treatment with dexamethasone reduced the seven-day mortality among septic shock patients and showed a trend towards reduction of 28-day mortality Introduction In septic shock , pulse pressure or cardiac output variation during passive leg raising are preload dependence indices reliable at predicting fluid responsiveness . Therefore , they may help to identify those patients who need intravascular volume expansion , while avoiding unnecessary fluid administration in the other patients . However , whether their use improves septic shock prognosis remains unknown . The aim of this study was to assess the clinical benefits of using preload dependence indices to titrate intravascular fluids during septic shock . Methods In a single-center r and omized controlled trial , 60 septic shock patients were allocated to preload dependence indices-guided ( preload dependence group ) or central venous pressure-guided ( control group ) intravascular volume expansion with 30 patients in each group . The primary end point was time to shock resolution , defined by vasopressor weaning . Results There was no significant difference in time to shock resolution between groups ( median ( interquartile range ) 2.0 ( 1.2 to 3.1 ) versus 2.3 ( 1.4 to 5.6 ) days in control and preload dependence groups , respectively ) . The daily amount of fluids administered for intravascular volume expansion was higher in the control than in the preload dependence group ( 917 ( 639 to 1,511 ) versus 383 ( 211 to 604 ) mL , P = 0.01 ) , and the same held true for red cell transfusions ( 178 ( 82 to 304 ) versus 103 ( 0 to 183 ) mL , P = 0.04 ) . Physiologic variable values did not change over time between groups , except for plasma lactate ( time over group interaction , P < 0.01 ) . Mortality was not significantly different between groups ( 23 % in the preload dependence group versus 47 % in the control group , P = 0.10 ) . Intravascular volume expansion was lower in the preload dependence group for patients with lower simplified acute physiology score II ( SAPS II ) , and the opposite was found for patients in the upper two SAPS II quartiles . The amount of intravascular volume expansion did not change across the quartiles of severity in the control group , but steadily increased with severity in the preload dependence group . Conclusions In patients with septic shock , titrating intravascular volume expansion with preload dependence indices did not change time to shock resolution , but result ed in less daily fluids intake , including red blood cells , without worsening patient outcome .Trial registration Clinical trials.gov NCT01972828 . Registered 11 October 2013 Introduction Sepsis is associated with the generation of oxygen free radicals and ( lacking ) decreased selenium plasma concentrations . High doses of sodium selenite might reduce inflammation by a direct pro-oxidative effect and may increase antioxidant cell capacities by selenium incorporation into selenoenzymes . We investigated the effects of a continuous administration of high doses of selenium in septic shock patients . Methods A prospect i ve , multicentre , placebo-controlled , r and omized , double-blind study was performed with an intention-to-treat analysis in severe septic shock patients with documented infection . Patients received , for 10 days , selenium as sodium selenite ( 4,000 μg on the first day , 1,000 μg/day on the nine following days ) or matching placebo using continuous intravenous infusion . The primary endpoint was the time to vasopressor therapy withdrawal . The duration of mechanical ventilation , the mortality rates in the intensive care unit , at hospital discharge , and at 7 , 14 , 28 and 180 days and 1 year after r and omization , and adverse events were recorded . Results Sixty patients were included ( placebo , n = 29 ; selenium , n = 31 ) . The median time to vasopressor therapy withdrawal was 7 days in both groups ( 95 % confidence interval = 5–8 and 6–9 in the placebo and selenium groups , respectively ; log-rank , P = 0.713 ) . The median duration of mechanical ventilation was 14 days and 19 days in the placebo and selenium groups , respectively ( P = 0.762 ) . Mortality rates did not significantly differ between groups at any time point . Rates of adverse events were similar in the two groups . Conclusion Continuous infusion of selenium as sodium selenite ( 4,000 μg on the first day , 1,000 μg/day on the nine following days ) had no obvious toxicity but did not improve the clinical outcome in septic shock patients . Trial Registration = NCT00207844 BACKGROUND In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock , mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal -directed therapy ( EGDT ) , in which intravenous fluids , vasopressors , inotropes , and blood transfusions were adjusted to reach central hemodynamic targets , than among those receiving usual care . We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary . METHODS In 31 emergency departments in the United States , we r and omly assigned patients with septic shock to one of three groups for 6 hours of resuscitation : protocol -based EGDT ; protocol -based st and ard therapy that did not require the placement of a central venous catheter , administration of inotropes , or blood transfusions ; or usual care . The primary end point was 60-day in-hospital mortality . We tested sequentially whether protocol -based care ( EGDT and st and ard-therapy groups combined ) was superior to usual care and whether protocol -based EGDT was superior to protocol -based st and ard therapy . Secondary outcomes included longer-term mortality and the need for organ support . RESULTS We enrolled 1341 patients , of whom 439 were r and omly assigned to protocol -based EGDT , 446 to protocol -based st and ard therapy , and 456 to usual care . Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids , vasopressors , inotropes , and blood transfusions . By 60 days , there were 92 deaths in the protocol -based EGDT group ( 21.0 % ) , 81 in the protocol -based st and ard-therapy group ( 18.2 % ) , and 86 in the usual-care group ( 18.9 % ) ( relative risk with protocol -based therapy vs. usual care , 1.04 ; 95 % confidence interval [ CI ] , 0.82 to 1.31 ; P=0.83 ; relative risk with protocol -based EGDT vs. protocol -based st and ard therapy , 1.15 ; 95 % CI , 0.88 to 1.51 ; P=0.31 ) . There were no significant differences in 90-day mortality , 1-year mortality , or the need for organ support . CONCLUSIONS In a multicenter trial conducted in the tertiary care setting , protocol -based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes . ( Funded by the National Institute of General Medical Sciences ; ProCESS Clinical Trials.gov number , NCT00510835 . ) Purpose : The Surviving Sepsis Campaign guidelines recommend hydrocortisone in septic shock only when fluid resuscitation and vasopressors fail to restore hemodynamic stability . Hydrocortisone administration modalities are supported only by low- grade recommendations . Our main objective here was to determine differences in 28-day mortality between two low-dose hydrocortisone regimens for the treatment of septic shock . Methods : We performed a multicenter , prospect i ve , r and omized , double-blind , pilot study in four adult medical intensive care units . Patients presenting septic shock were rapidly administered one of two regimens of hydrocortisone , either a 50-mg intravenous bolus every 6 h during 7 days ( 200-mg group ; n = 59 ) or a 100-mg initial bolus followed by a continuous infusion of 300 mg daily for 5 days ( 300-mg group ; n = 63 ) . Hydrocortisone was stopped abruptly at the end of treatment . Results : There were no significant differences between the 200-mg and 300-mg groups as concerns 28-day mortality ( respectively 52.5 % vs. 44.4 % [ RR 0.84 , 95 % CI , 0.58–1.22 , P = 0.47 ] ) , refractory shock incidence or delay from shock to vasopressor cessation . There were also no differences in adverse events between the groups . Shock relapse after hydrocortisone cessation was independent of hydrocortisone regimens , but it was associated with the persistence of infection and the use of etomi date . The resumption of hydrocortisone due to shock relapse was significantly more frequent in the 300-mg group . Conclusion : We found no differences in mortality or adverse events between the two hydrocortisone administration regimens . Shock relapse was significantly associated with the persistence of infection and the use of etomi date BACKGROUND Whether hydrocortisone reduces mortality among patients with septic shock is unclear . METHODS We r and omly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone ( at a dose of 200 mg per day ) or placebo for 7 days or until death or discharge from the intensive care unit ( ICU ) , whichever came first . The primary outcome was death from any cause at 90 days . RESULTS From March 2013 through April 2017 , a total of 3800 patients underwent r and omization . Status with respect to the primary outcome was ascertained in 3658 patients ( 1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group ) . At 90 days , 511 patients ( 27.9 % ) in the hydrocortisone group and 526 ( 28.8 % ) in the placebo group had died ( odds ratio , 0.95 ; 95 % confidence interval [ CI ] , 0.82 to 1.10 ; P=0.50 ) . The effect of the trial regimen was similar in six prespecified subgroups . Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group ( median duration , 3 days [ interquartile range , 2 to 5 ] vs. 4 days [ interquartile range , 2 to 9 ] ; hazard ratio , 1.32 ; 95 % CI , 1.23 to 1.41 ; P<0.001 ) . Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group ( median , 6 days [ interquartile range , 3 to 18 ] vs. 7 days [ interquartile range , 3 to 24 ] ; hazard ratio , 1.13 ; 95 % CI , 1.05 to 1.22 ; P<0.001 ) , but taking into account episodes of recurrence of ventilation , there were no significant differences in the number of days alive and free from mechanical ventilation . Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion ( 37.0 % vs. 41.7 % ; odds ratio , 0.82 ; 95 % CI , 0.72 to 0.94 ; P=0.004 ) . There were no significant between‐group differences with respect to mortality at 28 days , the rate of recurrence of shock , the number of days alive and out of the ICU , the number of days alive and out of the hospital , the recurrence of mechanical ventilation , the rate of renal‐replacement therapy , and the incidence of new‐onset bacteremia or fungemia . CONCLUSIONS Among patients with septic shock undergoing mechanical ventilation , a continuous infusion of hydrocortisone did not result in lower 90‐day mortality than placebo . ( Funded by the National Health and Medical Research Council of Australia and others ; ADRENAL Clinical Trials.gov number , NCT01448109 . PURPOSE The aim of this study was to show that 6 % hydroxyethyl starch ( HES ) 130/0.4 achieves a better resuscitation of the microcirculation than normal saline solution ( SS ) , during early goal -directed therapy ( EGDT ) in septic patients . MATERIAL S AND METHODS Patients with severe sepsis were r and omized for EGDT with 6 % HES 130/0.4 ( n = 9 ) or SS ( n = 11 ) . Sublingual microcirculation was evaluated by sidestream dark field imaging 24 hours after the beginning of EGDT . RESULTS On admission , there were no differences in Sequential Organ Failure Assessment score , mean arterial pressure , lactate , or central venous oxygen saturation . After 24 hours , no difference arose in those parameters . Sublingual capillary density was similar in both groups ( 21 ± 8 versus 20 ± 3 vessels/mm(2 ) ) ; but capillary microvascular flow index , percent of perfused capillaries , and perfused capillary density were higher in 6 % HES 130/0.4 ( 2.5 ± 0.5 versus 1.6 ± 0.7 , 84 ± 15 versus 53 ± 26 % , and 19 ± 6 versus 11 ± 5 vessels/mm(2 ) , respectively , P < .005 ) . CONCLUSIONS Fluid resuscitation with 6 % HES 130/0.4 may have advantages over SS to improve sublingual microcirculation . A greater number of patients would be necessary to confirm these findings Background : It is unknown whether fluid resuscitation with colloid or crystalloid in patients with severe sepsis or septic shock is associated with an improvement in clinical outcome . This r and omized controlled trial determined the feasibility of conducting a large trial testing resuscitation with pentastarchvs normal saline in early septic shock , powered for a difference in mortality . Methods : At three Canadian and one New Zeal and academic centre , 40 patients with early septic shock defined by at least two systemic inflammatory response syndrome criteria , infectious source , and persistent hypotension after ≥ 1 L of crystalloid fluid were recruited . Feasibility measures were patient recruitment , blinding of the study fluids , and acceptability of the goal directed algorithms . Boluses of blinded normal saline or pentastarch ( 500 mL − maximum 3 L or 28 mL·kg−1 ) were administered within goal directed care for the first 12 hr . Results : Of 161 patients screened , 121 were excluded and 40 patients were enrolled , for a recruitment rate of 0.75 patients / site/month . Only 57 % of physicians and 54 % of nurses correctly guessed the study fluid ( P = 0.46 and P = 0.67 , respectively ) . The goal directed algorithms were acceptable to 97 % of physicians . Conclusion : The ability to recruit patients in this pilot r and omized controlled trial was below expectations . Blinding of study fluids was adequate , and resuscitation algorithms were acceptable to most physicians . Methods to improve recruitment are required to enhance the feasibility of conducting a multicentre fluid resuscitation trial in early septic shock . Résumé Context e : Nous ne savons pas si la réanimation liquidienne avec des colloïdes ou des cristalloïdes chez les patients présentant un sepsis grave ou un choc septique est associée à un devenir clinique meilleur . Cette étude r and omisée contrôlée a déterminé la faisabilité d’une étude d’envergure testant la réanimation avec le pentastarch par rapport au sérum physiologique en début de choc septique , avec pour objectif primaire de détecter une différence dans les taux de mortalité . Method e : Quarante patients en début de choc septique , défini comme au moins deux critères du syndrome de réaction inflammatoire , une source d’infection et une hypotension persistante après ≥ 1 L de cristalloïde ont été recrutés dans trois centres universitaires canadiens et un centre néo-zél and ais . Les mesures de faisabilite étaient : le recrutement des patients , le masquage des liquides à l’étude , et I’acceptabilité des algorithmes dirigés vers des objectifs . Des bolus de normal sal in ou de pentastarch ( 500 mL — maximum 3 L ou 28 mL·kg−1 ) ont été administrés en aveugle dans le cadre de soins guidés dirigés vers des objectifs durant les 12 premieres heures . Result ats : Sur 161 patients dépistés , 121 ont été exclus et 40 patients recrutés dans le cadre de I’étude , avec un taux de recrutement de 0,75 patient/site/mois . Seulement 57 % des médecins et 54 % des infirmières ont réussi à deviner correctement le type de liquide à I’étude ( P = 0,46 etP = 0,67 , respectivement ) . Les algorithmes ont été jugés acceptables par 97 % des médecins . Conclusion : La capacité à recruter des patients pour cette étude pilote r and omisée contrôlée était moins importante qu’attendue . Le masquage des liquides était satisfaisant , et les algorithmes de réanimation ont été jugés acceptables par la majorité des médecins . Des méthodes dans le but d’améliorer le recrutement sont nécessaire pour accroître la faisabilité d’une étude multicentrique sur la réanimation liquidienne en début de choc septique BACKGROUND Predicting fluid responsiveness is crucial for fluid administration in septic shock patients . Midazolam and propofol decrease vascular tone and venous return , which may influence preload dependency . However , little is known about the effects of these two sedatives on preload dependency in septic shock patients . We evaluated the effects of sedation with propofol or midazolam on preload dependency in septic shock patients who have been fluid resuscitated . METHODS Forty-three septic shock patients who were undergoing early goal -directed therapy resuscitated within 24 h were enrolled . The patients were r and omly divided into the midazolam group and the propofol group . An initial passive leg-raising test ( PLR1 ) was performed to evaluate passive leg raising test ( PLR ) responsiveness . Then , the patients were infused with midazolam or propofol . After increasing the doses of the sedatives to titrate to a Ramsay 4 score , a second passive leg raising test ( PLR2 ) was conducted to evaluate PLR responsiveness . The primary end-point was the preload dependency before and after sedation with midazolam or propofol . RESULTS In the midazolam-PLR1-negative patients , there was no difference between the changes in the cardiac index induced by PLR1 ( PLR1-Δ cardiac function index [ CI ] ) and the changes in the cardiac index induced by PLR2 ( PLR2-Δ CI ) ( + 1.4 % ± 7.4 % versus + 1.7 % ± 6.4 % , P > 0.05 ) . However , in the propofol-PLR1-negative patients , there was a significant increase in the PLR-Δ CI after sedation to a Ramsay 4 score compared with a Ramsay 3 score ( + 7.3 % ± 4.8 % versus + 3.2 % ± 4.7 % , P = 0.008 ) . There were no differences between PLR1-Δ CI and PLR2-Δ CI within the midazolam-PLR1-positive patients or within the propofol-PLR1-positive patients . CONCLUSIONS In titrating the sedation level from a Ramsay 3 score to a Ramsay 4 score , propofol but not midazolam increased preload dependency in septic shock patients with fluid nonresponsiveness Introduction Recent clinical data suggest that early administration of vasopressin analogues may be advantageous compared to a last resort therapy . However , it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in septic shock . The aim of the present prospect i ve , r and omized , controlled pilot trial study was , therefore , to compare the impact of continuous infusions of either vasopressin or terlipressin , when given as first-line therapy in septic shock patients , on open-label norepinephrine requirements . Methods We enrolled septic shock patients ( n = 45 ) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation . Patients were r and omized to receive continuous infusions of either terlipressin ( 1.3 μg·kg-1·h-1 ) , vasopressin ( .03 U·min-1 ) or norepinephrine ( 15 μg·min-1 ; n = 15 per group ) . In all groups , open-label norepinephrine was added to achieve a mean arterial pressure between 65 and 75 mmHg , if necessary . Data from right heart and thermo-dye dilution catheterization , gastric tonometry , as well as laboratory variables of organ function were obtained at baseline , 12 , 24 , 36 and 48 hours after r and omization . Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors . Time-independent variables were compared with one-way ANOVA . Results There were no differences among groups in terms of systemic and regional hemodynamics . Compared with infusion of .03 U of vasopressin or 15 μg·min-1 of norepinephrine , 1.3 μg·kg-1·h-1 of terlipressin allowed a marked reduction in catecholamine requirements ( 0.8 ± 1.3 and 1.2 ± 1.4 vs. 0.2 ± 0.4 μg·kg-1·min-1 at 48 hours ; each P < 0.05 ) and was associated with less rebound hypotension ( P < 0.05 ) . At the end of the 48-hour intervention period , bilirubin concentrations were higher in the vasopressin and norepinephrine groups as compared with the terlipressin group ( 2.3 ± 2.8 and 2.8 ± 2.5 vs. 0.9 ± 0.3 mg·dL-1 ; each P < 0.05 ) . A time-dependent decrease in platelet count was only observed in the terlipressin group ( P < 0.001 48 hours vs. BL ) . Conclusions The present study provides evidence that continuous infusion of low-dose terlipressin – when given as first-line vasopressor agent in septic shock – is effective in reversing sepsis-induced arterial hypotension and in reducing norepinephrine requirements . Trial registration Clinical Trial.gov NCT00481572 BACKGROUND Sepsis bundles can decrease mortality in patients with severe sepsis or septic shock . However , current methods of measuring pressure , such as central venous pressure , are inadequate . This study investigated the effect of improved sepsis bundles informed by pulse-indicated continuous cardiac output . METHODS We compared the outcome of treatment with sepsis bundles informed by either conventional pressure measurements or pulse-indicated continuous cardiac output . Patients in 2 groups received fluid resuscitation , st and ard antibiotics , and oxygen therapy . RESULTS A total of 105 patients with septic shock were r and omly divided into 2 groups : the conventional sepsis bundle group ( n = 52 ) or the improved sepsis bundle group ( ISBG , n = 53 ) . The ISBG significantly reduced the mean Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores . Significantly fewer ISBG-treated patients received vasoactive drugs compared to conventional sepsis bundle group-treated patients . In addition , patients in the ISBG exhibited a significantly increased arterial blood lactate clearance rate and required less total fluid resuscitation and a shorter duration of mechanical ventilation and stay in the intensive care unit . CONCLUSIONS Pulse-indicated continuous cardiac output-directed sepsis bundles can reduce the severity of septic shock , provide more accurate fluid resuscitation , and reduce the duration of mechanical ventilation and stay in the intensive care unit Introduction Microcirculatory blood flow , and notably gut perfusion , is important in the development of multiple organ failure in septic shock . We compared the effects of dopexamine and norepinephrine ( noradrenaline ) with those of epinephrine ( adrenaline ) on gastric mucosal blood flow ( GMBF ) in patients with septic shock . The effects of these drugs on oxidative stress were also assessed . Methods This was a prospect i ve r and omized study performed in a surgical intensive care unit among adults fulfilling usual criteria for septic shock . Systemic and pulmonary hemodynamics , GMBF ( laser-Doppler ) and malondialdehyde were assessed just before catecholamine infusion ( T0 ) , as soon as mean arterial pressure ( MAP ) reached 70 to 80 mmHg ( T1 ) , and 2 hours ( T2 ) and 6 hours ( T3 ) after T1 . Drugs were titrated from 0.2 μg kg-1 min-1 with 0.2 μg kg-1 min-1 increments every 3 minutes for epinephrine and norepinephrine , and from 0.5 μg kg-1 min-1 with 0.5 μg kg-1 min-1 increments every 3 minutes for dopexamine . Results Twenty-two patients were included ( 10 receiving epinephrine , 12 receiving dopexamine – norepinephrine ) . There was no significant difference between groups on MAP at T0 , T1 , T2 , and T3 . Heart rate and cardiac output increased significantly more with epinephrine than with dopexamine – norepinephrine , whereas . GMBF increased significantly more with dopexamine – norepinephrine than with epinephrine between T1 and T3 ( median values 106 , 137 , 133 , and 165 versus 76 , 91 , 90 , and 125 units of relative flux at T0 , T1 , T2 and T3 , respectively ) . Malondialdehyde similarly increased in both groups between T1 and T3 . Conclusion In septic shock , at doses that induced the same effect on MAP , dopexamine – norepinephrine enhanced GMBF more than epinephrine did . No difference was observed on oxidative stress BACKGROUND Early goal -directed therapy ( EGDT ) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock . However , its effectiveness is uncertain . METHODS In this trial conducted at 51 centers ( mostly in Australia or New Zeal and ) , we r and omly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care . The primary outcome was all-cause mortality within 90 days after r and omization . RESULTS Of the 1600 enrolled patients , 796 were assigned to the EGDT group and 804 to the usual-care group . Primary outcome data were available for more than 99 % of the patients . Patients in the EGDT group received a larger mean ( ±SD ) volume of intravenous fluids in the first 6 hours after r and omization than did those in the usual-care group ( 1964±1415 ml vs. 1713±1401 ml ) and were more likely to receive vasopressor infusions ( 66.6 % vs. 57.8 % ) , red-cell transfusions ( 13.6 % vs. 7.0 % ) , and dobutamine ( 15.4 % vs. 2.6 % ) ( P<0.001 for all comparisons ) . At 90 days after r and omization , 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group , for rates of death of 18.6 % and 18.8 % , respectively ( absolute risk difference with EGDT vs. usual care , -0.3 percentage points ; 95 % confidence interval , -4.1 to 3.6 ; P=0.90 ) . There was no significant difference in survival time , in-hospital mortality , duration of organ support , or length of hospital stay . CONCLUSIONS In critically ill patients presenting to the emergency department with early septic shock , EGDT did not reduce all-cause mortality at 90 days . ( Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation ; ARISE Clinical Trials.gov number , NCT00975793 . ) BACKGROUND Early , goal -directed therapy ( EGDT ) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock . However , adoption has been limited , and uncertainty about its effectiveness remains . METHODS We conducted a pragmatic r and omized trial with an integrated cost-effectiveness analysis in 56 hospitals in Engl and . Patients were r and omly assigned to receive either EGDT ( a 6-hour resuscitation protocol ) or usual care . The primary clinical outcome was all-cause mortality at 90 days . RESULTS We enrolled 1260 patients , with 630 assigned to EGDT and 630 to usual care . By 90 days , 184 of 623 patients ( 29.5 % ) in the EGDT group and 181 of 620 patients ( 29.2 % ) in the usual-care group had died ( relative risk in the EGDT group , 1.01 ; 95 % confidence interval [ CI ] , 0.85 to 1.20 ; P=0.90 ) , for an absolute risk reduction in the EGDT group of -0.3 percentage points ( 95 % CI , -5.4 to 4.7 ) . Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids , vasoactive drugs , and red-cell transfusions and reflected by significantly worse organ-failure scores , more days receiving advanced cardiovascular support , and longer stays in the intensive care unit . There were no significant differences in any other secondary outcomes , including health-related quality of life , or in rates of serious adverse events . On average , EGDT increased costs , and the probability that it was cost-effective was below 20 % . CONCLUSIONS In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation , hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome . ( Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme ; ProMISe Current Controlled Trials number , IS RCT N36307479 . ) Purpose To quantify the effects of minor variations in the definition and measurement of systemic inflammatory response syndrome ( SIRS ) criteria and organ failure on the observed incidences of sepsis , severe sepsis and septic shock . Methods We conducted a prospect i ve , observational study in a tertiary intensive care unit in The Netherl and s between January 2009 and October 2010 . A total of 1,072 consecutive adults were included . We determined the upper and lower limits of the measured incidence of sepsis by evaluating the influence of the use of an automated versus a manual method of data collection , and variations in the number of SIRS criteria , concurrency of SIRS criteria , and duration of abnormal values required to make a particular diagnosis . Results The measured incidence of SIRS varied from 49 % ( most restrictive setting ) to 99 % ( most liberal setting ) . Subsequently , the incidences of sepsis , severe sepsis and septic shock ranged from 22 to 31 % , from 6 to 27 % and from 4 to 9 % for the most restrictive versus the most liberal measurement setting s , respectively . In non-infected patients , 39–98 % of patients had SIRS , whereas still 17–6 % of patients without SIRS had an infection . Conclusions The apparent incidence of sepsis heavily depends on minor variations in the definition of SIRS and mode of data recording . As a consequence , the current consensus criteria do not ensure uniform recruitment of patients into sepsis trials Introduction Resuscitation goals for septic shock remain controversial . Despite the normalization of systemic hemodynamic variables , tissue hypoperfusion can still persist . Indeed , lactate or oxygen venous saturation may be difficult to interpret . Our hypothesis was that a gastric intramucosal pH-guided resuscitation protocol might improve the outcome of septic shock compared with a st and ard approach aim ed at normalizing systemic parameters such as cardiac index ( CI ) . Methods The 130 septic-shock patients were r and omized to two different resuscitation goals : CI ≥ 3.0 L/min/m2 ( CI group : 66 patients ) or intramucosal pH ( pHi ) ≥ 7.32 ( pHi group : 64 patients ) . After correcting basic physiologic parameters , additional resuscitation consisting of more fluids and dobutamine was started if specific goals for each group had not been reached . Several clinical data were registered at baseline and during evolution . Hemodynamic data and pHi values were registered every 6 hours during the protocol . Primary end point was 28 days ' mortality . Results Both groups were comparable at baseline . The most frequent sources of infection were abdominal sepsis and pneumonia . Twenty-eight day mortality ( 30.3 vs. 28.1 % ) , peak Therapeutic Intervention Scoring System scores ( 32.6 ± 6.5 vs. 33.2 ± 4.7 ) and ICU length of stay ( 12.6 ± 8.2 vs. 16 ± 12.4 days ) were comparable . A higher proportion of patients exhibited values below the specific target at baseline in the pHi group compared with the CI group ( 50 % vs. 10.9 % ; P < 0.001 ) . Of 32 patients with a pHi < 7.32 at baseline , only 7 ( 22 % ) normalized this parameter after resuscitation . Areas under the receiver operator characteristic curves to predict mortality at baseline , and at 24 and 48 hours were 0.55 , 0.61 , and 0.47 , and 0.70 , 0.90 , and 0.75 , for CI and pHi , respectively . Conclusions Our study failed to demonstrate any survival benefit of using pHi compared with CI as resuscitation goal in septic-shock patients . Nevertheless , a normalization of pHi within 24 hours of resuscitation is a strong signal of therapeutic success , and in contrast , a persistent low pHi despite treatment is associated with a very bad prognosis in septic-shock patients Objectives Coupled plasma filtration adsorption ( CPFA , Bellco , Italy ) , to remove inflammatory mediators from blood , has been proposed as a novel treatment for septic shock . This multicenter , r and omised , non-blinded trial compared CPFA with st and ard care in the treatment of critically ill patients with septic shock . Design Prospect i ve , multicenter , r and omised , open-label , two parallel group and superiority clinical trial . Setting 18 Italian adult , general , intensive care units ( ICUs ) . Participants Of the planned 330 adult patients with septic shock , 192 were r and omised to either have CPFA added to the st and ard care , or not . The external monitoring committee excluded eight ineligible patients who were erroneously included . Interventions CPFA was to be performed daily for 5 days , lasting at least 10 h/day . Primary and secondary outcome measures The primary endpoint was mortality at discharge from the hospital at which the patient last stayed . Secondary endpoints were : 90-day mortality , new organ failures and ICU-free days within 30 days . Results There was no statistical difference in hospital mortality ( 47.3 % controls , 45.1 % CPFA ; p=0.76 ) , nor in secondary endpoints , namely the occurrence of new organ failures ( 55.9 % vs 56.0 % ; p=0.99 ) or free-ICU days during the first 30 days ( 6.8 vs 7.5 ; p=0.35 ) . The study was terminated on the grounds of futility . Several patients r and omised to CPFA were subsequently found to be undertreated . An a priori planned subgroup analysis showed those receiving a CPFA dose > 0.18 L/kg/day had a lower mortality compared with controls ( OR 0.36 , 95 % CI 0.13 to 0.99 ) . Conclusions CPFA did not reduce mortality in patients with septic shock , nor did it positively affect other important clinical outcomes . A subgroup analysis suggested that CPFA could reduce mortality , when a high volume of plasma is treated . Owing to the inherent potential biases of such a subgroup analysis , this result can only be viewed as a hypothesis generator and should be confirmed in future studies . Clinical Trials.gov NCT00332371 ; IS RCT N24534559 Background Setting lactate kinetics at > 30 % might improve the clinical outcomes of patients with sepsis-associated hyperlactatemia . The aim of this study was to explore the outcome benefits of stepwise lactate kinetics vs central venous oxygen saturation (ScvO2)-oriented hemodynamic therapy at 6 h as the protocol goal during early resuscitation . Methods The relevant parameters and adverse events after different targets in 360 r and omly assigned patients with sepsis-associated hyperlactatemia were recorded and compared . Results Heart rate ( HR ) at 48 h in the ScvO2 group was higher than in the lactate kinetics group ( 105 ± 19 bpm vs 99 ± 20 bpm , P = 0.040 ) . The liquid balance at 4 h , 12 h , and 24 h in the lactate kinetics group was larger than in the ScvO2 group ( 1535 ( 1271–1778 ) ml vs 826 ( 631–1219 ) ml , P < 0.001 ; 1688 ( 1173–1923 ) ml vs 1277 ( 962 − 1588 ) ml , P < 0.001 ; and 1510 ( 904–2087 ) ml vs 1236 ( 740–1808 ) ml , P = 0.005 ) , respectively . Mortality was higher in the ScvO2 group ( 27.9 % vs 18.3 % , P = 0.033 ) , but there was no significant difference between the two groups in the length of stay in the ICU or mechanical ventilation . In terms of new onset organ dysfunction , there was a significant difference between the two groups in total bilirubin at 48 h and 72 h. Based on the 60-day survival curves , there was significantly more mortality in the ScvO2 group than in the lactate kinetics group ( X2 = 4.133 , P = 0.042 ) . In addition , fewer adverse events occurred in the lactate kinetics group . Conclusions Stepwise lactate kinetics-oriented hemodynamic therapy can reduce mortality in patients with sepsis-associated hyperlactatemia compared with ScvO2-oriented therapy . Trial registration National Institutes of Health Clinical Trials Registry , NCT02566460 . Registered on 26 September 2015 Shenfu injection ( SFI ) derived from traditional Chinese medicine has been widely used in cardiovascular diseases . The objective of this study was to determine the effect of SFI and conventional early goal -directed therapy ( EGDT ) on organ functions and outcomes of septic shock patients . For this purpose , a total of 45 septic shock patients were r and omly divided into control group A ( 24 patients on EGDT ) and experimental group B ( 21 patients on SFI + EGDT ) . SFI was administered ( 100@20 mL/h ) twice daily . Hemodynamic status , lactic acid , and vasoactive drug use were observed before and after treatment . Other indicators included ventilator weaning time , ICU stay time , free of organ failure time , and 28-day hospital mortality . Regarding experimental group , compared with controls , BUN/creatinine decreased significantly at 3 , 5 , and 7 days while PaO2/FiO2 increased at 1 and 3 days ( P < 0.05 ) . APACHE-II and SOFA scores decreased in both groups at 3 , 5 , and 7 days ( P < 0.05 ) , whereas SOFA scores improved more in experimental group as compared with controls . Ventilator weaning time and ICU stay were significantly shorter in experimental group as compared with controls . In both groups , mean arterial pressure/systemic vascular resistance index post-treatment levels increased and lactic acid decreased at 6 , 12 , 24 , 48 , and 72 h ( P < 0.05 ) . Heart rate decreased at 24 , 48 , and 72 h ( P < 0.05 ) ; while gamma-glutamyl transpeptidase and glutamate oxaloacetate transaminase levels increased at 1 day and 1 and 3 days , respectively ( P < 0.05 ) . Combined use of SFI and EGDT can improve hemodynamics , reduce the damage to vital organs , and shorten ventilation and ICU stay times in septic shock patients Objectives : Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock . Retrospective analyses have suggested that there may be an interaction between these drugs , with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids . We aim ed to test for an interaction between vasopressin and corticosteroids in septic shock . Design : Prospect i ve open-label r and omized controlled pilot trial . Setting : Four adult ICUs in London teaching hospitals . Patients : Sixty-one adult patients who had septic shock . Interventions : Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone ( 50 mg 6 hourly ) or placebo . Plasma vasopressin levels were measured at 6–12 and 24–36 hours after hydrocortisone/placebo administration . Measurements and Main Results : Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo . The hydrocortisone group required a shorter duration of vasopressin therapy ( 3.1 d ; 95 % CI , 1.1–5.1 ; shorter in hydrocortisone group ) and required a lower total dose of vasopressin ( ratio , 0.47 ; 95 % CI , 0.32–0.71 ) compared with the placebo group . Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group ( 64 pmol/L difference at 6- to 12-hour time point ; 95 % CI , –32 to 160 pmol/L ) . Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported . There were no differences in mortality rates ( 23 % 28-day mortality in both groups ) or organ failure assessment s between the two treatment groups . Conclusions : Hydrocortisone spared vasopressin requirements , reduced duration , and reduced dose , when used together in the treatment of septic shock , but it did not alter plasma vasopressin levels . Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids Adenosine triphosphate-sensitive potassium channels are important regulators of arterial vascular smooth muscle tone and are implicated in the pathophysiology of catecholamine tachyphylaxis in septic shock . The present study was design ed as a prospect i ve , r and omized , double-blinded , clinical pilot study to determine whether different doses of glibenclamide have any effects on norepinephrine requirements , cardiopulmonary hemodynamics , and global oxygen transport in patients with septic shock . We enrolled 30 patients with septic shock requiring invasive hemodynamic monitoring and norepinephrine infusion of 0.5 μg·kg−1·min−1 or greater to maintain MAP between 65 and 75 mmHg . In addition to st and ard therapy , patients were r and omized to receive either 10 , 20 , or 30 mg of enteral glibenclamide . Systemic hemodynamics , global oxygen transport including arterial lactate concentrations , gas exchange , plasma glucose concentrations , and electrolytes were determined at baseline and after 3 , 6 , and 12 h after administration of the study drug . Glibenclamide decreased plasma glucose concentrations in a dose-dependent manner but failed to reduce norepinephrine requirements . None of the doses had any effects on cardiopulmonary hemodynamics , global oxygen transport , gas exchange , or electrolytes . These data suggest that oral glibenclamide in doses from 10 to 30 mg fails to counteract arterial hypotension and thus to reduce norepinephrine requirements in catecholamine-dependent human septic shock Objective : Fluid infusion , the most critical step in the resuscitation of patients with septic shock , needs preferably continuous invasive hemodynamic monitoring . The study was planned to evaluate the efficacy of ultrasonographically measured inferior vena cava collapsibility index ( IVC CI ) in comparison to central venous pressure ( CVP ) in predicting fluid responsiveness in septic shock . Material s and Methods : Thirty-six patients of septic shock requiring ventilatory support ( invasive/noninvasive ) were included . Patients with congestive heart failure , raised intra-abdominal pressure , and poor echo window were excluded from the study . They were r and omly divided into two groups based on mode of fluid resuscitation – Group I ( CVP ) and Group II ( IVC CI ) . Primary end-points were mean arterial pressure ( MAP ) of ≥65 mmHg and CVP > 12 mmHg or IVC CI < 20 % in Groups I and II , respectively . Patients were followed till achievement of end-points or maximum of 6 h. Outcome variables ( pulse rate , MAP , urine output , pH , base deficit , and ScvO2 ) were serially measured till the end of the study . Survival at 2 and 4 weeks was used as secondary end-point . Results : Primary end-point was reached in 31 patients ( 15 in Group I and 16 in Group II ) . Fluid infusion , by either method , had increased CVP and decreased IVC CI with result ant negative correlation between them ( Pearson correlation coefficient –0.626 ) . There was no significant difference in the amount of fluid infused and time to reach end-point in two groups . Comparison in outcome variables at baseline and end-point showed no significant difference including mortality . Conclusion : CVP and IVC CI are negatively correlated with fluid resuscitation , and both methods can be used for resuscitation , with IVC CI being noninferior to CVP The optimum septic shock vasopressor support strategy is currently debated . This study was performed to evaluate the efficacy and safety of norepinephrine ( NE ) and dopamine ( DA ) as the initial vasopressor in septic shock patients who were managed with a specific treatment protocol . A prospect i ve , r and omized , open-label , clinical trial was used in a medical intensive care unit comparing DA with NE as the initial vasopressor in fluid-resuscitated 252 adult patients with septic shock . If the maximum dose of the initial vasopressor was unable to maintain the hemodynamic goal , then fixed-dose vasopressin was added to each regimen . If additional vasopressor support was needed to achieve the hemodynamic goal , then phenylephrine was added . The primary efficacy end point was all-cause 28-day mortality . Secondary end points included organ dysfunction , hospital and intensive care unit length of stay , and safety ( primarily occurrence of arrhythmias ) . The 28-day mortality rate was 50 % ( 67/134 ) with DA as the initial vasopressor compared with 43 % ( 51/118 ) for NE treatment ( P = 0.282 ) . There was a significantly greater incidence of sinus tachycardia with DA ( 24.6 % ; 33/134 ) than NE ( 5.9 % ; 7/118 ) and arrhythmias noted with DA treatment ( 19.4 % ; 26/134 ) compared with NE treatment ( 3.4 % ; 4/118 ; P < 0.0001 ) , respectively . Logistic regression analysis identified Acute Physiologic and Chronic Health Evaluation II score ( P < 0.0001 ) and arrhythmia ( P < 0.015 ) as significant predictors of outcome . In this protocol -directed vasopressor support strategy for septic shock , DA and NE were equally effective as initial agents as judged by 28-day mortality rates . However , there were significantly more cardiac arrhythmias with DA treatment . Patients receiving DA should be monitored for the development of cardiac arrhythmias ( NCT00604019 ) Background : The current international guideline recommended 200 mg/day of hydrocortisone intravenously to treat septic shock . However , a subsequent study on cortisol metabolism actually showed an increase in cortisol level during sepsis . Hence , the smaller hydrocortisone dose of 100 mg/day might be sufficient and reduce steroid-associated complications . We aim ed to compare the clinical outcomes of minimized hydrocortisone dose of 100 mg to the currently recommended dose in the treatment of septic shock patients . Methods : A double-blinded r and omized controlled trial included 80 septic shock patients with hemodynamic instability despite fluid and vasopressive therapy . Participants were divided equally into two groups to treat with 100 mg/day or 200 mg/day of hydrocortisone , then stepwise down titrated and discontinued on day 8 . The outcome of interest was the hyperglycemic rate . Vital status , time to shock reversal , superinfection and gastrointestinal bleeding rates were also compared . Results : Patients with 100 mg hydrocortisone had significantly lower hyperglycemic rate compared with 200 mg , 63.9 % versus 86.5 % ( the adjusted hazard ratio [ HR ] , 0.08 ; 95 % confidence interval [ CI ] , 0.02–0.41 , P = 0.002 ) . Time to shock reversal was shorter in patients with 100 mg hydrocortisone , 2 days vs. 4 days , P = 0.031 . The 28-day mortality rate when adjusted for Simplified Acute Physiology Score II showed no significant difference ( HR , 0.68 ; 95 % CI , 0.37–1.24 , P = 0.209 ) . The reinfection and gastrointestinal bleeding rates were comparable between groups . Conclusion : Minimized daily hydrocortisone dosage of 100 mg could lower the occurrence of hyperglycemia without increasing mortality in septic shock , compared with the currently recommended dosage of 200 mg/day BACKGROUND There have been conflicting reports on the efficacy of recombinant human activated protein C , or drotrecogin alfa ( activated ) ( DrotAA ) , for the treatment of patients with septic shock . METHODS In this r and omized , double-blind , placebo-controlled , multicenter trial , we assigned 1697 patients with infection , systemic inflammation , and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA ( at a dose of 24 μg per kilogram of body weight per hour ) or placebo for 96 hours . The primary outcome was death from any cause 28 days after r and omization . RESULTS At 28 days , 223 of 846 patients ( 26.4 % ) in the DrotAA group and 202 of 834 ( 24.2 % ) in the placebo group had died ( relative risk in the DrotAA group , 1.09 ; 95 % confidence interval [ CI ] , 0.92 to 1.28 ; P=0.31 ) . At 90 days , 287 of 842 patients ( 34.1 % ) in the DrotAA group and 269 of 822 ( 32.7 % ) in the placebo group had died ( relative risk , 1.04 ; 95 % CI , 0.90 to 1.19 ; P=0.56 ) . Among patients with severe protein C deficiency at baseline , 98 of 342 ( 28.7 % ) in the DrotAA group had died at 28 days , as compared with 102 of 331 ( 30.8 % ) in the placebo group ( risk ratio , 0.93 ; 95 % CI , 0.74 to 1.17 ; P=0.54 ) . Similarly , rates of death at 28 and 90 days were not significantly different in other predefined subgroups , including patients at increased risk for death . Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group ( P=0.81 ) . CONCLUSIONS DrotAA did not significantly reduce mortality at 28 or 90 days , as compared with placebo , in patients with septic shock . ( Funded by Eli Lilly ; PROWESS-SHOCK Clinical Trials.gov number , NCT00604214 . ) BACKGROUND IV fluid represents a basic therapeutic intervention for septic shock . Unfortunately , the optimal administration of IV fluid to maximize patient outcomes and prevent complications is largely unknown . METHODS Patients with septic shock admitted to the medical ICUs of Barnes-Jewish Hospital ( January to December 2014 ) requiring vasoactive agents for at least 12 h following initial fluid resuscitation were r and omized to usual care or to targeted fluid minimization ( TFM ) guided by daily assessment s of fluid responsiveness . RESULTS Eighty-two patients were enrolled , 41 to usual care and 41 to TFM . For patients r and omized to TFM , the net median ( interquartile range ) fluid balance was less at the end of day 3 ( 1,952 mL [ 48 - 5,003 mL ] vs 3,124 mL [ 767 - 10,103 mL ] , P = .20 ) and at the end of day 5 ( 2,641 mL [ -1,837 to 5,075 mL ] vs 3,616 mL [ -1,513 mL to 9,746 mL ] , P = .40 ) . TFM appeared to be safe , as indicated by similar clinical outcomes including in-hospital mortality ( 56.1 % vs 48.8 % , P = .51 ) , ventilator days ( 8.0 days [ 3.25 - 15.25 days ] vs 5.0 days [ 3.0 - 9.0 days ] , P = .30 ) , renal replacement therapy ( 41.5 % vs 39.0 % , P = .82 ) , and vasopressor days ( 4.0 days [ 2.0 - 8.0 days ] vs 4.0 days [ 2.0 - 6.0 days ] , P = .84 ) . CONCLUSIONS This pilot study suggests that TFM in patients with septic shock can be performed using protocol -guided assessment s of fluid responsiveness . Larger trials of TFM in septic shock are needed . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT02473718 ; URL : www . clinical trials.gov Methylene blue increases blood pressure and myocardial function in septic shock mainly by inhibiting nitric oxide ( NO ) actions . However , a dose-dependency of methylene blue has not been established . Therefore , the compound is currently used as rescue treatment only . To evaluate dose-dependency , a prospect i ve , r and omized , double blind , single centre study was performed in 15 consecutive , mechanically ventilated patients with septic shock admitted to the intensive care unit , in whom methylene blue was infused at 1 mg/kg ( n=4 ) , 3 mg/kg ( n=6 ) or 7 mg/kg ( n=5 ) over 20 min . Hemodynamic parameters were measured before and after the infusion . Gastric tonometry was performed . Methylene blue treatment increased heart rate , cardiac index , mean arterial , pulmonary artery , pulmonary artery occlusion and central venous pressures , systemic vascular resistance , ventricular stroke work indices and O(2 ) delivery and uptake , and decreased lactate levels . Methylene blue had a dose-dependent effect on cardiac index , mean arterial , mean pulmonary artery and pulmonary artery occlusion pressures , left ventricular function , O(2 ) delivery and consumption and lactate levels . The drug dose-dependently increased the gastric-arterial blood PCO(2 ) gap . The data suggest that in human septic shock , methylene blue increases mean arterial blood pressure by an increase in cardiac index and systemic vascular resistance . The rise in cardiac index is caused by an increase in left ventricular filling and function , increasing tissue oxygenation , even at a dose of 1mg/kg . High doses of methylene blue may compromise splanchnic perfusion , even though further enhancing global hemodynamics , and should therefore , be avoided in future studies Background Physiologic dose hydrocortisone is part of the suggested adjuvant therapies for patients with septic shock . However , the association between the corticosteroid therapy and mortality in patients with septic shock is still not clear . Some authors considered that the mortality is related to the time frame between development of septic shock and start of low dose hydrocortisone . Thus we design ed a placebo‐controlled , r and omized clinical trial to assess the importance of early initiation of low dose hydrocortisone for the final outcome . Methods A total of 118 patients with septic shock were recruited in the study . All eligible patients were r and omized to receive hydrocortisone ( n = 58 ) or normal saline ( n = 60 ) . The study medication ( hydrocortisone and normal saline ) was initiated simultaneously with vasopressors . The primary end‐point was 28‐day mortality . The secondary end‐points were the reversal of shock , in‐hospital mortality and the duration of ICU and hospital stay . Results The proportion of patients with reversal of shock was similar in the two groups ( P = 0.602 ) ; There were no significant differences in 28‐day or hospital all‐cause mortality ; length of stay in the ICU or hospital between patients treated with hydrocortisone or normal saline . Conclusion The early initiation of low‐dose of hydrocortisone did not decrease the risk of mortality , and the length of stay in the ICU or hospital in adults with septic shock . Trial registration : www . clinical trials.gov NCT02580240 RATIONALE Intensive care unit (ICU)-based r and omized clinical trials ( RCTs ) among adult critically ill patients commonly fail to detect treatment benefits . OBJECTIVES Appraise the rates of success , outcomes used , statistical power , and design characteristics of published trials . METHODS One hundred forty-six ICU-based RCTs of diagnostic , therapeutic , or process/systems interventions published from January 2007 to May 2013 in 16 high-impact general or critical care journals were studied . MEASUREMENT AND MAIN RESULTS Of 146 RCTs , 54 ( 37 % ) were positive ( i.e. , the a priori hypothesis was found to be statistically significant ) . The most common primary outcomes were mortality ( n = 40 trials ) , infection-related outcomes ( n = 33 ) , and ventilation-related outcomes ( n = 30 ) , with positive results found in 10 , 58 , and 43 % , respectively . Statistical power was discussed in 135 RCTs ( 92 % ) ; 92 cited a rationale for their power parameters . Twenty trials failed to achieve at least 95 % of their reported target sample size , including 11 that were stopped early due to insufficient accrual/logistical issues . Of 34 superiority RCTs comparing mortality between treatment arms , 13 ( 38 % ) accrued a sample size large enough to find an absolute mortality reduction of 10 % or less . In 22 of these trials the observed control-arm mortality rate differed from the predicted rate by at least 7.5 % . CONCLUSIONS ICU-based RCTs are commonly negative and powered to identify what appear to be unrealistic treatment effects , particularly when using mortality as the primary outcome . Additional concerns include a lack of st and ardized methods for assessing common outcomes , unclear justifications for statistical power calculations , insufficient patient accrual , and incorrect predictions of baseline event rates Objective : To investigate the effect of early administration of granulocyte colony-stimulating factor ( G-CSF ) on hospital mortality in nonneutropenic patients with septic shock , excluding patients with melioidosis . Design : A r and omized , placebo-controlled , double-blinded clinical trial . Setting and Patients : Adult patients with septic shock admitted to the Royal Darwin Hospital Intensive Care Unit . Interventions : Patients were r and omized to receive G-CSF or placebo intravenously daily for 10 days , in addition to routine management of septic shock . Measurements : Primary outcome was hospital mortality . Secondary outcomes included intensive care unit mortality , intensive care unit and hospital length of stay , ventilator hours , and time to resolution of shock . Patient comorbidities , baseline and daily physiology , and organ function were collected . Results : Of 166 patients enrolled , 83 were allocated to receive G-CSF ( 81 included in analysis ) and 83 were allocated to receive placebo . At baseline , 30 % of patients had diabetes , 18 % were known to have renal impairment or failure , and 38 % had a history of hazardous alcohol use . The two groups had similar comorbidities at baseline and a similar severity of illness . The in-hospital mortality was 27 % in the G-CSF group and 25 % in the placebo group . Secondary end points were not different between groups . There was a higher rate of new organ failure in G-CSF – treated patients than placebo-treated patients ( 50 % vs. 33 % , p = .03 ) , most of which was accounted for by new liver dysfunction ( 11 % vs. 1 % , p = .007 ) . There was no significant difference in the proportion of patients with troponin I of > 0.08 mg/L ( 78 % vs. 66 % , p = .09 ) , and the prevalence of acute myocardial infa rct ion ( 6 % vs. 4 % , p = .55 ) was not different during the study . The median peak troponin I level was higher in the G-CSF group ( 0.5 vs. 0.14 mg/L , p = .007 ) , but baseline levels were not available . Conclusion : G-CSF does not improve outcomes in patients with septic shock , excluding melioidosis . Increased hepatic dysfunction and higher peak troponin levels in patients receiving G-CSF have not been reported in previous clinical trials and warrant further investigation BACKGROUND International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine . However , no large comparative trial has yet been done . We aim ed to compare the efficacy and safety of norepinephrine plus dobutamine ( whenever needed ) with those of epinephrine alone in septic shock . METHODS This prospect i ve , multicentre , r and omised , double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France . Participants were assigned to receive epinephrine ( n=161 ) or norepinephrine plus dobutamine ( n=169 ) , which were titrated to maintain mean blood pressure at 70 mm Hg or more . The primary outcome was 28-day all-cause mortality . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00148278 . FINDINGS There were no patients lost to follow-up ; one patient withdrew consent after 3 days . At day 28 , there were 64 ( 40 % ) deaths in the epinephrine group and 58 ( 34 % ) deaths in the norepinephrine plus dobutamine group ( p=0.31 ; relative risk 0.86 , 95 % CI 0.65 - 1.14 ) . There was no significant difference between the two groups in mortality rates at discharge from intensive care ( 75 [ 47 % ] deaths vs 75 [ 44 % ] deaths , p=0.69 ) , at hospital discharge ( 84 [ 52 % ] vs 82 [ 49 % ] , p=0.51 ) , and by day 90 ( 84 [ 52 % ] vs 85 [ 50 % ] , p=0.73 ) , time to haemodynamic success ( log-rank p=0.67 ) , time to vasopressor withdrawal ( log-rank p=0.09 ) , and time course of SOFA score . Rates of serious adverse events were also similar . INTERPRETATION There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock Background Few studies have reported the effect of different volume responsiveness evaluation methods on volume therapy results and prognosis . This study was carried out to investigate the effect of two volume responsiveness evaluation methods , stroke volume variation ( SVV ) and stroke volume changes before and after passive leg raising ( PLR‐&Dgr;SV ) , on fluid resuscitation and prognosis in septic shock patients . Methods Septic shock patients admitted to the Department of Critical Care Medicine of Zhejiang Hospital , China , from March 2011 to March 2013 , who were under controlled ventilation and without arrhythmia , were studied . Patients were r and omly assigned to the SVV group or the PLR‐&Dgr;SV group . The SVV group used the Pulse Indication Continuous Cardiac Output monitoring of SVV , and responsiveness was defined as SVV ≥12 % . The PLR‐&Dgr;SV group used & Dgr;SV before and after PLR as the indicator , and responsiveness was defined as & Dgr;SV ≥15 % . Six hours after fluid resuscitation , changes in tissue perfusion indicators ( lactate , lactate clearance rate , central venous oxygen saturation ( SCVO2 ) , base excess ( BE ) ) , organ function indicators ( white blood cell count , neutrophil percentage , platelet count , total protein , albumin , alanine aminotransferase , total and direct bilirubin , blood urea nitrogen , serum creatinine , serum creatine kinase , oxygenation index ) , fluid balance ( 6‐ and 24‐hour fluid input ) and the use of cardiotonic drugs ( dobutamine ) , prognostic indicators ( the time and rate of achieving early goal ‐directed therapy ( EGDT ) st and ards , duration of mechanical ventilation and intensive care unit stay , and 28‐ day mortality ) were observed . Results Six hours after fluid resuscitation , there were no significant differences in temperature , heart rate , blood pressure , SpO2 , organ function indicators , or tissue perfusion indicators between the two groups ( P > 0.05 ) . The 6‐ and 24‐hour fluid input was slightly less in the SVV group than in the PLR‐&Dgr;SV group , but the difference was not statistically significant ( P > 0.05 ) . The SVV group used significantly more dobutamine than the PLR‐&Dgr;SV group ( 33.3 % vs. 10.7 % , P = 0.039 ) . There were no significant differences in the time ( ( 4.8±1.4 ) h vs. ( 4.3±1.3 ) h , P=0.142 ) and rate of achieving EGDT st and ards ( 90.0 % vs. 92.9 % , P = 0.698 ) , or in the length of mechanical ventilation and ICU stay . The 28‐day mortality in the SVV group ( 16.7 % ( 5/30 ) ) was slightly higher than the PLR‐&Dgr;SV group ( 14.3 % ( 4/28 ) ) , but the difference was not statistically significant ( P = 0.788 ) . Conclusions In septic shock patients under controlled ventilation and without arrhythmia , using SVV or PLR‐&Dgr;SV methods to evaluate volume responsiveness has a similar effect on volume therapy results and prognosis . The evaluation and dynamic monitoring of volume responsiveness is more important for fluid resuscitation than the evaluation methods themselves . Choosing different methods to evaluate volume responsiveness has no significant influence on the effect of volume therapy and prognosis BACKGROUND AND OBJECTIVE Although there is controversy regarding the benefit of low-dose corticosteroid therapy in patients with septic shock , the Surviving Sepsis Campaign has advocated that low-dose intravenous hydrocortisone be used to treat adult septic shock patients . This study investigated the effect of the duration of a stress dose of hydrocortisone on survival of septic shock patients with relative adrenal insufficiency . METHODS One hundred and thirty consecutive patients who met the American College of Chest Physicians/Society of Critical Care Medicine criteria for septic shock were included in the study . An additional inclusion criterion was vasopressor support after fluid resuscitation . The primary end-point was 28-day mortality , and the secondary end-points were shock reversal and mortality in the intensive care unit and hospital . All eligible patients were prospect ively r and omized to receive hydrocortisone treatment for 3 or 7days . Hydrocortisone treatment was started at a dose of 50 mg every 6h . RESULTS Baseline data at recruitment did not differ between the two groups . After 28days , mortality did not differ between the 3- and 7-day treatment groups ( 33.8 % vs 36.9 % , P=0.629 ) . Mortality rates in the intensive care unit and hospital did not differ significantly between the two groups . The median time to withdrawal of vasopressor therapy was 5.0days in the 3-day treatment group and 6.4days in the 7-day treatment group ( P=0.102 ) . CONCLUSIONS This pilot study showed that in patients with septic shock and relative adrenal insufficiency , 28-day mortality did not differ between those treated with low-dose hydrocortisone for 3 or 7days Purpose We assessed the effects of a protocol restricting resuscitation fluid vs. a st and ard care protocol after initial resuscitation in intensive care unit ( ICU ) patients with septic shock . Methods We r and omised 151 adult patients with septic shock who had received initial fluid resuscitation in nine Sc and inavian ICUs . In the fluid restriction group fluid boluses were permitted only if signs of severe hypoperfusion occurred , while in the st and ard care group fluid boluses were permitted as long as circulation continued to improve . Results The co- primary outcome measures , resuscitation fluid volumes at day 5 and during ICU stay , were lower in the fluid restriction group than in the st and ard care group [ mean differences −1.2 L ( 95 % confidence interval −2.0 to −0.4 ) ; p < 0.001 and −1.4 L ( −2.4 to −0.4 ) respectively ; p < 0.001 ] . Neither total fluid inputs and balances nor serious adverse reactions differed statistically significantly between the groups . Major protocol violations occurred in 27/75 patients in the fluid restriction group . Ischaemic events occurred in 3/75 in the fluid restriction group vs. 9/76 in the st and ard care group ( odds ratio 0.32 ; 0.08–1.27 ; p = 0.11 ) , worsening of acute kidney injury in 27/73 vs. 39/72 ( 0.46 ; 0.23–0.92 ; p = 0.03 ) , and death by 90 days in 25/75 vs. 31/76 ( 0.71 ; 0.36–1.40 ; p = 0.32 ) . Conclusions A protocol restricting resuscitation fluid successfully reduced volumes of resuscitation fluid compared with a st and ard care protocol in adult ICU patients with septic shock . The patient-centred outcomes all pointed towards benefit with fluid restriction , but our trial was not powered to show differences in these exploratory outcomes .Trial registration NCT02079402 BACKGROUND The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock . However , whether this blood-pressure target is more or less effective than a higher target is unknown . METHODS In a multicenter , open-label trial , we r and omly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg ( high-target group ) or 65 to 70 mm Hg ( low-target group ) . The primary end point was mortality at day 28 . RESULTS At 28 days , there was no significant between-group difference in mortality , with deaths reported in 142 of 388 patients in the high-target group ( 36.6 % ) and 132 of 388 patients in the low-target group ( 34.0 % ) ( hazard ratio in the high-target group , 1.07 ; 95 % confidence interval [ CI ] , 0.84 to 1.38 ; P=0.57 ) . There was also no significant difference in mortality at 90 days , with 170 deaths ( 43.8 % ) and 164 deaths ( 42.3 % ) , respectively ( hazard ratio , 1.04 ; 95 % CI , 0.83 to 1.30 ; P=0.74 ) . The occurrence of serious adverse events did not differ significantly between the two groups ( 74 events [ 19.1 % ] and 69 events [ 17.8 % ] , respectively ; P=0.64 ) . However , the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group . Among patients with chronic hypertension , those in the high-target group required less renal-replacement therapy than did those in the low-target group , but such therapy was not associated with a difference in mortality . CONCLUSIONS Targeting a mean arterial pressure of 80 to 85 mm Hg , as compared with 65 to 70 mm Hg , in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days . ( Funded by the French Ministry of Health ; SEPSISPAM Clinical Trials.gov number , NCT01149278 . ) ABSTRACT We evaluated whether a goal -directed protocol , without measurement of central venous oxygen saturation , would improve survival in medical intensive care unit ( ICU ) patients with septic shock . This is a prospect i ve , controlled study in a 24-bed medical ICU at a tertiary care hospital . From a total of 241 consecutive patients with septic shock , 224 were r and omly assigned to receive therapy with or without a written protocol using central venous pressure , mean arterial pressure , and urine output as therapeutic goals . Baseline characteristics were similar between groups . Implementation of goal -directed therapy caused a more rapid reversal of persistent shock ( 47 ± 22.8 vs. 65.4 ± 32.1 h , P = 0.006 ) and decreases of ICU ( 50 % vs. 67.2 % , P = 0.009 ) and in-hospital ( 53.7 % vs. 71.6 % , P = 0.006 ) mortality rates compared with non- goal -directed therapy . Patients receiving goal -directed therapy also had less risk for developing central nervous system or renal failure than patients without . Patients with goal -directed therapy received more fluid during the period of persistent shock ( 136.2 ± 119 vs. 88.6 ± 57.7 mL h−1 , P = 0.034 ) and less delay in vasopressor administration ( 78 ± 22.2 vs. 104.4 ± 29 min , P = 0.001 ) than patients with non- goal therapy . Implementation of a goal -directed protocol improves survival and clinical outcomes in ICU patients with septic shock . These benefits may arise from adequate fluid resuscitation , earlier vasopressor administration , rapid shock reversal , and protection of major organ function . With central venous oxygen saturation measurement to detect tissue perfusion , the clinical outcomes may be further improved Aim of the Study : Pleiotropic effect of statins can modulate inflammation in septic shock . We tested the hypothesis whether statins can reduce mortality in septic shock . Patients and Methods : We conducted a r and omized double-blinded trial with treatment ( 40 mg dose of atorvastatin for 7 days ) and control ( placebo ) arm in adult septic shock patients admitted to the Intensive Care Unit . Primary ( 28-day mortality ) and secondary ( vasopressor- , ventilation- , and renal replacement therapy-free days ) outcomes , with lipid profile and adverse effects , were documented . Inflammatory biomarkers ( interleukin [IL]-1 , IL-6 , tumor-necrosis-factor [TNF]-α , interferon [ IFN ] , and C-reactive protein [ CRP ] ) , were also measured before ( day 1 [ D1 ] ) and after start of trial drug ( D4 and D7 ) . Results : Seventy-three septic shock patients with 36 and 37 included in the atorvastatin and placebo group , respectively . Both groups were equally matched . Twenty-eight-day mortality , event-free days , lipid profile , and adverse effects were also not significantly different between groups . Reduced levels of IL-1 , IL-6 , TNF-α , IFN , and CRP were observed in the atorvastatin group . Also observed were significant day-wise changes in inflammatory biomarkers . Conclusions : Atorvastatin-induced changes in inflammatory biomarkers did not confer mortality benefit in septic shock ( Clinical Trials.govNCT02681653 ) BACKGROUND Hydrocortisone is widely used in patients with septic shock even though a survival benefit has been reported only in patients who remained hypotensive after fluid and vasopressor resuscitation and whose plasma cortisol levels did not rise appropriately after the administration of corticotropin . METHODS In this multicenter , r and omized , double-blind , placebo-controlled trial , we assigned 251 patients to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days ; the dose was then tapered during a 6-day period . At 28 days , the primary outcome was death among patients who did not have a response to a corticotropin test . RESULTS Of the 499 patients in the study , 233 ( 46.7 % ) did not have a response to corticotropin ( 125 in the hydrocortisone group and 108 in the placebo group ) . At 28 days , there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin ( 39.2 % in the hydrocortisone group and 36.1 % in the placebo group , P=0.69 ) or between those who had a response to corticotropin ( 28.8 % in the hydrocortisone group and 28.7 % in the placebo group , P=1.00 ) . At 28 days , 86 of 251 patients in the hydrocortisone group ( 34.3 % ) and 78 of 248 patients in the placebo group ( 31.5 % ) had died ( P=0.51 ) . In the hydrocortisone group , shock was reversed more quickly than in the placebo group . However , there were more episodes of superinfection , including new sepsis and septic shock . CONCLUSIONS Hydrocortisone did not improve survival or reversal of shock in patients with septic shock , either overall or in patients who did not have a response to corticotropin , although hydrocortisone hastened reversal of shock in patients in whom shock was reversed . ( Clinical Trials.gov number , NCT00147004 . We analyze in the current study the impact of heptaminol hydrochloride ( Heptamyl ) administration in patients with septic shock requiring adrenergic support on the duration of vasopressor infusion and on catecholamine delay weaning . In this prospect i ve study were included 49 nonconsecutive patients with septic shock requiring vasopressor infusion and with stable hemodynamic parameters during more than 24 hours . All these patients were included in a r and om way to receive or not heptaminol hydrochloride . The primary end point was the effect of heptaminol hydrochloride administration on duration of weaning , defined as cessation of vasopressor support . There were 32 males ( 65 % ) and 17 females ( 35 % ) . The mean age ( ± st and ard deviation ) was 53.9 ± 22.2 years . Norepinephrine was the most commonly used vasopressor agent ( 73.4 % ) . The comparison between two groups ( with and without heptaminol hydrochloride ) showed that two groups had the same epidemiologic , clinical , and biologic findings on intensive care unit admission . In our study , we found that the introduction of Heptamyl was associated with a quick decrease of dose of dopamine and norepinephrine in comparison with the Heptamyl-free group . By comparing the two groups , we found that the delay of catecholamine weaning was significantly faster for the dopamine ( P = 0.008 ) and noradrenalin ( P = 0.001 ) in the Heptamyl group . Finally , the intensive care unit mortality rate and the hospital mortality rate were significantly lower in the Heptamyl group . Our study shows a reduction in norepinephrine and dopamine weaning duration in septic patients enrolled in the heptaminol hydrochloride group BACKGROUND Sepsis is characterized by metabolic disturbances , and previous data suggest a relative carnitine deficiency may contribute to metabolic dysfunction . Studies regarding safety and patient-centered efficacy of carnitine during septic shock are lacking . METHODS This was a double-blind r and omized control trial of levocarnitine ( L-carnitine ) infusion vs normal saline for the treatment of vasopressor-dependent septic shock . Patients meeting consensus definition for septic shock with a cumulative vasopressor index ≥ 3 and sequential organ failure assessment ( SOFA ) score ≥ 5 enrolled within 16 hours of the recognition of septic shock were eligible . The primary safety outcome was difference in serious adverse events ( SAEs ) per patient between groups . Efficacy outcomes included proportion of patients demonstrating a decrease in SOFA score of 2 or more points at 24 hours and short- and long-term survival . RESULTS Of the 31 patients enrolled , 16 were in the L-carnitine and 15 were in the placebo arm . There was no difference in SAEs between placebo and intervention ( 2.1 vs 1.8 SAEs per patient , P = .44 ) . There was no difference in the proportion of patients achieving a decrease in SOFA score of 2 or more points at 24 hours between placebo and treatment ( 53 % vs 44 % , P = .59 ) . Mortality was significantly lower at 28 days in the L-carnitine group ( 4/16 vs 9/15 , P = .048 ) , with a nonsignificant improved survival at 1 year ( P = .06 ) . CONCLUSION L-carnitine infusion appears safe in vasopressor-dependent septic shock . Preliminary efficacy data suggest potential benefit of L-carnitine treatment , and further testing is indicated BACKGROUND Terlipressin bolus infusion may reduce cardiac output and global oxygen supply . The present study was design ed to determine whether dobutamine may counterbalance the terlipressin-induced depression in mixed-venous oxygen saturation ( Svo ) in patients with catecholamine-dependent septic shock . METHODS Prospect i ve , r and omized , controlled study performed in a university hospital intensive care unit . Septic shock patients requiring a continuous infusion of norepinephrine ( 0.9 microg kg(-1 ) min(-1 ) ) to maintain mean arterial pressure ( MAP ) at 70 ( sd 5 ) mm Hg were r and omly allocated to be treated either with ( i ) sole norepinephrine infusion ( control , n=20 ) , ( ii ) a single dose of terlipressin 1 mg ( n=19 ) , or ( iii ) a single dose of terlipressin 1 mg followed by dobutamine infusion titrated to reverse the anticipated reduction in Svo2 ( n=20 ) . Systemic , pulmonary , and regional haemodynamic variables were obtained at baseline and after 2 and 4 h. Laboratory surrogate markers of organ (dys)function were tested at baseline and after 12 and 24 h. RESULTS Terlipressin ( with and without dobutamine ) infusion preserved MAP at 70 ( 5 ) mm Hg , while allowing to reduce norepinephrine requirements to 0.17 ( 0.2 ) and 0.2 ( 0.2 ) microg kg(-1 ) min(-1 ) , respectively [ vs1.4 ( 0.3 ) microg kg(-1 ) min(-1 ) in controls at 4 h ; each P<0.001 ] . The terlipressin-linked decrease in Svo2 was reversed by dobutamine at a mean dose of 20 ( 8) microg kg(-1 ) min(-1 ) [ Svo2 at 4 h : 59 (11)% vs 69 (12)% , P=0.028 ] . CONCLUSIONS In human catecholamine-dependent septic shock , terlipressin ( with and without concomitant dobutamine infusion ) increases MAP and markedly reduces norepinephrine requirements . Although no adverse events were noticed in the present study , potential benefits of increasing Svo2 after terlipressin bolus infusion need to be weighted against the risk of cardiovascular complications result ing from high-dose dobutamine The systemic inflammatory response is biologically complex , redundant , and activated by both infectious and noninfectious triggers . Its manipulation can cause both benefit and harm . More than 100 r and omized clinical trials have tested the hypothesis that modulating the septic response to infection can improve survival . With one short-lived exception , none of these has result ed in new treatments . The current challenge for sepsis research lies in a failure of concept and reluctance to ab and on a demonstrably ineffectual research model . Future success will necessitate large studies of clinical and biochemical epidemiology to underst and the course of illness , better integration of basic and clinical science , and the creation of stratification systems to target treatment towards those who are most likely to benefit Objective To explore translation , conversion and definition ambiguities , when using severity scoring systems in patients admitted to intensive care units ( ICUs ) . Design A prospect i ve study of the prognosis of acute renal failure in ICUs . Setting The study was conducted in 20 French ICUs . Patients 360 patients presenting with severe acute renal failure were studied during their ICU stay . Measurements and results The inter-observer variability of Apache II ( acute physiology and chronic health evaluation ) , SAPS ( simplified acute physiology score ) , and OSF ( organ-system failure ) was considered . For Apache II , we explored the uncertainty of measurements arising from conversion into SI units , the rounding procedures used for the non-inclusive intervals defined for quatitative parameters such as age , mean arterial pressure ( MAP ) or serum creatinite , the absence of definition of acute renal failure ( ARF ) and its consequence on doubling serum creatinine values , and the absence of guidelines in the case of spontaneous ventilation when arterial blood gases ( ABG ) and forced inspiratory oxygen ( FIO2 ) were not measured . The result ing variability was evaluated , calculating the lowest and the highest value of the scoring system for each patient . The mean difference by patient was greater than 1.5 ( p<0.0001 ) . Other examples were presented and discussed for SAPS and OSF . Conclusions Translation , conversion and definition ambiguities are a source of inter-observer variability and increase the risk of classification and /or selection biases . 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Fleisher LA , Fleischmann KE , Auerbach AD , et al. 2014 ACC/ AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery : executive summary : a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines . Circulation 2014 ; 130 : 2215–45 12 . collaborators C-t , Shakur H , Roberts I , et al. Effects of tranexamic acid on death , vascular occlusive events , and blood transfusion in trauma patients with significant haemorrhage ( CRASH-2 ) : a r and omised , placebo-controlled trial . Lancet 2010 ; 376 : 23–32 13 . Roberts I , Perel P , Prieto-Merino D , et al. Effect of tranexamic acid onmortality in patients with traumatic bleeding : prespecified analysis of data from r and omised controlled trial . BMJ 2012 ; 345 : e5839 14 . Kaluza GL , Joseph J , Lee JR , Raizner ME , Raizner AE . Catastrophic outcomes of noncardiac surgery soon after coronary stenting . J Am Coll Cardiol 2000 ; 35 : 1288–94 15 . Devereaux PJ , Yang H , Yusuf S , et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery ( POISE trial ) : a r and omised controlled trial . Lancet 2008 ; 371 : 1839–47 16 . Devereaux PJ , Sessler DI , Leslie K , et al. Clonidine in patients undergoing noncardiac surgery . N Engl J Med 2014 ; 370 : 1504–13 17 . Myles PS , Leslie K , ChanMT , et al. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery ( ENIGMA-II ) : a r and omised , single-blind trial . Lancet 2014 ; 384 : Purpose We compared hemodynamic and biological effects of the Cascade system , which uses very high volume hemofiltration ( HVHF ) ( 120 mL kg−1 h−1 ) , with those of usual care in patients with septic shock . Methods Multicenter , prospect i ve , r and omized , open-label trial in three intensive care units ( ICU ) . Adults with septic shock with administration of epinephrine/norepinephrine were eligible . Patients were r and omized to usual care plus HVHF ( Cascade group ) , or usual care alone ( control group ) . Primary end point was the number of catecholamine-free days up to 28 days after r and omization . Secondary end points were number of days free of mechanical ventilation , renal replacement therapy ( RRT ) or ICU up to 90 days , and 7- , 28- , and 90-day mortality . Results We included 60 patients ( 29 Cascade , 31 usual care ) . Baseline characteristics were comparable . Median number of catecholamine-free days was 22 [ IQR 11–23 ] vs 20 [ 0–25 ] for Cascade vs control ; there was no significant difference even after adjustment . There was no significant difference in number of mechanical ventilation-free days or ICU requirement . Median number of RRT-free days was 85 [ 46–90 ] vs 74 [ 0–90 ] for Cascade vs control groups , p = 0.42 . By multivariate analysis , the number of RRT-free days was significantly higher in the Cascade group ( up to 25 days higher after adjustment ) . There was no difference in mortality at 7 , 28 , or 90 days . Conclusion Very HVHF using the Cascade system can safely be used in patients presenting with septic shock , but it was not associated with a reduction in the need for catecholamines during the first 28 days CONTEXT Evaluation of trends in organ dysfunction in critically ill patients may help predict outcome . OBJECTIVE To determine the usefulness of repeated measurement the Sequential Organ Failure Assessment ( SOFA ) score for prediction of mortality in intensive care unit ( ICU ) patients . DESIGN Prospect i ve , observational cohort study conducted from April 1 to July 31 , 1999 . SETTING A 31-bed medicosurgical ICU at a university hospital in Belgium . PATIENTS Three hundred fifty-two consecutive patients ( mean age , 59 years ) admitted to the ICU for more than 24 hours for whom the SOFA score was calculated on admission and every 48 hours until discharge . MAIN OUTCOME MEASURES Initial SOFA score ( 0 - 24 ) , Delta-SOFA scores ( differences between subsequent scores ) , and the highest and mean SOFA scores obtained during the ICU stay and their correlations with mortality . RESULTS The initial , highest , and mean SOFA scores correlated well with mortality . Initial and highest scores of more than 11 or mean scores of more than 5 corresponded to mortality of more than 80 % . The predictive value of the mean score was independent of the length of ICU stay . In univariate analysis , mean and highest SOFA scores had the strongest correlation with mortality , followed by Delta-SOFA and initial SOFA scores . The area under the receiver operating characteristic curve was largest for highest scores ( 0.90 ; SE , 0.02 ; P<.001 vs initial score ) . When analyzing trends in the SOFA score during the first 96 hours , regardless of the initial score , the mortality rate was at least 50 % when the score increased , 27 % to 35 % when it remained unchanged , and less than 27 % when it decreased . Differences in mortality were better predicted in the first 48 hours than in the subsequent 48 hours . There was no significant difference in the length of stay among these groups . Except for initial scores of more than 11 ( mortality rate > 90 % ) , a decreasing score during the first 48 hours was associated with a mortality rate of less than 6 % , while an unchanged or increasing score was associated with a mortality rate of 37 % when the initial score was 2 to 7 and 60 % when the initial score was 8 to 11 . CONCLUSIONS Sequential assessment of organ dysfunction during the first few days of ICU admission is a good indicator of prognosis . Both the mean and highest SOFA scores are particularly useful predictors of outcome . Independent of the initial score , an increase in SOFA score during the first 48 hours in the ICU predicts a mortality rate of at least 50 % ABSTRACT We assessed the short-term effects of hypertonic fluid versus isotonic fluid administration in patients with septic shock . This was a double-blind , prospect i ve r and omized controlled trial in a 15-bed intensive care unit . Twenty-four patients with septic shock were r and omized to receive 250 mL 7.2 % NaCl/6 % hydroxyethyl starch ( HT group ) or 500 mL 6 % hydroxyethyl starch ( IT group ) . Hemodynamic measurements included mean arterial blood pressure ( MAP ) , central venous pressure , stroke volume index , stroke volume variation , intrathoracic blood volume index , gastric tonometry , and sublingual microcirculatory flow as assessed by sidestream dark field imaging . Systolic tissue Doppler imaging velocities of the medial mitral annulus were measured using echocardiography to assess left ventricular contractility . Log transformation of the ratio MAP divided by the norepinephrine infusion rate ( log MAP/NE ) quantified the combined effect on both parameters . Compared with the IT group , hypertonic solution treatment result ed in an improvement in log MAP/NE ( P = 0.008 ) , as well as an increase in systolic tissue Doppler imaging velocities ( P = 0.03 ) and stroke volume index ( P = 0.017 ) . No differences between the groups were found for preload parameters ( central venous pressure , stroke volume variation , intrathoracic blood volume index ) or for afterload parameters ( systemic vascular resistance index , MAP ) . Hypertonic solution treatment decreased the need for ongoing fluid resuscitation ( P = 0.046 ) . No differences between groups were observed regarding tonometry or the sublingual microvascular variables . In patients with septic shock , hypertonic fluid administration did not promote gastrointestinal mucosal perfusion or sublingual microcirculatory blood flow in comparison to isotonic fluid . Independent of changes in preload or afterload , hypertonic fluid administration improved the cardiac contractility and vascular tone compared with isotonic fluid . The need for ongoing fluid resuscitation was also reduced RATIONALE Fever control may improve vascular tone and decrease oxygen consumption , but fever may contribute to combat infection . OBJECTIVES To determine whether fever control by external cooling diminishes vasopressor requirements in septic shock . METHODS In a multicenter r and omized controlled trial , febrile patients with septic shock requiring vasopressors , mechanical ventilation , and sedation were allocated to external cooling ( n = 101 ) to achieve normothermia ( 36.5 - 37 ° C ) for 48 hours or no external cooling ( n = 99 ) . Vasopressors were tapered to maintain the same blood pressure target in the two groups . The primary endpoint was the number of patients with a 50 % decrease in baseline vasopressor dose after 48 hours . MEASUREMENTS AND MAIN RESULTS Body temperature was significantly lower in the cooling group after 2 hours of treatment ( 36.8 ± 0.7 vs. 38.4 ± 1.1 ° C ; P < 0.01 ) . A 50 % vasopressor dose decrease was significantly more common with external cooling from 12 hours of treatment ( 54 vs. 20 % ; absolute difference , 34 % ; 95 % confidence interval [ 95 % CI ] , -46 to -21 ; P < 0.001 ) but not at 48 hours ( 72 vs. 61 % ; absolute difference , 11 % ; 95 % CI , -23 to 2 ) . Shock reversal during the intensive care unit stay was significantly more common with cooling ( 86 vs. 73 % ; absolute difference , 13 % ; 95 % CI , 2 to 25 ; P = 0.021 ) . Day-14 mortality was significantly lower in the cooling group ( 19 vs. 34 % ; absolute difference , -16 % ; 95 % CI , -28 to -4 ; P = 0.013 ) . CONCLUSIONS In this study , fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock OBJECTIVES Vasopressor-induced vasoconstriction may compromise renal and splanchnic blood flow in patients with septic shock , result ing in secondary organ failures . The authors compared the effects of the vasodilatatory agent dopexamine against renal-dose dopamine and placebo in patients with norepinephrine therapy and septic shock , using 24-hour serum creatinine clearance ( C(crea ) ) as a major endpoint . The primary hypothesis to be tested was that dopexamine is more effective than dopamine and that dopamine shows better effects than placebo regarding organ failures and C(crea ) . DESIGN A prospect i ve , r and omized , controlled , double-blinded study . SETTING Intensive care unit in a tertiary care university hospital . PARTICIPANTS Sixty-one patients with septic shock defined according to established criteria . INTERVENTIONS Patients received either dopexamine ( 2 microg/kg/min , n = 20 ) , dopamine ( 3 microg/kg/min , n = 21 ) , or placebo ( n = 20 ) . RESULTS The trial groups were similar in terms of baseline characteristics . The authors found no significant differences among the dopexamine , dopamine , and placebo groups with regard to a comprehensive number of renal function parameters including C(crea ) and organ-failure scores . There was a significant increase in heart rate after dopexamine infusion ; other hemodynamic parameters remained unchanged in the dopexamine group . In a post hoc analysis that included only patients with renal impairment at study inclusion ( n = 28 ) , patients who received dopamine showed significant improvements in C(crea ) when compared with placebo . Dopexamine was not effective in this subgroup . CONCLUSIONS Dopexamine is no more effective than dopamine or placebo regarding renal function in patients with septic shock requiring norepinephrine . Both therapies do not influence organ-failure scores IMPORTANCE β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock . However , β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects . OBJECTIVE To investigate the effect of the short-acting β-blocker esmolol in patients with severe septic shock . DESIGN , SETTING , AND PATIENTS Open-label , r and omized phase 2 study , conducted in a university hospital intensive care unit ( ICU ) between November 2010 and July 2012 , involving patients in septic shock with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mm Hg or higher . INTERVENTIONS We r and omly assigned 77 patients to receive a continuous infusion of esmolol titrated to maintain heart rate between 80/min and 94/min for their ICU stay and 77 patients to st and ard treatment . MAIN OUTCOMES AND MEASURES Our primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period . Secondary outcomes included hemodynamic and organ function measures ; norepinephrine dosages at 24 , 48 , 72 , and 96 hours ; and adverse events and mortality occurring within 28 days after r and omization . RESULTS Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group . The median AUC for heart rate during the first 96 hours was -28/min ( IQR , -37 to -21 ) for the esmolol group vs -6/min ( 95 % CI , -14 to 0 ) for the control group with a mean reduction of 18/min ( P < .001 ) . For stroke volume index , the median AUC for esmolol was 4 mL/m2 ( IQR , -1 to 10 ) vs 1 mL/m2 for the control group ( IQR , -3 to 5 ; P = .02 ) , whereas the left ventricular stroke work index for esmolol was 3 mL/m2 ( IQR , 0 to 8) vs 1 mL/m2 for the control group ( IQR , -2 to 5 ; P = .03 ) . For arterial lactatemia , median AUC for esmolol was -0.1 mmol/L ( IQR , -0.6 to 0.2 ) vs 0.1 mmol/L for the control group ( IQR , -0.3 for 0.6 ; P = .007 ) ; for norepinephrine , -0.11 μg/kg/min ( IQR , -0.46 to 0.02 ) for the esmolol group vs -0.01 μg/kg/min ( IQR , -0.2 to 0.44 ) for the control group ( P = .003 ) . Fluid requirements were reduced in the esmolol group : median AUC was 3975 mL/24 h ( IQR , 3663 to 4200 ) vs 4425 mL/24 h(IQR , 4038 to 4775 ) for the control group ( P < .001 ) . We found no clinical ly relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements . Twenty-eight day mortality was 49.4 % in the esmolol group vs 80.5 % in the control group ( adjusted hazard ratio , 0.39 ; 95 % CI , 0.26 to 0.59 ; P < .001 ) . CONCLUSIONS AND RELEVANCE For patients in septic shock , open-label use of esmolol vs st and ard care was associated with reductions in heart rates to achieve target levels , without increased adverse events . The observed improvement in mortality and other secondary clinical outcomes warrants further investigation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01231698 IMPORTANCE Norepinephrine is currently recommended as the first-line vasopressor in septic shock ; however , early vasopressin use has been proposed as an alternative . OBJECTIVE To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock . DESIGN , SETTING , AND PARTICIPANTS A factorial ( 2 × 2 ) , double-blind , r and omized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015 , enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock . INTERVENTIONS Patients were r and omly allocated to vasopressin ( titrated up to 0.06 U/min ) and hydrocortisone ( n = 101 ) , vasopressin and placebo ( n = 104 ) , norepinephrine and hydrocortisone ( n = 101 ) , or norepinephrine and placebo ( n = 103 ) . MAIN OUTCOMES AND MEASURES The primary outcome was kidney failure-free days during the 28-day period after r and omization , measured as ( 1 ) the proportion of patients who never developed kidney failure and ( 2 ) median number of days alive and free of kidney failure for patients who did not survive , who experienced kidney failure , or both . Rates of renal replacement therapy , mortality , and serious adverse events were secondary outcomes . RESULTS A total of 409 patients ( median age , 66 years ; men , 58.2 % ) were included in the study , with a median time to study drug administration of 3.5 hours after diagnosis of shock . The number of survivors who never developed kidney failure was 94 of 165 patients ( 57.0 % ) in the vasopressin group and 93 of 157 patients ( 59.2 % ) in the norepinephrine group ( difference , -2.3 % [ 95 % CI , -13.0 % to 8.5 % ] ) . The median number of kidney failure-free days for patients who did not survive , who experienced kidney failure , or both was 9 days ( interquartile range [ IQR ] , 1 to -24 ) in the vasopressin group and 13 days ( IQR , 1 to -25 ) in the norepinephrine group ( difference , -4 days [ 95 % CI , -11 to 5 ] ) . There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group ( 25.4 % for vasopressin vs 35.3 % for norepinephrine ; difference , -9.9 % [ 95 % CI , -19.3 % to -0.6 % ] ) . There was no significant difference in mortality rates between groups . In total , 22 of 205 patients ( 10.7 % ) had a serious adverse event in the vasopressin group vs 17 of 204 patients ( 8.3 % ) in the norepinephrine group ( difference , 2.5 % [ 95 % CI , -3.3 % to 8.2 % ] ) . CONCLUSIONS AND RELEVANCE Among adults with septic shock , the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days . Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation , the confidence interval included a potential clinical ly important benefit for vasopressin , and larger trials may be warranted to assess this further . TRIAL REGISTRATION clinical trials.gov Identifier : IS RCT N 20769191 Objectives : To evaluate the effect of hemodynamic management guided by upper limits of cardiac filling volumes or pressures on duration s of mechanical ventilation and lengths of stay in critically ill patients with shock . Design : Prospect i ve , r and omized , clinical trial . Setting : Mixed intensive care unit of a large teaching hospital and mixed intensive care unit of a tertiary care , academic medical center . Patients : A total 120 septic ( n = 72 ) and nonseptic ( n = 48 ) shock patients , r and omized ( after stratification ) to transpulmonary thermodilution ( n = 60 ) or pulmonary artery catheter ( n = 60 ) between February 2007 and July 2009 . Interventions : Hemodynamic management was guided by algorithms including upper limits for fluid resuscitation of extravascular lung water ( < 10 mL/kg ) and global end-diastolic volume index ( < 850 mL/m2 ) in the transpulmonary thermodilution group and pulmonary artery occlusion pressure ( < 18–20 mm Hg ) in the pulmonary artery catheter group for 72 hrs after enrollment . Measurements and Main Results : Primary outcomes were ventilator-free days and lengths of stay in the intensive care unit and the hospital . Secondary outcomes included organ failures and mortality . Cardiac comorbidity was more frequent in nonseptic than in septic shock . Ventilator-free days , lengths of stay , organ failures , and 28-day mortality ( overall 33.3 % ) were similar between monitoring groups . Transpulmonary thermodilution ( vs. pulmonary artery catheter ) monitoring was associated with more days on mechanical ventilation and longer intensive care unit and hospital lengths of stay in nonseptic ( p = .001 ) but not in septic shock . In both conditions , fewer patients met the upper limit of volume than of pressure criteria at baseline and transpulmonary thermodilution ( vs. pulmonary artery catheter ) monitoring was associated with a more positive fluid balance at 24 hrs . Conclusions : Hemodynamic management guided by transpulmonary thermodilution vs. pulmonary artery catheter in shock did not affect ventilator-free days , lengths of stay , organ failures , and mortality of critically ill patients . Use of the a transpulmonary thermodilution algorithm result ed in more days on mechanical ventilation and intensive care unit length of stay compared with the pulmonary artery catheter algorithm in nonseptic shock but not in septic shock . This may relate to cardiac comorbidity and a more positive fluid balance with use of transpulmonary thermodilution in nonseptic shock . ( Crit Care Med 2012 ; 40:–1185 Purpose To test whether the polymyxin B hemoperfusion ( PMX HP ) fiber column reduces mortality and organ failure in peritonitis-induced septic shock ( SS ) from abdominal infections . Method Prospect i ve , multicenter , r and omized controlled trial in 18 French intensive care units from October 2010 to March 2013 , enrolling 243 patients with SS within 12 h after emergency surgery for peritonitis related to organ perforation . The PMX HP group received conventional therapy plus two sessions of PMX HP . Primary outcome was mortality on day 28 ; secondary outcomes were mortality on day 90 and a reduction in the severity of organ failures based on Sequential Organ Failure Assessment ( SOFA ) scores . Results Primary outcome : day 28 mortality in the PMX HP group ( n = 119 ) was 27.7 versus 19.5 % in the conventional group ( n = 113 ) , p = 0.14 ( OR 1.5872 , 95 % CI 0.8583–2.935 ) . Secondary endpoints : mortality rate at day 90 was 33.6 % in PMX-HP versus 24 % in conventional groups , p = 0.10 ( OR 1.6128 , 95 % CI 0.9067–2.8685 ) ; reduction in SOFA score from day 0 to day 7 was −5 ( −11 to 6 ) in PMX-HP versus −5 ( −11 to 9 ) , p = 0.78 . Comparable results were observed in the predefined subgroups ( presence of comorbidity ; adequacy of surgery , < 2 sessions of hemoperfusion ) and for SOFA reduction from day 0 to day 3 . Conclusion This multicenter r and omized controlled study demonstrated a non-significant increase in mortality and no improvement in organ failure with PMX HP treatment compared to conventional treatment of peritonitis-induced SS RATIONALE A decade after drotrecogin alfa ( activated ) ( DAA ) was released on the market worldwide , its benefit-to-risk ratio remains a matter of debate . OBJECTIVES The current investigator-led trial was design ed to evaluate the efficacy and safety of DAA , in combination with low-dose steroids , in adults with persistent septic shock . METHODS This was a multicenter ( 24 intensive care units ) , placebo-controlled , double-blind , 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were r and omly assigned to DAA alone ( 24 μg/kg/h for 96 h ) , hydrocortisone and fludrocortisone alone , their respective combinations , or their respective placebos . Primary outcome was mortality rate on Day 90 . MEASUREMENTS AND MAIN RESULTS On October 25 , 2011 , the trial was suspended after the withdrawal from the market of DAA . The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension . At the time trial was suspended , 411 patients had been recruited , 208 had received DAA , and 203 had received its placebo . There was no significant interaction between DAA and low-dose steroids ( P = 0.47 ) . On Day 90 , there were 99 deaths ( 47.6 % ) among the 208 patients receiving DAA and 94 deaths ( 46.3 % ) among the 203 patients receiving placebo ( P = 0.79 ) . There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events . CONCLUSIONS In adults with established and severe septic shock , DAA showed no evidence of benefit or harm . Clinical trial registered with www . clinical trials.gov ( NCT00625209 )

However , the correct assignment of dropouts was essential to the demonstration of efficacy , most conspicuously concerning the effect of the drug on disease progression . REVIEW ER 'S CONCLUSIONS The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment .

BACKGROUND Recombinant interferons have been shown to suppress both the clinical and magnetic resonance imaging ( MRI ) measures of disease activity in patients with relapsing remitting multiple sclerosis ( RRMS ) . OBJECTIVES We performed a Cochrane review of all r and omised , placebo-controlled trials of recombinant interferons in RRMS .

We performed yearly MRI analyses on 327 of the total 372 patients in a multicenter , r and omized , double-blind , placebo-controlled trial of interferon beta-1b ( IFNB ) . Clinical results are presented in the preceding companion paper . Baseline MRI characteristics were the same in all treatment groups . Fifty-two patients at one center formed a cohort for frequent MRIs ( one every 6 weeks ) for analysis of disease activity . The MRI results support the clinical results in showing a significant reduction in disease activity as measured by numbers of active scans ( median 80 % reduction , p = 0.0082 ) and appearance of new lesions . In addition , there was an equally significant reduction in MRI-detected burden of disease in the treatment as compared with placebo groups ( mean group difference of 23 % , p = 0.001 ) . These results demonstrate that IFNB has made a significant impact on the natural history of MS in these patients Fifty-eight patients with severe , progressive multiple sclerosis were prospect ively r and omized to one of three treatments : 20 received intravenous ACTH , 20 received high-dose intravenous cyclophosphamide plus ACTH , and 18 were placed on a regimen consisting of plasma exchange , low-dose oral cyclophosphamide , and ACTH . The three groups were similar in age , sex , duration and type of disease , and degree of disability . Before treatment and six months and one year after treatment , a disability-status score , ambulation index , and functional-status score were determined , and a quantitative neurologic examination was performed . In the ACTH group , the number of patients stabilized or improved was 8 of 20 at six months and 4 of 20 at one year ; in the cyclophosphamide-ACTH group , 18 of 20 at six months and 16 of 20 at one year ; and in the plasma exchange group , 11 of 18 at six months and 9 of 18 at one year . High-dose cyclophosphamide plus ACTH was most effective in halting progression of the disease at both 6 and 12 months ( at 12 months , cyclophosphamide-ACTH vs. ACTH , P = 0.0004 ; cyclophosphamide-ACTH vs. plasma exchange , P = 0.087 ) . Thus , progressive multiple sclerosis may be stabilized by short-term , intensive immunosuppression with cyclophosphamide plus ACTH Background and Objective : A phase III double-blind , placebo-controlled clinical trial demonstrated that interferon beta-la ( IFNβ-1a ) ( Avonex , Biogen ) significantly delayed progression of disability in relapsing MS patients . The primary clinical outcome was time from study entry until disability progression , defined as≥1.0 point worsening from baseline Kurtzke Exp and ed Disability Status Scale ( EDSS ) score persisting for at least two consecutive scheduled visits separated by 6 months . The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance . Methods : Post hoc analyses related to disability outcomes using data collected during the double-blind , placebo-controlled phase III clinical trial . Results : ( 1 ) Clinical efficacy related to disability did not depend on the definition of disability progression . A significant benefit in favor of IFNβ-1a was observed when ≥2.0 point worsening from baseline EDSS was required or when worsening was required to persist for ≥1.0 year . ( 2 ) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFNβ-1a recipients who reached the primary study outcome . ( 3 ) Significantly fewer IFNβ-1a recipients progressed to EDSS milestones of 4.0 ( relatively severe impairment ) or 6.0(unilateral assistance needed to walk ) . ( 4 ) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFNβ-1a treatment . Conclusions : The primary clinical outcome for the IFNβ-1a clinical trial underestimated clinical benefits of treatment . Results in this report demonstrate that IFNβ-1a treatment is associated with robust , clinical ly important beneficial effects on disability progression in relapsing MS patients BACKGROUND The Multiple Sclerosis Functional Composite ( MSFC ) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation ( Timed 25-Foot Walk ) , arm function ( 9-Hole Peg Test ) , and cognitive function ( Paced Auditory Serial Addition Test ) . The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a ( Avonex ) in patients with secondary progressive MS . OBJECTIVE To assess the practice effects , reliability , and validity of the MSFC clinical outcome measure . DESIGN Examining technicians underwent formal training using st and ardized material s. The MSFC was performed according to a st and ardized protocol . The 436 patients enrolled in the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial underwent 3 prebaseline MSFC testing sessions before r and omization . RESULTS Practice effects were evident initially for the MSFC but stabilized by the fourth administration . The Paced Auditory Serial Addition Test demonstrated the most prominent practice effects . The reliability of the MSFC was excellent , with an intraclass correlation coefficient for session 3 ( final prebaseline session ) vs session 4 ( baseline ) of 0.90 . The MSFC at baseline correlated moderately strongly with the Kurtzke Exp and ed Disability Status Scale . Among the MSFC components , the Timed 25-Foot Walk correlated most closely . Correlations among the 3 MSFC components were weak , suggesting they assess distinct aspects of neurologic function in patients with MS . CONCLUSIONS The MSFC demonstrated excellent intrarater reliability in this multinational phase 3 trial . Three prebaseline testing sessions were sufficient to compensate for practice effects . The pattern of correlations among the MSFC , its components , and the Kurtzke Exp and ed Disability Status Scale supported the validity of the MSFC BACKGROUND Although the risk of clinical attacks of multiple sclerosis seems to be significantly increased with viral upper respiratory tract infections ( URTI ) , serological evidence for the reported association remains controversial . In addition , although MRI is six to 10 times more sensitive than clinical exacerbations in indexing disease activity , any possible association between URTI and MRI activity has yet to be investigated . OBJECTIVES To examine the relation between URTI and disease activity , in multiple sclerosis patients participating in a placebo controlled trial of interferon β-1a , as indexed both by clinical exacerbation rate and by the number and volume of gadolinium - diethylenetriaminepenta acetic acid ( Gd-DTPA ) enhancing lesions on MRI . “ At risk ” periods were defined around symptomatic URTI , with or without serological confirmation . RESULTS The relative risk of clinical relapse for serologically unconfirmed symptomatic URTI was 2.1 ( p=0.004 ) . Raised antiviral antibody titres conferred a relative risk of multiple sclerosis exacerbations that was 3.4 times higher than the “ not at risk ” periods ( annual attack rates of 5.7 v 1.6 , respectively , p=0.006 ) . There was no definite relation between the number or the volume of active lesions on MRI and either symptomatic or serologically defined at risk periods . CONCLUSIONS These results confirm the previously reported association between viral infections and multiple sclerosis exacerbations and indicate that the relative risk may be even higher when viral infection is serologically confirmed . However , the results , perhaps because of the confounding effects of interferon β-1a , do not provide convincing evidence of increased blood-brain barrier breakdown or inflammation during periods of virally induced immune stimulation OBJECTIVE : To evaluate whether recombinant human interferon-beta-1a significantly affects disease activity as measured by a reduction in the number and volume of Gd enhancing lesions on monthly MRI . The study also evaluated the effect on six-monthly T2 weighted abnormality and relapse frequency . METHODS : After a baseline scan and a six month pretreatment period , 68 patients were r and omly assigned to receive either 3 MIU or 9 MIU of interferon-beta-1a by subcutaneous injection three times a week for six months . All patients were examined by Gd enhanced MRI every month in both pretreatment and treatment periods . The evaluation of Gd enhancing lesions was performed blind at the end of the study . RESULTS : The mean number of Gd enhancing lesions was higher during the pretreatment period than during treatment . This difference was statistically significant for the two different dose subgroups ( 3.5 v 1.8 , P < 0.001 for the 3 MIU group and 2.4 v 0.9 , P < 0.001 for the 9 MIU group , corresponding to a reduction of 49 % and 64 % respectively ) . The mean volume of Gd enhancing lesions also significantly decreased by 61 % ( 3 MIU group ) and 73 % ( 9 MIU group ) . These reductions were evident only after the first month of treatment . The six-monthly rate of new lesions as seen in T2 weighted images showed a similar trend of reduction with treatment ( 65 % and 70 % respectively ) . Lesion volume on T2 scans significantly increased during the pretreatment period whereas it remained almost stable during the treatment period in both groups . Clinical relapse rate was significantly reduced by treatment ( 53 % for the 3 MIU group , P < 0.001 ; 69 % for the 9 MIU group , P < 0.001 ) . CONCLUSION : Interferon-beta-1a seemed effective in reducing disease activity in relapsing-remitting multiple sclerosis at both the doses used A pilot study was undertaken to test the safety and establish the side effect profile of recombinant human interferon-beta 1b ( Betaseron , Berlex Laboratories , Richmond , CA ) , in patients with relapsing-remitting multiple sclerosis ( RRMS ) . During the initial dose finding period ( 24 weeks ) , five groups of 6 patients each were treated by subcutaneous injection three times each week with either 0.8 , 4 , 8 , or 16 million units ( mU ) of Betaseron or placebo ( WHO St and ard ) . Although some side effects were noted in all groups , a dose-related trend in reduction of exacerbation frequency and side-effect profile was noted . Patients given 16 mU had no exacerbations during the initial dosing period , but associated side effects led to dose reduction or dropout . An 8 mU dose was selected for further study after 24 weeks , and continuous dosing at 8 mU in 15 patients has now exceeded 6 years . Side effects abated over time . Neutralizing antibody developed in most patients , but titers were variable , fluctuated independently of clinical course , and tended to fall with prolonged treatment . A dose-dependent rise in neopterin levels was observed during the initial dosing period . This pilot study has demonstrated responsiveness to Betaseron , shown a stable safety profile over time , and established guidelines for a dosing regimen to evaluate and optimize further the efficacy of Betaseron in RRMS The immunological effects of long-term treatment with recombinant alpha-2 interferon ( rIFN-alpha 2 ) were investigated in multiple sclerosis ( MS ) patients treated with 2 X 10(6 ) units of IFN or a placebo three times per week for one year . A mild lymphopenia was observed in IFN patients who also showed a decrease in the absolute number of total T cells in the blood ( OKT3 binding cells ) ; however , the percentage of cells reacting with OKT3 , OKT4 , and OKT8 antibodies did not change significantly during the study . The percentage of cells reacting with the Leu-7 antibody , which recognizes NK cells , was unchanged . During MS exacerbations , placebo patients showed a tendency for decreased levels of OKT3 and OKT8 cells . In contrast , IFN patients did not demonstrate a decrease in either OKT3 or OKT8 cells during disease attacks . Concanavalin A (ConA)-induced suppressor cell activity was depressed in both IFN and placebo-treated patients during attacks . Lymphoproliferative responses to phytohemagglutinin , pokeweed mitogen , and ConA were unchanged . These studies demonstrate that long-term treatment with rIFN-alpha 2 induces a generalized T-cell lymphopenia , but at this dose does not significantly affect the profiles of T-cell subsets and suppressor cell function in MS patients Background : Episodic inflammation in the CNS during the early stages of MS results in progressive disability years later , presumably due to myelin and axonal injury . MRI demonstrates ongoing disease activity during the early disease stage , even in some patients who are stable clinical ly . The optimal MRI measure for the destructive pathologic process is uncertain , however . Methods : In this post-hoc study , MRI scans were analyzed from patients with relapsing MS participating in a placebo-controlled trial of interferon β-1a . The brain parenchymal fraction , defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour , was used to measure whole brain atrophy . The relationship between disease features and brain atrophy and effect of interferon β-1a were determined . Results : MS patients had significant brain atrophy that worsened during each of 2 years of observation . In many patients , brain atrophy worsened without clinical disease activity . Baseline clinical and MRI abnormalities were not strongly related to the rate of brain atrophy during the subsequent 2 years . Treatment with interferon β-1a result ed in a reduction in brain atrophy progression during the second year of the clinical trial . Conclusions : Patients with relapsing-remitting MS have measurable amounts of whole brain atrophy that worsens yearly , in most cases without clinical manifestations . The brain parenchymal fraction is a marker for destructive pathologic processes ongoing in relapsing MS patients , and appears useful in demonstrating treatment effects in controlled clinical trials Chronic systemic high-dose recombinant alpha 2a-interferon ( rIFNA ) therapy reduces exacerbation rate and MRI signs of disease activity in relapsing/remitting multiple sclerosis ( RR MS ) patients . In order to clarify the possible mechanisms underlying the clinical efficacy of rIFNA in MS , several immunologic studies were performed as a part of a pilot clinical trial . Twenty RR MS patients were treated with 9 x 10(6 ) IU of rIFNA ( n = 12 ) or placebo ( n = 8) intramuscularly every other day for 6 months . Cytokine production by cultured lymphocytes , major histocompatibility complex class II ( MHC-II ) antigen expression on cultured macrophages , peripheral blood ( PB ) and cerebrospinal fluid ( CSF ) lymphocyte phenotype , and IgG and beta 2 microglobulin levels were studied before therapy , after 6 months of therapy , and 6 months after stopping therapy . rIFNA therapy was associated with reduction of interferon-gamma and tumor necrosis factor-alpha production by PB lymphocytes ( p < 0.04 ) , and with slight , not significant , increase of transforming growth factor-beta 2 or interleukin (IL)-10 production . IL-4 was undetectable in the culture supernatants both before and after therapy . rIFNA therapy had no effect on macrophage MHC-II molecule expression . An increased percentage of CD8 + , CD8 + high CD11b+ low , and CD3- CD16 + CD56 + cells , and of CD4 + absolute cell number was observed in CSF after rIFNA therapy . After rIFNA administration , IgG level significantly increased both systemically ( p < 0.02 ) and intrathecally ( p < 0.001 ) . Serum beta 2 microglobulin level increased ( p < 0.01 ) , as well . Only 1 out of the 12 rIFNA treated patients developed neutralizing antibodies against rIFNA during therapy . Six months after stopping therapy all the immunologic changes returned to baseline . These data suggest that the beneficial effect of rIFNA therapy on MS disease activity is probably mediated by a downregulation of proinflammatory cytokine synthesis by PB lymphocytes rather than by macrophage MHC-II antigen expression . The immunologic effects of high-dose systemic rIFNA therapy are temporary and restricted to the period of drug administration Ten patients with multiple sclerosis who were treated with human fibroblast interferon ( IFN-B ) for 6 months showed a significant reduction in their exacerbation rates compared with their rates before treatment ( P < .01 ) . The IFN-B was administered intrathecally by serial lumbar punctures . There was no significant change in the exacerbation rates of ten multiple sclerosis control patients before and during the period of observation . The IFN-B recipients have now been on the study a mean of 1.5 years , the controls , 1.2 years . The clinical condition of five of the IFN-B recipients and one of the control patients has improved , whereas the condition of five of the controls and one of the IFN-B recipients has deteriorated ( P < .036 ) . These findings warrant cautious optimism about the efficacy of intrathecal IFN-B in altering the course of multiple sclerosis and support concepts of a viral or dysimmune etiology of the disease Sixteen patients with clinical ly definite MS admitted to a double blind r and omised controlled trial of intrathecal natural beta-IFN were followed for a mean of 22 months including the six month treatment period . Clinical response , evaluated in terms of relapse frequency and of progression rate , showed an increase in relapse rate in treated patients during the six month treatment period and , overall , no benefit in treated versus placebo patients . Serial evaluations were made of cerebrospinal fluid ( CSF ) cells , IgG , myelin basic protein and CSF and blood T-cell subsets . A rise in CSF IgG Index , MBP and DR+ cells in IFN-treated patients suggested an activation of intrathecal immune response in treated patients BACKGROUND A recombinant form of interferon beta-1b ( Betaseron ) was given Food and Drug Administration approval for use in the treatment of relapsing-remitting multiple sclerosis in 1993 based on a documented reduction in exacerbation rate . However , its effect on disease progression is less clear . It costs $ 11,000 per year and has documented adverse effects such as fatigue , feverlike symptoms , and depression . OBJECTIVES To evaluate a recombinant form of interferon beta-1b in the treatment of relapsing-remitting multiple sclerosis and to discuss treatment trade-offs and comprehensive quality -of-life ( QOL ) outcomes . METHODS We present a r and omized evaluation of treatment with a recombinant form of interferon beta-1b in 79 patients with multiple sclerosis who participated in a r and om allocation lottery and were followed up for 12 months , during which data on QOL and clinical outcomes were collected . The data were analyzed using the Extended Quality -Adjusted Time Without Symptoms and Toxicity ( Q-TWiST ) method , which evaluates treatment trade-offs by incorporating several QOL domains and patient preferences regarding these domains . RESULTS Over the 12 months of follow-up , the case patients reported 10.6 months of quality -adjusted time , while the control patients reported 10.4 months of quality -adjusted time ( P = .50 ) . CONCLUSIONS Thus , the first year of treatment with interferon beta-1b did not significantly improve or detract from QOL . Results are discussed in terms of acceptable trade-offs depending on the nature of therapy . Future observational and clinical studies should incorporate measures of patient preference We evaluated the long-lasting effects of systemic high-dose recombinant interferon alpha-2a ( rIFNA ) in relapsing-remitting ( RR ) MS after discontinuing treatment in a single-blind r and omized placebo-controlled trial with 20 RR clinical ly definite MS patients using either nine million IU intramuscular rIFNA ( n = 12 ) or placebo ( n = 8) every other day for 6 months . Follow-up continued for a further 6 months without IFN treatment . In rIFNA-treated patients , main outcome measures , significantly different from placebo during treatment , returned , after discontinuing treatment , to values similar to placebo or baseline . Active MRI lesions per patient increased from 0.08 + /- 0.08 to 1.2 + /- 0.4 ( p < 0.02 ) , number of patients with clinical MRI signs of disease activity from 2 of 12 to 8 of 12 ( p < 0.04 ) , lymphocyte IFN gamma production from 3.0 + /- 0.7 to 12.4 + /- 2.2 IU/mL ( p < 0.01 ) , lymphocyte tumor necrosis factor alpha production from 5.8 + /- 0.9 to 18.9 + /- 6.3 pg/mL ( p < 0.05 ) . All side effects of rIFNA treatment disappeared after discontinuing the drug . The reduction of clinical MRI signs of disease activity and the immunologic effects were temporary and restricted to the period of rIFNA administration . The depression of many immunologic and clinical MRI responses during drug administration and their simultaneous return to baseline after discontinuing the drug strongly argue that all observed changes were related to drug administration . NEUROLOGY 1996;47 : 123 - The accepted st and ard treatment of relapsing multiple sclerosis consists of medications for disease symptoms , including treatment for acute exacerbations . However , currently there is no therapy that alters the progression of physical disability associated with this disease . The purpose of this study was to determine whether interferon beta‐1a could slow the progressive , irreversible , neurological disability of relapsing multiple sclerosis . Three hundred one patients with relapsing multiple sclerosis were r and omized into a double‐blinded , placebo‐controlled , multicenter phase I11 trial of interferon beta‐la . Interferon beta‐la , 6.0 million units ( 30 μg ) , was administered by intramuscular injection weekly . The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Exp and ed Disability Status Scale ( EDSS ) . Interferon beta‐la treatment produced a significant delay in time to sustained EDSS progression ( p equals ; 0.02 ) . The Kaplan‐Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9 % in the placebo group and 21.9 % in the interferon beta‐la‐treated group . Patients treated with interferon beta‐la also had significantly fewer exacerbations ( p = 0.03 ) and a significantly lower number and volume of gadolinium‐enhanced brain lesions on magnetic resonance images ( pvalues ranging between 0.02 and 0.05 ) . Over 2 years , the annual exacerbation rate was 0.90 in placebo‐treated patients versus 0.61 in interferon beta‐la‐treated patients . There were no major adverse events related to treatment . Interferon beta‐ la had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability , exacerbation frequency , and disease activity measured by gadolinium‐enhanced lesions on brain magnetic resonance images . This treatment may alter the hndamen‐ tal course of relapsing multiple sclerosis Background : Interferon beta is an effective treatment for relapsing multiple sclerosis(MS ) . As with other protein drugs , neutralizing antibodies ( NAB ) can develop that reduce the effectiveness of treatment . Objectives : To determine the incidence and biological significance of NAB to interferon beta-1a ( IFN-β-1a ; Avonex ; Biogen , Cambridge , MA ) in MS patients . Methods : A two-step assay for NAB to IFN-β-1a was developed and used to assay serum sample s from participants in the phase III clinical trial of IFN-β-1a , and from patients in an ongoing open-label study of IFN-β1a . The biological significance of NAB to IFN-β-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and β-2 microglobulin , and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-β-1a therapy in patients who were NAB+ and NAB- . The incidence of NAB was compared in MS patients who had used only IFN-β-1a with the incidence in MS patients who had used only IFN-β-1b . Results : In patients in the open-label study , development of NAB to IFN-β-1a result ed in a titer-dependent reduction in neopterin induction after interferon injections . In patients in the phase III study , development of NAB was associated with a reduction in β-2 microglobulin induction . In the phase III study , a trend toward reduced benefit of IFN-β-1a on MRI activity in NAB+ versus NAB- patients was observed . The incidence of NAB to IFN-β-1a in the open-label study was approximately 5 % over 24 months of treatment of IFN-β-1a therapy , but was four- to sixfold higher using the same assay for patients exposed only to IFN-β-1b for a similar duration . There were no clinical , MRI , or CSF characteristics that were predictive of which patients would develop NAB . Conclusions : NAB directed against IFN-β have in vivo biological consequences in patients with MS . The frequency with which MS patients develop NAB against IFN-β is significantly greater with IFN-β-1b therapy compared with IFN-β-1a therapy . Treatment decisions in MS patients treated withIFN-β should take into account development of NAB Objective : To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS , based on annual MR studies from the Multiple Sclerosis Collaborative Research Group ( MSCRG ) trial of interferon β-1a ( Avonex ) . Methods : All subjects had mild to moderate disability , with baseline exp and ed disability status scores ranging from 1.0 to 3.5 , and at least two relapses in the 3 years before study entry . Atrophy measures included third and lateral ventricle width , brain width , and corpus callosum area . Results : Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years . Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years . Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width . Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions . Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement . Conclusion : In patients with relapsing MS and only mild to moderate disability , significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years . The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions . Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes Article abstract The fate of the neutralizing antibody ( NAB ) in MS patients treated with interferons remains unclear . We conducted a follow-up survey of NAB titers in 59 long-term treated patients from the London and Vancouver cohorts of the pivotal trial of interferon β-1b . NAB were measured with the myxovirus protein A assay and an ELISA , at a mean follow-up that exceeded 8 years . NAB disappeared in the majority of patients BACKGROUND Treatment with interferon beta has been shown to help patients with established multiple sclerosis , but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value . METHODS We conducted a r and omized , double-blind trial of 383 patients who had a first acute clinical demyelinating event ( optic neuritis , incomplete transverse myelitis , or brain-stem or cerebellar syndrome ) and evidence of prior sub clinical demyelination on magnetic resonance imaging ( MRI ) of the brain . After initial treatment with corticosteroids , 193 patients were r and omly assigned to receive weekly intramuscular injections of 30 microg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo . The study end points were the development of clinical ly definite multiple sclerosis and changes in findings on MRI of the brain . The trial was stopped after a preplanned interim efficacy analysis . RESULTS During three years of follow-up , the cumulative probability of the development of clinical ly definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group ( rate ratio , 0.56 ; 95 percent confidence interval , 0.38 to 0.81 ; P=0.002 ) . As compared with the patients in the placebo group , patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions ( P<0.001 ) , fewer new or enlarging lesions ( P<0.001 ) , and fewer gadolinium-enhancing lesions ( P<0.001 ) at 18 months . CONCLUSIONS Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinical ly definite multiple sclerosis BACKGROUND An intravenous rather than oral course of methylprednisolone is often prescribed for treating acute relapses in multiple sclerosis ( MS ) despite the lack of evidence to support this route of administration . Our double-blind placebo-controlled r and omised trial was design ed to compare the efficacy of commonly used intravenous and oral steroid regimens in promoting recovery from acute relapses in MS . METHODS 42 patients with clinical ly definite relapse in MS received oral , and 38 intravenous , methylprednisolone . Clinical measurements at entry and at 1 week , 4 weeks , 12 weeks , and 24 weeks included Kurtzke 's exp and ed disability status scale ( EDSS ) , Hauser 's Ambulatory Index , and an arm-function index . The primary outcome criterion was a difference between the two treatment groups of one or more EDSS grade s at 4 weeks . FINDINGS There were no significant differences between the two groups at any stage of the study in any measurement taken : the mean difference in EDSS at 4 weeks ( adjusted for baseline level ) was 0.07 grade s more in those taking oral steroids ( 95 % CI -0.46 to 0.60 ) . The most optimistic outcome for intravenous therapy is an average benefit of less than half a grade improvement on EDSS over oral treatment . INTERPRETATION Since our study did not show any clear advantage of the intravenous regime we conclude that it is preferable to prescribe oral rather than intravenous steroids for acute relapses in MS for reasons of patient convenience , safety , and cost We report a r and omized , double-blind , placebo-controlled pilot trial of systemic high-dose recombinant interferon alfa-2a ( rIFNA ) in 20 patients with relapsing-remitting ( RR ) multiple sclerosis ( MS ) . Patients received 9 million IU rIFNA ( n = 12 ) or placebo ( n = 8) intramuscularly every other day for 6 months . Clinical exacerbations or new or enlarging lesions on serial MRI occurred in two of 12 rIFNA-treated and in seven of eight placebo-treated patients ( p < 0.005 ) . There was only one enlarging MRI lesion in the rIFNA group , whereas 27 new or enlarging lesions were present in the placebo group ( p < 0.01 ) . Baseline lymphocyte interferon gamma production of 19.10 ± 7.12 IU/ml significantly decreased to 3.03 ± 0.66 IU/ml ( p < 0.04 ) in the rIFNA group , whereas production was unchanged in the placebo group . The rIFNA was tolerated without dropouts or serious side effects , but fever , malaise , fatigue ( interfering with daily activities in two patients ) , and leukopenia occurred frequently . Neuropsychological tests excluded neurotoxicity . High-dose systemic rIFNA might reduce clinical and MRI signs of disease activity in RR MS and should be investigated in larger trials A r and omized , double-blind , placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS . Twenty-four patients with frequent exacerbations were treated for 6-month periods , beginning with either 5 × l06 IU of interferon daily or placebo . A 6-month washout period followed each treatment . Exacerbation rates were reduced during interferon and placebo phases compared with pre- study rates ; a greater reduction occurred on interferon , particularly following placebo , possibly reflecting a learning phenomenon . Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo , whereas 9 patients with a progressive component continued to have active disease . These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS Patients receiving recombinant human interferon-beta 1a ( IFN-beta 1a ) produced in Chinese hamster ovary ( CHO ) cells were tested for the formation of neutralizing antibodies ( NABs ) to IFN-beta . Sample s were tested in an enzyme-linked immunosorbent assay ( ELISA ) , and if positive were then tested for neutralization of antiviral activity in an IFN-beta bioassay . A total of 793 patients with viral diseases , premalignant and malignant diseases , and multiple sclerosis received IFN-beta 1a in clinical studies . Long-term studies included 56 patients with cancer treated for 6 or 12 months and 334 patients with multiple sclerosis ( MS ) at the end of one year of treatment . All of the NAB-positive patients were found in the latter . Positivity in a single specimen was found in 14.4 % of the MS patients . The incidence of sustained neutralizing antibody titres ( i.e. positive in two tests at least 6 months apart ) was 6.9 % in this group . Comparison with results from other studies suggests that CHO-derived IFN-beta 1a induces less neutralizing antibody than IFN-beta 1b produced in E. coli The decision to use interferon beta ( IFN-b ) as a treatment for relapsing-remitting multiple sclerosis ( RRMS ) is based on both clinical characteristics and course of the disease . To better identify the profile of responders , the relationships between baseline clinical /MRI characteristics and therapeutical response was analyzed in 49 patients with RRMS r and omly assigned to receive subcutaneously 3 or 9 MIU of IFN-b-1a . The therapeutical response was evaluated as a per cent change in the mean number and volume of monthly Gd-enhancing lesions in both first ( early response ) and second ( late response ) 6-month period of treatment , compared to the 6-month pre-treatment period . A better early response was seen in patients with a lower number of relapses during the pre-treatment period , while the late response was favourably influenced by a lower baseline EDSS and the high dose . Our findings suggest that the effect of IFN-b-1a on disease MRI activity is dose-related and dependent on the relapse rate and the level of disability before treatment Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value , and for many such patients mortality reductions of about 25 % can be achieved . No important differences are clearly apparent among the benefits of different beta blockers , although some are more convenient than others ( or have slightly fewer side effects ) , and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit . If monitored , the side effects of long-term therapy are not a major problem , as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment . By contrast , although very early IV short-term beta blockade can definitely limit infa rct size , more reliable information about the effects of such treatment on mortality will not be available until a large trial ( ISIS ) reports later this year , with data on some thous and s of patients entered within less than 4 hours of the onset of pain . Our aim has been not only to review the 65-odd r and omized beta blocker trials but also to demonstrate that when many r and omized trials have all applied one general approach to treatment , it is often not appropriate to base inference on individual trial results . Although there will usually be important differences from one trial to another ( in eligibility , treatment , end-point assessment , and so on ) , physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related r and omized trials and not just a few particular trial results . Although most trials are too small to be individually reliable , this defect of size may be rectified by an overview of many trials , as long as appropriate statistical methods are used . Fortunately , robust statistical methods exist -- based on direct , unweighted summation of one O-E value from each trial -- that are simple for physicians to use and underst and yet provide full statistical sensitivity . These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another . ( Moreover , they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust . ) Their robustness , sensitivity , and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews

REVIEW ER 'S CONCLUSIONS It is suggested that parenting programmes can make a significant contribution to the improvement of psychosocial health in mothers . While the critical appraisal suggests some variability in the quality of the included studies , it is concluded that there is sufficient evidence to support their use with diverse groups of parents .

BACKGROUND The prevalence of mental health problems in women is 1:3 and such problems tend to be persistent . There is evidence from a range of studies to suggest that a number of factors relating to maternal psychosocial health can have a significant effect on the mother-infant relationship , and that this can have consequences for the psychological health of the child . It is now thought that parenting programmes may have an important role to play in the improvement of maternal psychosocial health . OBJECTIVES The objective of this review is to address whether group-based parenting programmes are effective in improving maternal psychosocial health including anxiety , depression and self-esteem .

The efficacy of group parent training was assessed in improving compliance and time on task in preschoolers with attention-deficit disorder with hyperactivity . Positive effects were obtained on measures of child compliance , but not on measures of attention . Parental compliance-management skills and overall style of interaction were also positively affected . The use of parent training for early intervention with ADDH children is discussed Aims : To assess the effectiveness of a parenting programme , delivered by health visitors in primary care , in improving the mental health of children and their parents among a representative general practice population . Methods : Parents of children aged 2–8 years who scored in the upper 50 % on a behaviour inventory were r and omised to the Webster-Stratton 10 week parenting programme delivered by trained health visitors , or no intervention . Main outcome measures were the Eyberg Child Behaviour Inventory and the Goodman Strengths and Difficulties Question naire to measure child behaviour , and the General Health Question naire , Abidin ’s Parenting Stress Index , and Rosenberg ’s Self Esteem Scale to measure parents ’ mental health . These outcomes were measured before and immediately after the intervention , and at six months follow up . Results : The intervention was more effective at improving some aspects of the children ’s mental health , notably conduct problems , than the no intervention control condition . The Goodman conduct problem score was reduced at immediate and six month follow up , and the Eyberg Child Behaviour Inventory was reduced at six months . The intervention also had a short term impact on social dysfunction among parents . These benefits were seen among families with children scoring in the clinical range for behaviour problems and also among children scoring in the non- clinical ( normal ) range . Conclusion : This intervention could make a useful contribution to the prevention of child behaviour problems and to mental health promotion in primary care This study evaluated the relative efficacy of two promising treatments of child abuse and child ne-glect : parent training and multisystemic therapy . Subjects included 18 abusive families and 15 ne-glectful families who were r and omly assigned to the treatment conditions . Self-report and observa-tional measures were used to evaluate the effects of treatment at three levels that have been associatedwith child maltreatment : individual functioning , family relations , and stress/social support . Statisti-cal analyses revealed that families who received either treatment showed decreased parental psychiat-ric symptomology , reduced overall stress , and a reduction in the severity of identified problems . Analyses of sequential observational measures revealed that multisystemic therapy was more effec-tive than parent training at restructuring parent-child relations . Parent training was more effectivethan multisystemic therapy at reducing identified social problems . The differentia ] inOuences of thetwo treatments were probably associated with differences in their respective treatment context s and epistemologies This study evaluated the effects of problem-solving skills training ( PSST ) and parent management training ( PMT ) on children ( N = 97 , ages 7 - 13 years ) referred for severe antisocial behavior . Children and families were assigned r and omly to 1 of 3 conditions : PSST , PMT , or PSST and PMT combined . It was predicted that ( a ) each treatment would improve child functioning ( reduce overall deviance and aggressive , antisocial , and delinquent behavior , and increase prosocial competence ) ; and ( b ) PSST and PMT combined would lead to more marked , pervasive , and durable changes in child functioning and greater changes in parent functioning ( parental stress , depression , and overall symptoms ) . Expectations were supported by results at posttreatment and 1-year follow-up . PSST and PMT combined led to more marked changes in child and parent functioning and placed a greater proportion of youth within the range of nonclinic ( normative ) levels of functioning OBJECTIVE To evaluate two different parent-based therapies for preschool attention-deficit/hyperactivity disorder ( ADHD ) in a community sample . METHOD Three-year-old children displaying a preschool equivalent of ADHD ( n = 78 ) were r and omly assigned to either a parent training ( PT ; n = 30 ) , a parent counseling and support ( PCO&S ; n = 28 ) , or a waiting-list control group ( n = 20 ) . The PT group received coaching in child management techniques . The PC&S group received nondirective support and counseling . Measures of child symptoms and mothers ' well-being were taken before and after intervention and at 15 weeks follow-up . RESULTS ADHD symptoms were reduced ( F2,74 = 11.64 ; p < .0001 ) and mothers ' sense of well-being was increased by PT relative to both other groups ( F2,74 = 10.32 ; p < .005 ) . Fifty-three percent of children in the PT group displayed clinical ly significant improvement ( chi 2 = 4.08 ; p = .048 ) . CONCLUSIONS PT is a valuable treatment for preschool ADHD . PC&S had little effect on children 's behavior . Constructive training in parenting strategies is an important element in the success of parent-based interventions . Psychostimulants are not a necessary component of effective treatment for many children with preschool ADHD OBJECTIVE The purpose was to report preliminary behavioral , social , and emotional results , and to project some potential economic results of a parenting and anger management program in a mountain state . METHOD Following local and state-wide needs assessment s , child abuse prevention was identified as the number two critical issue . An effective , research -based , preventive educational workshop program -- RETHINK Parenting and Anger Management -- was selected for testing and program evaluation . Measurable outcome objectives were written and assessment s were developed and tested . A one-group pretest-posttest design with a convenience sample of parents was used for the study . Seventy-five of 99 parents completed pretests before and posttests after participating in the 6-week series of skill-enhancing workshops . RESULTS Using a repeated measures analysis of variance , participants ' group mean anger control levels increased ( p = .016 ) . Their family conflict levels fell ( p = .006 ) . Their overall anger levels fell ( p = .000 ) . Their violence levels fell , verbal aggression levels fell ( p = .002 ) . Their partners ' violence levels also fell , verbal aggression levels fell ( p = .004 ) , and physical aggression levels fell ( p = .032 ) . In addition , participants reported increased knowledge levels ( 100 % ) , improved attitudes ( 97.3 % ) , improved behaviors ( 94.7 % ) , and decreased unrealistic expectations of their children ( 69.3 % ) . CONCLUSION The findings suggest that professional preventive education specialists may now have an effective program to assist parents in managing their anger . Further research is encouraged . When parents participate in 6 weeks of skill building with well-trained professionals , positive changes in parenting and anger management are possible This study examined the effects of parent training in music and multimodal stimulation on the quantity and quality of parent-neonate interactions and the weight gain and length of hospitalization of premature and low birthweight ( LBW ) infants in a Neonatal Intensive Care Unit ( NICU ) . Twenty sets of parents and premature LBW infants participated in the study . Parents in the experimental group ( n = 10 ) received approximately one hour of instruction in appropriate uses of music , multimodal stimulation including massage techniques , and signs of infant overstimulation and techniques for its avoidance . Parent-neonate interactions , specifically parent actions and responses and infant stress and nonstress behaviors , were observed for subjects in both groups . Infant stress behaviors were significantly fewer and appropriateness of parent actions and responses were significantly greater for experimental infants and parents than for control subjects . Parents in the experimental group also self-reported spending significantly more time visiting in the NICU than did parents of control infants . In addition , length of hospitalization was shorter and average daily weight gain was greater for infants whose parents received training , although these differences were not significant . A one month , postdischarge follow-up showed little difference between experimental and control group parent-infant interactions in the home Parents of 114 conduct-problem children , aged 3 - 8 years , were r and omly assigned to one of four groups : an individually administered videotape modeling treatment ( IVM ) , a group discussion videotape modeling treatment ( GDVM ) . a group discussion treatment ( GD ) , and a waiting-list control group . Compared ~4th the control group , all three treatment groups of mothers reported significantly fewer child behavior problems , more prosocial behaviors , and less spanking . Fathers in the GDVM and IVM conditions and teachers of children whose parents were in the GDVM and GD conditions also reported significant reductions in behavior problems compared ~4th control subjects . Home visit data indicated that all treatment groups of mothers , fathers , and children exhibited significant behavioral changes . There were relatively few differences between treatment groups on most outcome measures , although the differences found consistently favored the GDVM treatment . However , cost effectiveness was the major advantage of the IVM treatment This study provides evidence of the effectiveness of behaviorally based parenting skills classes provided by carefully trained and supervised group leaders who were not mental health clinicians . A program for parents of at-risk middle school students was evaluated in a r and omized controlled trial in 8 small Oregon communities . Parents ( N = 303 ) were r and omly assigned to immediate treatment or a wait-list condition . Data were analyzed using latent growth modeling . Participation in the program led to significant improvements in problem-solving interactions as indicated by parent reports and a Taped Situations Test . Parents ' over-reactivity and laxness toward their children 's behavior were reduced and their feelings toward their children improved significantly as a function of treatment . Parent-reported child antisocial behavior was also reduced Two family therapies were compared using teens with attention-deficit/hyperactivity disorder . Ninety-seven families were assigned to either 18 sessions of problem-solving communication training ( PSCT ) alone or behavior management training ( BMT ) for 9 sessions followed by PSCT for 9 sessions ( BMT/PSCT ) . Both treatments demonstrated significant improvement in ratings of parent-teen conflicts at the midpoint but did not differ . By posttreatment , both produced improvement on ratings and observations but did not differ . Significantly more families dropped out of PSCT alone than out of BMT/PSCT . At most , 23 % of families showed reliable change either by midpoint or by posttreatment , with no differences between therapies . Yet 31%-70 % of families were normalized . Group-level change and normalization rates support treatment efficacy , whereas indices of reliable change are less impressive The effectiveness of a parent training program for promoting positive parent-child relationships was examined among families of 2-year-olds . Forty-six mothers and fathers and their toddlers were assigned to either an intervention or comparison group . Intervention group parents participated in a 10-week program that focused on principles for effectively interacting with their toddlers . Parents completed measures of parenting self-efficacy , depression , stress , and perceptions of their toddler 's behaviors and were videotaped playing with their toddlers preintervention , postintervention , and 3 months following the intervention . Repeated measures ANOVAs showed that the parent training program led to significant increases in maternal self-efficacy , decreases in maternal stress , and improvements in the quality of mother-toddler interactions . No significant effects were found among fathers . Explanations for obtaining different outcomes for mothers and fathers are discussed and directions for future research are recommended A significant percentage of children with disruptive behavior disorders do not receive mental health assistance . Utilization is lowest among groups whose children are at greatest risk . To increase the availability , accessibility , and cost efficacy of parent training programs , this prospect i ve r and omized trial compared a large group community-based parent training program to a clinic-based individual parent training ( PT ) programs . All families of junior kindergartners in the Hamilton public and separate school boards were sent a checklist regarding problems at home . Those returning question naires above the 90th percentile were block r and omly assigned to : ( 1 ) a 12-week clinic-based individual parent training ( Clinic/Individual ) , ( 2 ) a 12-week community-based large group parent training ( Community/Group ) , or ( 3 ) a waiting list control condition . Immigrant families , those using English as a second language , and parents of children with severe behaviour problems were significantly more likely to enroll in Community/Groups than Clinic/Individual PT . Parents in Community/Groups reported greater improvements in behaviour problems at home and better maintenance of these gains at 6-month follow-up . A cost analysis showed that , with groups of 18 families , Community/Groups are more than six times as cost effective as Clinic/Individual programs The effectiveness of a behavioral parent training ( BPT ) intervention for improving maternal self-efficacy , maternal stress , and the quality of mother-toddler interactions has been demonstrated ( Gross , Fogg , & Tucker , 1995 ) . The 1-year follow-up of the 46 parents of toddlers ( assigned to an intervention or comparison group ) who participated in that study is reported . It was hypothesized that ( a ) BPT would lead to enduring positive changes in parenting self-efficacy , parenting stress , and parent-toddler interactions ; and ( b ) the amount of parent participation in the intervention would be correlated with greater gains in parent-child outcomes at 1 year . All the families were retained and significant gains in maternal self-efficacy , maternal stress , and mother-child interactions were maintained . Minimal BPT effects were found for fathers . BPT dosage was related to reductions in mother critical statements and negative physical behaviors at 1-year postintervention . The findings are consistent with self-efficacy theory and support parenting self-efficacy as a target for BPT in families of young children This study assessed the role of social support in the outcome of child management training ( CMT ) for single parents of conduct problem children and assessed the impact of adjunctive ally support training ( AST ) on treatment outcome . Single parents ( N = 22 ) with a child diagnosed as oppositional or conduct-disordered received CMT or CMT plus AST . Each group received the same 6-week parent training program and the AST group received an extra social support intervention . Measures of parent behavior , child deviance , social support ( SS ) , and parental depression were obtained at pre- and posttreatment and at 6-month follow-up . Both groups improved , and changes maintained at follow-up . AST produced no extra gains . Responders from either group were more likely than nonresponders to report high levels of SS from friends . Results emphasize the importance of SS and the difficulty of incorporating changes in SS into treatment programs Using a r and om sample of first-time mothers from an inner London borough , the relationship was examined between maternal depression and child behaviour problems at various stages after the birth of the child . Child problems at 14 months were unrelated to present or past maternal depression . Child problems at 27 and 42 months were related in an interactive way with present and past depression . There was little indication of behaviour problems preceding maternal depression . An examination of possible confounding factors in these relationships was also attempted Studied the effectiveness of parent and teacher training as a selective prevention program for 272 Head Start mothers and their 4-year-old children and 61 Head Start teachers . Fourteen Head Start centers ( 34 classrooms ) were r and omly assigned to ( a ) an experimental condition in which parents , teachers , and family service workers participated in the prevention program ( Incredible Years ) or ( b ) a control condition consisting of the regular Head Start program . Assessment s included teacher and parent reports of child behavior and independent observations at home and at school . Construct scores combining observational and report data were calculated for negative and positive parenting style , parent-teacher bonding , child conduct problems at home and at school , and teacher classroom management style . Following the 12-session weekly program , experimental mothers had significantly lower negative parenting and significantly higher positive parenting scores than control mothers . Parent-teacher bonding was significantly higher for experimental than for control mothers . Experimental children showed significantly fewer conduct problems at school than control children . Children of mothers who attended 6 or more intervention sessions showed significantly fewer conduct problems at home than control children . Children who were the " highest risk " at baseline ( high rates of noncompliant and aggressive behavior ) showed more clinical ly significant reductions in these behaviors than high-risk control children . After training , experimental teachers showed significantly better classroom management skills than control teachers . One year later the experimental effects were maintained for parents who attended more than 6 groups . The clinical ly significant reductions in behavior problems for the highest risk experimental children were also maintained . Implication s of this prevention program as a strategy for reducing risk factors leading to delinquency by promoting social competence , school readiness , and reducing conduct problems are discussed OBJECTIVE To assess the impact of maternal attention-deficit/hyperactivity disorder ( ADHD ) symptoms on the effectiveness of a parent training ( PT ) program for preschool ADHD . METHOD Eighty-three 3-year-old children with ADHD and their mothers selected from two community cohorts living in Hampshire , Engl and ( 1992 - 93 and 1995 - 96 , respectively ) , completed an 8-week PT program . ADHD symptoms and a number of other parent and child factors , including adult ADHD symptoms , were measured prior to the start of treatment ( week 1 : T1 ) , immediately after treatment ( week 8 : T2 ) , and at 15 weeks follow-up ( week 23 : T3 ) . RESULTS Mothers were divided into three groups on the basis of their scores ( T1 ) on the Adult AD/HD Rating Scale ( high , medium , low ) . Children of mothers in the high-ADHD group displayed no improvement after PT , whereas the levels of ADHD symptoms of the children of mothers in either the medium or low ADHD groups reduced substantially ( F(4,60 ) = 3.13 , p < .05 ) . This association persisted after other child and maternal factors were controlled for in multiple regression analyses ( beta > .30 , p < .05 ) . CONCLUSIONS High levels of maternal ADHD symptoms limit the improvement shown by children with ADHD after a program of PT . This effect was unrelated to other aspects of maternal mental health and child functioning . The treatment of parental ADHD may be a prerequisite for the success of psychosocial interventions for childhood ADHD The effect of a short-term group intervention to reduce self-blame and guilt in parents of children with severe disabilities was examined . Thirty-four mothers were r and omly assigned to treatment and waiting list control groups . They participated in classes led by a counselor on topics relating to cognitive processes associated with guilt and self-blame . Results showed significant reductions in measures of guilt , negative automatic thoughts , internal negative attributions , and depression . Theoretical and treatment literature concerning self-blame and guilt was briefly review ed and the derivative treatment was described This report discusses the development of a coping skill training program for parents of substance-abusing adolescents and presents preliminary data on the effects of the program on parent functioning and adolescent substance use . The behavioral-analytic model of program development was used to sample representative problematic situations experienced by parents of substance-abusing adolescents , obtain an effectiveness-scaling of responses to these situations , and derive alternate forms of a situational role-play measure of parental coping . These situations and scoring guidelines were then used to create the skill training program . Parents of substance-abusing adolescents not in treatment subsequently were r and omly assigned in a pilot investigation to either a skill training or delayed treatment condition . Skill training result ed in significant improvement in parental coping skills relative to delayed treatment . Moderate to large improvement in the parent 's report of their own functioning , family communication , and the teen 's marijuana use also favored the skill training group OBJECTIVE To assess the effectiveness of a behavioural programme introduced in the first 3 months of age in preventing infant crying and sleeping problems . Two issues were addressed : ( i ) which elements of the behavioural programme would parents implement ; and ( ii ) whether the behavioural programme was more effective in reducing infant crying and encouraging night-time sleeping than an educational intervention or the routine services . METHODOLOGY Mothers and newborns were assigned at r and om to the behavioural programme ( n = 205 ) , educational intervention ( n = 202 ) , or control ( n = 203 ) group . Behaviour diaries kept before r and omization and at 3 , 6 , 9 and 12 weeks of age were used to measure implementation of the interventions and infant behaviour , including crying and sleeping . Crying and sleeping problems were followed up using question naire measures at 9 months of age . RESULTS The educational intervention did not change parental care behaviour . One element of the behavioural programme , a focal feed between 10 PM and midnight , was not implemented . A second element , stretching of interfeed intervals after 3 weeks of age , was implemented initially , but not maintained at older ages . The third element , which asked parents to emphasise day and night differences in the environment , and to settle their babies in the cot and minimise interaction at night , was carried out by more parents in the behavioural group than in the other groups . This led to an increase of around 10 % in the number of babies who slept for 5 or more hours at night ( a definition of sleeping through the night ) at 12 weeks of age . Fewer behavioural programme parents sought help for crying and sleeping problems between 3 and 9 months of age . CONCLUSION The behavioural programme produced a modest increase in the number of infants who slept through the night by 12 weeks of age . The results are discussed in relation to other findings , which bear on the programme 's adoption for routine health-care policy and practice Twenty-four parents of oppositional preschoolers were r and omly assigned to either a selfdirected behavioral family intervention condition ( SD ) or to a waitlist control group ( WL ) . The self-directed parent training program , based on self-regulation principles , consisted of a written information package and weekly telephone consultations for 10 weeks . At posttest , in comparison to the WL group , children in the SD group had lower levels of behavior problems on parent report measures of child behavior . At posttreatment , parents in the SD condition reported increased levels of parenting competence and lower levels of dysfunctional parenting practice s as compared to parents in the WL condition . In addition , mothers reported lower levels of anxiety , depression , and stress as compared to mothers in the WL condition at posttreatment . Using mother 's reports , gains in child behavior and parenting practice s achieved at posttreatment were maintained at 4-month follow-up ! [ ] [ 1 ] Rating : R and omised controlled trials are often held up as the “ gold st and ard ” of medical research , and it is commonly believed that the size of a treatment effect is exaggerated in non-r and omised studies . In these days of evidence based medicine , however , where is the empirical evidence that this is so ? A widespread criticism of r and omised controlled trials is that they are based on highly selected individuals . Are there systematic differences between patients included and excluded in such trials , and do these influence the measured treatment effect ? These are just a few … [ 1 ] : An experimental research study was done to determine whether an educational intervention about attention deficit hyperactivity disorder ( ADHD ) would improve a mother 's knowledge about ADHD and her feelings of competence as a parent . 20 low socioeconomic status mothers who had a male child between the ages of 5 and 11 diagnosed with ADHD and placed on methylpheni date were r and omly selected for the study . An experimental group of 10 mothers was given a 5-week educational intervention on ADHD ; the remaining 10 mothers served as a control group . Differences between the experimental and non-experimental mothers in knowledge and opinions about ADHD and parental sense of competency were measured . Scores improved in parental satisfaction and parental sense of competency in mothers who participated in the educational intervention . The research findings support the idea that nurses can assist a family in learning and dealing with their child 's ADHD , a chronic condition Three variants of a behavioral family intervention ( BFI ) program known as Triple P were compared using 305 preschoolers at high risk of developing conduct problems . Families were r and omly assigned to enhanced BFI ( EBFI ) , st and ard BFI ( SBFI ) , self-directed BFI ( SDBFI ) , or wait list ( WL ) . At postintervention , the 2 practitioner-assisted conditions were associated with lower levels of parent-reported disruptive child behavior , lower levels of dysfunctional parenting , greater parental competence , and higher consumer satisfaction than the SDBFI and WL conditions . Overall , children in EBFI showed greater reliable improvement than children in SBFI , SDBFI , and WL . By 1-year follow-up , children in all 3 conditions achieved similar levels of clinical ly reliable change in observed disruptive behavior . However , the EBFI and SBFI conditions showed greater reliable improvement on parent-observed disruptive child behavior The effects of parent education programs on the parenting attitudes and abilities of 30 U.S. male inmates and on the self-perceptions of their children ( aged 8 - 17 years ) were examined . Inmates were pre- and post-tested with the Adult-Adolescent Parenting Inventory and the Index of Self-Esteem . The children were administered the Self-Perception Profile for Children or the Self-Perception Profile for Adolescents . Participants in the experimental group completed a 6-week program including parental training and behavior-management training . The control group 's 6-week program consisted of viewing family-related videotapes , answering questions , and discussing the contents of the videotapes . Parent education improved the attitudes of inmates toward appropriate parenting but did not significantly change their children 's self-perceptions Examined efficacy of an empirically based intervention using 70 divorced mothers who participated in a 12-session program or a wait-list condition . The program targeted five putative mediators : quality of the mother-child relationship , discipline , negative divorce events , contact with fathers , and support from nonparental adults . Posttest comparisons showed higher quality mother-child relationships and discipline , fewer negative divorce events , and better mental health outcomes for program participants than controls . More positive program effects occurred for mothers ' than children 's reports of variables and for families with poorest initial levels of functioning . Analyses indicated that improvement in the mother-child relationship partially mediated the effects of the program on mental health Abstract . Few attempts have been made to conduct r and omised control trials ( RCTs ) of interventions for pre-school children with autism . We report findings of a pilot RCT for a parent training intervention with a focus on the development of joint attention skills and joint action routines . Twenty-four children meeting ICD-10 criteria for childhood autism ( mean age = 23 months ) were identified using the CHAT screen and r and omised to the parent training group or to local services only . A follow-up was conducted 12 months later ( mean age = 35 months ) . There was some evidence that the parent training group made more progress in language development than the local services group . However , the present pilot study was compromised by several factors : a reliance on parental report to measure language , non-matching of the groups on initial IQ , and a lack of systematic checking regarding the implementation of the parent training intervention . Furthermore , three parents in the local services group commenced intensive , home-based behavioural intervention during the course of the study . The difficulties encountered in the conduct of RCTs for pre-school children with autism are discussed . Method ological challenges and strategies for future well- design ed RCTs for autism interventions are highlighted

Individuals with an additional X chromosome had mean IQs that were within broadly normal limits but lower than the respective comparison groups , with verbal IQ most affected . Cognitive outcomes were poorest for females with XXX . Males with XYY had normal-range IQs , but all three SCT groups ( XXX , XXY , and XYY ) had marked difficulties in speech and language , motor skills , and educational achievement . Nevertheless , most adults with SCTs lived independently . Less evidence was available for brain structure and for attention , social , and psychiatric outcomes . INTERPRETATION Individuals with SCTs are at risk of cognitive and behavioural difficulties .

AIM To review systematic ally the neurodevelopmental characteristics of individuals with sex chromosome trisomies ( SCTs ) .

CONTEXT Adults with Klinefelter 's syndrome ( KS ) are known to present disturbances of language skills and delayed learning abilities . OBJECTIVES The aim of this study was to assess brain morphometry in KS and to correlate eventual volumetric changes with performance on neuropsychological tests . PATIENTS Patients included 18 KS adults and 20 age-matched controls . METHODS All participants underwent prospect ively double-spin-echo brain magnetic resonance imaging and neuropsychological testing of verbal and nonverbal domains . On the axial stack of magnetic resonance imaging slices , regional brain volumes were measured either by automated segmentation ( full brain , total cerebrospinal fluid , and ventricular volume ) or manual drawing with help of a neuroanatomy atlas ( frontal , temporal , and parietal lobes , gray matter component of the lobes , cerebellar hemispheres , and hippocampal complexes ) . RESULTS KS patients performed significantly lower than controls on language -related tasks exploring verbal processing speed and verbal executive function . They were diagnosed with significant enlargement of ventricular volume and bilateral reduction of cerebellar hemispheres . Furthermore , after separation of participants according to h and edness and after correction of regional brain volumes for atrophy , a significant reduction of left temporal lobe volume was found in KS compared with controls . Ventricular volume was inversely correlated with cognitive function , whereas left temporal lobe volume was positively correlated with language -related tasks . CONCLUSION This study hypothesizes that supernumerary X-chromosome and /or congenital hypogonadism provoke structural alterations in the subcortical pathways involved in language processing , thus providing a neurobiological substrate for cognitive deficits in KS Inhibition is a central construct to the frontal lobe theory of ageing , yet its construct validity remains unproven . Furthermore , age effects on measures of inhibition are often reported without adequate control for the effects of global slowing on performance . We investigated inhibitory function in older adults in two experiments . In Experiment 1 , 49 people with ages between 59 and 86 ( mean=70 years 9 months S.D.=7.54 ) completed four analogues of the Stroop interference paradigm . To control for global slowing and to enable comparisons across all measures , we used a r and om effects model based on log-transformed response times . Age did not contribute significantly to the model and the estimated correlation between tasks was not significant . In Experiment 2 , 33 people with ages between 62 and 86 ( mean=73 years 4 months , S.D.=6.57 ) were compared on two measures of Stroop-like interference which were very similar in surface task dem and s. Age did not contribute significantly to the model but the estimated correlation between tasks was robust ( r=0.714 ) . We conclude that age may make little contribution to inhibitory function independently of other factors such as speed and intelligence . Second , that the level of individual consistency in the performance of measures of inhibition will depend on the similarity of the tasks used Objective : This study focuses on variation in brain morphology associated with supernumerary X chromosome and Klinefelter syndrome ( KS ) . Using an unselected birth cohort of KS subjects and high-resolution MRI , the authors investigated the neuroanatomic consequences of the 47,XXY karyotype in the presence and absence of exogenous testosterone supplementation . Methods : Regional brain volumes were measured in 10 subjects with KS and 10 age-matched control men . Five of the KS subjects had received testosterone supplementation since puberty ( KS+T ) and five had not ( KS−T ) . Results : KS subjects showed significant ( p < 0.01 ) reduction in left temporal lobe gray matter volumes compared with normal control subjects . Differences in left temporal gray volumes were also significant between the KS+T and KS−T groups ( p < 0.01 ) . Verbal fluency scores were significantly different between the KS+T and KS−T groups as well . Conclusion : Supernumerary X chromosome material in men is associated with a reduction in left temporal lobe gray matter , a finding that is consistent with the verbal and language deficits associated with KS . Also , relative preservation of gray matter in the left temporal region is associated with exposure to exogenous and rogen during development . A history of testosterone supplementation also appears to be associated with increased verbal fluency scores in KS patients This double-blind , controlled study of XYY and XXY men found in a birth cohort of 4,591 tall men born in Copenhagen assessed evidence of delinquent and aggressive behavior and explored the role of hormonal determinants in the behavioral and psychological differences noted among groups . Information from social records , a structured psychological interview , and projective tests did not support the notion that men with sex chromosome anomalies are particularly violent or aggressive . Hormonally , XYY men had significantly higher concentrations of testosterone , luteinizing hormone ( LH ) , and follicle-stimulating hormone ( FSH ) than matched control groups . In contrast , XXY men had higher levels of LH , FSH , and prolactin , but low concentrations of testosterone . There was a significantly positive relation among all subjects as well as XY controls alone between plasma testosterone level and evidence of criminal convictions . A proportionate increase in testosterone levels was noted when subjects were divided into nondelinquents , delinquents without violent convictions , and delinquents with violent convictions . The relation between testosterone level and criminal behavior was not reflected in measures of aggression derived from the psychological interview and projective tests . There was no specific evidence that testosterone is a mediating factor in the criminal behavior of XYY men Children with sex chromosome abnormalities ( SCA ) are known to be at risk for developmental delays . These risks were identified 2 decades ago by seven international research groups who prospect ively followed children ascertained after birth . Subsequently , some of these investigators suggested the course of prenatally identified children with SCA may be different from children in earlier studies . The first such evidence was published by Robinson et al. [ 1992 : Am J Med Genet 44:365 - 368 ] , who compared 20 prenatally diagnosed children to the original postnatally diagnosed cohort . The following report presents an up date and expansion of that research and includes 51 children and adolescents prenatally diagnosed with SCA , now 7 - 18 years of age . Results confirm that this cohort of prenatally diagnosed children has a milder developmental course than children ascertained postnatally . The study provides new information to health professionals counseling families faced with prenatal diagnosis of SCA A prospect i ve study was made of 42 children who were found at birth to have sex chromosome aberrations . The mean developmental quotient of the XXY and XXX groups was in the dull-normal range , whereas developmental quotients of 3 XYY children were low normal . The commonest deficits were in language and gross motor skills , with highest incidence in the XXX group . Many of the children had behavior problems , but no specific pattern was associated with an individual chromosome aberration . The XXX group experienced a linear growth spurt after 4 years of age . With one exception there were only mild dysmorphic features , none of them specifically associated with any subgroup . Of 17 children followed up to school age , almost two thirds evidence d learning and /or behavior problems . There was a high incidence of birth problems particularly in XXX children ( seven of ten ) , and of social problems , psychiatric illness and learning difficulties in their families . In 14 cases , the parent-child relationship was disturbed , result ing in behavior problems . These findings make it improbable that the children 's generally poor developmental and behavioral performance were solely attributable to their chromosomal constitution

Completed trials of problem drinkers that compared interventions for problem drinking to no intervention reported reduced motor-vehicle crashes and related injuries , falls , suicide attempts , domestic violence , assaults and child abuse , alcohol-related injuries and injury emergency visits , hospitalizations and deaths . REVIEW ERS ' CONCLUSIONS Interventions for problem drinking appear to reduce injuries and their antecedents ( e.g. falls , motor vehicle crashes , suicide attempts ) . Because injuries account for much of the morbidity and mortality from problem drinking , larger studies are warranted to evaluate the effect of treating problem drinking on injuries

BACKGROUND Alcohol consumption has been linked with injuries through motor vehicle crashes , falls , drowning , fires and burns , and violence . In the US , half of the estimated 100,000 deaths attributed to alcohol each year are due to intentional and unintentional injuries . The identification of effective interventions for the reduction of unintentional and intentional injuries due to problem drinking is , therefore , an important public health goal . OBJECTIVES To assess the effect of interventions for problem drinking on subsequent injury risk .

Recognizing the need to offer alternative methods of brief interventions , this study developed correspondence treatments for low-dependent problem drinkers and evaluated their impact . One hundred and twenty-one problem drinkers were recruited by media advertisements and were r and omly allocated to a full cognitive-behavioural treatment programme ( CBT ) or to a minimal intervention condition ( MI ) that gave information regarding alcohol misuse and instructions to record drinking++ . As predicted , CBT was more effective than MI in reducing alcohol consumption over the 4-month controlled trial period . CBT produced a 50 % fall in consumption , bringing the average intake of subjects within recommended maximum levels . Treatment gains at 6 months were well maintained to 12 months . High levels of consumer satisfaction , a high representation of women and a substantial participation from isolated rural areas attested to the feasibility of the correspondence programme as an alternative treatment . However , some drinking occasions still involved high intake for a significant subgroup of subjects , and this issue will be addressed in future programmes . The results supported the use of correspondence delivery as a means of promoting early engagement and equity of access between city and country areas Alcoholics from two hospital-based treatment centers participated in an experimental test of the effects of extended aftercare on inpatient recovery rates . At discharge from inpatient treatment , subjects were r and omly assigned either to an experimental group scheduled to be called by a center counselor every 2 weeks for 1 year or to a control group that experienced only the usual treatment . Follow-up interviews conducted approximately 12 months after hospital discharge found that the experimental group had no higher recovery rates than the control group . There was weak evidence that the calls reduced the burden that alcoholics place on community control and service agencies . There was no evidence that either the phone calls were more effective for some patients than for others or that some kinds of phone calls were more effective than others . Although most subjects said they liked the calls , wanted them to continue and perceived them as " good treatment , " only one subject gave the calls credit for helping him maintain sobriety BACKGROUND Alcohol use in older adults is common . It is associated with depression , hypertension , diabetes , drug interactions , accidents , and increased rates of emergency department visits and hospitalizations . METHODS A controlled clinical trial ( Project GOAL --Guiding Older Adult Lifestyles ) tested the efficacy of brief physician advice in reducing the alcohol use and use of health care services of older adult problem drinkers . Twenty-four community-based primary care practice s in Wisconsin ( 43 family physicians and internists ) participated in the trial . Of the 6073 patients screened , 105 men and 53 women met inclusion criteria and were r and omized into a control group ( n = 71 ) or an intervention group ( n = 87 ) . Intervention group patients received two 10- to 15-minute physician-delivered counseling sessions that included advice , education , and contracting using a scripted workbook . A total of 146 patients ( 92.4 % ) participated in the 12-month follow-up procedure . RESULTS No significant differences were found between the control and intervention groups at baseline in alcohol use , age , socioeconomic status , depression , onset of alcohol use , smoking status , activity level , or use of mood-altering drugs . The older adults who received the physician intervention demonstrated a significant reduction in 7-day alcohol use , episodes of binge drinking , and frequency of excessive drinking ( P < .005 ) compared with the control group at 3 , 6 , and 12 months after the intervention . There was a 34 % reduction in 7-day alcohol use , 74 % reduction in mean number of binge-drinking episodes , and 62 % reduction in the percentage of older adults drinking more than 21 drinks per week in the intervention group compared with the control group . There were no significant changes in health status . Patterns of health care utilization were not extensively analyzed because of the small number of events . CONCLUSIONS This study provides the first direct evidence that brief physician advice can decrease alcohol use by older adults in community-based primary care practice BACKGROUND Studies suggest that 14 % of women age 18 to 40 drink alcohol above recommended limits . Of special concern is the increasing use of alcohol by women during pregnancy . This article reports 48 month follow-up data from a sub analysis of a trial for early alcohol treatment ( Project TrEAT ) focused on women of childbearing age . METHODS Project TrEAT was conducted in the offices of 64 primary care , community-based physicians from 10 Wisconsin counties . Of 5979 female patients ages 18 to 40 who were screened for problem drinking , 205 were r and omized into an experimental group ( n = 103 ) or control group ( n = 102 ) . The intervention consisted of two 15 min , physician-delivered counseling visits that included advice , education , and contracting by using a scripted workbook . A total of 174 subjects ( 85 % ) completed the 48 month follow-up procedures . RESULTS No significant differences were found between the experimental and control groups at baseline for alcohol use , age , socioeconomic status , smoking , depression or anxiety , conduct disorder , lifetime drug use , or health care utilization . The trial found a significant treatment effect in reducing both 7 day alcohol use ( p = 0.0039 ) and binge drinking episodes ( p = 0.0021 ) over the 48 month follow-up period . Women in the experimental group who became pregnant during the follow-up period had the most dramatic decreases in alcohol use . A logistic regression model based on a 20 % or greater reduction in drinking found an odds ratio of 1.93 ( confidence interval 1.07 - 3.46 ) in the sample exposed to physician intervention . Age , smoking , depression , conduct disorder , antisocial personality disorder , and illicit drug use did not reduce drinking significantly . No significant differences were found in health care utilization and health status between groups . CONCLUSIONS This trial provides the first direct evidence that brief intervention is associated with sustained reductions in alcohol consumption by women of childbearing age . The results have enormous implication s for the U.S. health care system The mortality experience of convicted drinking drivers ( second offenders ) ( N = 347 ) r and omly assigned to rehabilitation and control groups in two Ontario cities was examined . Over a follow-up period ranging between 8 and 13 years , 14 ( 11.0 % ) of the controls and 17 ( 7.7 % ) of the rehabilitation group died . Direct comparisons of the r and omly assigned control and treatment groups revealed a tendency for lower total mortality and significantly lower mortality from accidental and violent death in those assigned to rehabilitation . Additional comparisons involving a combined rehabilitation group ( N = 487 ) ( rehabilitation participants r and omly and not r and omly assigned ) confirmed these observations BACKGROUND Employee-assistance programs sponsored by companies or labor unions identify workers who abuse alcohol and refer them for care , often to inpatient rehabilitation programs . Yet the effectiveness of inpatient treatment , as compared with a variety of less intensive alternatives , has repeatedly been called into question . In this study , anchored in the work site , we compared the effectiveness of m and atory in-hospital treatment with that of required attendance at the meetings of a self-help group and a choice of treatment options . METHODS We r and omly assigned a series of 227 workers newly identified as abusing alcohol to one of three rehabilitation regimens : compulsory inpatient treatment , compulsory attendance at Alcoholics Anonymous ( AA ) meetings , and a choice of options . Inpatient backup was provided if needed . The groups were compared in terms of 12 job-performance variables and 12 measures of drinking and drug use during a two-year follow-up period . RESULTS All three groups improved , and no significant differences were found among the groups in job-related outcome variables . On seven measures of drinking and drug use , however , we found significant differences at several follow-up assessment s. The hospital group fared best and that assigned to AA the least well ; those allowed to choose a program had intermediate outcomes . Additional inpatient treatment was required significantly more often ( P less than 0.0001 ) by the AA group ( 63 percent ) and the choice group ( 38 percent ) than by subjects assigned to initial treatment in the hospital ( 23 percent ) . The differences among the groups were especially pronounced for workers who had used cocaine within six months before study entry . The estimated costs of inpatient treatment for the AA and choice groups averaged only 10 percent less than the costs for the hospital group because of their higher rates of additional treatment . CONCLUSIONS Even for employed problem drinkers who are not abusing drugs and who have no serious medical problems , an initial referral to AA alone or a choice of programs , although less costly than inpatient care , involves more risk than compulsory inpatient treatment and should be accompanied by close monitoring for signs of incipient relapse OBJECTIVE Alcoholism is the leading risk factor for injury . The authors hypothesized that providing brief alcohol interventions as a routine component of trauma care would significantly reduce alcohol consumption and would decrease the rate of trauma recidivism . METHODS This study was a r and omized , prospect i ve controlled trial in a level 1 trauma center . Patients were screened using a blood alcohol concentration , gamma glutamyl transpeptidase level , and short Michigan Alcoholism Screening Test ( SMAST ) . Those with positive results were r and omized to a brief intervention or control group . Reinjury was detected by a computerized search of emergency department and statewide hospital discharge records , and 6- and 12-month interviews were conducted to assess alcohol use . RESULTS A total of 2524 patients were screened ; 1153 screened positive ( 46 % ) . Three hundred sixty-six were r and omized to the intervention group , and 396 to controls . At 12 months , the intervention group decreased alcohol consumption by 21.8+/-3.7 drinks per week ; in the control group , the decrease was 6.7+/-5.8 ( p = 0.03 ) . The reduction was most apparent in patients with mild to moderate alcohol problems ( SMAST score 3 to 8) ; they had 21.6+/-4.2 fewer drinks per week , compared to an increase of 2.3+/-8.3 drinks per week in controls ( p < 0.01 ) . There was a 47 % reduction in injuries requiring either emergency department or trauma center admission ( hazard ratio 0.53 , 95 % confidence interval 0.26 to 1.07 , p = 0.07 ) and a 48 % reduction in injuries requiring hospital admission ( 3 years follow-up ) . CONCLUSION Alcohol interventions are associated with a reduction in alcohol intake and a reduced risk of trauma recidivism . Given the prevalence of alcohol problems in trauma centers , screening , intervention , and counseling for alcohol problems should be routine OBJECTIVE The study aim was to test whether a brief motivational intervention , with or without a booster session , would improve drinking-related outcomes more than st and ard Emergency Department ( ED ) treatment . METHOD The study population consisted of 539 ( 78 % male ) injured patients treated in the ED and discharged to the community following their treatment . Injured patients met inclusion criteria if they were assessed as hazardous or harmful drinkers by scoring eight or more on the AUDIT and /or having alcohol in their system at the time of their injury or ED visit . Patients were r and omly assigned to either st and ard care ( SC ) , brief intervention ( BI ) or brief intervention plus a booster session ( BIB ) . At 1-year follow-up , 447 patients ( 83 % of the sample ) were re-interviewed to measure alcohol-related negative consequences , injuries and drinking . RESULTS Patients receiving BIB , but not B1 patients , reduced alcohol-related negative consequences and alcohol-related injuries more than did those in the SC group . All three groups reduced their days of heavy drinking . Patients with histories of hazardous drinking responded to BIB , whether or not they had consumed alcohol prior to their injury . CONCLUSIONS Together , these results indicate that the effects of a booster session that is added to a brief intervention in the ED can be helpful to injured patients with a history of hazardous or harmful drinking , irrespective of whether they have consumed alcohol prior to their injury The ' Pressures to Change ' approach to working with the partners of drinkers is a structured procedure for promoting change in resistant drinkers . In this study 22 women and one man were r and omly allocated to two treatment conditions and one no-treatment waiting list control condition in an experimental evaluation of the procedure . Group 1 was treated individually and Group 2 was treated as a group . Almost two-thirds of the drinking partners of clients in treatment made a significant move towards change , compared with none of the drinkers in the waiting list control condition OBJECTIVE Project TrEAT ( Trial for Early Alcohol Treatment ) was design ed to test the efficacy of brief physician advice in reducing alcohol use and health care utilization in problem drinkers . DESIGN R and omized controlled clinical trial with 12-month follow-up . SETTING A total of 17 community-based primary care practice s ( 64 physicians ) located in 10 Wisconsin counties . PARTICIPANTS Of the 17695 patients screened for problem drinking , 482 men and 292 women met inclusion criteria and were r and omized into a control ( n=382 ) or an experimental ( n=392 ) group . A total of 723 subjects ( 93 % ) participated in the 12-month follow-up procedures . INTERVENTION The intervention consisted of two 10- to 15-minute counseling visits delivered by physicians using a scripted workbook that included advice , education , and contracting information . MAIN OUTCOME MEASURES Alcohol use measures , emergency department visits , and hospital days . RESULTS There were no significant differences between groups at baseline on alcohol use , age , socioeconomic status , smoking status , rates of depression or anxiety , frequency of conduct disorders , lifetime drug use , or health care utilization . At the time of the 12-month follow-up , there were significant reductions in 7-day alcohol use ( mean number of drinks in previous 7 days decreased from 19.1 at baseline to 11.5 at 12 months for the experimental group vs 18.9 at baseline to 15.5 at 12 months for controls ; t=4.33 ; P<.001 ) , episodes of binge drinking ( mean number of binge drinking episodes during previous 30 days decreased from 5.7 at baseline to 3.1 at 12 months for the experimental group vs 5.3 at baseline to 4.2 at 12 months for controls ; t=2.81 ; P<.001 ) , and frequency of excessive drinking ( percentage drinking excessively in previous 7 days decreased from 47.5 % at baseline to 17.8 % at 12 months for the experimental group vs 48.1 % at baseline to 32.5 % at 12 months for controls ; t=4.53 ; P<.001 ) . The chi2 test of independence revealed a significant relationship between group status and length of hospitalization over the study period for men ( P<.01 ) . CONCLUSIONS This study provides the first direct evidence that physician intervention with problem drinkers decreases alcohol use and health re source utilization in the US health care system Patients ( N = 114 ) consecutively entering a medical service with ulcer , cirrhosis or pancreatitis , currently drinking and not currently active in alcoholism treatment were r and omly assigned to motivational intervention ( MI ) or to a control group . Increased utilization of alcoholism programs and self-reported sobriety at 10 weeks were assessed . MI consisted of three separate discussion s of the relationship of the patient 's disease to continued drinking and the compassionate offer of treatment . Two persons skilled in treatment also met with each MI subject and discussed treatment possibilities for them , facilitating entrance if desired . Patients in both the MI and control group were treated for their medical condition by a medical team and alcoholism treatment was always recommended . Outcome was evaluated for the period from the 10th to the 16th week after return to the community by interview of patient and household contacts and by the keeping of appointments . There were no differences between the control and MI groups , with at least 38 % remaining sober for the 10-week interval ; the study size was sufficient to detect reliably a 30 % improvement . We conclude that additional motivational intervention to this level was not beneficial to the hospitalized alcoholic with disease . There was a statistically significant increase in sobriety among patients who either undertook alcoholism therapy , accepted all parts of the study or kept clinical appointments BACKGROUND This report describes the 48-month efficacy and benefit-cost analysis of Project TrEAT ( Trial for Early Alcohol Treatment ) , a r and omized controlled trial of brief physician advice for the treatment of problem drinking . METHODS Four hundred eighty-two men and 292 women , ages 18 - 65 , were r and omly assigned to a control ( n = 382 ) or intervention ( n = 392 ) group . The intervention consisted of two physician visits and two nurse follow-up phone calls . Intervention components included a review of normative drinking , patient-specific alcohol effects , a worksheet on drinking cues , drinking diary cards , and a drinking agreement in the form of a prescription . RESULTS Subjects in the treatment group exhibited significant reductions ( p < 0.01 ) in 7-day alcohol use , number of binge drinking episodes , and frequency of excessive drinking as compared with the control group . The effect occurred within 6 months of the intervention and was maintained over the 48-month follow-up period . The treatment sample also experienced fewer days of hospitalization ( p = 0.05 ) and fewer emergency department visits ( p = 0.08 ) . Seven deaths occurred in the control group and three in the treatment group . The benefit-cost analysis suggests a 43,000 dollars reduction in future health care costs for every 10,000 dollars invested in early intervention . The benefit-cost ratio increases when including the societal benefits of fewer motor vehicle events and crimes . CONCLUSIONS The long-term follow-up of Project TrEAT provides the first direct evidence that brief physician advice is associated with sustained reductions in alcohol use , health care utilization , motor vehicle events , and associated costs . The report suggests that a patient 's personal physician can successfully treat alcohol problems and endorses the implementation of alcohol screening and brief intervention in the US health care system OBJECTIVE The purpose of the research was to determine whether the effectiveness of a traditional DUI ( Driving Under the Influence ) group intervention program could be enhanced by the addition of two brief individual intervention sessions and a follow-up . The differential effectiveness of the individual intervention component was examined for four offender subgroups ( young minorities , problem drinkers , women and depressed offenders ) that had been previously identified as at high risk or vulnerable . METHOD Adjudicated first DUI offenders ( N = 4,074 ) , of whom 776 ( 19 % ) were female , were r and omly assigned to a st and ard first-offender program or an enhanced st and ard program that included two short individual sessions and a brief follow-up session . The setting was a m and ated first-offender program in 10 Mississippi locations . RESULTS Depressed offenders who were assigned to the enhanced program were 35 % less likely to recidivate than those assigned to the st and ard program . The effectiveness of the two programs did not differ significantly for offenders who self-reported low depression . No significant interaction effects were found between program type and age , minority status or gender . After depressed mood was controlled for , problem-drinker status was not related to program effectiveness ; however , problem drinkers had higher depression rates . CONCLUSIONS Results suggest that the combination of a st and ard first-offender program with brief individual counseling can be effective for DUI offenders who report depressed mood and who are at high risk for recidivism . A five-item screen for sad/depressed mood from a widely used DUI risk assessment instrument identified offenders who benefited from the enhanced intervention 151 problem drinkers ( 105 men and 46 women ) were recruited from the general medical and psychiatric services of a district general hospital and were allocated r and omly to a community-based day centre ( ACCEPT ) or st and ard hospital inpatient and outpatient services . 115 patients ( 79 % ) were followed up at 12 months . The group as a whole showed improvement in all outcome indices at the 3-month follow-up , and this was maintained at 6 and 12 months . Patients assigned to ACCEPT services cl aim ed to have reduced their alcohol intake ( 55 % ) more than their hospital counterparts ( 37 % ) , and this was confirmed by their informants . Patients referred from the psychiatric services reduced their alcohol intake more than those from general medical services . It is concluded that treatment at a community day centre is at least as cost effective as hospital treatment of alcohol abuse BACKGROUND Alcohol as a cause of death in middle-aged patients is well-known from clinical studies . A similarly important correlation in the general population of urban middle-aged men is highly underestimated . Health screening investigations have shown that mortality related to alcohol is five times more common in non participants than in participants . From the mid-70s , the Malmoe Screening and Intervention Study ( MSIS ) commenced screening investigations including a large number of residents of Malmoe . One goal was to find intervention programs for individuals in an early development of problem drinking , thereby preventing development of serious complications of endstage alcoholism . Herein , we report on the mortality of heavy drinkers ( drinking more than 40 g alcohol/day ) who were r and omized to an intervention or control procedure and whose median survival was 13 years postentry into the MSIS . METHODS Health-screened men , aged 45 - 49 years at the initial screening examination and displaying serum gamma-glutamyltransferase ( GT ) in the top decentile of the GT distribution , were included . A total of 978 out of 11,257 participants met this criteria . A r and omized intervention and control study was performed for four years and consisted of men ( n = 667 ) who were born between 1927 - 1937 and who had two consecutive high GT values within 3 weeks along with heavy alcohol consumption . Half the individuals were informed of the test results and invited for further assessment by a senior physician ( n = 365 ) . The principles for brief intervention ( DiClemente et al.,1991 ; Miller and Sanchez , 1993 ; National Institute of Alcohol Abuse and Alcoholism , 1999 ) were applied . The other half of the men ( n = 302 ) were left with the information that they had a high GT value and were followed up with laboratory checkups every 2nd year . Mortality was followed up until 1991 and information on deaths was obtained from hospital and police records , necropsy reports , and death certificates . RESULTS Long-term follow-up of mortality for 10 - 16 years ( median , 13 years ) showed that 124 of the 978 men had died ( 12.7 % ) . Autopsy was performed in 96.5 % of the cases . In 59 men ( 48 % ) , death was alcohol-related . In the intervention group ( n = 365 ) , 38 ( 10.4 % ) men were dead and in the control group ( n = 302 ) , 42 ( 13.9 % ) men had died . There was a statistically significant difference ( p = 0.026 ) , with advantage for treatment . Less alcohol-related deaths and deaths occurring later during follow-up were found in the intervention group compared with the control group . The difference between the groups in total mortality , coronary heart disease , and cancer death was not statistically significant . CONCLUSIONS These findings support previous results from the MSIS study indicating that long-term intervention in urban males with alcohol-induced GT increases may be beneficial in terms of survival The objective of the study was to determine the effectiveness of advice from general practitioners to heavy drinking men ( consuming 350 - 1050 grams of alcohol per week ) to reduce their alcohol consumption . One hundred and fifty-four men recruited from eight general practice s were allocated r and omly to treatment and control groups . Men in the treatment group received advice from their own general practitioner . At one year follow-up , when analyzed according to intention to treat , the treatment group had reduced their consumption by an excess of 65 grams of alcohol per week when compared with the control group ( p less than 0.05 ) . General practitioners should be recommended to screen for alcohol consumption amongst their patients and to give advice to those found to be at risk because of their drinking The importance of previous suicidal behavior for the treatment of alcoholics was analyzed in a long-term outpatient treatment study . In a series of 72 patients , 21 patients , ( 29 % ) , 17 men and 4 women , had previously made at least one suicide attempt or had seriously threatened to kill themselves ( 3 cases ) . In comparison with the other alcoholics , those with previous suicidal behavior had a similar attrition rate , they were not more troublesome in treatment , and they had the same rate of favorable outcome during the third year after start of treatment . They differed from the other alcoholics in having a more severe abuse and a less favorable outcome during the initial part of the treatment . In conclusion , our results support the possibility of a long-term outpatient treatment strategy in alcoholics with previous suicide attempts This study evaluated the use of a brief motivational interview ( MI ) to reduce alcohol-related consequences and use among adolescents treated in an emergency room ( ER ) following an alcohol-related event . Patients aged 18 to 19 years ( N = 94 ) were r and omly assigned to receive either MI or st and ard care ( SC ) . Assessment and intervention were conducted in the ER during or after the patient 's treatment . Follow-up assessment s showed that patients who received the MI had a significantly lower incidence of drinking and driving , traffic violations , alcohol-related injuries , and alcohol-related problems than patients who received SC . Both conditions showed reduced alcohol consumption . The harm-reduction focus of the MI was evident in that MI reduced negative outcomes related to drinking , beyond what was produced by the precipitating event plus SC alone To date , the published controlled trials on exposure to alcohol cues have had an abstinence treatment goal . A modification of cue exposure ( CE ) for moderation drinking , which incorporated priming doses of alcohol , could train participants to stop drinking after 2 to 3 drinks . This study examined the effects of modified CE within sessions , combined with directed homework practice . Nondependent problem drinkers who requested a moderation drinking goal were r and omly allocated to modified CE or st and ard cognitive-behavior therapy ( CBT ) for alcohol abuse . Both interventions were delivered in 6 90-min group sessions . Eighty-one percent of eligible participants completed treatment and follow-up assessment . Over 6 months , CE produced significantly greater reductions than CBT in participants ' reports of drinking frequency and consumption on each occasion . No pretreatment variables significantly predicted outcome . The modified CE procedure appears viable for nondependent drinkers who want to adopt a moderate drinking goal

Conclusion No universally accepted criteria for diagnosing paediatric flat foot was found within existing literature , and psychometric data for foot posture measures and definitions used was limited .

Background Flexible flat foot is a normal observation in typically developing children , however , some children with flat feet present with pain and impaired lower limb function . The challenge for health professionals is to identify when foot posture is outside of expected findings and may warrant intervention . Diagnoses of flexible flat foot is often based on radiographic or clinical measures , yet the validity and reliability of these measures for a paediatric population is not clearly understood . The aim of this systematic review was to investigate how paediatric foot posture is defined and measured within the literature , and if the psychometric properties of these measures support any given diagnoses .

INTRODUCTION The limitations of clinical methods for appraising foot posture are well documented . A new measure , the Foot Posture Index is proposed , and its development and validation described . METHODS A four-phase development process was used : ( i ) to derive a series of c and i date measures , ( ii ) to define an appropriate scoring system , ( iii ) to evaluate the validity of components and modify the instrument as appropriate , and ( iv ) to investigate the predictive validity of the finalised instrument relative to static and dynamic kinematic models . Methods included initial concurrent validation using Rose 's Valgus Index , determination of inter-item reliability , factor analysis , and benchmarking against three dimensional kinematic models derived from electromagnetic motion tracking of the lower limb . RESULTS Thirty-six c and i date components were reduced to six in the final instrument . The draft version of the instrument predicted 59 % of the variance in concurrent Valgus Index scores and demonstrated good inter item reliability ( Cronbach 's alpha = 0.83 ) . The relevant variables from the motion tracking lower limb model predicted 58 - 80 % of the variance in the six components retained in the final instrument . The finalised instrument predicted 64 % of the variance in static st and ing posture , and 41 % of the variance in midstance posture during normal walking . CONCLUSION The Foot Posture Index has been subjected to thorough evaluation in the course of its development and a final version is proposed comprising six component measures that performed satisfactorily during the validation process . The Foot Posture Index assessment is quick and simple to perform and allows a multiple segment , multiple plane evaluation that offers some advantages over existing clinical measures of foot posture Previous methods of measuring footprints for the purpose of classifying foot type are review ed . A planimetric method is presented for characterizing footprints using the ratio of the area of the middle third of the footprint to the entire footprint area ( excluding the toes ) . This ' arch index ' during 50 % body weight st and ing provides an objective measure for comparative purpose s with a measured reliability , within day and between day , of 0.96 and 0.94 respectively . Values measured from footprints taken during other activities show variable responses in different subjects . Examples of the arch index taken from static footprints of various feet are presented and data are reported from 107 r and omly selected subjects during half body weight stance . Criteria are suggested for the classification of footprints as high , normal , and flat arch Objective : Although boys are frequently reported to have flatter feet than girls , there has been little systematic research to confirm or explain this structural difference between the genders . The objective of this study was to determine whether flat-footedness was moderated by gender in Australian preschool children and , if so , to determine the cause of this between-gender difference in structure of the plantar surface of the foot . Methods : Foot anthropometry , Arch Index derived from plantar footprints , and midfoot plantar fat pad thickness measured by ultrasound were obtained for the left and right feet of 52 girls and 36 boys ( mean age , 4.2 ± 0.6 years ) . The children were recruited from 10 r and omly selected preschools from the Illawarra region of New South Wales , Australia . Results : In agreement with previous research , the preschool boys displayed significantly flatter feet than the girls ( P ≤ 0.04 ) . Although there were no between-gender differences in structural foot dimensions , the boys had a significantly thicker midfoot fat pad than the girls by approximately 0.4 and 0.5 mm on both the right and left feet , respectively . Conclusions : The increased incidence of flat-footedness in boys compared with girls of the same age seems to be caused by a thicker plantar fat pad in the medial midfoot in boys . This suggests that the development of the medial longitudinal arch may be progressing at a slower rate in boys than in girls , and that intervention for a flexible flat foot , particularly for young boys , may be unnecessary Developmental Coordination Disorder ( DCD ) is a neurodevelopmental disorder characterised by impaired motor co-ordination and awkward gait . Despite self-reported findings of pes planus and joint hypermobility in children with DCD , there is little objective evidence regarding the clinical management of the foot in children with DCD . The aims of this research were to report clinical findings of foot posture and lower limb hypermobility in children with DCD and to evaluate the impact of foot orthoses on spatio-temporal gait parameters . Children with DCD were recruited into the study . Participants were r and omly assigned to an intervention group who received foot orthoses at the start of their rehabilitation programme or to a second group who received foot orthoses at the end of their intervention programme . Foot posture was assessed with the Foot Posture Index and lower limb hypermobility assessed with the Lower Limb Assessment Score . The effect of foot orthoses was evaluated through assessment of spatio-temporal gait characteristics at baseline and post-rehabilitation programme . Fourteen children were recruited ( mdn age 7.5 years ) with nine children assigned to the group receiving orthoses early ( mdn age 8 years ) and five children assigned to the post-rehabilitation orthoses group ( mdn age 6.5 years ) . A pes planus foot posture ( FPI score=8 ) and lower limb hypermobility ( LLAS score=11 ) were observed . Changes in spatio-temporal gait parameters failed to reach significance ( p>.012 ) following orthotic invention but demonstrated a trend towards a decreased cadence and increased double support duration . Despite non-significant findings this work offers preliminary support for podiatric intervention in the rehabilitation of children with DCD . Further work is required to underst and the biomechanics of gait in children with DCD and appreciate the role of podiatry as a component of multidisciplinary care BACKGROUND Flatfoot , or pes planus , is one of the most common foot posture problems in children that may lead to lower-extremity pain owing to a potential increase in plantar pressure . First , we compared plantar pressure distribution between children with and without flatfoot . Second , we examined the reliability and accuracy of a simple metric for characterization of foot posture : the Clarke angle . Third , we proposed a mathematical model to predict plantar pressure magnitude under the medial arch using body mass and the Clarke angle . METHODS Sixty children with flatfoot and 33 aged-matched controls were recruited . Measurements included in-shoe plantar pressure distribution , ground reaction force , Clarke angle , and radiography assessment . The measured Clarke angle was compared with radiographic measurements , and its test-retest reliability was determined . A mathematical model was fitted to predict plantar pressure distribution under the medial arch using easy-to-measure variables ( body mass and the Clarke angle ) . RESULTS A high correlation was observed between the Clarke angle and radiography measurements ( r > 0.9 ; P < 10(-6 ) ) . Excellent between- and within-day test-retest reliability for Clarke angle measurement ( intraclass correlation coefficient , > 0.9 ) was observed . Results also suggest that pressure magnitude under the medial arch can be estimated using the Clarke angle and body mass ( R(2 ) = 0.95 ; error , < 0.04 N/cm(2 ) [ 2 % ] ) . CONCLUSIONS This study suggests that the Clarke angle is a practical , reliable , and sensitive metric for quantification of medial arch height in children and could be recommended for research and clinical applications . It can also be used to estimate plantar pressure under the medial arch , which , in turn , may assist in the timely intervention and prognosis of prospect i ve problems associated with flatfoot posture Both feet of two hundred and seventy two children aged between five years six months and ten years and eleven months were studied using a footprint technique called the arch index ( Al ) , and the vertical height of the navicular ( NH ) as non invasive techniques of objective measures of the medial longitudinal arch ( MLA ) . In addition to age the study investigated the influence of gender , limb dominance , and body weight . The study found the existence of a relationship between the two measures of the MLA . There was no significant difference in NH measures between males and females and body weight did not affect the NH . The NH changed with age , suggesting it provides a useful , easily obtained clinical measure . The Al measures were slightly more reliable than the NH but showed less change with age Flat feet in children are common , and at times symptomatic , but the relationship between function and symptoms or impairment is still unclear . We undertook a prospect i ve , observational study comparing children with paediatric flexible flat foot ( PFF ) and children with neutral feet ( NF ) using three dimensional gait analysis ( 3DGA ) . It was hypothesised that children with PFF would demonstrate differences in both spatio-temporal parameters of gait and foot and ankle kinematics compared to the NF group and that these differences would correlate with impaired quality of life ( QoL ) . The kinematic differences were expected to be most marked in hindfoot coronal plane motion and forefoot sagittal and transverse plane motion . Eighty-three children between the ages of 8 and 15 were recruited in this study : Forty-two were classified as having PFF and forty-one as NF . Each child underwent 3DGA and completed the Oxford Ankle Foot Question naire for Children ( OxAFQ_C ) . Reduced OxAFQ_C physical domain scores in the PFF children were associated with slower walking speed ( p=0.014 ) and reduced normalised stride length ( p=0.008 ) . PFF children also demonstrated significantly increased hindfoot eversion and forefoot supination during gait . Significant differences between groups were not observed for other foot and ankle joint motions . Increased maximum hindfoot eversion and increased forefoot supination correlated strongly with lower QoL scores in PFF children . These data further our underst and ing of the functional characteristics that lead to impaired QoL in PFF children . These findings will help guide the surveillance and management of children with this ubiquitous condition Childhood obesity exerts abnormally high stresses on developing foot structures which can lead to structural deformity of the foot . Screening for foot problems in children with overweight helps detect interior risks restricting normal lifestyle in these individuals . The purpose of this study was to investigate the effects of excess weight on the structure and function of the developing foot in students aged 7–14 years . A total of 667 participants were recruited for this cross‐sectional study via a multi‐level cluster sampling method ( r and omization was used within each cluster ) . All subjects ( 340 boys and 327 girls ) attended primary and secondary schools in Isfahan City , Iran . The children 's feet were evaluated using clinical assessment s and footprint‐based measures whilst fully weight bearing . Significant differences were observed in the frequency of flatfoot between normal weight , overweight and obese groups ( P < 0.001 ) ; participants who were more overweight had flatter feet . Children with higher weight also had a more pronated heel , less dorsiflexion range and higher reported pain within physical activity . This study indicated that childhood obesity is associated with structural foot and ankle deformities and activity‐related foot pain In making treatment decisions , doctors and patients must take into account relevant r and omised controlled trials ( RCTs ) and systematic review s. Relevance depends on external validity ( or generalisability)--ie , whether the results can be reasonably applied to a definable group of patients in a particular clinical setting in routine practice . There is concern among clinicians that external validity is often poor , particularly for some pharmaceutical industry trials , a perception that has led to underuse of treatments that are effective . Yet research ers , funding agencies , ethics committees , the pharmaceutical industry , medical journals , and governmental regulators alike all neglect external validity , leaving clinicians to make judgments . However , reporting of the determinants of external validity in trial publications and systematic review s is usually inadequate . This review discusses those determinants , presents a checklist for clinicians , and makes recommendations for greater consideration of external validity in the design and reporting of RCTs BACKGROUND The purpose s of this study were 1 ) to determine the intrarater and interrater reliability of the arch height index measurement system device , 2 ) to establish population normative values for the arch height index in recreational runners , and 3 ) to compare arch height index values between the right and left feet and between genders . METHODS Eleven subjects were used to establish intrarater and interrater reliability of the arch height index measurement system . This system was then used to measure the arch height index of 100 recreational runners . RESULTS Measurements taken with the arch height index measurement system device exhibited high intrarater and interrater reliability . The mean + /- SD arch height index of the recreational runners was 0.340 + /- 0.030 . Men had larger feet than women , but the arch height index between genders was similar . CONCLUSIONS The arch height index measurement system device is reliable to use between testers while simplifying the measurement procedure for recording the arch height index . The arch height index may be helpful in identifying potential structural factors that predispose individuals to lower-extremity injuries OBJECTIVE . To analyse the association between overweight and obesity and foot structure in children older than 9 years of age , whose longitudinal medial arch ( MLA ) should be practically established . DESIGN , SETTING AND SUBJECT . A cross-sectional study of 245 children ( age : 13.22±1.8 years ) from four r and omly selected schools ( Zaragoza , Spain ) . Body mass index ( BMI ) was calculated and normal-weight , overweight and obese groups were defined . Footprints for both feet were collected . MEASUREMENTS . Foot angle ( FA ) and Chippaux-Smirak index ( CSI ) were calculated from the footprints . Height and body mass were measured to calculate the BMI . RESULTS . Mean values of FA and CSI in the normal-weight group indicated the presence of a normal MLA ; however , in the overweight they indicated an intermediary MLA and in the obese group , a low MLA . Comparison among the groups showed a decrease of FA ( p<0.01 ) and an increase of CSI ( p<0.01 ) with increasing weight associated with a lower MLA . A low but significant correlation ( p<0.0001 ) was found between the z-score BMI and footprint parameters . CONCLUSIONS . In children aged 9 to 16.5 years , the increase of body mass is related to a lower MLA . The MLA is lower in these obese children than in the younger ones studied in previous works probably due to the continuous bearing of excessive mass from childhood . A lower MLA could cause health problems . An assessment of foot structure in these children is recommended as the classification of the foot arch type can help decide if treatment to avoid these problems is necessary

Expert opinion : So far , transcutaneous oxygen measurements are most often used to measure tissue oxygenation in PAD patients , but evidence seems too low to define this technique as a gold st and ard , and implementing this technique for home monitoring is difficult .

Introduction : Peripheral arterial disease ( PAD ) may cause symptoms due to impaired tissue perfusion of the lower extremity . So far , assessment of PAD is mainly performed by determination of stenosis or occlusion in the large arteries and does not focus on microcirculation . Several diagnostic techniques have been recently introduced that may enable tissue perfusion measurements in the lower limb ; however , most have not yet been implemented in clinical daily practice . This systematic review provides an overview of these diagnostic techniques and their ability to accurately detect PAD by peripheral tissue perfusion .

BACKGROUND The most severe diabetic foot ulcers are those related with critical ischemia , which is primarily diagnosed with non-invasive diagnostics . However , these diagnostics have several disadvantages . For example , they only provide global indications of the (macro)level of ischemia . A potential solution can be found in novel optical imaging techniques for local assessment of the microcirculation in diabetic foot ulcers . This review provides an overview of these imaging techniques ( Laser Doppler Perfusion Imaging , Laser Speckle Contrast Imaging , Photoacoustic Imaging and Hyperspectral Imaging ) and their applicability for the diagnostic assessment of microcirculation in diabetic foot ulcers . METHOD For each technique , the following parts are described : a ) their technical background ; b ) general clinical applications ; and , c ) its application for microcirculation assessment in diabetic foot ulcers . Parts a-b are based on a narrative review of the literature , part c on a systematic review that was performed in the data base Scopus , covering the period from January 1 , 2000 to November 31 , 2017 . RESULTS Each of these techniques has specific advantages and disadvantages for imaging microcirculation . Potential clinical use depends on measurement aims , and clinical relevance . However , none of the techniques has a strongly established clinical relevance yet : we found a limited number of publications describing clinical outcomes . Future research is needed to determine which technique is the most clinical ly relevant for the assessment of microcirculation in diabetic foot ulcers . CONCLUSION Although promising , the currently available novel optical techniques need to be further improved technically and prospect i ve trials are necessary to evaluate their clinical value AIMS Diagnosis of vascular involvement in diabetic foot ulceration ( DFU ) remains challenging . We conducted a proof of concept study to investigate the feasibility of microwave radiometry ( MWR ) thermometry for non-invasive differential diagnosis of critical limb ischemia ( CLI ) in subjects with DFU . METHODS This prospect i ve , multi-center , study included 80 participants , divided into four groups ( group N : normal control subjects ; group DN : participants with diabetes and verified neuropathic ulcers without vascular involvement ; group DC : participants with diabetes and CLI and group NDC : participants with CLI without diabetes ) . Vascular disease was confirmed with angiography . All patients underwent MWR ( RTM-01-RES : University of Bolton , UK ) to record mean tissue temperatures at various pre-determined foot sites . Comparisons of temperature measurements between study groups were performed using one-way ANOVA and Dunn tests . ROC analysis was performed to determine sensitivity , specificity and cut-off value of MWR for CLI diagnosis . RESULTS Temperatures recorded in vicinity to the foot ulcers of participants with diabetes and CLI were similar to those with CLI without diabetes , but significantly lower than in subjects with neuropathic ulcers without vascular involvement and normal controls ( group DC:29.30 ° C±1.89 vs. group NDC:29.18 ° C±1.78vs . group N:33.01 ° C±0.45 vs. group DN:33.39 ° C±1.37;P<.0001 ) . According to ROC analysis , cut-off temperature value to diagnose CLI was < 31.8 ° C ( area under the curve : 0.984 ; 95 % CI : 0.965 - 1.005;P<.001 ) , with a sensitivity of 100.0 % ( 95%CI : 90.26 - 100.0 ) and specificity of 88.37 % ( 95 % CI : 74.92 - 96.11 ) . CONCLUSIONS Tissue temperatures in vicinity to ulcers were significantly lower in participants with CLI , with or without diabetes , compared to non-ischemic controls . MWR could be used for differential diagnosis of arterial ischemia in subjects with DFU OBJECTIVE Foot ulceration remains a major health problem for diabetic patients and has a major impact on the cost of diabetes treatment . We tested a hyperspectral imaging technology that quantifies cutaneous tissue hemoglobin oxygenation and generated anatomically relevant tissue oxygenation maps to assess the healing potential of diabetic foot ulcers ( DFUs ) . RESEARCH DESIGN AND METHODS A prospect i ve single-arm blinded study was completed in which 66 patients with type 1 and type 2 diabetes were enrolled and followed over a 24-week period . Clinical , medical , and diabetes histories were collected . Transcutaneous oxygen tension was measured at the ankles . Superficial tissue oxyhemoglobin ( oxy ) and deoxyhemoglobin ( deoxy ) were measured with hyperspectral imaging from intact tissue bordering the ulcer . A healing index derived from oxy and deoxy values was used to assess the potential for healing . RESULTS Fifty-four patients with 73 ulcers completed the study ; at 24 weeks , 54 ulcers healed while 19 ulcers did not heal . When using the healing index to predict healing , the sensitivity was 80 % ( 43 of 54 ) , the specificity was 74 % ( 14 of 19 ) , and the positive predictive value was 90 % ( 43 of 48 ) . The sensitivity , specificity , and positive predictive values increased to 86 , 88 , and 96 % , respectively , when removing three false-positive osteomyelitis cases and four false-negative cases due to measurements on a callus . The results indicate that cutaneous tissue oxygenation correlates with wound healing in diabetic patients . CONCLUSIONS Hyperspectral imaging of tissue oxy and deoxy may predict the healing of DFUs with high sensitivity and specificity based on information obtained from a single visit BACKGROUND Hyperspectral imaging technology is a novel method of using transcutaneous measurement of oxyhemoglobin ( HT-Oxy ) and deoxyhemoglobin ( HT-Deoxy ) concentrations to create a two-dimensional , color-coded " oxygen map . " The aims of this study were to compare the use of a hyperspectral imaging device with the transcutaneous oxygen measurement ( TCOM ) , ankle-brachial index ( ABI ) , and severity of peripheral vascular disease ( PVD ) and to assess their correlations . METHODS This prospect i ve study recruited 294 participants divided into three distinct groups composed of healthy volunteers and patients with PVD . Patients underwent measurements of lower limbs at a st and ardized point over the head of the first metatarsal on the plantar aspect using the hyperspectral imaging device , generating four outputs including HT-Oxy , HT-Deoxy , oxygen saturation ( HT-Sat ) , and skin temperature , and the TCOM system , generating transcutaneous partial pressure of oxygen ( TcpO2 ) and carbon dioxide ( TcpCO2 ) . Demographic data , severity of PVD , ABI , and other pertinent information were obtained from both the participants and medical records . RESULTS Interoperator reliability ranged from 86 % to 94 % across the four hyperspectral imaging device outputs , whereas intraoperator reliability ranged from 92 % to 94 % . The HT-Oxy , HT-Sat , TcpCO2 , and ABI of the diseased limb correlated significantly with the severity of PVD . HT-Sat significantly correlated with TcpO2 ( R = 0.19 ) , TcpCO2 ( R = -0.26 ) , ABI ( R = 0.42 ) , and skin temperature ( R = 0.56 ) . HT-Deoxy also correlated with TcpCO2 ( R = 0.27 ) . CONCLUSIONS This study demonstrates the reliability of hyperspectral imaging in comparison to TCOM , ABI , skin temperature , and severity of PVD in a series of patients . Its correlation to other established modalities and low interoperator and intraoperator variability could enable this modality to be a useful screening tool in PVD Background The early diagnosis of atherosclerotic disease is essential for developing preventive strategies in population s at high risk and acting when the disease is still asymptomatic . A low ankle-arm index is a good marker of vascular events and may be diminished without presenting symptomatology ( silent peripheral arterial disease ) . The aim of the study is to know the prevalence and associated risk factors of peripheral arterial disease in the general population . Methods We performed a cross-sectional , multicentre , population -based study in 3786 individuals > 49 years , r and omly selected in 28 primary care centres in Barcelona ( Spain ) . Peripheral arterial disease was evaluated using the ankle-arm index . Values < 0.9 were considered as peripheral arterial disease . Results The prevalence ( 95 % confidence interval ) of peripheral arterial disease was 7.6 % ( 6.7 - 8.4 ) , ( males 10.2 % ( 9.2 - 11.2 ) , females 5.3 % ( 4.6 - 6.0 ) ; p < 0.001).Multivariate analysis showed the following risk factors : male sex [ odds ratio ( OR ) 1.62 ; 95 % confidence interval 1.01 - 2.59 ] ; age OR 2.00 per 10 years ( 1.64 - 2.44 ) ; inability to perform physical activity [ OR 1.77 ( 1.17 - 2.68 ) for mild limitation to OR 7.08 ( 2.61 - 19.16 ) for breathless performing any activity ] ; smoking [ OR 2.19 ( 1.34 - 3.58 ) for former smokers and OR 3.83 ( 2.23 - 6.58 ) for current smokers ] ; hypertension OR 1.85 ( 1.29 - 2.65 ) ; diabetes OR 2.01 ( 1.42 - 2.83 ) ; previous cardiovascular disease OR 2.19 ( 1.52 - 3.15 ) ; hypercholesterolemia OR 1.55 ( 1.11 - 2.18 ) ; hypertriglyceridemia OR 1.55 ( 1.10 - 2.19 ) . Body mass index ≥25 Kg/m2 OR 0.57 ( 0.38 - 0.87 ) and walking > 7 hours/week OR 0.67 ( 0.49 - 0.94 ) were found as protector factors . Conclusions The prevalence of peripheral arterial disease is low , higher in males and increases with age in both sexes . In addition to previously described risk factors we found a protector effect in physical exercise and overweight OBJECTIVE To vali date micro-lightguide spectrophotometry ( O2C ) in patients with lower limb ischemia and to compare results with those obtained from toe blood pressure . METHODS We prospect ively examined 59 patients , 24 of whom complained of claudication , 31 had critical ischemia , and four were asymptomatic . Diabetes was present in 19 ( 32 % ) patients . Saturation ( SO(2 ) ) and flow measured with O2C were determined with the limb in the horizontal position followed by a 55-cm elevation . Toe pressures were determined in the horizontal position only . In addition , 13 patients were examined before and , on average , 3 days after revascularization . RESULTS Median SO(2 ) was 62 % ( 25%-75 % percentile : 37%-75 % ) with the limb in the horizontal position and 16 % ( 3%-41 % ) with the limb elevated . Comparing the individual toe pressures with SO(2 ) values measured in the horizontal position and elevated position revealed a significant correlation ( r(s ) = 0.40 ; P < .01 and r(s ) = 0.56 ; P < .01 , respectively ) . A low SO(2 ) ( ie , < 40 % in the horizontal position and < 20 % in the elevated position ) was highly predictive of a toe pressure of 40 mm Hg or less . In the horizontal position , the positive predictive value was 100 % , whereas the negative predictive value was 47 % . The similar figures in the elevated position were a positive predictive value of 97 % and a negative predictive value of 68 % . Postoperatively , SO(2 ) increased significantly from 27 % ( P25%-75 % : 11%-75 % ) to 79 % ( 68%-87 % ) in the horizontal position ( P = .008 ) and from 14 % ( P25%-75 % : 2%-39 % ) to 55 % ( 30%-73 % ) in the elevated position ( P = .011 ) , respectively . Looking at the individual 13 cases in which revascularization was performed , three patients had a partial reconstruction ( ie , superficial femoral artery occlusion distal to a central reconstruction or reconstruction to a popliteal blind segment ) . These patients had significantly lower postoperative SO(2 ) as well as toe pressure compared with the 10 patients with unobstructed flow to the foot . CONCLUSIONS O2C was easy to use , fast , and painless . The most useful finding was the high predictive value of a low saturation and the rise in O2C values after successful revascularization OBJECTIVE Vascular optical tomographic imaging ( VOTI ) is a novel imaging modality that is capable of detecting hemoglobin concentrations in tissue . VOTI is non-invasive , non-ionizing and does not require contrast injection . This technology was applied to the diagnosis of peripheral arterial disease ( PAD ) within lower extremities of diabetic patients with calcified arteries . This could be of substantial benefit as these patients suffer from comorbidities such as arterial incompressibility , which complicates diagnosis and monitoring . METHODS Forty individuals ( 10 non-diabetic patients with PAD , 10 diabetic patients with PAD , and 20 healthy volunteers ) were enrolled in a diagnostic pilot study using the VOTI system . The patients were imaged during at high pressure cuff occlusion . RESULTS The VOTI system was capable of quantifying the blood volume changes within the foot during the thigh cuff occlusion and outputting diagnostic parameters , such as change in hemoglobin concentration , enabling the assessment of foot perfusion . This study result ed in a statistically significant difference between the healthy cohort and both the non-diabetic and the diabetic PAD cohorts ( p = .006 , p = .006 ) . Receiver operating characteristic ( ROC ) curve analysis showed that PAD diagnosis could be made with over 80 % sensitivity or specificity depending on the characteristic cutoff point . In addition , VOTI was capable of providing the locations of under-perfused regions within the foot and evaluating the severity of arterial disease , even within diabetic patients with calcified arteries , who are traditionally difficult to diagnose . CONCLUSION VOTI can effectively diagnose PAD independently of arterial compressibility , making it very useful for assessing vascular disease in diabetic patients OBJECTIVE Adequate tissue oxygenation is known to be essential for the healing of diabetic foot ulcers , but hypoxia has also been shown to be a potent stimulus for growth . There are no studies looking specifically at ulcer oxygen levels during the healing process . We measured the serial microvascular oxygen saturation ( SaO2 ) of the foot ulcer , the ulcer margin , and a control site using the Erlangen micro lightguide spectrophotometer ( EMPHO II ; Bodenseewerk Geratetechnik , Erlangen , Germany ) to study serial changes during healing . RESEARCH AND DESIGN METHODS Studied over 9 months were 14 patients with neuropathy with a total of 24 foot ulcer sites . Of these patients , four ( seven ulcers ) had significant ischemia as determined by the ankle-brachial pressure index ( ABPI ) and transcutaneous oxygen tension . RESULTS Of 21 ulcer sites with serial measurements , only 13 ulcers healed . In those ulcers , a significant reduction ( P<0.05 ) in SaO2 occurred with healing . SaO2 dropped from 58 % at initial presentation ( mean area 2.6 cm2 ) to 47 % at midsize ( mean area 1.2 cm2 at 5.2 weeks ) and finally reduced to 45 % just before it healed . Similar trends were also seen around the margin of the ulcers ( initial 49 % , midsize 45 % , and final 41 % ; P = 0.1 ) . However , there were no such changes on the control sites ( 43 , 40 , and 40 % ; P = 0.5 ) or within the eight ulcers that did not heal ( 46 , 42 , and 53 % ; P = 0.2 ) . CONCLUSIONS Serial microvascular oxygen measurements may be used to identify at an early stage those ulcers that are unlikely to heal and , therefore , need surgical intervention BACKGROUND Simplified contrast-enhanced ultrasound ( CEUS ) can be used to evaluate muscle perfusion in peripheral arterial disease ( PAD ) . Here , we report its diagnostic accuracy for detecting symptomatic PAD . Additionally , we hypothesize that the extent of collateral formation is reflected by CEUS . METHODS Ultrasound contrast agent was injected into an antecubital vein of 58 control subjects and 52 symptomatic PAD patients and its appearance in the calf muscle was evaluated . Interreader variability was tested using 118 raw data films . Arterial collateralization of PAD patients was assessed by angiographic imaging . RESULTS PAD patients showed a significantly longer median time to peak intensity ( TTP , 36.9s ) than control subjects ( 19.4s , p<0.001 ) with longer TTPs in advanced PAD stages . The area under the receiver operating characteristic curve was 0.942 and the mean TTP difference between two blinded readers was 0.28s . A TTP cut off at 30.5s was associated with 91 % positive predictive value . PAD patients with good collateralization showed a significantly shorter TTP ( 34.1s ) than patients with poor collateralization ( 44.0 s , p=0.008 ) but not a higher ankle-brachial index ( ABI ) . CONCLUSIONS CEUS accurately displays perfusion deficits of the calf muscle in symptomatic PAD patients . The degree of arterial collateralization is reflected by CEUS and not by ABI Objectives Laser speckle flowgraphy is a new method that enables the rapid evaluation of foot blood flow without contact with the skin . We used laser speckle flowgraphy to evaluate foot blood flow in peripheral arterial disease patients before and after surgical revascularization . Material s and methods A prospect i ve single-center study . Thirty-one patients with 33 limbs that underwent surgical revascularization for peripheral arterial disease were included . Pre- and postoperative foot blood flows were measured on the plantar surface via laser speckle flowgraphy and skin perfusion pressure . The laser speckle flowgraphy device was used to visualize the blood flow distribution of the target skin and processed the pulse wave velocity of synchronized heart beats . The mean blood flow , which was expressed as the area of the pulse wave as the beat strength of skin perfusion on laser speckle flowgraphy converted into a numerical value , was assessed as dynamic changes following surgery . Beat strength of skin perfusion was also investigated in non-peripheral arterial disease controls ( 23 patients /46 limbs ) . Results The suitability of beat strength of skin perfusion in non-peripheral arterial disease controls was achieved ; the beat strength of skin perfusion value was significantly higher in every area of interest in non-peripheral arterial disease controls compared to that in peripheral arterial disease limbs at the preoperative stage ( 105.8 ± 8.2 vs. 26.3 ± 8.2 ; P < 0.01 ) . Although the pulse wave before surgery was visually flat in peripheral arterial disease patients , the pulse wave was remarkably and immediately improved through surgical revascularization . Beat strength of skin perfusion showed a dynamic change in foot blood flow ( 26.3 ± 8.2 at preoperation , 98.5 ± 6.7 immediately after surgery , 107.6 ± 5.7 at seven days after surgery , P < 0.01 for each compared to preoperation ) that correlated with an improvement in skin perfusion pressure . Conclusions Laser speckle flowgraphy is a noninvasive , contact-free modality that is easy to implement , and beat strength of skin perfusion is a useful indicator of foot circulation during the perioperative period . Further analysis with a larger number of cases is necessary to establish appropriate clinical use

Although summarized evidence showed that metformin did not affect left ventricular function , this antidiabetic drug could improve myocardial oxygen consumption concomitant to reducing prominent markers of heart failure such as n-terminal pro-brain natriuretic peptide and low-density lipoprotein levels , inconsistently between diabetic and nondiabetic patients . Effective modulation of some heart failure – related outcomes with metformin treatment was related to its beneficial effects in ameliorating insulin resistance and blocking pro-inflammatory markers such as the aging-associated cytokine CCL11 ( C-C motif chemokine lig and 11 ) .

Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes ( T2D ) ; however , information on its impact on heart failure – related outcomes remains inconclusive . The current systematic review explored evidence from r and omized clinical trials ( RCTs ) reporting on the impact of metformin in modulating heart failure – related markers in patients with or without T2D .

Objective Metformin has had a ' black box ' contraindication in diabetic patients with heart failure ( HF ) , but many believe it to be the treatment of choice in this setting . Therefore , we attempted to conduct a pilot study to evaluate the feasibility of undertaking a large r and omized controlled trial with clinical endpoints . Study Design The pilot study was a r and omized double blinded placebo controlled trial . Patients with HF and type 2 diabetes were screened in hospitals and HF clinics in Edmonton , Alberta , Canada ( population ~1 million ) . Major exclusion criteria included the current use of insulin or high dose metformin , decreased renal function , or a glycosylated hemoglobin < 7 % . Patients were to be r and omized to 1500 mg of metformin daily or matching placebo and followed for 6 months for a variety of functional outcomes , as well as clinical events . Results Fifty-eight patients were screened over a six month period and all were excluded . Because of futility with respect to enrollment , the pilot study was ab and oned . The mean age of screened patients was 77 ( SD 9 ) years and 57 % were male . The main reasons for exclusion were : use of insulin therapy ( n = 23 ; 40 % ) , glycosylated hemoglobin < 7 % ( n = 17 ; 29 % ) and current use of high dose metformin ( n = 12 ; 21 % ) . Overall , contraindicated metformin therapy was the most commonly prescribed oral antihyperglycemic agent ( n = 27 ; 51 % ) . On average , patients were receiving 1,706 mg ( SD 488 mg ) of metformin daily and 12 ( 44 % ) used only metformin . Conclusion Despite uncertainty in the scientific literature , there does not appear to be clinical uncertainty with regards to the safety or effectiveness of metformin in HF making a definitive r and omized trial virtually impossible . Trial registration Clinical Trials.gov Identifier : Objectives Pre clinical and clinical studies suggested cardioprotective effects of metformin treatment . In the GIPS-III trial , 4 months of metformin treatment did not improve left ventricular ejection fraction in patients presenting with ST-elevation myocardial infa rct ion ( STEMI ) . Here , we report the 2-year follow-up results . Methods Between January 2011 and May 2013 , 379 STEMI patients without diabetes undergoing primary percutaneous coronary intervention were r and omized to a 4-month treatment with metformin ( 500 mg twice daily ) ( N = 191 ) or placebo ( N = 188 ) in the University Medical Center Groningen . Two-year follow-up data was collected to determine its effect on predefined secondary endpoints : the incidence of major adverse cardiac events ( MACE ) , its individual components , all-cause mortality , and new-onset diabetes . Results For all 379 patients all-cause mortality data were available . For seven patients ( 2 % ) follow-up data on MACE was limited , ranging from 129 to 577 days . All others completed the 2-year follow-up visit . Incidence of MACE was 11 ( 5.8 % ) in metformin and 6 ( 3.2 % ) in placebo treated patients [ hazard ratio ( HR ) 1.84 , confidence interval ( CI ) 0.68–4.97 , P = 0.22 ] . Three patients died in the metformin group and one in the placebo treatment group . Individual components of MACE were also comparable between both groups . New-onset diabetes mellitus was 34 ( 17.8 % ) in metformin and 32 ( 17.0 % ) in placebo treated patients ( odds ratio 1.15 , CI 0.66–1.98 , P = 0.84 ) . After multivariable adjustment the incidence of MACE was comparable between the treatment groups ( HR 1.02 , CI 0.10–10.78 , P = 0.99 ) . Conclusions Four months metformin treatment initiated at the time of hospitalization in STEMI patients without diabetes did not exert beneficial long-term effects . Trial registration clinical trials.gov Identifier : NCT01217307 OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity Thiazolidinediones ( TZD ) have become a powerful tool for lowering insulin resistance . The problem of cardiovascular adverse events including fluid retention and risk of heart failure should be well known and recognised . We aim ed to evaluate the long-term effects of rosiglitazone on cardiac function and fluid dynamics . Forty-six type 2 diabetic patients were r and omised to treatment with rosiglitazone or metformin or to a control group . There are no significant differences between the groups in the duration of diabetes , HbA1c , plasma brain natriuretic peptide ( BNP ) levels , body mass index and myocardial performance indexes ( MPIs ) before the treatment . After three and six months all these parameters were repeated . Rosiglitazone increased plasma BNP levels and worsened MPIs 3 months after the start of treatment . Also left ventricular end-systolic volume increased and weight gain was observed . But these results were statistically non-significant ( all p>0.05 ) . When we continued rosiglitazone treatment to six months the increase in BNP levels became soft and statistically significant improvements were seen in MPIs ( p<0.01 ) . Also left ventricular end-systolic volume decreased significantly ( p=0.004 ) and weight gain was stopped . In patients with type 2 diabetes , TZD treatment might have slight adverse effects on ventricular contractility and fluid dynamics at the beginning of the therapy . However , these changes seem to stabilise in the long term BACKGROUND The efficacy of thiazolidinediones , as compared with other oral glucose-lowering medications , in maintaining long-term glycemic control in type 2 diabetes is not known . METHODS We evaluated rosiglitazone , metformin , and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind , r and omized , controlled clinical trial involving 4360 patients . The patients were treated for a median of 4.0 years . The primary outcome was the time to monotherapy failure , which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter ( 10.0 mmol per liter ) , for rosiglitazone , as compared with metformin or glyburide . Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin , insulin sensitivity , and beta-cell function . RESULTS Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15 % with rosiglitazone , 21 % with metformin , and 34 % with glyburide . This represents a risk reduction of 32 % for rosiglitazone , as compared with metformin , and 63 % , as compared with glyburide ( P<0.001 for both comparisons ) . The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin . Glyburide was associated with a lower risk of cardiovascular events ( including congestive heart failure ) than was rosiglitazone ( P<0.05 ) , and the risk associated with metformin was similar to that with rosiglitazone . Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide ( P<0.001 for all comparisons ) . CONCLUSIONS The potential risks and benefits , the profile of adverse events , and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00279045 [ Clinical Trials.gov ] . )

Although all of the studies were rated of good method ological quality , none of the biomarkers had both high sensitivity and specificity when compared to self-report . There was some evidence that a combination of biomarkers , or combining biomarkers with self-report , increases accuracy . In summary , the blood biomarkers examined were of limited use in screening for low and moderate alcohol consumption in pregnancy when compared to self-report . However , certain biomarkers , such and CDT and PEth may complement self-report and help improve the accuracy of diagnosis

Accurate and early identification of women at risk from alcohol consumption during pregnancy allows education and support programmes to be targeted at those most in need . We aim ed to conduct a systematic review to compare the efficacy of blood analysis and maternal self-report in detecting at risk women during pregnancy . This review investigated diagnostic accuracy .

OBJECTIVES : To determine the prevalence and characteristics of fetal alcohol spectrum disorders ( FASD ) among first grade students ( 6- to 7-year-olds ) in a representative Midwestern US community . METHODS : From a consented sample of 70.5 % of all first grade rs enrolled in public and private schools , an over sample of small children ( ≤25th percentile on height , weight , and head circumference ) and r and omly selected control c and i date s were examined for physical growth , development , dysmorphology , cognition , and behavior . The children ’s mothers were interviewed for maternal risk . RESULTS : Total dysmorphology scores differentiate significantly fetal alcohol syndrome ( FAS ) and partial FAS ( PFAS ) from one another and from unexposed controls . Alcohol-related neurodevelopmental disorder ( ARND ) is not as clearly differentiated from controls . Children who had FASD performed , on average , significantly worse on 7 cognitive and behavioral tests and measures . The most predictive maternal risk variables in this community are late recognition of pregnancy , quantity of alcoholic drinks consumed 3 months before pregnancy , and quantity of drinking reported for the index child ’s father . From the final multidisciplinary case findings , 3 techniques were used to estimate prevalence . FAS in this community likely ranges from 6 to 9 per 1000 children ( midpoint , 7.5 ) , PFAS from 11 to 17 per 1000 children ( midpoint , 14 ) , and the total rate of FASD is estimated at 24 to 48 per 1000 children , or 2.4 % to 4.8 % ( midpoint , 3.6 % ) . CONCLUSIONS : Children who have FASD are more prevalent among first grade rs in this Midwestern city than predicted by previous , popular estimates Objectives To determine the prevalence , patterns , and predictors of alcohol consumption prior to and during various intervals of pregnancy in the U.S. Methods Alcohol-related , pregnancy-related , and demographic data were derived from computer-assisted telephone interviews with 4,088 r and omly selected control mothers from the National Birth Defects Prevention Study who delivered live born infants without birth defects during 1997–2002 . Alcohol consumption rates and crude and adjusted odds ratios ( OR ) were calculated . Results 30.3 % of all women reported drinking alcohol at some time during pregnancy , of which 8.3 % reported binge drinking ( 4 + drinks on one occasion ) . Drinking rates declined considerably after the first month of pregnancy , during which 22.5 % of women reported drinking , although 2.7 % of women reported drinking during all trimesters of pregnancy and 7.9 % reported drinking during the 3rd trimester . Pre-pregnancy binge drinking was a strong predictor of both drinking during pregnancy ( adjusted OR = 8.52 , 95 % CI = 6.67–10.88 ) and binge drinking during pregnancy ( adjusted OR = 36.02 , 95 % CI = 24.63–52.69 ) . Other characteristics associated with both any drinking and binge drinking during pregnancy were non-Hispanic white race/ethnicity , cigarette smoking during pregnancy , and having an unintended pregnancy . Conclusions Our study revealed that drinking during pregnancy is fairly common , three times the levels reported in surveys that ask only about drinking during the month before the survey . Women who binge drink before pregnancy are at particular risk for drinking after becoming pregnant . Sexually active women of childbearing ages who drink alcohol should be advised to use reliable methods to prevent pregnancy , plan their pregnancies , and stop drinking before becoming pregnant BACKGROUND In Canada the incidence of Fetal Alcohol Spectrum Disorder ( FASD ) is estimated to be 1 in 100 live births . FASD is the leading cause of developmental and cognitive disabilities in Canada . Only one study has examined the cost of FASD in Canada . In that study we did not include prospect i ve data for infants under the age of one year , costs for adults beyond 21 years or costs for individuals living in institutions . OBJECTIVE To calculate a revised estimate of direct and indirect costs associated with FASD at the patient level . METHODS Cross-sectional study design was used . Two-hundred and fifty ( 250 ) participants completed the study tool . Participants included caregivers of children , youth and adults , with FASD , from day of birth to 53 years , living in urban and rural communities throughout Canada participated . Participants completed the Health Services Utilization Inventory ( HSUI ) . Key cost components were elicited : direct costs : medical , education , social services , out-of-pocket costs ; and indirect costs : productivity losses . Total average costs per individual with FASD were calculated by summing the costs for each in each cost component , and dividing by the sample size . Costs were extrapolated to one year . A stepwise multiple regression analysis was used to identify significant determinants of costs and to calculate the adjusted annual costs associated with FASD . RESULTS Total adjusted annual costs associated with FASD at the individual level was $ 21,642 ( 95 % CI , $ 19,842 ; $ 24,041 ) , compared to $ 14,342 ( 95 % CI , $ 12,986 ; $ 15,698 ) in the first study . Severity of the individual 's condition , age , and relationship of the individual to the caregiver ( biological , adoptive , foster ) were significant determinants of costs ( p < 0.001 ) . Cost of FASD annually to Canada of those from day of birth to 53 years old , was $ 5.3 billion ( 95 % CI , $ 4.12 billion ; $ 6.4 billion ) . CONCLUSIONS Study results demonstrated the cost burden of FASD in Canada was profound . Inclusion of infants aged 0 to 1 years , adults beyond the age of 21 years and costs associated with residing in institutions provided a more accurate estimate of the costs of FASD . Implication s for practice , policy , and research are discussed . Key words : Alcohol , pregnancy , cost , economic burden , fetal alcohol spectrum disorder OBJECTIVE We examined the use of alcohol during early pregnancy in urban Swedish women , the ability of Swedish antenatal care to identify alcohol-related risk pregnancies and the utility of some potential tools for improving its performance . METHOD Women attending regular antenatal care were r and omized to regular assessment only ( control , n = 156 ) or intensified screening ( intervention , n = 147 ) . In the intervention group , alcohol use was determined using the Timeline Followback ( TLFB ) interview , alcohol use habits with the Alcohol Use Disorder Inventory Test ( AUDIT ) , and biomarkers for alcohol use were analyzed . Data were typically obtained in pregnancy week 12 . RESULTS In the intervention group as a whole , average absolute alcohol consumption during the first 6 weeks of pregnancy was low but highly variable ( mean [ SD ] = 24.9 [ 50.5 ] g/week ; 4.8 [ 6.0 ] episodes for the entire 6 week period ) ; 22 women ( 15 % ) drank at levels exceeding 70 g/week during any 2 or more weeks and /or in a heavy episodic drinking pattern , 60 g/episode , on 2 or more episodes . The AUDIT had a moderate sensitivity ( 54 % ) to identify these subjects . Biomarkers identified subjects with somatic illness rather than high alcohol consumption . In the control group , only 4 ( 3 % ) were identified as using alcohol , indicating a probable underestimation of alcohol use by regular antenatal screening procedures ( p = .0001 ) . CONCLUSIONS An unexpected proportion of pregnant women in urban Sweden consume alcohol at levels likely to produce adverse effects . Regular antenatal care did not identify most of these risk pregnancies . The TLFB identified pregnant women with risk use of alcohol during pregnancy who were only partly identified by analyzing prepregnancy alcohol use patterns with the AUDIT . Elevated laboratory markers likely indicated somatic illness rather than harmful drinking BACKGROUND The prevalence and characteristics of fetal alcohol spectrum disorders ( FASD ) were determined in this fourth study of first- grade children in a South African community . METHODS Active case ascertainment methods were employed among 747 first- grade pupils . The detailed characteristics of children within the continuum of FASD are contrasted with r and omly selected , normal controls on ( i ) physical growth and dysmorphology ; ( ii ) cognitive/behavioral characteristics ; and ( iii ) maternal risk factors . RESULTS The rates of specific diagnoses within the FASD spectrum continue to be among the highest reported in any community in the world . The prevalence ( per 1,000 ) is as follows : fetal alcohol syndrome (FAS)-59.3 to 91.0 ; partial fetal alcohol syndrome (PFAS)-45.3 to 69.6 ; and alcohol-related neurodevelopmental disorder (ARND)-30.5 to 46.8 . The overall rate of FASD is therefore 135.1 to 207.5 per 1,000 ( or 13.6 to 20.9 % ) . Clinical profiles of the physical and cognitive/behavioral traits of children with a specific FASD diagnosis and controls are provided for underst and ing the full spectrum of FASD in a community . The spectral effect is evident in the characteristics of the diagnostic groups and summarized by the total ( mean ) dysmorphology scores of the children : FAS = 18.9 ; PFAS = 14.3 ; ARND = 12.2 ; and normal controls , alcohol exposed = 8.2 and unexposed = 7.1 . Documented drinking during pregnancy is significantly correlated with verbal ( r = -0.253 ) and nonverbal ability ( r = -0.265 ) , negative behaviors ( r = 0.203 ) , and total dysmorphology score ( r = 0.431 ) . Other measures of drinking during pregnancy are significantly associated with FASD , including binge drinking as low as 3 drinks per episode on 2 days of the week . CONCLUSIONS High rates of specific diagnoses within FASD were well documented in this new cohort of children . FASD persists in this community . The data reflect an increased ability to provide accurate and discriminating diagnoses throughout the continuum of FASD OBJECTIVE To study the activities of serum gamma-glutamyltransferase ( GGT ) , aspartate and alanine aminotransferases ( AST , ALT ) , and their ratio ( AST/ALT ) , mean erythrocyte cell volume ( MCV ) and urinary dolichol output in alcohol-abusing pregnant women , and compare the results to those of abstinent pregnant women . DESIGN Prospect i ve descriptive study . SETTING Special outpatient clinic for pregnant problem-drinkers in the department of Obstetrics and Gynaecology , Helsinki University Central Hospital , Finl and . SUBJECTS 25 pregnant women referred to the special clinic at between 12 and 24 weeks gestation , they consumed at least 150 g of ethanol weekly , and a control group of 20 abstinent pregnant women matched for age , parity and smoking habits . INTERVENTIONS The women were encouraged to visit the clinic at 2 - 4 week intervals . At each visit blood and urine sample s were obtained , and the women were interviewed on their alcohol consumption during the previous weeks and encouraged to abstain in the future . MEAN OUTCOME MEASURES Neonatal condition , fetal alcohol effects ( FAE ) in the newborn . Serum activities of GGT , AST and ALT , the AST/ALT ratio , the MCV , and the urinary concentration of dolichol in alcohol-abusing women with either healthy or FAE infants , compared with those of abstinent women with healthy infants . RESULTS Of the 25 alcohol-abusing women 13 gave birth to infants with FAE and 12 to healthy infants . All the women in the control group gave birth to healthy infants . GGT , AST and ALT activities were increased in all alcohol-abusing women , regardless whether the infant had FAE or not . GGT was the best of these markers , GGT activities above the 95th normal centile were found in 33 % of the sample s from all alcohol-abusing women . The AST/ALT ratio , MCV and urinary dolichol concentration were poor indicators of abusive drinking . CONCLUSIONS Maternal alcohol abuse is difficult to assess by laboratory tests . Of the commonly used and easily available tests , GGT proved to be the best in our study In order to investigate prospect ively in pregnant women a correlation between serum levels of a biological marker of alcohol and the clinical status of the newborn , we measured the gamma-glutamyltransferase ( GGT ) in 630 women between 14 and 20 weeks of pregnancy . In 7 % of the cases , an elevated value was observed while history confirmed alcohol consumption in only 1 % . Preliminary statistical analysis established upon the blind examination of 308 newborns show a correlation between maternal GGT levels and birthweight as well as the pre- and perinatal complications . However , the sensitivity of this test is weak BACKGROUND The prevalence and characteristics of fetal alcohol syndrome ( FAS ) and partial FAS ( PFAS ) in the United States ( US ) are not well known . METHODS This active case ascertainment study in a Rocky Mountain Region City assessed the prevalence and traits of children with FAS and PFAS and linked them to maternal risk factors . Diagnoses made by expert clinical dysmorphologists in multidisciplinary case conferences utilized all components of the study : dysmorphology and physical growth , neurobehavior , and maternal risk interviews . RESULTS Direct parental ( active ) consent was obtained for 1278 children . Averages for key physical diagnostic traits and several other minor anomalies were significantly different among FAS , PFAS , and r and omly-selected , normal controls . Cognitive tests and behavioral checklists discriminated the diagnostic groups from controls on 12 of 14 instruments . Mothers of children with FAS and PFAS were significantly lower in educational attainment , shorter , later in pregnancy recognition , and suffered more depression , and used marijuana and methamphetamine during their pregnancy . Most pre-pregnancy and pregnancy drinking measures were worse for mothers of FAS and PFAS . Excluding a significant difference in simply admitting drinking during the index pregnancy ( FAS and PFAS=75 % vs. 39.4 % for controls ) , most quantitative intergroup differences merely approached significance . This community 's prevalence of FAS is 2.9 - 7.5 per 1000 , PFAS is 7.9 - 17.7 per 1000 , and combined prevalence is 10.9 - 25.2 per 1000 or 1.1 - 2.5 % . CONCLUSIONS Comprehensive , active case ascertainment methods produced rates of FAS and PFAS higher than predicted by long-st and ing , popular estimates

Marik PE , And rews L , Maini B. The incidence of deep venous thrombosis in ICU patients . Cook D , Meade M , Guyatt G , et al. Dalteparin versus unfractionated heparin in critically ill patients .

Schonhofer B , Kohler D. Prevalence of deep-vein thrombosis of the leg in patients with acute exacerbation of chronic obstructive pulmonary disease . Respiration . Harris LM , Curl GR , Booth FV , Hassett JM , Jr , Leney G , Ricotta JJ . Screening for asymptomatic deep vein thrombosis in surgical intensive care patients . Cook D , McMullin J , Hodder R , et al. Prevention and diagnosis of venous thromboembolism in critically ill patients : a Canadian survey . Crit Care . Ibrahim EH , Iregui M , Prentice D , Sherman G , Kollef MH , Shannon W. Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis . Prevalence of deep venous thrombosis among patients in medical intensive care . Kurtoglu M , Yanar H , Bilsel Y , et al. Venous thromboembolism prophylaxis after head and spinal trauma : intermittent pneumatic compression devices versus low molecular weight heparin . Limpus A , Chaboyer W , McDonald E , Thalib L. Mechanical thromboprophylaxis in critically ill patients : a systematic review and meta- analysis .

The efficacy of low-dose heparin in preventing fatal postoperative pulmonary embolism has been investigated in a multicentre prospect i ve r and omised trial . 4121 patients over the age of forty years undergoing a variety of elective major surgical procedures were included in the trial ; 2076 of these were in the control group and 2045 patients received heparin . The two groups were well matched for age , sex , weight , blood-group , and other factors which could predispose to the development of venous thromboembolism . 180 ( 4 - 4 % ) patients died during the postoperative period , 100 in the control and 80 in the heparin group : 72 % of deaths in the control and 66 % in the heparin group had necropsy examination . 16 patients in the control group and 2 in the heparin group were found at necropsy to have died due to acute massive pulmonary embolism ( P smaller than 0 - 005 ) . In addition , emboli found at necropsy in 6 patients in the control group and 3 in the heparin group were considered either contributory to death or an incidental finding since death in these patients was attributed to other causes . Taking all pulmonary emboli together , the findings were again significant ( P smaller than 0 - 005 ) . Of 1292 patients in whom the 125-I-fibrinogen test was performed to detect deep-vein thrombosis ( D.V.T. ) 667 were in the control group and 625 in the heparin group . The frequency of isotopic D.V.T. was reduced from 24 - 6 % in the control group 7 - 7 % in the heparin group ( P smaller 0 - 005 ) . In 30 patients D.V.T. was detected at necropsy ; 24 in the control and 6 in the heparin group ( P smaller 0 - 005 ) . 32 patients in the control group and 11 in the heparin group developed clinical ly diagnosed D.V.T. which was confirmed by venography ( P smaller than 0 - 005 ) . In addition , 24 patients in the control and 8 in the heparin group were treated for clinical ly suspected pulmonary emoblism . The difference in the number of patients requiring treatment for D.V.T. and /or pulmonary embolism in the two groups was again significant ( P smaller than 0 - 005 ) . 9 patients were found at necropsy to have died from haemorrhage ; 5 were in the control and 4 in the heparin group . A careful objective analysis of operative and postoperative bleeding in 1475 patients showed no statistically significant difference in the blood-transfusion requirements or in the fall in the postoperative haemoglobin level either in the individual operative groups or in the group as a whole . However , the difference in the number of patients who developed wound haematoma in the heparin and control groups was significant ( P smaller 0 - 01 ) . The results of the trial indicate that this form of prophylaxis can now be recommended for use on a large scale in " high-risk " patients undergoing major surgery Venous thromboembolism is a serious complication following gynecologic surgery and is particularly common in patients with malignancy . A previous study of subcutaneous low-dose heparin given as one dose preoperatively and every 12 hours postoperatively failed to show a benefit in gynecologic oncology patients . In the present study , two more intense regimens of low-dose heparin were evaluated . Three hundred four patients were assigned r and omly to receive no prophylaxis ( controls ) , subcutaneous heparin 5000 units 2 hours before surgery and every 8 hours postoperatively ( low-dose heparin ) ( regimen I ) , or 5000 units heparin subcutaneously every 8 hours preoperatively ( between two and nine doses ) and every 8 hours postoperatively ( regimen II ) . All patients had thromboembolism surveillance with the fibrinogen uptake test and clinical evaluation . Eighty-four percent had a malignancy . Thromboemboli were diagnosed in 19 of 103 control patients , ten of 104 regimen I patients , and six of 97 regimen II patients , a statistically significant difference ( P < .008 ) . When compared with the control group , the study groups had no evidence of increased bleeding complications or alteration of laboratory coagulation indicators . ( Obstet Gynecol 75 : 684 , 1990 Summary Background Data : The epidemiology of venous thromboembolism ( VTE ) after cancer surgery is based on clinical trials on VTE prophylaxis that used venography to screen deep vein thrombosis ( DVT ) . However , the clinical relevance of asymptomatic venography-detected DVT is unclear , and the population of these clinical trials is not necessarily representative of the overall cancer surgery population . Objective : The aim of this study was to evaluate the incidence of clinical ly overt VTE in a wide spectrum of consecutive patients undergoing surgery for cancer and to identify risk factors for VTE . Methods : @RISTOS was a prospect i ve observational study in patients undergoing general , urologic , or gynecologic surgery . Patients were assessed for clinical ly overt VTE occurring up to 30 ± 5 days after surgery or more if the hospital stay was longer than 35 days . All outcome events were evaluated by an independent Adjudication Committee . Results : A total of 2373 patients were included in the study : 1238 ( 52 % ) undergoing general , 685 ( 29 % ) urologic , and 450 ( 19 % ) gynecologic surgery . In-hospital prophylaxis was given in 81.6 % and postdischarge prophylaxis in 30.7 % of the patients . Fifty patients ( 2.1 % ) were adjudicated as affected by clinical ly overt VTE ( DVT , 0.42 % ; nonfatal pulmonary embolism , 0.88 % ; death 0.80 % ) . The incidence of VTE was 2.83 % in general surgery , 2.0 % in gynecologic surgery , and 0.87 % in urologic surgery . Forty percent of the events occurred later than 21 days from surgery . The overall death rate was 1.72 % ; in 46.3 % of the cases , death was caused by VTE . In a multivariable analysis , 5 risk factors were identified : age above 60 years ( 2.63 , 95 % confidence interval , 1.21–5.71 ) , previous VTE ( 5.98 , 2.13–16.80 ) , advanced cancer ( 2.68 , 1.37–5.24 ) , anesthesia lasting more than 2 hours ( 4.50 , 1.06–19.04 ) , and bed rest longer than 3 days ( 4.37 , 2.45–7.78 ) . Conclusions : VTE remains a common complication of cancer surgery , with a remarkable proportion of events occurring late after surgery . In patients undergoing cancer surgery , VTE is the most common cause of death at 30 days after surgery A prospect i ve study of a series of 77 patients on adjuvant radiochemotherapy following surgery for high- grade gliomas was conducted to evaluate the risk of deep vein thrombosis and identify risk factors . We found a 20.8 % risk of deep vein thrombosis at 12 months ( st and ard error = 4.8 % ) and a 31.7 % risk ( st and ard error = 7.4 % ) at 24 months ( Kaplan-Meier method ) . Twenty patients ( 26 % ) developed deep vein thrombosis with a maximum incidence within the first 7 months after surgery when chemotherapy was still being administered , often with corticosteroids . The risk factors identified were histology ( glioblastoma versus anaplastic astrocytoma , P = 0.032 , log rank test ; 0.0485 L-ratio ) and the presence of paresis ( P = 0.010 , log rank test ; 0.0161 L-ratio ) . A borderline tendency was found for an association between the deep vein thrombosis site and the side of paresis ( P = 0.103 , Fisher 's exact test ) . Four patients ( 5 % ) had massive pulmonary embolism , which was fatal in 3 ( 4 % ) BACKGROUND Hemato-oncology patients treated with intensive chemotherapy usually require the placement of a central venous catheter ( CVC ) . CVCs are frequently complicated by catheter-related central venous thrombosis ( CVT ) , which has been associated with an increased risk of pulmonary embolism and catheter-related infection . OBJECTIVES To determine the efficacy and safety of thromboprophylaxis with s.c . low-molecular-weight heparin ( nadroparin ) administered once daily in a r and omized placebo-controlled , double-blind trial in patients with hematologic malignancies . PATIENTS AND METHODS Consecutive patients with hematologic malignancies requiring intensive chemotherapy including autologous stem cell transplantation were eligible . The patients were r and omized to receive nadroparin 2850 antifactor Xa units once daily or placebo s.c . for 3 weeks . Venography was performed on day 21 after CVC insertion . Secondary outcomes were bleeding and catheter-related infection . RESULTS In total , 113 patients were r and omized to nadroparin or placebo , and 87 patients ( 77 % ) underwent venography . In total , 11 venographically proven catheter-related CVTs were diagnosed . The frequency of catheter-related CVT was not significantly different between study groups , namely four catheter-related CVTs in the placebo group [ 9 % ; 95 % CI : 0.002 - 0.16 ] vs. seven catheter-related CVTs in the nadroparin group ( 17 % ; 95 % CI : 0.06 - 0.28 ) . In addition , no difference in the incidence of catheter-related infection or bleeding was observed between the groups . CONCLUSION This study showed that the actual risk for catheter-related CVT in patients with hematologic malignancies is lower than suggested in earlier studies in cancer patients . Although prophylactic administration of nadroparin appeared to be safe in this group of patients with a high risk of bleeding , it can not be recommended for the prevention of catheter-related CVT or catheter-related infection in patients with hematologic malignancies BACKGROUND An intravenous course of st and ard ( unfractionated ) heparin with the dose adjusted to prolong the activated partial-thromboplastin time to a desired length is the st and ard initial in-hospital treatment for patients with deep-vein thrombosis , but fixed-dose subcutaneous low-molecular-weight heparin appears to be as effective and safe . Because the latter treatment can be given on an outpatient basis , we compared the two treatments in symptomatic out patients with proximal-vein thrombosis but no signs of pulmonary embolism . METHODS We r and omly assigned patients to adjusted-dose intravenous st and ard heparin administered in the hospital ( 198 patients ) or fixed-dose subcutaneous low-molecular-weight heparin administered at home , when feasible ( 202 patients ) . We compared the treatments with respect to recurrent venous thromboembolism , major bleeding , quality of life , and costs . RESULTS Seventeen of the 198 patients who received st and ard heparin ( 8.6 percent ) and 14 of the 202 patients who received low-molecular-weight heparin ( 6.9 percent ) had recurrent thromboembolism ( difference , 1.7 percentage points ; 95 percent confidence interval , -3.6 to 6.9 ) . Major bleeding occurred in four patients assigned to st and ard heparin ( 2.0 percent ) and one patient assigned to low-molecular-weight heparin ( 0.5 percent ; difference , 1.5 percentage points ; 95 percent confidence interval , -0.7 to 2.7 ) . Quality of life improved in both groups . Physical activity and social functioning were better in the patients assigned to low-molecular-weight heparin . Among the patients in that group , 35 percent were never admitted to the hospital at all , and 40 percent were discharged early . This treatment was associated with a mean reduction in hospital days of 67 percent , ranging from 29 percent to 86 percent in the various study centers . CONCLUSIONS In patients with proximal-vein thrombosis , treatment with low-molecular-weight heparin at home is feasible , effective , and safe BACKGROUND The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention . To test this hypothesis , the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial ( P-1 ) in 1992 . METHODS Women ( N=13388 ) at increased risk for breast cancer because they 1 ) were 60 years of age or older , 2 ) were 35 - 59 years of age with a 5-year predicted risk for breast cancer of at least 1.66 % , or 3 ) had a history of lobular carcinoma in situ were r and omly assigned to receive placebo ( n=6707 ) or 20 mg/day tamoxifen ( n=6681 ) for 5 years . Gail 's algorithm , based on a multivariate logistic regression model using combinations of risk factors , was used to estimate the probability ( risk ) of occurrence of breast cancer over time . RESULTS Tamoxifen reduced the risk of invasive breast cancer by 49 % ( two-sided P<.00001 ) , with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups , respectively . The decreased risk occurred in women aged 49 years or younger ( 44 % ) , 50 - 59 years ( 51 % ) , and 60 years or older ( 55 % ) ; risk was also reduced in women with a history of lobular carcinoma in situ ( 56 % ) or atypical hyperplasia ( 86 % ) and in those with any category of predicted 5-year risk . Tamoxifen reduced the risk of noninvasive breast cancer by 50 % ( two-sided P<.002 ) . Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69 % , but no difference in the occurrence of estrogen receptor-negative tumors was seen . Tamoxifen administration did not alter the average annual rate of ischemic heart disease ; however , a reduction in hip , radius ( Colles ' ) , and spine fractures was observed . The rate of endometrial cancer was increased in the tamoxifen group ( risk ratio = 2.53 ; 95 % confidence interval = 1.35 - 4.97 ) ; this increased risk occurred predominantly in women aged 50 years or older . All endometrial cancers in the tamoxifen group were stage I ( localized disease ) ; no endometrial cancer deaths have occurred in this group . No liver cancers or increase in colon , rectal , ovarian , or other tumors was observed in the tamoxifen group . The rates of stroke , pulmonary embolism , and deep-vein thrombosis were elevated in the tamoxifen group ; these events occurred more frequently in women aged 50 years or older . CONCLUSIONS Tamoxifen decreases the incidence of invasive and noninvasive breast cancer . Despite side effects result ing from administration of tamoxifen , its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease PURPOSE AND METHODS Associations between thromboembolism and malignancy , usually widespread , and between thromboembolism and hormonal and /or chemotherapy have been previously reported . We performed a r and omized trial of tamoxifen 30 mg/d for 2 years ( T ) versus T plus 6 months of intravenous chemotherapy with cyclophosphamide , methotrexate , and fluorouracil ( CMF ) for postmenopausal women with involved axillary nodes and positive estrogen receptor ( ER ) or progesterone receptor ( PgR ) status following primary therapy for breast cancer . RESULTS We observed one or more thromboembolic events in 48 of 353 women ( 13.6 % ) allocated to receive T plus CMF in comparison to five of 352 women ( 2.6 % ) r and omized to receive T alone ( P < .0001 ) . Six women in the T plus CMF arm , but none r and omized to receive T alone , suffered two thromboembolic events while an study therapy . There were also significantly more women who developed severe ( grade 3 to 5 ) thromboembolic events in the T plus CMF arm than in the T arm ( 34 v five ; P < .0001 ) . Most thromboembolic events ( 39 of 54 ) occurred while women were actually receiving chemotherapy ( P < .0001 ) . Thromboembolic complications result ed in more days in hospital and more deaths than any other complication of therapy , including infection , in this trial . CONCLUSION Thromboembolism related to the addition of CMF chemotherapy to tamoxifen as adjuvant therapy in this group of women represents a relatively common and serious complication that may outweigh any benefits offered by this additional therapy Objective To compare the effectiveness and safety of low-dose unfractionated heparin and a low-molecular-weight heparin as prophylaxis against venous thromboembolism after colorectal surgery . Methods In a multicenter , double-blind trial , patients undergoing resection of part or all of the colon or rectum were r and omized to receive , by subcutaneous injection , either calcium heparin 5,000 units every 8 hours or enoxaparin 40 mg once daily ( plus two additional saline injections ) . Deep vein thrombosis was assessed by routine bilateral contrast venography performed between postoperative day 5 and 9 , or earlier if clinical ly suspected . Results Nine hundred thirty-six r and omized patients completed the protocol and had an adequate outcome assessment . The venous thromboembolism rates were the same in both groups . There were no deaths from pulmonary embolism or bleeding complications . Although the proportion of all bleeding events in the enoxaparin group was significantly greater than in the low-dose heparin group , the rates of major bleeding and reoperation for bleeding were not significantly different . Conclusions Both heparin 5,000 units subcutaneously every 8 hours and enoxaparin 40 mg subcutaneously once daily provide highly effective and safe prophylaxis for patients undergoing colorectal surgery . However , given the current differences in cost , prophylaxis with low-dose heparin remains the preferred method at present The records of 2,673 patients r and omized according to seven consecutive Eastern Cooperative Oncology Group ( ECOG ) studies of adjuvant therapy for breast cancer were review ed for the occurrence of vascular complications . All protocol s opened and closed between June 1977 and July 1987 . The objectives of the present study were ( 1 ) to compare the frequency of vascular complications among patients who received adjuvant therapy for breast cancer with patients on observation , and ( 2 ) to estimate the contribution of chemotherapy and hormonal therapy to the occurrence of venous and arterial thrombi . The frequency of thrombosis , both venous and arterial combined , was 5.4 % among patients who received adjuvant therapy and was 1.6 % among patients on observation ( P = .0002 ) . Premenopausal patients who received chemotherapy and tamoxifen had significantly more venous complications than those who received chemotherapy without tamoxifen ( 2.8 % v 0.8 % , P = .03 ) . Postmenopausal patients who received tamoxifen and chemotherapy had significantly more venous thrombi than those who received tamoxifen alone ( 8.0 % v 2.3 % , P = .03 ) or those who were observed ( 8.0 % v 0.4 % , P less than .0001 ) . Premenopausal patients who received tamoxifen and chemotherapy had a 1.6 % frequency of arterial thrombosis , significantly more than patients who received chemotherapy alone ( 1.6 % v 0.0 % , P = .004 ) . The frequency of arterial thrombosis among postmenopausal patients was not significantly correlated with adjuvant therapy . In conclusion , patients who received adjuvant therapy for breast cancer had a 5.4 % frequency of thromboembolic complications , significantly more than those who were observed . The combination of chemotherapy and tamoxifen was associated with more venous and arterial thromboembolic complications than chemotherapy alone in premenopausal patients and with more venous thrombi than tamoxifen alone among postmenopausal patients BACKGROUND Cancer patients receiving chemotherapy experience thromboembolic complications associated with the use of long-term indwelling central venous catheters ( CVCs ) . This prospect i ve , double-blind , placebo-controlled , multicenter study evaluated whether prophylactic treatment with a low molecular weight heparin could prevent clinical ly relevant catheter-related thrombosis . PATIENTS AND METHODS Patients with cancer undergoing chemotherapy for at least 12 weeks ( n=439 ) were r and omly assigned , in a 2:1 ratio , to receive either dalteparin ( 5000 IU ) or placebo , by subcutaneous injection , once daily for 16 weeks . Patients underwent upper extremity evaluation with either venography or ultrasound at the time of a suspected catheter-related complication ( CRC ) or upon completion of study medication . The primary end point , as determined by a blinded adjudication committee , was the occurrence of a CRC , defined as the first occurrence of any one of the following : clinical ly relevant catheter-related thrombosis that was symptomatic or that required anticoagulant or fibrinolytic therapy ; catheter-related clinical ly relevant pulmonary embolism ; or catheter obstruction requiring catheter removal . RESULTS There was no significant difference in the frequency of CRCs between the dalteparin arm ( 3.7 % ) and the placebo arm ( 3.4 % ; P=0.88 ) , corresponding to a relative risk of 1.0883 ( 95 % confidence interval 0.37 - 3.19 ) . No difference in the time to CRC was observed between the two arms ( P=0.83 ) . There was no significant difference between the dalteparin and placebo groups in terms of major bleeding ( 1 versus 0 ) or overall safety . CONCLUSIONS Dalteparin prophylaxis did not reduce the frequency of thromboembolic complications after CVC implantation in cancer patients . Dalteparin was demonstrated to be safe over 16 weeks of treatment in these patients Risk of venous thromboembolism ( VTE ) is elevated in cancer , but individual risk factors can not identify a sufficiently high-risk group of out patients for thromboprophylaxis . We developed a simple model for predicting chemotherapy-associated VTE using baseline clinical and laboratory variables . The association of VTE with multiple variables was characterized in a derivation cohort of 2701 cancer out patients from a prospect i ve observational study . A risk model was derived and vali date d in an independent cohort of 1365 patients from the same study . Five predictive variables were identified in a multivariate model : site of cancer ( 2 points for very high-risk site , 1 point for high-risk site ) , platelet count of 350 x 10(9)/L or more , hemoglobin less than 100 g/L ( 10 g/dL ) and /or use of erythropoiesis-stimulating agents , leukocyte count more than 11 x 10(9)/L , and body mass index of 35 kg/m(2 ) or more ( 1 point each ) . Rates of VTE in the derivation and validation cohorts , respectively , were 0.8 % and 0.3 % in low-risk ( score = 0 ) , 1.8 % and 2 % in intermediate-risk ( score = 1 - 2 ) , and 7.1 % and 6.7 % in high-risk ( score > /= 3 ) category over a median of 2.5 months ( C-statistic = 0.7 for both cohorts ) . This model can identify patients with a nearly 7 % short-term risk of symptomatic VTE and may be used to select cancer out patients for studies of thromboprophylaxis BACKGROUND The incidence of venous thromboembolism after diagnosis of specific cancers and the effect of thromboembolism on survival are not well defined . METHODS The California Cancer Registry was linked to the California Patient Discharge Data Set to determine the incidence of venous thromboembolism among cancer cases diagnosed between 1993 and 1995 . The incidence and timing of thromboembolism within 1 and 2 years of cancer diagnosis and the risk factors associated with thromboembolism and death were determined . RESULTS Among 235 149 cancer cases , 3775 ( 1.6 % ) were diagnosed with venous thromboembolism within 2 years , 463 ( 12 % ) at the time cancer was diagnosed and 3312 ( 88 % ) subsequently . In risk-adjusted models , metastatic disease at the time of diagnosis was the strongest predictor of thromboembolism . Expressed as events per 100 patient-years , the highest incidence of thromboembolism occurred during the first year of follow-up among cases with metastatic-stage pancreatic ( 20.0 ) , stomach ( 10.7 ) , bladder ( 7.9 ) , uterine ( 6.4 ) , renal ( 6.0 ) , and lung ( 5.0 ) cancer . Adjusting for age , race , and stage , diagnosis of thromboembolism was a significant predictor of decreased survival during the first year for all cancer types ( hazard ratios , 1.6 - 4.2 ; P<.01 ) . CONCLUSIONS The incidence of venous thromboembolism varied with cancer type and was highest among patients initially diagnosed with metastatic-stage disease . The incidence rate of thromboembolism decreased over time . Diagnosis of thromboembolism during the first year of follow-up was a significant predictor of death for most cancer types and stages analyzed . For some types of cancer , the incidence of thromboembolism was sufficiently high to warrant prospect i ve clinical trials of primary thromboprophylaxis PURPOSE In this multicenter , r and omized , placebo-controlled clinical trial , we studied whether warfarin 1 mg daily reduces the incidence of symptomatic central venous catheter ( CVC ) -associated thrombosis in patients with cancer . PATIENTS AND METHODS Two hundred fifty-five patients with cancer who required a CVC for at least 7 days were r and omly assigned to receive warfarin 1 mg or placebo . RESULTS There were 11 ( 4.3 % ) symptomatic CVC-associated thromboses among 255 patients , with no difference in the incidence of symptomatic CVC-associated thrombosis between patients taking warfarin 1 mg daily ( six of 130 patients ; 4.6 % ) and patients taking placebo ( five of 125 patients ; 4.0 % ; hazard ratio , 1.20 ; 95 % CI , 0.37 to 3.94 ) . Warfarin had no effect on CVC life span ( 84 days v 63 days in control and warfarin groups , respectively ; 95 % confidence limit , -16 to 55 days ; P = .09 ) , and it did not affect the number of premature CVC removals ( 23.2 % v 25.4 % in control and warfarin groups , respectively ; 95 % confidence limit of difference -8.34 to 12.71 ; P = .68 ) or the frequency of major bleeding episodes ( 2 % v 0 % in control and warfarin groups , respectively ; P = .5 , Fisher 's exact test ) . CONCLUSION Symptomatic CVC-associated thrombosis in patients with cancer , although significant , is less common than previously reported . In this study , the administration of warfarin 1 mg daily did not reduce the incidence of symptomatic CVC-associated thrombosis in patients with cancer . However , the low rate of symptomatic CVC-associated thrombosis means that a much larger trial is required to address this issue definitively The optimal administration regimens of low molecular weight heparins ( LMWHs ) have not yet been established . The aim of this study was to compare the efficacy and safety of 2500 and 5000 XaI units of the LMWH dalteparin in patients undergoing elective general surgery for malignant and benign abdominal disease . Prophylaxis was started in the evening before surgery and given once-daily every evening thereafter . The study was design ed as a prospect i ve , r and omized , double-blind , multicentre trial . Some 66.4 per cent of patients were operated on for a malignant disorder . The primary endpoint was deep vein thrombosis ( DVT ) detected with the fibrinogen uptake test . Bleeding complications were recorded and classified . Analysis was made both on an intention to treat basis and in patients given correct prophylaxis ( 86.3 per cent ) . A total of 2097 patients were r and omized and 27 excluded after r and omization . A technically correct fibrinogen uptake test was obtained in 1957 patients . The incidence of DVT was significantly lower in patients given 5000 XaI units , this being true for both correct prophylaxis ( 6.8 versus 13.1 per cent , P < 0.001 ) , on an intention to treat basis ( 6.6 versus 12.7 per cent , P < 0.001 ) , and in patients with malignant disease ( 8.5 versus 14.9 per cent , P < 0.001 ) . Sixty-seven patients ( 3.2 per cent ) died within 30 days with no difference between the groups . There were two cases of fatal pulmonary embolism . The frequency of bleeding complications in the whole series was higher in patients r and omized to 5000 XaI units ( 4.7 versus 2.7 per cent , P = 0.02 ) , although this was not the case in those operated on for malignant disease ( 4.6 versus 3.6 per cent , P not significant ) . Dalteparin in the dose of 5000 XaI units started in the evening before surgery has a good thromboprophylactic effect in high-risk general surgery at the cost of a small bleeding risk . In patients with malignant disease there was no increased risk of bleeding . The overall frequency of fatal pulmonary embolism with dalteparin is extremely low , even in this high-risk group of patients PURPOSE To compare chemohormonal therapy , chemotherapy alone , and hormonal therapy alone in postmenopausal patients with estrogen receptor (ER)-positive operable breast cancer and positive axillary nodes with respect to survival and disease-free survival ( DFS ) . PATIENTS AND METHODS Eight hundred ninety-two postmenopausal women with ER-positive , node-positive breast cancer were enrolled by the Southwest Oncology Group ( SWOG ) from July 1979 to March 1989 and 74 by the Eastern Cooperative Oncology Group ( ECOG ) between June 1987 and March 1989 . Patients were stratified according to number of involved nodes and type of primary surgery and r and omized to receive the following : ( 1 ) tamoxifen 10 mg twice daily by mouth for 1 year ; ( 2 ) cyclophosphamide 60 mg/m2/d by mouth for 1 year , methotrexate 15 mg/m2 intravenously ( IV ) weekly for 1 year , fluorouracil ( 5-FU ) 400 mg/m2 IV weekly for 1 year , vincristine .625 mg/m2 IV weekly for the first 10 weeks , and prednisone during weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 ( CMFVP ) ; or ( 3 ) the combination of tamoxifen and CMFVP . RESULTS The median follow-up duration is 6.5 years , with a maximum of 12.8 years . Treatment arms are not significantly different with respect to either survival or DFS ( log-rank , 2 df , P = .82 and .23 , respectively ) . The 5-year survival rate is 77 % for the tamoxifen arm , 78 % for CMFVP , and 75 % for the combination . No significant differences were observed in node or receptor level subsets . Severe or worse toxicity was experienced by 56 % of patients on CMFVP and 61 % on CMFVP plus tamoxifen , compared with 5 % on tamoxifen alone . CONCLUSION CMFVP chemotherapy , either alone or in combination with tamoxifen , has not been shown to be superior to tamoxifen alone in the treatment of postmenopausal women with node-positive , ER-positive , operable breast cancer The National Surgical Adjuvant Breast and Bowel Project ( NSABP ) conducted a r and omized clinical trial to determine whether tamoxifen ( TAM ) plus chemotherapy is more effective than TAM alone in improving disease-free survival ( DFS ) , distant disease-free survival ( DDFS ) , and survival ( S ) of positive-node , TAM-responsive patients aged greater than or equal to 50 years . Women were r and omized among three treatment groups : ( 1 ) TAM alone , ( 2 ) Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) , cyclophosphamide , and TAM ( ACT ) , or ( 3 ) melphalan ( L-PAM ) , fluorouracil ( 5-FU ) , and TAM ( PFT ) . The PFT arm was later modified so that new patients also received Adriamycin ( PAFT ) . Findings from 1,124 eligible patients through 3 years of follow-up indicated a significantly better DFS for ACT-treated patients than for those receiving TAM alone ( 84 % v 67 % ; P = .0004 ) . An advantage in DDFS and S was also observed after ACT therapy ( 83 % v 73 % [ P = .04 in the former ] and 93 % v 85 % [ P = .04 in the latter ] ) . Both the DFS and DDFS of PAFT-treated patients were better than in those treated by TAM alone ( 83 % v 66 % , P = .0002 and 85 % v 73 % , P = .003 ) . PFT patients also fared better in DFS and DDFS than TAM patients ( 81 % v 72 % , P = .07 and 85 % v 74 % , P = .02 ) . Odds ratios consistently favored the three TAM-plus-chemotherapy groups . No significant S advantage is as yet evident in favor of the PAFT or PFT groups . Of importance is the failure of these studies to demonstrate an unfavorable interaction between the drug regimens used and the TAM , which was administered simultaneously . The findings related to the use of PAFT and PFT are of more biologic than clinical significance since L-PAM is rarely used in the treatment of breast cancer . The major conclusion from this study is the observance of a better outcome in positive-node breast cancer patients aged greater than or equal to 50 years from the use of postoperative prolonged TAM and short-course AC therapy ( completed in 63 days ) than from prolonged TAM therapy alone BACKGROUND There is not enough clinical evidence to make a strong recommendation on the optimal duration of thromboprophylaxis using low-molecular weight heparins ( LMWH ) in patients undergoing major cancer surgery . PATIENTS AND METHODS CANBESURE is a r and omized , double-blind study which enrolled patients admitted for abdominal or pelvic surgery for cancer . They received 3500 IU of bemiparin subcutaneously once daily for 8 days and were then r and omized to receive either bemiparin or placebo for 20 additional days . Bilateral venography was performed after 20 days and evaluated blinded . The primary efficacy outcome was the composite of deep vein thrombosis ( DVT ) , non-fatal pulmonary embolism ( PE ) and all-cause mortality at the end of double-blind period . Major venous thromboembolism ( proximal deep-vein thrombosis , non-fatal pulmonary embolism and venous thromboembolism-related deaths ) was also evaluated . The primary safety outcome was major bleeding . RESULTS Six hundred and twenty-five and 488 patients were included in the safety and main efficacy analyzes , respectively . The primary efficacy outcome occurred in 25 out of 248 patients ( 10.1 % ) in the bemiparin group and 32 out of 240 ( 13.3 % ) in the placebo group ( relative risk reduction 24.4 % ; 95 % CI : -23.7 - 53.8 % ; P = 0.26 ) . At the end of double-blind period , major venous thromboembolism occurred in 2 ( 0.8 % ) and 11 ( 4.6 % ) patients , respectively ( relative risk reduction 82.4 % ; 95 % CI : 21.5 - 96.1 % ; P = 0.010 ) . No significant difference was found in major bleedings . CONCLUSIONS Four weeks compared with 1 week of prophylaxis with bemiparin after abdominal or pelvic cancer surgery did not significantly reduce the primary efficacy outcome , but decreased major venous thromboembolism ( VTE ) without increasing hemorrhagic complications OBJECTIVE To determine whether very low doses of warfarin are useful in thrombosis prophylaxis in patients with central venous catheters . DESIGN Patients at risk for thrombosis associated with chronic indwelling central venous catheters were prospect ively and r and omly assigned to receive or not to receive 1 mg of warfarin , beginning 3 days before catheter insertion and continuing for 90 days . Subclavian , innominate , and superior vena cava venograms were done at onset of thrombosis symptoms or after 90 days in the study . RESULTS One hundred twenty-one patients entered the study , and 82 patients completed the study . Of 42 patients completing the study while receiving warfarin , 4 had venogram-proven thrombosis . All 4 had symptoms from thrombosis . Of 40 patients completing the study while not receiving warfarin , 15 had venogram-proven thrombosis , and 10 had symptoms from thrombosis ( P less than 0.001 ) . There were no measurable changes in the coagulation values assayed due to this warfarin dose , except in occasional patients who had become anorectic because of their disease or chemotherapy . CONCLUSIONS Very low doses of warfarin can protect against thrombosis without inducing a hemorrhagic state . This approach may be applicable to other groups of patients PURPOSE Peripherally inserted central catheters ( PICCs ) are frequently used to deliver outpatient courses of intravenous therapy . However , the rates and risks of complication for this device have not been well-studied . Our objective was to determine the incidence and risk factors of PICC-related complications with a 1-year prospect i ve observational study . PATIENTS AND METHODS All PICCs inserted in adult and pediatric patients at Memorial Sloan-Kettering Cancer Center ( MSKCC ) were followed prospect ively . The device insertion team , inpatient nurses , and various home-care companies and outside institutions collected longitudinal data . RESULTS Three hundred fifty-one PICCs were inserted during the study period and followed for a total of 10,562 catheter-days ( median placement , 15 days ; range , 1 to 487 days ) . Two hundred five PICCs ( 58 % ) were managed by home-care companies and outside institutions , and 146 PICCs ( 42 % ) were managed exclusively at MSKCC . For these 205 PICCs , 131 nurses from 74 home-care companies and institutions were contacted for follow-up clinical information . In all , 115 ( 32.8 % ) of 351 PICCs were removed as a result of a complication , for a rate of 10.9 per 1,000 catheter-days . Patients with hematologic malignancy or bone marrow transplant were more likely to develop a complication , whereas those with metastatic disease were less likely . CONCLUSION Complications occur frequently among cancer patients with PICCs , and long-term follow-up is onerous . Despite a high complication rate , the ease of insertion and removal argues for continued PICC use in the cancer population PURPOSE AND METHODS Data from a r and omized phase III trial in early breast cancer , comparing surgery followed by one short intensive course of perioperative fluorouracil , doxorubicin , and cyclophosphamide ( FAC ) versus surgery alone , were analyzed for the occurrence of thromboembolic complications within 6 weeks after surgery . RESULTS Twenty-seven of 1,292 patients assigned to the perioperative chemotherapy treatment arm ( 2.1 % ) and 10 of 1,332 patients on observation ( 0.8 % ) developed thromboembolic events ( P = .004 ) . The frequency of thromboembolic complications was higher among postmenopausal women compared with premenopausal women ( 2.0 % v 0.6 % , P = .003 ) . Patients who had mastectomy had a higher frequency of thromboembolic disease than those who had tumorectomy ( 2.3 % v 0.7 % , P < .001 ) . Three deaths occurred after pulmonary embolism , all of them in the perioperative chemotherapy treatment arm . CONCLUSION These results suggest a contributing role of perioperative chemotherapy to thromboembolic disease , especially in postmenopausal women and women undergoing mastectomy . Antithrombosis prophylaxis should be considered in the case of adjuvant perioperative chemotherapy PURPOSE The extent of venous thromboembolism ( VTE ) associated with central vein catheters ( CVC ) in cancer patients remains unclear . The aim of this study was to evaluate the efficacy and safety of the low molecular weight heparin , enoxaparin , in the prevention of VTE . PATIENTS AND METHODS In a multicenter , double-blind study , consecutive cancer patients scheduled for CVC insertion were r and omly assigned to receive either subcutaneous enoxaparin 40 mg once a day or placebo . Treatment was started 2 hours before CVC insertion and continued for 6 weeks . The primary end points of the study were deep vein thrombosis ( DVT ) , confirmed by venography of the CVC limb performed 6 weeks after r and omization , or clinical ly overt pulmonary embolism , confirmed by objective testing during the study drug administration . Patients were assessed for bleeding complications . RESULTS Three hundred eighty-five patients were r and omized , of which 321 ( 83.4 % ) underwent venography . A venography was adequate for adjudication in 155 patients in each treatment group . A DVT was observed in 22 patients ( 14.1 % ) treated with enoxaparin and in 28 patients ( 18.0 % ) treated with placebo , corresponding to a relative risk of 0.78 ( 95 % CI , 0.47 to 1.31 ) . No major bleeding occurred . Five patients ( 2.6 % ) in the enoxaparin group and two patients ( 1.0 % ) in the placebo group died during the treatment period . CONCLUSION In this study , no difference in the rate of CVC-related VTE was detected between patients receiving enoxaparin and patients receiving placebo . The dose of enoxaparin used in this study proved to be safe . Clinical trials evaluating higher enoxaparin doses could optimize the efficacy of this agent for this indication PURPOSE Thrombosis of long-term central venous catheters ( CVC ) is a serious complication that causes morbidity and interrupts the infusion of chemotherapy , intravenous medication , and blood products . We performed a prospect i ve study to examine the incidence , risk factors , and long-term complications of symptomatic catheter-related thrombosis ( CRT ) in adults with cancer . PATIENTS AND METHODS Consecutive patients with cancer , undergoing insertion of a CVC , were enrolled and prospect ively followed while their catheter remained in place plus 4 subsequent weeks or a maximum of 52 weeks , whichever came first . Patients with symptomatic CRT were followed for an additional 52 weeks from the date of CRT diagnosis . The end points were symptomatic CRT , symptomatic pulmonary embolism ( PE ) , postphlebitic syndrome , and catheter life span . RESULTS Over 76,713 patient-days of follow-up , 19 of 444 patients ( 4.3 % ) had symptomatic CRT in 19 of 500 catheters ( 0.3 per 1,000 catheter-days ) . The median time to CRT was 30 days and the median catheter life span was 88 days . Significant baseline risk factors for CRT were : more than one insertion attempt ( odds ratio [ OR ] = 5.5 ; 95 % CI , 1.2 to 24.6 ; P = .03 ) ; ovarian cancer ( OR = 4.8 ; 95 % CI , 1.5 to 15.1 ; P = .01 ) ; and previous CVC insertion ( OR = 3.8 ; 95 % CI , 1.4 to 10.4 ; P = .01 ) . Nine of the 19 CRT patients were treated with anticoagulants alone , eight patients were treated with anticoagulants and catheter removal , while two patients did not receive anticoagulation . None had recurrent CRT or symptomatic PE . Postphlebitic symptoms were infrequent . CONCLUSION In adults with cancer , the incidence of symptomatic CRT is low and long-term complications are uncommon Cancer patients undergoing surgery are at a high risk of venous thromboembolism , but few studies have described the rate of autopsy-confirmed fatal pulmonary embolism after heparin thromboprophylaxis . In a post hoc analysis of a r and omized study ( MC-4 ) , which compared the efficacy and safety of certoparin ( 3000 anti-Xa IU , subcutaneously , once-daily ) with unfractionated heparin ( 5000 IU , subcutaneously , three-times daily ) in 23078 patients undergoing surgery lasting more than 30 min , the incidence of autopsy-confirmed fatal pulmonary embolism , death and bleeding in the cancer patients ( n=6124 ) was compared with non-cancer patients ( n=16954 ) . Fatal pulmonary embolism was significantly more frequent in cancer patients ( 0.33 % [ 20/6124 ] ) than in non-cancer patients ( 0.09 % [ 15/16954 ] , relative risk ( RR ) , 3.7 [ 95 % confidence intervals ( CI ) , 1.80 , 7.77 ] , p=0.0001 ) at 14 days post-prophylaxis . Perioperative mortality was also significantly higher in cancer patients than in noncancer patients ( 3.14 % [ 192/6124 ] vs. 0.71 % [ 120/16954 ] , RR , 4.54 [ 95 % CI , 3.59 , 5.76 ] , p=0.0001 ) , as were blood loss ( p<0.0001 ) , and transfusion requirements ( p<0.0001 ) . Prevention of venous thromboembolism in cancer surgical patients remains a clinical challenge One hundred eighty-five patients undergoing operation for gynecologic malignancy participated in a r and omized controlled trial of low-dose heparin prophylaxis . Prospect i ve surveillance for deep venous thrombosis was performed with daily fibrinogen 125I counting in the legs and impedance plethysmography . Twelve of 97 ( 12.4 % ) patients in the control group and 13 of 88 ( 14.8 % ) patients in the low-dose heparin group developed a venous thromboembolic complication . There was no statistical difference in the incidence of proximal deep vein thrombosis , calf vein thrombosis , or pulmonary emboli between the control and low-dose heparin groups . Low-dose heparin does not afford any prophylactic benefit to patients undergoing major pelvic operative procedures for gynecologic malignancy Patients receiving chemotherapy for metastatic breast cancer are at high risk of thromboembolic disease . Long-term oral anticoagulant therapy is needed but increases the risk of haemorrhagic complications . We have assessed the safety and efficacy of warfarin in very low doses as prophylaxis . Women receiving chemotherapy for metastatic breast cancer were r and omly assigned either very-low-dose warfarin ( 152 patients ) or placebo ( 159 ) . The warfarin dose was 1 mg daily for 6 weeks and was then adjusted to maintain the prothrombin time at an international normalised ratio ( INR ) of 1.3 to 1.9 . Study treatment continued until 1 week after the end of chemotherapy . The average daily dose from initiation of titration was 2.6 ( SD 1.2 ) mg for the warfarin group and the mean INR was 1.52 . The mean time at risk of thrombosis was 199 ( 126 ) days for warfarin-treated patients and 188 ( 137 ) days for placebo recipients ( p = 0.45 ) . There were 7 thromboembolic events ( 6 deep-vein thrombosis , 1 pulmonary embolism ) in the placebo group and 1 ( pulmonary embolism ) in the warfarin group , a relative risk reduction of about 85 % ( p = 0.031 ) . Major bleeding occurred in 2 placebo recipients and 1 warfarin-treated patient . There was no detectable difference in survival between the treatment groups . Very-low-dose warfarin is a safe and effective method for prevention of thromboembolism in patients with metastatic breast cancer who are receiving chemotherapy BACKGROUND Abdominal surgery for cancer carries a high risk of venous thromboembolism , but the optimal duration of postoperative thromboprophylaxis is unknown . METHODS We conducted a double-blind , multicenter trial in which patients undergoing planned curative open surgery for abdominal or pelvic cancer received enoxaparin ( 40 mg subcutaneously ) daily for 6 to 10 days and were then r and omly assigned to receive either enoxaparin or placebo for another 21 days . Bilateral venography was performed between days 25 and 31 , or sooner if symptoms of venous thromboembolism occurred . The primary end point with respect to efficacy was the incidence of venous thromboembolism between days 25 and 31 . The primary safety end point was bleeding during the three-week period after r and omization . The patients were followed for three months . RESULTS The intention-to-treat analysis of efficacy included 332 patients . The rates of venous thromboembolism at the end of the double-blind phase were 12.0 percent in the placebo group and 4.8 percent in the enoxaparin group ( P=0.02 ) . This difference persisted at three months ( 13.8 percent vs. 5.5 percent , P=0.01 ) . Three patients in the enoxaparin group and six in the placebo group died within three months after surgery . There were no significant differences in the rates of bleeding or other complications during the double-blind or follow-up periods . CONCLUSIONS Enoxaparin prophylaxis for four weeks after surgery for abdominal or pelvic cancer is safe and significantly reduces the incidence of venographically demonstrated thrombosis , as compared with enoxaparin prophylaxis for one week BACKGROUND Central vein catheters , which are used in the treatment of cancer patients , are prone to thrombotic complications of the catheter or adjacent vein . Previous studies suggest that 1 mg warfarin daily ( minidose ) can significantly reduce that risk . AIMS This , study aims to establish whether minidose warfarin could reduce catheter-related thrombosis in adult patients with haematological malignancies . METHODS Patients were r and omly selected to receive warfarin or not . The end-points studied were : ( i ) occlusion by thrombus , ( ii ) removal of catheter for other reasons or ( iii ) 90 days free of thrombus . RESULTS There was no significant difference in the incidence of catheter thrombosis or venous thrombosis and no significant variation in catheter survival between the study and control groups . CONCLUSIONS This study found no benefit of the routine use of minidose warfarin for prophylaxis of central vein ' catheter thrombosis in patients with haematological malignancies and therefore does not support the routine use of minidose warfarin for prophylaxis in such patients Central venous access devices are often essential for the administration of chemotherapy to patients with malignancy , but its use has been associated with a number of complications , mainly thrombosis . The true incidence of upper extremity deep vein thrombosis ( DVT ) in this setting is difficult to estimate since there are very few studies in which DVT diagnosis was based on objective tests , but its sequelae include septic thrombophlebitis , loss of central venous access and pulmonary embolism . We performed an open , prospect i ve study in which all cancer patients who underwent placement of a long-term Port-a-Cath ( Pharmacia Deltec Inc ) subclavian venous catheter were r and omized to receive or not 2500 IU sc of Fragmin once daily 90 days . Venography was routinely performed 90 days after catheter insertion , or sooner if DVT symptoms had appeared . Our aims were : 1 ) to investigate the effectiveness of low doses of Fragmin in preventing catheter-related DVT ; and 2 ) to try to confirm if patients with high platelet counts are at a higher risk to develop subclavian DVT , as previously suggested . On the recommendation of the Ethics Committee , patient recruitment was terminated earlier than planned : DVT developed in 1/16 patients ( 6 % ) taking Fragmin and 8/13 patients ( 62 % ) without prophylaxis ( Relative Risk 6.75 ; 95 % CI : 1.05 - 43.58 ; p = 0.002 , Fisher exact test ) . No bleeding complications had developed . As for prediction of DVT , there was a tendency towards a higher platelet count in those patients who subsequently developed DVT , but differences failed to reach any statistical significance ( 286 + /- 145 vs 207 + /- 81 x 10(9)/1 ; p = 0.067 ) . According to our experience , Fragmin at the dosage used proved to be both effective and safe in these patients In a cooperative group study of 433 breast cancer patients treated with 2 years of postmastectomy chemotherapy , 22 ( 5 % ) developed venous thromboses of various types . Two patients died . None of the patients had demonstrable tumor metastases at the time of the venous thrombosis , although seven had metastases a median of 11 months after the thromboses . Thirteen living patients have not had tumor recurrences . No patient developed thrombosis after the chemotherapy was completed . It is possible that one or more of the chemotherapeutic agents initiated the clotting problems . Thrombophlebitis is a possible problem occurring during adjuvant chemotherapy for breast cancer and requires prompt treatment Thromboembolic disease has long been recognized as a complication of cancer . Recent reports have suggested that drugs used in the treatment of cancer , including chemotherapeutic agents and hormones , may contribute to this risk , but it has not been possible to separate the effect of these drugs from that of the cancer . We performed a r and omized trial comparing 12 weeks of chemohormonal therapy ( using cyclophosphamide , methotrexate , fluorouracil , vincristine , prednisone , doxorubicin , and tamoxifen ) with 36 weeks of chemotherapy ( using cyclophosphamide , methotrexate , fluorouracil , vincristine , and prednisone ) in patients with Stage II breast cancer . Among 205 patients r and omly assigned to treatment , there were 14 episodes of thrombosis ( 6.8 percent ) . These 14 episodes occurred during 979 patient-months of chemotherapy ; by comparison , there were no events during 2413 patient-months without therapy . During the first 12 weeks of the study , five patients in the 12-week group and four patients in the 36-week group had thrombosis . During the subsequent 24 weeks , when only patients in the 36-week group were still receiving chemotherapy , there was no thrombosis in the 12-week group , but there were five additional events in the 36-week group ( P = 0.03 ) . These findings suggest that chemotherapy contributes to thrombosis in patients with breast cancer BACKGROUND Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism . Limited data support the clinical benefit of antithrombotic prophylaxis . METHODS In this double-blind , multicenter trial , we evaluated the efficacy and safety of the ultra-low-molecular-weight heparin semuloparin for prevention of venous thromboembolism in patients receiving chemotherapy for cancer . Patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy were r and omly assigned to receive subcutaneous semuloparin , 20 mg once daily , or placebo until there was a change of chemotherapy regimen . The primary efficacy outcome was the composite of any symptomatic deep-vein thrombosis , any nonfatal pulmonary embolism , and death related to venous thromboembolism . Clinical ly relevant bleeding ( major and nonmajor ) was the main safety outcome . RESULTS The median treatment duration was 3.5 months . Venous thromboembolism occurred in 20 of 1608 patients ( 1.2 % ) receiving semuloparin , as compared with 55 of 1604 ( 3.4 % ) receiving placebo ( hazard ratio , 0.36 ; 95 % confidence interval [ CI ] , 0.21 to 0.60 ; P<0.001 ) , with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism . The incidence of clinical ly relevant bleeding was 2.8 % and 2.0 % in the semuloparin and placebo groups , respectively ( hazard ratio , 1.40 ; 95 % CI , 0.89 to 2.21 ) . Major bleeding occurred in 19 of 1589 patients ( 1.2 % ) receiving semuloparin and 18 of 1583 ( 1.1 % ) receiving placebo ( hazard ratio , 1.05 ; 95 % CI , 0.55 to 1.99 ) . Incidences of all other adverse events were similar in the two study groups . CONCLUSIONS Semuloparin reduces the incidence of thromboembolic events in patients receiving chemotherapy for cancer , with no apparent increase in major bleeding . ( Funded by Sanofi ; Clinical Trials.gov number , NCT00694382 . )

The findings from this review do not suggest that there should be any significant change from accepted conventional practice procedures when the pulp of the carious tooth is considered .

BACKGROUND There is a range of treatment options for the management of the pulp in extensively decayed teeth . These include direct and indirect pulp capping , pulpotomy or pulpectomy . If the tooth is symptomatic or if there are periapical bone changes , then endodontic treatment is required . However , if the tooth is asymptomatic but the caries is extensive , there is no consensus as to the best method of management . In addition , there has been a recent move towards using alternative material s and methods such as the direct or indirect placement of bonding agents and mineral trioxide aggregate . Most studies have investigated the management of asymptomatic carious teeth with or without an exposed dental pulp using various capping material s ( e.g. calcium hydroxide , Ledermix , Triodent , Biorex , etc . ) . However , there is no long term data regarding the outcome of management of asymptomatic , carious teeth according to different regimens . OBJECTIVES This study aims to assess the effectiveness of techniques used to treat asymptomatic carious teeth and maintain pulp vitality .

Microleakage is related to recurrent decay , inflammation of vital pulps , and reinfection of previously treated root canals . The purpose of this investigation was to compare the abilities of new adhesive cements and conventional nonadhesive controls to prevent microleakage under stainless steel crowns on primary anterior teeth . St and ardized preparations were made , and stainless steel crowns were adapted . Specimens were assigned r and omly to cement groups : zinc phosphate ( ZP ) , polycarboxylate ( PC ) , glass-ionomer ( GI ) , resin-modified glass-ionomer ( RMGI ) , RMGI with a dentin bonding agent ( RMGI + DBA ) , adhesive composite resin ( ACR ) and zinc oxide eugenol ( ZOE ) . Specimens were stored in water , aged artificially , stained , embedded , and sectioned , and the microleakage was measured . Group means and st and ard errors were calculated . ANOVA discerned differences among groups ( P < 0.0001 ) , and Turkey 's multiple comparisons testing ( P < 0.05 ) ranked the groups from least to most microleakage as follows : [ RMGI + DBA , RMGI , ACR , GI ] , [ ZP ] , and [ PC , ZOE ] . The adhesive cements significantly reduced microleakage In the last years several dental adhesives have been developed . They are supposed to chemically adhere to dentin and a liner to protect the pulp is not used . The aim of this study was to compare the short-term pulpal reaction , in an intra-toothpair study , between a dental adhesive , Scotchbond 2 , and a lining system , Tubulitec , in combination with P-50 in surface-sealed cavities . Deep buccal cavities in 16 human pairs of premolars , 32 teeth , were restored in vivo with a light cured composite resin , P-50 . To minimize bacterial contamination all cavities were treated with a cleanser , Tubulicid , and the cavities were surface-sealed with temporary cement , Coltosol . One tooth in each pair , the test , was treated with Scotchprep Dentin Primer and Scotchbond 2 Light Cure Dental Adhesive . In the other tooth in the pair , the control , Tubulitec Primer and Liner were used . The teeth were extracted after 6 - 14 days . The sections were evaluated for degree of inflammation and the presence of bacteria . Irrespective of treatment of dentin the majority of teeth , 23 , including one pulpal exposure , revealed no inflammation or a few inflammatory cells . In four test teeth , including one pulpal exposure , and two controls , growth of bacteria was found on the cavity walls and slight or moderate inflammation was seen in the corresponding pulps . In one test and two control teeth slight inflammation was seen but no bacteria could be detected . In the absence of bacteria Scotchbond 2 did not seem to irritate the pulp . ( ABSTRACT TRUNCATED AT 250 WORDS Three intermediary base material s , a zinc oxide-eugenol ( Cavitec ) and two calcium hydroxide liners ( Life and Dycal ) , were selected at r and om for use as a base beneath amalgam or composite restorations on humans following complete caries removal . Life and Dycal , selected at r and om , were also used as direct and indirect pulp capping agents as clinical ly indicated . Clinical evaluations of signs and symptoms were made before treatment and at one-week , six-month , and one-year intervals following treatment . Histological evaluations were performed on three complete caries removal teeth and 18 direct pulp capping teeth six months following treatment . No significant differences in clinical symptomatology result ed between the material s in the complete caries removal group or the indirect and direct pulp capping groups Concern about the survival of microorganisms in deep carious lesions may often lead to unnecessary exposure of the pulp during final excavation . There are reasons , therefore , to initiate systematic studies on the alternative procedure known as stepwise excavation . Clinical evaluation of stepwise excavation was performed on 31 deep carious lesions considered to result in pulp perforation by traditional excavation . This study examines the clinical and microbiological alterations during the final excavation performed during long intervals ( 6 - 12 months ) after the initial treatment that included peripheral dentine excavation and removal of the central cariogenic biomass and the superficial necrotic dentine . The dentine colour and consistency were assessed by means of st and ardized scales before application of a Ca(OH)2 compound and a temporary sealing for 6 - 12 months . Re assessment s were performed before the after final excavation . Microbiological dentine sample s were obtained in 19 r and omly selected lesions by a sterile bur , transferred to and diluted in reduced transport fluid , and plated on tryptic soy agar . After anaerobic incubation at 37 degrees C for 7 days , total colony-forming units per millilitre were counted from ( 1 ) peripheral excavated and hard dentine ( control ) , ( 2 ) central demineralized dentine before and final excavation , and ( 3 ) central dentine after the final excavation . Six sample s of central demineralized dentine were without any cultivable flora increasing to 9 sample s after the final excavation . The clinical dentine changes occurring during stepwise excavation were characterized by enhanced hardness of the dentine which was associated with a marked reduction in bacterial growth after the final excavation . Despite the presence of bacteria in the excavated dentine none of the carious lesions result ed in pulp perforation , suggesting that the initial removal of the cariogenic biomass appears to be essential for control of caries progression . Stepwise excavation is not only an appropriate treatment of deep carious lesions but is also considered a suitable model for microbiological studies to determine the bacteria persisting in clinical ly excavated lesions In a prospect i ve study , partial pulpotomy was performed on six permanent molars with deep carious lesions and pulpal involvement . The bleeding pulp was irrigated with normal tap water until bleeding had stopped and the exposed pulp was covered with calcium hydroxide followed by zinc oxide eugenol , and finally covered with a semipermanent restoration . All teeth showed hard tissue barrier formation , both clinical ly and radiographically , within three months and were free from subjective and objective symptoms through the observation period ( average observation period was 26 months ) . The patients also experienced the therapy positively . These findings and those of others have helped gain more recognition for partial pulpotomy as a strong possible alternative therapy when pulps are exposed by deep carious lesions and a bleeding pulp is exposed during the excavation process . The rationale for this therapy is to remove the infected and /or inflamed pulpal areas beneath the carious lesion and disintegrated tissue . A rapid and simplified procedure would allow the general practitioner to perform this procedure when necessary at dental clinics , without specialist facilities under conditions that avoid unnecessary contamination of the pulp STATEMENT OF PROBLEM The penetration of oral fluids and bacteria at the interface between the cavity walls and amalgam restorations , which is known as marginal leakage , is one of the problems facing restorative dentistry today . This may cause secondary caries and the irritation of the pulp . PURPOSE This in vitro study tested and compared the sealing ability of a cavity varnish and a dental adhesive for decreasing the marginal leakage of high copper amalgam fillings by chemical diffusion technique . MATERIAL AND METHODS The sample s were r and omly divided into three groups . The cavities in the first group were filled with high copper amalgam . In the second and third groups , the cavities were treated with Copalite and Panavia EX adhesives , respectively , before the amalgam fillings were performed . After the periods of 2 hours , 48 hours , 1 week , and 1.5 and 6 months , the amount of calcium diffused through the interface area into the deionized water was measured with inductively coupled plasma . RESULTS Six-month results revealed that using a dental adhesive as an interfacial sealer had significant advantages to reduce microleakage when compared with a conventional copal varnish PURPOSE The purpose of this prospect i ve and r and omized in vivo study was to compare the clinical and radiographic outcomes of an adhesive resin system vs a calcium hydroxide liner for protection of the dentin-pulp complex of primary molars treated with indirect pulp treatment . METHODS Forty-eight primary molars with deep occlusal caries , but without preoperative signs and symptoms of irreversible pulpitis , received indirect pulp treatment and were restored with a composite resin ( Z100 ) . The teeth were r and omly divided into 2 groups according to the material used for protection of the dentin-pulp complex : ( 1 ) adhesive resin system ( Scotchbond Multi Purpose ) ; and ( 2 ) calcium hydroxide liner ( Dycal ) . These teeth were evaluated clinical ly and radiographicaly for 2 years . RESULTS After 2 years , 83 % ( 19/23 ) of the teeth treated with calcium hydroxide and 96 % ( 24/25 ) of teeth treated with only the adhesive resin system presented a successful outcome , as determined by clinical and radiographic examination . Interradicular and /or periapical lesions were the most predominant signs of treatment failure , since 3 out of 23 teeth treated with calcium hydroxide and 1 out of 25 teeth treated with only adhesive resin presented this outcome . One tooth treated with the calcium hydroxide liner was diagnosed with internal root resorption at the 18-month examination . Of the 5 teeth diagnosed from radiographs as a failure of the indirect pulp treatment , none presented clinical signs/symptoms of pulpitis or necrosis such as the presence of fistula , enhanced tooth mobility , or pain . CONCLUSIONS This study demonstrates that protection of the dentin-pulp complex of primary molars with an adhesive resin system results in similar clinical and radiographic 2-year outcomes as compared to calcium hydroxide when indirect pulp treatment is performed in Class I composite restorations OBJECTIVES To analyze the relationship between the cavity depth and liners with postoperative sensitivity of resin composite restorations . METHODS A clinical follow-up was conducted on 319 resin composite restorations made in the final year of an undergraduate program over a 3-year period . Along with the analyses of cavity type , cavity depth , type of pulpal protection and the material s used , the postoperative sensitivity was also examined on each restoration . RESULTS Thirty-nine percent of the restorations had no protective layer ( Group 1 ) . As the depth of the prepared cavities increased , the restorations received one of the three pulpal protection methods ; a calcium hydroxide base ( Group 2 ) , glass ionomer cement ( Group 3 ) , or protection with a calcium hydroxide base in combination with glass ionomer cement ( Group 4 ) . The incidence of postoperative sensitivity showed no significant difference among Groups 1 , 2 and 3 , but was significantly lower in Group 1 than in Group 4 . The restorations made in shallow and medium depth cavities demonstrated significantly less-postoperative sensitivity than those made in deep cavities . The newer generation dentine-bonding agents showed a significantly lower incidence of postoperative sensitivity than the early generation group . CONCLUSIONS Postoperative sensitivity in resin composite restorations was not related to the absence of protective layers but increased with the depth of cavities restored with the resin composite . The type of dentine-bonding agents could also be responsible for postoperative sensitivity PURPOSE To evaluate clinical ly and microscopically the human pulp response when directly capped with an adhesive system or calcium hydroxide over short ( 9 - 12 days ) and long ( 53 - 204 days ) experimental periods . MATERIAL S AND METHODS Fifty-one sound human premolars scheduled for orthodontic extraction , had their pulp horns gently exposed with a diamond point . Debris in the pulp wound was washed out with a sterile saline solution . The pulps were then capped with either an adhesive system ( Scotchbond Multi- Purpose Plus ) or calcium hydroxide . All teeth were subsequently restored with resin-based composite ( Z-100 ) according to the manufacturer 's instructions . After the experimental periods , the teeth were extracted and processed for light microscopic examination . RESULTS Short-term : the pulp tissue capped with SBMP-P exhibited dilated and congested blood vessels associated with a moderate inflammatory response and blanching of pulp cell nuclei . Long-term : no evidence of healing and bridge formation was observed . A persistent mild inflammatory pulp response was present . Micro-abscesses were detected in three cases associated with bacterial infiltration . Calcium hydroxide stimulated early pulp repair and dentin bridging which extended into the longest period The aim of this research was to analyse the long-term clinical behaviour of two dental material s applied as filling under silver amalgam restorations : glass-ionomer cement ( GIC ) and composite resin with adhesive system ( CR ) . In this study , 117 posterior teeth ( 29 premolars and 88 molars ) were selected with carious lesions which result ed in great loss of dentin and cusps with unsupported enamel . After caries removal , cavities were prepared and totally filled with GIC or with CR . In a following visit , new cavities were prepared , leaving the employed filling material as a base and support for the enamel , which were then restored with silver amalgam . Restorations were evaluated periodically after 6 months and up to 5 years . Both fracture and pulpal involvement rates were low . Although differences could be observed in the behaviour of the material s , statistical survival estimation showed that the performances of GIC and CR as filling material were similar . There was a significant association both between kind of tooth ( molar or premolar ) and long-term survival of the restorations ; and between degree of unsupported enamel and the same long-term survival . Our results confirmed that the technique in which GIC or CR are used as filling under silver amalgam restorations is clinical ly acceptable Two hundred direct pulp capping procedures were conducted in the present study . One hundred of them were performed with the CO2 laser , and 100 were conducted conventionally as a control by using a calcium hydroxide preparation . Follow-up examinations were performed after 1 wk and monthly for 12 months after treatment . Thermal tests were used for vitality assessment s and laser Doppler flowmetry for direct measurement of pulpal blood . In the group of pulps treated with the CO2 laser , the last recall examination at 12 months demonstrated that 89 teeth remained vital , corresponding to a success rate of 89 % . In the control group , the success rate was considerably lower ( 68 % ) . Exposure sizes and mean patient age were nearly identical in both groups . The CO2 laser seems to be a valuable aid in direct pulp capping The aim was to assess the prevalence of pulp exposure after stepwise versus direct complete excavation of permanent posterior teeth with deep carious lesions . The material , representing 116 patients aged 6 - 16 yrs ( mean = 10.2 yrs ) , consisted of 127 teeth with radiographs revealing carious lesions to such a depth that pulp exposure could be expected if direct complete excavation was performed . Teeth with clinical symptoms , other than transient pain shortly before treatment , were not accepted . The teeth were r and omly selected for either treatment procedure . Stepwise excavation implied removal of the bulk of carious tissue and application of calcium hydroxide , followed by sealing of the cavity with zinc-oxide eugenol cement . After a period of 8 - 24 weeks the rest of the carious dentin was removed and the cavity sealed with calcium hydroxide , zinc-oxide-eugenol ( ZOE ) and a restorative material . Direct complete excavation entailed removal of all carious dentin followed by sealing as mentioned above . In case of pulp exposure , pulp treatment was performed . The pulp was exposed in 40 of the teeth treated by direct complete excavation . The corresponding figure for those treated by stepwise excavation was 17.5 % . The difference was statistically significant . The teeth with no pulp exposure after direct or stepwise excavation showed normal clinical and radiographic conditions at the last check-up ( mean = 43 months ) AIM To test the hypothesis that dentine and pulp protection by conditioning- and -sealing is no less effective than using a conventional calcium hydroxide lining . METHODOLOGY A cohort of healthy adults requiring a new or replacement restoration in a posterior tooth was recruited in six general practice s. All procedures received local Ethics Committee approval . Exclusion criteria included signs and symptoms of pulp necrosis or inflammation , and patients unable to commit to a long-term trial . Cavity preparations were r and omized to receive a calcium hydroxide lining or conditioning- and -sealing with a smear-removing bonding system . Choice of bulk restorative material ( composite resin or amalgam ) was at the discretion of the dentist . The key outcome measure was evidence of pulpal breakdown identified at unscheduled ( emergency ) or scheduled recall examinations . Postoperative sensitivity was recorded on 100 mm VAS at 24 h , 4 days and 7 days . Pulp status was assessed at 6 , 12 , 24 and 36 month recall , and at any emergency recall appointment . The relationship between pre-treatment and treatment variables and pulp breakdown was assessed by logistic regression ( P = 0.05 ) . RESULTS A total of 602 teeth were recruited , with comparable numbers of cavities lined ( 288 , 47.8 % ) or conditioned and sealed ( 314 , 52.2 % ) . The majority ( 492 , 81.7 % ) were replacement restorations , and amalgam was the most common bulk restorative material ( 377 , 62.6 % ) . A total of 390 ( 64.8 % ) restored teeth were review ed at 6 months , 307 ( 51 % ) at 12 months , 363 ( 60.3 % ) at 24 months , and 279 ( 46.3 % ) at 36 months post-restoration . Sixteen cases of pulp breakdown were identified within 36 months of restoration placement , 11 presenting as emergencies and five detected at routine recall examination . Logistic regression showed that preoperative pain , cavity treatment by lining or conditioning- and -sealing and the use of rubber dam isolation had no association with pulp breakdown . Pulp breakdown was associated with deep or pulpally exposed cavities ( P < 0.001 , odds ratio 7.8 ) and with composite rather than amalgam restorations ( P = 0.001 , odds ratio 2.13 ) . Re-coding to identify teeth with pulp exposures revealed that pulpal exposure was the key determinant of adverse pulp outcomes ( P < 0.0001 , odds ratio 28.4 ) and that composite resin restorations were again more likely to be associated with pulp breakdown than amalgam ( P = 0.017 , odds ratio 3.92 ) . CONCLUSIONS Considered within the context of routine primary dental care : Dentists can be confident that pulps will be equally well protected from post-restorative breakdown up to 36 months by calcium hydroxide lining and conditioning- and -sealing with adhesive resins . Residual dentine thickness appears to be a key determinant of pulp responses after restorative dental treatment . In deep and pulpally exposed cavities in posterior teeth , composites were associated with more pulpal breakdown than amalgams The purpose of this multicenter , prospect i ve clinical study was to assess the treatment results following endodontic therapy using a glass ionomer cement sealer ( Ketac-Endo ) and to relate the results to various clinical factors . A total of 486 teeth were treated by three operators , using the " st and ardized technique " for canal preparation and either single cone or laterally condensed gutta-percha , in one or multiple treatment sessions . Six to 18 months postoperatively , the treatment results were assessed clinical ly and radiographically , and related to preoperative , intraoperative , and postoperative factors using a chi 2 analysis with 5 % level of significance . Of 378 followed-up teeth , there was a 78.3 % success , 15.6 % incomplete healing , and 6.1 % failure . Statistically , differences in the results were related to the number of canals ( p < 0.04 ) , primary treatment and retreatment ( p < 0.02 ) , pulp vitality ( p < 0.001 ) , periapical lesion ( p < 0.001 ) , preoperative symptoms ( p < 0.003 ) , operative complications ( p < 0.001 ) , and absence of restoration ( p < 0.03 ) . It was concluded that these treatment results were compatible with those reported in previous studies , and supported the clinical use of Ketac-Endo as an acceptable endodontic sealer The effects of inflammatory activity following surgical intervention can injure pulp tissues ; in severe cases it can lead to pulpal complications . With this article , the authors report on the effects of cavity preparation and restoration events and how they can interact together to reduce or increase the severity of pulpal inflammatory activity in 202 restored Class V cavities . Although some inflammatory activity was observed in the absence of bacteria , the severity of pulpal inflammatory activity was increased when cavity restorations became infected . Zinc oxide eugenol and resin-modified glass ionomer cement prevented bacterial microleakage in cavity restorations , with no severe inflammatory activity observed with these material s. Bacteria were observed in cavities restored with enamel bonding resin and adhesive bonded composites and were associated with severe grade s of inflammatory activity . The cavity remaining dentin thickness influenced the grade of inflammatory activity . In the absence of infection , the grade of inflammatory activity decreased after 20 weeks post-operatively . In the presence of infection , the grade of pulpal inflammation remained stable until a minimum of 30 weeks had elapsed D uring restorative treatment of teeth in which there are deep carious lesions adjacent to the vital pulp tissues , it is customary to remove all decalcified and stained dentine , thus risking exposure of the pulp . A number of investigations1 - 5 have shown that decayed dentine could be retained , at least temporarily , so that pulpal injury could be avoided during initial cavity preparation . Although residual carious dentine left in the tooth cavity probably contains an appreciable number of microorganisms , there is little evidence available to indicate that such microbes are harmful if they are left in the cavity under a serviceable restoration . Although there have been reports of the successful clinical use of zinc oxide and eugeno16s g and calcium hydroxide4 > 5l lo for indirect pulp capping , clinical studies of the effects of these agents on microorganisms in carious dentine have not been published . The purpose of this investigation was to determine whether the soft residual layer of carious dentine in teeth treated by the indirect pulp-capping method is contaminated with cultivable microorganisms prior to treatment and whether this layer , if contaminated , can be rendered sterile by capping with either calcium hydroxide or zinc oxide and eugenol Direct pulp capping of carious-exposed pulp was performed on 44 teeth . We evaluated the success rates of these cases , and analyzed the relationships between the success rates and their clinical findings . Furthermore , we examined the length of time necessary for adequate postoperative follow-up . The success rate in this study was 81.8 % . Age of the patients , type of teeth , responses to thermal stimuli and percussion , and the diameter of pulpal exposure had no bearing on the success rate . However , the degree of bleeding on pulpal exposure was related to the success rate ( p = 0.042 ) . The success rates of cases in which postoperative follow-up periods were 3 to 18 months were similar ( 80 to 83 % ) , whereas those with follow-up for 21 months ( 91.7 % ) and 24 months ( 100 % ) showed higher success rates . These results showed that direct pulp capping was applicable to carious-exposed pulp , and the degree of bleeding is indicative of the prognosis of this treatment . The length of time necessary for adequate postoperative follow-up was suggested to be 21 months Abstract The efficacy of a calcium hydroxide preparation ( Calnex ) alone and in combination with a proprietary corticosteroid/antibiotic medicament ( Ledermix ) has been tested as a pulp dressing using intraoral comparisons in human first permanent m and ibular molars which were clinical ly diagnosed as having a chronic partial pulpitis associated with a painful active carious lesion . A total of 260 teeth in 130 patients were treated . The patients were divided into two age groups , those less than 7·5 years and those older than 13 years at operation , chosen to represent patients with teeth which were , respectively , newly erupted with incomplete apices and mature with closed apices . Assessment of 174 teeth in 87 patients was undertaken by direct inspection for bridge formation at the exposure site and for an associated vital bleeding pulp , at a six-month post-operative period There was no significant difference in the results obtained with calcium hydroxide alone ( Calnex ) and with calcium hydroxide ( Calnex ) plus a proprietary corticosteroid ( Ledermix ) in either age group , though the association between bridging and vitality was stronger in the older age group

CONCLUSION Tamsulosin increases the rate of spontaneous passage of distal ureterolithiasis ( ≤ 10 mm )

OBJECTIVES The lifetime prevalence of ureterolithiasis is approximately 13 % for men and 7 % for women in the United States . Tamsulosin , an α-antagonist , has been used as therapy to facilitate the expulsion of lithiasis . Whether it is a good treatment for distal lithiasis remains controversial . We conducted a systematic review and meta- analysis to evaluate the effect of tamsulosin on the passage of distal ureterolithiasis .

OBJECTIVES To study the efficacy of alfuzosin compared with tamsulosin in the management of lower ureteral stones . METHODS A total of 102 patients with stones < 1 cm size and located in the lower ureter were enrolled in the present study and r and omized into 3 equal groups . Group 1 patients ( n = 34 ) received 0.4 mg tamsulosin daily , group 2 patients ( n = 34 ) received 10 mg alfuzosin daily , and group 3 patients ( n = 34 ) received placebo ( control group ) . The patients were given 75 mg diclofenac injection intramuscularly on dem and and were followed up for 4 weeks . RESULTS The average stone size for groups 1 , 2 , and 3 was comparable ( 6.17 , 6.70 , and 6.35 mm , respectively ) . Stone expulsion was observed in 28 of 34 patients ( 82.3 % ) in group 1 , 24 of 34 patients ( 70.5 % ) in group 2 , and 12 of 34 patients ( 35.2 % ) in group 3 . The average expulsion time for groups 1 , 2 , and 3 was 12.3 , 14.5 , and 24.5 days , respectively . The results of both study groups ( groups 1 and 2 ) were superior to those in the placebo group ( P = .003 and P = .001 , respectively ) , but the study failed to show any statistically significant differences between tamsulosin and alfuzosin ( P = .25 ) . Alfuzosin was associated with fewer side effects than tamsulosin , especially in terms of retro grade ejaculation . CONCLUSIONS Medical treatment of lower ureteral calculi with tamsulosin and alfuzosin result ed in a significantly increased stone expulsion rate , decreased expulsion time , and a reduced need for analgesic therapy Purpose We evaluated and compared the efficacy of tamsulosin and alfuzosin in the medical treatment of symptomatic , uncomplicated distal ureteral stones . Material s and Methods A total of 87 patients with distal ureteral stones of ≤10 mm were r and omly divided into 3 groups . Group I patients ( n=29 ) received 0.4 mg tamsulosin daily , group II patients ( n=30 ) received 10 mg alfuzosin daily , and group III patients ( n=28 ) were not given tamsulosin or alfuzosin . Patients in all groups received Diclofenac sodium regularly for 1 week and then on dem and . Follow-up was done on a weekly basis for 30 days . Results The mean stone size was comparable in the 3 groups ( 4.97±2.24 , 5.47±2.13 , and 5.39±1.81 mm , respectively ) . The stone expulsion rate was 86.2 % , 76.6 % , and 50 % in groups I , II , and III , respectively . The difference in groups I and II with respect to group III was significant ( p=0.0028 and 0.035 ) . The mean expulsion time for groups I to III was 7.52±7.06 , 8.26±7.34 , and 13.90±6.99 days , respectively . The expulsion time was significantly shorter in groups I and II than in group III ( p=0.0097 and 0.026 ) . Patients taking tamsulosin and alfuzosin had fewer pain attacks than did group III patients ( 1.24±0.57 vs. 1.43±0.67 vs. 1.75±1.17 ) . Only 3 cases of drug side effects , 2 in group I and 1 in group II , were recorded . Conclusions The use of tamsulosin or alfuzosin for the medical treatment of lower ureteric stones proved to be safe and effective . Moreover , tamsulosin did not have any significant benefits over alfuzosin Background : Alpha – 1 blockers decrease the tension and release the spasm of smooth muscles and thus lessen the obstruction and irritation symptoms in the lower urinary tract ( LUTS ) . They make a faster passing of calculi from the terminal part of the ureters possible . Objectives : The goal of this study was to objective ly assess the improvement of difficulties caused by obstructions in ureterolithiasis localized in the lower part of the ureters of 104 r and omly chosen patients ( pts . ) in a double-blind study . Methods : During a period of 2 and half years ( June 1999–January 2002 ) 104 pts . suffering from ureterolithiasis of the lower urinary tract were treated and observed . Patients were divided into two groups : A ( n:53 ; later only 51 were evaluated ) which was subjected to st and ard treatment and group B ( n:51 ) where the st and ard treatment was supplemented by the alpha – 1 blocker . As alpha – 1 blocker one capsule of Tamsulosin /OMNIC 0.4 / was administered daily . Results : With alpha – 1 blocker , we have registered a more speedy passing of calculi from the terminal parts of ureters in 17.6 % of pts . Recurrence of renal colics was less frequent and occurred in one of eight pts . as compared with group A ( without the alpha – 1 blocker ) where a recurrence of the renal colic was observed in about every fifth pts . In group A ( n:51 ) , 62.8 % of the pts . passed the calculi , whereas in group B ( n:51 ) , where st and ard treatment was supplemented by the administration of the alpha – 1 blocker Tamsulosin , this percentage increased to 80.4 % . Conclusion : The treatment by alpha – 1 blockers considerably decreased not only LUTS but also helped to accelerate the passing of minor calculi from the terminal parts of the ureters of 80.4 % of pts . It seems that alpha – 1 blockers potentiate the spasmoanalgetic action of drugs used in st and ard methods of treatment BACKGROUND Numerous r and omised trials have confirmed the efficacy of medical expulsive therapy with tamsulosin in patients with distal ureteral stones ; however , to date , no r and omised , double-blind , placebo-controlled trials have been performed . OBJECTIVE The objective of this trial was to evaluate the efficacy of medical expulsive therapy with tamsulosin in a r and omised , double-blind , placebo-controlled setting . DESIGN , SETTING , AND PARTICIPANTS Patients presenting with single distal ureteral stones < or = 7 mm were included in this trial . INTERVENTION Patients were r and omised in a double-blind fashion to receive either tamsulosin or placebo for 21 d. The medication was discontinued after either stone expulsion or intervention . Abdominal computed tomography was performed to assess the initial and final stone status . MEASUREMENTS AND LIMITATIONS : The primary end point was the stone expulsion rate . Secondary end points were time to stone passage , the amount of analgesic required , the maximum daily pain score , safety of the therapy , and the intervention rate . RESULTS Ten of 100 r and omised patients were excluded from the analysis . No statistically significant differences in patient characteristics and stone size ( median : 4.1 mm [ tamsulosin arm ] vs 3.8 mm [ placebo arm ] , p=0.3 ) were found between the two treatment arms . The stone expulsion rate was not significantly different between the tamsulosin arm ( 86.7 % ) and the placebo arm ( 88.9 % ; p=1.0 ) . Median time to stone passage was 7 d in the tamsulosin arm and 10 d in the placebo arm ( log-rank test , p=0.36 ) . Patients in the tamsulosin arm required significantly fewer analgesics than patients in the placebo arm ( median : 3 vs 7 , p=0.011 ) . A caveat is that the exact time of stone passage was missing for 29 patients . CONCLUSIONS Tamsulosin treatment does not improve the stone expulsion rate in patients with distal ureteral stones < or = 7 mm . Nevertheless , patients may benefit from a supportive analgesic effect . CLINICAL TRIALS.GOV : NCT00831701 PURPOSE To evaluate the efficacy of the addition of tamsulosin to our st and ard expulsive pharmacologic therapy for the treatment of distal-ureteral stones . PATIENTS AND METHODS A series of 96 patients referred to our department for the management of symptomatic distal-ureteral calculi were r and omly divided into group 1 ( N = 46 ) who received diclofenac ( 100 mg/daily ) plus aescin ( 80 mg/daily ) and group 2 ( N = 50 ) who received the same therapy plus tamsulosin ( 0.4 mg/daily ) for a maximum of 2 weeks . There were no differences between the groups with respect to age , sex , or stone size . The primary endpoint was the expulsion rate . Expulsion time , need for analgesics , need for hospitalization , and drug side effects were the secondary endpoints . RESULTS The expulsion rate was significantly higher in group 2 ( 90 % ) than in group 1 ( 58.7 % ; P = 0.01 ) , and group 2 achieved stone passage in a shorter time ( mean 4.4 v 7.5 days , respectively ; P = 0.005 ) . Lower analgesic use was found in group 2 ( P = 0.003 ) , as well as significantly fewer hospitalizations for recurrent colic ( P = 0.01 ) . Both groups experienced few side effects associated with expulsive therapy . CONCLUSIONS A conservative approach should be considered as an option in the management of uncomplicated distal-ureteral stones . Even if the best pharmacologic expulsive regimen remains to be established , the use of the selective alpha-blocker tamsulosin is recommended in this setting OBJECTIVES To evaluate whether alpha1-blockers have any impact on stone clearance in patients with lower ureteral stones who underwent either shock wave lithotripsy ( SWL ) or were followed up with st and ard hydration , analgesics , and anti-inflammatory treatment . METHODS A total of 78 patients ( 56 men and 22 women ) who had lower ureteral stones located at the distal 5 cm of the ureter were divided into four groups . The first group consisted of 30 patients ( 38.5 % ) with stones less than 5 mm ( range 3 to 5 ) who were r and omly divided into two subgroups . Group 1 consisted of 15 patients ( 19.2 % ) who were followed up with oral hydration and diclofenac sodium . Group 2 consisted of 15 patients ( 19.2 % ) who received tamsulosin 0.4 mg daily in addition to the st and ard regimens . The second two groups consisted of 48 patients ( 61.5 % ) with stones greater than 5 mm ( range 6 to 15 ) who underwent SWL . These patients were also r and omly divided between those who did not ( group 3 , n = 24 ) and those who did ( group 4 , n = 24 ) receive tamsulosin 0.4 mg daily . All patients were re-evaluated with plain abdominal x-rays and helical computed tomography 15 days after the beginning of treatment . RESULTS Of the 78 patients , 36 ( 46.2 % ) became stone free . The stone-free rate was 20 % , 53.3 % , 33.3 % , and 70.8 % for group 1 , 2 , 3 , and 4 , respectively . The best results were achieved in those who underwent SWL plus tamsulosin treatment ( group 4 ) . The differences between the stone-free rates for groups 3 versus 4 ( P = 0.019 ) and the tamsulosin versus control groups ( P = 0.0015 ) were statistically significant . CONCLUSIONS The addition of tamsulosin to conventional treatment seemed beneficial in terms of stone clearance of lower ureteral stones , and this effect was more evident for larger stones , especially when combined with SWL Low-dose ( 0.2 mg/day ) and st and ard-dose ( 0.4 mg/day ) tamsulosin were studied in a r and omized controlled trial of 75 out patients with distal ureteroliths in Thail and . Group 1 ( n = 25 ; control ) received oral sodium diclofenac 50 mg twice a day for 10 days ; group 2 ( n = 25 ) received oral sodium diclofenac 50 mg twice a day for 10 days , with oral tamsulosin 0.2 mg once a day up to 28 days ; and group 3 ( n = 25 ) received oral sodium diclofenac 50 mg twice a day for 10 days , with oral tamsulosin 0.4 mg once a day up to 28 days . For groups 1 , 2 and 3 , respectively , the expulsion rates were 4 % , 40 % and 68 % ( significantly different for group 1 vs group 2 , and for group 1 vs group 3 ) and mean expulsion times were 23.00 , 9.30 and 10.76 days . Both doses of tamsulosin increased stone expulsion rate and decreased expulsion time in comparison with the control , and have been shown to be safe and effective in Asian patients PURPOSE Recent studies show the interesting efficacy of different drug combinations for the spontaneous expulsion of distal ureteral stones . We performed a r and omized , prospect i ve study to assess and compare the efficacy of 3 drugs as medical expulsive therapy for distal ureteral calculi . MATERIAL S AND METHODS A total of 210 symptomatic patients with distal ureteral calculi greater than 4 mm were r and omly allocated to home treatment with phloroglucinol , tamsulosin or nifedipine ( groups 1 to 3 , respectively ) . Each group was given a corticosteroid drug and antibiotic prophylaxis with an injectable nonsteroidal anti-inflammatory drug was also used on dem and . The primary end point was the expulsion rate and the secondary end points were expulsion time , analgesic use , need for hospitalization and endoscopic treatment as well as the number of workdays lost , quality of life and drug side effects RESULTS The expulsion rate was significantly higher in group 2 ( 97.1 % ) than in groups 1 ( 64.3 % , p < 0.0001 ) or 3 ( 77.1 % , p < 0.0001 ) . Group 2 significantly achieved stone passage in a shorter time than the other 2 groups and showed a significantly decreased number of hospitalizations as well as a better decrease in endoscopic procedures performed to remove the stone . The control of renal colic pain was significantly superior in group 2 compared with the other groups , result ing in fewer workdays lost . Group 3 showed lower analgesic use and decreased workdays lost compared with group 1 . No difference in side effects was observed among the groups . CONCLUSIONS Medical expulsive therapy should be considered for distal ureterolithiasis without complications before ureteroscopy or extracorporeal lithotripsy . The use of tamsulosin in this treatment regimen produced stone expulsion in almost all cases in a short time , allowing complete home patient treatment PURPOSE To evaluate the clinical role of an alpha(1a-1d)-specific blocker in the medical expulsive therapy of symptomatic lower ureteral stones . MATERIAL S AND METHODS This prospect i ve study was carried out from May 2005 to December 2006 and involved 95 patients . All patients , who had symptomatic lower ureteral stones < 10 mm diameter , were enrolled in this prospect i ve study , and were r and omly divided into three groups using the statistical software programs Plus 1.0 and Plus 2.10 . Group 1 ( 32 patients ) received tamsulosin ( 0.4 mg daily ) , group 2 ( 32 patients ) received terazosin ( 2 mg daily ) , group 3 ( 31 patients ) acted as controls . All patients were diagnosed with x-rays of the kidneys , ureters , and bladder , urinary ultrasonography , and intravenous urography . All patients received the same analgesic regimen and sublingual buprenorphine on dem and . The number of colic episodes , lower urinary tract symptoms , analgesic dosages , and the number of days required for spontaneous passage of the stones were all recorded in a diary . RESULTS Expulsion was observed in 26 of 32 patients in group 1 ( 81 % ) , 25 of 32 in group 2 ( 78 % ) , and 17 of 31 in group 3 ( 55 % ) . The average expulsion time for groups 1 , 2 , and 3 were 6.3 , 6.3 , and 10.1 days , respectively . Mean analgesic dosage per patient in groups 1 , 2 , and 3 were 231 , 256 , and 347 mg , respectively . A statistically significant difference was observed between groups 1 and 2 with respect to group 3 for all three of these parameters . Adverse effects were also seen in 5 of 32 patients in group 2 ( 16 % ) , a statistically significant difference with regard to groups 1 and 3 . CONCLUSIONS Medical treatment with alpha(1a-1d)-blocker proved to be safe and effective as demonstrated by the increased stone expulsion rate and reduced expulsion time , as well as the need for analgesics STUDY OBJECTIVE The alpha-adrenergic antagonist tamsulosin hydrochloride has become an increasingly common adjunct in the treatment of ureteral calculi ; however , its efficacy in a general emergency department ( ED ) population has not been investigated . METHODS We conducted a r and omized , controlled trial of adult ED patients with distal ureteral calculi diagnosed by computed tomography scan . Patients were r and omized to receive either a 10-day course of ibuprofen and oxycodone plus tamsulosin or ibuprofen and oxycodone alone . The primary outcome measure was successful spontaneous ureteral stone expulsion at 14 days . Secondary outcomes included time to stone passage , self-reported pain scores , number of colicky pain episodes , unscheduled return ED/ primary care visits , number of days of missed work/usual function , amount of analgesic used , and adverse events . RESULTS Eighty subjects were enrolled in the study , with 77 completing the trial . Mean stone size was 3.6 mm ( 95 % confidence interval [ CI ] 3.4 to 3.9 ) . Successful spontaneous stone expulsion at 14 days was similar between the groups , with 27 ( 77.1 % ) subjects in the tamsulosin group and 24 ( 64.9 % ) subjects in the st and ard therapy group reporting spontaneous stone passage , a difference of 12 % ( 95 % CI -8.4 % to 32.8 % ) . At 2- , 5- , and 14-day follow-up , there were no clinical ly important ( or statistically significant ) differences between the groups for any secondary outcome measure . No adverse events were reported in either group . CONCLUSION In this cohort of adult ED patients with distal ureteral calculi , treatment with tamsulosin did not substantially improve any of the studied outcome measures compared with treatment with ibuprofen and oxycodone alone OBJECTIVES To evaluate the activity of the therapeutic agents ( tamsulosin and /or tolterodine ) used to accelerate the expulsion of stones and to reduce the probable complications during observation of the medical treatment of distal ureteral stones to allow spontaneous passage . METHODS A total of 120 patients with distal ureteral stones were included in the study . Patients with stones less than 10 mm and allowing urinary flow were included in the study . The patients were studied in four r and omly divided groups . Group 1 patients received tamsulosin 0.4 mg/day , group 2 patients received tamsulosin 0.4 mg/day plus tolterodine 2 mg ( twice a day ) , group 3 patients received tolterodine 2 mg ( twice a day ) , and group 4 patients did not receive any medical treatment ( control group ) . RESULTS Differences among the four groups in patient age and stone dimension were not statistically significant ( P > 0.05 ) . The stone expulsion rates were greater ( P < 0.05 ) in groups 1 and 2 than in groups 3 and 4 . A significant variation ( P < 0.05 ) regarding the time to stone expulsion was observed in groups 1 and 2 . CONCLUSIONS In our study , the use of tamsulosin for the expulsion of distal ureteral stones was effective ; however , the use of tolterodine provided no additional advantages Alpha1-adrenoblocker tamsulosin reduces muscle spasm in the ureteric wall , decreases peristalsis below and raises pressure above the stone thus facilitating stone passage . Patients on tamsulosin had spontaneous stone passage in 73.8 % cases while only 22.4 % patients on routine therapy became stone free . Tamsulosin also shortens hospital stay . Use of tamsulosin 0.4 mg daily in patients with distal ureteric stones is pathogenetically vali date d , is highly clinical ly and cost effective OBJECTIVE To study the impact of tamsulosin on the rate of spontaneous passage of distal ureteral stones . METHODS A total of 100 patients with stones sized 10 mm or smaller , located in the distal part of the ureter were included . Patients were r and omly assigned to 2 equal groups . Group 1 received 0.4 mg tamsulosin once daily and group 2 received placebo . The investigators and the patients were masked to the type of treatment . Patients were followed-up until passage of the stone , or for a maximum of 4 weeks . The number of pain episodes , need for analgesia , stone expulsion rate and time , and possible side effects of medications were observed in both groups . RESULTS Apart from 4 patients in the placebo group who were lost to follow-up , all patients complied with the prescribed medications and continued the study . Stone expulsion occurred in 41 of 50 patients ( 82 % ) in group 1 and in 28 of 46 patients ( 61 % ) in group 2 ( P = .02 ) . The chance of stone expulsion was 3 times higher in the tamsulosin group ( relative risk [ RR ] = 2.93 ; 95 % CI , 1.152 - 7.45 ) . In group 1 , patients with stones sized < or = 5 mm showed a significantly higher expulsion rate compared to those with larger stones ( > 5 mm ) . Age , gender , and stone laterality had no significant impact on the expulsion rate . The expulsion time was significantly shorter in the tamsulosin group ( 6.4 + /- 2.77 days vs 9.87 + /- 5.4 days for groups 1 and 2 , respectively ) . Moreover , the frequency of pain episodes , the need for diclofenac , and its total dosage were significantly lower in the tamsulosin group . Side effects observed in both groups were comparable and mild , and no patient withdrew because of them . CONCLUSIONS Tamsulosin is a safe and effective drug that enhances spontaneous passage of distal ureteral stones sized 10 mm or smaller It has recently been demonstrated that specific adrenoceptors subtypes ( α1A/α1D ) are prevalent in the distal part of the ureter , a finding supporting the interesting results obtained by different groups with the use of tamsulosin in the treatment of distal ureteral calculi . We performed a prospect i ve r and omized study to evaluate the effects of the addition of tamsulosin on our st and ard pharmacological therapy for the treatment of selected ureteral stones . A total of 64 patients referred to our department for the management of symptomatic ureteral calculi were considered . Patients were r and omly divided into two treatment groups : group A ( n=32 ) who received diclofenac ( 100 mg/daily ) plus aescin ( 80 mg/daily ) and group B ( n=32 ) who received the same therapy plus tamsulosin ( 0.4 mg/daily ) for a maximum of 2 weeks . No significant differences were found between the groups for age , gender distribution and mean stone size measured in the single largest dimension at presentation . The stone expulsion rate was 60 % ( 19/32 patients ) for group A and 88 % for ( 28/32 ) for group B with a mean expulsion time of 7.4±2.2 ( range 3.5–12 ) and 4.8±2.7 days ( range 1.8–10.5 ) , respectively . Group B showed a significant advantage in terms of both expulsion rate ( P=0.01 ) and expulsion time ( P=0.005 ) . Different analgesics from those used in the st and ard treatment regimen were required in ten patients in group A ( 31 % ) but only three patients in group B ( 9 % ) . This difference was significant ( P=0.003 ) . Hospitalization for recurrent colic was needed in 21 % of patients in group A ( 7/32 ) and in 9 % in group B ( 3/32 ) ( P=0.01 ) . Only two patients in each group ( 6 % ) experienced minor side effects associated with the expulsive therapy . Our data confirm the efficacy of tamsulosin in the treatment of distal ureteral stones up to 1 cm . This selective α-blocker should therefore be included in the pharmacological regimen of patients when a conservative approach is considered in the treatment of ureteral lithiasis OBJECTIVES To assess the clinical efficacy of the addition of a corticosteroid drug to tamsulosin in the medical-expulsive therapy of distal ureterolithiasis . METHODS Sixty consecutive patients with a symptomatic distal ureteral stone were included in our study and r and omized to one of two home treatment groups . Group 1 patients ( n = 30 ) received tamsulosin ( 0.4 mg daily ) , and group 2 patients ( n = 30 ) were treated with a corticosteroid drug ( deflazacort , 30 mg daily ) plus tamsulosin . The treatment duration was until stone expulsion or 28 days , whichever came first . The primary endpoint of the study was the stone expulsion rate . The secondary endpoints were the expulsion time ; use of analgesics ; number of emergency room admissions , hospitalizations , and workdays lost ; drug side effects ; and quality of life of the patients ( EuroQol question naire , EQ-5D ) during treatment . RESULTS The two groups had a similar expulsion rate ( 90 % for group 1 and 96.7 % for group 2 ; P = 0.612 ) , but the expulsion time was significantly reduced in group 2 patients ( P = 0.036 ) . During the treatment period , we did not observe significant differences between the two groups in the number of emergency room visits or hospitalizations , analgesic use , number of workdays lost , or incidence of drug side effects . The quality of life of the patients during therapy , as determined using the EQ-5D , was similar in both groups . CONCLUSIONS The use of a corticosteroid drug in association with tamsulosin seemed to induce more rapid stone expulsion . In addition , tamsulosin alone as medical-expulsive therapy for distal ureteral calculi had excellent expulsive effectiveness PURPOSE alpha1-Adrenergic blockers have recently been shown to increase the rate of spontaneous passage of distal ureteral stones . We compared efficacy of 3 different alpha1-adrenergic blockers for this purpose . MATERIAL S AND METHODS A total of 114 patients between 18 and 65 years old who had lower ureteral stones were included in the study . Patients were r and omly divided into 4 groups . Group 1 consisted of 28 patients and acted as the control group . Group 2 comprised 29 patients who received tamsulosin , group 3 was 28 patients receiving terazosin and group 4 was 29 patients receiving doxazosin . These agents were given for up to a month and hydration was also recommended simultaneously . Every week patients were controlled with x-rays of the kidneys , ureters , bladder and urinary ultrasonography . Meanwhile the number of pain episodes , analgesic dosage and the number of days for spontaneous passage of the calculi through the ureter were also recorded . RESULTS There were no differences between the groups with respect to age , weight , height , sex and stone size . The calculi passed through the ureter spontaneously in 15 patients in group 1 ( 53.57 % ) , in 23 patients in group 2 ( 79.31 % ) , in 22 patients in group 3 ( 78.57 % ) , and in 22 patients in group 4 ( 75.86 % ) . In groups 2 to 4 the number of pain episodes , expulsion time and analgesic dosage were found to be lower compared with those in group 1 . CONCLUSIONS alpha1-Adrenergic blockers increase the frequency of spontaneous passage of the distal ureteral calculi . All 3 agents tested were equally efficacious Purpose To compare the efficiency and spontaneous expulsion rates of tamsulosin and Rowatinex in patients with distal ureteral stones . Methods Between March and July 2009 , 90 patients with distal ureteral stones < 10 mm in size were included in the study . Patients were r and omized in 3 groups : Group 1 ( n = 31 , those received 0.4 mg tamsulosin once daily ) , Group 2 ( n = 30 , those received 100 mg Rowatinex capsules 3 times a day ) , and Group 3 ( n = 29 , those received diclofenac 100 mg once daily ) . All patients were followed up for 10 days . Results and conclusions Mean age of the patients was 42.4 ± 16.1 ( range , 22–75 ) , 46.5 ± 16.5 ( range , 22–76 ) , and 43.5 ± 16.6 ( range , 18–71 ) years in Groups 1–3 , respectively . On admission , 37.8 % had hematuria and 78.9 % had lower urinary tract symptoms ( LUTS ) . No statistically significant differences were detected between the three groups regarding patient age , gender , mean stone size , stone location , stone site , additional analgesic requirement , number of ureteral colics during the treatment , and upper urinary tract dilation . The mean stone expulsion time was 3.5 days in Group 1 , 6 days in Group 2 , and 7 days in Group 3 ( P = 0.02 ) . Stone expulsion rate was significantly high in Group 1 compared to Group 2 ( P = 0.002 ) . Similarly , stone expulsion rate was significantly high in Group 1 compared to Group 3 ( P = 0.001 ) . Medical treatment with tamsulosin seems to be effective in patients with distal ureteral stones < 10 mm in size . However , use of Rowatinex does not seem to have any significant effect on clearance rate of distal ureteral calculi Objective . To evaluate the potential role of tamsulosin in the medical treatment of distal ureteral stones . Material and methods . Ninety patients with symptomatic distal ureteral calculi were enrolled . They were r and omly divided into two groups : Group A ( n=45 ) received diclofenac 100 mg on dem and for 4 weeks plus levofloxacin 250 mg daily for the first week and were well hydrated ; and Group B ( n=45 ) received the same therapy plus tamsulosin 0.4 mg/daily for 4 weeks . Abdominal ultrasound scans and KUB X-rays were performed weekly . Stone expulsion rates , time to expulsion , pain episodes and analgesic usage were determined . Intervention by means of shock-wave lithotripsy ( SWL ) or ureteroscopy was evaluated . Results . The stone expulsion rate was 51.1 % for Group A , compared to 88.9 % for Group B ( p=0.001 ) . The average time to expulsion was 12.53±2.12 days for Group A and 7.32±0.78 days for Group B ( p=0.04 ) . The number of pain episodes was significantly lower in Group B and mean use of analgesics was lower for Group B ( 0.14±0.5 vials ) than Group A ( 2.78±2.7 vials ) . Twenty-two patients in Group A failed to pass their stones after 4 weeks but only five in Group B. Of the patients who were not stone-free , 19 were treated with SWL and eight underwent ureteroscopy . Conclusion . Our study reveals the efficacy of tamsulosin for the treatment of distal ureteral stones . Tamsulosin should be added to the st and ard medical approach for treating these stones PURPOSE To evaluate efficacy and outcome of tamsulosin therapy for 4 mm-10 mm uncomplicated distal ureteral stones . MATERIAL S AND METHODS A total of 150 patients ( adults with newly diagnosed single unilateral distal ureteral 4 mm-10 mm stones ) were double blindly r and omized into GA or GB . All patients received traditional treatment of hydration and analgesia as needed . Additionally , patients received either placebo ( GA ) or 0.4 mg tamsulosin ( GB ) oral tablets once daily . Treatment and follow up were continued for up to 4 weeks . Endpoints were spontaneous stone passage rates ( SPR ) and passage time for different stone sizes within 4 weeks study period . RESULTS Analysis included 75 patients , in each group , with comparable characteristics . Overall SPR was 56 % in GA and 81.3 % in GB ; achieving significant absolute risk reduction ( ARR = 25.3 % ; p < 0.01 ) and number needed to treat ( NNT ) of 3.95 . SPR for stones < or= 6 mm was 69.2 % in GA versus 90.7 % in GB ( ARR = 21.5 % , p < 0.01 ) . For stones 7 mm-10 mm , SPR was 26.1 % in GA and 57.1 % in GB ( ARR = 31.0 % , p < 0.01 ) . NNT for < or= 6 mm and 7 mm-10 mm stones was 4.65 and 3.23 , respectively ( p < 0.05 ) . Median time for passage of < or= 6 mm stones was 17 versus 9 days in GA and GB ; while for 7 mm-10 mm stones it was 20 versus 15 days , respectively . During the first two weeks , 77.8 % of < or= 6 mm stones in GB have passed versus 23.8 % of 7 mm-10 mm stones . Analgesia consumption was significantly less in GB ( p < 0.01 ) . No significant adverse effects were observed . CONCLUSIONS Tamsulosin therapy for uncomplicated distal ureteral calculi augments SPR , shortens passage time and decrease need for analgesia . Particularly , tamsulosin shortens the passage time for smaller stones , and augments the passage rate for larger stones To evaluate , in a prospect i ve r and omized pilot study , the effectiveness and safety of tamsulosin , administered in patients with distal ureteric stones and who have already undergone an unsuccessful first cycle of medical expulsive therapy ( MET )

Conclusion : While the evidence base is still in its infancy for other therapy approaches , there was clearer evidence that functional connectivity both predicts and is altered by cognitive behavioural therapy . Connections from prefrontal cortex appear especially key , perhaps given their role in cognitive appraisal of lower order affective , motivational and cognitive processes .

Objective : While there is now strong evidence that psychological therapies can alter the activity of individual brain regions , their impact on the functional integration between regions has not yet been systematic ally evaluated . This area is important given that brain dysconnectivity has been implicated across almost all psychiatric disorders . Accordingly , we sought to establish connectivity predictors and mechanisms of effective psychological therapies . We further establish whether connectivity changes represent normalisation of disorder pathophysiology or compensatory changes .

R and omized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy ( iCBT ) for patients with social anxiety disorder ( SAD ) . The present study investigated anxiety-related neural changes after iCBT for SAD . The amygdala is a critical hub in the neural fear network , receptive to change using emotion regulation strategies and a putative target for iCBT . Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3 T assessing neural changes during an affective face processing task . Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement ( CGI-I ) scale . ICBT yielded better outcome than ABM ( 66 % vs. 25 % CGI-I responders ) . A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT . Changes in the amygdala were related to a behavioral measure of social anxiety . Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral ( dlPFC ) cortices . Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general Background : Cognitive behavioral therapy ( CBT ) is an effective treatment for panic disorder with agoraphobia ( PD/AG ) . It is unknown , how variants of CBT differentially modulate brain networks involved in PD/AG . This study was aim ed to evaluate the effects of therapist-guided ( T+ ) versus self-guided ( T- ) exposure on the neural correlates of fear conditioning in PD/AG . Method : In a r and omized , controlled multicenter clinical trial in medication-free patients with PD/AG who were treated with 12 sessions of manualized CBT , functional magnetic resonance imaging ( fMRI ) was used during fear conditioning before ( t1 ) and after CBT ( t2 ) . Quality -controlled fMRI data from 42 patients and 42 healthy subjects ( HS ) were obtained . Patients were r and omized to two variants of CBT ( T+ , n = 22 , and T- , n = 20 ) . Results : The interaction of diagnosis ( PD/AG , HS ) , treatment group ( T+ , T- ) , time point ( t1 , t2 ) and stimulus type ( conditioned stimulus : yes , no ) revealed activation in the left hippocampus and the occipitotemporal cortex . The T+ group demonstrated increased activation of the hippocampus at t2 ( t2 > t1 ) , which was positively correlated with treatment outcome , and a decreased connectivity between the left inferior frontal gyrus and the left hippocampus across time ( t1 > t2 ) . Conclusion : After T+ exposure , contingency-encoding processes related to the posterior hippocampus are augmented and more decoupled from processes of the left inferior frontal gyrus , previously shown to be dysfunctionally activated in PD/AG . Linking single procedural variants to neural substrates offers the potential to inform about the optimization of targeted psychotherapeutic interventions IMPORTANCE Cognitive behavioral therapy ( CBT ) for social anxiety disorder ( SAD ) is thought to enhance cognitive re appraisal in patients with SAD . Such improvements should be evident in cognitive re appraisal -related prefrontal cortex responses . OBJECTIVE To determine whether CBT for SAD modifies cognitive re appraisal -related prefrontal cortex neural signal magnitude and timing when implementing cognitive re appraisal with negative self-beliefs . DESIGN R and omized clinical trial of CBT for SAD vs wait-list control group during a study that enrolled patients from 2007 to 2010 . SETTING University psychology department . PARTICIPANTS Seventy-five patients with generalized SAD r and omly assigned to CBT or wait list . INTERVENTION Sixteen sessions of individual CBT for SAD . MAIN OUTCOME MEASURES Negative emotion ratings and functional magnetic resonance imaging blood oxygen-level dependent signal when reacting to and cognitively reappraising negative self-beliefs embedded in autobiographical social anxiety situations . RESULTS During reactivity trials , compared with wait list , CBT produced ( 1 ) greater reduction in negative emotion ratings and ( 2 ) greater blood oxygen-level dependent signal magnitude in the medial prefrontal cortex . During cognitive re appraisal trials , compared with wait list , CBT produced ( 3 ) greater reduction in negative emotion ratings , ( 4 ) greater blood oxygen level-dependent signal magnitude in the dorsolateral and dorsomedial prefrontal cortex , ( 5 ) earlier temporal onset of dorsomedial prefrontal cortex activity , and ( 6 ) greater dorsomedial prefrontal cortex-amygdala inverse functional connectivity . CONCLUSIONS AND RELEVANCE Modulation of cognitive re appraisal -related brain responses , timing , and functional connectivity may be important brain changes that contribute to the effectiveness of CBT for social anxiety . This study demonstrates that clinical ly applied neuroscience investigations can eluci date neurobiological mechanisms of change in psychiatric conditions . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00380731 Social anxiety disorder patients suffer from excessive anxious responses in social interaction leading to avoidance behavior and social impairment . Although the amygdala has a central role in perception and processing of threatening cues , little is known about the involved networks and corresponding dysfunctions in social anxiety . Therefore , this study aims to investigate the functional connectivity network of the amygdala in patients with social anxiety disorder and to identify regions that might influence amygdalar reactivity via modulatory pathways . Ten patients with anxiety disorders ( social and /or panic ) and 27 healthy controls underwent a facial emotion processing task as well as 6-min functional MRI at resting state . Individual voxel-wise functional connectivity maps were calculated using the amygdala as seed region . Group comparisons were done by r and om-effects analysis in SPM . Patients exhibited an amygdala hyperactivation during the emotional task and decreased functional coupling of the left amygdala with the medial orbitofrontal cortex and the posterior cingulate cortex/precuneus . The strength of this functional connectivity showed a negative association with the severity of state anxiety . In addition , an exploratory analysis revealed further reduced functional connectivity and a marked functional separation between the medial orbitofrontal and anterior cingulate cortices in the patient group . Our results suggest alterations within the amygdalar functional connectivity network in social anxiety disorder . Combined with the amygdalar hyperactivation our findings corroborate the proposed dysfunction of the fronto-amygdalar inhibition in anxiety disorders and indicate a modulatory influence of the anterior and posterior cingulate cortices on threat perception and processing BACKGROUND Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment . Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia ( PD/A ) . Cognitive-behavioral therapy ( CBT ) is an effective treatment for PD/A. However , the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown . METHODS In a r and omized , controlled , multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT , functional magnetic resonance imaging ( fMRI ) was used during fear conditioning before and after CBT . Quality -controlled fMRI data from 42 patients and 42 healthy subjects were obtained . RESULTS After CBT , patients compared to control subjects revealed reduced activation for the conditioned response ( CS+ > CS- ) in the left inferior frontal gyrus ( IFG ) . This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2 . Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the " fear network " ( amygdalae , insulae , anterior cingulate cortex ) across time . CONCLUSIONS This study demonstrates the link between cerebral correlates of cognitive ( IFG ) and emotional ( " fear network " ) processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments One component of mindfulness training ( MT ) is the development of interoceptive attention ( IA ) to visceral bodily sensations , facilitated through daily practice s such as breath monitoring . Using functional magnetic resonance imaging ( fMRI ) , we examined experience-dependent functional plasticity in accessing interoceptive representations by comparing graduates of a Mindfulness-Based Stress Reduction course to a waitlisted control group . IA to respiratory sensations was contrasted against two visual tasks , controlling for attentional requirements non-specific to IA such as maintaining sensation and suppressing distraction . In anatomically partitioned analyses of insula activity , MT predicted greater IA-related activity in anterior dysgranular insula regions , consistent with greater integration of interoceptive sensation with external context . MT also predicted decreased recruitment of the dorsomedial prefrontal cortex ( DMPFC ) during IA , and altered functional connectivity between the DMPFC and the posterior insula , putative primary interoceptive cortex . Furthermore , meditation practice compliance predicted greater posterior insula and reduced visual pathway recruitment during IA . These findings suggest that interoceptive training modulates task-specific cortical recruitment , analogous to training-related plasticity observed in the external senses . Further , DMPFC modulation of IA networks may be an important mechanism by which MT alters information processing in the brain , increasing the contribution of interoception to perceptual experience Background Given the variable response to cognitive – behavioral therapy ( CBT ) when added to antipsychotic medication in psychosis and the evidence for a role of pretherapy level of frontal lobe – based cognitive function in responsiveness to CBT in other disorders , this study examined whether pretherapy brain activity associated with working memory neural network predicts clinical responsiveness to CBT in schizophrenia . Methods Fifty-two out patients stable on medication with at least one distressing symptom of schizophrenia and willing to receive CBT in addition to their usual treatment and 20 healthy participants underwent functional magnetic resonance imaging during a parametric n-back task . Subsequently , 26 patients received CBT for psychosis ( CBT+treatment-as-usual [ TAU ] , 19 completers ) for 6–8 months , and 26 continued with TAU alone ( 17 completers ) . Symptoms in both patient groups were assessed ( blindly ) at entry and follow-up . Results The CBT+TAU and TAU-alone groups did not differ clinical ly or in performance at baseline . The CBT+TAU group showed significant improvement in relation to the TAU-alone group , which showed no change , at follow-up . Stronger dorsolateral prefrontal cortex ( DLPFC ) activity ( within the normal range ) and DLPFC – cerebellum connectivity during the highest memory load condition ( 2-back > 0-back ) were associated with post-CBT clinical improvement . Conclusions DLPFC activity and its connectivity with the cerebellum predict responsiveness to CBT for psychosis in schizophrenia . These effects may be mediated by PFC – cerebellum contributions to executive processing Neuroimaging research has demonstrated that ventromedial prefrontal cortex ( vmPFC ) encodes value signals that can be modulated by top-down cognitive input such as semantic knowledge , price incentives , and monetary favors suggesting that such biases may have an identified biological basis . It has been hypothesized that mindfulness training ( MT ) provides one path for gaining control over such top-down influences ; yet , there have been no direct tests of this hypothesis . Here , we probe the behavioral and neural effects of MT on value signals in vmPFC in a r and omized longitudinal design of 8 weeks of MT on an initially naïve subject cohort . The impact of this within-subject training was assessed using two paradigms : one that employed primary rewards ( fruit juice ) in a simple conditioning task and another that used a well-vali date d art-viewing paradigm to test bias of monetary favors on preference . We show that MT behaviorally censors the top-down bias of monetary favors through a measurable influence on value signals in vmPFC . MT also modulates value signals in vmPFC to primary reward delivery . Using a separate cohort of subjects we show that 8 weeks of active control training ( ACT ) generates the same behavioral impact also through an effect on signals in the vmPFC . Importantly , functional connectivity analyses show that value signals in vmPFC are coupled with bilateral posterior insula in the MT groups in both paradigms , but not in the ACT groups . These results suggest that MT integrates interoceptive input from insular cortex in the context of value computations of both primary and secondary rewards

No consistent evidence showed that IIT reduced long-term mortality , infection rates , length of stay , or the need for renal replacement therapy . Risk for IIT-associated hypoglycemia was increased in all hospital setting s. LIMITATIONS Method ological shortcomings and inconsistencies limit the data in perioperative care , myocardial infa rct ion , and stroke or brain injury setting s. Differences in insulin protocol s and patient and hospital characteristics may affect generalizability across treatment setting s. CONCLUSION No consistent evidence demonstrates that IIT targeted to strict glycemic control compared with less strict glycemic control improves health outcomes in hospitalized patients . Furthermore , IIT is associated with an increased risk for severe hypoglycemia .

BACKGROUND The benefits and harms of intensive insulin therapy ( IIT ) titrated to strict glycemic targets in hospitalized patients remain uncertain . PURPOSE To evaluate the benefits and harms of IIT in hospitalized patients .

OBJECTIVE There is conflicting evidence regarding the benefit of intravenous insulin therapy on mortality following acute myocardial infa rct ion ( AMI ) . The goal of the current study was to determine whether improved glycemic control , achieved through an insulin/dextrose infusion with a variable rate of insulin , reduces mortality among hyperglycemic patients with AMI . RESEARCH DESIGN AND METHODS Subjects suffering AMI with either known diabetes or without diabetes but blood glucose level ( BGL ) > or = 7.8 mmol/l were r and omized to receive insulin/dextrose infusion therapy for at least 24 h to maintain a BGL < 10 mmol/l or conventional therapy . RESULTS A total of 240 subjects were recruited . Insulin/dextrose infusion did not reduce mortality at the inpatient stage ( 4.8 vs. conventional 3.5 % , P = 0.75 ) , 3 months ( 7.1 vs 4.4 % , P = 0.42 ) , or 6 months ( 7.9 vs. 6.1 % , P = 0.62 ) . There was , however , a lower incidence of cardiac failure ( 12.7 vs. 22.8 % , P = 0.04 ) and reinfa rct ion within 3 months ( 2.4 vs. 6.1 % , P = 0.05 ) . When analyzed by mean BGL achieved during the first 24 h , mortality was lower among subjects with a mean BGL < or = 8 mmol/l , compared with subjects with a mean BGL > 8 mmol/l ( 2 vs. 11 % at 6 months , P = 0.02 ) . CONCLUSIONS We did not find a reduction in mortality among patients who received insulin/dextrose infusion therapy . However , it remains possible that tight glycemic control with insulin therapy following AMI improves outcomes PURPOSE Hospitalized patients with type 2 diabetes mellitus traditionally receive insulin on a sliding-scale regimen , but the benefits of this approach are unclear . The purpose of this study was to compare the effects of the sliding scale insulin regimen with those of routine diabetes medications on hyperglycemia , hypoglycemia and length of hospitalization in diabetic patients hospitalized for other conditions . METHODS This was a multicenter , r and omized controlled trial conducted in family medicine inpatient services . One hundred fifty-three patients with type 2 diabetes mellitus hospitalized for other conditions were r and omized to receive routine diabetes medications ( control ) or the combination of a st and ard sliding-scale insulin regimen and routine diabetes medications ( intervention ) . The outcome measures included frequency of hyperglycemia and hypoglycemia ( glycemic events ) , and length of hospitalization . RESULTS No differences were identified between treatment groups in the frequency of glycemic events . In the intervention group , 33.3 % of patients developed hyperglycemia compared to 34.6 % in the control group ( P = .87 ) . Six patients developed hypoglycemia in the intervention group , compared with 7 in the control group ( P = .83 ) . There was no difference in length of hospitalization ( P = .86 ) . Regardless of treatment assignment , patients receiving intermediate-acting insulin ( OR , 2.8 ; 95 % CI , 1.2–6.5 ) , those with blood glucose values greater than 250 mg/dL at baseline ( OR , 6.3 ; 95 % CI , 2.3 – 17.2 ) and those receiving corticosteroids ( OR , 9.1 ; 95 % CI , 3.1 – 27.0 ) were more likely to have glycemic events . CONCLUSIONS The use of the sliding scale insulin regimen in combination with routine diabetes medications does not affect the rate of hyperglycemia , hypoglycemia or length of hospitalization in patients with type 2 diabetes mellitus hospitalized for other conditions OBJECTIVE Recent studies suggest that strict perioperative glycemic control improves clinical outcomes after cardiothoracic surgery . However , optimal methods and targets for controlling blood glucose ( BG ) levels in this setting have not been established . Currently published intensive insulin infusion protocol s ( IIPs ) have important practical limitations , which may affect their utility . In this article , the authors present their experience with a safe , effective , nurse-driven IIP , which was implemented simultaneously in 2 cardiothoracic intensive care units ( CTICUs ) . DESIGN Prospect i ve cohort study . SETTING Tertiary referral hospital and community teaching hospital . PARTICIPANTS CTICU patients . INTERVENTIONS A st and ardized , intensive IIP was used for all patients admitted to both CTICUs . Hourly BG levels , relevant baseline variables , and clinical interventions were collected prospect ively from the active hospital chart and CTICU nursing records . MEASUREMENTS AND MAIN RESULTS The IIP was used 137 times in 118 patients . The median time required to reach target BG levels ( 100 - 139 mg/dL ) was 5 hours . Once BG levels decreased below 140 mg/dL , 58 % of 2,242 subsequent hourly BG values fell within the narrow target range , 73 % within a " clinical ly desirable " range of 80 to 139 mg/dL , and 94 % within a " clinical ly acceptable " range of 80 to 199 mg/dL. Only 5 ( 0.2 % ) BG values were less than 60 mg/dL , with no associated adverse clinical events . CONCLUSIONS The IIP safely and effectively improved glycemic control in 2 CTICUs , with minimal hypoglycemia . Based on prior studies showing the benefits of strict glycemic control , the implementation of this IIP should help to reduce morbidity and mortality in CTICU patients OBJECTIVES We tested how insulin-glucose infusion followed by multidose insulin treatment in diabetic patients with acute myocardial infa rct ion affected mortality during the subsequent 12 months of follow-up . BACKGROUND Despite significant improvements in acute coronary care , diabetic patients with acute myocardial infa rct ion still have a high mortality rate . METHODS A total of 620 patients were studied : 306 r and omized to treatment with insulin-glucose infusion followed by multidose subcutaneous insulin for > or = 3 months and 314 to conventional therapy . RESULTS The two groups were well matched for baseline characteristics . Blood glucose decreased from 15.4 + /- 4.1 to 9.6 + /- 3.3 mmol/liter ( mean + /- SD ) in the infusion group during the 1st 24 h , and from 15.7 + /- 4.2 to 11.7 + /- 4.1 among control patients ( p < 0.0001 ) . After 1 year 57 subjects ( 18.6 % ) in the infusion group and 82 ( 26.1 % ) in the control group had died ( relative mortality reduction 29 % , p = 0.027 ) . The mortality reduction was particularly evident in patients who had a low cardiovascular risk profile and no previous insulin treatment ( 3-month mortality rate 6.5 % in the infusion group vs. 13.5 % in the control group [ relative reduction 52 % , p = 0.046 ] ; 1-year mortality rate 8.6 % in the infusion group vs. 18.0 % in the control group [ relative reduction 52 % , p = 0.020 ] ) . CONCLUSIONS Insulin-glucose infusion followed by a multidose insulin regimen improved long-term prognosis in diabetic patients with acute myocardial infa rct ion CONTEXT While glucose control is recommended by professional societies for patients with hyperglycemia hospitalized with acute myocardial infa rct ion ( AMI ) , enthusiasm for glucose lowering is tempered , in part , by concerns of inducing hypoglycemia . Yet , whether episodic hypoglycemia that occurs as a result of glucose-lowering therapy is harmful in patients with AMI is unknown . OBJECTIVE To determine whether the mortality risk associated with hypoglycemic events is similar in patients who develop hypoglycemia spontaneously and those who develop it as a result of insulin therapy . DESIGN , SETTING , AND PATIENTS Retrospective cohort study using data from Health Facts , a contemporary data base of patients hospitalized across the United States in 40 hospitals between January 1 , 2000 , and December 31 , 2005 . Of all the patients in the data base , 7820 patients were hospitalized with AMI and were hyperglycemic on admission ( glucose level > or = 140 mg/dL ) . Patients were stratified based on whether they developed a hypoglycemic event ( r and om glucose level < 60 mg/dL ) during subsequent hospitalization . Logistic regression models were used to evaluate the association between hypoglycemia and in-hospital mortality within subgroups of patients who were and were not treated with insulin therapy . MAIN OUTCOME MEASURE All-cause in-hospital mortality . RESULTS Among patients treated or not treated with insulin , those with hypoglycemia were older and had more comorbidity . Hypoglycemia was associated with increased mortality in patients not treated with insulin ( 18.4 % [ 25/136 ] mortality in patients with hypoglycemia vs 9.2 % [ 425/4639 ] in those without hypoglycemia ; P<.001 ) , but not in those treated with insulin ( 10.4 % [ 36/346 ] mortality in patients with hypoglycemia vs 10.2 % [ 276/2699 ] in those without hypoglycemia ; P = .92 ) . After multivariable adjustment , there was a significant interaction between hypoglycemia and insulin therapy ( P value for interaction = .01 ) . Hypoglycemia was a predictor of higher mortality in patients who were not treated with insulin ( odds ratio , 2.32 [ 95 % confidence interval , 1.31 - 4.12 ] vs patients without hypoglycemia ) , but not in patients treated with insulin ( odds ratio , 0.92 [ 95 % confidence interval , 0.58 - 1.45 ] vs patients without hypoglycemia ) . CONCLUSIONS While hypoglycemia was associated with increased mortality in patients with AMI , this risk was confined to patients who developed hypoglycemia spontaneously . In contrast , iatrogenic hypoglycemia after insulin therapy was not associated with higher mortality risk CONTEXT Hyperglycemia is common in critically ill patients , even in those without diabetes mellitus . Aggressive glycemic control may reduce mortality in this population . However , the relationship between mortality , the control of hyperglycemia , and the administration of exogenous insulin is unclear . OBJECTIVE To determine whether blood glucose level or quantity of insulin administered is associated with reduced mortality in critically ill patients . DESIGN , SETTING , AND PATIENTS Single-center , prospect i ve , observational study of 531 patients ( median age , 64 years ) newly admitted over the first 6 months of 2002 to an adult intensive care unit ( ICU ) in a UK national referral center for cardiorespiratory surgery and medicine . MAIN OUTCOME MEASURES The primary end point was intensive care unit ( ICU ) mortality . Secondary end points were hospital mortality , ICU and hospital length of stay , and predicted threshold glucose level associated with risk of death . RESULTS Of 531 patients admitted to the ICU , 523 underwent analysis of their glycemic control . Twenty-four-hour control of blood glucose levels was variable . Rates of ICU and hospital mortality were 5.2 % and 5.7 % , respectively ; median lengths of stay were 1.8 ( interquartile range , 0.9 - 3.7 ) days and 6 ( interquartile range , 4.5 - 8.3 ) days , respectively . Multivariable logistic regression demonstrated that increased administration of insulin was positively and significantly associated with ICU mortality ( odds ratio , 1.02 [ 95 % confidence interval , 1.01 - 1.04 ] at a prevailing glucose level of 111 - 144 mg/dL [ 6.1 - 8.0 mmol/L ] for a 1-IU/d increase ) , suggesting that mortality benefits are attributable to glycemic control rather than increased administration of insulin . Also , the regression models suggest that a mortality benefit accrues below a predicted threshold glucose level of 144 to 200 mg/dL ( 8.0 - 11.1 mmol/L ) , with a speculative upper limit of 145 mg/dL ( 8.0 mmol/L ) for the target blood glucose level . CONCLUSIONS Increased insulin administration is positively associated with death in the ICU regardless of the prevailing blood glucose level . Thus , control of glucose levels rather than of absolute levels of exogenous insulin appear to account for the mortality benefit associated with intensive insulin therapy demonstrated by others Good blood glucose control in hospitalized adults leads to reduced mortality . Intravenous ( IV ) insulin has been shown to be an effective way to achieve tight control of blood glucose . Managing IV insulin is a labor-intensive task for nurses and is generally done in intensive care units with high nurse-to-patient ratios . In this 3-month study , intermediate-care general medicine units with a nurse-to-patient ratio of 1 to 5 or 6 were evaluated for effectiveness of monitoring IV insulin . The project , which relied on intensive in-service education , an audit tool , and continuous positive feedback for nurses , yielded positive results Admission hyperglycemia has been associated with increased hospital mortality in critically ill patients ; however , it is not known whether hyperglycemia in patients admitted to general hospital wards is associated with poor outcome . The aim of this study was to determine the prevalence of in-hospital hyperglycemia and determine the survival and functional outcome of patients with hyperglycemia with and without a history of diabetes . We review ed the medical records of 2030 consecutive adult patients admitted to Georgia Baptist Medical Center , a community teaching hospital in downtown Atlanta , GA , from July 1 , 1998 , to October 20 , 1998 . New hyperglycemia was defined as an admission or in-hospital fasting glucose level of 126 mg/dl ( 7 mmol/liter ) or more or a r and om blood glucose level of 200 mg/dl ( 11.1 mmol/liter ) or more on 2 or more determinations . Hyperglycemia was present in 38 % of patients admitted to the hospital , of whom 26 % had a known history of diabetes , and 12 % had no history of diabetes before the admission . Newly discovered hyperglycemia was associated with higher in-hospital mortality rate ( 16 % ) compared with those patients with a prior history of diabetes ( 3 % ) and subjects with normoglycemia ( 1.7 % ; both P < 0.01 ) . In addition , new hyperglycemic patients had a longer length of hospital stay , a higher admission rate to an intensive care unit , and were less likely to be discharged to home , frequently requiring transfer to a transitional care unit or nursing home facility . Our results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without a history of diabetes . Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome than patients with a known history of diabetes or normoglycemia BACKGROUND Hyperglycemia is common among patients admitted to intensive care units , and carries the risk for complications and prolonged ICU stay . With intensive insulin control of blood glucose , morbidity and mortality can be reduced . OBJECTIVES To determine whether intensive or conventional insulin control of blood glucose in hyperglycemic ICU patients correlated with the prognosis . METHODS Following admission to the ICU , hyperglycemic patients were r and omly assigned to a group treated intensively with insulin targeting glucose at 110 - 140 mg/dl , or to a conventional insulin therapy group , where glucose , upon exceeding 200 mg/dl , was controlled at 140 - 200 mg/dl . Rates of morbidity and mortality , hypoglycemic episodes , and insulin dosage were compared . RESULTS In the 41 patients treated intensively with insulin the glucose level was 142 + /- 14 mg/dl , as compared to 174+/-20 mg/dl in the 48 patients on conventional insulin treatment . Both groups were similar in age , acute physiology and chronic health evaluation score . Morbidity was also similar , except for increased vascular damage in the conventional treatment group and slightly shorter ICU stay in the intensive therapy group . Both groups had similar in-ICU , in-hospital , and 28 day mortalities , and similar rates of hypoglycemic episodes . The daily dosage of insulin was significantly higher with the conventional treatment ( P= 0.004 ) . CONCLUSIONS Intensive insulin treatment did not affect the mortality or morbidity rates in ICU patients . The increased insulin dosage of conventional insulin treatment was attributable to the group 's higher prevalence of diabetes . Future studies should address this bias and determine the optimal glucose target Background —This study sought to determine whether tight glycemic control with a modified glucose-insulin-potassium ( GIK ) solution in diabetic coronary artery bypass graft ( CABG ) patients would improve perioperative outcomes . Methods and Results —One hundred forty-one diabetic patients undergoing CABG were prospect ively r and omized to tight glycemic control ( serum glucose , 125 to 200 mg/dL ) with GIK or st and ard therapy ( serum glucose < 250 mg/dL ) using intermittent subcutaneous insulin beginning before anesthesia and continuing for 12 hours after surgery . GIK patients had lower serum glucose levels ( 138±4 versus 260±6 mg/dL ; P < 0.0001 ) , a lower incidence of atrial fibrillation ( 16.6 % versus 42 % ; P = 0.0017 ) , and a shorter postoperative length of stay ( 6.5±0.1 versus 9.2±0.3 days ; P = 0.003 ) . GIK patients also showed a survival advantage over the initial 2 years after surgery ( P = 0.04 ) and decreased episodes of recurrent ischemia ( 5 % versus 19 % ; P = 0.01 ) and developed fewer recurrent wound infections ( 1 % versus 10 % , P = 0.03 ) . Conclusions —Tight glycemic control with GIK in diabetic CABG patients improves perioperative outcomes , enhances survival , and decreases the incidence of ischemic events and wound complications ABSTRACT Background : Hyperglycemia is common in hospitalized patients ; however , glycemic control obtained during hospitalization is often suboptimal . No methods for achievement of proper glycemic control in this population have been vali date d in the in-hospital setting . Aims : To study the effect of a novel intensive subcutaneous insulin protocol on the quality of in-hospital glycemic control . Methods : Included in this prospect i ve controlled study were all diabetic patients admitted to the internal medicine departments in a tertiary medical center during a 1-year period . The study was divided into pre-intervention ( n = 94 ) , intervention ( n = 102 ) and post-intervention ( n = 79 ) periods . During the intervention period all hospitalized diabetic patients with blood glucose > 200 mg/dL were treated with an intensive multi-injection protocol consisting of two or four times daily regular/NPH insulin injections . Results : Mean glucose level throughout hospitalization was 178.7 ± 47 mg/dL in the intervention period versus 198.8 ± 60 mg/dL in the pre-intervention period ( p < 0.05 ) . During the intervention period , the difference between mean admission and discharge day glucose levels was 43 mg/dL in patients treated with four times daily insulin injections , in contrast to no change noted in the other treatment groups . During the post-intervention period the rate of implementation of the intensive protocol by the internal medicine teams declined to 47.5 % , in contrast to a 78.4 % implementation rate during the intervention period . This decline was associated with deterioration of glycemic control . Conclusions : The use of intensified insulin regimen improved the glycemic control of hospitalized diabetic patients . Successful incorporation of such intensive protocol s into daily medical routines requires close involvement and continuous physician guidance by the hospital diabetes team Objectives : Evaluate the impact of a tight glucose control ( TGC ) protocol during the first week of admission in critically injured trauma patients . Methods : A prospect i ve quasi-experimental interrupted time-series design was used to evaluate the impact of TGC [ 24-month preintervention phase ( no TGC ) vs. 24-month postintervention phase ] . Patients were stratified by serum glucose level on day 1 to 7 ( low , 0–150 mg/dL ; medium-high , 151–219 mg/dL ; and high , ≥220 mg/dL ) , age , gender , and injury severity . Patients were further stratified by pattern of glucose control ( all low , all medium high , all high , improving , worsening , highly variable ) . Outcome was measured by ventilator days , infection , hospital ( HLOS ) and ICU ( ILOS ) length of stay , and mortality . Results : One thous and twenty-one patients were evaluated in the preintervention phase as compared with 1108 patients in the postintervention phase . There was no significant difference in mechanism of injury ( 83 % vs. 84 % blunt ) , gender ( 74 % vs. 73 % male ) , age ( 44 vs. 43 years ) , and Injury Severity Score ( ISS ) ( 26 vs. 25 ) . The TGC group was more likely to be in the all low and improving pattern of glucose control ( P < 0.001 ) . The incidence of infection significantly decreased ( over the first 2 weeks ) from 29 % to 21 % in the TGC group ( P < 0.001 ) . Ventilator days ( OR = 3.9 , 1.8 , 8.1 ) , ILOS ( OR = 4.3 , 2.1 , 7.5 ) , and HLOS ( OR = 5.5 , 2.2 , 11 ) and mortality ( OR = 1.4 , 1.1 , 10 ) were significantly higher in the non-TGC group when controlled for age , ISS , obesity , and diabetes ( P < 0.01 ) . Conclusion : The positive outcomes associated with the implementation of a TGC protocol necessitates further evaluation in a r and omized prospect i ve trial CONTEXT Elevated blood glucose levels occur frequently in the critically ill . Tight glucose control by intensive insulin treatment markedly improves clinical outcome . OBJECTIVE AND DESIGN This is a r and omized controlled trial comparing blood glucose control by a laptop-based model predictive control algorithm with a variable sampling rate [ enhanced model predictive control ( eMPC ) ; version 1.04.03 ] against a routine glucose management protocol ( RMP ) during the peri- and postoperative periods . SETTING The study was performed at the Department of Cardiac Surgery , University Hospital . PATIENTS A total of 60 elective cardiac surgery patients were included in the study . INTERVENTIONS Elective cardiac surgery and treatment with continuous insulin infusion ( eMPC ) or continuous insulin infusion combined with iv insulin boluses ( RMP ) to maintain euglycemia ( target range 4.4 - 6.1 mmol/liter ) were performed . There were 30 patients r and omized for eMPC and 30 for RMP treatment . Blood glucose was measured in 1- to 4-h intervals as requested by each algorithm during surgery and postoperatively over 24 h. MAIN OUTCOME MEASURES Mean blood glucose , percentage of time in target range , and hypoglycemia events were used . RESULTS Mean blood glucose was 6.2 + /- 1.1 mmol/liter in the eMPC vs. 7.2 + /- 1.1 mmol/liter in the RMP group ( P < 0.05 ) ; percentage of time in the target range was 60.4 + /- 22.8 % for the eMPC vs. 27.5 + /- 16.2 % for the RMP group ( P < 0.05 ) . No severe hypoglycemia ( blood glucose < 2.9 mmol/liter ) occurred during the study . Mean insulin infusion rate was 4.7 + /- 3.3 IU/h in the eMPC vs. 2.6 + /- 1.7 IU/h in the RMP group ( P < 0.05 ) . Mean sampling interval was 1.5 + /- 0.3 h in the eMPC vs. 2.1 + /- 0.2 h in the RMP group ( P < 0.05 ) . CONCLUSIONS Compared with RMP , the eMPC algorithm was more effective and comparably safe in maintaining euglycemia in cardiac surgery patients Introduction Intensive insulin therapy ( IIT ) with tight glycemic control may reduce mortality and morbidity in critically ill patients and has been widely adopted in practice throughout the world . However , there is only one r and omized controlled trial showing unequivocal benefit to this approach and that study population was dominated by post-cardiac surgery patients . We aim ed to determine the association between IIT and mortality in a mixed population of critically ill patients . Methods We conducted a cohort study comparing three consecutive time periods before and after IIT protocol implementation in a Level 1 trauma center : period I ( no protocol ) ; period II , target glucose 80 to 130 mg/dL ; and period III , target glucose 80 to 110 mg/dL. Subjects were 10,456 patients admitted to intensive care units ( ICUs ) between 1 March 2001 and 28 February 2005 . The main study endpoints were ICU and hospital mortality , Sequential Organ Failure Assessment score , and occurrence of hypoglycemia . Multivariable regression analysis was used to evaluate mortality and organ dysfunction during periods II and III relative to period I. Results Insulin administration increased over time ( 9 % period I , 25 % period II , and 42 % period III ) . Nonetheless , patients in period III had a tendency toward higher adjusted hospital mortality ( odds ratio [ OR ] 1.15 , 95 % confidence interval [ CI ] 0.98 , 1.35 ) than patients in period I. Excess hospital mortality in period III was present primarily in patients with an ICU length of stay of 3 days or less ( OR 1.47 , 95 % CI 1.11 , 1.93 There was an approximately fourfold increase in the incidence of hypoglycemia from periods I to III . Conclusion A policy of IIT in a group of ICUs from a single institution was not associated with a decrease in hospital mortality . These results , combined with the findings from several recent r and omized trials , suggest that further study is needed prior to widespread implementation of IIT in critically ill patients OBJECTIVE To determine the safety and efficacy of an intensive insulin regimen compared with a conventional insulin regimen in general intensive care unit patients . METHODS A phase II , r and omised controlled trial was conducted in 70 critically ill patients in a closed multidisciplinary ICU of a university-affiliated tertiary hospital . We assessed patient characteristics at baseline . Trial process measures included number of blood glucose measurements per day and number in target range , type and quantity of caloric intake , patient outcome and insulin dosing . The primary outcome was the median blood glucose concentration . Secondary outcome measures were incidence of hypoglycaemia ( blood glucose level < 2.2 mmol/L ) , clinical sequelae of hypoglycaemia and hospital mortality . RESULTS Thirty-five patients were r and omised to each of the two groups . More blood glucose sample s were taken per day in the intensive insulin group ( 16 versus 9 ) , but the number of sample s in the normoglycaemic range was 48.5 % , compared with 79.8 % within the target glucose range in the conventional insulin group . The median ( interquartile range ) blood glucose concentrations in the intensive and conventional insulin therapy groups were 5.4 ( 5.1 - 5.7 ) mmol/L and 7.9 ( 7.2 - 9.0 ) mmol/L , respectively ( difference , 2.5 mmol/L ; P < 0.0001 ) . Five patients ( 14.3 % ) in the intensive insulin therapy group became hypoglycaemic versus none in the conventional insulin therapy group . There were no detected clinical sequelae of hypoglycaemia . CONCLUSION The intensive insulin regimen was effective in achieving the target blood glucose concentration , with clear separation from the conventional insulin regimen . Although the incidence of hypoglycaemia was increased , there was no detectable harm UNLABELLED We attempted to develop an insulin administration protocol that maintains normoglycemia in patients undergoing cardiac surgery and to study the effects of intraoperative blood glucose management on serum levels of creatine phosphokinase isoenzyme BB ( CK-BB ) and S-100 protein . Twenty nondiabetic patients were r and omly allocated to receive either " tight control " of blood glucose with a st and ardized IV insulin infusion intraoperatively ( Group TC ) or " no control " of blood glucose intraoperatively ( Group NC ) . Perioperative serum levels of glucose , CK-BB , and S-100 protein were determined in all patients . Group TC patients received 90.0 + /- 49.2 units of insulin , whereas Group NC patients received none . Despite insulin , both Group TC ( P = 0.00026 ) and Group NC ( P = 0.00003 ) experienced similar significant increases in blood glucose levels during hypothermic cardiopulmonary bypass . However , mean blood glucose level upon intensive care unit arrival was significantly decreased in Group TC , compared with Group NC ( 84.7 + /- 41.0 mg/dL , range 32 - 137 mg/dL vs 201.4 + /- 67.5 mg/dL , range 82 - 277 mg/dL , respectively ; P = 0.0002 ) . Forty percent of Group TC patients required treatment for postoperative hypoglycemia ( blood glucose level < 60 mg/dL ) . Substantial interindividual variability existed in regard to insulin resistance . The investigation was terminated after we realized that normoglycemia was unattainable with the study protocol and that postoperative hypoglycemia was unpredictable . All patients in both groups experienced similar significant increases in postoperative serum levels of CK-BB and S-100 protein . These results indicate that " tight control " of intraoperative blood glucose in nondiabetic patients undergoing cardiac surgery was unattainable with the study protocol and may initiate postoperative hypoglycemia . IMPLICATION S The appropriate intraoperative management of hyperglycemia and whether it adversely affects neurologic outcome in patients after cardiac surgery remains controversial . This investigation reveals that attempting to maintain normoglycemia in this setting with insulin may initiate postoperative hypoglycemia Background : In patients with acute ischaemic stroke , hyperglycaemia has been retrospectively associated with negative outcome . There is an ongoing discussion as to which treatment algorithm , if any , provides the most effective prospect i ve intervention . Here we test the safety and feasibility of an intravenous insulin-only infusion protocol design ed for pragmatic routine clinical use . Methods : 40 ischaemic stroke patients with onset < 24 h ago , admitted to our stroke unit , were r and omized either to the study regimen ( 50 IU insulin in 50 ml 0.9 % saline solution applied intravenously via a perfusor pump ) , with the aim of reaching and maintaining blood glucose levels between 4.44 mmol/l ( 80 mg/dl ) and 6.11 mmol/l ( 110 mg/dl ) , or were treated with insulin subcutaneously if concentrations were above 11.10 mmol/l ( 200 mg/dl ) . Treatment was continued for 5 days . Primary outcome was the number of hypoglycaemic ( < 3.33 mmol/l ; < 60 mg/dl ) and severe hyperglycaemic ( > 16.65 mmol/l ; > 300 mg/dl ) events . Results : Hypoglycaemic events were significantly more common in patients treated intensively ( total n = 25 ; incidence rate ratio , IRR = 5.3 ; 95 % CI = 1.2–22.4 ; p < 0.05 ) . Symptomatic events were rare ( total n = 5 ) . Severe hyperglycaemia was associated with conventional treatment ( IRR = 4.9 ; 95 % CI = 1.5–15.9 ; p < 0.05 ) . Though those treated intensively attained near-normoglycaemic levels quicker and had significantly lower blood glucose levels over the study period ( 6.49 ± 2.19 mmol/l vs. 8.01 ± 3.06 mmol/l ; 95 % CI = –1.78 to –1.28 , p < 0.0005 ) , treatment imposes considerable strain on both patients and caregivers . Conclusions : The intensive intravenous insulin infusion protocol effectively lowers blood glucose levels with an increased risk of manageable hypoglycaemic events . However , a highly motivated and trained staff seems essential , limiting feasibility outside of specialty care setting Background and Purpose — Hyperglycemia may worsen brain injury during acute cerebral infa rct ion . We tested the feasibility and tolerability of aggressive hyperglycemia correction with intravenous insulin compared with usual care during acute cerebral infa rct ion . Methods — We conducted a r and omized , multicenter , blinded pilot trial for patients with cerebral infa rct ion within 12 hours after onset , a baseline glucose value ≥8.3 mmol/L ( ≥150 mg/dL ) , and a National Institutes of Health Stroke Scale score of 3 to 22 . Patients were r and omized 2:1 to aggressive treatment with continuous intravenous insulin or subcutaneous insulin QID as needed ( usual care ) . Target glucose levels were < 7.2 mmol/L ( < 130 mg/dL ) in the aggressive-treatment group and < 11.1 mmol/L ( < 200 mg/dL ) in the usual-care group . Glucose was monitored every 1 to 2 hours , and the protocol treatments continued for up to 72 hours . Final clinical outcomes were assessed at 3 months . Results — We r and omized 46 patients ( 31 to aggressive treatment and 15 to usual care ) . All patients in the aggressive-treatment group and 11 ( 73 % ) in the usual-care group had diabetes ( P=0.008 ) . Glucose levels were significantly lower in the aggressive-treatment group throughout protocol treatment ( 7.4 vs 10.5 mmol/L [ 133 vs 190 mg/dL ] , P<0.001 ) . Hypoglycemia < 3.3 mmol/L ( < 60 mg/dL ) occurred only in the aggressive-treatment group ( 11 patients , 35 % ) , 4 ( 13 % ) of whom had brief symptoms , including only 1 ( 3 % ) neurologic . Final clinical outcomes were nonsignificantly better in the aggressive-treatment group . Conclusions — The intravenous insulin protocol corrected hyperglycemia during acute cerebral infa rct ion significantly better than usual care without major adverse events and should be investigated in a clinical efficacy trial OBJECTIVE Hyperglycemia worsens outcomes in critical illness . This r and omized , double-blind , placebo-controlled clinical trial tested whether insulin treatment of hyperglycemia during cardiopulmonary bypass would reduce neurologic , neuro-ophthalmologic , and neurobehavioral outcomes after coronary artery bypass grafting . METHODS Three hundred eighty-one nondiabetic patients undergoing isolated coronary artery bypass grafting were given infusions of insulin or placebo when their blood glucose concentration exceeded 100 mg/dL during cardiopulmonary bypass . The primary outcome measure was the combined incidence of new neurologic , neuro-ophthalmologic , or neurobehavioral deficits or neurologic death observed at 4 to 8 days postoperatively . This same measure was assessed secondarily at 6 weeks and 6 months . Length of hospital stay was also compared as a secondary assessment . RESULTS The 2 groups were well matched at baseline . The insulin-treated group had significantly lower blood glucose concentrations during bypass . Sixty-six percent of subjects in the insulin-treated group and 67 % of subjects in the control group demonstrated a new or worsening neurologic , neuro-ophthalmologic , or neurobehavioral deficit or neurologic death at the 4- to 8-day assessment . Outcomes were also similar in the 2 groups at 6 weeks ( 37 % and 39 % incidence , respectively ) and 6 months ( 30 % and 25 % , respectively ) . Median lengths of stay were 7 and 6 days , respectively , in the treatment and control groups . None of these outcome differences was statistically significant . CONCLUSION Attempted control of hyperglycemia during cardiopulmonary bypass had no significant effect on the combined incidence of neurologic , neuro-ophthalmologic , or neurobehavioral deficits or neurologic death and failed to shorten the length of hospital stay . These results do not contradict those of other studies showing that aggressive control of hyperglycemia in the postoperative period will improve outcome Objective Elevated blood glucose is associated with poor outcome in patients resuscitated from out-of-hospital cardiac arrest ( OHCA ) . Our aim was to determine whether strict glucose control with intensive insulin treatment improves outcome of OHCA patients . Design A r and omized , controlled trial . Setting Two university hospital intensive care units . Patients Ninety patients resuscitated from OHCA with ventricular fibrillation detected as the initial rhythm were treated with therapeutic hypothermia . Interventions Patients were r and omized into two treatment groups : a strict glucose control group ( SGC group ) , with a blood glucose target of 4–6 mmol/l , or a moderate glucose control group ( MGC group ) , with a blood glucose target of 6–8 mmol/l . Both groups were treated with insulin infusion for 48 h , because a control group with no treatment was considered unethical . Measurements and results Baseline data were similar in both groups . In the SGC group 71 % of the glucose measurements were within the target range compared with 41 % in the MGC group . Median glucose was 5.0 mmol/l in the SGC group and 6.4 mmol/l in the MGC group . The occurrence of moderate hypoglycemic episodes was 18 % in the SGC group and 2 % in the MGC group ( p = 0.008 ) . No episodes of severe hypoglycemia occurred . Mortality by day 30 was 33 % in the SGC group and 35 % in the MGC group ( p = 0.846 ) ; the difference was 2 % ( 95 % CI –18 % to + 22 % ) . Conclusions We found no additional survival benefit from strict glucose control compared with moderate glucose control with a target between 6 and 8 mmol/l in OHCA patients OBJECTIVE To compare two subcutaneous insulin strategies for glycemic management of hyperglycemia in non – critically ill hospitalized patients with diabetes during enteral nutrition therapy ( ENT ) . RESEARCH DESIGN AND METHODS Fifty in patients were prospect ively r and omized to receive sliding-scale regular insulin ( SSRI ) alone ( n = 25 ) or in combination with insulin glargine ( n = 25 ) . NPH insulin was added for persistent hyperglycemia in the SSRI group ( glucose > 10 mmol/l ) . RESULTS Glycemic control was similar in the SSRI and glargine groups ( mean ± SD study glucose 8.9 ± 1.6 vs. 9.2 ± 1.6 mmol/l , respectively ; P = 0.71 ) . NPH insulin was added in 48 % of the SSRI group subjects . There were no group differences in frequency of hypoglycemia ( 1.3 ± 4.1 vs. 1.1 ± 1.8 % ; P = 0.35 ) , total adverse events , or length of stay . CONCLUSIONS Both insulin strategies ( SSRI with the addition of NPH for persistent hyperglycemia and glargine ) demonstrated similar efficacy and safety in non – critically ill hospitalized patients with type 2 diabetes during ENT BACKGROUND Hyperglycemia in patients undergoing coronary artery bypass grafting ( CABG ) is associated with adverse outcome . Although insulin infusion strategies are increasingly used to improve outcome , a pathophysiological rationale is currently lacking . The present study was design ed to quantify the effects of a perioperative hyperinsulinemic normoglycemic clamp on the neurohumoral stress response during CABG . METHODS Forty-four nondiabetic patients , scheduled for elective CABG , were r and omized to either a control group ( n = 22 ) receiving st and ard care or to a clamp group ( n = 22 ) receiving additionally a perioperative hyperinsulinemic ( regular insulin at a fixed rate of 0.1 IU.kg(-1).h(-1 ) ) normoglycemic ( plasma glucose between 3.0 and 6.0 mmol.liter(-1 ) ) clamp during 26 h. We measured the endocrine response of the hypothalamus-pituitary-adrenal ( HPA ) axis , the sympathoadrenal axis , and glucagon , as well as plasma glucose and insulin at regular intervals from the induction of anesthesia at baseline through the end of the second postoperative day ( POD ) . RESULTS There were no differences in clinical outcome between the groups . In the control group , hyperglycemia developed at the end of surgery and remained present until the final measurement point on POD2 , whereas plasma insulin levels remained unchanged until the morning of POD1 . In the intervention group , normoglycemia was well maintained during the clamp , whereas insulin levels ranged between 600 and 800 pmol.liter(-1 ) . In both groups , plasma ACTH and cortisol increased from 6 h after discontinuation of cardiopulmonary bypass onward . However , during the clamp period , a marked reduction in the HPA axis response was found in the intervention group , as reflected by a 47 % smaller increase in area under the curve in plasma ACTH ( P = 0.035 ) and a 27 % smaller increase in plasma cortisol ( P = 0.002 ) compared with the control group . Compared with baseline , epinephrine and norepinephrine increased by the end of the clamp interval until POD2 in both groups . Surprisingly , the area under the curve of epinephrine levels was 47 % higher ( P = 0.026 ) after the clamp interval in the intervention group as compared with the control group . CONCLUSION A hyperinsulinemic normoglycemic clamp during CABG delays and attenuates the HPA axis response during the first 18 h of the myocardial reperfusion period , whereas after the clamp , plasma epinephrine is higher . The impact of delaying cortisol responses on clinical outcome of CABG remains to be eluci date Background : A growing body of evidence suggests that hyperglycemia is an independent predictor of increased cardiovascular risk . Aggressive glycemic control in the intensive care decreases mortality . The benefit of glycemic control in noncardiac surgery is unknown . Methods : In a single-center , prospect i ve , unblinded , active-control study , 236 patients were r and omly assigned to continuous insulin infusion ( target glucose 100–150 mg/dl ) or to a st and ard intermittent insulin bolus ( treat glucose > 150 mg/dl ) in patients undergoing peripheral vascular bypass , abdominal aortic aneurysm repair , or below- or above-knee amputation . The treatments began at the start of surgery and continued for 48 h. The primary endpoint was a composite of all-cause death , myocardial infa rct ion , and acute congestive heart failure . The secondary endpoints were blood glucose concentrations , rates of hypoglycemia ( < 60 mg/dl ) and hyperglycemia ( > 150 mg/dl ) , graft failure or reintervention , wound infection , acute renal insufficiency , and duration of stay . Results : The groups were well balanced for baseline characteristics , except for older age in the intervention group . There was a significant reduction in primary endpoint ( 3.5 % ) in the intervention group compared with the control group ( 12.3 % ) ( relative risk , 0.29 ; 95 % confidence interval , 0.10–0.83 ; P = 0.013 ) . The secondary endpoints were similar . Hypoglycemia occurred in 8.8 % of the intervention group compared with 4.1 % of the control group ( P = 0.14 ) . Multivariate analysis demonstrated that continuous insulin infusion was a negative independent predictor ( odds ratio , 0.28 ; 95 % confidence interval , 0.09–0.87 ; P = 0.027 ) , whereas previous coronary artery disease was a positive predictor of adverse events . Conclusion : Continuous insulin infusion reduces perioperative myocardial infa rct ion after vascular surgery In this paper , the design of an expert proportional-integral-derivative ( PID ) control system for blood glucose regulation in patients , such as the intensive care population , is described . The control system applied the concept of expert system , and proportional , integral and derivative control in clinical sliding table technique , to effect a control algorithm in the form of an " active " sliding table that is used to prescribe insulin infusion rates . This combination provided dynamic properties to the sliding table control . Clinical results have shown a comparable performance between the control system and routine clinical treatment , in terms of blood glucose level maintained . Nevertheless , the control system is sensitive to sensor reading artefact , particularly in the lower ranges of blood glucose level , m and ating manual intervention OBJECTIVE Diabetes mellitus is a risk factor for death after coronary artery bypass grafting . Its relative risk may be related to the level of perioperative hyperglycemia . We hypothesized that strict glucose control with a continuous insulin infusion in the perioperative period would reduce hospital mortality . METHODS All patients with diabetes undergoing coronary artery bypass grafting ( n = 3554 ) were treated aggressively with either subcutaneous insulin ( 1987 - 1991 ) or with continuous insulin infusion ( 1992 - 2001 ) for hyperglycemia . Predicted and observed hospital mortalities were compared with both internal and external ( Society of Thoracic Surgeons 1996 ) multivariable risk models . RESULTS Observed mortality with continuous insulin infusion ( 2.5 % , n = 65/2612 ) was significantly lower than with subcutaneous insulin ( 5.3 % , n = 50/942 , P < .0001 ) . Likewise , glucose control was significantly better with continuous insulin infusion ( 177 + /- 30 mg/dL vs 213 + /- 41 mg/dL , P < .0001 ) . For internal comparison , multivariable analysis showed that continuous insulin infusion was independently protective against death ( odds ratio 0.43 , P = .001 ) . Conversely , cardiogenic shock , renal failure , reoperation , nonelective operative status , older age , concomitant peripheral or cerebral vascular disease , decreasing ejection fraction , unstable angina , and history of atrial fibrillation increased the risk of death . For external comparison , observed mortality with continuous insulin infusion was significantly less than that predicted by the model ( observed/expected ratio 0.63 , P < .001 ) . Multivariable analysis revealed that continuous insulin infusion added an independently protective effect against death ( odds ratio 0.50 , P = .005 ) to the constellation of risk factors in the Society of Thoracic Surgeons risk model . CONCLUSION Continuous insulin infusion eliminates the incremental increase in in-hospital mortality after coronary artery bypass grafting associated with diabetes . The protective effect of continuous insulin infusion may stem from the effective metabolic use of excess glucose to favorably alter pathways of myocardial adenosine triphosphate production . Continuous insulin infusion should become the st and ard of care for glycometabolic control in patients with diabetes undergoing coronary artery bypass grafting There is now widespread appreciation of the importance of maintaining glucose levels as close to the normal range as possible among out patients with diabetes . However , the importance of tight glucose control in in patients is less well established . During the past several years , it has become apparent that hyperglycemia in hospitalized patients , especially those in the postoperative setting , is associated with poorer outcomes . In addition , two r and omized trials have shown improved outcomes with intensive glucose management in acutely ill patients . Based on these studies and our own experience , we propose guidelines and a framework for improving the glycemic control of hospitalized patients AIMS The study evaluated the associations between glycometabolic parameters at admission and during hospitalization and 2 year all-cause mortality risk in an unselected cohort of consecutive patients with diabetes admitted for unstable angina or non-Q-wave myocardial infa rct ion to a university hospital during 1988 - 98 . METHODS AND RESULTS A total of 713 consecutive patients with diabetes were included . During 2 years of follow-up , 242 ( 34 % ) patients died . All analyses were retrospective using prospect ively collected clinical data . The primary study endpoint was 2 year all-cause mortality collected from the Swedish cause-specific mortality register . In unadjusted analyses , high admission blood glucose ( highest vs. lowest quartile : hazard ratio ( HR ) 2.66 ; 95 % confidence interval ( CI ) 1.83 , 3.86 ) and hypoglycaemia recorded during hospitalization ( hypoglycaemia vs. normal : HR 1.77 ; 95 % CI 1.09 , 2.86 ) were both significantly associated with increased 2 year all-cause mortality risk . These associations remained significant after multivariable adjustment . CONCLUSION In the setting of acute coronary syndromes ( ACS ) among patients with diabetes , hyperglycaemia on arrival and hypoglycaemia during hospitalization are both independently associated with worse adjusted all-cause 2 year mortality risk . These observations suggest that the avoidance of both hyper- and hypoglycaemia during ACS events may be of similar importance , and glucose modulation remains an important objective to address in future r and omized trials OBJECTIVE To examine the practical difficulties in managing hyperglycaemia in critical illness and to present recently developed model-based glycaemic management protocol s to provide tight control . BACKGROUND Hyperglycaemia is prevalent in critical care . Current published protocol s require significant added clinical effort and have highly variable results . No currently published methods successfully address the practical clinical difficulties and patient variation , while also providing safe , tight control . METHODS We developed a unique model-based approach that manages both nutritional inputs and exogenous insulin infusions . Computerised glycaemic control methods and proof-of-concept clinical trial results are presented . The protocol has been simplified to a set of tables and adopted as a clinical practice change . Eight pilot test cases are presented to demonstrate the overall approach . RESULTS Computerised control methods lowered blood glucose ( BG ) levels to the range 4.0 - 6.1 mmol/L within 10 hours . Over 90 % of pre-set hourly blood glucose targets were achieved within measurement error . Eight pilot tests of the simplified , table-based SPRINT protocol , covering 1651 patient-hours produced an average BG level of 5.7 mmol/L ( SD , 0.9 mmol/L ) . BG levels were in the 4.0 - 6.1 mmol/L b and for 60 % of the controlled time . Just under 90 % of measurements were in the range 4.0 - 7.0 mmol/L , with 96 % in the range 4.0 - 7.75 mmol/L. There were no hypoglycaemic episodes , with a minimum glucose level of 3.2 mmol/L , and no additional clinical intervention was required . SUMMARY The overall approach of modulating nutrition as well as insulin challenges the current practice of relying on insulin alone to reduce glycaemic levels , which often results in large variability and poor control . The protocol was developed from model-based analysis and proof-of-concept clinical trials , and then generalised to a simple , clinical practice improvement . The results show extremely tight control within safe glycaemic b and OBJECTIVE This study was undertaken to determine whether GIK infusion improves hemodynamic performance by reducing the use of inotropic agents , as well as the morbidity of diabetic patients su bmi tted to CABG . METHODS Patients with type 2 DM referred for CABG were r and omized to receive GIK or subcutaneous insulin from anesthetic induction up to 12 hours postoperatively . The primary clinical outcome was the cardiac index ( CI ) and the secondary clinical outcomes were the remaining hemodynamic parameters ; the use of inotropics and vasodilators , the glycemic control ( maintenance of plasma glucose levels ) , and the postoperative morbidity . Hemodynamic and laboratory measurements were performed in the first 24 hours postoperatively , and the patients were followed up for 30 days to detect any surgery-related complications . RESULTS Twenty-four patients were r and omly included in the study . IC did not show significant difference ( mean cardiac index at 24 hours in both GIK group 3.49+/-0.94 and Control group 3.38+/-0.75 ; p=0.74 ) . The GIK group revealed lower blood glucose levels in the infusion period ( glucose at 12 hours GIK group 195.6+/-68.25 versus Control group 269.6+/-78.48 ; p=0.02 ) , with a lower incidence of hyperglycemia in the GIK group , two ( 16 % ) against eight ( 64 % ) in the control group ( RR 0.25 ; 95 % CI 0.07 - 0.94 ; p=0.03 ) . Postoperative infectious complications were less frequent in the GIK group than in Control group , three ( 25 % ) against 10 ( 80 % ) , respectively ( RR 0.30 ; 95 % CI 0.11 - 0.83 ; p=0.01 ) . CONCLUSIONS Studies have proven that GIK improves hemodynamic performance of both patients with or without DM su bmi tted to CABG , what was not confirmed in this study . The use of GIK neither improved the CI improvement nor reduced the use of inotropic drugs , but it provided better glucose control . Secondary clinical outcome , including postoperative infections , was more frequent in the control group Although there have been reports in the surgical literature regarding the negative effects of preoperative hyperglycemia on outcome , the impact of elevated preoperative serum glucose levels in trauma patients is unknown . Our objectives were to determine whether preoperative hyperglycemia was associated with a greater morbidity and mortality in trauma patients who underwent surgical intervention upon admission . Prospect i ve data was collected on 252 consecutive nondiabetic trauma patients admitted for ≥3 days who went directly to the OR from the resuscitation area . Patients were stratified by preoperative serum glucose level ( < 200 vs. ≥200 mg/dL ) age , gender , Injury Severity Score ( ISS ) , and other preexisting risk factors . Outcome was measured by incidence of infection , hospital ( HLOS ) and ICU ( ILOS ) length of stay , and mortality . Multiple linear regression models were used to evaluate serum glucose in relation to other preoperative risk factors . Blunt trauma accounted for the majority ( 86 % ) of the injuries . Orthopedic procedures were the most common ( 36 % ) followed by neurosurgical ( 22 % ) , abdominal ( 22 % ) , and thoracic ( 6 % ) . Patients with elevated serum glucose had a significantly greater incidence of infection , HLOS , ILOS , and mortality matched per age and ISS . Elevated serum glucose on admission is an accurate predictor of postoperative infection , HLOS , ILOS , and mortality . A r and omized prospect i ve trial evaluating the impact of preoperative glucose control is warranted OBJECTIVE To determine whether once-daily insulin glargine could provide better glycemic control after an abdominal surgical procedure than the traditional use of sliding scale regular insulin ( SSRI ) . METHODS Because 20 % to 30 % of patients undergoing gastric bypass have a history of overt diabetes and another 5 % to 10 % are estimated to have impaired glucose tolerance , we chose to study these patients . We treated 81 patients with postoperative blood glucose levels of more than 144 mg/dL after a Roux-en-Y gastric bypass surgical procedure . They were r and omized to receive either SSRI or insulin glargine either directly or after initial intravenous insulin infusion in the intensive care unit ( ICU ) . RESULTS Overall , the mean blood glucose level after SSRI therapy was 154 + /- 33 mg/dL , and the mean blood glucose value after insulin glargine treatment was 134 + /- 30 mg/dL ( P<0.01 ) . The mean blood glucose level for patients first treated with intravenous insulin infusion in the ICU was 125 mg/dL , in comparison with 145 mg/dL in the non-ICU patients whose treatment began directly with 0.3 U/kg of insulin glargine . Of 926 blood glucose measurements , only 3 were less than 60 mg/dL. CONCLUSION In this study , control of postoperative hyperglycemia was significantly better with use of insulin glargine in comparison with SSRI therapy , and hypoglycemia was very infrequent BACKGROUND : Critically ill cardiothoracic patients are prone to hyperglycemia and an increased risk of surgical site infections postoperatively . Aggressive insulin treatment is required to achieve tight glycemic control ( TGC ) and improve outcomes . OBJECTIVE : To examine and report on the performance of an insulin infusion protocol to maintain TGC , defined as a blood glucose level of 80–150 mg/dL , in critically ill cardiothoracic surgical patients . METHODS : A nurse-driven insulin infusion protocol was developed and initiated in postoperative cardiothoracic surgical intensive care patients with or without diabetes . In this before — after cohort study , 2 periods of measurement were performed : a 6–month baseline period prior to the initiation of the insulin infusion protocol ( control group , n = 174 ) followed by a 6–month intervention period in which the protocol was used ( TGC group , n = 168 ) . RESULTS : Findings showed percent and time of blood glucose measurements within the TGC range ( control 47 % vs TGC 61 % ; p = 0.001 ) , AUC of glucose exposure > 150 mg/dL versus time for the first 24 hours of the insulin infusion ( control 28.4 vs TGC 14.8 ; p < 0.001 ) , median time to blood glucose < 150 mg/dL ( control 9.4 h vs TGC 2.1 h ; p < 0.001 ) , and percent blood glucose < 65 mg/dL as a marker for hypoglycemia ( control 9.8 % vs TGC 16.7 % ; NS ) . CONCLUSIONS : An insulin infusion protocol design ed to achieve a goal blood glucose range of 80–150 mg/dL efficiently and significantly improved TGC in critically ill postoperative cardiothoracic surgery patients without significantly increasing the incidence of hypoglycemia BACKGROUND Diabetes mellitus is a risk factor for deep sternal wound infection after open heart surgical procedures . We previously showed that elevated postoperative blood glucose levels are a predictor of deep sternal wound infection in diabetic patients . Therefore , we hypothesized that aggressive intravenous pharmacologic control of postoperative blood glucose levels would reduce the incidence of deep sternal wound infection . METHODS In a prospect i ve study of 2,467 consecutive diabetic patients who underwent open heart surgical procedures between 1987 and 1997 , perioperative blood glucose levels were recorded every 1 to 2 hours . Patients were classified into two sequential groups : the control group included 968 patients treated with sliding-scale-guided intermittent subcutaneous insulin injections ( SQI ) ; the study group included 1,499 patients treated with a continuous intravenous insulin infusion in an attempt to maintain a blood glucose level of less than 200 mg/dL. There were no differences between these groups with respect to age , sex , procedure , bypass time , antibiotic prophylaxis , or skin preparation methods . RESULTS Compared with subcutaneous insulin injections , continuous intravenous insulin infusion induced a significant reduction in perioperative blood glucose levels , which led to a significant reduction in the incidence of deep sternal wound infection in the continuous intravenous insulin infusion group ( 0.8 % [ 12 of 1,499 ] ) versus the intermittent subcutaneous insulin injection group ( 2.0 % [ 19 of 968 ] , p = 0.01 by the chi2 test ) . Multivariate logistic regression revealed that continuous intravenous insulin infusion induced a significant decrease in the risk of deep sternal wound infection ( p = 0.005 ; relative risk , 0.34 ) , whereas obesity ( p < 0.03 ; relative risk , 1.06 ) and use of an internal thoracic artery pedicle ( p = 0.1 ; relative risk , 2.0 ) increased the risk of deep sternal wound infection . CONCLUSIONS Use of perioperative continuous intravenous insulin infusion in diabetic patients undergoing open heart surgical procedures significantly reduces major infectious morbidity and its associated socioeconomic costs OBJECTIVE The aim of this study was to compare a st and ard insulin protocol with a computer-guided glucose management system to determine which method achieves tighter glucose control . DESIGN A prospect i ve , r and omized trial . SETTING A cardiothoracic intensive care unit ( ICU ) in a large academic medical center . PARTICIPANTS Forty patients with diabetes mellitus who were scheduled for cardiac surgery . INTERVENTIONS After induction of anesthesia and for the first 9 hours in the ICU , each subject received a st and ardized infusion of a 10 % glucose solution at a rate of 1.0 mL/kg/h ( ideal body weight ) . The subjects were then r and omized to have their glucose controlled by either a paper-based insulin protocol or by a computer-guided glucose management system ( CG ) . The desired range for blood glucose was set between 90 and 150 mg/dL. MEASUREMENTS AND MAIN RESULTS There were no differences between groups in baseline characteristics . Patients in the CG group spent more time in the desired range during both the intraoperative phase ( 49 % v 27 % , p = 0.001 ) and the ICU phase ( 84 % v 60 % , p < 0.0001 ) . There were no statistical differences between groups in the number of hypoglycemia episodes . CONCLUSIONS The computer-guided glucose management system achieved tighter blood glucose control than a st and ard paper-based protocol in diabetic patients undergoing cardiac surgery . However , the low proportion of blood glucose recordings within the desired range in both groups during the intraoperative period reflects the challenges associated with achieving normoglycemia during cardiac surgery Objective : The role of intensive insulin therapy in medical surgical intensive care patients remains unclear . The objective of this study was to examine the effect of intensive insulin therapy on mortality in medical surgical intensive care unit patients . Design : R and omized controlled trial . Setting s : Tertiary care intensive care unit . Patients : Medical surgical intensive care unit patients with admission blood glucose of > 6.1 mmol/L or 110 mg/dL. Intervention : A total of 523 patients were r and omly assigned to receive intensive insulin therapy ( target blood glucose 4.4–6.1 mmol/L or 80–110 mg/dL ) or conventional insulin therapy ( target blood glucose 10–11.1 mmol/L or 180–200 mg/dL ) . Measurements and Main Outcomes : The primary end point was intensive care unit mortality . Secondary end points included hospital mortality , intensive care unit and hospital length of stay , mechanical ventilation duration , the need for renal replacement therapy and packed red blood cells transfusion , and the rates of intensive care unit acquired infections as well as the rate of hypoglycemia ( defined as blood glucose ≤2.2 mmol/L or 40 mg/dL ) . There was no significant difference in intensive care unit mortality between the intensive insulin therapy and conventional insulin therapy groups ( 13.5 % vs. 17.1 % , p = 0.30 ) . After adjustment for baseline characteristics , intensive insulin therapy was not associated with mortality difference ( adjusted hazard ratio 1.09 , 95 % confidence interval 0.70–1.72 ) . Hypoglycemia occurred more frequently with intensive insulin therapy ( 28.6 % vs. 3.1 % of patients ; p < 0.0001 or 6.8/100 treatment days vs. 0.4/100 treatment days ; p < 0.0001 ) . There was no difference between the intensive insulin therapy and conventional insulin therapy in any of the other secondary end points . Conclusions : Intensive insulin therapy was not associated with improved survival among medical surgical intensive care unit patients and was associated with increased occurrence of hypoglycemia . Based on these results , we do not advocate universal application of intensive insulin therapy in intensive care unit patients . Trial Registration : Current Controlled Trials registry ( IS RCT N07413772 ) http://www.controlled-trials.com/IS RCT N07413772/07413772 ; 2005 OBJECTIVE To assess the efficacy and safety of intravenous ( IV ) insulin administration with use of our institution 's old protocol ( pre-nomogram phase ) as compared with our new insulin nomogram ( post-nomogram phase ) , which titrates insulin dose based on the rate of change of plasma glucose values and uses multipliers to determine the new insulin infusion rate . METHODS Hospitalized adults receiving an IV insulin infusion in our tertiary care medical center were enrolled in this study after informed consent was obtained . The study was an observational analysis conducted before and after implementation of the new insulin infusion nomogram . Measurements included episodes of hypoglycemia and incidence of the following errors in the insulin infusion process : ( 1 ) episodes of documented failure to increase insulin infusion rate despite persistent hyperglycemia and ( 2 ) number of times the IV infusion was stopped without subcutaneous administration of insulin . RESULTS Overall , 66 patients were analyzed ( 38 in the pre-nomogram phase and 28 in the post-nomogram phase ) . The new nomogram reduced by nearly 3-fold ( from 0.89 + /- 0.68 to 0.36 + /- 0.49 occurrence per patient per 24 hours ; P<0.001 ) the mean incidence of failure to give insulin subcutaneously before discontinuation of IV insulin infusion . Moreover , the nomogram nearly eliminated the error of caregiver nonresponsiveness to persistent hyperglycemia : mean incidence 0.39 + /- 0.65 occurrence per patient per 24 hours before implementation of the new nomogram versus 0.02 + /- 0.09 afterward ( P<0.002 ) . There was no statistically significant difference in episodes of hypoglycemia between the 2 study groups . CONCLUSION Safe IV administration of insulin through error prevention is essential . Implementation of a new IV insulin infusion nomogram , which adjusts insulin infusion using multipliers , reduces errors and improves glycemic control without increasing hypoglycemic episodes Stress-induced hyperglycaemia is prevalent in intensive care , impairing the immune response . Nutritional support regimes with high glucose content further exacerbate the problem . Tight glucose control has been shown to reduce mortality by up to 43 % if levels are kept below 6.1 mmol/L. This research develops a control algorithm with insulin and nutritional inputs for targeted glucose control in the critically ill . Ethics approval for this research was granted by the Canterbury Ethics Committee . Proof-of-concept clinical pilot trials were conducted on intubated , insulin-dependent Christchurch ICU patients ( n=7 ) on constant nutritional support . A target 10 - 15 % reduction in glucose level per hour for a desired glucose level of 4 - 6 mmol/L was set . 43 % and 91 % of glucose targets were achieved within + /-5 and + /-20 % , respectively . The mean error was 8.9 % ( 0.5 mmol/L ) , with an absolute range [ 0 , 2.9 ] mmol/L. End glucose levels were 40 % lower compared to initial values . All large target errors are attributable to sudden changes in patient physiology at low glucose values , rather than systemic deficiencies . Target errors are consistent with and explainable by published sensor error distributions . The results show that intensive model-based glucose management with nutrition control reduced absolute glucose levels progressively while reducing the severity of glycaemic fluctuation even with significant inter-patient variability and time-varying physiological condition . Trials spanning longer periods of time are in development to verify the short-term pilot studies performed and to test the adaptability of the controller . Clinical ly , these results indicate potential in clinical use to reduce ICU mortality as well as reduce risk of severe complications BACKGROUND Critically ill postsurgical patients fare better with intensive control of blood glucose level . The link between glucose control and outcome is less well studied for medical intensive care patients . Whether intensive glucose control requires additional staffing is unclear . OBJECTIVES To compare intensive glucose control with modified conventional control in the medical intensive care unit and to assess compliance with glucose targets , incidence of hypoglycemia , and staffing adequacy . METHODS Medical intensive care patients who had been receiving mechanical ventilation for less than 24 hours were r and omized to intensive or modified conventional protocol s for glucose control . Nurses were trained before participating in the study and were interviewed after its completion . RESULTS Five subjects were r and omized to each protocol . Mean blood glucose levels were 5.8 ( SD 1.5 ) mmol/L ( 105.3 [ SD 26.3 ] mg/dL ) for the intensive group and 9.8 ( SD 2.5 ) mmol/L ( 177.4 [ SD 45.5 ] mg/dL ) for the modified conventional group ( P < .001 ) . Fifty percent of glucose levels met target values in the intensive group , and 72 % of glucose levels met target values in the modified conventional group ( P < .001 ) . Severe hypoglycemia ( glucose < 2.2 mmol/L [ < 40 mg/dL ] ) occurred rarely and without complication . Nurses suggested protocol s might be improved by using smaller steps in adjusting insulin dosage and reported that simultaneously caring for more than 1 study subject was taxing . CONCLUSIONS Target levels for blood glucose were achieved with both protocol s. Severe hypoglycemia was rare and uncomplicated regardless of type of glucose control . Additional staffing may be needed for intensive glucose control Background : Hyperglycaemia on presentation with acute ischaemic stroke ( AIS ) is associated with poor outcome , but intervention is unproven . We investigated the safety and tolerability of one method of glycaemic control . Methods : Patients within 24 h of AIS and plasma glucose 8–20 mmol/l were r and omised to receive either rigorous glycaemic control ( RC ) or st and ard management ( SM ) for 48 h. RC comprised i.v . insulin at a variable rate adjusted for target glucose concentration of 5–8 mmol/l , and intravenous crystalloid . The SM group received intravenous crystalloid alone in an open-label design . Results : Thirteen patients were r and omised to RC and 12 to SM ( age 75 ± 6.2 years ; 40 % male ; 20 % lacunar stroke ; time to treatment 8 ± 6.1 h ; plasma glucose 10.6 ± 0.9 mmol/l ; known diabetes 52 % ; NIHSS 8 , range 2–28 ) . The glucose concentration-time curve was reduced in the RC group ( AUC 324 ± 15 versus 385 ± 28 h·mmol/l , p = 0.04 ) . By 48 h , plasma glucose in both groups was 6.8 ± 1.1 and 7.5 ± 1.3 mmol/l respectively , but mean hourly insulin requirements in the RC group had dropped from 3.25 ± 0.32 units to 1.25 ± 0.5 units ( p < 0.01 ) . One transient episode of hypoglycaemic symptoms occurred in the RC group . Conclusion : Glycaemic control with sliding scale insulin for 48 h is feasible and well-tolerated after AIS . Treatment after 48 h may be unnecessary BACKGROUND Intensive insulin therapy reduces morbidity and mortality in patients in surgical intensive care units ( ICUs ) , but its role in patients in medical ICUs is unknown . METHODS In a prospect i ve , r and omized , controlled study of adult patients admitted to our medical ICU , we studied patients who were considered to need intensive care for at least three days . On admission , patients were r and omly assigned to strict normalization of blood glucose levels ( 80 to 110 mg per deciliter [ 4.4 to 6.1 mmol per liter ] ) with the use of insulin infusion or to conventional therapy ( insulin administered when the blood glucose level exceeded 215 mg per deciliter [ 12 mmol per liter ] , with the infusion tapered when the level fell below 180 mg per deciliter [ 10 mmol per liter ] ) . There was a history of diabetes in 16.9 percent of the patients . RESULTS In the intention-to-treat analysis of 1200 patients , intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality ( 40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group , P=0.33 ) . However , morbidity was significantly reduced by the prevention of newly acquired kidney injury , accelerated weaning from mechanical ventilation , and accelerated discharge from the ICU and the hospital . Although length of stay in the ICU could not be predicted on admission , among 433 patients who stayed in the ICU for less than three days , mortality was greater among those receiving intensive insulin therapy . In contrast , among 767 patients who stayed in the ICU for three or more days , in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent ( P=0.009 ) and morbidity was also reduced . CONCLUSIONS Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU . Although the risk of subsequent death and disease was reduced in patients treated for three or more days , these patients could not be identified before therapy . Further studies are needed to confirm these preliminary data . ( Clinical Trials.gov number , NCT00115479 . Objective : To investigate whether tight glycemic control , in patients with sepsis , may restore a normal fibrinolysis by lowering plasminogen activator inhibitor (PAI)-1 levels . Design : Prospect i ve r and omized clinical trial . Setting : Three Italian university hospital intensive care units . Patients : Ninety patients with severe sepsis/septic shock . Interventions : Patients were r and omized to receive either tight glycemic control ( treatment group , target glycemia , 80–110 mg/dL ) or conventional glycemic control ( control group , target glycemia , 180–200 mg/dL ) . Measurements : Inflammation , coagulation , and fibrinolysis markers were assessed , along with Sepsis-related Organ Failure Assessment scores , > 28 days . Main Results : In the whole population , at enrolment , inflammation and coagulation were activated in > 80 of 90 patients , whereas fibrinolysis , as assessed by PAI-1 activity and concentration , was impaired in only 34 patients . The extent of the inflammatory reaction or of the coagulation activation was unrelated to outcome . In contrast , 90-day mortality rate of the 34 patients in whom fibrinolysis was definitely inhibited at study entry was twice that of the 56 patients in whom fibrinolysis was intact ( 44 % vs. 21 % , p = 0.02 ) . After r and omization , during the study , daily glycemia averaged 112 ± 23 mg/dL in the treatment group and 159 ± 31 mg/dL in controls ( p < 0.001 ) , with total daily administered insulin 57 ± 59 IU and 36 ± 44 IU , respectively ( p < 0.001 ) . A small , but significant , enhancement of fibrinolysis could be observed in the treatment group , as indicated by the time course of PAI-1 activity ( p < 0.001 ) , PAI-1 concentration ( p = 0.004 ) , and plasmin – antiplasmin complexes ( p < 0.001 ) . Morbidity , rated with the Sepsis-related Organ Failure Assessment score , became significantly lower ( p = 0.03 ) in the treatment group . Conclusions : Fibrinolysis inhibition , in severe sepsis/septic shock , seems to have a relevant pathogenetic role . In this context , tight glycemic control seems to reduce , with time , the fibrinolytic impairment and morbidity BACKGROUND Similar to cardiac surgery patients , medical-surgical critically ill patients may benefit from intensive insulin therapy . The objectives of this pilot trial were to evaluate the feasibility of a r and omized trial of intensive insulin therapy with respect to ( a ) achieving target glucose values in the 2 ranges of 5 to 7 and 8 to 10 mmol/L and ( b ) uncovering problems with the protocol in anticipation of a larger trial . SETTING The trial was conducted in a 15-bed medical-surgical university-affiliated intensive care unit ( ICU ) . METHODS We included patients older than 18 years , expected to be in ICU for more than 72 hours , with a glucose value of more than 10 mmol/L within 48 hours of ICU admission . Exclusion criteria were diabetic ketoacidosis , severe hepatic failure or hepatic resection , pancreatitis , glucose of less than 2.2 mmol/L on admission to hospital , insulin infusion on admission to ICU , planned withdrawal of life support , and inability to obtain informed consent . Patients underwent concealed r and om allocation to a target glucose range of 5 to 7 or 8 to 10 mmol/L using pretested algorithms of insulin infusions . Dedicated glucometer measurement of arterial glucose values was calibrated daily to values measured in the laboratory . RESULTS We enrolled 20 patients with a mean ( SD ) Acute Physiology and Chronic Health Evaluation ( APACHE ) II score of 32 ( 10.2 ) ; 14 were insulin-dependent pre-ICU , and all were medical admissions . Mean glucose values were different in the 2 groups ( 7.1 + /- 2.6 vs 9.4 + /- 2.1 mmol/L , P < .001 ) . Although the intensive insulin therapy group had more glucose measurements performed than the control group , a similar proportion of values were within the target range ( 682 [ 42.4 % ] of 1607 values in the 5- to 7-mmol/L range ; 250 [ 38.7 % ] of 660 values in the 8- to 10-mmol/L range , P = .35 ) . Glucose values of less than 2.5 mmol/L developed 7 times in 5 patients , 4 of whom were in the intensive insulin therapy group ; however , no adverse consequences were documented . As expected , there were no differences in clinical ly important outcomes . CONCLUSIONS In this pilot trial of ICU patients with high illness severity , glucose values were in the 2 target ranges only 40 % of the time , using well-accepted initiation and maintenance insulin infusion algorithms . A large r and omized trial of glycemic control is feasible in this population to examine clinical ly important outcomes , but will require refined insulin algorithms and more comprehensive behavior change strategies to achieve target values Hyperglycaemia occurs in a substantial portion of critically ill patients in our intensive care units . Near normalization of elevated blood glucose levels with IV insulin may improve outcome . However , currently published IV insulin protocol are not ideal ; most are relatively complex and often result in hypoglycaemia . We design ed a protocol that would be practical to use while incorporating the necessary complexities required to achieve good glucose control , coupled with a low incidence hypoglycaemia OBJECTIVES In this study we considered the question of whether adjunction of glucose-insulin-potassium ( GIK ) infusion to primary coronary transluminal angioplasty ( PTCA ) is effective in patients with an acute myocardial infa rct ion ( MI ) . BACKGROUND A combined treatment of early and sustained reperfusion of the infa rct -related coronary artery and the metabolic modulation with GIK infusion has been proposed to protect the ischemic myocardium . METHODS From April 1998 to September 2001 , 940 patients with an acute MI and eligible for PTCA were r and omly assigned , by open-label , to either a continuous GIK infusion for 8 to 12 h or no infusion . RESULTS The 30-day mortality was 23 of 476 patients ( 4.8 % ) receiving GIK compared with 27 of 464 patients ( 5.8 % ) in the control group ( relative risk [ RR ] 0.82 , 95 % confidence interval [ CI ] 0.46 to 1.46 ) . In 856 patients ( 91.1 % ) without signs of heart failure ( HF ) ( Killip class 1 ) , 30-day mortality was 5 of 426 patients ( 1.2 % ) in the GIK group versus 18 of 430 patients ( 4.2 % ) in the control group ( RR 0.28 , 95 % CI 0.1 to 0.75 ) . In 84 patients ( 8.9 % ) with signs of HF ( Killip class > or = 2 ) , 30-day mortality was 18 of 50 patients ( 36 % ) in the GIK group versus 9 of 34 patients ( 26.5 % ) in the control group ( RR 1.44 , 95 % CI 0.65 to 3.22 ) . CONCLUSIONS Glucose-insulin-potassium infusion as adjunctive therapy to PTCA in acute MI did not result in a significant mortality reduction in all patients . In the subgroup of 856 patients without signs of HF , a significant reduction was seen . The effect of GIK infusion in patients with signs of HF ( Killip class > or = 2 ) at admission is uncertain Objective : Intensive insulin therapy to normalize blood glucose may improve outcome in intensive care unit patients . We prospect ively evaluated the implementation of an intensive insulin protocol in medical intensive care patients to identify and overcome obstacles that this complex therapy creates . Design : This prospect i ve , quality assessment study was design ed to establish a st and ard protocol for glucose control in critically ill patients . Setting : The study took place in the medical intensive care unit at the Medical University of South Carolina , a tertiary care center . Patients : Patients diagnosed with sepsis and two consecutive blood glucose measurements of > 120 mg/dL were included in the study . Interventions : The protocol , targeting blood glucose of 80–120 mg/dL , was a multidisciplinary initiative involving extensive education of house staff before subject enrollment . Based on predefined criteria , patients were monitored daily for glycemic control , inclusion criteria , and protocol adherence . Protocol improvements were assessed at 6 and 12 months via nursing surveys . Measurements and Main Results : Seventy patients receiving insulin infusion for > 8 hrs were included in data analysis , accounting for 4,920 glucose readings . Eighty-six hypoglycemic events were recorded , with the number of events decreasing from 7.6 % to 0.3 % by the final version of the protocol . Average duration on protocol was 6 days , and average time to target range was 5.4 hrs . Identifiable causes of hypoglycemia and survey results led to four protocol revisions by study completion . Conclusions : In comparison to studies suggesting that normoglycemia is an easily achievable goal , our protocol often recorded glucose values < 80 mg/dL , although values < 60 mg/dL were rare and usually due to protocol violations . In the interval before automated glucose-sensing insulin infusion devices become available for the intensive care unit , the current protocol is available to assist others in achieving target glucose levels shown to improve mortality rate in an intensive care unit population OBJECTIVES Evaluate the impact of an intensive insulin therapy and conventional glucose control protocol during staying in neurological intensive care unit ( NICU ) on infection rate , days in NICU , in-hospital mortality and long-term neurological outcome in severe traumatic brain injury ( TBI ) patients . METHODS A total of 240 patients with severe TBI ( GCS score 3 - 8 ) admitted to NICU were prospect ively enrolled and r and omly assigned either to conventional insulin therapy or to intensive insulin therapy . Patients in intensive glucose control group ( n=121 ) received continuous insulin infusion to maintain glucose levels between 4.4 m mol/l ( 80 mg/dl ) and 6.1 m mol/l ( 110 mg/dl ) . Patients in the conventional treatment group ( n=119 ) were not given insulin unless glucose levels were greater than 11.1 m mol/l ( 200mg/dl ) . Both groups were treated with insulin infusion to maintain normoglycemia after leaving NICU . Comparison was made against conventional insulin therapy using a r and omized trial design . The primary outcomes is the mortality rate at 6 months follow-up . The second outcomes including ICU infection rate , duration of ICU stay , in-hospital mortality rate and neurologic outcome at 6 months follow-up . RESULTS There was no significant difference in gender ( 66 % vs. 67 % male ) , age ( 46+/-11 years vs. 45+/-10 years ) , APACHE II score ( 30 vs. 29 ) , TISS-28 score ( 47 vs. 46 ) , and Glasgow Coma Score ( GCS , 5.3 vs. 5.3 ) between the two groups . Overall mortality rates at 6 months follow-up were similar in the 2 groups ( 61 of 117 , 52.1 % vs. 62 of 116 , 53.4 % ; P=0.8 ) . The infection rate during the study was significantly higher in patients who received conventional insulin therapy than that in patients who received intensive insulin therapy ( 46.2 % vs. 31.4 % ; P<0.05 ) . The days stay in NICU was shorter in intensive insulin control group than that in conventional therapy group [ 4.2 days vs. 5.6 days ( medians ) P<0.05 ] . The in-hospital mortality during the study was similar in conventional and intensive therapy groups ( 34 of 119 , 28.6 % vs. 35 of 121 , 28.9 % in the conventional and intensive insulin therapy groups ; P=0.85 ) . The neurologic outcome according to Glasgow Outcome Score ( GOS ) at 6 months ( GOS 5 and 4 ) was better in the intensive insulin therapy group ( 34 of 117 , 29.1 % ) than that in the conventional therapy group ( 26 of 116 , 22.4 % , P<0.05 ) . CONCLUSIONS Mortality rates at 6 months follow-up are not affected by intensive glucose control in patients with severe TBI . Intensive insulin therapy decreases infection rate and days in NICU and improves the neurological outcome at 6 months follow-up , while has no obvious influence on in-hospital mortality of severe TBI patients STUDY OBJECTIVE To evaluate the effectiveness , safety , and associated patient outcomes of a simplified , nurse-directed insulin nomogram design ed to achieve intensive blood glucose level control ( target range 90 - 144 mg/dl ) . DESIGN Prospect i ve study with a retrospective control group . SETTING A medical-surgical intensive care unit ( ICU ) in a quaternary care , university-affiliated hospital in an urban center . PATIENTS Eighty-six critically ill adult patients ( aged > or=18 yrs ) requiring blood glucose control , with 42 in the retrospective control group and 44 in the prospect i ve nomogram group . INTERVENTION Control patients received insulin subcutaneously or intravenously based on ad hoc insulin sliding scales ; nomogram patients received intravenous insulin at a rate specified by the nomogram , based on capillary blood glucose levels measured at the bedside . MEASUREMENTS AND MAIN RESULTS Insulin infusion in the prospect i ve patient group was titrated by the bedside nurse based on a predefined nomogram to attain the target blood glucose level . The retrospective control group was used as a comparison to assess the safety and effectiveness of the nomogram . Fewer patients in the nomogram ( 32 % ) than control ( 67 % ) group had a diagnosis of diabetes mellitus on admission . Overall , blood glucose levels in the nomogram group were within the target range 52 % of the time versus 20 % in the control group ( p<0.001 ) . Morning blood glucose levels were significantly lower compared with the control group ( mean+/-SD 128+/-32 vs 176+/-50 mg/dl , p<0.001 ) . Nomogram patients achieved target blood glucose levels faster than control patients ( median 15 vs 66 hrs , p<0.0001 ) . This improved blood glucose control remained statistically significant after adjusting for baseline differences in diabetes status . Hyperglycemia occurred less often in the nomogram than the control group ( 14 % vs 53 % , p<0.0001 ) , and hypoglycemia occurred more often ( 3.8 % vs 2.2 % , p=0.004 ) . The frequency of severe hypoglycemia was similar in both groups ( 0.2 % vs 0.4 % , p = NS ) . Such control required slightly more blood glucose checks/day in the nomogram group ( 7.1+/-1.5 vs 5.8+/-1.1 , p<0.001 ) . No significant reduction was observed in duration of vasopressor or antibiotic therapy or in length of stay in the ICU . CONCLUSION This study demonstrated that intensive blood glucose control is achievable using a nurse-directed nomogram . This improved control was achieved , regardless of diabetes status of the patient , without substantially compromising safety or increasing re source use Objective Tight glycaemic control ( TGC ) in critically ill patients improves clinical outcome , but is difficult to establish The primary objective of the present study was to compare glucose control in medical ICU patients applying a computer-based enhanced model predictive control algorithm ( eMPC ) extended to include time-variant sampling against an implemented glucose management protocol . Design Open r and omised controlled trial . Setting Nine-bed medical intensive care unit ( ICU ) in a tertiary teaching hospital . Patients and participants Fifty mechanically ventilated medical ICU patients . Interventions Patients were included for a study period of up to 72 h. Patients were r and omised to the control group ( n = 25 ) , treated by an implemented insulin algorithm , or to the eMPC group ( n = 25 ) , using the laptop-based algorithm . Target range for blood glucose ( BG ) was 4.4–6.1 mM. Efficacy was assessed by mean BG , hyperglycaemic index ( HGI ) and BG sampling interval . Safety was assessed by the number of hypoglycaemic-episodes < 2.2 mM. Each participating nurse filled-in a question naire regarding the usability of the algorithm . Measurements and main results BG and HGI were significantly lower in the eMPC group [ BG 5.9 mM ( 5.5–6.3 ) , median ( IQR ) ; HGI 0.4 mM ( 0.2–0.9 ) ] than in control patients [ BG 7.4 mM ( 6.9–8.6 ) , p < 0.001 ; HGI 1.6 mM ( 1.1–2.4 ) , p < 0.001 ] . One hypoglycaemic episode was detected in the eMPC group ; no such episodes in the control group . Sampling interval was significantly shorter in the eMPC group [ eMPC 117 min ( ± 34 ) , mean ( ± SD ) , vs 174 min ( ± 27 ) ; p < 0.001 ] . Thirty-four nurses filled-in the question naire . Thirty answered the question of whether the algorithm could be applied in daily routine in the affirmative . Conclusions The eMPC algorithm was effective in maintaining tight glycaemic control in severely ill medical ICU patients Abstract Objective Aggressive glycemic control improves mortality and morbidity in critically ill adults , however implementation of such a strategy can be logistically difficult . This study evaluates the efficiency and safety of a nurse-managed insulin protocol in critically ill adults . Design Combined retrospective- prospect i ve before-after cohort study . Setting Twenty-one bed , medical/surgical ICU in a tertiary care hospital . Patients Two cohorts of 50 consecutive ICU patients requiring insulin infusions . Intervention Patients in the control cohort received insulin infusions titrated according to target blood glucose ranges and sliding scales at the physician ’s discretion . Patients in the interventional cohort received an insulin infusion adjusted using a st and ardized protocol targeting a blood glucose of 4.5–6.1 mmol/l ( 81–110 mg/dl ) . Measurements and main results Efficiency was measured by comparing the time to reach , and the time spent within , the target range between cohorts . Safety was assessed by comparing the incidence of severe hypoglycemia , the frequency of rescue dextrose administration and the cumulative time that the infusion was held for hypoglycemia between cohorts . Patients in the interventional cohort reached their target more rapidly ( 11.3±7.9 vs 16.4±12.6 h ; p=0.028 ) and maintained their blood glucose within the target range longer ( 11.5±3.7 vs 7.1±5.0 h/day ; p<0.001 ) than controls . The st and ardized protocol yielded a four-fold reduction in the incidence of severe hypoglycemia ( 4 vs 16 % ; p=0.046 ) and reduced the median frequency of dextrose rescue therapy ( 0 [ 0–0.91 ] vs 0.17 [ 0–1.2 ] episodes/patient per day ; p=0.01 ) as compared to controls . ConclusionS t and ardization of intensive insulin therapy improves the efficiency and safety of glycemic control in critically ill adults We conducted a r and omized , prospect i ve study to assess the effect of i.v . insulin on blood glucose control , development of ketone bodies and hormonal changes in 60 well-controlled , non-insulin-dependent diabetics ( NIDDM ) undergoing major surgery . In group A , patients were given only 0.9 % saline ; in group B , patients were given insulin as a continuous i.v . infusion ( 1.25 u. h-1 ) ; in group C , patients were given insulin 10 u. i.v . boluses every 2 h. Patients in all three groups were given insulin 5 u. when their intraoperative blood glucose concentration increased to greater than 11.1 mmol litre-1 . Blood glucose concentrations were measured every 15 min , from just before induction of anaesthesia to 2 h after surgery . Plasma lactate , pyruvate , ketone body , C-peptide and counter-regulatory hormone concentrations were also measured . Blood glucose concentrations in the three groups did not differ significantly . There was a mild-to-moderate increase in plasma ketone body concentrations in group A , but without any deleterious consequences . Plasma C-peptide concentrations decreased significantly in groups B and C , especially in patients given bolus injections of insulin . Plasma growth hormone concentrations also increased significantly in group B and C patients . This study indicated that the " no insulin -- no glucose " regimen was a simple , effective way to control blood glucose in well-controlled NIDDM patients , provided blood glucose was measured frequently and insulin used appropriately OBJECTIVE To describe a novel method of safe and effective intensive management of inpatient hyperglycemia with use of cost-effective protocol s directed by a glucose management service ( GMS ) . METHODS An intravenous insulin protocol was design ed to achieve a glycemic target of 80 to 110 mg/dL. When stable in patients were transferred from the intravenous protocol to a subcutaneous insulin protocol , which consisted of basal long-acting and pr and ial and supplemental rapid-acting insulins , the blood glucose target was 80 to 150 mg/dL. Glucose levels were review ed by the GMS at least daily for protocol adjustments , when necessary . RESULTS The intravenous insulin protocol was used in 276 patients , and 4,058 capillary blood glucose levels were recorded . Glycemic target levels ( 80 to 110 mg/dL ) were achieved , on average , 10.6 + /- 5.2 hours after initiation of insulin drip therapy . The mean capillary blood glucose level during the study interval was 135.3 + /- 49.9 mg/dL. Hypoglycemia ( < or = 60 mg/dL ) was recorded in 1.5 % of glucose values , and hyperglycemia ( > or = 400 mg/dL ) was recorded in only 0.06 % . The subcutaneous insulin protocol was used in 922 patients , and 18,067 capillary glucose levels were documented . The mean blood glucose level was 145.6 + /- 55.8 mg/dL during the study period . The blood glucose target of 80 to 150 mg/dL was achieved in 58.6 % , whereas 74.3 % of glycemic values were in the clinical ly acceptable range ( 80 to 180 mg/dL ) . Hypoglycemia ( < or = 60 mg/dL ) occurred in 1.3 % of capillary blood glucose values , and hyperglycemia ( > or = 400 mg/dL ) occurred in 0.4 % of values . CONCLUSION Vali date d protocol s dedicated to the achievement of strict glycemic goals were implemented by a GMS and result ed in substantial improvements in glycemic control on the surgical inpatient services , with a reduced frequency of hypoglycemia . The protocol s and the GMS have been well received by the inpatient nursing and surgical staff members , and all of this has been done in a cost-effective manner OBJECTIVE To evaluate a fully automated algorithm for the establishment of tight glycemic control in critically ill patients and to compare the results with different routine glucose management protocol s of three intensive care units ( ICUs ) across Europe ( Graz , Prague , and London ) . RESEARCH DESIGN AND METHODS Sixty patients undergoing cardiac surgery ( age 67 + /- 9 years , BMI 27.7 + /- 4.9 kg/m2 , 17 women ) with postsurgery blood glucose levels > 120 mg/dl ( 6.7 mmol/l ) were investigated in three different ICUs ( 20 per center ) . Patients were r and omized to either blood glucose management ( target range 80 - 110 mg/dl [ 4.4 - 6.1 mmol/l ] ) by the fully automated model predictive control ( MPC ) algorithm ( n = 30 , 10 per center ) or implemented routine glucose management protocol s ( n = 30 , 10 per center ) . In all patients , arterial glucose was measured hourly to describe the glucose profile until the end of the ICU stay but for a maximum period of 48 h. RESULTS Compared with routine protocol s , MPC treatment result ed in a significantly higher percentage of time within the target glycemic range ( % median [ min-max ] : 52 [ 17 - 92 ] vs. 19 [ 0 - 71 ] ) over 0 - 24 h ( P < 0.01 ) . Improved glycemic control with MPC treatment was confirmed in patients remaining in the ICU for 48 h ( 0 - 24 h : 50 [ 17 - 71 ] vs. 21 [ 4 - 67 ] , P < 0.05 , and 24 - 48 h : 65 [ 38 - 96 ] vs. 25 [ 8 - 79 ] , P < 0.05 , for MPC [ n = 16 ] vs. routine protocol [ n = 13 ] , respectively ) . Two hypoglycemic events ( < 54 mg/dl [ 3.0 mmol/l ] ) were observed with routine protocol treatment . No hypoglycemic event occurred with MPC . CONCLUSIONS The data suggest that the MPC algorithm is safe and effective in controlling glycemia in critically ill postsurgery patients Purpose An optimal target for glucose control in ICU patients remains unclear . This prospect i ve r and omized controlled trial compared the effects on ICU mortality of intensive insulin therapy ( IIT ) with an intermediate glucose control . Methods Adult patients admitted to the 21 participating medico-surgical ICUs were r and omized to group 1 ( target BG 7.8–10.0 mmol/L ) or to group 2 ( target BG 4.4–6.1 mmol/L ) . Results While the required sample size was 1,750 per group , the trial was stopped early due to a high rate of unintended protocol violations . From 1,101 admissions , the outcomes of 542 patients assigned to group 1 and 536 of group 2 were analysed . The groups were well balanced . BG levels averaged in group 1 8.0 mmol/L ( IQR 7.1–9.0 ) ( median of all values ) and 7.7 mmol/L ( IQR 6.7–8.8 ) ( median of morning BG ) versus 6.5 mmol/L ( IQR 6.0–7.2 ) and 6.1 mmol/L ( IQR 5.5–6.8 ) for group 2 ( p < 0.0001 for both comparisons ) . The percentage of patients treated with insulin averaged 66.2 and 96.3 % , respectively . Proportion of time spent in target BG was similar , averaging 39.5 % and 45.1 % ( median ( IQR ) 34.3 ( 18.5–50.0 ) and 39.3 (26.2–53.6)% ) in the groups 1 and 2 , respectively . The rate of hypoglycaemia was higher in the group 2 ( 8.7 % ) than in group 1 ( 2.7 % , p < 0.0001 ) . ICU mortality was similar in the two groups ( 15.3 vs. 17.2 % ) . Conclusions In this prematurely stopped and therefore underpowered study , there was a lack of clinical benefit of intensive insulin therapy ( target 4.4–6.1 mmol/L ) , associated with an increased incidence of hypoglycaemia , as compared to a 7.8–10.0 mmol/L target . ( Clinical Trials.gov # NCT00107601 , EUDRA-CT Number : 200400391440 ) OBJECTIVE To compare continuous insulin infusion ( CII ) and intermittent subcutaneous insulin therapy for preventing supraventricular tachycardia . The authors propose that continuous insulin therapy is more effective to reduce supraventricular tachycardias . DESIGN A prospect i ve r and omized study . SETTING This study was performed in 2 different centers between April 2005 and February 2007 : Gülhane Military Medical Academy and University of Süleyman Demirel . PARTICIPANTS Two hundred diabetic patients were included in this prospect i ve r and omized study . Patients were divided into 2 groups according to their insulin therapy in 2 different centers . INTERVENTIONS Group 1 included 100 diabetes mellitus ( DM ) patients , and CIIs were administrated . These patients received a CII infusion titrated per protocol in the perioperative period ( Portl and protocol ) . Group 2 also included 100 DM patients , and subcutaneous insulin was injected every 4 hours in a directed attempt to maintain blood glucose levels below 200 mg/dL. Sliding scale dosage of insulin was titrated to each patient 's glycemic response during the prior 4 hours . MEASUREMENTS AND MAIN RESULTS There were 5 hospital mortalities in the intermittent insulin group . The causes of death were pump failure in 3 patients and ventricular fibrillation in 2 patients . There were 2 hospital mortalities in the CII group ( p = 0.044 ) . Thirty-six patients in the intermittent insulin group and 21 patients in the CII group required positive inotropic drugs after cardiopulmonary bypass ( p = 0.028 ) . Low cardiac output developed in 28 and 16 patients in the intermittent and CII groups , respectively ( p = 0.045 ) . Univariate analysis identified positive inotropic drug requirement ( p = 0.011 , odds ratio [ OR ] = 3.41 ) , ejection fraction ( EF ) ( p = 0.001 , OR = 0.92 ) , cross-clamp time ( p = 0.046 , OR = 0.97 ) , left internal mammary artery ( p = 0.023 , OR = 0.49 ) , chronic obstructive pulmonary disease ( COPD ) ( forced expiratory volume in 1 second < 75 % of predicted value ( p = 0.009 , OR = 2.02 ) , intra-aortic balloon pump ( p = 0.045 , OR = 1.23 ) , body mass index ( p = 0.035 OR = 5.60 ) , and CII ( p < 0.001 , OR = 0.36 ) as predictors of SVT . Stepwise multivariate analysis confirmed the significance of some of the previously mentioned variables as predictors of SVT . The value of -2 log likelihood of multivariate analyses was 421.504 . These were EF ( p < 0.001 , OR = 0.91 ) , positive inotropic drug requirement ( p < 0.001 , OR = 3.94 ) , COPD ( p = 0.036 , OR = 2.11 ) , and CII ( p < 0.001 , OR = 0.19 ) . CONCLUSION Continuous insulin therapy in the perioperative period reduces infectious complications , such as sternal wound infection and mediastinitis , cardiac mortality caused by pump failure , and the risk of development of supraventricular tachycardias OBJECTIVE To investigate an optimized glucose-insulin-potassium ( GIK ) solution regimen as an alternate myocardial protective strategy in off-pump coronary artery bypass graft ( OP-CAB ) surgery and as a supplement to conventional coronary artery bypass graft ( CABG ) surgery using cardiopulmonary bypass ( CPB ) . DESIGN Prospect i ve , r and omized , placebo-controlled . SETTING Single institution , cardiothoracic specialty hospital . PARTICIPANTS Forty-four patients scheduled for elective multivessel coronary artery surgery using either conventional CPB ( n = 22 ) or OP-CAB techniques ( n = 22 ) . INTERVENTIONS Preischemic , ischemic , and postischemic administration of GIK solution was carried out , optimally dosed to ensure nonesterified fatty acid ( NEFA ) suppression , and supplemented with magnesium , a glycolytic enzymatic cofactor . MEASUREMENTS AND MAIN RESULTS GIK solution therapy reduced plasma NEFA levels ( p < 0.001 ) in OP-CAB surgery and CPB groups but failed to affect the incidence of non-Q wave perioperative myocardial infa rct ion , incidence of postoperative atrial fibrillation , incidence of postoperative infection , reduction in creatinine clearance , or duration of postoperative intensive care unit or hospital length of stay . After adjusting for GIK solution therapy , OP-CAB surgery result ed in significantly less ischemic injury ( troponin I > 15 microg/L , 19.0 % v 91.3 % ; p = 0.0001 ) and reduced postoperative infections ( 14.3 % v 43.5 % ; p = 0.049 ) . CONCLUSION GIK solution therapy achieved NEFA suppression and an insignificant trend toward reduced biochemical parameters of ischemic injury in OP-CAB surgery and CPB groups , but no major clinical benefit ( perioperative myocardial infa rct ion , intensive care unit length of stay , or hospital length of stay ) was shown after elective CABG surgery in low-risk patients . Compared with CPB , OP-CAB surgery significantly reduced ischemic injury and postoperative infections STUDY OBJECTIVE To compare the effect of two different perioperative insulin management regimes on patients undergoing either major surgery ( vascular surgery ) or minor surgery ( vitrectomy ) . DESIGN Prospect i ve , double-blind r and omized trial . PATIENTS 48 insulin-treated type 2 diabetics aged 18 to 85 years were studied . SETTING University medical center . INTERVENTIONS Patients were divided into four groups of 12 patients each : Groups A and B ( major surgery ) , Groups C and D ( minor surgery ) . Group A and C patients were treated with a continuous modified glucose-insulin-potassium infusion according to blood glucose levels after intubation . Patients assigned to Groups B and D were treated with intermittent intravenous ( IV ) insulin injections when glucose levels exceeded 12 mmol L(-1 ) . MEASUREMENTS Glucose and potassium levels were measured every 15 minutes and 30 minutes during surgery and up to 4 hours post-surgery . Plasma levels of lactate , cortisol , glycerol , and free fatty acids were measured in arterial sample s after intubation ( S1 ) , after extubation ( S2 ) , and 4 hours after surgery ( S3 ) . MAIN RESULTS There were no significant differences of the patient characteristics among the four groups . There was no significant difference in the time course of plasma glucose levels and hormone variables measured among the four groups . One episode of hyperglycemia in Group D during the postoperative period was treated with 12 IV units of insulin . One patient in Group A and one in Group B received potassium intraoperatively ( 15 and 29 mmoL , respectively ) . Postoperatively , two other patients of Group A received 19 and 12,5 mmoL , respectively , and one of Group B received 20 mmoL potassium . CONCLUSIONS Both regimens result ed in relatively stable and comparable blood glucose levels throughout the perioperative period of the minor and major surgeries without differences in metabolic control as measured by levels of lactate , cortisol , glycerol and free fatty acids . Simplicity would favor the intermittent regimen to manage insulin treated type 2 diabetics BACKGROUND Recent data have demonstrated that intensive glycemic control during critical illness improves outcome . The purpose of our study was to evaluate the effect of a computerized hospital insulin protocol ( CHIP ) on glycemic control and outcome in critically ill trauma patients . METHODS Two , 6-month cohorts were compared , one 6 months prior to chip implementation ( pre-CHIP ) and one from the 6-month period after implementation ( post-CHIP ) , using finger stick blood glucose values and demographic , injury severity , and outcome variables for adult patients with intensive care unit length of stay ( LOS ) > or = 72 hours . Infectious morbidity was based upon the National Trauma Registry of the American College of Surgeons definitions . Differences between cohorts were assessed using Student 's t test and Fisher 's exact test for continuous and categorical variables . RESULTS The 129 pre- and 128 post-CHIP patients were well matched for demographics and injury severity . Significant reductions in mean finger stick blood glucose , rates of ventilator- associated pneumonia , central venous line infection , total infections , and all LOS categories were demonstrated in the post-CHIP cohort . However , mortality was significantly higher in the post-CHIP cohort . CONCLUSION This preliminary study demonstrates significant morbidity and LOS reductions with the use of a CHIP , but significantly increased mortality . Further prospect i ve studies are necessary to assess the effects of intensive glycemic control on outcome after injury , particularly in sub population s who might be adversely affected Objective : To perform an analysis of healthcare re source utilization with intensive insulin therapy , which has recently been shown to reduce morbidity and mortality rates of mechanically ventilated critically ill patients in a surgical intensive care unit . Design : A post hoc cost analysis . Setting : Surgical intensive care unit . Patients : Patients were 1548 mechanically ventilated patients admitted to a surgical intensive care unit . Interventions : A post hoc cost analysis was conducted based on data collected prospect ively as part of a large r and omized controlled trial . The analysis performed was a healthcare re source utilization analysis in which the cost of hospitalization in the intensive care unit was determined based on length of stay and the frequency of crucial cost-generating morbid events occurring in the intensive and conventional insulin treatment groups . Sensitivity analyses were performed to evaluate the robustness of the findings . Discounting of costs was not performed as treatment was limited to the intensive care stay and follow-up was not continued beyond hospitalization . Measurements and Main Results : In the intensive treatment group , total treatment cost was 109,838 Euros ( 144 Euros per patient ) . In the conventional treatment group , total treatment cost was 56,359 Euros ( 72 Euros per patient ) . The excess cost of intensive insulin therapy was 72 Euros per patient . The total hospitalization cost in the intensive treatment group was 6,067,237 Euros ( 7931 Euros per patient ) compared with 8,275,394 Euros ( 10,569 Euros per patient ) in the conventional treatment group . The excess cost of intensive care unit hospitalization in the conventional vs. intensive treatment group was 2638 Euros per patient . These intensive care unit benefits were not offset by additional costs for care on regular wards . Conclusions : Intensive insulin therapy , which reduces morbidity and mortality rates of mechanically ventilated patients admitted to a surgical intensive care unit , is associated with substantial cost savings compared with conventional insulin therapy . LEARNING OBJECTIVES On completion of this article , the reader should be able to : Describe intensive insulin therapy . Identify the costs of conventional and intensive insulin therapy . Use this information in a clinical setting . Dr. Van den Berghe has disclosed that she is the recipient of grant/ research funding from LifeScan and NovoNordisk . Dr. Hilleman has disclosed that he was on the speakers bureau of Roche and was/is on the speakers bureau of Abbott , LifeScan , and Pfizer . Mr. Wouters and Dr. Kesteloot have disclosed that they have no financial relationships with or interests in any commercial companies pertaining to this educational activity . The authors have disclosed that the use of insulin has not been approved by the FDA as discussed in this article . Wolters Kluwer Health had identified and resolved all faculty conflicts of interest regarding this educational activity . Visit the Critical Care Medicine Web site ( www.ccmjournal.org ) for information on obtaining continuing medical education credit Postoperative glucose control directly affects the incidence of deep sternal wound infection and death after patients with diabetes have undergone coronary artery bypass grafting . We compared the effect upon glucose control of continuous insulin infusion with that of glucometer-guided insulin injection after coronary artery bypass . Our prospect i ve , r and omized , controlled study involved patients with diabetes mellitus who underwent coronary artery bypass grafting in our hospital from January 2001 through January 2003 . Immediately after surgery , patients were r and omly assigned to receive continuous insulin infusion or conventional glucometer-guided injection to maintain blood glucose at a level between 150 and 200 mg/dL. The adequacy of postoperative blood glucose control and clinical outcome were evaluated . Of 93 patients studied , the incidence of sternal wound infection was 3.9 % among infusion patients and 4.8 % among injection patients ( P=0.587 ) . There was no significant difference in mortality rates ( infusion , 3.9 % ; injection , 2.4 % ; P=0.573 ) . Satisfactory blood glucose levels were achieved in significantly more patients undergoing infusion than injection ( 64.7 % vs 28.6 % , P < 0.001 ) . In the injection group , significantly more blood glucose measurements were required to achieve control ( 23.4 vs 16.5 , P=0.001 ) , and good control was attained much sooner in the infusion group ( 21.4 vs 30.5 hr , P=0.013 ) . We conclude that continuous insulin infusion provides better control of postoperative blood glucose levels after coronary artery bypass grafting in patients with diabetes than does glucometer-guided insulin injection OBJECTIVE To investigate whether hyperglycemia in glucose-intolerant patients without diabetes could lead to increased nosocomial infections in the surgical intensive-care unit ( ICU ) . METHODS A prospect i ve , r and omized , controlled clinical trial was conducted in the surgical ICU of a large teaching hospital in Hartford , Connecticut . Adult patients admitted to a 12-bed surgical ICU requiring treatment of hyperglycemia ( glucose values > or = 140 mg/dL ) were r and omly assigned to receive st and ard insulin therapy ( target glucose range , 180 to 220 mg/dL ) or strict insulin therapy ( target glucose range , 80 to 120 mg/dL ) throughout their ICU stay . Demographic data , comorbidities , and confounding variables were analyzed . Outcome measures included mean daily serum glucose values , mean daily insulin doses , and number of nosocomial infections during the ICU stay . RESULTS The study was completed by 61 critically ill surgical patients ( 27 in the st and ard glucose control group and 34 in the strict glucose control group ) . A significant reduction ( P<0.001 ) in mean daily glucose level was achieved in the strict glycemic control group ( 125 + /- 36 mg/dL ) in comparison with the st and ard glycemic control group ( 179 + /- 61 mg/dL ) . Furthermore , a significant reduction ( P<0.05 ) in the incidence of total nosocomial infections , including intravascular device , bloodstream , intravascular device-related bloodstream , and surgical site infections , was observed in the strict glucose control group in comparison with the st and ard glucose control group . The incidence of hypoglycemia ( glucose levels < 60 mg/dL ) was significantly increased ( P<0.001 ) in the strict glycemic control group in comparison with the st and ard glycemic control group ( 32 % versus 7.4 % of patients or 0.8 % versus 0.1 % of total serum glucose values , respectively ) . CONCLUSION Strict glycemic control is a safe and effective method for reducing the incidence of nosocomial infections in a predominantly nondiabetic , general surgical ICU patient population We compared two intravenous insulin regimens among 58 consecutive surgical patients who required perioperative insulin infusions . Patients were r and omized to either a st and ard glucose-insulin-potassium ( GIK ) infusion or a more complex , tailored two-pump protocol . Both methods provided similar overall glycemic control . However , the two-pump regimen result ed in a significantly greater proportion of finger-prick results in the target range both preoperatively ( 47.4 % vs 60.1 % ) and postoperatively ( 52.0 % vs 66.4 % ) . The length of stay ( 15 vs 16 days ) , duration of infusion ( 15 vs 16 hours , and number of medical and nursing incidents ( 18 % vs 20 % ) were similar : Although the two-punip protocol required more changes to the administration rate ( 2 vs 10 ) , this method was preferred by the nursing staff over the GIK regimen , result ed in more stable glucose control , and is likely to be associated with fewer clinical errors Hyperglycaemia following subarachnoid haemorrhage ( SAH ) is well recognized and has been shown to be associated with a worse prognosis . It is currently unclear whether this is a secondary phenomenon reflecting the magnitude of the stress response or whether it contributes directly to the pathophysiological disturbances within the brain . There is significant experimental work on ischaemic stroke to suggest that hyperglycaemia increases infa rct volume . The authors propose that controlling blood glucose following SAH is safe and that it might improve outcome . All patients admitted with SAH were treated with insulin to control plasma glucose with a target range of 5.0 – 7.0 mmol/l . Episodes of hypoglycaemia were recorded . Outcome was assessed at 3 months using the Glasgow Outcome Scale . Fifty-five patients were recruited . 32/3389 ( 0.94 % ) of glucose readings fell below 3.5 mmol/l . All were treated with i.v . glucose without evidence of clinical deterioration . Insulin treatment for hyperglycaemia following SAH is feasible and safe . A r and omised trial is required to assess any effect on outcome BACKGROUND Frequently , the use of insulin is considered for metabolic control in postoperative patients with non-insulin-dependent diabetes mellitus ( NIDDM ) . We sought to determine the best method for control of glucose in NIDDM non-insulin patients during postoperative care . METHODS Two algorithms were developed : subcutaneous administration of insulin ( SC ) , and continuous intravenous infusion ( IV ) . A r and omized , controlled clinical trial was design ed . In addition , both experimental groups were compared with a non-concurrent routinely managed group ( RM ) with insulin administration under no predetermined algorithm . Eligible patients were those subjected to major surgery under general anesthesia or spinal blockade . They were followed for 48 h after surgery . Target variables were capillary and central blood glucose , insulin dose administered , urine glucose and ketone strip determination , and development of hyper- or hypoglycemia . RESULTS A total of 62 patients were studied ( RM = 25 , SC = 19 , IV = 18 ) . Results for both experimental algorithms were similar except for the IV group that required less insulin per hour compared to SC ( 0.64 vs. 0.34 U/h ; p = 0.0003 ) . The RM control group showed poor control in all capillary glucose measurements ( 194.9 + /- 26.8 mg/dL ) compared with the two experimental algorithms ( SC = 129.9 + /- 21 ; IV = 131.6 + /- 20.4 ) ( p < 0.05 ) . More hyperglycemia events appeared in the RM group ( p = 0.016 ) . Only one hypoglycemia event occurred in the IV group . CONCLUSIONS Postoperative control of NIDDM is similar with both tested methods . The use of any of the algorithms studied improves metabolic control substantially because it st and ardizes postoperative management of the diabetic patient with timely determination of capillary blood glucose and insulin administration . However , IV administration has the advantage of accomplishing adequate control with a smaller insulin dose Background Although stringent glycemic control is beneficial for patients with diabetes who are hospitalized in a Cardiac Care Unit ( CCU ) , implementation is difficult in part because of the imperative to avoid hypogolycemia with its particularly deleterious consequences in this setting . We therefore explored the potential value of use of a continuous glucose monitoring system to enhance glycemic control in the CCU and sought to identify pitfalls that could be overcome to increase its utility . Method This study was performed with a continuous glucose monitoring system ( CGMS ) manufactured by MiniMed ( Northridge , California , USA ) , a division of Medtronic , Inc. The device used was originally design ed for home use and was a prototype . Twenty patients with elevated concentrations of blood glucose who were hospitalized in our CCU were studied after r and omization to st and ard care for diabetes or st and ard care supplemented by use of a CGMS . Results To optimize glycemic control , the need for favorable modifications in the prototype device initially design ed for home use were identified and implemented as were the value of intense in-service training of nurses and optimal interactions with patients and their families . Conclusions Use of the CGMS was found to be helpful to nursing personnel . Acceptance of the use of the device , however , was contingent upon enabling patients to overcome fear underlying their often subconscious resistance to the use of insulin in the CCU by emphasizing differentiation of such usage from an increased probability of insulin dependence after recovery Background : Glycemic control is increasingly being recognized as a priority in the treatment of critically ill patients . Titration and monitoring of insulin infusions involve frequent blood glucose measurement to achieve target glucose ranges and prevent adverse events related to hypoglycemia . Therefore , it is imperative that bedside glucose testing methods be safe and accurate . Objective : To determine the accuracy and clinical impact of three common methods of bedside point-of-care testing for glucose measurements in critically ill patients receiving insulin infusions . Design : Prospect i ve observational study . Setting : A 21-bed mixed medical/surgical intensive care unit of a tertiary care teaching hospital . Patients : Thirty consecutive critically ill patients who were vasopressor-dependent ( n = 10 ) , had significant peripheral edema ( n = 10 ) , or were admitted following major surgery ( n = 10 ) . Measurements : Findings from three different methods of glucose measurement were compared with central laboratory measurements : ( 1 ) glucose meter analysis of capillary blood ( fingerstick ) ; ( 2 ) glucose meter analysis of arterial blood ; and ( 3 ) blood gas/chemistry analysis of arterial blood . Patients were enrolled for a maximum of 3 days and had a maximum of nine sets of measurements determined during this time . Results : Clinical agreement with the central laboratory was significantly better with arterial blood analysis ( 69.9 % and 76.5 % for glucose meter and blood gas/chemistry analysis , respectively ) than with capillary blood analysis ( 56.8 % ; p = .039 and .001 , respectively ) . During hypoglycemia , clinical agreement was only 26.3 % with capillary blood analysis and 55.6 % and 64.9 % for glucose meter and blood gas/chemistry analysis of arterial blood ( p = .010 and < .001 , respectively ) . Glucose meter analysis of both arterial and capillary blood tended to provide higher glucose values , whereas blood gas/chemistry analysis of arterial blood tended to yield lower glucose values . Conclusions : The magnitude of the differences in the glucose values offered by the four different methods of glucose measurement led to frequent clinical disagreements regarding insulin dose titration in the context of an insulin infusion protocol for aggressive glucose control AIMS To document the impact of intensive insulin therapy during intensive care on long-term ( 4 years ) outcome of high-risk cardiac surgery patients . METHODS AND RESULTS In this pre-planned sub- analysis and follow-up study of a large , r and omized controlled trial on the effects of intensive insulin therapy during critical illness , we assessed long-term outcome in the 970 patients who had been admitted after high-risk cardiac surgery ( mean+/-SD EuroSCORE of 6.0+/-3.7 ; EuroSCORE-predicted hospital mortality of 9.9 % ; observed hospital mortality of 7.5 % in the conventional insulin group and 3.4 % in the intensive insulin group ) . Long-term outcome was quantified as : ( a ) 4 years survival ; ( b ) incidence of hospital re-admission ; ( c ) level of activity and medical care requirements at 4 years as assessed by the Karnofsky score ; and ( d ) perceived health-related quality -of-life at 4 years as assessed by the Nottingham Health Profile . Four years after ICU admission , the number of post-hospital discharge deaths was similar in the two study groups , reflecting maintenance of the acute survival benefit with intensive insulin therapy . Survivors who had been treated with intensive insulin during ICU stay revealed a similar risk for hospital re-admission and a comparable level of dependency on medical care . There was no effect on quality -of-life in the total group , whereas the increased survival of sicker patients with at least 3 days of insulin therapy evoked a more compromised perceived quality -of-life , in particular regarding social and family life . CONCLUSION The short-term survival benefit obtained with insulin-titrated glycaemic control during intensive care after cardiac surgery was maintained after 4 years , without inducing increased medical care requirements but possibly at the expense of compromised perceived quality of social and family life Background : Intensive insulin therapy to maintain blood glucose at or below 6.11 mm reduces morbidity and mortality after cardiac surgery and morbidity in medical intensive care unit ( ICU ) patients . The authors investigated the clinical safety and outcome effects of intensive insulin therapy compared to conventional insulin therapy in patients receiving postoperative intensive care after neurosurgical procedures . Methods : In this prospect i ve r and omized controlled trial , 483 patients undergoing elective or emergency brain surgery were prospect ively and r and omly assigned either to intensive insulin therapy ( 241 patients ) , receiving insulin titrated to maintain blood glucose levels within the range of 4.44–6.11 mm , or to conventional insulin therapy ( 242 patients ) , receiving insulin to maintain blood glucose levels below 11.94 mm . Primary endpoint was incidence of hypoglycemia ( defined as blood glucose < 2.78 mm ) . Efficacy measures included the length of ICU stay , infection rate , and 6 months follow-up Glasgow outcome scale score and overall survival . Results : Hypoglycemia episodes were more frequent in patients receiving intensive insulin therapy , median ( min – max ) : 8 ( 0–23 ) versus 3 ( 0–4 ) ; P < 0.0001 . The length of stay in the ICU was shorter ( 6 vs. 8 days ; P = 0.0001 ) , and the infection rate was lower ( 25.7 % vs. 39.3 % ; P = 0.0018 ) . Glasgow outcome scale score and overall survival at 6 months were similar in the two groups . Conclusions : Intensive insulin therapy in patients admitted to a postoperative neurosurgical ICU after brain surgery is associated with iatrogenic hypoglycemia , but it can also reduce the infection rate and shorten the ICU stay BACKGROUND Hyperglycaemia after acute stroke is a common finding that has been associated with an increased risk of death . We sought to determine whether treatment with glucose-potassium-insulin ( GKI ) infusions to maintain euglycaemia immediately after the acute event reduces death at 90 days . METHODS Patients presenting within 24 h of stroke onset and with admission plasma glucose concentration between 6.0 - 17.0 mmol/L were r and omly assigned to receive variable-dose-insulin GKI ( intervention ) or saline ( control ) as a continuous intravenous infusion for 24 h. The purpose of GKI infusion was to maintain capillary glucose at 4 - 7 mmol/L , with no glucose intervention in the control group . The primary outcome was death at 90 days , and the secondary endpoint was avoidance of death or severe disability at 90 days . Additional planned analyses were done to determine any differences in residual disability or neurological and functional recovery . The trial was powered to detect a mortality difference of 6 % ( sample size 2355 ) , with 83 % power , at the 5 % two-sided significance level . This study is registered as an International St and ard R and omised Controlled Trial ( number IS RCT N 31118803 ) FINDINGS The trial was stopped due to slow enrolment after 933 patients were recruited . For the intention-to-treat data , there was no significant reduction in mortality at 90 days ( GKI vs control : odds ratio 1.14 , 95 % CI 0.86 - 1.51 , p=0.37 ) . There were no significant differences for secondary outcomes . In the GKI group , overall mean plasma glucose and mean systolic blood pressure were significantly lower than in the control group ( mean difference in glucose 0.57 mmol/L , p<0.001 ; mean difference in blood pressure 9.0 mmHg , p<0.0001 ) . INTERPRETATION GKI infusions significantly reduced plasma glucose concentrations and blood pressure . Treatment within the trial protocol was not associated with significant clinical benefit , although the study was underpowered and alternative results can not be excluded

Home-based HCT is protective against intimate partner violence , stigmatizing behavior , having multiple sexual partners , and having casual sexual partners .

BACKGROUND Human immunodeficiency virus counselling and testing is a critical and essential gateway to Human immunodeficiency virus prevention , treatment , care and support services . Though some primary studies indicate that home-based counselling and testing is more effective than facility based counselling and testing to reduce stigma and risky sexual behavior , to the best of the author 's knowledge , no systematic review has tried to establish consistency in the findings across population s. OBJECTIVES The objective of this review was to determine the effectiveness of home-based Human immunodeficiency virus counselling and testing in reducing Human immunodeficiency virus-related stigma and risky sexual behavior among adults and adolescents .

Background A large , district-wide , home-based HIV counselling and testing ( HBHCT ) programme was implemented in Bushenyi district of Ug and a from 2004 to 2007 . This programme provided free HBHCT services to all consenting adults of Bushenyi district and had a very high uptake and acceptability . We measured population -level changes in knowledge of HIV status , stigma and HIV-risk behaviours before and after HBHCT to assess whether widespread HBHCT had an effect on trends of risky sexual behaviours and on stigma and discrimination towards HIV . Methods Serial cross-sectional surveys were carried out before and after the implementation of HBHCT programme in Bushenyi district of Ug and a. A total of 1402 r and omly selected adults ( 18 to 49 years ) were interviewed in the baseline survey . After the implementation , a different set of r and omly selected 1562 adults was interviewed using the same question naire . Data was collected on socio-demographic characteristics , sexual behaviour , whether respondents had ever tested for HIV and stigma and discrimination towards HIV/AIDS . Results The proportion of people who had ever tested for HIV increased from 18.6 % to 62 % ( p<0.001 ) . Among people who had ever tested , the proportion of people who shared HIV test result with a sexual partner increased from 41 % to 57 % ( p<0.001 ) . The proportion of persons who wanted infection status of a family member not to be revealed decreased from 68 % to 57 % ( p<0.001 ) . Indicators of risk behaviour also improved ; the proportion of people who exchanged money for sex reduced from 12 % to 4 % ( p<0.001 ) , who used a condom when money was exchanged during a sexual act increased from 39 % to 80 % ( p<0.001 ) and who reported genital ulcer/discharge decreased from 22 % to 10 % ( p<0.001 ) . Conclusion These data suggest that HBHCT rapidly increased the uptake of HCT and may have led to reduction in high-risk behaviours at population level as well as reduction in stigma and discrimination . Because HBCT programmes are cost-effective , they should be considered for implementation in delivery of HIV services especially in areas where access to HCT is low Objective : Effective behavioral HIV prevention is needed for stable HIV-discordant couples at risk for HIV , especially those without access to biomedical prevention . This analysis addressed whether HIV testing and counseling with ongoing counseling and condom distribution lead to reduced unprotected sex in HIV-discordant couples . Methods : Partners in Prevention HSV/HIV Transmission Study was a r and omized trial conducted from 2004 to 2008 assessing whether acyclovir reduced HIV transmission from HSV-2/HIV-1–coinfected persons to HIV-uninfected sex partners . This analysis relied on self-reported behavioral data from 508 HIV-infected South African participants . The exposure was timing of first HIV testing and counseling : 0–7 , 8–14 , 15–30 , or > 30 days before baseline . In each exposure group , predicted probabilities of unprotected sex in the last month were calculated at baseline , month 1 , and month 12 using generalized estimating equations with a logit link and exchangeable correlation matrix . Results : At baseline , participants who knew their HIV status for less time experienced higher predicted probabilities of unprotected sex in the last month : 0–7 days , 0.71 ; 8–14 days , 0.52 ; 15–30 days , 0.49 ; > 30 days , 0.26 . At month 1 , once all participants had been aware of being in HIV-discordant relationships for ≥1 month , predicted probabilities declined : 0–7 days , 0.08 ; 8–14 days , 0.08 ; 15–30 days , 0.15 ; > 30 days , 0.14 . Lower predicted probabilities were sustained through month 12 : 0–7 days , 0.08 ; 8–14 days , 0.11 ; 15–30 days , 0.05 ; > 30 days , 0.19 . Conclusions : Unprotected sex declined after HIV-positive diagnosis and declined further after awareness of HIV discordance . Identifying HIV-discordant couples for behavioral prevention is important for reducing HIV transmission risk Introduction Hope is an essential dimension of successful coping in the context of illnesses such as HIV/AIDS , because positive expectations for the future alleviate emotional distress , enhance quality of life and have been linked to the capacity for behavioural change . The social environment ( e.g. family , peers ) is a regulator of hope for people living with HIV/AIDS ( PLWHA ) . In this regard , the dual aim of this article is ( 1 ) to analyze the influence of a peer adherence support ( PAS ) intervention and the family environment on the state of hope in PLWHA and ( 2 ) to investigate the interrelationship between the two determinants . Methods The Effective AIDS Treatment and Support in the Free State study is a prospect i ve r and omized controlled trial . Participants were recruited from 12 public antiretroviral treatment ( ART ) clinics across five districts in the Free State Province of South Africa . Each of these patients was assigned to one of the following groups : a control group receiving st and ard care , a group receiving additional biweekly PAS or a group receiving PAS and nutritional support . Latent cross-lagged modelling ( Mplus ) was used to analyse the impact of PAS and the family environment on the level of hope in PLWHA . Results The results of the study indicate that neither PAS nor the family environment has a direct effect on the level of hope in PLWHA . Subsequent analysis reveals a positive significant interaction between family functioning and PAS at the second follow-up , indicating that better family functioning increases the positive effect of PAS on the state of hope in PLWHA . Conclusions The interplay between well-functioning families and external PAS generates higher levels of hope , which is an essential dimension in the success of lifelong treatment . This study provides additional insight into the important role played by family dynamics in HIV/AIDS care , and it underscores the need for PAS interventions that are sensitive to the context s in which they are implemented Background Among people living with HIV ( PLHIV ) on antiretroviral therapy ( ART ) , it is important to determine how quality of life ( QOL ) may be improved and HIV-related stigma can be lessened over time . This study assessed the effect of peer support on QOL and internal stigma during the first year after initiating ART among a cohort of PLHIV in north-eastern Vietnam . Methods A sub- sample study of a r and omised controlled trial was implemented between October 2008 and November 2010 in Quang Ninh , Vietnam . In the intervention group , participants ( n = 119 ) received adherence support from trained peer supporters who visited participants ’ houses biweekly during the first two months , thereafter weekly . In the control group , participants ( n = 109 ) were treated according to st and ard guidelines , including adherence counselling , monthly health check and drug refills . Basic demographics were measured at baseline . QOL and internal stigma were measured using a Vietnamese version of the WHOQOL-HIVBREF and Internal AIDS-related Stigma Scale instruments at baseline and 12 months . T-tests were used to detect the differences between mean values , multilevel linear regressions to determine factors influencing QOL . Results Overall , QOL improved significantly in the intervention group compared to the control group . Among participants initiating ART at clinical stages 3 and 4 , education at high school level or above and having experiences of a family member dying from HIV were also associated with higher reported QOL . Among participants at clinical stage 1 and 2 , there was no significant effect of peer support , whereas having children was associated with an increased QOL . Viral hepatitis was associated with a decreased QOL in both groups . Lower perceived stigma correlated significantly but weakly with improved QOL , however , there was no significant relation to peer support . Conclusion The peer support intervention improved QOL after 12 months among ART patients presenting at clinical stages 3 and 4 at baseline , but it had no impact on QOL among ART patients enrolled at clinical stages 1 and 2 . The intervention did not have an effect on Internal AIDS-related stigma . To improve QOL for PLHIV on ART , measures to support adherence should be context ualized in accordance with individual clinical and social needs An extensive multi-disciplinary literature examines the effects of learning one 's HIV status on subsequent risky sexual behaviors . However , many of these studies rely on non-experimental design s ; use self-reported outcome measures , or both . This study investigates the effects of a r and omly assigned home based HIV testing and counseling ( HTC ) intervention on risky sexual behaviors and schooling investments among school-age females in Malawi . The study finds no overall effects on HIV , Herpes Simplex Virus ( HSV-2 ) , or achievement test scores at follow-up . However , among the small group of individuals who tested positive for HIV , a large increase in the probability of contracting HSV-2 is found , with this effect stronger among those surprised by their test results . Similarly , those surprised by HIV-negative test results see a significant improvement in achievement test scores , consistent with increased returns to investments in human capital . The finding of increased HSV-2 prevalence among HIV-positive individuals suggests that the conventional wisdom that those who learn they are HIV-positive will adopt safer sexual practice s should be treated with caution This paper evaluates an experiment in which individuals in rural Malawi were r and omly assigned monetary incentives to learn their HIV results after being tested . Distance to the HIV results centers was also r and omly assigned . Without any incentive , 34 percent of the participants learned their HIV results . However , even the smallest incentive doubled that share . Using the r and omly assigned incentives and distance from results centers as instruments for the knowledge of HIV status , sexually active HIV-positive individuals who learned their results are three times more likely to purchase condoms two months later than sexually active HIV-positive individuals who did not learn their results ; however , HIV-positive individuals who learned their results purchase only two additional condoms than those who did not . There is no significant effect of learning HIV-negative status on the purchase of condoms OBJECTIVE Antiretroviral therapy ( ART ) significantly decreases HIV-associated morbidity , mortality , and HIV transmission through HIV viral load suppression . In high HIV prevalence setting s , outreach strategies are needed to find asymptomatic HIV positive persons , link them to HIV care and ART , and achieve viral suppression . METHODS We conducted a prospect i ve intervention study in two rural communities in KwaZulu-Natal , South Africa , and Mbabara district , Ug and a. The intervention included home HIV testing and counseling ( HTC ) , point-of-care CD4 count testing for HIV positive persons , referral to care , and one month then quarterly lay counselor follow-up visits . The outcomes at 12 months were linkage to care , and ART initiation and viral suppression among HIV positive persons eligible for ART ( CD4≤350 cells/μL ) . FINDINGS 3,393 adults were tested for HIV ( 96 % coverage ) , of whom 635 ( 19 % ) were HIV positive . At baseline , 36 % of HIV positive persons were newly identified ( 64 % were previously known to be HIV positive ) and 40 % were taking ART . By month 12 , 619 ( 97 % ) of HIV positive persons visited an HIV clinic , and of 123 ART eligible participants , 94 ( 76 % ) initiated ART by 12 months . Of the 77 participants on ART by month 9 , 59 ( 77 % ) achieved viral suppression by month 12 . Among all HIV positive persons , the proportion with viral suppression ( < 1,000 copies/mL ) increased from 50 % to 65 % ( p=<0.001 ) at 12 months . INTERPRETATION Community-based HTC in rural South Africa and Ug and a achieved high testing coverage and linkage to care . Among those eligible for ART , a high proportion initiated ART and achieved viral suppression , indicating high adherence . Implementation of this HTC approach by existing community health workers in Africa should be evaluated to determine effectiveness and costs Home-based voluntary HIV counselling and testing ( HB-VCT ) has been reported to have a high uptake , but it has not been rigorously evaluated . We design ed a model for HB-VCT appropriate for wider scale-up , and investigated the acceptance of home-based counselling and testing , equity in uptake and negative life events with a cluster-r and omized trial . Thirty six rural clusters in southern Zambia were pair-matched based on baseline data and r and omly assigned to the intervention or the control arm . Both arms had access to st and ard HIV testing services . Adults in the intervention clusters were offered HB-VCT by local lay counsellors . Effects were first analysed among those participating in the baseline and post-intervention surveys and then as intention-to-treat analysis . The study was registered with www.controlled-trials.com , number IS RCT N53353725 . A total of 836 and 858 adults were assigned to the intervention and control clusters , respectively . In the intervention arm , counselling was accepted by 85 % and 66 % were tested ( n = 686 ) . Among counselled respondents who were cohabiting with the partner , 62 % were counselled together with the partner . At follow-up eight months later , the proportion of adults reporting to have been tested the year prior to follow-up was 82 % in the intervention arm and 52 % in the control arm ( Relative Risk ( RR ) 1.6 , 95 % CI 1.4 - 1.8 ) , whereas the RR was 1.7 ( 1.4 - 2.0 ) according to the intention-to-treat analysis . At baseline the likelihood of being tested was higher for women vs. men and for more educated people . At follow-up these differences were found only in the control communities . Measured negative life events following HIV testing were similar in both groups . In conclusion , this HB-VCT model was found to be feasible , with a very high acceptance and to have important equity effects . The high couple counselling acceptance suggests that the home-based approach has a particularly high HIV prevention potential HIV-related stigma continues to be a prominent barrier to testing , treatment and care . However , few studies have investigated changes in stigma over time and the factors contributing to these changes , and there is no evidence of the impact of HIV testing and counselling on stigma . This study was nested within a pair-matched cluster-r and omized trial on the acceptance of home-based voluntary HIV counselling and testing conducted in a rural district in Zambia between 2009 and 2011 , and investigated changes in stigma over time and the impact of HIV testing and counselling on stigma . Data from a baseline survey ( n = 1500 ) and a follow-up survey ( n = 1107 ) were used to evaluate changes in stigma . There was an overall reduction of seven per cent in stigma from baseline to follow-up . This was mainly due to a reduction in individual stigmatizing attitudes but not in perceived stigma . The reduction did not differ between the trial arms ( β = -0.22 , p = 0.423 ) . Being tested for HIV was associated with a reduction in stigma ( β = -0.57 , p = 0.030 ) , and there was a trend towards home-based Voluntary Counselling and Testing having a larger impact on stigma than other testing approaches ( β = -0.78 , p = 0.080 vs. β = -0.37 , p = 0.551 ) , possibly explained by a strong focus on counselling and the safe environment of the home . The reduction observed in both arms may give reason to be optimistic as it may have consequences for disclosure , treatment access and adherence . Yet , the change in stigma may have been affected by social desirability bias , as extensive community mobilization was carried out in both arms . The study underscores the challenges in measuring and monitoring HIV-related stigma . Adjustment for social desirability bias and inclusion of qualitative methods are recommended for further studies on the impact of HIV testing on stigma Background : HIV testing male partners of pregnant women may decrease HIV transmission to women and promote uptake of prevention of mother-to-child HIV transmission ( PMTCT ) interventions . However , it has been difficult to access male partners in antenatal care ( ANC ) clinics . We hypothesized that home visits to offer HIV testing to partners of women attending ANC would increase partner HIV testing . Methods : Women attending their first ANC were enrolled , interviewed using smartphone audio-computer-assisted self-interviews and r and omized to home visits or written invitations for male partners to come to clinic , if they were married or cohabiting , unaccompanied by partners and had no prior couple HIV counselling and testing ( CHCT ) . Enrolled men were offered CHCT ( HIV testing and mutual disclosure ) . Prevalence of CHCT , male HIV seropositivity , couple serodiscordance and intimate partner violence , reported as physical threat from partner , were compared at 6 weeks . Results : Among 495 women screened , 312 were eligible , and 300 r and omized to clinic-based or home-based CHCT . Median age was 22 years ( interquartile range 20–26 years ) , and 87 % were monogamous . CHCT was significantly higher in home-visit than in clinic-invitation arm ( n = 128 , 85 % vs. n = 54 , 36 % ; P < 0.001 ) . Home-arm identified more HIV-seropositive men ( 12.0 vs. 8.0 % ; P = 0.248 ) and more HIV-discordant couples ( 14.7 vs. 4.7 % ; P = 0.003 ) . There was no difference in intimate partner violence . Conclusion : Home visits of pregnant women were safe and result ed in more male partner testing and mutual disclosure of HIV status . This strategy could facilitate prevention of maternal HIV acquisition , improve PMTCT uptake and increase male HIV diagnosis Objective To assess the effect of home based HIV counselling and testing on the prevalence of HIV testing and reported behavioural changes in a rural subdistrict of South Africa . Design Cluster r and omised controlled trial . Setting 16 communities ( clusters ) in uMzimkhulu subdistrict , KwaZulu-Natal province , South Africa . Participants 4154 people aged 14 years or more who participated in a community survey . Intervention Lay counsellors conducted door to door outreach and offered home based HIV counselling and testing to all consenting adults and adolescents aged 14 - 17 years with guardian consent . Control clusters received st and ard care , which consisted of HIV counselling and testing services at local clinics . Main outcome measures Primary outcome measure was prevalence of testing for HIV . Other outcomes were HIV awareness , stigma , sexual behaviour , vulnerability to violence , and access to care . Results Overall , 69 % of participants in the home based HIV counselling and testing arm versus 47 % in the control arm were tested for HIV during the study period ( prevalence ratio 1.54 , 95 % confidence interval 1.32 to 1.81 ) . More couples in the intervention arm had counselling and testing together than in the control arm ( 2.24 , 1.49 to 3.03 ) . The intervention had broader effects beyond HIV testing , with a 55 % reduction in multiple partners ( 0.45 , 0.33 to 0.62 ) and a stronger effect among those who had an HIV test ( 0.37 , 0.24 to 0.58 ) and a 45 % reduction in casual sexual partners ( 0.55 , 0.42 to 0.73 ) . Conclusions Home based HIV counselling and testing increased the prevalence of HIV testing in a rural setting with high levels of stigma . Benefits also included higher uptake of couple counselling and testing and reduced sexual risk behaviour . Trial registration Current Controlled Trials IS RCT N31271935 BACKGROUND Use of antiretroviral treatment for HIV-1 infection has decreased AIDS-related morbidity and mortality and prevents sexual transmission of HIV-1 . However , the best time to initiate antiretroviral treatment to reduce progression of HIV-1 infection or non-AIDS clinical events is unknown . We reported previously that early antiretroviral treatment reduced HIV-1 transmission by 96 % . We aim ed to compare the effects of early and delayed initiation of antiretroviral treatment on clinical outcomes . METHODS The HPTN 052 trial is a r and omised controlled trial done at 13 sites in nine countries . We enrolled HIV-1-serodiscordant couples to the study and r and omly allocated them to either early or delayed antiretroviral treatment by use of permuted block r and omisation , stratified by site . R and om assignment was unblinded . The HIV-1-infected member of every couple initiated antiretroviral treatment either on entry into the study ( early treatment group ) or after a decline in CD4 count or with onset of an AIDS-related illness ( delayed treatment group ) . Primary events were AIDS clinical events ( WHO stage 4 HIV-1 disease , tuberculosis , and severe bacterial infections ) and the following serious medical conditions unrelated to AIDS : serious cardiovascular or vascular disease , serious liver disease , end-stage renal disease , new-onset diabetes mellitus , and non-AIDS malignant disease . Analysis was by intention-to-treat . This trial is registered with Clinical Trials.gov , number NCT00074581 . FINDINGS 1763 people with HIV-1 infection and a serodiscordant partner were enrolled in the study ; 886 were assigned early antiretroviral treatment and 877 to the delayed treatment group ( two individuals were excluded from this group after r and omisation ) . Median CD4 counts at r and omisation were 442 ( IQR 373 - 522 ) cells per μL in patients assigned to the early treatment group and 428 ( 357 - 522 ) cells per μL in those allocated delayed antiretroviral treatment . In the delayed group , antiretroviral treatment was initiated at a median CD4 count of 230 ( IQR 197 - 249 ) cells per μL. Primary clinical events were reported in 57 individuals assigned to early treatment initiation versus 77 people allocated to delayed antiretroviral treatment ( hazard ratio 0·73 , 95 % CI 0·52 - 1·03 ; p=0·074 ) . New-onset AIDS events were recorded in 40 participants assigned to early antiretroviral treatment versus 61 allocated delayed initiation ( 0·64 , 0·43 - 0·96 ; p=0·031 ) , tuberculosis developed in 17 versus 34 patients , respectively ( 0·49 , 0·28 - 0·89 , p=0·018 ) , and primary non-AIDS events were rare ( 12 in the early group vs nine with delayed treatment ) . In total , 498 primary and secondary outcomes occurred in the early treatment group ( incidence 24·9 per 100 person-years , 95 % CI 22·5 - 27·5 ) versus 585 in the delayed treatment group ( 29·2 per 100 person-years , 26·5 - 32·1 ; p=0·025 ) . 26 people died , 11 who were allocated to early antiretroviral treatment and 15 who were assigned to the delayed treatment group . INTERPRETATION Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes . The clinical benefits recorded , combined with the striking reduction in HIV-1 transmission risk previously reported , provides strong support for earlier initiation of antiretroviral treatment . FUNDING US National Institute of Allergy and Infectious Diseases

The interventions being evaluated consisted of time limited therapeutically based programmes which did not prove more effective than st and ard shelter or drop-in services for most outcomes and in most studies . There were favourable changes from baseline in outcomes for most particpants in therapy interventions and also in st and ard services . The review discussion section included consideration of the relevance of the findings for LMIC setting s. AUTHORS ' CONCLUSIONS Analysis across the included studies found no consistently significant benefit for the ' new ' interventions compared to st and ard services for street-connected children and young people .

BACKGROUND Numbers of street-connected children and young people run into many millions worldwide and include children and young people who live or work in street environments . Whether or not they remain connected to their families of origin , and despite many strengths and resiliencies , they are vulnerable to a range of risks and are excluded from mainstream social structures and opportunities . OBJECTIVES To summarise the effectiveness of interventions for street-connected children and young people that promote inclusion and reintegration and reduce harms .

Examination of differences between primary alcohol and drug abusing adolescents can provide valuable direction to intervention efforts , though little research in this area has been conducted . The current study compared primary alcohol and primary drug abusing runaway adolescents who were r and omly assigned to family therapy or treatment as usual . Baseline differences , as well as response to treatment , were examined separately for alcohol and drug use and by gender . Although few baseline differences were found , hierarchical linear modeling indicated that alcohol and drug abusing male and female adolescents responded differently to therapy . Primary drug using males showed poorer alcohol use outcomes than did primary alcohol abusers . Specifically , alcohol use increased for primary drug using males receiving family therapy , while drug use decreased in all groups . Findings suggest that alcohol and drug use outcomes might be improved at treatment planning through consideration of client 's gender and primary alcohol versus drug use PURPOSE We evaluate the efficacy of a short family intervention in reducing sexual risk behavior , drug use , and delinquent behaviors among homeless youth . METHODS A r and omized controlled trial of 151 families with a homeless adolescent aged 12 to 17 years . Between March 2006 and June 2009 , adolescents were recruited from diverse sites in Southern California and were assessed at recruitment ( baseline ) , and at 3 , 6 , and 12 months later . Families were r and omly assigned to an intervention condition with five weekly home-based intervention sessions or a control condition ( st and ard care ) . Main outcome measures reflect self-reported sexual risk behavior , substance use , and delinquent behaviors over the past 90 days . RESULTS Sexual risk behavior ( e.g. , mean number of partners ; p < .001 ) , alcohol use ( p = .003 ) , hard drug use ( p < .001 ) , and delinquent behaviors ( p = .001 ) decreased significantly more during 12 months in the intervention condition compared with the control condition . Marijuana use , however , significantly increased in the intervention condition compared with the control condition ( p < .001 ) . CONCLUSIONS An intervention to reengage families of homeless youth has significant benefits in reducing risk over 12 months Runaway youth report a broader range and higher severity of substance-related , mental health and family problems relative to non-runaway youth . Most studies to date have collected self-report data on the family and social history ; virtually no research has examined treatment effectiveness with this population . This study is a treatment development project in which 124 runaway youth were r and omly assigned to ( 1 ) ecologically based family therapy ( EBFT ) or ( 2 ) service as usual ( SAU ) through a shelter . Youth completed an intake , posttreatment , 6 and 12 months follow-up assessment . Youth assigned to EBFT reported greater reductions in overall substance abuse compared to youth assigned to SAU while other problem areas improved in both conditions . Findings suggest that EBFT is an efficacious intervention for this relatively severe population of youth This prospect i ve review was design ed to determine the effectiveness of a broad-spectrum health intervention program for homeless and runaway youth . Diagnosis , treatment , and counseling for drug use , sexually transmitted diseases ( STDs ) , and other health issues were provided all new admissions to a residential care facility during a 2-month enrollment . Education was continued during a 9-month follow-up period based on the program entitled Bright Futures , previously developed and published by the National Center for Education in Maternal and Child Health . Sixty percent of the 106 study residents had STDs on admission and 7 % developed new STDs after completing therapy and undergoing counseling . Drug dependence was reduced from 41 % to 3 % , and 42 % achieved full-time or part-time employment . Fifty-nine percent completed hepatitis B immunization with the 3-dose series . This experience suggests that an organized program of interventions in a residential care facility for homeless teenagers can significantly reduce drug dependence and STDs The broad objective of this study was to underst and the incidence and severity of aggression among sexually abused girls who were trafficked and who were then further used for commercial sexual exploitation ( referred to subsequently as sexually abused trafficked girls ) . In addition , the impact of counseling for minimizing aggression in these girls was investigated . A group of 120 sexually abused trafficked Indian girls and a group of 120 nonsexually abused Indian girls , aged 13 to 18 , participated in the study . The sexually abused trafficked girls were purposively selected from four shelters located in and around Kolkata , India . The nonsexually abused girls were selected r and omly from four schools situated near the shelters , and these girls were matched by age with the sexually abused trafficked girls . Data were collected using a Background Information Schedule and a st and ardized psychological test , that is , The Aggression Scale . Results revealed that 16.7 % of the girls were first sexually abused between 6 and 9 years of age , 37.5 % between 10 and 13 years of age , and 45.8 % between 14 and 17 years of age . Findings further revealed that 4.2 % of the sexually abused trafficked girls demonstrated saturated aggression , and 26.7 % were highly aggressive , that is , extremely frustrated and rebellious . Across age groups , the sexually abused trafficked girls suffered from more aggression ( p < .05 ) , compared with the nonvictimized girls . Psychological interventions , such as individual and group counseling , were found to have a positive impact on the sexually abused trafficked girls . These findings should motivate counselors to deal with sexually abused children . It is also hoped that authorities in welfare homes will underst and the importance of counseling for sexually abused trafficked children , and will appoint more counselors for this purpose Homeless youth face various health challenges . The effectiveness of a short intervention to promote sexual health in 572 homeless 16—23-year-olds ( M = 19.467 + 1.89 ) was conducted using a quasi-experimental repeated measures design . Data collected at three time points ( pre-intervention , immediately post-intervention and follow-up ) via laptop computers were analyzed using multivariate general linear mixed models . A significant condition by time interaction was found for self-reported AIDS/STD knowledge ; intervention participants had higher scores at first post-test . Females scored significantly higher on cognitive and behavioral outcomes while males reported significantly more sexual risk-taking behaviors . Findings support gender-specific interventions Runaway youth are 6–12 times more likely to become infected with HIV than other youth . Using a quasi-experimental design , the efficacy of an HIV prevention program was evaluated over 2 years among 2 groups of runaways : ( 1 ) those at 2 shelters who received Street Smart , an intensive HIV intervention program , and ( 2 ) youth at 2 control shelters . Street Smart provided youth with access to health care and condoms and delivered a 10-session skill-focused prevention program based on social learning theory to youth . Prior to analysis of the intervention 's outcomes , propensity scores were used to identify comparable subgroups of youth in the intervention ( n = 101 ) and control conditions ( n = 86 ) . Compared to females in the control condition , females in the intervention condition significantly reduced their unprotected sexual acts at 2 years and alcohol use , marijuana use , and the number of drugs used over 12 months . Male adolescents in the intervention condition showed significant reductions in marijuana use over 6 months compared to control youth . Adolescent HIV prevention programs must proactively identify mechanisms for maintaining behavior change over the long-term , and innovative research design s are needed to allow examination of agency-level interventions While many studies provide useful information on the risk behaviors in which homeless youth engage , few prior studies evaluate Human Immunodeficiency Virus ( HIV ) risk related reduction strategies . In this study , homeless youth ( n = 180 ) were recruited from a drop-in center and r and omly assigned to one of two conditions , either an integrated individual cognitive-behavioral treatment and HIV prevention intervention that focused on skills building and education or to treatment as usual . All youth were assessed at entry into the program and at 3 and 6 month follow-up points . Findings showed an interaction between treatment condition , age and time . In the interaction , youth assigned to the integrated treatment reported greater condom usage than youth assigned to treatment as usual , with younger youth assigned to treatment as usual showing no change in condom use . The number of sexual partners reported by youth in both treatment conditions was also reduced over time . However , youth in both conditions continued to engage in other high-risk behaviors . The integrated treatment findings are promising and suggest that interventions which target both HIV risk behavior in addition to other life areas ( substance use , mental health and housing ) among homeless youth may be necessary in order to significantly impact high-risk behaviors among this unique group The short-term results of a r and omized trial testing a brief feedback and motivational intervention for substance use among homeless adolescents are presented . Homeless adolescents ages 14 - 19 ( N = 285 ) recruited from drop-in centers at agencies and from street intercept were r and omly assigned to either a brief motivational enhancement ( ME ) group or 1 of 2 control groups . The 1-session motivational intervention presented personal feedback about patterns of risks related to alcohol or substance use in a style consistent with motivational interviewing . Follow-up interviews were conducted at 1 and 3 months postintervention . Youths who received the motivational intervention reported reduced illicit drug use other than marijuana at 1-month follow-up compared with youths in the control groups . Treatment effects were not found with respect to alcohol or marijuana . Post hoc analyses within the ME group suggested that those who were rated as more engaged and more likely to benefit showed greater drug use reduction than did those rated as less engaged . Limitations of the study are discussed as are implication s for development of future substance use interventions for this high-risk group This prospect i ve review was design ed to determine the effectiveness of a broad-spectrum health intervention program for homeless and runaway youth . Diagnosis , treatment , and counseling for drug use , sexually transmitted diseases ( STDs ) , and other health issues were provided to all new admissions to a residential care facility during a 7(1/2)-year enrollment . Education was continued during a minimum follow-up period of 9 months based on the program entitled Bright Futures , previously developed and published by the National Center for Education in Maternal and Child Health . Fifty-four percent of the study residents had STDs on admission , and 9 % developed new STDs after completing therapy and undergoing counseling . Drug dependence was reduced from 47 % to 4 % , and 46 % achieved full-time or part-time employment . Sixty-three percent completed hepatitis B immunization with the 3-dose series . This experience suggests that an organized program of interventions in a residential care facility for homeless teenagers can significantly reduce drug dependence and STDs ABSTRACT This study compared the costs and outcomes associated with three treatment programs that served 149 individuals with dual disorders ( i.e. , individuals with co-occurring severe mental illness and substance use disorders ) who were homeless at baseline . The three treatment programs were : Integrated Assertive Community Treatment ( IACT ) , Assertive Community Treatment only ( ACTO ) , and st and ard care ( Control ) . Participants were r and omly assigned to treatment and followed for a period of 24 months . Clients in the IACT and ACTO programs were more satisfied with their treatment program and reported more days in stable housing than clients in the Control condition . There were no significant differences between treatment groups on psychiatric symptoms and substance use . The average total costs associated with the IACT and Control conditions were significantly less than the average total costs for the ACTO condition A brief motivational intervention with 117 homeless adolescents was evaluated using a r and omized design and 3-month follow-up . The intervention was design ed to raise youths ' concerns about their substance use , support harm reduction , and encourage greater service utilization at a collaborating agency . The study was design ed to strengthen initial promising results of an earlier study ( P. L. Peterson , J. S. Baer , E. A. Wells , J. A. Ginzler , & S. B. Garrett , 2006 ) . Several modifications in the clinical protocol were included to enhance engagement with the intervention . Analyses revealed no significant benefits for intervention participants when homeless youths ' substance use rates were compared with those of control participants . Service utilization during the intervention period increased for those receiving the intervention but returned to baseline levels at follow-up . Participants reported overall reductions in substance use over time . Differences between sampling methods for the current and previous study are discussed , as are the limitations of brief interventions with this population . Future research needs to eluci date mechanisms of change and service engagement for highly vulnerable youth OBJECTIVE This research examined the impact of completing a question naire about blood donation on subsequent donation behavior among a large sample of experienced blood donors . DESIGN Participants ( N=4672 ) were r and omly assigned to an experimental condition that received a postal question naire measuring cognitions about donation or a control condition that did not receive a question naire . MAIN OUTCOME MEASURES Number of registration s at blood drives and number of successful blood donations were assessed using objective records both 6 months and 12 months later . RESULTS Findings indicated that , compared to control participants , the mean frequency of number of registration s at blood drives among participants in the experimental group was 8.6 % greater at 6 months ( p<.0.007 ) , and was 6.4 % greater at 12 months ( p<.035 ) . Significant effects were also observed for successful blood donations at 6 months ( p<.001 ) and 12 months ( p<.004 ) . CONCLUSION These findings provide the first evidence that the mere measurement is relevant to promoting consequential health behaviors . Implication s of the research for intervention evaluation are discussed This study examined the effects of cognitive-behavioral group therapy ( CBT ) on the self-esteem , depression , and self-efficacy of runaway adolescents residing in a shelter in Seoul , South Korea . The study used a control group pretest-posttest design . The experimental group and the control group consisted of 14 and 13 male subjects , respectively , with subjects having been r and omly assigned to these groups . The experimental group participated in a CBT that consisted of eight sessions over an 8-week period ; the control group did not participate in the program . To examine the effects of the CBT on dependent variables , the Wilcoxon signed rank test was used . The scores on depression decreased significantly ( z = -2.325 , p = .02 ) and those on self-efficacy increased significantly ( z = -2.098 , p = .03 ) after the intervention in the experimental group . There was no significant change on self-esteem ( z = -1.19 , p = .23 ) . In the control group , the scores on depression , self-esteem , and self-efficacy did not change significantly after the intervention period . The CBT developed in this study consisted of structured and specific content that could be usefully applied to runaway adolescents residing in a shelter The purpose of this study was to evaluate the Drug Prevention in Youth risk reduction program that was implemented in shelters for runaway/homeless youths in the Southeastern United States . The program focuses on knowledge , attitudes and skills that can help this group of high risk young people minimize the serious negative consequences of drug abuse . An evaluation strategy was developed so comparisons could be made between peer-led , adult-led and non-intervention groups . Dependent sample s t tests and least squares ANCOVAS were used to measure pretest-posttest differences both within and between groups . Results indicate that the peer-led groups were more successful than the other two groups , and that program effects were the most powerful with the youngest group of shelter clients . Process evaluation revealed important factors related to group leader training and group management . It is concluded that well-trained and motivated peer/near peer leaders have particularly valuable contributions to make with regard to drug abuse risk reduction for shelter clients Comprehensive intervention for homeless , street living youth that addresses substance use , social stability , physical and mental health issues has received very little attention . In this study , street living youth aged 14 - 22 were recruited from a drop-in center and r and omly assigned to the Community Reinforcement Approach ( CRA ) or treatment as usual ( TAU ) through a drop-in center . Findings showed that youth assigned to CRA , compared to TAU , reported significantly reduced substance use ( 37 % vs. 17 % reduction ) , depression ( 40 % vs. 23 % ) and increased social stability ( 58 % vs. 13 % ) . Youth in both conditions improved in many other behavioral domains including substance use , internalizing and externalizing problems , and emotion and task oriented coping . This study indicates that homeless youth can be engaged into treatment and respond favorably to intervention efforts . However , more treatment development research is needed to address the barriers associated with serving these youth There is a dearth of research that examines the impact of family systems therapy on problems among sexually and /or physically abused youth . Given this void , differential outcome and predictors of substance use change were evaluated for abused , as compared with nonabused , runaway adolescents who were r and omly assigned to family therapy or treatment as usual . Abused adolescents reported lower family cohesion at baseline , although both abused and nonabused adolescents showed similar substance use reductions . Utilizing hierarchical linear modeling , we found that substance use changed with change in cohesion over time . These findings link change in family functioning to change in adolescent substance use , supporting fiamily systems theory . Findings suggest that a potent target of intervention involves focus on increasing positive communication interactions BACKGROUND Youth who are homeless and on their own are among the most marginalized individuals in the United States and face multiple risks , including use of substances . This study investigates how the use of alcohol , cigarettes , and marijuana among homeless youth may be influenced by characteristics of their social networks . METHODS Homeless youth aged 13 - 24 were r and omly sample d from 41 service and street sites in Los Angeles County ( N=419 ) . Predictors of substance use were examined using linear regression analysis ( for average number of drinks and average number of cigarettes per day ) and negative binomial regression analysis ( for frequency of past month marijuana use ) . RESULTS Youth with more substance users in their networks reported greater alcohol , cigarette , and marijuana consumption regardless of whether these network members provided tangible or emotional support . Marijuana use was more frequent for youth who met more network members through homeless setting s , but less frequent among those who met more network members through treatment or AA/NA . Greater alcohol use occurred among youth who met more network members through substance use-related activities . Youth having more adults in positions of responsibility in their networks consumed less alcohol , and those with more school attendees in their networks consumed less alcohol and cigarettes . CONCLUSIONS Findings highlight the importance of social context in underst and ing substance use among homeless youth . Results also support the relevance of network-based interventions to change social context for substance-using youth , in terms of both enhancing pro-social influences and reducing exposure to substance use

The evidence from this review supports the use of general anaesthesia combined with a femoral nerve block for surgery and postoperative analgesia , or alternatively spinal anaesthesia with local anaesthetic plus spinal morphine .

The PROSPECT Working Group , a collaboration of anaesthetists and surgeons , conducts systematic review s of postoperative pain management for different surgical procedures ( http://www.postoppain.org ) .

Thirty – two patients scheduled for total knee arthroplasty were r and omized to receive an identical epidural blockade initiated 30 min before surgical incision ( N = 16 ) , or at closure of the surgical wound ( N=16 ) . Before induction of general anaesthesia the epidural catheter was tested with bupivacaine 7.5 mg ml‐1 , 2 ml . General anaesthesia was induced with thiopentone , pancuronium or atracurium , and fentanyl 0.1–0.3 mg , and maintained with N2O/O2 and enflurane . The epidural regimen consisted of a bolus of 16 ml of bupivacaine 7.5 mg ml‐1 plus morphine 2 mg , and continuous infusion of bupivacaine 1.25 mg ml‐1 plus morphine 0.05 mg – ml‐1 , 4 mlh‐1 for the first 24 h , and bupivacaine 0.625 mg ml‐1 plus morphine 0.05 mg·ml‐1 , 4 ml . h‐1 , for the next 24 h after operation . Additional morphine 2.5–5 mg was administered i.v . or i.m . for the first 24 h postoperatively , and ketobemidone or morphine 5–10 mg orally or rectally from 24 h to 7 d postoperatively , on request . Paracetamol 1000 mg every 8 h was administered from 48 h to 7 days postoperatively . No significant differences were observed in request for additional opioids , or in pain scores at rest or during mobilisation of the operated limb , during or after cessation of the epidural regimen . These results do not suggest timing of analgesia with a conventional , continuous epidural regimen to be of major clinical importance in patients undergoing total knee arthroplasty This prospect i ve , controlled study compared cold compressive dressings with wool and crepe in the postoperative management of patients undergoing total knee replacement ( TKR ) . Forty TKR patients were assessed for blood loss , pain , swelling , and range of motion . Patients in the cold compression group had less blood loss through suction drainage ( 982 mL versus 768 mL ) . A higher proportion of patients in the treatment group did not require blood transfusion postoperatively . Mean opiate requirements were lower in the cold compression group ( 0.57 versus 0.71 mg/kg/48 hours ) . The cold compression device appeared to reduce blood loss and pain following TKR BACKGROUND We studied whether a small dose of clonidine added to a ropivacaine-fentanyl mixture improves epidural analgesia without provoking side effects typically related to larger amounts of epidural clonidine . METHODS In this r and omized , double-blinded study , patients ( < or = 85 yr , ASA I-III ) underwent total knee arthroplasty ( TKA ) performed under spinal anaesthesia . After the operation , patients received an epidural infusion consisting of ropivacaine 2 mg ml(-1 ) and fentanyl 5 microg ml(-1 ) either without ( Group RF , n=33 ) or with clonidine 2 microg ml(-1 ) ( Group RFC , n=36 ) . The infusion rate was adjusted within the range 3 - 7 ml h(-1 ) . RESULTS Average rate of infusion was slightly smaller in Group RFC than in Group RF ( mean ( sd ) 4.7 ( 0.72 ) vs 5.2 ( 0.8 ) ml h(-1 ) , P=0.004 ) . Compared with the RF group , patients in the RFC group required significantly less rescue pain medication , that is i.m . oxycodone ( median ( 25th , 75th percentile ) 0 ( 0 , 7 ) vs 7 ( 0 , 12 ) mg , P=0.027 ) . Arterial pressure and heart rate were slightly lower in Group RFC throughout the study period ( mean difference between the groups 5 mm Hg ( P<0.002 ) and 3 min(-1 ) ( P=0.12 ) , respectively ) . The groups did not differ statistically with respect to nausea , motor block , and sedation . CONCLUSIONS The small amount of clonidine added to the low-dose ropivacaine-fentanyl mixture reduced the need for opioid rescue pain medication after TKA . Clonidine slightly decreased arterial pressure and heart rate without jeopardizing haemodynamics . Otherwise , the side effect profiles were comparable in both groups 68 consecutive patients who had primary knee arthroplasties because of arthrosis were r and omized to postoperative continuous passive motion ( CPM ) or active physical therapy ( APT ) . Rehabilitation in both groups was initiated on the first postoperative day . The CPM group sustained less postoperative knee swelling with more rapid initial improvement in knee flexion than did the APT group , but there were no differences between the groups in knee flexion at discharge . Postoperative pain rating and hospitalization times were similar in the two groups During a two-year period , eighty-nine patients who were scheduled to have a total knee arthroplasty for the treatment of degenerative osteoarthrosis were r and omly assigned to one of two groups : resurfacing of the patella or retention of the patella . All patients received the same posterior cruciate-sparing prosthesis , and all operations were performed by , or under the direct supervision of , one of us . Three patients died in the early postoperative period . The remaining eighty-six patients ( 118 knees ; fifty-eight that had had resurfacing of the patella and sixty that had not ) formed the study group . They were followed for a mean of thirty months ( range , twenty-four to forty-four months ) . Evaluation was performed with use of the clinical scoring system of The Knee Society , a patient-satisfaction question naire , specific questions regarding patellofemoral symptoms and function , and radiographs . All clinical evaluations were performed by the same research nurse , without the involvement of a physician , in a blinded manner ( neither the nurse nor the patient had knowledge of whether the patella had been resurfaced ) . Preoperatively , the mean Knee Society score , on a scale ranging from 0 to 200 points , was 89.7 points ( range , 33 to 132 points ) ; postoperatively , this score improved to a mean of 172.7 points ( range , 98 to 200 points ) . With the numbers available for study , we could detect no significant difference between the knees that had had patellar resurfacing and those that had not with regard to the over-all score ( p = 0.63 ) , the subscore for pain ( p = 0.56 ) , or the subscore for function ( p = 0.77 ) . We also could detect no difference between the treatment groups , with the numbers available , with regard to patient satisfaction or the responses to questions involving the function of the patellofemoral joint , including the ability to exit from an automobile , to rise from a chair , and to climb stairs . Thirty-two patients had bilateral total knee replacement with resurfacing of the patella in one knee and retention of the patella in the other . These patients expressed no clear preference for either knee . Eight ( 13 per cent ) of the sixty knees that had not had resurfacing were painful anteriorly compared with four ( 7 per cent ) of the fifty-eight that had ; this was not a significant difference ( p = 0.38 ) , with the numbers available . The anterior pain that was noted postoperatively was predominantly of new onset ; it had not been observed preoperatively in three of the four knees that had had resurfacing or in four of the eight that had not . No additional treatment options were offered to the patients who had anterior pain in the knee after resurfacing . However , six ( 10 per cent ) of the sixty knees that had not had resurfacing had it subsequently , because of anterior pain in the knee , after the twelfth postoperative month ( range , fifteen to thirty-nine months ) . The pain decreased in four of these knees . Thus , total knee arthroplasty with retention of the patella yielded clinical results that were comparable with those after total knee arthroplasty with patellar resurfacing , but it was associated with a 10 per cent prevalence of the need for subsequent resurfacing . The prevalence of anterior pain after total knee arthroplasty was not influenced by whether or not the patella had been resurfaced . The postoperative clinical scores , the postoperative development of anterior pain , and the need for subsequent resurfacing were not predicted by the presence of preoperative anterior pain , obesity , or the grade of chondromalacia observed intraoperatively . Because of the short duration of follow-up , these results should be considered preliminary . Additional follow-up is planned Sixty patients undergoing total knee replacement were r and omized to receive either a cold compression dressing ( Cryo/Cuff , Aircast , UK ) or a modified Robert Jones b and age immediately after surgery . The cold compression dressing was used for a minimum of 6 h per day throughout the hospital stay , and the modified Robert Jones b and age remained in place for 48 h from the time of operation . The 2 groups of patients were compared during their hospital stay for blood loss , range of movement , pain scores and need for analgesia . No difference was found between the 2 groups except for less blood loss in the surgical drains in the cold compression group ( P<0.05 ) . Postoperative complications were seen in both groups , but no complication was associated with either the cold compression dressing or the modified Robert Jones b and age . RésuméEtude r and omisée de 60 patients qui , immédiatement après une arthroplastie totale du genou ont eu soit un pansement compressif froid de type “ Cryocuff ” soit un pansement compressif de type Robert Jones . Le pansement froid a été utilisé 6 heures par jour pendant la durée de l'hospitalisation t and is que le pansement compressif de type Robert Jones a été laisse en place pendant 48 heures après l'opération . Aucune différence statistiquement significative n'a pu être mise en évidence entre les deux groupes , à l'exception des pertes sanguines dans le drainage , moins importantes dans le premier groupe de patients . Nous avons eu des complications post opératoires dans les deux groupes mais aucune corrélation n'a pu être établie entre ces complications et le type de b and age appliqué Background : Patient‐controlled epidural analgesia ( PCEA ) has been found to be an effective method for pain relief during labour and after surgery . The goal of this study was to compare the efficacy of bupivacaine – fentanyl PCEA and continuous epidural infusion with the same mixture for treatment of pain after total knee arthroplasty We report the results of a prospect i ve r and omised trial which assessed the role of the posterior cruciate ligament ( PCL ) following total knee replacement ( Genesis I ; Smith and Nephew , Memphis , Tennessee ) . Over a four-year period , 211 patients underwent total knee replacement by the senior author ( TJW ) . They were r and omised at surgery to have the PCL either retained , excised or substituted with a posterior stabilised insert . If it was not possible to retain the ligament due to soft-tissue imbalance , it was released from its tibial insertion until suitable tension was obtained . This created a fourth group , those who were intended preoperatively to have the ligament retained , but in whom it was partially released as a result of findings at the time of surgery . All patients were evaluated using the Knee Society rating system ( adapted from Insall ) . A total of 188 patients ( 212 knees ) was available for follow-up at a mean of 3.5 years after surgery . Preoperatively , there was a varus deformity in 191 knees ( 90 % ) and a valgus deformity in 21 ( 10 % ) . There were no statistical differences in the knee or function scores or the range of movement between the excised , retained and substituted groups . There were , however , significantly worse knee and function scores in the group in whom the PCL was released ( p = 0.002 ) Purpose We previously established that a 5 mg·kg−1 intraoperative dose can reduce the nausea/vomiting associated with tramadol patient-controlled analgesia ( PCA ) . This study was conducted to identify the most appropriate initial dose to improve the quality of tramadol PCA . Methods During general anesthesia , 60 patients undergoing knee arthroplasty were r and omly allocated to receive 1.25 mg·kg−1 ( Group I ) , 2.5 mg·kg−1 ( Group II ) , 3.75 mg·kg−1 ( Group III ) , or 5 mg·kg−1 ( Group IV ) tramadol . The emergence condition was recorded . The titration of additional tramadol 20 mg + metoclopramide 1 mg doses by PCA every five minutes was performed in the postanesthesia care unit ( PACU ) until the visual analogue scale ( VAS ) score was ≤ 3 . An investigator blinded to study group recorded the VAS and side effects every ten minutes . Results In the PACU , significantly more tramadol ( 8.4 ± 3.1vs 4.3 ± 2.1 , 2.5 ± 1.8 , and 0.4 ± 0.3,P < 0.05 ) , and a higher incidence ( 15/15vs 5/15 , 3/15 , and 2/15,P < 0.05 ) of PCA use was observed in Group I compared to Groups II – IV . VAS was significantly higher in Group I than in Groups II – IV at zero and ten minutes ( P < 0.05 ) . Unexpected delayed emergence anesthesia ( > 30 min ) was observed in Group III ( n = 1 ) and in Group IV ( n = 2 ) . Sedation was more important in Groups III and IV than in Groups I and II ( P < 0.05 ) . Conclusion When considering efficacy and side-effect profile , 2.5 mg·kg−1 of tramadol is the optimal intraoperative dose of this drug to provide effective postoperative analgesia with minimal sedation . RésuméObjectifIl a été antérieurement établi qu’une dose peropératoire de 5 mg·kg−1 pouvait réduire les nausées et vomissements associés à l’analgésie auto-contrôlée ( AAC ) . La présente étude voulait préciser la dose initiale la plus appropriée à une meilleure qualité de l’AAC au tramadol . MéthodePendant l’anesthésie générale , 60 patients subissant une arthroplastie du genou ont été répartis au hasard et ont reçu 1,25 mg·kg−1 ( Groupe I ) , 2,5 mg·kg−1 ( Groupe II ) , 3,75 mg·kg−1 ( Groupe III ) ou 5 mg·kg−1 ( Groupe IV ) de tramadol . Les conditions du réveil ont été notées . Le titrage de doses supplémentaires de 20 mg de tramadol + 1 mg de métoclopramide administrées par AAC toutes les cinq minutes a été réalisé à la salle de réveil ( SDR ) jusqu’à l’obtention d’un score ≤ 3 à l’échelle visuelle analogique ( EVA ) . Un expérimentateur impartial a enregistré les scores de l’EVA et les effets secondaires toutes les dix minutes . RésultatsÀ la SDR , une quantité significativement plus importante de tramadol ( 8,4 ± 3,1 vs 4,3 ± 2,1 , 2,5 ± 1,8 et 0,4 ± 0,3 , P < 0,05 ) et une incidence plus élevée ( 15/15 vs 5/15 , 3/15 et 2/15 , P < 0,05 ) d’utilisation d’AAC ont été observées dans le Groupe I , comparé aux Groupes II – IV . Les scores à l’EVA ont été significativement plus élevés dans le Groupe I que dans les Groupes II – IV à zéro et dix minutes ( P < 0,05 ) . Un délai imprévu du retour à la conscience ( > 30 min ) a été observé chez les patients du Groupe III ( n = 1 ) et du Groupe IV ( n = 2 ) . La sédation a été plus importante dans les Groupes III et IV que dans les Groupes I et II ( P < 0,05 ) . ConclusionS i on considère l’efficacité et les effets secondaires , on peut affirmer que 2,5 mg·kg−1 de tramadol constitue la dose peropératoire optimale permettant de fournir une analgésie postopératoire efficace et une sédation minimale Background : We hypothesised that any peripheral action of morphine may contibute to improved postoperative analgesia . The aim of this study was to evaluate the analgesic efficacy of morphine administered preoperatively into an exsanguinated limb prior to total knee arthroplasty Total knee arthroplasty ( TKA ) may result in severe pain , and single-injection femoral nerve blocks ( SFNB ) have been demonstrated to have a limited duration of analgesia . Continuous femoral nerve blocks ( CFNB ) can prolong the analgesic duration of SFNB . We prospect ively r and omized 36 patients undergoing TKA to CFNB versus SFNB and evaluated the effect on hospital length of stay ( LOS ) as the primary outcome within a st and ardized clinical pathway . Secondary outcomes included visual analog scale ( VAS ) pain scores , opioid consumption , and long-term functional recovery at 12 wk . Mean VAS resting scores were significantly lower among patients who received CFNB versus SFNB : first day ( 1.7 vs 3.3 [ P = 0.002 ] ) and second day ( 0.9 vs 3.2 [ P < 0.0001 ] ) after surgery . Mean maximal VAS scores during physical therapy were significantly lower among patients who received CFNB versus SFNB : first day ( 4.7 vs 6.3 [ P = 0.01 ] ) and second day ( 3.9 vs 6.1 [ P = 0.0005 ] ) after surgery . Mean oxycodone consumption was significantly lower among patients who received CFNB versus SFNB : 15 mg versus 40 mg ( P = < 0.0001 ) on the first day after surgery ; 20 mg versus 43 mg ( P = 0.0004 ) on the second day after surgery . There was no difference in hospital LOS ( 3.8 vs 3.9 days ) or long-term functional recovery ( 117 ° versus 113 ° knee flexion at 12 wk ) between the two groups . The lack of effect provided by increased duration of analgesia ( from CFNB ) after TKA may now have minimal impact on hospital LOS and long-term functional recovery in the contemporary healthcare environment within the United States We have evaluated the effect of oral and i.v . tenoxicam on postoperative pain after unilateral total knee replacement in a double-blind , r and omized , controlled study . Tenoxicam was administered to two groups of patients , either before ( 40 mg orally ) or after ( 40 mg i.v . ) surgery , then at 24 h after surgery ( 40 mg i.v . ) and at the end of each day for 8 days ( 20 mg orally ) . A third group were given placebo at all times . All patients had access to PCA morphine for the first 48 h and then co-dydramol tablets for the duration of the study . We studied 101 patients , mean age 67 yr . There was no significant reduction in the requirement for PCA morphine for the duration of the study in either of the treatment groups , or for co-dydramol in the first 2 days , but tenoxicam significantly reduced the need for co-dydramol over the remaining 7 days . There were no significant differences in mobility between groups . There was a high incidence of adverse events reported , with a similar number in each of the three groups In a blinded , placebo-controlled study , the nonsteroidal antiinflammatory drug piroxicam , in combination with the partial morphine agonist/antagonist buprenorphine , was compared with buprenorphine alone for analgesic effect and side-effects in a 10-day period following total replacement of the hip or knee . 117 patients entered and 81 completed the study . The patients receiving piroxicam consumed less buprenorphine . There were no differences concerning side-effects between the two treatment groups , apart from a tendency towards less nausea after the third postoperative day in the group receiving piroxicam The purpose of this study was to determine if intra-articular injection of morphine or bupivacaine significantly decreased postoperative pain as well as the use of intravenous narcotics for pain relief in patients undergoing total knee arthroplasty ( TKA ) . In a prospect i ve , double-blind , r and omized fashion , 105 patients undergoing TKA were divided into the following 4 groups defined by the intra-articular injection they received : group 1 ( n = 27 ) received saline solution , group 2 ( n = 26 ) received morphine sulfate ( 5 mg ) , group 3 ( n = 24 ) received bupivacaine ( 50 mg ) , and group 4 ( n = 28 ) received a combination of morphine sulfate and bupivacaine . The injections were administered immediately after wound closure by the Hemovac drainage tubing that remained clamped for 45 minutes after surgery to allow for absorption . Before surgery and at 2 , 4 , 6 , 24 , and 48 hours after surgery , pain intensity was recorded using a visual analog scale . Postoperative supplemental intravenous morphine and /or meperidine was administered via a patient-controlled analgesia device , and 24-hour drug usage was tabulated . Results were suggestive of a modest short-term reduction in pain scores in the morphine and bupivacaine treatment groups compared with placebo ( saline ) ; however , results were statistically significant only at 4 hours because of the great variability in the pain score data . The total amount of postoperative pain medication used in the first 24 hours after surgery was not statistically significant between the 4 treatment groups . Thus , the results put into question the benefit of postoperative intra-articular administration of morphine or bupivacaine in patients undergoing TKA Postoperative analgesia after two extradural tramadol regimens was compared with that obtained using a st and ard extradural morphine regimen in patients undergoing total knee replacement . Extradural anaesthesia with light general anaesthesia was used . Patients received extradurally either : tramadol 50 mg by bolus injection followed by infusion ( 5mg.h‐1 for 12 h and 2.5mg.h‐1 for a further 12 h ) ( group T50 ) , tramadol 100 mg by bolus injection followed by infusion ( 10 mg.h‐1 for 12 h and 5mg.h‐1 for a further 12 h ) ( group T100 ) or morphine sulphate 2 mg by bolus injection followed by infusion ( 0.2 mg.h‐1 for 12 h and at 0.1 mg.h‐1 for a further 12 h ) ( group M ) . Analgesia was allocated according to a controlled double‐blind design . Visual analogue pain scores were markedly poorer ( p < 0.05 ) and patient‐controlled analgesic consumption was significantly greater ( p < 0.01 ) in the two tramadol groups when compared with the morphine group . The study was discontinued after recruitment of 12 patients , as analgesia was deemed inadequate in those receiving tramadol extradurally . However , further study of this drug may be warranted to examine its effectiveness where postoperative pain is expected to be less severe , and to assess the effect of larger extradural doses and of co‐administration of tramadol and morphine by this route Femoral nerve block ( FNB ) does not consistently produce anesthesia of the obturator nerve . In this single-blind , r and omized , controlled study we added a selective obturator nerve block ( ONB ) to FNB to analyze its influence on postoperative analgesia after total knee replacement ( TKR ) . Before general anesthesia , 90 patients undergoing TKR received FNB ( Group 1 ) , FNB and selective ONB ( Group 2 ) , or placebo FNB ( Group 3 ) . Postoperative analgesia was further provided by morphine IV via patient-controlled analgesia . Analgesic efficacy and side effects were recorded in the first 6 h after surgery . Adductor strength decreased by 18 % ± 9 % in Group 1 and by 78 % ± 22 % in Group 2 ( P < 0.0001 ) . Total morphine consumption was reduced in Group 2 compared with Groups 1 and 3 ( P ≤ 0.0001 ) . Patients in Group 2 reported lower pain scores than those in Groups 1 and 3 ( P = 0.0003 ) . The incidence of nausea was more frequent in Groups 1 and 3 ( P = 0.01 ) . We conclude that FNB does not produce complete anesthesia of the obturator nerve . Single-shot FNB does not provide additional benefits on pain at rest over opioids alone in the early postoperative period . The addition of an ONB to FNB improves postoperative analgesia after TKR Purpose The purpose of this study was to evaluate the effect of perioperative oral clonidine on postoperative analgesia and PCA morphine requirements in adult patients after major orthopaedic knee surgery . Methods In this prospect i ve , double blind , placebo-controlled study 44 patients undergoing either total knee replacement or hemiarthroplasty of the knee were r and omly assigned to receive oral placebo or clonidine ( 5 μg · kg−1 ) 1.5 hr before surgery , and at 12 hr , and 24 hr after the initial dose . Five patients were subsequently withdrawn from study . No other preoperative drugs were given . Preoperative sedation score was recorded . A st and ardized general anaesthetic was administered to all patients . Postoperative blood pressure , heart rate , PCA morphine use , visual analogue score ( VAS ) for pain , sedation , nausea , and pruritus were recorded for 36 hr postoperatively . Results The cumulative PCA morphine used was 37 % lower after clonidine 57.3 ± 26.8 mg ( mean ± SD ) compared with placebo 91 ± 31.6 mg ( P = 0.031 ) . There was no difference in pain or sedation scores postoperatively but patients who received clonidine were more se date d preoperatively ( P < 0.001 ) and had a lower mean arterial blood pressure throughout the period of study by 10 to 26 mmHg ( P < 0.0001 ) . Clonidine reduced the incidence of postoperative nausea ( 25 % vs 74 % ) ( P < 0.01 ) and vomiting compared with placebo ( 10 % vs 53 % ) ( P < 0.01 ) and required less antiemetic ( dimenhydrinate 37.5 ± 20.9 mg vs 82.1 ± 49.4 mg ) but not statistically significant ( P = 0.065 ) . Conclusions Oral clonidine is a useful component to postoperative balanced analgesia as it decreases PCA morphine requirements and decreases the incidence of nausea and vomiting . RésuméObjectifCette étude visait à évaluer chez des adultes l’influence de la clonidine orale périopératoire sur l’analgésie postopératoire et les besoins de morphine après une chirurgie orthopédique majeure du genou . MéthodesPour cette étude prospect i ve , à double aveugle et contrôlée avec placebo , 44 patients opérés pour remplacement total ou hémiarthroplastie du genou étaient répartis pour recevoir soit un placebo soit de la clonidine ( 5 μg · kg−1 ) per os 1,5 h avant la chirurgie , et à la 12e h et à la 24e h après la dose initiale . Par la suite , cinq patients étaient exclus de l’étude . Aucun autre médicament préopératoire n’était administré . Les scores de sédation préopératoire étaient enregistrés . Une anesthésie générale normalisée était administrée à tous les patients . En postopératoire , la pression artérielle , la fréquence cardiaque , l’utilisation de la morphine en PCA , le score sur échelle visuelle analogique ( EVA ) de la douleur , la sédation , la nausée et le prurit étaient enregistrés pendant les 36 premiére heures postopératoires . RésultatsAprès la clonidine , la dose cumulative de morphine de 57,3 ± 26,8 mg ( moyenne ± ET ) en PCA , était de 37 % inférieure à la dose après placebo de 91 ± 31,6 mg ( P = 0,031 ) . Il n’y avait aucune différence au regard des scores de douleur et de sédation , mais la sédation était plus profonde en préopératoire chez les patients sous clonidine ( P < 0,001 ) et ces derniers avaient une pression artérielle inférieure de 10 à 26 mmHg pendant l’étude ( P < 0,0001 ) . La clonidine diminuait l’incidence des nausées ( 25 % vs 74 % ; P < 0,01 ) et des vomissements ( 10 % vs 53 % ; P < 0,05 ) postopératoires comparativement au placebo et nécessitait moins d’antiémétique ( dimenhydrinate 37,5 ± 20,9 mg vs 82,1 ± 49,4 mg ) mais de façon non significative ( P = 0,065 ) . Conclusion En diminuant les besoins de morphine en PCA et en réduisant l’incidence des nausées et des vomissements , la clonidine orale constitue en composante efficace de l’analgésie postopératoire équilibrée Background : Whether to resurface the patella during a primary total knee arthroplasty performed for the treatment of degenerative osteoarthritis remains a controversial issue . Parameters that have been suggested as being useful in guiding this decision include patient height and weight , the presence of anterior knee pain preoperatively , and the grade of chondromalacia encountered intraoperatively . The purpose of this study was to determine whether these parameters were predictive of the clinical result following total knee arthroplasty with or without patellar resurfacing . Methods : Eighty-six patients ( 118 knees ) undergoing primary total knee arthroplasty for the treatment of osteoarthritis were enrolled in a prospect i ve , r and omized , double-blind study . All patients received the same posterior-cruciate-sparing total knee prosthetic components . Patients were r and omized to treatment with or without resurfacing of the patella . Evaluations consisted of the determination of a Knee Society clinical score , the completion of a patient satisfaction question naire , specific questions relating to patellofemoral symptoms , and radiographs . Sixty-seven patients ( ninety-three knees ) were followed for a minimum of five years ( range , sixty to eighty-four months ; average , 70.5 months ) . Results : With the numbers available , there was no significant difference between the groups treated with and without resurfacing with regard to the overall Knee Society score or the pain and function subscores . Obesity , the degree of patellar chondromalacia , and the presence of preoperative anterior knee pain did not predict postoperative clinical scores or the presence of postoperative anterior knee pain . Conclusions : The occurrence of anterior knee pain could not be predicted with any clinical or radiographic parameter studied . On the basis of these results , it seems likely that postoperative anterior knee pain is related either to the component design or to the details of the surgical technique , such as component rotation , rather than to whether or not the patella is resurfaced We tested the effect of epinephrine added to 20 mL ropivacaine 0.5 % and 0.2 % on postoperative analgesia via a femoral catheter after total knee replacement . Forty-one patients undergoing total knee replacement under combined peripheral block/general anesthesia were r and omly allocated to two groups . After insertion of a femoral catheter , 21 patients in the Ropivacaine-Epinephrine ( ROPI-EPI ) group received 20 mL ropivacaine 0.5 % plus epinephrine 1:200,000 , whereas 20 patients in the Ropivacaine group ( ROPI ) received 20 mL plain ropivacaine 0.5 % . Thereafter , a sciatic block with 30 mL bupivacaine 0.5 % plus epinephrine 1:200,000 was performed in all patients , followed by general anesthesia . After surgery , patient-controlled analgesia ( PCA ) with ropivacaine 0.2 % plus epinephrine 1:200,000 for Group ROPI-EPI and plain ropivacaine 0.2 % for Group ROPI was available via the femoral catheter ( 200 mL ropivacaine 0.2 % ± epinephrine , bolus 20 mL , lockout 120 min ) . The patients were instructed to use PCA when the knee pain score was > 3 cm . The interval between the initial ropivacaine injection and the first PCA injection determined the duration of 20 mL ropivacaine 0.5 % ± epinephrine , whereas the interval between the first and second PCA injection determined the duration of 20 mL ropivacaine 0.2 % ± epinephrine . The average duration of ropivacaine 0.5 % was 657 ± 345 min for the ROPI-EPI group and 718 ± 423 min for the ROPI group ( NS ) , whereas for ropivacaine 0.2 % , the average duration was 409 ± 245 min for the ROPI-EPI group and 419 ± 339 min for the ROPI group ( not significant ) . We conclude that epinephrine does not influence the duration of analgesia of the ropivacaine concentrations investigated OBJECTIVE To determine the effectiveness of a preoperative exercise/education program on functional recovery , health related quality of life ( HRQOL ) , health service utilization , and costs following primary total knee arthroplasty ( TKA ) . METHODS One hundred thirty-one subjects were r and omized to either the control ( n = 66 ) or treatment ( n = 65 ) group 6 weeks before TKA surgery . Patients in the treatment group underwent a 4-week exercise/education program before surgery . All subjects were assessed 6 weeks preoperatively ( before the exercise/education intervention ) , immediately preoperatively ( after the exercise/education intervention ) , and 3 , 6 and 12 months after surgery utilizing the Western Ontario McMaster Osteoarthritis Index , the SF-36 , and knee range of motion ( ROM ) and strength measures . Data on length of stay , numbers of community rehabilitation or homecare visits following discharge from the surgical hospital , and the costs associated with these services were also collected . RESULTS Subjects were similar in demographic characteristics and all measurements at the baseline assessment . No differences were seen in knee measurements ( ROM and strength ) , pain , function , or HRQOL between the 2 groups following the intervention program or at any postoperative measurement point . Patients in the treatment group used fewer postoperative rehabilitation services and stayed for a shorter time in hospital than the control group , but these differences did not attain statistical significance . CONCLUSION The exercise/education intervention did not alter functional recovery or HRQOL following TKA . Health service utilization was less in the treatment group , but our study was underpowered to attain statistical significance for these measures This prospect i ve , r and omized investigation evaluated the efficacy of cryotherapy on subjective responses after both open and arthroscopic procedures on the shoulder . Seventy patients were r and omly assigned to one of two study groups : ( 1 ) continuous cryotherapy group and ( 2 ) age-matched control group . Visual analog scales were used to assess subjective responses on postoperative days 1 , 7 , 14 , and 21 . On day 1 , patients receiving cryotherapy reported significantly less pain during sleep and significantly more comfort in bed and rated their sleep as more restful than the control subjects . During days 7 through 21 , cryotherapy subjects reported a significant reduction in frequency and intensity of pain , as well as less pain during shoulder rehabilitation , than the control subjects . These results indicate that cryotherapy is an effective method for postoperative pain control because it decreases the severity and frequency of pain and allows a return to normal sleep patterns while increasing overall postoperative comfort and satisfaction Background : Femoral and sciatic nerve block may improve post‐operative analgesia following total knee replacement A r and omized , double-blind study of 38 patients undergoing total knee replacement was undertaken to compare the efficacy and respiratory effects of low-dose spinal morphine and patient-controlled i.v . morphine against patient-controlled i.v . morphine alone . Patients received either morphine 0.3 mg or saline 0.3 ml with 0.5 % heavy spinal bupivacaine 2 - 2.5 ml . Respiratory effects were measured continuously for 14 h postoperatively with an Edentec 3711 respiratory monitor . There was an improvement in pain relief in the intrathecal morphine group , with significantly lower median VAS pain scores on movement at 4 h ( 0 ( median 0 - 1.5 ) vs 5 ( 1.25 - 7.75 ) P < 0.01 ) , 12 h ( 2 ( 1 - 5 ) vs 6 ( 3 - 8 ) P < 0.01 ) and 24 h ( 3 ( 1 - 5 ) vs 5 ( 3 - 7 ) P < 0.05 ) postoperatively , despite using significantly less patient-controlled morphine ( 20 mg ( 10.25 - 26.25 ) vs 38.5 mg ( 27 - 51 ) P < 0.01 ) in the first 24 h. There was a small but statistically significant reduction in the median oxygen saturation ( SpO2 ) in the intrathecal morphine group 97 (95 - 99)% compared with the placebo group 99 (97 - 99)% ( P < 0.05 ) . Although marked disturbances in respiratory pattern were observed in both groups , none of the patients in the study had severe hypoxaemia ( SpO2 < 85 % > 6 min h-1 ) and there was no significant difference in the incidence of mild ( SpO2 < 94 % > 12 min h-1 ) or moderate ( SpO2 < 90 % > 12 min h-1 ) hypoxaemia or in the incidence of episodes of apnoea or hypopnoea in the two groups Patients with moderate or severe pain following knee arthroplasty and washout from st and ard patient-controlled analgesia ( PCA ) were r and omized to receive 20 mg of an extended-release ( ER ) oxymorphone formulation ( n = 65 ) or placebo ( n = 61 ) q12h for 1 day . Oxymorphone PCA was used as rescue analgesic . Oxymorphone ER provided significant improvements over placebo for most st and ard single-dose analgesic parameters , including mean total pain relief ( TOTPAR ) over 0 to 12 hours ( 19.30 vs. 13.72 ; p = 0.0056 ) , as well as for all multiple-dose ( 24-h ) efficacy assessment s. Oxymorphone-treated patients used significantly less rescue PCA than those who received placebo ( p < 0.02 ) . Adverse events such as nausea and constipation were typical of opioids , and laboratory and physical findings were similar between groups . Oxymorphone ER was effective and generally well tolerated . A single dose was active from 2 hours until > or = 12 hours after administration . Comparisons with other oral opioids are warranted , especially in the setting of outpatient and day surgery BACKGROUND Postoperative analgesia with the use of parenteral opioids or epidural analgesia can be associated with troublesome side effects . Good perioperative analgesia facilitates rehabilitation , improves patient satisfaction , and may reduce the hospital stay . We investigated the analgesic effect of locally injected drugs around a total knee prosthesis . METHODS Sixty-four patients undergoing total knee arthroplasty were r and omized either to receive a periarticular intraoperative injection containing ropivacaine , ketorolac , epimorphine , and epinephrine or to receive no injection . The perioperative analgesic regimen was st and ardized . All patients in both groups received patient-controlled analgesia for twenty-four hours after the surgery , and this was followed by st and ard analgesia . Visual analog scores for pain , during activity and at rest , and for patient satisfaction were recorded preoperatively and postoperatively and at the six-week follow-up examination . The consumption of patient-controlled analgesia at specific postoperative time-points and the overall analgesic requirement were measured . RESULTS The patients who had received the injection used significantly less patient-controlled analgesia at six hours , at twelve hours , and over the first twenty-four hours after the surgery . In addition , they had higher visual analog scores for patient satisfaction and lower visual analog scores for pain during activity in the post-anesthetic-care unit and four hours after the operation . No cardiac or central nervous system toxicity was observed . CONCLUSIONS Intraoperative periarticular injection with multimodal drugs can significantly reduce the requirements for patient-controlled analgesia and improve patient satisfaction , with no apparent risks , following total knee arthroplasty STUDY DESIGN Seventy patients undergoing de novo lumbar microdiscectomy were prospect ively r and omized into a control group and a group in which cold intraoperative wound irrigation along with postoperative wound cooling was used . Postoperative analgesia requirements and length of hospital stay were analyzed and correlated . OBJECTIVES To evaluate the role of intraoperative cold irrigation and postsurgical cooling in minimizing postoperative lumbar discectomy pain . SUMMARY OF BACKGROUND DATA Regulated hypothermia has been used frequently in pain reduction ; however , the efficacy of such a strategy in lumbar disc procedures has not been established . METHODS Seventy patients ( 43 men and 27 women ) , operated on the first time for lumbar disk herniation were prospect ively r and omized into two groups . A st and ard microdiscectomy was performed on all patients . In cohort A the wound site was irrigated with a cold ( 18 C ) 5 % bacitracin solution for 5 minutes . Additionally , a cooling microtemperature pump was placed on the wound site for 24 hours after surgery . The patients in the control group ( cohort B ) were treated in a st and ard fashion without additional hypothermic therapy . All patients received postoperative analgesia through a self-administered morphine pump . The amount of postoperative analgesia received was calculated in morphine equivalents per kilogram . The length of hospital stay was also noted . RESULTS The total amount of pain medication was significantly smaller in cohort A than in the control group ( cohort B ) . For the statistical analysis of the results , covariate analyses for both the length of hospital stay and the morphine dose were used , demonstrating a statistically significant difference with P = 0.0001 . No postoperative wound infection was noted in either group . CONCLUSIONS Intraoperative and postoperative wound site cooling is a safe , inexpensive , and efficient therapeutic method . It reduces the patients ' postoperative pain , promotes earlier ambulation and decreases the length of hospital stay The effects of using a tourniquet during total knee arthroplasty were studied in 80 patients r and omly allocated to two groups , either with or without a tourniquet . The groups were similar in mean age , gender , preoperative knee score and radiographic grading and the patients were all operated on by the same surgeon using one type of prosthesis . There was no significant difference between the two groups in operating time or total blood loss but postoperative pain was less in the patients in whom a tourniquet had not been used . They achieved straight-leg raising and knee flexion earlier and had fewer superficial wound infections and deep-vein thromboses . Total knee arthroplasty can be safely performed without the use of the tourniquet with the benefit that several adverse effects associated with its use can be avoided STUDY OBJECTIVE To compare epidural anesthesia and analgesia with spinal anesthesia with intravenous morphine analgesia for its effect on range of motion ( ROM ) and early rehabilitation after total knee replacement . DESIGN R and omized prospect i ve study . SETTING Tertiary care , academic medical center . PATIENTS Thirty-eight patients scheduled for total knee replacement . INTERVENTIONS Patients were r and omized into 2 groups . One group received spinal anesthesia with 0.5 % bupivacaine and analgesia with intravenous patient-controlled analgesia morphine , dem and mode only . The other group was given epidural anesthesia with 1.0 % ropivacaine with 1:200,000 epinephrine and analgesia with 0.2 % ropivacaine at 8 mL/h , maintained for 7 days . Both groups had compression stocking for deep venous thrombosis ( DVT ) prophylaxis , urinary catheter for the first 24 hours , and duplex scanning at days 3 and 10 . The spinal group received low molecular-weight heparin for DVT prophylaxis . MEASUREMENTS Data collected included pain scores at rest , and with ROM , frequency of DVT , and patient satisfaction . Data were evaluated with Wilcoxon rank sum test for continuous variables and Fisher exact test for categorical variables . Data were considered significant at P < .05 . MAIN RESULTS All 38 patients finished the study , 22 in the spinal group and 16 in the epidural group . There was no difference in demographics between groups . The pain sores at rest and with ROM were significantly less in the epidural group . ROM was better in the epidural group compared with the spinal group after day 1 . No DVT was detected on day 3 or 10 in either group . No patient in either group required reinsertion of bladder catheter for urinary retention . CONCLUSION By using epidural analgesia in the first 7 days postoperatively , we achieved improved early rehabilitation due to excellent pain relief effect and an antithrombotic effect with an efficacy comparable to low molecular-weight heparin AIMS AND OBJECTIVES To assess the effectiveness of pre- and post-operative physiotherapy at home for unilateral total knee replacement ( TKR ) . METHODS In this pragmatic r and omized controlled trial set in participants ' homes ( four primary care trust areas ) and physiotherapy out patients in a South Yorkshire teaching hospital trust , 160 osteoarthritis patients waiting for unilateral TKR were r and omly allocated to intervention ( home ) group ( n=80 ) or control ( hospital outpatient ) group ( n=80 ) . The intervention group had pre- and post-operative home visits for assessment and treatment by a community physiotherapist . Outcome measures were health-related quality of life ( HRQoL ) , measured by the Western Ontario McMaster Osteoarthritis index ( WOMAC ) and the Short Form 36 health survey ( SF-36 ) pre-operatively and at 12 weeks post-TKR operation ; patient satisfaction ; and NHS re source use . RESULTS No significant differences were observed between the two treatment groups in the primary outcome measure , the WOMAC pain score , or any other HRQoL score . The home group had a significantly greater mean number of physiotherapy sessions than the hospital group [ mean difference 5.2 sessions , 95 % confidence interval (CI)=-6.3 to -4.1 ; P=0.001 ] . There was no significant difference in the total NHS costs per patient between groups . However , home physiotherapy for TKR was significantly more expensive ( mean difference-pound136.5 , 95 % CI=- pound160 to-pound113 ; P=0.001 ) . Patients were equally satisfied with physiotherapy at home or in hospital ; however , more of the home group would choose their location for physiotherapy again . CONCLUSIONS Although home physiotherapy was as effective and as acceptable to patients as hospital outpatient physiotherapy for unilateral TKR , it was more expensive . Additional pre-operative home physiotherapy did not improve patient-perceived health outcomes BACKGROUND This multicentre , double-blind , placebo-controlled study compared the opioid-sparing effectiveness and clinical safety of parecoxib sodium over 48 h , in 195 postoperative patients after routine total knee replacement surgery . METHODS Elective total primary knee arthroplasty was performed under spinal anaesthesia , with a single dose of spinal bupivacaine 10 - 20 mg , and intraoperative sedation with midazolam 0.5 - 1.0 mg i.v . , or propofol < 6 mg kg(-1)h(-1 ) . Patients were r and omized to receive either parecoxib sodium 20 mg twice daily ( bd ) i.v . ( n=65 ) , parecoxib sodium 40 mg bd i.v . ( n=67 ) , or placebo ( n=63 ) at the completion of surgery , and after 12 , 24 , and 36 h. Morphine ( 1 - 2 mg ) was taken by patient-controlled analgesia or by bolus doses after 30 min . RESULTS Patients receiving parecoxib sodium 20 mg bd and 40 mg bd consumed 15.6 % and 27.8 % less morphine at 24 h than patients taking placebo ( both P<0.05 ) . Both doses of parecoxib sodium administered with morphine provided significantly greater pain relief than morphine alone from 6 h ( P<0.05 ) . A global evaluation of study medication demonstrated a greater level of satisfaction among patients taking parecoxib sodium than those taking placebo . Parecoxib sodium administered in combination with morphine was well tolerated . However , a reduction in opioid-type side-effects was not demonstrated in the parecoxib sodium groups . CONCLUSION Parecoxib sodium provides opioid-sparing analgesic effects in postoperative patients We have compared 0.5 % bupivacaine 75 mg ( group A ; n = 15 ) with three 0.5 % bupivacaine 75 mg-ketamine mixtures for extradural block in 59 ASA I-III patients undergoing total knee replacement in a r and omized , double-blind study . The following doses of preservative-free 1 % ketamine were used : 0.3 mg kg-1 ( group B : n = 14 ) ; 0.5 mg kg-1 ( group C : n = 5 ) ; and 0.67 mg kg-1 ( group D : n = 15 ) . Level of sensory block , degree of motor weakness and sedation scores were recorded before and after operation . Duration of postoperative analgesia was also noted . There was no difference between groups in median maximum level of sensory block ( group A : T4 ( range T10-T2 ) ; group B : T4 ( T10-T2 ) ; group C : T4 ( T8-T2 ) ; and group D : T3 ( T8-C3 ) ) or in the degree of motor block . Thirty-three of the 44 patients who received ketamine showed signs of systemic absorption ( blurred vision , sedation ) within 10 min of injection . There was no significant difference between groups in median duration of analgesia ( group A : 240 ( range 115 - 340 ) min ; group B : 198 ( 97 - 460 ) min ; group C : 150 ( 122 - 448 ) min ; and group D : 210 ( 130 - 390 ) min ) . No patient suffered any adverse psychomimetic effects . We conclude that at the doses used , addition of ketamine to extradural bupivacaine did not improve extradural block in adult patients undergoing total knee replacement OBJECTIVE To evaluate the efficacy of continuous passive motion ( CPM ) in the postoperative management of patients undergoing total knee arthroplasty . DESIGN A r and omized controlled single-blind trial of CPM plus st and ardized rehabilitation vs st and ard rehabilitation alone . SETTING A referral hospital for arthritis and musculoskeletal care . PATIENTS Consecutive patients with end-stage osteoarthritis or rheumatoid arthritis undergoing primary total knee arthroplasty who had at least 90 degrees of passive knee flexion . One hundred fifty-four patients were eligible and 102 patients agreed to participate and were r and omized . Ninety-three patients completed the study protocol . INTERVENTION Continuous passive motion machines programmed for rate and specified arc of motion within 24 hours of surgery with range increased daily as tolerated with st and ardized rehabilitation program compared with st and ardized rehabilitation program alone . MAIN OUTCOME MEASURES Primary outcomes were pain , active and passive knee range of motion , swelling ( or circumference ) , quadriceps strength at postoperative day 7 , as well as complications , length of stay , and active and passive range of motion and function at 6 weeks . RESULTS Use of CPM increased active flexion and decreased swelling and the need for manipulations but did not significantly affect pain , active and passive extension , quadriceps strength , or length of hospital stay . At 6 weeks there were no differences between the two groups in either range of motion or function . In this series , use of CPM result ed in a net savings of $ 6764 over conventional rehabilitation in achieving these results . CONCLUSION For the average patient undergoing total knee arthroplasty , CPM is more effective in improving range of motion , decreasing swelling , and reducing the need for manipulation than is conventional therapy and lowers cost Patellar resurfacing in total knee arthroplasty remains controversial . This study evaluates the results of resurfacing and nonresurfacing the patella in a r and omized controlled , clinical trial at a minimum of 10 years followup . One hundred knees ( 90 patients ) with osteoarthritis were enrolled in a prospect i ve r and omized clinical trial using a posterior – cruciate-retaining total knee arthroplasty . Patients were r and omized to receive resurfacing or retention of the patella . Evaluations were done preoperatively and yearly , up to a minimum of 10 years ( range , 10.1–11.5 years ) postoperatively . Disease-specific ( Knee Society clinical rating score ) and functional ( stair climbing , flexion/extension torques , patellar examination ) outcomes were measured . Patient satisfaction , anterior knee pain , and patellofemoral question naires were completed . Intraoperative grading of the articular cartilage was done . No patients were lost to followup ; 45 patients remained alive . Nine revisions ( in nine of 90 knees ; 10 % ) were done in seven patients in the nonresurfaced group ( 15 % of knees ) and in two patients in the resurfaced group ( 5 % of knees ) . No significant difference was found between the groups regarding revision rates , Knee Society clinical rating scores , and functional , patient satisfaction , anterior knee pain , patellofemoral , and radiographic outcomes . Intraoperative cartilage quality was not a predictor of outcome . This study currently is the longest followup of a r and omized controlled , clinical trial that examines patellar resurfacing in total knee arthroplasty . The results showed no significant difference between the groups for all outcome measures at a minimum of 10 years of followup Evidence of pre‐emptive analgetic effect of opioid would offer great potential benefit to patients with postoperative pain , a better pain relief with less opioid . The aim of this double blind r and omised trial was to study the effect of intramuscular morphine premedication on postoperative pain Background and objective : To investigate the interactions of postoperative pain and endocrine stress response , three groups of 21 patients each with total knee arthroplasty were compared in a r and omized , prospect i ve design . For postoperative pain management , a three-in-one block , an epidural catheter analgesia or an intravenous patient-controlled analgesia was used . Methods : After st and ardized balanced anaesthesia , the pain intensity was measured by a visual analogue scale ( VAS ) . For detection of epinephrine , norepinephrine , antidiuretic hormone , adrenocorticotropic hormone and cortisol in the plasma , blood sample s were taken at six time points before and up to 180 min after the start of pain therapy . In addition , systolic arterial pressure , heart rate , partial arterial oxygen saturation , nausea , vomiting and satisfaction of the patients were recorded . Results : Within 15 min after the start of pain therapy , VAS in all groups was similarly reduced from > 40 mm to a range < 10 mm ( P < 0.001 ) . Initially , all endocrine stress variables exceeded the normal range . Epidural anaesthesia led to a significant decrease of epinephrine and norepinephrine concentrations , while an increase was observed in the group with patient-controlled analgesia , and the decrease in patients with the three-in-one block was less than in patients receiving epidural anaesthesia ( P = 0.001 ) . Differences in antidiuretic hormone , adrenocorticotropic hormone and cortisol were less pronounced . Systolic arterial pressure decreased significantly in all groups , particularly in patients with epidural anaesthesia . Partial arterial oxygen saturation and the incidence of nausea and vomiting were comparable . All patients were satisfied with the methods used . Conclusions : All methods of pain management led to sufficient analgesia , but they were not accompanied by an adequate reduction in endocrine stress response . Thus , postoperative pain is only a secondary stressor and sufficient analgesia with subjective well-being does not prove a stress-free state . With regard to the reduction of sympathoadrenergic stress response , epidural anaesthesia is superior to the three-in-one block and patient-controlled analgesia . Epidural anaesthesia is recommended particularly for high-risk patients with hypertension , coronary heart disease and diabetes mellitus . In these patients , the reduction of a ' hidden ' endocrine stress response in addition to prevention of pain is of special interest This study was design ed to determine the effects of a single-injection femoral nerve block ( FNB ) using 30 mL of 0.5 % bupivacaine with epinephrine 1:200,000 , on pain control following total knee arthroplasty ( TKA ) . Forty patients were r and omly distributed into 2 groups : Group A received general anesthesia plus a FNB ( n = 19 ) , whereas Group B received general anesthesia plus a FNB with 30 mL of preservative-free saline ( n = 21 ) . The amount of morphine used , sedation , and average pain perception were measured for the first 24 hours and daily postoperatively . Group A used significantly less morphine ( 48.1 mg ) compared with Group B , which used 76.2 mg during the first 24 hours after surgery ( P = 0.003 ) . Group A 's sedation scale was significantly less than group B 's ( 2.26 vs 2.67 ) ( P = 0.045 ) . The average pain perception was significantly different ( P = .002 ) . Postoperative management of pain following TKA can be improved through a preoperative single-injection FNB with 0.5 % bupivacaine plus epinephrine 1:200,000 . The cost is minimal , risks appear acceptable , and the procedure is efficacious We studied the effects of the timing of tourniquet release in 88 patients r and omly allocated for release after wound closure and b and aging ( group A ) , or before the quadriceps layer had been closed allowing control of bleeding before suture ( group B ) . The groups were similar in mean age , weight , gender , preoperative knee score , radiographic grading , and prosthesis implanted . Patients in group B had less postoperative pain , achieved earlier straight-leg raising , and had fewer wound complications . Five patients in group A had to return to theatre , three for manipulation under anaesthesia , one for secondary closure of wound dehiscence , and one for drainage of a haematoma . The last patient later developed a deep infection , which was treated by a two-stage revision . There were no significant differences between the two groups in operating time , or the decrease in haemoglobin concentration at 48 hours postoperatively . Some of the adverse effects of the use of a tourniquet for knee surgery can be significantly reduced by early tourniquet release , with haemostasis before the quadriceps mechanism and the wound are closed Purpose To compare the postoperative analgesic efficacy and safety of intrathecal ( IT ) néostigmine and IT morphine in patients undergoing total knee replacement under spinal anesthesia . Methods : Sixty patients scheduled for elective total knee replacement under spinal anesthesia were r and omly divided into three equal groups which received IT 0.5 % hyperbaric bupivacaine 15 mg with either normal saline 0.5 ml _ , néostigmine 50 μg , or morphine 300μg . The maximal level of sensory block , duration of analgesia , time to use of rescue analgesics , the overall 24-hr and four-hour interval visual analogue scale ( VAS ) pain score , and the incidence of adverse effects were recorded for 24 hr after administration . Results There was no significant difference in maximal level of sensory block among the three groups . The morphine group had a later onset of postsurgical pain and longer time to first rescue analgesics than the néostigmine group ( P < 0.05 ) . Overall 24-hr VAS pain scores were significantly higher in the saline groupvs the morphine and néostigmine groups ( P < 0.05 ) . Motor block lasted significantly longer in the néostigmine group than in the morphine and saline groups ( P < 0.05 ) . The incidence of adverse effects was similar in the néostigmine and morphine groups except for pruritus ( 70 % ) occurring more frequently in the morphine group than in the néostigmine and saline groups ( 0 % ; P < 0.05 ) . Overall satisfaction rates were better in the néostigmine group than in the morphine and saline groups ( P < 0.05 ) . Conclusions IT néostigmine 50 μg produced postoperative analgesia lasting about seven hours with fewer side effects and better satisfaction ratings than IT morphine 300 μg . RésuméObjectifComparer l’efficacité et l’innocuité analgésique postopératoire de l’administration intrathécale ( IT ) de néostigmine et de morphine chez des patients devant subir une arthroplastie totale du genou sous rachianesthésie . MéthodeSoixante patients devant recevoir une prothèse totale de genou sous rachianesthésie ont été répartis au hasard en trois groupes égaux . Ils ont reçu 15 mg de bupivacaine hyperbare IT à 0,5 % et , soit 0,5 mL de solution salée , soit 50 μg de néostigmine , soit 300 μg de morphine . Le niveau maximal du bloc sensitif , la durée de l’analgésie , l’heure des premières dem and es d’analgésiques de secours , les scores de douleur des 24 h d’observation et de chaque intervalle de quatre heures selon l’échelle visuelle analogique ( EVA ) et l’incidence d’effets indésirables ont été enregistrés pendant 24 h après l’administration médicamenteuse . RésultatsLe niveau maximal de blocage sensitif n’a pas présenté de différence intergroupe significative . Chez les patients avec morphine , la douleur post-chirurgicale s’est installée plus tard et leur première dem and e d’analgésie de secours a donc eu lieu plus tard que chez les patients avec néostigmine ( P < 0,05 ) . Les scores de douleur à l’EVA ont été , sur 24 h , signifcativement plus élevés avec la solution salée vs la morphine ou la néostigmine ( P < 0,05 ) . La durée du blocage moteur a été signifcativement plus longue avec la néostigmine qu’avec la morphine ou la solution salée ( P < 0,05 ) . L’incidence d’effets indésirables a été similaire avec la néostigmine et la morphine , sauf pour le prurit ( 70 % ) qui a été plus fréquent avec la morphine qu’avec la néostigmine ou la solution salée ( 0 % ; P < 0,05 ) . Le taux de satisfaction générale a été meilleur avec la néostigmine qu’avec la morphine ou la solution salée ( P < 0,05 ) Background and Objectives . In an effort to further decrease postoperative opioid requirements and improve analgesia in patients undergoing elective knee joint replacement , a study was made of the effectiveness of adding morphine to an intra‐articular bupivacaine injection given immediately following surgery . Methods . In r and om , double‐blind fashion , 75 patients received a 31‐mL intra‐articular injection consisting of either 30 mL 0.5 % bupivacaine with 1:200,000 epinephrine and 1 mL normal saline ( group BUP ) , 30 mL 0.5 % bupivacaine with 1:200,000 epinephrine and 1 mg ( 1 mL ) preservative‐free morphine ( group BUP‐MORPH ) , or 30 mL normal saline with 1:200,000 epinephrine and 1 mg preservative‐free morphine ( group MORPH ) . Postoperative analgesia was supplied by patient controlled analgesia ( PCA ) with morphine . Patients were assessed at 1 , 2 , 4 , and 24 hours for pain ( visual analog and verbal rating scales ) , morphine utilization , and side effects . Knee range of motion was measured before operation and at hospital discharge . Results . There was no difference among the three groups in PCA morphine requirements , pain scores by either scale , range of motion , or incidence of side effects , including somnolence , urinary retention , nausea and vomiting , and pruritus . Conclusion . The addition of 1 mg morphine to an intra‐articular injection of 30 mL 0.5 % bupivacaine with 1:200,000 epinephrine given at wound closure does not improve analgesia in patients undergoing elective knee joint replacement Purpose To compare the efficacy of a continuous posterior lumbar plexus ( PSOAS ) block to a continuous three-in-one femoral nerve ( FEM ) block in patients undergoing primary total knee replacement ( TKR ) . Methods Sixty patients were r and omly allocated to receiveiv patient-controlled morphine analgesia ( PCA ) , PCA plus a continuous FEM block with 30 mL ropivacaine 0.5 % and epinephrine 1:200,000 bolus followed by an infusion of ropivacaine 0.2 % at 12 mL · hr−1 for 48 hr , or PCA plus a continuous PSOAS block with the same bolus and infusion regimen as the FEM group . Postoperative morphine consumption , verbal analogue scale pain scores at rest and during physiotherapy and evidence of sensory and motor blockades were noted . Results Both regional techniques significantly reduced 48 hr morphine consumption ( FEM 37.3 ± 34.7 mg , P = 0.0002 ; PSOAS 36.1 ± 25.8 mg , P < 0.0001 ) compared to PCA ( 72.2 ± 26.6 mg ) . Pain scores at rest , six and 24 hr after TKR were lower in the FEM and PSOAS groups compared to the PCA group ( P < 0.0001 ) . Although sensory and motor blockades of the obturator nerve were achieved more often in the PSOAS group than in the FEM group ( P < 0.0001 ) , morphine consumption and pain scores did not differ between the two groups . Conclusion Both continuous PSOAS block and continous threein-one FEM block provided better analgesia than PCA but no differences were seen between the two regional techniques . RésuméObjectifComparer l’efficacité d’un bloc continu du plexus lombaire par voie postérieure ( PSOAS ) à celle d’un bloc trois- en- un du nerf fémoral ( FEM ) pour l’analgésie postopératoire des patients subissant une arthroplastie totale du genou (ATG).MéthodeSoixante patients ont été divisés au hasard en trois groupes égaux et ont reçu l’analgésie iv auto- contrôlée ( AAC ) avec morphine , l’AAC plus un bloc FEM avec 30 mL de ropivacaïne 0,5 % et adrénalinée à 1:200 000 suivi d’une perfusion de ropivacaïne 0,2 % à 12 mL · h−1 pour 48 h , ou l’AAC plus un bloc PSOAS continu . La consommation de morphine , le score de douleur par l’échelle verbale analogique ( EVA ) au repos et durant la kinésithérapie , et les blocs sensitifs et moteurs ont été notés . RésultatsLes deux types de bloc , comparés à l’AAC , réduisent la consommation totale ( 48 h ) de morphine ( AAC 72,2 ± 26,6 mg ; FEM 37,3 ± 34,7 mg , P = 0,0002 ; PSOAS 36,1 ± 25,8 mg , P < 0,0001 ) et les scores de douleur au repos , à six et 24 h après l’ATG ont été plus bas dans les groupes FEM et PSOAS comparés au groupe d’AAC ( P < 0,0001 ) . Le blocage du nerf obturateur ( sensitif et moteur ) est plus constant avec le bloc PSOAS qu’avec le bloc FEM ( P < 0,0001 ) mais les deux techniques ont un effet similaire sur la consommation de morphine et les ÉVA . Conclusion Comparativement à l’AAC , les deux blocs continus du plexus lombaire offrent une meilleure analgésie postopératoire mais il n’y a pas de différence entre les deux types de bloc quant à la consommation de morphine et aux ÉVA Background and Objectives Continuous-infusion femoral nerve block ( FNB ) improves analgesia and rehabilitation after total knee replacement . In this study , we investigated the efficacy of single-injection FNB to achieve similar results . Methods A total of 30 patients were prospect ively and r and omly assigned to receive 40-mL injections of either 0.25 % bupivacaine ( group B ) or saline ( group S ) after total knee replacement . Blinded observers evaluated the patients for postoperative pain , morphine consumption , ambulating distances , and maximal knee flexion ; pain was scored on the visual analog scale ( VAS ) . Results Compared with group S patients , group B patients had significantly lower VAS pain scores ( P < .01 in the postoperative anesthesia care unit , P < .05 on the day after surgery ) ; group B patients also showed significantly lower total morphine use ( P < .05 ) and a lower incidence of morphine-related side effects . Significantly more group B than group S patients could ambulate on the day after surgery ( 93 % v 46 % , P < .05 ) , and mean ambulatory distance was significantly better for group B than group S patients at discharge ( 166 ± 37 v 117 ± 24 feet , P < .01 ) . Knee flexion was significantly better for group B than group S patients on the second day after surgery ( 70 ° v 60 ° , P < .01 ) , but the between-group difference was no longer statistically significant at discharge . Mean length of acute hospitalization was significantly shorter for group B ( 3 days ; range , 3 to 5 days ) than group S patients ( 4 days ; range , 3 to 6 days , P < .05 ) . Conclusions Single-injection FNB provided effective analgesia , facilitated early ambulation , and reduced the length of acute hospitalization in patients undergoing total knee replacement The aim of this prospect i ve , r and omized , and controlled study was to evaluate the efficacy of cold compressive dressings ( Cryo/Cuff ) and epidural anesthesia ( EDA ) in the postoperative management of primary unicondylar knee arthroplasty . Sixty patients ( 61 knees ) were r and omized into 3 groups . No significant difference between groups was detected with respect to subjective pain , bleeding , swelling , range of motion , and function . The consumption of morphine was , however , significantly higher in the control group the first 24 hours than both the EDA group ( P < .001 ) and the Cryo group ( P = .028 ) . There was no significant difference in morphine consumption between the 2 treatment groups . Based on the results of this study , Cryo/Cuff seems to be a rational , effective , risk-free , and well-tolerated alternative to EDA to reduce pain and morphine after unicondylar knee arthroplasty Epidural analgesia with local anaesthetic minimizes the catabolic response to surgery . To determine whether this could enhance the rate of recovery following orthopaedic surgery , 51 patients undergoing bilateral one-stage total knee arthroplasty were allocated to receive infusions of either continuous epidural bupivacaine/fentanyl or continuous intravenous fentanyl to compare the efficacy of these modes of pain relief on postoperative clinical outcomes and rates of rehabilitation . Infusions were maintained for 36 to 48 hours in a post-anaesthesia care unit ( PACU ) . Postoperatively , pain relief ( visual analogue scale ) , attainment of physical therapy goals and cardiopulmonary complications were measured daily for 7 days . Epidural analgesia with a combination of bupivacaine and fentanyl did not result in any measurable improvement in rehabilitation milestones or reduction in postoperative complications following bilateral total knee arthroplasty than with fentanyl infusions alone Total knee replacement ( TKR ) produces severe postoperative pain . Peripheral nerve blocks can be used as analgesic adjuncts for TKR , but the efficacy of femoral nerve blocks alone is controversial . The sciatic nerve innervates posterior regions of the knee ; thus , performance of both sciatic and femoral nerve blocks may be necessary to improve analgesia after TKR . We performed this study to determine whether peripheral nerve blocks improve analgesia after TKR . In a r and omized , double-blind fashion , 36 patients undergoing TKR received either femoral , sciatic-femoral , or sham nerve blocks after a st and ardized spinal anesthetic . Further postoperative analgesia was provided by patient-controlled IV morphine and ketorolac . Pain at rest and with physical therapy , morphine use , nausea , pruritus , sedation , and patient satisfaction were assessed . Patients receiving peripheral nerve blocks reported better analgesia at rest for at least 8 h after transfer to the hospital ward ( P < 0.05 ) . Morphine use was decreased by approximately 50 % in the peripheral nerve block groups until the second postoperative day ( P < 0.02 ) . Side effect profiles and patient satisfaction were similar between groups . We conclude that femoral nerve blocks improve analgesia and decrease morphine use after TKR . The addition of a sciatic nerve block to the femoral nerve block did not further improve analgesic efficacy . Implication s : Performance of femoral nerve blocks improves analgesia and decreases the need for morphine after total knee replacement surgery . The addition of a sciatic nerve block to the femoral nerve block does not provide additional benefits . ( Anesth Analg 1998;87:93 - 7 Abstract . Sixty patients were operated on for primary gonarthrosis by means of a cemented , posterior cruciate preserving total knee and were r and omly allocated to postoperative drainage or nondrainage . The primary criterion was duration of hospital stay . Secondary criteria included serial evaluation of knee pain , knee flexion , knee circumference , calculated blood loss after 7 days , complications , reoperations , and the need for blood transfusions . There was no difference between the two groups in any of the criteria during the entire follow-up . There was a nonsignificant trend to a decreased calculated blood loss in the nondrained group and significantly less transfused blood units in the nondrained group . Lack of drainage does not increase complication risk after total knee prosthesis implantation . We therefore recommend using no routine drainage after this procedure Patellar resurfacing in total knee arthroplasty is a topic debated in the literature . Concerns include fracture , dislocation , loosening , and extensor mechanism injury . Residual anterior knee pain has been reported when the patella is not resurfaced . One hundred patients with osteoarthritic knees were prospect ively r and omized to either have their patella resurfaced or left not resurfaced . All patients were treated with a single prosthesis that featured an anatomically design ed patellofemoral articulation ( Anatomic Medullary Knee , DePuy , Warsaw , IN ) Two patients in the unresurfaced group and one in the resurfaced group required repeat surgery for patellofemoral complications . At 8- to 10-year follow-up evaluations , Knee Society Clinical Ratings scores were not different between the 2 groups . Rates of anterior knee pain with walking and stair climbing were significantly less in the resurfaced group . Eighty percent of patients with a resurfaced patella were extremely satisfied with their total knee arthroplasty versus 48 % without patellar resurfacing . When satisfied and extremely satisfied patients were grouped together , there was no difference between the 2 groups The medial parapatellar approach has become the st and ard technique in total knee arthroplasty ( TKA ) . However , recent studies have reported superior results regarding functional recovery when using the midvastus approach . It was the aim of this study to evaluate the early functional outcome of both surgical techniques . In a prospect i ve , double-blinded , r and omized study , 50 patients for TKA were consecutively operated on either by the medial parapatellar or the midvastus approach . Exclusion criteria were defined as previous open knee surgery and leg deformity of more than 10 ° varus or valgus . TKA was performed in all patients by one surgeon using the same type of implants in both groups . Pain scores ( VAS ) were documented and follow-up data including quadriceps strength and proprioception were obtained 3 weeks and 6 weeks postoperatively . Both groups were comparable in preoperative demographic data . Postoperatively , patients in the midvastus group demonstrated significantly lower pain in rest ( VAS : mean 2.25 vs. 3.03 ) and under movement ( VAS : mean 2.92 vs. 3.13 ) . Further , they showed superior isometric quadriceps strength at 3 weeks ( 41.4 vs. 27.6 Nm ) and 6 weeks ( 47.6 vs. 35.5 Nm ) . Moreover , this group showed a superior postoperative proprioception , while the range of motion was similar in both groups . The midvastus approach offers advantages over the st and ard parapatellar arthrotomy , in the early rehabilitation period . No adverse effects were observed associated with this approach . Therefore , the midvastus approach should be considered as a valuable alternative in TKA Postoperative pain after total knee arthroplasty ( TKA ) is severe and can complicate early physical therapy . We tested the hypothesis that intrathecal clonidine would improve postoperative analgesia for TKA using a hyperbaric bupivacaine spinal anesthetic . In a double-blinded , placebo-controlled protocol , 81 ASA physical status I – III patients undergoing either a single or bilateral TKA were r and omized into 4 groups with the following 2-mL solutions added to 15 mg of hyperbaric bupivacaine : 1 ) sterile saline , 2 ) morphine ( 250 & mgr;g ) , 3 ) morphine ( 250 & mgr;g ) with clonidine ( 25 & mgr;g ) , and 4 ) morphine ( 250 & mgr;g ) with clonidine ( 75 & mgr;g ) . At 1 , 2 , 4 , 6 , 12 , and 24 h postoperatively , we measured visual analog scales ( VAS ) , cumulative IV morphine consumption , hemodynamics , nausea , ancillary drugs , and side effects . Our primary comparison was between the clonidine with morphine groups versus the morphine group . We found that the combined administration of intrathecal clonidine and morphine decreased 24 h IV morphine consumption by 13 mg ( P = 0.028 ) when compared with intrathecal morphine alone . This corresponded to a decrease in the VAS score of 1.3 cm at 24 h postoperatively ( P = 0.047 ) . Adverse side effects were similar among all groups with the exception of more relative hypotension in the clonidine groups through postoperative hour 6 . We conclude that the coadministration of intrathecal clonidine and morphine decreases the 24-h IV morphine consumption and improves the 24-h VAS score when compared with intrathecal morphine alone This study assessed the efficacy of local , continuous infusion of bupivacaine for pain control following total knee arthroplasty . Eleven men and 19 women with an average age of 65 years ( range : 43 - 83 years ) r and omly received either 0.25 % bupivacaine or normal saline by local infusion pump . St and ard wound drainage also was implemented . Pain was assessed with a visual analog scale along with patient-controlled analgesia dem and , narcotic delivery , and nonsteroidal anti-inflammatory administration . Drug lost to drainage also was assessed . Mean preoperative visual analog scores were similar between the saline and bupivacaine groups ( 6.5 + /- 1.4 and 6.1 + /- 2.0 , respectively ; P = .535 ) . By the end of the second postoperative day , scores decreased to 3.4 + /- 3.2 for the saline group and 2.5 + /- 1.6 for the bupivacaine group . Although postoperative reductions were statistically significant ( P = .007 ) , the main treatment effect was not ( P = .404 ) . Mean narcotic dem and and usage were 87 + /- 114.1 requests with usage of 11.8 + /- 12.3 mg for the saline group and 96 + /- 104.8 requests with usage of 7.5 + /- 3.8 mg for the bupivacaine group ( P = .505 ) . Cumulative ketorolac administration was 47 + /- 52.2 mg for the saline group and 83.6 + /- 64.9 mg for the bupivacaine group ( P=.100 ) . Hydrocodone-acetaminophen usage also was similar between the saline and bupivacaine groups ( 88 + /- 43.9 mg and 64.6 + /- 35 mg , respectively ) ( P = .112 ) . Drug lost to drainage was estimated to be 27 % . These findings suggest continuous local analgesic infusion after total knee arthroplasty does not offer significant improvements in either pain relief or medication use . Drug loss from drainage may exceed 25 % and may compromise analgesic effectiveness Background The authors compared the analgesic effects and quality of rehabilitation of three analgesic techniques after total-hip arthroplasty in a double-blind , r and omized trial . Methods Forty-five patients were assigned to 1 of 3 groups , patient-controlled analgesia with morphine ( PCA ) , femoral nerve block ( FNB ) , or psoas compartment block ( PCB ) . At the end of the procedure performed under general anesthesia , nerve blocks using 2 mg/kg of 0.375 % bupivacaine and 2 μg/kg of clonidine were performed in the FNB ( n = 16 ) and PCB ( n = 15 ) groups . In the recovery room , all 3 groups received initial intravenous morphine titration if their pain score was higher than 30 on a 100-mm visual analog scale ( VAS ) , and then a PCA device was initiated . Morphine consumption was the primary end point to assess postoperative analgesia . Results After extubation ( H0 ) , morphine titration was higher in the PCA group ( P < .05 ) . During the first 4 postoperative hours ( H0 to H4 ) , morphine consumption per hour and VAS pain score were lower in the PCB group ( P < .05 ) . After H4 , there was no difference in morphine consumption and VAS among groups , either at rest or during mobilization . After H4 , morphine consumption remained lower than 0.5 mg/h , and VAS remained lower than 30 mm in the 3 groups . In 4 patients of the PCB group , an epidural diffusion was noted . Hip mobility and length of stay in the rehabilitation center were not different among the groups . Conclusions PCA is an efficient and safe analgesia technique . FNB and PCB should not be used routinely after total-hip arthroplasty Twenty-two patients were r and omly allocated to systemic opioids or epidural morphine the first 10 days after total knee arthroplasty . Pain was recorded daily in a visual analogue scale , and knee motion was measured on Day 10 . Pain was lower in the epidural group , with no difference in knee flexion or range of motion Forty – two patients scheduled for total knee arthroplasty ( n = 20 ) or hip arthroplasty ( n = 22 ) were r and omly allocated to receive either continuous epidural bupivacaine/morphine for 48 h postoperatively plus oral piroxicam , or general anaesthesia followed by a conventional intramuscular opioid and acetaminophen regimen . Patients undergoing knee– or hip arthroplasty treated with epidural analgesia had significantly lower pain scores during mobilization under the 48 h epidural infusion compared with patients receiving conventional treatment , while no important differences were observed after cessation of the epidural regimen . However , the achieved pain relief had no impact on postoperative convalescence parameters , such as ambulation , patient activity including need for nursing care , fatigue or hospital stay . Late postoperative pain , fatigue and conservative attitudes and routines in the postoperative care , were the most important reasons limiting mobilization and activity . We conclude that effective early ( 48 h ) postoperative pain relief with balanced analgesia does not per se lead to important improvements in convalescence and hospital stay Background Concurrent head-to-head comparisons of healthcare interventions regarding cost-utility are rare . The concept of favorable cost-effectiveness of total hip or knee arthroplasty is thus inadequately verified . Patients and methods In a trial involving several thous and patients from 10 medical specialties , 223 patients who were enrolled for hip or knee replacement surgery were asked to fill in the 15D health-related quality of life ( HRQoL ) survey before and after operation . Results Mean ( SD ) HRQoL score ( on a 0–1 scale ) increased in primary hip replacement patients ( n = 96 ) from 0.81 ( 0.084 ) preoperatively to 0.86 ( 0.12 ) at 12 months ( p < 0.001 ) . In revision hip replacement ( n = 24 ) the corresponding scores were 0.81 ( 0.086 ) and 0.82 ( 0.097 ) respectively ( p = 0.4 ) , and in knee replacement ( n = 103 ) the scores were 0.81 ( 0.093 ) and 0.84 ( 0.11 ) respectively ( p < 0.001 ) . Of 15 health dimensions , there were statistically significant improvements in moving , usual activities , discomfort and symptoms , distress , and vitality in both primary replacement groups . Mean cost per quality -adjusted life year ( QALY ) gained during a 1-year period was € 6,710 for primary hip replacement , € 52,274 for revision hip replacement , and € 13,995 for primary knee replacement . Interpretation Hip and knee replacement both improve HRQoL. The cost per QALY gained from knee replacement is twice that gained from hip replacement We assessed different yardsticks for outcome 4 ( 3 - 5 ) years after surgery in a prospect i ve , r and omized study of 42 patients , where 3 design s of cemmentless knee prostheses were used . The prognosis with regard to loosening , previously obtained by radiostereometry after 2 years of follow-up , was utilized . Patients with a prognosis of stable implant fixation ( two thirds ) were compared with those where loosening was predicted ( one third ) . Hospital for Special Surgery score and Visual Analogue Scales regarding pain at rest , " first step " pain , pain during activity and global function , showed consistent postoperative improvements , but no differences between the design and prognosis groups were found . Radiolucent lines were registered both as yes/no and number of zones . Lines and prognosis were associated , but not lines and design groups . Quality of life assessment by the Nottingham Health Profile question naire showed that the poor prognosis group had increased pain and significant disturbances of sleep and emotions , as well as difficulty in enjoying hobbies and holiday activities . No differences were found between the design groups . Altogether , the patients showed profiles comparable to a healthy reference group . We conclude that the Nottingham Health Profile is a sensitive , relevant and simple measure of outcome after knee arthroplasty The postoperative analgesic effects of intra-articular injections of bupivacaine and /or morphine were examined prospect ively in 437 patients who had total knee replacement for osteoarthritis . They were divided r and omly into four groups . Group I received 10 mg of morphine ( 1 ml ) and 9 ml of saline , group II received 10 ml of bupivacaine ( 2.5 mg/ml ) , group III received 10 ml of saline , and group IV received 10 mg of morphine ( 1 ml ) and 9 ml of bupivacaine ( 2.5 mg/ml ) . All analgesics administered in the first 24 hours after operation were recorded . The patients rated their pain on the McGill-Melzack scale at 1 , 6 , 12 and 24 hours . No significant differences were found between any of the groups in the use of Demoral and /or Toradol in 24 hours , the length of stay in hospital or the pain rating at 1 , 6 , 12 or 24 hours . Patients in groups I and IV , whose injections included morphine , used significantly more morphine in the first 24 postoperative hours than did groups II or III The epidural administration of morphine and fentanyl delay the regression of sensory anesthesia in postoperative patients receiving epidural bupivacaine . This study was performed to determine any differential effects of two lipid-soluble opioids upon regression of sensory anesthesia during coadministration with epidural bupivacaine . Forty-eight patients scheduled for total knee replacement underwent lumbar epidural catheterization and received 1.5 % etidocaine with 1:200,000 epinephrine to establish sensory anesthesia to approximately T6 bilaterally . Patients were r and omized by the investigational pharmacy to receive either : ( a ) bupivacaine without opioid ( control ) ( n = 16 ) , or ( b ) bupivacaine with 1 mg/mL of meperidine ( n = 16 ) , or ( c ) bupivacaine with 3 micrograms/mL of fentanyl ( n = 16 ) in a double-blind fashion . Intraoperatively , 0.5 % bupivacaine + /- opioid was administered by epidural infusion at a rate of 10 mL/h . Postoperatively , the bupivacaine concentration was decreased to 0.25 % ( + /- the same opioid ) , and the infusion rate was decreased to 4 mL/h . Pinprick sensory anesthesia and verbal numerical pain score were recorded each hour after surgery by a blinded investigator . For each patient , the study was considered terminated when the cephalad level of sensory anesthesia bilaterally decreased five dermatomal segments or the pain score reached " 5 " ( moderate pain ) . Patients receiving epidural infusions of bupivacaine and meperidine had a significantly slower regression of sensory anesthesia and slower development of pain . There was no difference in the rate of regression of sensory anesthesia or the development of pain among patients receiving bupivacaine alone or bupivacaine with fentanyl We design ed this study to evaluate the effect of small-dose IV ketamine in combination with continuous femoral nerve block on postoperative pain and rehabilitation after total knee arthroplasty . Continuous femoral nerve block was started with 0.3 mL/kg of 0.75 % ropivacaine before surgery and continued in the surgical ward for 48 h with 0.2 % ropivacaine at a rate of 0.1 mL · kg−1 · h−1 . Patients were r and omly assigned to receive an initial bolus of 0.5 mg/kg ketamine followed by a continuous infusion of 3 & mgr;g · kg−1 · min−1 during surgery and 1.5 & mgr;g · kg−1 · min−1 for 48 h ( ketamine group ) or an equal volume of saline ( control group ) . Additional postoperative analgesia was provided by patient-controlled IV morphine . Pain scores and morphine consumption were recorded over 48 h. The maximal degree of active knee flexion tolerated was recorded daily until hospital discharge . Follow-up was performed 6 wk and 3 mo after surgery . The ketamine group required significantly less morphine than the control group ( 45 ± 20 mg versus 69 ± 30 mg ; P < 0.02 ) . Patients in the ketamine group reached 90 ° of active knee flexion more rapidly than those in the control group ( at 7 [ 5–11 ] versus 12 [ 8–45 ] days , median [ 25%–75 % interquartile range ] ; P < 0.03 ) . Outcomes at 6 wk and 3 mo were similar in each group . These results confirm that ketamine is a useful analgesic adjuvant in perioperative multimodal analgesia with a positive impact on early knee mobilization . No patient in either group reported sedation , hallucinations , nightmares , or diplopia , and no differences were noted in the incidence of nausea and vomiting between the two groups Background : After total knee arthroplasty , patients regularly suffer from severe pain . It is unclear whether epidural or systemic pain therapy is superior in terms of postoperative pain relief , patients ’ comfort and side effects . A new therapeutic approach , intraarticular opioids , has been suggested with the detection of opioid receptors in inflamed tissue . This method has proven suitable for clinical use in small operations ( e.g. knee arthroscopy ) . In this study , we compared epidural analgesia and intraarticular application of morphine plus “ on‐dem and ” intravenous analgesia to “ on‐dem and ” intravenous analgesia alone BACKGROUND Previous studies have shown that dextromethorphan ( DM ) , a N-methyl-D-aspartate ( NMDA ) receptor antagonist , produces a preemptive analgesic effect on post-operative pain . The aim of this study was to further examine the preemptive analgesic effect of intramuscular ( i.m . ) DM injection on unilateral total knee replacement ( TKR ) . METHODS Sixty-four ASA I-III patients scheduled for unilateral TKR surgery were r and omly allocated into three groups in a prospect i ve double-blind manner . All patients received epidural anesthesia without any premedication . An initial bolus dose of 2 % lidocaine ( 15 - 20 mL ) followed by a maintenance dose of 8 - 10 mL/h was decided . Fentanyl ( 1.5 micrograms/kg ) and diazepam ( 2 mg ) were given i.v . before epidural catheter insertion . The epidural catheter was placed via the L2-L3 or L3-L4 interspace and advanced for 5 cm cephalad [ corrected ] . Patients received i.m . injection of 20 mg chlorpheniramine ( CPM ) before surgery as control ( group C , n = 22 ) . For the study groups , patients were given an i.m . injection containing 40 mg DM and 20 mg CPM , before ( group B , n = 22 ) or after surgery ( group A , n = 20 ) , respectively . Postoperation , patients received intravenous morphine by means of a patient controlled analgesia ( PCA ) device for pain relief . The time to the first pull of PCA trigger , morphine consumption , worse pain scores ( resting and incidental ) , and analgesics related side effects were recorded at 1 , 2 , 4 , 8 , 24 , 48 and 72 h after surgery . RESULTS The time from the end of operation to the first PCA trigger were 31.2 + /- 5.2 min in group C , 67.3 + /- 11.1 min in group B ( P < 0.05 , compared with group C ) and 61.8 + /- 7.2 min in group A ( P < 0.05 , compared with group C ) respectively . The relevant pain score at resting , observed at the 8 h postoperatively was respectively 4.2 + /- 0.1 in group C , 3.7 + /- 0.2 in group B ( P < 0.05 , compared with group C ) and 3.4 + /- 0.2 in group A ( P < 0.05 , compared with group C ) ; and at the 24 h was 3.1 + /- 0.2 in group C , 2.4 + /- 0.2 in group B ( P < 0.05 , compared with group C ) and 2.5 + /- 0.1 in group A ( P < 0.05 , compared with group C ) respectively . There were no significant differences in actual morphine delivery and frequency of PCA triggering at all time among the three groups . Moreover , there was also no significant statistic difference in morphine-associated side effects among the three groups . CONCLUSIONS In the present study , we failed to observe any preemptive analgesic effect of DM ( 40 mg , i.m . ) on postoperative pain in patients who received TKR under epidural anesthesia , however , DM given either before or after surgery augmented other analgesic ( morphine ) to offer a better pain relief We assessed the risks and benefits of the administration of fentanyl during spinal anesthesia in the elderly . Forty patients ( 70 - 83 yr ) undergoing knee or hip replacement were studied . Preoperatively , cognitive function ( minimental state examination [ MMSE ] ) , associated pathology , medications , and treatment were evaluated . Patients had spinal anesthesia with 12.5 mg bupivacaine plus saline ( SS ; n = 21 ) or 25 micro gram fentanyl ( FN ; n = 19 ) . The number of ailments and drugs per patient were 2.5 and 2.3 , respectively ; 35%-44 % of disorders were untreated , 16%-26 % were symptomatic , and 33 % were adequately treated . Groups were comparable regarding demographic data and characteristics of the spinal block . Group FN had more pruritus ( P < 0.02 ) and lower SaO2 ( P < 0.007 ) , but prevalence of side effects was similar . Pain intensity ( visual analog scale [ VAS ] , facial expression test [ FET ] ) at the time of analgesia request ( TAR ) was lower in Group FN ( P < 0.01 ) . A poor correlation between VAS and FET ( range 0.42 - 0.58 ) was obtained . MMSE at hospital discharge was no different from preoperative values . Our results show that 25 micro gram of spinal fentanyl do not modify spinal anesthesia in the elderly , but induces pruritus and O2 desaturation . The decrease in postoperative pain intensity and the preservation of cognitive function would justify the use of spinal fentanyl in the elderly . ( Anesth Analg 1996;83:537 - 41 This study tested the effect of a preoperative pain communication intervention on older adults ’ ability to obtain pain relief after a total knee arthroplasty . A posttest-only experimental design was used to compare older adults r and omly assigned to ( a ) view a pain management and pain communication film , ( b ) view the pain management film only , or ( c ) receive st and ard care only . Initial method adjustments decreased potential error in the study . Adjustments included testing only total knee arthroplasty patients receiving st and ard physical therapy and omitting unreliable measures from the analyses . Recruitment of the st and ard care group was halted when differences emerged between the remaining groups . Older adults in the communication group reported significantly less sensory pain on postoperative Day 1 than older adults in the pain management only group . Teaching older adults both pain communication skills and pain management information before surgery might result in greater pain relief during the early postoperative period Objective : To assess the feasibility of comparing two types of exercise regime aim ing to improve mobility and function following knee arthroplasty . Design : A single-blind r and omized controlled trial . Subjects : Patients with primary , unilateral knee osteoarthritis undergoing elective knee joint replacement . Intervention : Home-based traditional exercise group ( TEG ) or home-based functional exercise group ( FEG ) following discharge from hospital . Outcome measures : These included goniometry ; a knee-specific pain score , leg extensor power and a walking test . Patients were followed up at three , six and 12 months after surgery . Results : Forty-seven patients met the study criteria , 24 were r and omized to the TEG and 23 to the FEG . There were marked improvements in mobility , leg extensor power and pain in the year after surgery ( MANOVA p < 0.001 ) . There were no statistically significant differences between the two exercise groups . Knee flexion decreased during the follow-up period and had not recovered by 12 months . Retention of patients was a problem , with nearly 50 % lost to follow-up at 12 months . These patients were assessed as having low motivation during inpatient rehabilitation ( p < 0.05 ) . Conclusions : There were trends in favour of the FEG that were of clinical relevance . A definitive study would need a sample size of at least 100 patients in each arm . It is essential to develop strategies to combat loss to follow-up This prospect i ve , r and omized , double-blinded study assessed the efficacy of patient-controlled analgesia ( PCA ) techniques for extended “ 3-in-1 ” block after total knee arthroplasty . A total of 45 patients were divided into three groups of 15 . Over 48 h , all patients received 0.125 % bupivacaine with 1 & mgr;g/mL clonidine via a femoral nerve sheath catheter in the following manner : as a continuous infusion at 10 mL/h in Group 1 ; as a continuous infusion at 5 mL/h plus PCA boluses ( 2.5 mL/30 min ) in Group 2 ; or as PCA boluses only ( 10 mL/60 min ) in Group 3 . Pain scores , sensory block , supplemental analgesia , bupivacaine consumption , side effects , and satisfaction scores were recorded . Pain scores and supplemental analgesia were comparable in the three groups . Bupivacaine consumption was significantly less in Groups 2 and 3 than in Group 1 ( P < 0.01 ) , and in Group 3 than in Group 2 ( P < 0.01 ) . Side effects and satisfaction were comparable in the three groups . We conclude that extended “ 3-in-1 ” block provides efficient pain relief after total knee arthroplasty and that , compared with a continuous infusion , PCA techniques reduce the local anesthetic consumption without compromise in patient satisfaction or visual analog scale scores . Of the two PCA techniques tested , PCA boluses ( 10-mL lockout ; time , 60 min ) of 0.125 % bupivacaine with 1 & mgr;g/mL clonidine was associated with the smallest local anesthetic consumption , and is , therefore , the recommended extended “ 3-in-1 ” block technique . Implication s We demonstrated that , after total knee arthroplasty , an extended “ 3-in-1 ” block consisting of patient-controlled analgesia boluses ( 10 mL/60 min ) of 0.125 % bupivacaine with 1 & mgr;g/mL clonidine provides efficient postoperative analgesia and significantly minimizes local anesthetic consumption Background : Femoral and sciatic nerve block may not provide complete post‐operative analgesia following total knee replacement . This study was design ed to evaluate whether the addition of an obturator nerve block to combined femoral and sciatic nerve block improves the quality of post‐operative analgesia following primary total knee replacement Purpose To compare analgesia after intraoperative single shot “ 3-in-1 ” femoral nerve block ( FNB ) in combination with general anesthesia using ropivacaine 0.25 % , ropivacaine 0.5 % with bupivacaine 0.25 % for total knee replacement ( TKR ) . Methods We performed a r and omized , double-blind study in 48 patients for elective TKR under general anesthesia . Patients were r and omized to one of four groups ( C : sham block , R1 : “ 3-in-1 ” FNB using 30 mL of ropivacaine 0.25 % , R2 : “ 3-in-1 ” FNB using 30 mL of ropivacaine 0.5 % , B : “ 3-in-1 ” FNB using 30 mL of bupivacaine 0.25 % ) . Verbal pain score ( VPS ) both at rest and movement were assessed for 48 hr after TKR ( 0 = none ; 1 = mild ; 2 = moderate ; 3=severe ) . Total morphine consumption and its associated side effects , duration of hospitalization after operation were also compared . Results There were no differences in patients ’ physical characteristics , intraoperative morphine usage , operation time , tourniquet time or length of hospitalization between the four groups . When compared with group C , the VPS was significantly lower in groups R1 , R2 and B at one , four , eight , 24 and 48 hr after TKR(P < 0.05 ) . The morphine requirement of groups R1 , R2 and B were also significantly lower when comparing with group C up to 48 hr postoperatively ( P < 0.05 ) . There were no significant differences in VPS and postoperative morphine requirement at any time between groups R1 , R2 and B. Conclusion “ 3-in-1 ” FNB with ropivacaine provided analgesia that was clinical ly comparable to that of bupivacaine up to 48 hr after TKR . Increasing the concentration of ropivacaine from 0.25 % to 0.5 % failed to improve the postoperative analgesia of “ 3-in-1 ” FNB.RésuméObjectifComparer l’analgésie fournie par l’administration peropératolre d’un bloc “ 3 en 1 ” du nerf fémoral ( BNF ) en une dose unique , combinée à l’anesthésle générale , avec de la ropivacaïne à 0,25 % , ou à 0,5 % , ou de la bupivacaïne à 0,25 % pour la mise en place d’une prothèse totale de genou (PTG).MéthodeL’étude r and omisée et à double Insu comprend 48 patients qui reçoivent une PTG non urgente sous anesthésie générale . On forme quatre groupes ( T : groupe témoin avec bloc fictif , R1 : BNF “ 3 en 1 ” avec 30 mL de roplvacaïne à 0,25 % , R2 : BNF “ 3 en 1 ” avec 30 mL de roplvacaïne à 0,5 % , B : BNF “ 3 en 1 ” avec 30 mL de bupivacaïne à 0,25 % ) . Les scores de l’échelle verbale de douleur ( EVD ) au repos et pendant le mouvement sont notés pendant 48 h après la PTG ( 0 = aucune ; 1 = légère ; 2 = modérée ; 3 = sévère ) . La consommation totale de morphine et ses effets secondaires et la durée de l’hospitalisation postopératoire sont comparés . RésultatsLes caractéristiques physiques des patients , la consommation de morphine peropératolre , la durée de l’intervention , le temps de garrot ou la durée de l’hospitalisation sont comparables dans les quatre groupes . Comparé à celui du groupe T , le score à l’EVD des groupes R1 , R2 et B est slgnlfcatlvement plus bas à une , quatre , huit , 24 et 48 h après la PTG ( P < 0,05 ) . Les besoins de morphine dans les groupes R1 , R2 et B sont aussi slgnlfcatlvement plus bas que ceux du groupe C jusqu’à 48 h après l’opération ( P < 0,05 ) . Les scores EVD et la consommation de morphine postopératoire demeurent comparables en tout temps dans les groupes R1 , R2 et B. Conclusion Le BNF “ 3 en 1 ” avec de la roplvacaïne fournit une analgésie expérimentale comparable à celle de la bupivacaïne jusqu’à 48 h après une PTG . L’augmentation de la concentration de roplvacame de 0,25 % à 0,5 % ne permet pas d’améliorer l’analgésie postopératoire du BNF “ 3 en 1 ” Purpose This dose-response study was design ed to determine the most appropriate dose of ropivacaine 0.5 % injected via an indwelling femoral catheter for perioperative peripheral analgesia for total knee replacement ( TKR ) . Methods 84 patients were allocated r and omly to four groups and received , via a femoral catheter , either 15 , 20 , 25 or 30 mL of ropivacaine 0.5 % in a double-blind fashion . An anterior sciatic block with 20 mL bupivacaine 0.5 % was also performed . The evolution of sensory block of femoral , obturator and lateral femoral cutaneous nerves and motor block of femoral nerve were tested every five minutes during the first 30 min . The percentage of patients with complete sensory block of both femoral and obturator nerves determined success rate . General anesthesia was then induced . After surgery , patient-controlled analgesia ( PCA ) with ropivacaine 0.2 % was available via the femoral catheter . The interval between the initial injection and the first PCA administration determined duration of action . Results The duration of action was not different between the four solutions tested i.e. , 534 ± 379 min for 15 mL , 799 ± 364 min for 20 mL , 624 ± 342 min for 25 mL and 644 ± 266 min for 30 mL. The percentage of patients with complete sensory femoral and obturator blocks was , respectively , 60 % , 95 % , 85 % and 70 % for 15 , 20 , 25 and 30 mL ( P = 0.008/15 mL vs 20 mL ) . Conclusion Although there is no difference in duration of analgesia , because of better sensory spread , 20 mL of ropivacaine 0.5 % appears to be the most appropriate dose for peripheral analgesia after TKR.ObjectifL’étude dose-réponse visait à déterminer la meilleure dose de ropivacaïne à 0,5 % injectée par cathéter fémoral à demeure pour l’analgésie périopératoire périphérique lors d’une arthroplastie totale du genou (ATG).MéthodeNous avons réparti au hasard , en quatre groupes , 84 patients qui ont reçu par cathéter fémoral 15 , 20 , 25 ou 30 mL de ropivacaïne à 0,5 % en double insu . Un bloc sciatique antérieur a aussi été réalisé avec 20 mL de bupivacaïne à 0,5 % . L’évolution du bloc sensitif des nerfs fémoral , obturateur et cutané latéral de la cuisse et du bloc moteur du nerf fémoral a été vérifiée toutes les cinq minutes pendant les 30 premières minutes . Le pourcentage de patients qui présentait un bloc sensitif complet des nerfs fémoral et obturateur a déterminé le taux de succès . L’anesthésie générale a ensuite été induite . Après l’opération , l’analgésie auto-contrôlée ( AAC ) avec de la ropivacaïne à 0,2 % était disponible par cathéter fémoral . L’intervalle entre l’injection initiale et la première administration d’AAC a donné la durée d’action . RésultatsLa durée d’action a été comparable dans tous les groupes : 534 ± 379 min avec 15 mL , 799 ± 364 min avec 20 mL , 624 ± 342 min avec 25 mL et 644 ± 266 min avec 30 mL. Le pourcentage de patients présentant un bloc sensitif complet des nerfs fémoral et obturateur a été respectivement de 60 % , 95 % , 85 % et 70 % pour les doses de 15 , 20 , 25 et 30 mL ( P = 0,008/15 mL vs20 mL ) . Conclusion Même si la durée de l’analgésie est équivalente , grâce à une meilleure diffusion sensitive , 20 mL de ropivacaïne à 0,5 % semble être la dose la plus appropriée pour l’analgésie périphérique après une ATG Thirty healthy patients undergoing lumbar spine surgery were r and omly assigned to one of two groups for postoperative pain relief . Group 1 received morphine via patient controlled analgesia and local cooling of the wound by an externally applied cooling pad while group 2 received patient controlled analgesia alone . There was a significant reduction in morphine consumption when local cooling was applied ( 18.6 mg versus 30.2 mg at 12h , 29.0 mg versus 49.6 mg at 24 h , p < 0.05 ) . Patients were also significantly more satisfied with their overall postoperative pain management when cooling therapy was used The effectiveness of an intra-articular injection of bupivacaine , administered before the incision or after closure of the wound , was studied in an effort to decrease the need for postoperative narcotics and to improve analgesia for patients who have elective knee replacement . Eighty-two patients received two intra-articular injections in a r and om , double-blind fashion . Twenty-eight of them received thirty milliliters of 0.5 per cent bupivacaine and 1:200,000 epinephrine in saline solution before the incision and an injection of thirty milliliters of plain saline solution after closure of the wound ( Group 1 ) . Twenty-seven patients received an injection of thirty milliliters of plain saline solution before the incision and thirty milliliters of 0.5 per cent bupivacaine and 1:200,000 epinephrine in saline solution after closure of the wound ( Group 2 ) . Twenty-seven patients were given thirty milliliters of plain saline solution ( a placebo ) for both injections ( Group 3 ) . The patients who had received bupivacaine after closure of the wound ( Group 2 ) used less morphine from the patient-controlled analgesia pumps than the patients who had received bupivacaine before the incision ( Group 1 ) and the patients who had received the placebo ( Group 3 ) . In the first twenty-four hours after the operation , the administration of morphine ( mean and st and ard deviation ) was 59 ± 27 milligrams for Group 2 compared with 68 ± 30 milligrams for Group 1 ( p = 0.26 ) and 81 ± 30 milligrams for Group 3 ( p = 0.006 ) . At the time of discharge from the hospital , the patients in Group 2 also had a significantly greater mean range of motion ( 85.2 ± 8.0 degrees ) compared with that of the patients in Groups 1 ( 80.6 ± 6.8 degrees , p = 0.02 ) and 3 ( 80.1 ± 6.2 degrees , p = 0.009 ) . However , there was no difference among the groups with respect to the effectiveness of the analgesia , as measured with use of either the visual-analog or the verbal pain-rating scale , or in the prevalence of side effects , including somnolence , urinary retention , nausea and vomiting , or pruritus . Serum concentrations of bupivacaine were well below toxic levels . It was our conclusion that that an intra-articular injection of thirty milliliters of 0.5 per cent bupivacaine and 1:200,000 epinephrine in saline solution after closure of the wound decreases the need for narcotics and increases the range of motion after an elective knee replacement . The clinical importance of the amount of increased motion is question able and needs longer-term monitoring STUDY OBJECTIVE To compare propofol plus spinal anesthesia during spontaneous ventilation using the Laryngeal Mask Airway and propofol plus fentanyl anesthesia during mechanical ventilation with an endotracheal tube on quality of recovery after anesthesia . DESIGN Prospect i ve , r and omized study . SETTING Hirosaki National Hospital . PATIENTS 150 patients ( aged > 70 years ) undergoing total knee arthroplasty . INTERVENTIONS Patients were divided r and omly into two groups , to receive spontaneous ventilation with a Laryngeal Mask Airway during propofol-spinal anesthesia , or to receive propofol-fentanyl anesthesia with mechanical ventilation via endotracheal tube . MEASUREMENTS Quality of anesthesia recovery such as nausea , vomiting , headache , pain throat , hoarse voice , back pain , dizziness , feeling comfortable , dreaming , recovery times in recovery of anesthesia , recovery times , postoperative pain , confusion , was assessed . MAIN RESULTS The frequency of postoperative pain throat , hoarse voice , and nausea was significantly lower in the propofol-spinal anesthesia group than the propofol-fentanyl anesthesia group . The time to extubation , emergence , response to comm and s , and orientation were significantly faster ( p < 0.001 ) in the propofol-spinal anesthesia group than the propofol-fentanyl anesthesia group . The frequency of postoperative confusion occurring in the propofol-spinal anesthesia group during the first 24 hours was significantly lower than that of the propofol-fentanyl anesthesia group ( p = 0.03 ) . CONCLUSIONS Propofol-spinal anesthesia provided better and faster recovery than did propofol-fentanyl anesthesia for elderly patients undergoing total knee arthroplasty The authors conducted a r and omized , prospect i ve study comparing epidural morphine with patient-controlled intravenous ( iv ) morphine in 30 patients recovering from total hip or total knee arthroplasty . Six , 18 , and 24 hr postoperatively , patients used a 10 cm visual-analogue scale to indicate both their current degree of discomfort and the maximum discomfort they had experienced since the previous evaluation . Pain at the time of evaluation did not differ between patients receiving epidural ( 2.6 + /- 0.4 cm , mean + /- SEM ) and patient-controlled iv morphine ( 3.4 + /- 0.3 cm ) . However , patients who received epidural morphine recalled less pain during the period preceding evaluation ( 4.2 + /- 0.5 cm ) than did those receiving patient-controlled analgesia ( 5.5 + /- 0.4 cm , P less than 0.05 ) . Patients receiving epidural morphine were more likely to require treatment for pruritus ( 4 of 15 ) than patients who received patient-controlled iv morphine ( none of 15 , P less than 0.05 ) . Minimum respiratory rates were lower in patients receiving epidural morphine ( 15.0 + /- 0.3 ) than in those receiving patient-controlled analgesia ( 16.5 + /- 0.4 , P less than 0.05 ) , but no patients required treatment for respiratory depression . The authors conclude that epidural morphine may provide more consistent analgesia following joint replacement surgery than patient-controlled morphine ; however , there is a higher incidence of side-effects with the epidural technique Either epidural analgesia or femoral nerve blockade improves analgesia and rehabilitation after total knee arthroplasty . No study has evaluated the combination of femoral nerve blockade and epidural analgesia . In this prospect i ve , r and omized , blinded study we investigated combining femoral nerve blockade with epidural analgesia . Forty-one patients received a single-injection femoral nerve block with 0.375 % bupivacaine and 5 & mgr;g/mL epinephrine ; 39 patients served as controls . All patients received combined spinal-epidural anesthesia and patient-controlled epidural analgesia with 0.06 % bupivacaine and 10 & mgr;g/mL hydromorphone . Average duration of epidural analgesia was 2 days . All patients received the same st and ardized physical therapy intervention . Median visual analog scale ( VAS ) scores with physical therapy were significantly lower for 2 days among patients who received a femoral nerve block versus controls : 3 versus 4 ( day 1 ) , 2.5 versus 4 ( day 2 ) ; P < 0.05 . Median VAS pain scores at rest were 0 in both groups on days 1 and 2 . Flexion range of motion was improved on postoperative day 2 ( 70 ° versus 63 ° ; P < 0.05 ) . No peripheral neuropathies occurred . We conclude that the addition of femoral nerve blockade to epidural analgesia significantly improved analgesia for the first 2 days after total knee arthroplasty A r and omised double-blind study compared the dose-response relationship of intrathecal diamorphine ( 0 , 0.25 , 0.75 , 1.5 , and 2.5 mg ) for postoperative pain relief , in 35 subjects who underwent total knee replacement surgery . Assessment s commenced 2 h after the opioid injection and continued for 20 h. Pain , analgesic effect , supplementary analgesic requirements and adverse effects were noted . Intrathecal diamorphine was unable to delay the initial perception of discomfort . It was , however , capable of postponing the onset of severe pain requiring analgesic supplementation ( control 5.25 h vs approximately 8 h : P less than 0.05 ) . There was no significant difference in the quality of analgesia between the groups . Pruritus was the only undesirable feature unique to intrathecal diamorphine administration . Intrathecal diamorphine was safe and was not associated with clinical ly apparent respiratory depression . Its effects were inconsistent and its use was associated with irritating side effects . Possible explanations for the erratic behaviour of the diamorphine are discussed We prospect ively r and omised 100 patients undergoing cemented total knee replacement to receive either a single deep closed-suction drain or no drain . The total blood loss was significantly greater in those with a drain ( 568 ml versus 119 ml , p < 0.01 ; 95 % CI 360 to 520 ) although those without lost more blood into the dressings ( 55 ml versus 119 ml , p < 0.01 ; 95 % CI -70 to 10 ) . There was no statistical difference in the postoperative swelling or pain score , or in the incidence of pyrexia , ecchymosis , time at which flexion was regained or the need for manipulation , or in the incidence of infection at a minimum of five years after surgery in the two groups . We have been unable to provide evidence to support the use of a closed-suction drain in cemented knee arthroplasty . It merely interferes with mobilisation and complicates nursing . Reinfusion drains may , however , prove to be beneficial This r and omized study analyzed the effectiveness of postoperative transcutaneous electrical nerve stimulation ( TENS ) used continuously for the first three postoperative days following total knee replacement ( TKR ) for 1 ) pain relief , 2 ) knee flexion arc , 3 ) narcotic dosage , and 4 ) hospital stay . Group 1 ( N = 18 ) received sensory threshold TENS and group 2 ( N = 18 ) received subthreshold TENS . Both groups also used continuous passive motion during their hospitalization as did patients from group 3 ( control , N = 12 ) that did not receive TENS . Pain decrease from postoperative day 1 - 3 was 50 % for group 1 patients and 38 % for group 2 patients , as measured by the visual analog scale . Wilcoxon Rank Sum did not show a significant difference ( p > 0.05 ) for pain relief or hospital stay for these two groups . Analysis of variance failed to show significant differences ( p > 0.05 ) for knee flexion arc or narcotic dosage for the three groups . Although not statistically significant , an observed decrease in pain may be the only indication for postoperative TENS after TKR . J Orthop Sports Phys Ther 1990;11(12):599 - 604 Pain relief and maximization of knee joint range of motion ( ROM ) are the two major goals in the postoperative management of the total knee arthroplasty ( TKA ) patient . Epidural bupivacaine infusions have been reported to be safe and effective for pain control in obstetric anesthesia , chronic pain management , and postoperative pain relief . The purpose of this study was to evaluate the effect of continuous epidural bupivacaine on postoperative pain and progressive knee ROM as well as to record the incidence of urinary retention and other side effects or complications . Continuous epidural bupivacaine infusion was found to provide safe , effective analgesia for TKA patients in the immediate postoperative period . Excellent pain relief with reduced narcotic requirements was observed in the patients as compared to intramuscular narcotic analgesia . No complications occurred and serum bupivacaine levels remained well below toxic levels . Short term clinical orthopaedic outcome was improved , and patient , surgeon , and nurse acceptance of the technique was excellent Introduction To evaluate the clinical and radiographic results immediately after total knee arthroplasty , we compared the parapatellar and subvastus approach . Material s and methods Fifty-two patients with osteoarthritis were r and omly assigned to two groups . The measurement was based on clinical and radiographic features . Results There was a significant difference in passive range of motion . Patients in the subvastus approach group revealed a full knee extension and flexion of 90 ° significantly earlier than those in the parapatellar group . However , on the day of discharge , both groups were comparable . Radiological assessment revealed analogous results in both groups . Correction of varus or valgus deformity was required in 48 patients . Conclusion Regardless of the surgical approach , the anteroposterior tibial femoral angle improved significantly in both groups . Concerning pain , operation time , blood loss , blood substitution and complications , no major differences could be seen Postoperative pain after total knee arthroplasty ( TKA ) is severe , and achieving adequate analgesia remains a clinical challenge . We tested the hypothesis that , in patients having unilateral TKA under intrathecal ( IT ) anesthesia , the addition of a femoral nerve block would provide superior analgesia when compared with IT morphine and demonstrate fewer adverse side effects . In a single-blinded and controlled trial , 41 ASA I – III patients undergoing unilateral TKA were r and omized into 2 groups . Both groups received 15 mg of IT hyperbaric bupivacaine for the surgical anesthetic . Group ITM received 250 & mgr;g of IT morphine and group FNB received an ultrasound-assisted femoral nerve block with 40 mL of 0.5 % ropivacaine , 5 & mgr;g/mL of epinephrine , and 75 & mgr;g of clonidine . At 1 , 2 , 4 , 6 , 12 , and 24 h postoperatively , we measured visual analog scales for pain , cumulative IV morphine consumption , hemodynamics , and side effects . There were no statistically significant differences in morphine consumption , pain at rest , or pain with movement . However , group FNB had fewer perioperative side effects including nausea , vomiting , and pruritus ( P < 0.05 for each event ) . This corresponded to a decrease in patient satisfaction in group ITM , in which 20 % of the patients rated their experience as “ unsatisfactory ” ( P < 0.05 ) . We conclude that , in comparison with IT morphine , a single injection femoral nerve block provides equivalent analgesia but with a significant reduction in side effects for patients having TKA under bupivacaine intrathecal anesthesia Following surgery , total knee arthroplasty ( TKA ) patients experience considerable pain . All available effective analgesia agents produce some unwanted side effects . Sixty consenting elective TKA patients were r and omized to receive bupivacaine 20 mL 0.5 % ( 100 mg ) or 20 mL normal saline injected into the joint space after capsule closure . Patients were interviewed up to 24 hours after surgery for pain and pain relief . Narcotic usage was recorded . The bupivacaine group had lower pain scores and reduced narcotics during the 24-hour period , with a 23-minute shorter time to discharge from the postanesthesia care unit than the placebo group ( P = .02 ) . Although a bupivacaine bolus injected at capsule closure results in decreased pain levels ( P = .07 ) and narcotic consumption ( P = .09 ) , it is not statistically significantly better than placebo In a r and omized double-blind study we examined the effect of adding diamorphine 0.25 mg and 0.5 mg to intrathecal bupivacaine anaesthesia for major orthopaedic surgery . Duration of postoperative analgesia was considerably greater in patients given either doses of intrathecal diamorphine than in a control group of patients given bupivacaine alone ( P less than 0.001 ) . However , there was no significant difference between the two diamorphine doses ( 0.25 mg and 0.5 mg ) , each providing prolonged analgesia ( 10.8 and 9.9 h , respectively ) . Although there was no evidence of late respiratory depression , the frequency of adverse effects , in particular urinary retention , nausea and vomiting , was high in both groups receiving intrathecal diamorphine This study compares the clinical results of the medial trivector approach to the st and ard parapatellar approach in primary total knee arthroplasty . Ten patients undergoing simultaneous bilateral total knee arthroplasty were included in this study . Right and left knees were r and omized for a st and ard medial parapatellar arthrotomy or a medial trivector approach . Patients were assessed by the number of days to achieve straight leg raising and range of motion at discharge . In addition , knee scores were obtained at 6 weeks and 6 months with careful assessment of any pain or tenderness around the quadriceps mechanism . At 6 months , patients were tested on a KINCOM machine assessing their concentric and eccentric quadriceps strength . While there was no difference in total range of motion at the time of discharge , patients undergoing a medial trivector approach achieved independent straight-leg raising 2 days sooner than patients undergoing a st and ard medial parapatellar arthrotomy . No significant differences existed in knee scores , pain scores , or range of motion at 6 weeks or 6 months . KINCOM testing at 6 months revealed the knees undergoing trivector approach to be 15 % stronger in concentric contractions . No complications were encountered with the use of the medial trivector approach in these patients . Subjectively , patients reported less discomfort and more strength in the knees having undergone a medial trivector approach . The medial trivector approach may enhance postoperative recovery without adversely affecting the quadriceps function following total knee arthroplasty . The medial trivector approach to the knee does not weaken quadriceps muscle function or adversely affect clinical results of total knee arthroplasty This multicenter , r and omized , double-blind , placebo-controlled study evaluated the analgesic efficacy and opioid-sparing effects of valdecoxib , a potent COX-2 specific inhibitor , in patients undergoing knee replacement . Patients received morphine by patient-controlled analgesia ( PCA ) , and valdecoxib 40 mg or 80 mg daily , or placebo , for up to two days . Efficacy was assessed by the cumulative amount of morphine administered over 48 hours , pain intensity and patient 's evaluation of medication . Morphine consumption over 48 hours by patients receiving valdecoxib 40 mg or 80 mg daily plus morphine was 83.7 % and 75.8 % ( P < 0.05 ) of the total amount consumed by patients receiving morphine alone . Patients receiving valdecoxib 40 mg and 80 mg daily experienced significantly lower maximum pain intensity on Day 2 ( P < 0.05 ) , and rated their study medication significantly higher than patients receiving morphine alone . Valdecoxib plus morphine was well tolerated . Thus , valdecoxib in combination with morphine provides multi-modal analgesia that reduces pain and opioid use and increases patient satisfaction following knee replacement surgery BACKGROUND Peripheral neural blockade appears to provide effective analgesia with potentially less morbidity than central neuraxial techniques . We compared the relative benefits of combined femoral ( 3-in-1 ) and sciatic nerve block with epidural blockade for postoperative knee arthroplasty analgesia . METHODS Sixty patients , ASA I-III , undergoing unilateral knee replacement were prospect ively r and omized to receive either a lumbar epidural infusion or combined single-shot femoral ( 3-in-1 ) and sciatic blocks ( combined blocks ) . All patients received st and ard general anaesthesia . Visual analogue pain scores and rescue opioid requirements were recorded at four time points postoperatively . Patient satisfaction , morbidity , block insertion time , perioperative blood loss and rehabilitation indices were also assessed . RESULTS In both groups , pain on movement was well controlled at discharge from recovery and 6 h postoperatively but increased at 24 and 48 h. Median ( 95 % CI ) analogue scale scores were 0 ( 0 - 0 ) , 15 ( 0 - 30 ) , 55 ( 38 - 75 ) and 54 ( 30 - 67 ) mm for epidural block and 0.5 ( 0 - 22 ) , 21.5 ( 10 - 28 ) , 40 ( 20 - 50 ) and 34.5 ( 21 - 55 ) mm for combined block . VAS pain scores with the combined blocks were significantly lower at 24 h ( P=0.004 ) . Total morphine usage was low in both groups : median epidural group 17 mg ( 8 - 32 ) versus combined blocks 13 mg ( 7.8 - 27.5 ) . Patient satisfaction was high in both groups with median ( 95 % CI ) scores of 100 ( 85 - 100 ) , 83 ( 70 - 100 ) and 82 ( 57 - 90 ) mm for epidural and 90 ( 73 - 100 ) , 100 ( 77 - 100 ) and 97 ( 80 - 100 ) mm for combined blocks ( not significant ) . Perioperative blood loss and rehabilitation indices were also similar . CONCLUSIONS Combined femoral ( 3-in-1 ) and sciatic blocks offer a practical alternative to epidural analgesia for unilateral knee replacements Background : Some controversy exists in the literature on the benefit of epidurals compared to patient‐controlled intravenous analgesia ( PCA ) . Also , the dose of ropivacaine for epidural analgesia when combined with morphine remains uncertain . The aim of this study was to compare the epidural vs. PCA technique and high‐dose vs. low‐dose ropivacaine combined with morphine during knee replacement surgery Background : Anterior knee pain following total knee arthroplasty is a common complaint and typically is attributed to the patellofemoral joint . The purpose of the present study was to compare the outcome of resurfacing and nonresurfacing of the patella , particularly with regard to anterior knee pain , and to clarify the indications for patellar resurfacing at the time of total knee arthroplasty . Methods : We performed a prospect i ve , r and omized study of 514 consecutive primary press-fit condylar total knee replacements . The patients were r and omized to either resurfacing or retention of the patella . They were also r and omized to either a cruciate-substituting or a cruciate-retaining prosthesis as part of a separate trial . The mean duration of follow-up was 5.3 years ( range , two to 8.5 years ) , and the patients were assessed with use of the Knee Society rating , a clinical anterior knee pain score , and the British Orthopaedic Association patient-satisfaction score . The assessment was performed without the examiner knowing whether the patella had been resurfaced . At the time of follow-up , there were 474 knees . Thirty-five patients who had a bilateral knee replacement underwent resurfacing on one side only . Results : The overall prevalence of anterior knee pain was 25.1 % ( fifty-eight of 231 knees ) in the nonresurfacing group , compared with 5.3 % ( thirteen of 243 knees ) in the resurfacing group ( p < 0.0001 ) . There was one case of component loosening . Ten of eleven patients who underwent secondary resurfacing had complete relief of anterior knee pain . The overall postoperative knee scores were lower in the nonresurfacing group , and the difference was significant among patients with osteoarthritis ( p < 0.01 ) . There was no significant difference between the resurfacing and nonresurfacing groups with regard to the postoperative function score . Patients who had a bilateral knee replacement were more likely to prefer the resurfaced side . Conclusions : As the present study showed a significantly higher rate of anterior knee pain following arthroplasty without patellar resurfacing , we recommend patellar resurfacing at the time of total knee replacement when technically possible . Level of Evidence : Therapeutic study , Level I-1a ( R and omized controlled trial [ significant difference ] ) . See Instructions to Authors for a complete description of levels of evidence Background and objective : We assessed the analgesic efficacy of postoperative epidural infusions of ropivacaine 0.1 and 0.2 % combined with sufentanil 1 μg mL−1 in a prospect i ve , r and omized , double-blinded study . Methods : Twenty-two ASA I-III patients undergoing elective total-knee replacement were included . Lumbar epidural blockade using ropivacaine 0.75 % was combined with either propofol sedation or general anaesthesia for surgery . After surgery , the epidural infusion was commenced . Eleven patients in each group received either an epidural infusion of ropivacaine 0.1 % with 1 μg mL−1 sufentanil ( Group 1 ) or ropivacaine 0.2 % with 1 μg mL−1 sufentanil ( Group 2 ) at a rate of 5 - 9 mL h−1 . All patients had access to intravenous pirinatrimide ( piritramide ) via a patient-controlled analgesia ( PCA ) device . Results : Motor block was negligible for the study duration in both groups . There was no significant difference with the 100 mm visual analogue scale ( VAS ) scores , with the consumption of rescue analgesia or with patient satisfaction . Patients in Group 1 experienced significantly less nausea ( P < 0.05 ) than those in Group 2 . Both treatment regimens provided effective postoperative analgesia with only a minimal use of supplemental opioid PCA . Conclusions : We recommend the use of ropivacaine 0.1 % with 1 μg mL−1 sufentanil for postoperative analgesia after total knee replacement as it provides efficient pain relief with no motor block of the lower limbs . In addition , compared with 0.2 % ropivacaine with sufentanil , the mixture reduces local anaesthetic consumption without compromise in patient satisfaction or VAS scores . Patients even experience less nausea BACKGROUND Although numerous methods of postoperative analgesia have been investigated in an attempt to improve pain control after total knee arthroplasty , parenteral narcotics still play a major role in postoperative pain management . Local anesthetics have the advantage of blocking pain conduction at its origin and minimizing the systemic side effects associated with postoperative narcotic use . This study was performed to evaluate the benefits and safety of a multimodal analgesia protocol that included periarticular injection of large doses of local anesthetics in patients undergoing total knee arthroplasty . METHODS We compared morphine consumption during the first twenty-four hours after unilateral total knee arthroplasty in forty-two patients who had been r and omized to receive either ( 1 ) a perioperative infiltration mixture , consisting principally of local anesthetic , and self-administered morphine or ( 2 ) self-administered morphine only . Narcotics consumption , pain control , medication-related side effects , plasma levels of the local anesthetic ( ropivacaine ) , and postoperative rehabilitation were monitored . RESULTS Although there was high satisfaction and good pain control in both groups , morphine consumption was significantly lower in the local analgesia group than it was in the control group ( 28.8 + /- 17.4 mg compared with 50.3 + /- 25.4 mg twenty-four hours after surgery , and 46.7 + /- 19.4 mg compared with 68.6 + /- 38.6 mg forty hours after surgery ) . Both groups achieved a similar amount of knee flexion on the fifth postoperative day . Over the five-day period after the procedure , the patients in the local analgesia group reported a total of 2.6 + /- 3.9 hours of nausea compared with 7.1 + /- 12.2 hours in the control group . No complications related to the infiltration of the local anesthetic were observed , and all plasma concentrations of the local anesthetic were below the toxic range . CONCLUSIONS This multimodal perioperative analgesia protocol that included infiltration of a local anesthetic offered improved pain control and minimal side effects to patients undergoing total knee arthroplasty . Our study also confirmed the safety of the protocol We have investigated the value of a 3-in-1 nerve block , followed by a continuous low-dose infusion of bupivacaine into the femoral nerve sheath for postoperative analgesia after total knee replacement . Thirty-seven patients were r and omly allocated to either a control group or a study group . The study group had a catheter placed in the ipsilateral femoral nerve sheath . A 3-in-1 nerve block was then performed in the study group with injection of 30 mL of 0.25 % bupivacaine through the catheter . This was followed by a continuous infusion of 0.125 % bupivacaine at 6 mL/h . The study group had significantly lower pain scores 4 and 24 h postoperatively ( P less than 0.01 ) and required less postoperative opioid analgesic medication ( P less than 0.01 ) than the control group . The authors conclude that a continuous low-dose infusion into the femoral nerve sheath results in better pain relief than conventional intramuscularly administered narcotics after total knee arthroplasty Background : Reliance on “ as-needed ” analgesia following total knee arthroplasty may lead to inadequate control of pain and delayed recovery of function . Preemptive use of controlled-release opioids may improve pain control , accelerate recovery , and reduce the need for inpatient rehabilitative services . This study was design ed to determine whether controlled-release opioids enhance post-arthroplasty pain control and facilitate functional recovery during rehabilitation . Methods : Fifty-nine patients admitted for inpatient rehabilitation following unilateral total knee arthroplasty were r and omized to receive OxyContin ( controlled-release oxycodone ) ( twenty-nine patients ) or a placebo ( thirty patients ) every twelve hours . Both groups could receive on-request , immediate-release oxycodone ( 5 mg every four hours ) . The dose of study medication was increased on the basis of the frequency of requests for immediate-release oxycodone . Measures of interest included pain ratings as determined with a visual-analog scale , changes in the range of motion of the knee and quadriceps strength , and improvements in selected Functional Independence Measure scores during the first eight physical therapy sessions . The duration of the hospital stay for rehabilitation also was compared between the two groups . Results : Baseline demographic , clinical , and functional characteristics were similar between the OxyContin and placebo groups . Compared with the placebo group , the patients who received OxyContin reported significantly less pain as well as significantly greater range of motion of the knee ( passive motion , p = 0.036 ; active motion , p < 0.001 ) and quadriceps strength ( p = 0.001 ) by the eighth physical therapy session . The patients who received OxyContin also were discharged from the rehabilitation hospital at an average of 2.3 days earlier than the patients in the placebo group ( p = 0.013 ) . Conclusions : Preemptive use of controlled-release oxycodone during rehabilitation following total knee arthroplasty leads to improved pain control , more rapid functional recovery , and a reduced need for inpatient rehabilitative services BACKGROUND Cyclooxygenase (COX)-2-specific inhibitors demonstrate analgesic efficacy comparable with that of conventional nonsteroidal anti-inflammatory drugs but are associated with reduced gastrointestinal side effects and an absence of antiplatelet activity . Thus , they can be administered to patients undergoing spinal fusion surgery without an added risk of bleeding . However , concerns regarding a possible deleterious effect on bone-healing have limited their routine use . Celecoxib , a COX-2 inhibitor , recently was approved for the treatment of acute pain . The goals of the present study were to examine the analgesic efficacy of celecoxib and to determine the incidence of nonunion at one year following spinal fusion surgery . METHODS Eighty patients who were scheduled to undergo spinal fusion received either celecoxib or placebo one hour before the induction of anesthesia and every twelve hours after surgery for the first five postoperative days . Pain scores and morphine use were recorded one hour after arrival in the post-anesthesia care unit and at four , eight , twelve , sixteen , twenty , and twenty-four hours later . Intraoperative blood loss was recorded . The status of the fusion was determined radiographically at the time of the one-year follow-up . RESULTS There were no differences in demographic data or blood loss between the two groups . Pain scores were lower in the celecoxib group at one , four , eight , sixteen , and twenty hours postoperatively . There were no differences between the two groups with regard to the pain scores at twelve and twenty-four hours postoperatively . Morphine use was lower in the celecoxib group at all postoperative time-intervals . There was no difference between the celecoxib group and the placebo group with regard to the incidence of nonunion at the time of the one-year follow-up ( 7.5 % [ three of forty ] compared with 10 % [ four of forty ] ) . CONCLUSIONS The perioperative administration of celecoxib result ed in a significant reduction in postoperative pain and opioid use following spinal fusion surgery . In addition , the short-term administration of this COX-2-specific non-steroidal anti-inflammatory drug had no apparent effect on the rate of nonunion at the time of the one-year follow-up Abstract . We conducted a prospect i ve , r and omised study on primary total knee replacements to evaluate the effects of tourniquet use on total calculated blood loss using Gross formula , post-operative measured blood loss , operating time , need for blood transfusion , post-operative pain , analgesia requirement and knee flexion . Forty patients were operated on with the use of an arterial tourniquet with pressure of 350 mmHg ( group A ) , and 40 patients without the use of a tourniquet ( group B ) . Total calculated blood loss was significantly increased ( P=0.0165 ) without the use of a tourniquet . There was no significant difference in measured blood loss or operating time . The median units of blood given were similar in both groups . In spite of autologous transfusions 14 % of patients received additional homologous transfusions . At 6 h post-operatively pain was significantly less ( P=0.0458 ) in group B but was similar at 24 and 48 h. There was no significant difference in analgesia requirement . The mean change in total flexion in group B was significantly better ( P<0.001 ) at 5 days than in group A , but knee flexion was similar at 10 days and 3 months . Knee arthroplasty operations without the use of a tourniquet cause a greater blood loss but have only small benefits in the early post-operative period . Résumé . Une étude prospect i ve et r and omisée a été réalisée sur 80 arthroplasties totales du genou consécutives de première intention dans le but d'évaluer l'effet de l'utilisation du garrot pneumatique sur les pertes sanguines totales calculées selon la formule de Gross , les pertes sanguines mesurées par drainage aspiratif , la durée opératoire , la nécessité de transfusion sanguine , la douleur post-opératoire , le besoin d'antalgique et la récupération de la flexion du genou . Quarante patients ont été opérés avec un garrot pneumatique gonflé à 350 mmg ( group A ) , et quarante sans garrot pneumatique ( group B ) . Les pertes sanguines totales calculées étaient plus élevées de façon significative ( P=0.0165 ) dans le groupe B. Il n'y avait pas de différence significative entre les deux groupes sur les pertes sanguines mesurées par drainage aspiratif et la durée opératoire . Le nombre de culots globulaires nécessaire était le même dans les deux groupes . Malgré un protocol e d'autotransfusion , 14 % des patients ont eu une transfusion homologue complémentaire . La douleur post-opératoire était significativement moindre ( P=0.0458 ) à la sixième heure dans le groupe B mais était identique à 24 et 48 heures . Il n'y avait pas de différence sur la consommation d'antalgique . La flexion dans le groupe B était meilleure ( P<0.001 ) au cinquième jour que dans le groupe A , mais était identique à 10 jours et au troisième mois post-opératoire pour les deux groupes . La non-utilisation d'un garrot pneumatique apporte quelques bénéfices dans la période post-opératoire immédiate mais est responsable d'une majoration des pertes sanguines totales calculées Reduction of nociceptive input through blockade of N-methyl-d-aspartate ( NMDA ) receptors has been reported . We compared the effects of epidural S(+)-ketamine versus placebo on postoperative pain in a r and omized , double-blinded study in 37 patients undergoing unilateral knee arthroplasty . After lumbar epidural anesthesia with ropivacaine ( 10 mg/mL , 10–20 mL ) , 19 patients received 0.9 % epidural saline , and 18 patients received 0.25 mg/kg epidural S(+)-ketamine 10 min before surgical incision . After surgery , patient-controlled epidural analgesia with ropivacaine was provided . During the first 8 h after surgery , visual analog scale pain rating was similar between groups . Twenty-four and 48 h after surgery , patients anesthetized with ropivacaine had higher visual analog scale ratings at rest and during movement ( P < 0.05 ) than patients anesthetized with S(+)-ketamine and ropivacaine . Forty-eight hours after surgery , patients anesthetized with ropivacaine also consumed more ropivacaine ( 558 ± 210 mg ) ( P < 0.01 ) than those anesthetized with S(+)-ketamine and ropivacaine ( 319 ± 204 mg ) . Adverse events were similar between groups . Patients who received S(+)-ketamine and ropivacaine rated the quality of their pain therapy better than those who received ropivacaine alone ( P < 0.05 ) . We conclude that the combination of S(+)-ketamine and ropivacaine in epidural anesthesia increases postoperative pain relief when compared with ropivacaine UNLABELLED We prospect ively studied the continuous " modified " femoral three-in-one block for postoperative pain after total knee arthroplasty . Sixty-two patients undergoing elective knee arthroplasty under spinal anesthesia with bupivacaine ( B ) and fentanyl were r and omized to receive 0.2 % B , 0.1 % B , or placebo at 10 mL/h for 48 h after an initial bolus of 30 mL of the same solution via the femoral block catheter . The catheters were inserted under the fascia iliaca using a " double pop " technique and a peripheral nerve stimulator and were advanced 15 - 20 cm cranially . Venous plasma levels of B , desbutylbupivacaine , and 4-hydroxy B were measured daily for 3 days . All patients received patient-controlled analgesia with morphine and indomethacin suppositories for 48 h. Using computed tomography , we evaluated the catheter location for 20 patients . The catheter tips , located superior to the upper third of the sacroiliac joint in the psoas sheath , were labeled as ideally located . The group receiving 0.2 % B had a larger block success rate , smaller morphine consumption in the immediate postoperative period ( 15 vs 22 mg ) and during the first postoperative day ( 9 vs 18 mg ) , and achieved a greater range of motion in the immediate postoperative period ( 91 degrees + /- 10 degrees vs 80 degrees + 13 degrees ) . Visual analog scores for pain during both rest and activity were low but similar between the groups . Forty percent of the catheters evaluated were ideally located . Ideal location and use of 0.2 % B result ed in 100 % success of blockade of all three nerves . The S1 root was blocked in up to 76 % of patients . The plasma levels of B , 4-hydroxy B , and desbutylbupivacaine were below the toxic range during the infusion . We conclude that continuous fascia iliaca block with 0.2 % B results in opioid-sparing and improved range of motion during the immediate postoperative period . Larger doses of bupivacaine may safely be used in the immediate postoperative period if needed . IMPLICATION S Continuous fascia iliaca block with 0.2 % bupivacaine reduces opioid requirements and improves range of motion in the immediate postoperative period compared with a placebo and 0.1 % bupivacaine . Plasma levels are below the toxic range with this dose . Only 40 % of the catheters are positioned in the ideal location . With the smaller dose of bupivacaine , the success rate with this block is small Before proceeding to longer-term studies , we have studied the early clinical results of a new mobile-bearing total knee prosthesis in comparison with an established fixed-bearing device . Patients requiring bilateral knee replacement consented to have their operations under one anaesthetic using one of each prosthesis . They also agreed to accept the r and om choice of knee ( right or left ) and to remain ignorant as to which side had which implant . Outcomes were measured using the American Knee Society Score ( AKSS ) , the Oxford Knee Score ( OKS ) , and determination of the range of movement and pain scores before and at one year after operation . Preoperatively , there was no systematic difference between the right and left knees . One patient died in the perioperative period and one mobile-bearing prosthesis required early revision for dislocation of the meniscal component . At one year the mean AKSS , OKS and pain scores for the new device were slightly better ( p < 0.025 ) than those for the fixed-bearing device . There was no difference in the range of movement . We believe that this is the first controlled , blinded trial to compare early function of a new knee prosthesis with that of a st and ard implant . It demonstrates a small but significant clinical advantage for the mobile-bearing design In a prospect i ve r and omised trial we evaluated the use of a post-operative closed-suction drain in unicompartmental knee replacement ( UKR ) . Seventy-eight patients were divided into two groups : one without a post-operative closed-suction drain ( Group A ) and one with a drain ( Group B ) . Both groups were matched for age , sex and pre-operative haemoglobin . In group A we observed a lower day one post-operative analgesic requirement , smaller knee circumference 3 days post-operatively and less local wound complications . Drain usage in UKR result ed in no significant advantage in post-operative pain , range of motion and hospital stay . Post-operative drainage does , however , increase the cost of the procedure both in labour and equipment expenditure . No deep infections occurred in either group during the follow-up period . We conclude that avoiding post-operative closed-suction drainage in UKR does not influence the outcome This study is the first to evaluate whether continuous cryotherapy can relieve pain soon after total hip arthroplasty ( THA ) . Patients who had undergone THA for osteoarthritis were divided into 2 prospect i ve , r and omized groups : the cryotherapy group was fitted with a computer-controlled cooling device for 4 days , and the control group was not . The pain scores measured on a visual analog scale between days 1 and 4 following surgery were significantly lower for the cryotherapy group than for the control group . Furthermore , postoperative analgesic use by the cryotherapy group was significantly lower than by the control group . The results of this study support the potential benefit of a cold compressive device for pain reduction during the postoperative recovery of patients undergoing THA This study compared the effects of preoperative physical therapy or general cardiovascular conditioning exercises with the routine procedure of no preoperative physical therapy on patients undergoing primary total knee replacement . Thirty patients were r and omly assigned to 1 of 3 groups . Group 1 was the control group . Group 2 participated in a physical therapy program design ed to strengthen the upper and lower limbs and improve knee range of motion . Group 3 participated in a cardiovascular conditioning program , consisting of arm ergometry , cycle ergometry , aquatic exercises , and aerobic activity . All patients were evaluated preoperatively and postoperatively using the Hospital for Special Surgery Knee Rating , the Arthritis Impact Measurement Scale , and the Quality of Well Being instrument . Both experimental groups tolerated their respective exercise protocol s extremely well . All 3 groups showed significant improvement postoperatively as measured by the Hospital for Special Surgery Knee Rating , the Arthritis Impact Measurement Scale and the Quality of Well Being measurement scales . However , neither type of preoperative exercise added to the degree of improvement after surgery at any of the postoperative evaluations Our objective in a r and omized , multicenter , double-blind , parallel-group , placebo- and active-controlled study was to evaluate and compare the analgesic effectiveness of single intravenous ( IV ) doses of parecoxib sodium 20 and 40 mg , morphine 4 mg , and ketorolac 30 mg in the postsurgical orthopedic pain model . After undergoing unilateral total knee replacement surgery , 208 healthy adult patients were r and omized to receive placebo or a study drug within 6 hours of discontinuation of patient-controlled analgesia on postoperative day 1 . Onset of analgesia was similarly rapid with IV parecoxib sodium 40 mg , morphine , and ketorolac . Level and duration of analgesia were significantly superior with parecoxib sodium than with morphine and were similar for parecoxib sodium and ketorolac . Parecoxib sodium was safe and well tolerated . In conclusion , IV parecoxib sodium 40 mg is as effective as ketorolac 30 mg and is more effective than morphine 4 mg and therefore has potential widespread utility in acute postoperative pain management In this study , we assessed the influence of three analgesic techniques on postoperative knee rehabilitation after total knee arthroplasty (TKA).Forty-five patients scheduled for elective TKA under general anesthesia were r and omly divided into three groups . Postoperative analgesia was provided with IV patient-controlled analgesia ( PCA ) with morphine in Group A , continuous 3-in-1 block in Group B , and epidural analgesia in Group C. Immediately after surgery , the three groups started identical physical therapy regimens . Pain scores , supplemental analgesia , side effects , degree of maximal knee flexion , day of first walk , and duration of hospital stay were recorded . Patients in Groups B and C reported significantly lower pain scores than those in Group A. Supplemental analgesia was comparable in the three groups . Compared with Groups A and C , a significantly lower incidence of side effects was noted in Group B. Significantly better knee flexion ( until 6 wk after surgery ) , faster ambulation , and shorter hospital stay were noted in Groups B and C. However , these benefits did not affect outcome at 3 mo . We conclude that , after TKA , continuous 3-in-1 block and epidural analgesia provide better pain relief and faster knee rehabilitation than IV PCA with morphine . Because it induces fewer side effects , continuous 3-in-1 block should be considered the technique of choice . Implication s : In this study , we determined that , after total knee arthroplasty , loco-regional analgesic techniques ( epidural analgesia or continuous 3-in-1 block ) provide better pain relief and faster postoperative knee rehabilitation than IV patient-controlled analgesia with morphine . Because it causes fewer side effects than epidural analgesia , continuous 3-in-1 block is the technique of choice . ( Anesth Analg 1998;87:88 - 92 We evaluated the effects of adding clonidine for continuous peripheral nerve infusions . Sixty patients undergoing total knee arthroplasty under combined single-injection sciatic block and continuous femoral infusion were r and omly allocated to three groups : block induction with 0.75 % ropivacaine followed by 0.2 % ropivacaine ( group control ; n = 20 ) ; block induction with 0.75 % ropivacaine and 1 & mgr;g/kg clonidine followed by 0.2 % ropivacaine ( group cloni-bolus ; n = 20 ) , and block induction with 0.75 % ropivacaine and 1 & mgr;g/kg clonidine followed by 0.2 % ropivacaine with 1 & mgr;g/mL clonidine ( group cloni-infusion ; n = 20 ) . After surgery , continuous femoral infusion was provided with a patient-controlled infusion pump ( basal infusion rate , 6 mL/h ; incremental dose , 2 mL ; lockout time , 15 min ) . The median ( range ) onset time of surgical block was 15 min ( 5–30 min ) in group control , 10 min ( 5–35 min ) in group cloni-bolus , and 10 min ( 5–30 min ) in group cloni-infusion ( P = 0.07 ) . No differences were reported among groups in the degree of pain measured with the visual analog scale . The total consumption of local anesthetic solution after a 24-h infusion was 170 mL ( 144–220 mL ) in group control , 169 mL ( 144–260 mL ) in group cloni-bolus , and 164 mL ( 144–248 mL ) in group cloni-infusion ( P = 0.51 ) ; after the second day of infusion , total consumption was 168 mL ( 144–200 mL ) in group control , 156 mL ( 144–288 mL ) in group cloni-bolus , and 150 mL ( 144–210 mL ) in group cloni-infusion ( P = 0.48 ) . Hemodynamic profiles and sedation were similar in the three groups . Motor function impairment after 48 h of infusion was observed in 27 % of cloni-infusion patients but in only 6 % of both the control and cloni-bolus groups ( P = 0.05 ) . We conclude that adding clonidine 1 & mgr;g/mL to local anesthetic for continuous femoral nerve block does not improve the quality of pain relief but has the potential for delaying recovery of motor function Background and Objectives : The benefit of adding a sciatic nerve block to the femoral block to improve analgesia after total knee replacement is controversial . The aim of this study is to address this controversy in a prospect i ve , comparative , and r and omized study . Methods : Patients were allocated r and omly to receive a continuous femoral nerve block or continuous blocks of both the femoral and sciatic nerves . Stimulating catheters were used in all cases . A loading dose of 15 mL ropivacaine 0.75 % was injected into each catheter , followed by administration of ropivacaine 0.2 % ( 2 - 5 mL/h infusion via the femoral catheter ; bolus 10 mL repeated every 12 hours in the sciatic catheter ) . The primary outcome was visual analog scale ( VAS ) scores ( 0 = no pain , 100 mm = worst pain ) in postanesthesia care unit and in the 48-hour period after surgery . The secondary outcomes were amplitude of knee flexion , morphine consumption , and occurrence of postoperative nausea and vomiting ( PONV ) . Results : The VAS scores at rest were significantly higher when there was only continuous femoral nerve block than when there was both continuous femoral and sciatic nerve blocks . This difference progressively decreased and disappeared at 36 hours after surgery . The combined femoral and sciatic blocks decreased the morphine consumption by 81 % and significantly decreased the occurrence of PONV . Conclusion : During the 36 hours immediately after total knee replacement , the combination of continuous femoral and sciatic nerve blocks improves analgesia while decreasing morphine consumption and PONV Background : The management of the patella in total knee arthroplasty is still problematic . We aim ed to identify differences in the clinical outcome of total knee arthroplasty according to whether or not patellar resurfacing had been performed in a prospect i ve , r and omized study of 220 osteoarthritic knees . Methods : Two hundred and twenty total knee arthroplasties in 201 patients were r and omly assigned to be performed with either resurfacing or retention of the patella , and the results were followed for a mean of forty-eight months ( range , thirty-six to seventy-nine months ) in a double-blind ( both patient and clinical evaluator blinded ) , prospect i ve study . Evaluation was performed annually by an independent observer and consisted of assessment with the Knee Society clinical rating system , specific evaluation of anterior knee pain , a stair-climbing test , and radiographic examination . Results : Fifteen ( 12 % ) of the 128 knees without patellar resurfacing and nine ( 10 % ) of the ninety-two knees with patellar resurfacing underwent a revision or another type of reoperation related to the patellofemoral articulation . This difference was not significant ( chi square with one degree of freedom = 0.206 , p = 0.650 ) . At the time of the latest follow-up , there was a significantly higher incidence of anterior pain ( chi square with one degree of freedom = 5.757 , p = 0.016 ) in the knees that had not had patellar resurfacing . Conclusions : Patients who underwent patellar resurfacing had superior clinical results in terms of anterior knee pain and stair descent . However , anterior knee pain still occurred in patients with patellar resurfacing , and nine ( 10 % ) of the ninety-two patients in that group underwent a revision or another type of reoperation involving the patellofemoral joint . Weight but not body mass index was associated with the development of anterior knee pain in the patients without patellar resurfacing , a finding that suggests that patellofemoral dysfunction may be a function of joint loading rather than obesity A prospect i ve r and omized study was performed to evaluate the role of cold compressive dressings in the postoperative treatment of total knee arthroplasty ( TKA ) . Eighty consecutive unilateral and ten bilateral primary total knee replacements were evaluated in terms of blood loss , pain relief , and range of motion . Patients in the cold compression group demonstrated an average of 548 ml in suction drainage , whereas those in the control group averaged 807 ml . This result ed in an average 3.1 mg hemoglobin drop in the cold compression group and 4.7 mg in the control group . When body habitus and weight were taken into account in the cold compression group , an average total blood loss of 1298 cc was calculated , with 744 ml arising from soft tissue extravasation . The corresponding total blood loss calculated average was 1908 ml in the control group , with 1101 ml attributed to soft tissue extravasation . Total injectable morphine per kilogram per initial 48 hours averaged 0.53 mg in the cold compression patients and 0.69 mg in the control patients . In the cold compression knees , range of motion averaged 86 degrees before operation , 53 degrees on postoperative day ( POD ) 7 , and 77 degrees on POD 14 . In the control knees , range of motion averaged 88 degrees before operation , 44 degrees on POD 7 , and 65 degrees on POD 14 . The use of cold compression in the postoperative period of TKA results in a dramatic decrease in blood loss . In addition , mild improvements are seen in early return of motion and injectable narcotic pain needs in the postoperative period PURPOSE To examine the difference between compression b and aging and cold therapy after total knee arthroplasty . SAMPLE Eighty-four postoperative , unilateral , total knee replacement , surgical clients . PROCEDURE Clients were r and omized into two groups : those receiving compression b and aging , and those receiving cryo-pad technology . Subjects were assessed for total length of stay , blood loss , blood transfusion , swelling , flexion , pain , and opiate use . FINDINGS Unlike other studies , the results of these data showed no significant differences between groups on the measured outcomes . A simple cost benefit analysis shows that the compression b and age is cheaper and more labor efficient than the cold therapy as delivered by cryo-pad technology The optimal dose of intrathecal morphine for postoperative analgesia after major surgery is a matter of debate , with some uncertainty concerning the therapeutic potential and safety of intrathecal morphine in the dose range 0.3–1.0 mg . This r and omised double‐blind study compared the efficacy and side‐effect profile of 0.2 mg and 0.5 mg intrathecal morphine in 70 patients undergoing knee replacement surgery . The primary endpoint was the number of patients requiring rescue analgesia ( tramadol ) during the first 24 h postoperatively . Secondary endpoints included consumption of tramadol and the incidence of adverse effects . Fewer patients in the 0.5‐mg group required rescue analgesia in the first 24 h than in the 0.2‐mg group ( 16 ( 48 % ) vs 28 ( 85 % ) , respectively ; p = 0.003 ) . Median ( IQR [ range ] ) tramadol consumption was lower in the 0.5‐mg group than in the 0.2‐mg group ( 0 ( 0–100 [ 0–350 ] ) mg vs 100 ( 50–100 [ 0–350 ] ) mg , respectively ; p = 0.02 ) . The incidence of adverse effects was similar in both groups . This study has demonstrated that 0.5 mg intrathecal morphine produces better analgesia than 0.2 mg after knee replacement without any increase in side‐effects OBJECTIVE To evaluate the effectiveness of a new intensive functional rehabilitation ( IFR ) program on functional ability and quality of life ( QOL ) in persons who underwent a first total knee arthroplasty ( TKA ) . DESIGN R and omized controlled trial . SETTING Ambulatory care . PARTICIPANTS Seventy-seven people with knee osteoarthritis . INTERVENTION Two months after TKA , subjects were r and omly assigned to either a group with IFR ( n=38 ) , who received 12 supervised rehabilitation sessions combined with exercises at home between months 2 and 4 after TKA , or to a control group ( n=39 ) , who received st and ard care . All participants were evaluated by a blind evaluator at baseline ( 2mo after TKA ) , immediately after IFR ( 2mo later ; POST1 ) , and 2 and 8 months later ( POST2 and POST3 ) . Main outcome measures The primary outcome measure with respect to effectiveness was the 6-minute walk test ( 6MWT ) at POST2 . Secondary outcome measures were the 6MWT at the other evaluations and the Western Ontario and McMaster Universities Osteoarthritis Index and Medical Outcomes Study 36-Item Short-Form Health Survey . RESULTS Subjects in the IFR group walked longer distances ( range , 23 - 26 m ) in 6 minutes at the 3 POST evaluations than subjects in the control group . At POST1 and POST2 , they also had less pain , stiffness , and difficulty in performing daily activities . Positive changes in QOL in favor of the IFR were found only at POST2 . CONCLUSIONS The IFR was effective in improving the short-term and mid-term functional ability after uncomplicated primary TKA . The magnitude of the IFR effect on the primary outcome was modest but consistent . More intensive rehabilitation should be promoted in the subacute recovery period after TKA , to optimize functional outcomes in the first year after surgery

It was also evident that there were negligible differences in the psychometric properties of online versus paper versions of the online screening tools .

Background According to the World Health Organization , the alarming increase in rates of depression globally has become a serious concern . In 2010 , the prevalence rate of depression in South Africa was 4.6 % . Given the context of South Africa where the majority of the population have limited access to healthcare facilities and 59.3 % of the population have access to the Internet , an online depression screening tool would have much to offer . Objective To determine whether online depression screening tools would be suitable for use in South Africa . Methods This study presents a systematic review of online depression screening tools to determine whether one would be suitable for use in South Africa .

OBJECTIVES Despite the high prevalence of both mental illness and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome ( AIDS ) in developing countries , there are few data on the association between different forms of mental illness and sexual risk behaviours in re source -poor setting s. The objective of this study was to examine the association between mental illness and HIV risk behaviours in a South African township . STUDY DESIGN A cross-sectional study was performed among 645 individuals living in households selected at r and om . METHODS A self-administered translated question naire investigated sexual risk behaviours [ including sexual partners , condom use , casual sexual contacts , and sex in exchange for money , drugs or a place to stay ( transactional sex ) ] , depression ( measured using the Center for Epidemiological Studies Depression Scale ) , alcohol abuse ( from the Alcohol Use Disorders Identification Test ) , and post-traumatic stress disorder ( based on the Life Event Checklist ) . RESULTS Of the 645 individuals who completed the survey , 33 % reported depression , 17 % reported alcohol abuse , and 15 % reported post-traumatic stress disorder . After adjusting for demographic characteristics , the presence of any of these three conditions was strongly associated with experiences of forced sex [ adjusted odds ratio ( AOR ) 2.53 ; 95 % confidence intervals ( CI ) 1.60 - 4.02 ] , transactional sex ( AOR 2.88 ; 95 % CI 1.29 - 6.48 ) and increased condom use ( AOR 2.07 ; 95 % CI 1.32 - 3.25 ) . CONCLUSIONS These findings emphasize the substantial burden of mental illness in this setting , and its association with forced and transactional sex . The temporal nature of these associations is not always clear from this cross-sectional study , and additional prospect i ve research is required . Public health interventions are needed to address the dual burden of HIV/AIDS and mental illness in this and similar setting Background The 10-item Centre for Epidemiological Studies Depression Scale ( CES-D-10 ) is a depression screening tool that has been used in the South African National Income Dynamics Study ( NIDS ) , a national household panel study . This screening tool has not yet been vali date d in South Africa . This study aim ed to establish the reliability and validity of the CES-D-10 in Zulu , Xhosa and Afrikaans . The CES-D-10 ’s psychometric properties were also compared to the Patient Health Question naire ( PHQ-9 ) , a depression screening tool already vali date d in South Africa . Methods Stratified r and om sample s of Xhosa , Afrikaans and Zulu-speaking participants aged 15 years or older ( N = 944 ) were recruited from Cape Town Metro and Ethekwini districts . Face-to-face interviews included socio-demographic questions , the CES-D-10 , Patient Health Question naire ( PHQ-9 ) , and WHO Disability Assessment Schedule 2.0 ( WHODAS ) . Major depression was determined using the Mini International Neuropsychiatric Interview . All instruments were translated and back-translated to English . Construct validity was examined using exploratory factor analysis with varimax rotation . Receiver Operating Characteristics ( ROC ) curves were used to investigate the CES-D-10 and PHQ-9 ’s criterion validity , and compared using the DeLong method . Results Overall , 6.6 , 18.0 and 6.9 % of the Zulu , Afrikaans and Xhosa sample s were diagnosed with depression , respectively . The CES-D-10 had acceptable internal consistency across sample s ( α = 0.69–0.89 ) , and adequate concurrent validity , when compared to the PHQ-9 and WHODAS . The CES-D-10 area under the Receiver Operator Characteristic curve was good to excellent : 0.81 ( 95 % CI 0.71–0.90 ) for Zulu , 0.93 ( 95 % CI 0.90–0.96 ) for Afrikaans , and 0.94 ( 95 % CI 0.89–0.99 ) for Xhosa . A cut-off of 12 , 11 and 13 for Zulu , Afrikaans and Xhosa , respectively , generated the most balanced sensitivity , specificity and positive predictive value ( Zulu : 71.4 , 72.6 % and 16.1 % ; Afrikaans : 84.6 % , 84.0 % , 53.7 % ; Xhosa : 81.0 % , 95.0 % , 54.8 % ) . These were slightly higher than those generated for the PHQ-9 . The CES-D-10 and PHQ-9 otherwise performed similarly across sample s. Conclusions The CES-D-10 is a valid , reliable screening tool for depression in Zulu , Xhosa and coloured Afrikaans population Background Self-report measures can guide clinical decisions and are useful when evaluating treatment outcomes . However , many clinicians do not use self-report measures systematic ally in their clinical practice . Internet-based question naires could facilitate administration , but the psychometric properties of the online version of an instrument should be explored before implementation . The recommendation from the International Test Commission is to test the psychometric properties of each question naire separately . Objective Our objective was to compare the psychometric properties of paper- and -pencil versions and Internet versions of two question naires measuring depressive symptoms . Methods The 87 participating patients were recruited from primary care and psychiatric care within the public health care system in Sweden . Participants completed the Beck Depression Inventory ( BDI-II ) and the Montgomery-Åsberg Depression Rating Scale — Self-rated ( MADRS-S ) , both on paper and on the Internet . The order was r and omized to control for order effects . Symptom severity in the sample ranged from mild to severe depressive symptoms . Results Psychometric properties of the two administration formats were mostly equivalent . The internal consistency was similar for the Internet and paper versions , and significant correlations were found between the formats for both MADRS-S ( r = .84 ) and the BDI-II ( r = .89 ) . Differences between paper and Internet total scores were not statistically significant for either question naire nor for the MADRS-S question dealing with suicidality ( item 9 ) when analyzed separately . The score on the BDI-II question about suicidality ( item 9 ) was significantly lower when administered via the Internet compared with the paper score , but the difference was small ( effect size , Cohen ’s [ d ] = 0.14 ) . There were significant main effects for order of administration on both question naires and significant interaction effects between format and order . This should not , however , pose a problem in clinical use as long as the administration format is not changed when repeated measurements are made . Conclusions The MADRS-S can be transferred to online use without affecting the psychometric properties in a clinical ly meaningful way . The full BDI-II also seems to retain its properties when transferred ; however , the item measuring suicidality in the Internet version needs further investigation since it was associated with a lower score in this study . The use of online question naires offers clinicians a more practical way of measuring depressive symptoms and has the potential to save re sources

Results Animal and human data combined to show a core aversion-related network , consisting of similar cortical ( i.e. MCC , PCC , AI , DMPFC , RTG , SMA , VLOFC ; see results section or abbreviation section for full names ) and subcortical ( i.e. Amyg , BNST , DS , Hab , Hipp/Parahipp , Hyp , NAc , NTS , PAG , PBN , raphe , septal nuclei , Thal , LC , midbrain ) regions . In addition , a number of regions appeared to be more involved in pain-related ( e.g. sensory cortex ) or non-pain-related ( e.g. amygdala ) aversive processing . Conclusions This investigation suggests that aversive processing , at the most basic level , relies on similar neural substrates , and that differential responses may be due , in part , to the recruitment of additional structures as well as the spatio-temporal dynamic activity of the network . This network perspective may provide a clearer underst and ing of why components of this circuit appear dysfunctional in some psychiatric and pain-related disorders

Background Identification of potentially harmful stimuli is necessary for the well-being and self-preservation of all organisms . However , the neural substrates involved in the processing of aversive stimuli are not well understood . For instance , painful and non-painful aversive stimuli are largely thought to activate different neural networks . However , it is presently unclear whether there is a common aversion-related network of brain regions responsible for the basic processing of aversive stimuli .

Neuroimaging studies have demonstrated activations in the anterior cingulate cortex ( ACC ) related to the affective component of pain , but not to stimulus intensity . However , it is possible that the low spatial resolution of positron emission tomography , as used in the majority of these studies , obscured areas coding stimulus intensity . We revisited this issue , using a parametric single-trial functional magnetic resonance imaging design , and investigated pain , stimulus intensity , and stimulus awareness ( i.e. , pain unrelated ) responses within the ACC in nine healthy volunteers . Four different stimulus intensities ranging from warm to painful ( 300–600 mJ ) were applied with a thulium yttrium – aluminum granate infrared laser in a r and omized order and rated by the subjects on a five point scale ( P0–P4 ) . Pain-related regions in the ventral posterior ACC showed a response that did not distinguish between innocuous trials ( P0 and P1 ) but showed a positive linear relationship with the blood oxygenation level-dependent contrast signal for painful trials ( P2–P4 ) . Regions in the dorsal anterior ACC along the cingulate sulcus differentiated between P0 ( not perceived ) and P1 but exhibited no additional signal increase with P2 ; these regions are related to stimulus awareness and probably to cognitive processing . Most importantly , we identified a region in the dorsal posterior ACC showing a response that discriminated between nonpainful trials ( P0 and P1 ) ; therefor , this region was simply related to basic sensory processing and not to pain intensity . Stimulus-related activations were all located adjacent to the cingulate motor area , highlighting the strategic link of stimulus processing and response generation in the posterior ACC Although behavioral studies suggest that pain distress may alter the perception of somatic stimulation , neural correlates underlying such alteration remain to be clarified . The present study was aim ed to test the hypothesis that expectation of pain might amplify brain responses to somatosensory stimulation in the anterior cingulate cortex ( ACC ) and the region including parietal operculum and posterior insula ( PO/PI ) , both of which may play roles in regulating pain-dependent behavior . We compared brain responses with and subjective evaluation of physically identical nonpainful warm stimuli between two psychologically different context s : one linked with pain expectation by presenting the nonpainful stimuli r and omly intermixed with painful stimuli and the other without . By applying the event-related functional magnetic resonance imaging technique , brain responses to the stimuli were assessed with respect to signal changes and activated volume , setting regions of interest on activated clusters in ACC and bilateral PO/PI defined by painful stimuli . As a result , the uncertain expectation of painful stimulus enhanced transient brain responses to nonpainful stimulus in ACC and PO/PI . The enhanced responses were revealed as a higher intensity of signal change in ACC and larger volume of activated voxels in PO/PI . Behavioral measurements demonstrated that expectation of painful stimulus amplified perceived unpleasantness of innocuous stimulus . From these findings , it is suggested that ACC and PO/PI are involved in modulation of affective aspect of sensory perception by the uncertain expectation of painful stimulus Abstract Although individual differences in fear and anxiety modulate the pain response and may even cause more suffering than the initiating physical stimulus , little is known about the neural systems mediating this relationship . The present study provided the first examination of the neural correlates of individual differences in the tendency to ( 1 ) feel anxious about the potentially negative implication s of physical sensations , as measured by the anxiety sensitivity index ( ASI ) , and ( 2 ) fear various types of physical pain , as indexed by the fear of pain question naire ( FPQ ) . In separate sessions , participants completed these question naires and experienced alternating blocks of noxious thermal stimulation ( 45–50 ° C ) and neutral thermal stimulation ( 38 ° C ) during the collection of whole‐brain fMRI data . Regression analyses demonstrated that during the experience of pain , ASI scores predicted activation of a medial prefrontal region associated with self‐focused attention , whereas FPQ scores predicted activation of a ventral lateral frontal region associated with response regulation and anterior and posterior cingulate regions associated with monitoring and evaluation of affective responses . These functional relationships can not be wholly explained by generalized anxiety ( indexed by STAI‐T scores ) , which did not significantly correlate with activation of any regions . The present findings may help clarify both the impact of individual differences in emotion on the neural correlates of pain , and the roles in anxiety , fear , and pain processing played by medial and orbitofrontal systems Cortical activity patterns to thermal painful stimuli of two different sizes were examined in normal volunteers using functional magnetic resonance imaging ( fMRI ) . Seven right-h and ed subjects were studied when the painful stimulus applied to the right h and fingers covered either 1,074-mm(2)-area large stimulator or 21-mm(2)-area small stimulator . Stimulus temperatures were adjusted to give rise to equivalent moderately painful ratings . fMRI signal increases and decreases were determined for the contralateral parietal and motor areas . When the overall activity in these regions was compared across subjects , increased fMRI activity was observed over more brain volume with the larger stimulator , whereas decreased fMRI activity was seen in more brain volume for the smaller stimulator . The individual subject and group-averaged activity patterns indicated regional specific differences in increased and decreased fMRI activity . The small stimulator result ed in decreased fMRI responses throughout the upper body representation in both primary somatosensory and motor cortices . In contrast , no decreased fMRI signals were seen in the secondary somatosensory cortex and in the insula . In another seven volunteers , the effects of the size of the thermal painful stimulus on vibrotactile thresholds were examined psychophysically . Painful stimuli were delivered to the fingers and vibrotactile thresholds were measured on the arm just distal to the elbow . Consistent with the fMRI results in the primary somatosensory cortex , painful thermal stimuli using the small stimulator increased vibrotactile thresholds on the forearm , whereas similarly painful stimuli using the large stimulator had no effect on forearm vibrotactile thresholds . These results are discussed in relation to the cortical dynamics for pain perception and in relation to the center-surround organization of cortical neurons Activation studies have shown that in response to evocative visual stimuli , brain activity increases in the visual cortex and limbic areas . However , non-affective characteristics of these images , such as color composition and visual complexity , confound the interpretation of these results . To address this issue , we had subjects rate over 100 images on aversive intensity ( facial mutilation , dead bodies ) and semantic complexity ( number of objects subjects could name ) . From these images , we assembled digitized image sets of non-aversive , mild and strong intensity , balanced on semantic complexity and content ( human faces and figures ) , and adjusted for color composition . A fourth condition consisted of a fixation cross on a blank screen . Thirteen subjects underwent eight positron emission tomography scans using the [ (15)O ] water methodology . Measurement of skin conductance was recorded simultaneously . All picture conditions , relative to the blank screen , activated the amygdalae and bilateral orbitofrontal cortex , while we found activation trends associated with increasing aversive content in the sub-lenticular region . Skin conductance increased during all picture conditions . Relative to the non-aversive pictures , aversive image content caused modulation of occipital and occipital-temporal cortex . These results demonstrated activation of the amygdala to salient , arousing stimuli , and not just aversive stimuli . In addition , they suggest that pictorial complexity , as indexed by our semantic measure , does not account for the modulation of visual cortex by aversive , emotional stimuli Previous functional neuroimaging studies have characterized brain systems mediating associative learning using classical delay conditioning paradigms . In the present study , we used event-related functional magnetic resonance imaging to characterize neuronal responses mediating aversive trace conditioning . During conditioning , neutral auditory tones were paired with an aversive sound [ unconditioned stimulus ( US ) ] . We compared neuronal responses evoked by conditioned ( CS+ ) and nonconditioned ( CS− ) stimuli in which a 50 % pairing of CS+ and the US enabled us to limit our analysis to responses evoked by the CS+ alone . Differential responses ( CS+ vs CS− ) , related to conditioning , were observed in anterior cingulate and anterior insula , regions previously implicated in delay fear conditioning . Differential responses were also observed in the amygdala and hippocampus that were best characterized with a time × stimulus interaction , indicating rapid adaptation of CS+-specific responses in medial temporal lobe . These results are strikingly similar to those obtained with a previous delay conditioning experiment and are in accord with a preferential role for medial temporal lobe structures during the early phase of conditioning . However , an additional activation of anterior hippocampus in the present experiment supports a view that its role in trace conditioning is to maintain a memory trace between the offset of the CS+ and the delayed onset of the US to enable associative learning in trace conditioning Functional neuroimaging studies in humans have shown that nociceptive stimuli elicit activity in a wide network of cortical areas commonly labeled as the " pain matrix " and thought to be preferentially involved in the perception of pain . Despite the fact that this " pain matrix " has been used extensively to build models of where and how nociception is processed in the human brain , convincing experimental evidence demonstrating that this network is specifically related to nociception is lacking . The aim of the present study was to determine whether there is at least a subset of the " pain matrix " that responds uniquely to nociceptive somatosensory stimulation . In a first experiment , we compared the fMRI brain responses elicited by a r and om sequence of brief nociceptive somatosensory , non-nociceptive somatosensory , auditory and visual stimuli , all presented within a similar attentional context . We found that the fMRI responses triggered by nociceptive stimuli can be largely explained by a combination of ( 1 ) multimodal neural activities ( i.e. , activities elicited by all stimuli regardless of sensory modality ) and ( 2 ) somatosensory-specific but not nociceptive-specific neural activities ( i.e. , activities elicited by both nociceptive and non-nociceptive somatosensory stimuli ) . The magnitude of multimodal activities correlated significantly with the perceived saliency of the stimulus . In a second experiment , we compared these multimodal activities to the fMRI responses elicited by auditory stimuli presented using an oddball paradigm . We found that the spatial distribution of the responses elicited by novel non-target and novel target auditory stimuli resembled closely that of the multimodal responses identified in the first experiment . Taken together , these findings suggest that the largest part of the fMRI responses elicited by phasic nociceptive stimuli reflects non nociceptive-specific cognitive processes The amygdala has been implicated in fundamental functions for the survival of the organism , such as fear and pain . In accord with this , several studies have shown increased amygdala activity during fear conditioning and the processing of fear-relevant material in human subjects . In contrast , functional neuroimaging studies of pain have shown a decreased amygdala activity . It has previously been proposed that the observed deactivations of the amygdala in these studies indicate a cognitive strategy to adapt to a distressful but in the experimental setting unavoidable painful event . In this positron emission tomography study , we show that a simple context ual manipulation , immediately preceding a painful stimulation , that increases the anticipated duration of the painful event leads to a decrease in amygdala activity and modulates the autonomic response during the noxious stimulation . On a behavioral level , 7 of the 10 subjects reported that they used coping strategies more intensely in this context . We suggest that the altered activity in the amygdala may be part of a mechanism to attenuate pain-related stress responses in a context that is perceived as being more aversive . The study also showed an increased activity in the rostral part of anterior cingulate cortex in the same context in which the amygdala activity decreased , further supporting the idea that this part of the cingulate cortex is involved in the modulation of emotional and pain networks The allocation of attention modulates negative emotional processing in the amygdala . However , the role of passive exposure time to emotional signals in the modulation of amygdala activity during active task performance has not been examined . In two functional Magnetic Resonance Imaging ( fMRI ) experiments conducted in two different groups of healthy human subjects , we examined activation in the amygdala due to cued anticipation of painful stimuli while subjects performed a simple continuous performance task ( CPT ) with either a fixed or a parametrically varied trial duration . In the first experiment ( N = 16 ) , engagement in the CPT during a task with fixed trial duration produced the expected attenuation of amygdala activation , but close analysis suggested that the attenuation occurred during the period of active engagement in CPT , and that amygdala activity increased proportionately during the remainder of each trial , when subjects were passively exposed to the pain cue . In the second experiment ( N = 12 ) , the duration of each trial was parametrically varied , and we found that amygdala activation was linearly related to the time of passive exposure to the anticipatory cue . We suggest that amygdala activation during negative anticipatory processing depends directly on the passive exposure time to the negative cue Although pathological muscle pain involves a significantly larger population than any other pain condition , the central mechanisms are less explored than those of cutaneous pain . The aims of the study were to establish the pain matrix for muscle pain in the full head volume and , further , to explore the possibility of a functional segregation to nonpainful and painful stimuli within the area of the parasylvian cortex corresponding to the secondary somatosensory area . Additionally , we speculate that a r and omization of nonpainful and painful stimuli may target specific structures related to stimulus salience . We used event-related functional magnetic resonance imaging ( MRI ) and the high sensitivity of the 3-T MRI scanner to study the central processing of acute muscle pain induced by intramuscular electrostimulation . Brief nonpainful and painful stimuli ( 1-ms duration , interstimulus interval = 12 s ) were r and omly applied to the left abductor pollicis brevis of 10 subjects . The data disclose a pain matrix for muscle pain similar to that for cutaneous pain . Individual analysis suggests separate representations within the area bounded by the upper bank of the Sylvian fissure ( SF ) and the circular sulcus of insula ( CSI ) . Nonpainful stimulation activated the superficial parietal operculum adjoining the SF , while the painful condition additionally targeted the deeper parietal operculum bordering the CSI . R and omization of stimuli of different intensities likely introduces cognitive components that engage neural substrates servicing the appreciation of stimulus salience in the context of affect-laden pain imposition The time course of amygdala activation during aversive conditioning is a matter of debate . While some research ers reported rapid habituation , others found stable or no amygdalar responses to conditioned stimuli at all . In the present event-related fMRI study , we investigated whether the activity of the amygdala during aversive conditioning depends on attentional conditions . Subjects underwent aversive delay conditioning by pairing an electrical shock ( unconditioned aversive stimulus ) with a visual conditioned stimulus ( CS+ ) . For each singular presentation of the CS+ or a nonconditioned visual stimulus ( CS- ) , subjects attended in r and om order to features that either differed between both stimuli ( identification task ) or that did not differ ( distraction task ) . For the identification task trials , increased responses of the left amygdala to CS+ versus CS- were rapidly established but absent at the end of the conditioning trials . In contrast , under the distraction condition , amygdala activation to CS+ versus CS- was present during the late but not the early phase of conditioning . The results suggest that the time course of amygdala activity during aversive associative learning is strongly modulated by an interaction of attention and time We mapped regional brain activity and peripheral psychophysiologic responses , occurring in response to evocative emotional stimuli , and examined whether task instructions could modulate limbic activation . Ten subjects viewed pictures with neutral or aversive emotional content during simultaneous measurement of peripheral psychophysiology and brain activity with [15O]water positron emission tomography ( PET ) . Cognitive task was manipulated by having the subjects rate the pictures or perform a recognition memory task . Aversive pictures , relative to neutral pictures , increased cerebral activity in bilateral amygdala , thalamic/hypothalamic area , midbrain , and left lateral prefrontal cortex , along with greater skin conductance responses ( SCR ) . Voxel-by-voxel correlation coefficients between regional brain activity and SCR showed significant positive correlation peaks in the thalamus and right amygdala . Limbic activation was significantly greater during the rating condition compared to the recognition condition , suggesting that when task dem and s modify emotional responses , this modulation can occur at the level of limbic activity Pain is a unique class of sensory experience from the perspective of salience . Nonpainful somatosensory stimuli usually require behavioral relevance or voluntary attention to maintain salience . In contrast , painful stimuli tend to have sustained salience even without explicit behavioral relevance or voluntary attention . We have previously identified a frontal-parietal-cingulate network of regions responding transiently to nonpainful sensory events . This network is sensitive to the task relevance and novelty of sensory events and likely represents the salience of events in the sensory environment . Since pain can remain salient for a prolonged period , we hypothesized that this network should show transient responses to the onset or offset of a nonpainful stimulus , but sustained responses throughout the duration of a painful stimulus . To test this hypothesis , we used functional MRI to examine the response of these regions to sustained ( 60-s ) periods of painful and nonpainful transcutaneous electrical nerve stimulation . As predicted , the temporoparietal , inferior frontal , and anterior cingulate cortex showed only transient responses to the onset or offset of nonpainful stimulation , but a sustained response throughout the duration of painful stimulation . These regions therefore show tonic responses to stimuli with tonic salience , supporting a general role for these areas in representing stimulus salience . The thalamus and putamen also responded tonically throughout painful but not nonpainful stimulation . Previous studies have implicated the basal ganglia in supporting voluntary sustained attention . Our findings suggest that the basal ganglia may play a more general role in supporting sustained salience , whether through voluntary or involuntary mechanisms BACKGROUND Intense and rapidly changing mood states are a major feature of borderline personality disorder ( BPD ) ; however , there have only been a few studies investigating affective processing in BPD , and in particular no neurofunctional correlates of abnormal emotional processing have been identified so far . METHODS Six female BPD patients without additional major psychiatric disorder and six age-matched female control subjects underwent functional magnetic resonance imaging ( fMRI ) to measure regional cerebral hemodynamic changes following brain activity when viewing 12 st and ardized emotionally aversive slides compared to 12 neutral slides , which were presented in r and om order . RESULTS Our main finding was that BPD subjects but not control subjects were characterized by an elevated blood oxygenation level dependent fMRI signal in the amygdala on both sides . In addition , activation of the medial and inferolateral prefrontal cortex was seen in BPD patients . Both groups showed activation in the temporo-occipital cortex including the fusiform gyrus in BPD subjects but not in control subjects . CONCLUSIONS Enhanced amygdala activation in BPD is suggested to reflect the intense and slowly subsiding emotions commonly observed in response to even low-level stressors . Borderline subjects ' perceptual cortex may be modulated through the amygdala leading to increased attention to emotionally relevant environmental stimuli Functional magnetic resonance imaging ( fMRI ) studies consistently demonstrate an enhanced activation of the visual cortex in reaction to emotionally salient visual stimuli . This increase of activation is probably modulated by top-down processes , that are initiated in emotion processing structures , specifically the amygdala and the orbitofrontal cortex . In the present fMRI study , a differential fear conditioning paradigm was applied to investigate this assumed modulation . Hemodynamic responses towards a neutral visual stimulus ( CS+ ) predicting an electrical stimulation ( UCS ) were compared with responses towards a neutral and unpaired stimulus ( CS- ) . Thereby , particularly the time courses of neural responses were considered . Skin conductance measures were concurrently recorded . Our results show that the differentiation between CS+ and CS- within the amygdala and the extended visual cortex was accomplished during a late acquisition phase . In the orbitofrontal cortex the differentiation occurred at an earlier stage and was then sustained throughout acquisition . It is suggested that these altering activation patterns are reflecting different phases of learning , integrating the analyzed regions to varying degrees . Additionally , the results indicate that statistical analyses comprising a temporal variation of hemodynamic responses are more likely to detect amygdala activation & NA ; Previous functional imaging studies have demonstrated a number of discrete brain structures that increase activity with noxious stimulation . Of the commonly identified central structures , only the anterior cingulate cortex shows a consistent response during the experience of pain . The insula and thalamus demonstrate reasonable consistency while all other regions , including the lentiform nucleus , somatosensory cortex and prefrontal cortex , are active in no more than half the current studies . The reason for such discrepancy is likely to be due in part to method ological variability and in part to individual variability . One aspect of the methodology which is likely to contribute is the stimulus intensity . Studies vary considerably regarding the intensity of the noxious and non‐noxious stimuli delivered . This is likely to produce varying activation of central structures coding for the intensity , affective and cognitive components of pain . Using twelve healthy volunteers and positron emission tomography ( PET ) , the regional cerebral blood flow ( rCBF ) responses to four intensities of stimulation were recorded . The stimulation was delivered by a CO2 laser and was described subjectively as either warm ( not painful ) , pain threshold ( just painful ) , mildly painful or moderately painful . The following group subtractions were made to examine the changing cerebral responses as the stimulus intensity increased : ( 1 ) just painful − warm ; ( 2 ) mild pain − warm ; and ( 3 ) moderate pain − warm . In addition , rCBF changes were correlated with the subjective stimulus ratings . The results for comparison ‘ 1 ’ indicated activity in the contralateral prefrontal ( area 10/46/44 ) , bilateral inferior parietal ( area 40 ) and ipsilateral premotor cortices ( area 6 ) , possibly reflecting initial orientation and plans for movement . The latter comparisons and correlation analysis indicated a wide range of active regions including bilateral prefrontal , inferior parietal and premotor cortices and thalamic responses , contralateral hippocampus , insula and primary somatosensory cortex and ipsilateral perigenual cingulate cortex ( area 24 ) and medial frontal cortex ( area 32 ) . Decreased rCBF was observed in the amygdala region . These responses were interpreted with respect to their contribution to the multidimensional aspects of pain including fear avoidance , affect , sensation and motivation or motor initiation . It is suggested that future studies examine the precise roles of each particular region during the central processing of pain The capacity to anticipate aversive circumstances is central not only to successful adaptation but also to underst and ing the abnormalities that contribute to excessive worry and anxiety disorders . Forecasting and reacting to aversive events mobilize a host of affective and cognitive capacities and corresponding brain processes . Rapid event-related functional magnetic resonance imaging ( fMRI ) in 21 healthy volunteers assessed the overlap and divergence in the neural instantiation of anticipating and being exposed to aversive pictures . Brain areas jointly activated by the anticipation of and exposure to aversive pictures included the dorsal amygdala , anterior insula , dorsal anterior cingulate cortex ( ACC ) , right dorsolateral prefrontal cortex ( DLPFC ) , and right posterior orbitofrontal cortex ( OFC ) . Anticipatory processes were uniquely associated with activations in rostral ACC , a more superior sector of the right DLPFC , and more medial sectors of the bilateral OFC . Activation of the right DLPFC in anticipation of aversion was associated with self-reports of increased negative affect , whereas OFC activation was associated with increases in both positive and negative affect . These results show that anticipation of aversion recruits key brain regions that respond to aversion , thereby potentially enhancing adaptive responses to aversive events Changes in regional cerebral blood flow ( rCBF ) have previously been demonstrated in a number of cortical and subcortical regions , including the cerebellum , midbrain , thalamus , lentiform nucleus , and the insula , prefrontal , anterior cingulate , and parietal cortices , in response to experimental noxious stimuli . Increased anterior cingulate responses in patients with chronic regional pain and depression to noxious stimulation distant from the site of clinical pain have been observed . We suggested that this may represent a generalized hyperattentional response to noxious stimuli and may apply to other types of chronic regional pain . Here these techniques are extended to a group of patients with nonspecific chronic low back pain . Thirty-two subjects , 16 chronic low back pain patients and 16 controls , were studied using positron emission tomography . Thermal stimuli , corresponding to the experience of hot , mild , and moderate pain , were delivered to the back of the subject 's right h and using a thermal probe . Each subject had 12 measurements of rCBF , 4 for each stimulus . Correlation of rCBF with subjective pain experience revealed similar responses across groups in the cerebellum , midbrain ( including the PAG ) , thalamus , insula , lentiform nucleus , and midcingulate ( area 24 ' ) cortex . These regions represented the majority of activations for this study and those recorded by other imaging studies of pain . Although some small differences were observed between the groups these were not considered sufficient to suggest abnormal nociceptive processing in patients with nonspecific low back pain

Baseline drug resistance and HIV co-infection were significant risk factors for ADR . There was a trend of positive association with non-adherence which is likely to contribute to the outcome of ADR .

BACKGROUND Studies looking at acquired drug resistance ( ADR ) are diverse with respect to geographical distribution , HIV co-infection rates , retreatment status and programmatic factors such as regimens administered and directly observed therapy . Our objective was to examine and consoli date evidence from clinical studies of the multifactorial aetiology of acquired rifamycin and /or isoniazid resistance within the scope of a single systematic review . This is important to inform policy and identify key areas for further studies .

BACKGROUND Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin . The US Public Health Service Study 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase ( the last 4 months ) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients . This report concerns only the HIV-seropositive part of the trial , which has ended . The HIV-seronegative part will stop follow-up in 2001 . METHODS Adults with culture-positive , drug-susceptible pulmonary tuberculosis who completed 2 months of four-drug ( isoniazid , rifampin , pyrazinamide , ethambutol ) treatment ( induction phase ) were r and omly assigned 900 mg isoniazid and 600 mg rifapentine once weekly , or 900 mg isoniazid and 600 mg rifampin twice weekly . All therapy was directly observed . Statistical analysis used univariate , Kaplan-Meier , and logistic and proportional hazards regression methods . FINDINGS 71 HIV-seropositive patients were enrolled : 61 completed therapy and were assessed for relapse . Five of 30 patients in the once-weekly isoniazid/rifapentine group relapsed , compared with three of 31 patients in the twice-weekly isoniazid/rifampin group ( log rank chi2=0.69 , p=0.41 ) . However , four of five relapses in the once-weekly isoniazid/rifapentine group had monoresistance to rifamycin , compared with none of three in the rifampin group ( p=0.05 ) . Patients who relapsed with rifamycin monoresistance were younger ( median age 29 vs 41 years ) , had lower baseline CD4 cell counts ( median 16 vs 144 microL ) , and were more likely to have extrapulmonary involvement ( 75 % vs 18 % , p=0.03 ) and concomitant therapy with antifungal agents ( 75 % vs 9 % , p=0.006 ) . No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date . INTERPRETATION Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly isoniazid/rifapentine continuation-phase regimen . Until more effective regimens have been identified and assessed in clinical trials , HIV-seropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen BACKGROUND The occurrence of acquired rifamycin resistance despite use of directly observed therapy for tuberculosis is associated with advanced human immunodeficiency virus ( HIV ) disease and highly intermittent administration of antituberculosis drugs . Beyond these associations , the pathogenesis of acquired rifamycin resistance is unknown . METHODS We performed a pharmacokinetic sub study of patients in a trial of treatment with twice-weekly rifabutin and isoniazid . RESULTS A total of 102 ( 60 % ) of 169 patients in the treatment trial participated in the pharmacokinetic sub study , including 7 of 8 patients in whom tuberculosis treatment failure or relapse occurred in association with acquired rifamycin-resistant mycobacteria ( hereafter , " ARR failure or relapse " ) . The median rifabutin area under the concentration-time curve ( AUC(0 - 24 ) ) was lower for patients with than for patients without ARR failure or relapse ( 3.3 vs. 5.2 microg*h/mL ; P = .06 , by the Mann-Whitney exact test ) . In a multivariate analysis adjusted for CD4 + T cell count , the mean rifabutin AUC(0 - 24 ) was significantly lower for patients with ARR failure or relapse than for other patients ( 3.0 microg*h/mL [ 95 % confidence interval { CI } , 1.9 - 4.5 ] vs. 5.2 microg*h/mL [ 95 % CI , 4.6 - 5.8 ] ; P = .02 , by analysis of covariance ) . The median isoniazid AUC(0 - 12 ) was not significantly associated with ARR failure or relapse ( 20.6 vs. 28.0 microg*h/mL ; P = .24 , by the Mann-Whitney exact test ) . However , in a multivariate logistic regression model that adjusted for the rifabutin AUC(0 - 24 ) , a lower isoniazid AUC(0 - 12 ) was associated with ARR failure or relapse ( OR , 10.5 ; 95 % CI , 1.1 - 100 ; P = .04 ) . CONCLUSIONS Lower plasma concentrations of rifabutin and , perhaps , isoniazid were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly therapy BACKGROUND It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis ( MDR-tuberculosis ) emergence . The level of nonadherence associated with emergence of MDR-tuberculosis is unknown . Performance of a r and omized controlled trial in which some patients are r and omized to nonadherence would be unethical ; therefore , other study design s should be utilized . METHODS We performed hollow fiber studies for both bactericidal and sterilizing effect , with inoculum spiked with 0.5 % rifampin- and isoniazid-resistant isogenic strains in some experiments . St and ard therapy was administered daily for 28 - 56 days , with extents of nonadherence varying between 0 % and 100 % . Sizes of drug-resistant population s were compared using analysis of variance . We also explored the effect of pharmacokinetic variability on MDR-tuberculosis emergence using computer-aided clinical trial simulations of 10 000 Cape Town , South Africa , tuberculosis patients . RESULTS Therapy failure was only encountered at extents of nonadherence ≥60 % . Surprisingly , isoniazid- and rifampin-resistant population s did not achieve ≥1 % proportion in any experiment and did not achieve a higher proportion with nonadherence . However , clinical trial simulations demonstrated that approximately 1 % of tuberculosis patients with perfect adherence would still develop MDR-tuberculosis due to pharmacokinetic variability alone . CONCLUSIONS These data , based on a pre clinical model , demonstrate that nonadherence alone is not a sufficient condition for MDR-tuberculosis emergence BACKGROUND Based on a hollow-fiber system model of tuberculosis , we hypothesize that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic variability . METHODS Clinical and pharmacokinetic data were prospect ively collected from 142 tuberculosis patients in Western Cape , South Africa . Compartmental pharmacokinetic parameters of isoniazid , rifampin , and pyrazinamide were identified for each patient . Patients were then followed for up to 2 years . Classification and regression tree analysis was used to identify and rank clinical predictors of poor long-term outcome such as microbiologic failure or death , or relapse . RESULTS Drug concentrations and pharmacokinetics varied widely between patients . Poor long-term outcomes were encountered in 35 ( 25 % ) patients . The 3 top predictors of poor long-term outcome , by rank of importance , were a pyrazinamide 24-hour area under the concentration-time curve ( AUC ) ≤ 363 mg·h/L , rifampin AUC ≤ 13 mg·h/L , and isoniazid AUC ≤ 52 mg·h/L. Poor outcomes were encountered in 32/78 patients with the AUC of at least 1 drug below the identified threshold vs 3/64 without ( odds ratio = 14.14 ; 95 % confidence interval , 4.08 - 49.08 ) . Low rifampin and isoniazid peak and AUC concentrations preceded all cases of acquired drug resistance . CONCLUSIONS Low drug AUCs are predictive of clinical outcomes in tuberculosis patients Background Development of resistance to antituberculosis drugs during treatment ( i.e. , acquired resistance ) can lead to emergence of resistant strains and consequent poor clinical outcomes . However , it is unknown whether Mycobacterium tuberculosis complex species and lineage affects the likelihood of acquired resistance . Methods We analyzed data from the U.S. National Tuberculosis Surveillance System and National Tuberculosis Genotyping Service for tuberculosis cases during 2004–2011 with assigned species and lineage and both initial and final drug susceptibility test results . We determined univariate associations between species and lineage of Mycobacterium tuberculosis complex bacteria and acquired resistance to isoniazid , rifamycins , fluoroquinolones , and second-line injectables . We used Poisson regression with backward elimination to generate multivariable models for acquired resistance to isoniazid and rifamycins . Results M. bovis was independently associated with acquired resistance to isoniazid ( adjusted prevalence ratio = 8.46 , 95 % CI 2.96–24.14 ) adjusting for HIV status , and with acquired resistance to rifamycins ( adjusted prevalence ratio = 4.53 , 95 % CI 1.29–15.90 ) adjusting for homelessness , HIV status , initial resistance to isoniazid , site of disease , and administration of therapy . East Asian lineage was associated with acquired resistance to fluoroquinolones ( prevalence ratio = 6.10 , 95 % CI 1.56–23.83 ) . Conclusions We found an association between mycobacterial species and lineage and acquired drug resistance using U.S. surveillance data . Prospect i ve clinical studies are needed to determine the clinical significance of these findings , including whether rapid genotyping of isolates at the outset of treatment may benefit patient management OBJECTIVES To determine rates of drug resistance to Mycobacterium tuberculosis and associated risk factors , including HIV infection . DESIGN Prospect i ve cohort study of patients with pulmonary tuberculosis . SETTING The study population comprised 28,522 men working on four goldmines in Westonaria , Gauteng . Health care is provided at a 240-bed mine hospital , Gold Fields West Hospital , and its primary health care facilities . SUBJECTS All 425 patients with culture-positive pulmonary tuberculosis identified in 1995 . OUTCOME MEASURES Tuberculosis drug resistance on enrollment and after 6 months ' treatment . RESULTS There were 292 cases of new tuberculosis , 77 of recurrent disease and 56 prevalent cases in treatment failure . Two hundred and seven patients ( 48.7 % ) were HIV infected . Primary resistance to one or more drugs ( 9 % ) was similar to the 11 % found in a previous study done on goldminers in 1989 . Primary multidrug resistance ( 0.3 % ) was also similar ( 0.8 % ) . Acquired multidrug resistance was 18.1 % : 6.5 % for recurrent disease and 33.9 % in treatment failure cases . Neither HIV infection nor the degree of immunosuppression as assessed by CD4 + lymphocyte counts was associated with drug resistance at the start or end of treatment . New patterns of drug resistance were present in 9 of 52 patients in treatment failure at 6 months , 1 of whom was HIV-infected . CONCLUSION Primary and acquired drug resistance rates are stable in this population and are not affected by the high prevalence of HIV infection RATIONALE The outcome of fully intermittent thrice-weekly antituberculosis treatment of various duration s in HIV-associated tuberculosis is unclear . OBJECTIVES To compare the efficacy of an intermittent 6-month regimen ( Reg6 M : 2EHRZ(3)/4HR(3 ) [ ethambutol , 1,200 mg ; isoniazid , 600 mg ; rifampicin , 450 or 600 mg depending on body weight < 60 or > or = 60 kg ; and pyrazinamide , 1,500 mg for 2 mo ; followed by 4 mo of isoniazid and rifampicin at the same doses ] ) versus a 9-month regimen ( Reg9 M : 2EHRZ(3)/7HR(3 ) ) in HIV/tuberculosis ( TB ) . METHODS HIV-infected patients with newly diagnosed pulmonary or extrapulmonary TB were r and omly assigned to Reg6 M ( n = 167 ) or Reg9 M ( n = 160 ) and monitored by determination of clinical , immunological , and bacteriological parameters for 36 months . Primary outcomes included favorable responses at the end of treatment and recurrences during follow-up , whereas the secondary outcome was death . Intent-to-treat and on-treatment analyses were performed . All patients were antiretroviral treatment-naive during treatment . MEASUREMENTS AND MAIN RESULTS Of the patients , 70 % had culture-positive pulmonary TB ; the median viral load was 155,000 copies/ml and the CD4(+ ) cell count was 160 cells/mm(3 ) . Favorable response to antituberculosis treatment was similar by intent to treat ( Reg6 M , 83 % and Reg9 M , 76 % ; P = not significant ) . Bacteriological recurrences occurred significantly more often in Reg6 M than in Reg9 M ( 15 vs. 7 % ; P < 0.05 ) although overall recurrences were not significantly different ( Reg6 M , 19 % vs. Reg9 M , 13 % ) . By 36 months , 36 % of patients undergoing Reg6 M and 35 % undergoing Reg9 M had died , with no significant difference between regimens . All 19 patients who failed treatment developed acquired rifamycin resistance ( ARR ) , the main risk factor being baseline isoniazid resistance . CONCLUSIONS Among antiretroviral treatment-naive HIV-infected patients with TB , a 9-month regimen result ed in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen . ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment . Clinical Trials Registry Information : ID # NCT00376012 registered at www . clinical trials.gov SETTING Damien Foundation tuberculosis ( TB ) control projects in Bangladesh . OBJECTIVE To assess the effectiveness of extending the intensive phase ( P1 ) of treatment by 1 month for patients who are smear-positive after 2 months of a 6-month regimen containing rifampicin ( RMP ) throughout . DESIGN Prospect i ve operational study r and omising P1 extension for new smear-positive cases with any number of acid-fast bacilli in the 2-month smear ( 2M+ ) . Smear-defined failures and relapses underwent culture and drug susceptibility testing in addition to DNA sequencing of the rpoB gene before and after treatment . RESULTS Of 16,708 patients evaluated , 12,967 were smear-negative at 2 months ( 2M- ) ; 1871 and 1870 2M+ were r and omised to no extension or extension . Respectively 0.3 % ( 95%CI 0.2 - 0.4 ) , 1.2 % ( 95%CI 0.7 - 1.8 ) and 2.0 % ( 95%CI 1.4 - 2.8 ) smear- and culture-positive failures , and 1.2 % ( 95%CI 1.0 - 1.4 ) , 2.6 % ( 95%CI 1.9 - 3.4 ) and 0.9 % ( 95%CI 0.5 - 1.4 ) relapses were detected . Extension significantly reversed the relative risk ( RR ) of relapse of 2M+ vs. 2M- patients from 2.2 ( 95%CI 1.6 - 3.0 ) to 0.7 ( 95%CI 0.4 - 1.2 ) . The RR for failure remained high , at 7.3 ( 95%CI 4.7 - 11.5 ) with and 4.2 ( 95%CI 2.5 - 7.2 ) without extension . More multi-drug resistance was found after extension , but acquired RMP resistance was similar in all arms . The fair sensitivity of the 2-month smear for failure or relapse ( 40 % ) was offset by a very low positive predictive value ( 3 % ) . CONCLUSIONS Extension of P1 is very inefficient with this 6-month regimen . Operational research should define appropriate algorithms allowing an earlier switch to the next higher regimen for those in need , using follow-up smears for screening RATIONALE Rifabutin was recommended in place of rifampin during treatment of HIV-related tuberculosis ( TB ) to facilitate concomitant potent antiretroviral therapy , but this approach has not been evaluated in a prospect i ve study . OBJECTIVE To evaluate the activity of intermittent rifabutin-based therapy . METHODS Patients with culture-confirmed TB were treated under direct supervision with 2 mo of rifabutin , isoniazid , pyrazinamide , and ethambutol ( given daily , thrice-weekly , or twice-weekly per the local tuberculosis control program ) , followed by 4 mo of twice-weekly rifabutin plus isoniazid . MEASUREMENTS Culture-positive treatment failure or relapse . MAIN RESULTS A total of 169 eligible patients were enrolled . Most had advanced HIV disease ; the median CD4 cell count and HIV-RNA level were 90 cells/mm3 ( interquartile range , 35 - 175 ) and 5.3 log10 copies/ml ( interquartile range , 4.8 - 5.7 ) , respectively . Nine ( 5.3 % ) patients had culture-positive treatment failure ( n = 3 ) or relapse ( n = 6 ) . Eight of these nine ( 89 % ) cases had isolates with acquired rifamycin resistance . Treatment failure or relapse was associated with baseline CD4 lymphocyte count , being 12.3 % ( 9/73 ; 95 % confidence interval , 6.5 - 22.0 % ) among patients with CD4 < 100 cells/mm3 versus 0 % ( 0/65 ; 95 % confidence interval , 0.0 - 4.5 % ) among those with higher CD4 lymphocyte counts ( p < 0.01 ) . One hundred thirty-seven ( 81 % ) patients received antiretroviral therapy during TB treatment . Adverse events were common , but only two patients ( 1 % ) permanently discontinued study drugs . CONCLUSIONS Intermittent rifabutin-based therapy for HIV-related TB was well tolerated , but there was a high risk of treatment failure or relapse with acquired rifamycin resistance among patients with low CD4 lymphocyte counts The fluctuation test shows that Mycobacterium tuberculosis mutates to resistance to isoniazid , streptomycin , ethambutol and rifampin spontaneously and at r and om . The average mutation rates for the drugs , in the same order , were calculated to be 2.56 x 10(-8 ) , 2.95 x 10(-8 ) , 10(-7 ) , and 2.25 x 10(-10 ) mutation per bacterium per generation . The relatively high mutation rate to ethambutol resistance and the low mutation rate to rifampin resistance were confirmed by analyzing the increase in the proportion of mutants with time in a growing population of the tubercle bacilli . The highest proportions of mutants to be expected in unselected population s of the tubercle bacilli were calculated from the results of fluctuation tests Patients with silicotuberculosis have been reported to respond poorly to antituberculosis chemotherapy . Therefore , in a study in Hong Kong , 240 Chinese male patients with both silicosis and pulmonary tuberculosis were all prescribed treatment three times weekly with streptomycin , isoniazid , rifampin , and pyrazinamide , allocated at r and om to be given for a total duration of either 6 ( M6 regimen ) or 8 months ( M8 regimen ) in a concurrent comparison . Those with a history of previous antituberculosis chemotherapy received ethambutol as well for the first 3 months . The intake in the M6 regimen was terminated when preliminary results showed that it was inadequate , and a further 53 patients were assigned to the M8 series . Of 91 assessable patients in the concurrent comparison with susceptible strains pretreatment , 44 % were culture negative at 1 month , 80 % at 2 months , and 98 % at 3 months , and 1 had an unfavorable bacteriologic response during chemotherapy . During 3 yr of assessment , bacteriologic relapse after chemotherapy occurred in 22 % of the M6 compared with 7 % of the M8 patients ( p less than 0.025 , log-rank test ) . Inadequate chemotherapy was received by 12 % of the 240 patients in the concurrent comparison because of default and by 22 % because of adverse effects , but by 3 yr 92 % of patients with susceptible strains pretreatment in each series had a favorable status following retreatment for relapse or for initially inadequate chemotherapy when required . The results show that patients with silicosis require at least 8 months of treatment CONTEXT Fixed-dose combinations ( FDCs ) of drugs for treatment of tuberculosis have been advocated to prevent the emergence of drug resistance . OBJECTIVE To assess the efficacy and safety of a 4-drug FDC for the treatment of tuberculosis . DESIGN , SETTING , AND PATIENTS The Study C trial , a parallel-group , open-label , noninferiority , r and omized controlled trial conducted in 11 sites in Africa , Asia , and Latin America between 2003 and 2008 . Patients were 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis . INTERVENTIONS Patients were r and omized to receive daily treatment with 4 drugs ( rifampicin , isoniazid , pyrazinamide , ethambutol ) given as an FDC ( n = 798 patients ) or separately ( n = 787 ) in the 8-week intensive phase of treatment . MAIN OUTCOME MEASURE Favorable treatment outcome , defined as negative culture result at 18 months post r and omization and not having already been classified as unfavorable . Noninferiority was dependent on consistent results from a per- protocol and modified intention-to-treat analysis , using 2 different models for the latter , classifying all changes of treatment or refusal to continue treatment ( eg , bacteriological failure/relapse , adverse event , default , drug resistance ) as unfavorable ( model 1 ) and classifying changes of treatment for reasons other than therapeutic outcomes according to their 18-month bacteriological outcome if available ( post hoc model 2 ) . The prespecified noninferiority margin was 4 % . RESULTS In the per- protocol analysis , 555 of 591 patients ( 93.9 % ) had a favorable outcome in the FDC group vs 548 of 579 ( 94.6 % ) in the separate-drugs group ( risk difference , -0.7 % [ 90 % confidence interval { CI } , -3.0 % to 1.5 % ] ) . In the model 1 analysis , 570 of 684 patients ( 83.3 % ) had a favorable outcome in the FDC group vs 563 of 664 ( 84.8 % ) in the separate-drugs group ( risk difference , -1.5 % [ 90 % CI , -4.7 % to 1.8 % ] ) . In the post hoc model 2 analysis , 591 of 658 patients ( 89.8 % ) in the FDC group and 589 of 647 ( 91.0 % ) in the separate-drugs group had a favorable outcome ( risk difference , -1.2 % [ 90 % CI , -3.9 % to 1.5 % ] ) . Adverse events related to trial drugs were similarly distributed among treatment groups . CONCLUSIONS Compared with a regimen of separately administered drugs , a 4-drug FDC regimen for treatment of tuberculosis satisfied prespecified noninferiority criteria in 2 of 3 analyses . Although the results do not demonstrate full noninferiority of the FDCs compared with single drugs given separately using the strict definition applied in this trial , use of FDCs is preferred because of potential advantages associated with the administration of FDCs compared with separate-drug formulations . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00216333

Results of this review show empirical evidence to support the efficacy of physical activity for the population with Parkinson 's disease . Aerobic training exercise significantly improved the participants ' scores on the Unified Parkinson 's Disease Rating Scale , the Beck Depression Inventory , and the Quality of Life of the patients . Qigong improved scores in UPDRS-III and decreased incidences of multiple non-motor symptoms and depression . Furthermore , a balance-training program , such as Tai Chi , can improve postural stability and Quality of Life . CONCLUSIONS Physical activity may assuage the degeneration of motor skills and depression as well as increase the Quality of Life of Parkinson 's disease patients , with aerobic training producing the best results . These findings suggest that physical activity , notably aerobic training , could be a good exercise strategy for patients with Parkinson 's disease

AIM In this paper we aim ed to systematic ally review the literature on physical activity 's effect on depressive symptoms in Parkinson disease . BACKGROUND Depression is a common symptom of Parkinson 's disease and is associated with increased disability , rapid progression of motor symptoms , mortality , and adverse effects on Quality of Life .

Purpose : To establish the effect of a 6-week programme of cycle ergometry training on exercise tolerance , balance , activities of daily living ( ADL ) and quality of life in individuals with Parkinson ’s disease ( PD ) . Method : Twenty-three subjects were recruited from the Parkinson ’s data base of the neurology service in a large urban teaching hospital . Quasi-experimental study of interrupted time-series design was conducted with subjects acting as their own control . Assessment s were carried out at baseline , week 7 following the control phase , and week 14 following the intervention phase . Intervention consisted of 30-min cycle ergometry training once weekly . Outcome measures included Six Minute Walk Test , Physiological Cost Index , Berg Balance Scale , Timed Up and Go Test ( TUAG ) , ADL and mobility sections of the Unified Parkinson ’s disease Rating Scale ( UPDRS ) and the Parkinson ’s disease question naire ( PDQ ) . Results : Statistically significant improvements were noted for the Berg Balance Scale ( p = 0.003 ) , TUAG ( p = 0.019 ) and ADL ( p = 0.006 ) and mobility ( p = 0.021 ) sections of the UPDRS . A trend towards improvement was found for exercise tolerance . No significant effect on quality of life was found . Conclusion : A 6-week programme of cycle ergometry training did not significantly influence exercise tolerance in this sample , but improved balance , functional abililty and PD-related disability were noted . Implication s for Rehabilitation Individuals with Parkinson ’s disease demonstrate lower levels of exercise tolerance than healthy controls . Individuals with Parkinson ’s disease could participate in 30 min of cycle ergometry training , with no rest periods required . Cycle ergometry training has a positive effect on balance , function and PD-related disability Background People with idiopathic Parkinson ’s disease ( PD ) frequently have low activity levels , poor mobility and reduced quality of life . Although increased physical activity may improve mobility , balance and wellbeing , adherence to exercises and activity programs over the longer term can be challenging , particularly for older people with progressive neurological conditions such as PD . Physical activities that are engaging and enjoyable , such as dancing , might enhance adherence over the long term . The objective of this study was to evaluate the feasibility of a r and omized controlled trial of Irish set dancing compared with routine physiotherapy for people with mild to moderately severe PD . Methods Twenty-four people with idiopathic PD referred for movement rehabilitation were r and omized to receive st and ard physiotherapy exercises or Irish set dancing classes once per week plus a weekly home program for 6 months ( 12 in each group ) . The feasibility and safety of the proposed RCT protocol was the main focus of this evaluation . The primary outcome was motor disability measured by the motor component of the UPDRS , which was assessed prior to and after therapy by trained assessors blinded to group assignment . The Timed Up and Go , the Berg Balance Scale and the modified Freezing of Gait Question naire were secondary measures . Quality of life of the people with PD was evaluated using the PDQ-39 . Results Both the Irish set dancing and physiotherapy exercise program were shown to be feasible and safe . There were no differences between groups in the rate of adverse events such as falls , serious injuries , death or rates of admission to hospital . The physiotherapists who provided usual care remained blind to group allocation , with no change in their st and ard clinical practice . Compliance and adherence to both the exercise and dance programs were very high and attrition rates were low over the 6 months of therapy . Although improvements were made in both groups , the dance group showed superior results to st and ard physiotherapy in relation to freezing of gait , balance and motor disability . Conclusions Irish dancing and physiotherapy were both safe and feasible in this sample from Venice , with good adherence over a comparatively long time period of 6 months . A larger multi-centre trial is now warranted to establish whether Irish set dancing is more effective than routine physiotherapy for enhancing mobility , balance and quality of life in people living with idiopathic PD.Trial registration EudraCT number 2012 - 005769 - AIM To investigate the effects of an aerobic training in subjects with Parkinson 's disease ( PD ) as compared to a medical Chinese exercise ( Qigong ) . METHODS DESIGN r and omized controlled trial with a cross over design . SETTING PD out- patients referred to a Neurorehabilitation facility for the management of motor disability . SUBJECTS 26 PD patients in Hoehn and Yahr stage II to III under stable medication were r and omly allocated to either Group AT1+QG2 ( receiving 20 aerobic training sessions followed by 20 ' ' Qigong ' ' group sessions with 2 month interval between the interventions ) , or Group QG1+AT2 ( performing the same treatments with an inverted sequence ) . MAIN OUTCOME MEASURES clinical effects of treatment were sought through the Unified Parkinson 's Disease Rating Scale ( UPDRS ) , Brown 's Disability Scale ( B'DS ) , six-Minute Walking Test ( 6MWT ) , Borg scale for breathlessness , Beck Depression Inventory ( BDI ) and Parkinson 's Disease Question naire-39 items ( PDQ-39 ) . A spirometry test and maximum cardiopulmonary exercise test ( CPET ) were also performed to determine the pulmonary function , the metabolic and cardio-respiratory requests at rest and under exercise . All measures were taken immediately before and at the completion of each treatment phase . RESULTS The statistical analysis focusing on the evolution of motor disability and quality of life revealed a significant interaction effect between group and time for the 6MWT ( time x group effect : F : 5.4 P=0.002 ) and the Borg scale ( time x group effect : F : 4.2 P=0.009 ) . Post hoc analysis showed a significant increase in 6MWT and a larger decrease in Borg score after aerobic training within each subgroup , whereas no significant changes were observed during Qigong . No significant changes over time were detected through the analysis of UPDRS , B'DS , BDI and PDQ-39 scores . The analysis of cardiorespiratory parameters showed significant interaction effects between group and time for the Double Productpeak ( time x group effect : F : 7.7 P=0.0003 ) , the VO(2peak ) ( time x group effect : F : 4.8 P=0.007 ) , and the VO(2)/kg ratio ( time x group effect : F : 4.3 P=0.009 ) , owing to their decrease after aerobic training to an extent that was never observed after Qigong treatment . CONCLUSIONS Aerobic training exerts a significant impact on the ability of moderately disabled PD patients to cope with exercise , although it does not improve their self-sufficiency and quality of life BACKGROUND Depression is a major health problem for community-dwelling elderly adults . Since limited re sources are available to decrease the high prevalence of depressive symptoms among the elderly adults , improved support for them can be provided if we can determine which intervention is superior in ridding depressive symptoms . OBJECTIVE To compare the effectiveness of the physical fitness exercise program and the cognitive behavior therapy program on primary ( depressive symptoms ) and secondary outcomes ( 6-min walk distance , quality of life , and social support ) for community-dwelling elderly adults with depressive symptoms . DESIGN AND SETTING S A prospect i ve r and omized control trial was conducted in three communities in northern Taiwan . PARTICIPANTS The elderly adults in the three communities were invited to participate by mail , phone calls , and posters . There were a total of 57 participants who had depressive symptoms and all without impaired cognition that participated in this trial . None of the participants withdrew during the 9 months of follow-up for this study . METHODS Fifty-seven participants were r and omly assigned to one of the three groups : the physical fitness exercise program group , the cognitive behavior therapy ( CBT ) group , or the control group . The primary ( Geriatric Depression Scale-15 , GDS-15 ) , and secondary outcomes ( 6-min walk distance , SF-36 , and Inventory of Socially Supportive Behaviors scales , ISSB ) were collected immediately ( T2 ) , at 3 months ( T3 ) , and at 6 months after the interventions ( T4 ) . RESULTS After the interventions , the CBT group participants demonstrated significantly lower symptoms of depression ( p=0.009 ) at T2 and perceived more social support from those around them ( p<0.001 , < 0.001 and = 0.004 , respectively ) at three time-point comparisons than the control group . Moreover , after intervention , participants in the physical fitness exercise program group had decreased GDS-15 scores at three time-point comparisons ( p=0.003 , 0.012 and 0.037 , respectively ) , had a substantially greater 6-min walk distance ( p=0.023 ) , a better quality of life ( p<0.001 ) , and a better perceived social support at T2 ( p<0.001 ) . CONCLUSIONS Immediately after a 12-week intervention , there were significant decreases in depressive symptoms and more perceived social support amongst those in the CBT group . When considering the effectiveness in the decrease of depressive symptoms longer term , the increase in the 6-min walk distance and raising the patients ' quality of life , physical fitness exercise program may be a better intervention for elderly adults with depressive symptoms Background . Novel rehabilitation strategies have demonstrated potential benefits for motor and non-motor symptoms of Parkinson 's disease ( PD ) . Objective . To compare the effects of Lee Silverman Voice Therapy BIG ( LSVT BIG therapy ) versus a general exercise program ( combined treadmill plus seated trunk and limb exercises ) on motor and non-motor symptoms of PD . Methods . Eleven patients with early-mid stage PD participated in the prospect i ve , double-blinded , r and omized clinical trial . Both groups received 16 one-hour supervised training sessions over 4 weeks . Outcome measures included the Unified Parkinson 's Disease Rating Scale ( UPDRS ) , Beck Depression Inventory ( BDI ) , Beck Anxiety Inventory ( BAI ) and Modified Fatigue Impact Scale ( MFIS ) . Five patients performed general exercise and six patients performed LSVT BIG therapy . Post-intervention evaluations were conducted at weeks 4 , 12 and 24 . Results . The combined cohort made improvements at all follow-up evaluations with statistical significance for UPDRS total and motor , BDI , and MFIS ( P < 0.05 ) . Conclusion . This study demonstrated positive effects of general exercise and LSVT BIG therapy on motor and non-motor symptoms of patients with PD . Our results suggest that general exercise may be as effective as LSVT BIG therapy on symptoms of PD for patients not able to readily access outpatient LSVT BIG therapy Introduction The health benefits of exercise are well established . However , the relationship between exercise volume and intensity and health benefits remains unclear , particularly the benefits of low-volume and intensity exercise . Purpose The primary purpose of this investigation was , therefore , to examine the dose – response relationship between exercise volume and intensity with derived health benefits including volumes and intensity of activity well below international recommendations . Methods Generally healthy , active participants ( n = 72 ; age = 44 ± 13 years ) were assigned r and omly to control ( n = 10 ) or one of five 13-week exercise programs : ( 1 ) 10-min brisk walking 1 × /week ( n = 10 ) , ( 2 ) 10-min brisk walking 3 × /week ( n = 10 ) , ( 3 ) 30-min brisk walking 3 × /week ( n = 18 ) , ( 4 ) 60-min brisk walking 3 × /week ( n = 10 ) , and ( 5 ) 30-min running 3 × /week ( n = 14 ) , in addition to their regular physical activity . Health measures evaluated pre- and post-training including blood pressure , body composition , fasting lipids and glucose , and maximal aerobic power ( VO2max ) . Results Health improvements were observed among programs at least 30 min in duration , including body composition and VO2max : 30-min walking 28.8–34.5 mL kg−1 min−1 , 60-min walking 25.1–28.9 mL kg−1 min−1 , and 30-min running 32.4–36.4 mL kg−1 min−1 . The greater intensity running program also demonstrated improvements in triglycerides . Conclusion In healthy active individuals , a physical activity program of at least 30 min in duration for three sessions/per week is associated with consistent improvements in health status Background . Postural instability ( PI ) is a disabling sign of Parkinson ’s disease ( PD ) not easily amenable to treatment with medication . Objective . To evaluate the effects of balance training on PI in patients with PD . Methods . A total of 64 patients with PI were r and omly assigned to the experimental group ( n = 33 ) for balance training or to the control group ( n = 31 ) for general physical exercises . Each patient received 21 treatment sessions of 50 minutes each . Patients were evaluated by a blinded rater before and after treatment as well as 1 month posttreatment using the Berg Balance Scale ( BBS ) , Activities-Specific Balance Confidence Scale ( ABC ) , postural transfer test , self-destabilization of the center of foot pressure test , number of falls , Unified Parkinson ’s Disease Rating Scale ( UPDRS ) , modified Hoehn and Yahr ( H&Y ) Staging Scale , and Geriatric Depression Scale ( GDS ) . Results .At the end of treatment , the experimental group showed significant improvements in all outcome measures , except for the UPDRS and the H&Y scale . Improvement was maintained at the 1-month follow-up in all outcome measures except for the GDS . No significant changes in performance were observed in the control group . Conclusions . A program of balance training can improve PI in patients with PD Objective : To investigate the incidence of parkinsonism and Parkinson disease ( PD ) in the general population using in-person screening along with clinical data . Methods : In the Rotterdam study , a prospect i ve population -based cohort study of people aged ≥55 years , the authors assessed age- and sex-specific incidence rates of parkinsonism and PD among 6,839 participants who were free of parkinsonism at baseline . Case finding involved in-person screening at baseline and two follow-up visits , and additional information was obtained through continuous monitoring of the cohort by computer linkage to general practitioners ’ and pharmacy records . Results : After a mean follow-up period of 5.8 years , 132 subjects with incident parkinsonism were identified , of whom 67 ( 51 % ) had PD . The incidence of parkinsonism and PD increased with age , with incidence rates for PD increasing from 0.3 per 1000 person-years in subjects aged 55 to 65 years , to 4.4 per 1000 person-years for those aged ≥85 years . The overall age-adjusted incidence rate of any parkinsonism was not different in men and women , but men seem to have a higher risk for PD ( male-to-female ratio , 1.54 ; 95 % CI , 0.95 to 2.51 ) . Conclusion : Incidence rates for parkinsonism and Parkinson disease were higher than those reported by most previous studies , possibly because of the authors ’ intensive case-finding methods involving in-person screening Irrespective of limited evidence , not only traditional physiotherapy , but also a wide array of complementary methods are applied by patients with Parkinson 's disease ( PD ) . We evaluated the immediate and sustained effects of Qigong on motor and nonmotor symptoms of PD , using an add-on design . Fifty-six patients with different levels of disease severity ( mean age/st and ard deviation [ SD ] , 63.8/7.5 years ; disease duration 5.8/4.2 years ; 43 men [ 76 % ] ) were recruited from the outpatient movement disorder clinic of the Department of Neurology , University of Bonn . We compared the progression of motor symptoms assessed by Unified Parkinson 's Disease Rating Scale motor part ( UPDRS-III ) in the Qigong treatment group ( n = 32 ) and a control group receiving no additional intervention ( n = 24 ) . Qigong exercises were applied as 90-minute weekly group instructions for 2 months , followed by a 2 months pause and a second 2-month treatment period . Assessment s were carried out at baseline , 3 , 6 , and 12 months . More patients improved in the Qigong group than in the control group at 3 and 6 months ( P = 0.0080 at 3 months and P = 0.0503 at 6 months ; Fisher 's exact test ) . At 12 months , there was a sustained difference between groups only when changes in UPDRS-III were related to baseline . Depression scores decreased in both groups , whereas the incidence of several nonmotor symptoms decreased in the treatment group only Background Depression is common in people with Parkinson ’s disease ( PD ) , and exercise is known to improve depression and PD . However , lack of motivation and low self-efficacy can make exercise difficult for people with PD and comorbid depression ( PD-Dep ) . A combined group exercise and chronic disease self-management ( CDSM ) program may improve the likeli-hood that individuals will engage in exercise and will show a reduction in depression symptoms . The purpose of this study was to compare changes in depression in PD-Dep between individual versus group exercise plus CDSM and to examine participant adherence and perception of the interventions . Methods Participants ( N=30 ) were r and omized to either Enhanced EXerCisE thErapy for PD ( EXCEED ; group CDSM and exercise ) or self-guided CDSM plus exercise . Outcomes were change in depression assessed with the Montgomery – Asberg Depression Rating Scale ( MADRS ) , cognition , apathy , anxiety , sleep , quality of life , motor function , self-efficacy , and patient satisfaction . Results Both groups showed significant improvement in MADRS ( P<0.001 ) with no significant group difference . Individuals in EXCEED group enjoyed the group dynamics but noted difficulty with the fixed-time sessions . Conclusion Both group CDSM plus exercise and self-guided CDSM plus exercise can improve depression in PD-Dep . These findings suggest that development of a remotely delivered group-based CDSM format plus manualized exercise program could be useful for this population OBJECTIVES Parkinson 's disease ( PD ) results in a range of non-motor deficits that can affect mood , cognition , and language , and many of these issues are unresponsive to pharmacological intervention . Aerobic exercise can improve mood and cognition in healthy older adults , although only a few studies have examined exercise effects on these domains in PD . The current study assesses the effects of aerobic exercise on aspects of cognition , mood , and language production in people with PD . METHODS This study compares the effects of aerobic exercise to stretch-balance training and a no-contact control group in participants with idiopathic PD . The aerobic and stretch-balance groups trained three times a week for 16 weeks , while controls continued normal activities . Outcome measures included disease severity , mood , cognition ( speed of processing , memory , and executive function ) , and language production ( picture descriptions ) . Cognition and language were assessed in single and dual task conditions . RESULTS Depressive symptoms increased only in the control group ( p<.02 ) . Executive function improved in the aerobic exercise group only in the single task ( p=.007 ) and declined in controls in the dual task . Completeness of picture descriptions improved significantly more in the aerobic group than in the stretch-balance group ( p<.02 ) . CONCLUSIONS Aerobic exercise is a viable intervention for PD that can be protective against increased depressive symptoms , and can improve several non-motor domains , including executive dysfunction and related aspects of language production . ( JINS , 2016 , 22 , 878 - 889 ) Research has revealed that exercise is effective for reducing symptoms of depression and anxiety . The mechanisms by which these reductions occur , however , have not been widely studied . To examine several potential theories , a prospect i ve , r and omized , 7-week exercise intervention was conducted . Untrained participants were r and omly assigned to an aerobic exercise group or to a stretching-control group . Participants completed several question naires to assess psychological variables , including measures of depression and anxiety , and blood was drawn at pre- and post-test to measure serum serotonin levels . A mixed- design ANOVA revealed that the exercise group had lower levels of depression than the stretching-control group after the intervention . The exercise group also showed a larger percentage decrease in serotonin than the stretching-control group . This reduction in blood serotonin after exercise is similar to the effects of selective serotonin reuptake inhibitors . Additionally , percent change in serotonin was found to partially mediate the relationship between exercise and depression The benefits of physical exercise on cognitive functioning have been reported in the literature , but the potential benefits to slow the eventual decline in executive functioning ( EF ) caused by neurodegeneration from Parkinson 's Disease ( PD ) have rarely been studied . Thus the objective of this study was to analyze the effects of a multimodal physical exercise program on EF in older people with Parkinson 's disease . The EF of the older people was evaluated by neuropsychological testing , and for confounding variables such as attention , depressive symptoms and anxiety , before and after intervention . The 20 participants were assigned into Control ( CG ) and Trained ( TG ) Groups . The TG participated in generalized physical training for 6 months . The ANOVA showed a significant interaction ( p<.05 ) that indicated a beneficial contribution of training on EF . No significant interactions were found in the results for confounding variables between groups and pre- and post-intervention , which supports the beneficial findings of physical exercise training on EF

More limited evidence suggests that these improvements can be maintained over the 12 months after the end of treatments and that there are few harms with behavioral interventions . Potential adverse effects were greater than for behavioral interventions alone and varied in severity . Despite important gaps , available research supports at least short-term benefits of comprehensive medium- to high-intensity behavioral interventions in obese children and adolescents

CONTEXT : Targeted systematic review to support the up date d US Preventive Services Task Force ( USPSTF ) recommendation on screening for obesity in children and adolescents . OBJECTIVES : To examine the benefits and harms of behavioral and pharmacologic weight-management interventions for overweight and obese children and adolescents . CONCLUSIONS : Over the past several years , research into weight management in obese children and adolescents has improved in quality and quantity .

OBJECTIVE To assess height growth over 10 years in children treated for obesity . DESIGN Longitudinal , prospect i ve follow-up of a series of r and omized , controlled weight control trials . SETTING Specialized pediatric weight control clinic . PARTICIPANTS One hundred fifty-eight 6- to 12-year-old obese children who were followed up for 10 years after treatment . INTERVENTIONS Family-based behavioral weight control . MEASUREMENTS /MAIN RESULTS At entry the height percentiles of the obese children were significantly higher ( 71.6 percentile ) than same-sex parent ( 52.0 percentile ) or midparent ( 51.5 percentile ) height ( an estimate of parental contribution to height ) . After an average growth of 22.7 cm , children were 2.2 cm taller than their same-sex parent and decreased to an average height percentile of 57.8 . Multiple regression analysis showed that child sex , age , baseline height and percent overweight , midparent height , and height change of the child from baseline to 5 years accounted for 94 % of the variance in growth . Child percent overweight change made no contribution to predicting height change . Comparison between children obese and nonobese at 10 years showed no differences in growth . CONCLUSIONS Moderate energy restriction with dietary guidance by overweight children did not negatively influence long-term growth CONTEXT The prevalence of overweight and obesity in children and adolescents is increasing rapidly . In this population , behavioral therapy alone has had limited success in providing meaningful , sustained weight reduction , and pharmacological treatment has not been extensively studied . OBJECTIVE To determine the efficacy and safety of orlistat in weight management of adolescents . DESIGN , SETTING , AND PATIENTS Multicenter , 54-week ( August 2000-October 2002 ) , r and omized , double-blind study of 539 obese adolescents ( aged 12 - 16 years ; body mass index [ BMI ] > or=2 units above the 95th percentile ) at 32 centers in the United States and Canada . INTERVENTIONS A 120-mg dose of orlistat ( n = 357 ) or placebo ( n = 182 ) 3 times daily for 1 year , plus a mildly hypocaloric diet ( 30 % fat calories ) , exercise , and behavioral therapy . MAIN OUTCOME MEASURES Change in BMI ; secondary measures included changes in waist and hip circumference , weight loss , lipid measurements , and glucose and insulin responses to oral glucose challenge . RESULTS There was a decrease in BMI in both treatment groups up to week 12 , thereafter stabilizing with orlistat but increasing beyond baseline with placebo . At the end of the study , BMI had decreased by 0.55 with orlistat but increased by 0.31 with placebo ( P = .001 ) . Compared with 15.7 % of the placebo group , 26.5 % of participants taking orlistat had a 5 % or higher decrease in BMI ( P = .005 ) ; 4.5 % and 13.3 % , respectively , had a 10 % or higher decrease in BMI ( P = .002 ) . At study end , weight had increased 0.53 kg with orlistat and 3.14 kg with placebo ( P<.001 ) . Dual-energy x-ray absorptiometry showed that this difference was explained by changes in fat mass . Waist circumference decreased in the orlistat group but increased in the placebo group ( -1.33 cm vs + 0.12 cm ; P<.05 ) . Generally mild to moderate gastrointestinal tract adverse events occurred in 9 % to 50 % of the orlistat group and in 1 % to 13 % of the placebo group . CONCLUSIONS In combination with diet , exercise , and behavioral modification , orlistat statistically significantly improved weight management in obese adolescents compared with placebo . The use of orlistat for 1 year in this adolescent population did not raise major safety issues although gastrointestinal adverse events were more common in the orlistat group BACKGROUND The prevalence of overweight and obesity in children and adolescents is increasing in both the United States and Mexico . OBJECTIVE The goal of this article was to assess the efficacy and safety of sibutramine in obese Mexican adolescents . METHODS This was a 6-month , r and omized , double-blind , placebo-controlled , prospect i ve clinical trial of sibutramine QD . Male and female patients aged 14 to 18 years with sex-specific body mass index ( BMI ) for age and sex > 85th percentile were eligible . The primary end points for the trial were the baseline versus end point absolute values for body weight , BMI , and percentage of the initial BMI ( % BMI ) ; secondary end points were waist circumference and percentage of the initial waist circumference ( % waist ) . These were measured at days -15 , 0 , 30 , 60 , 90 , 120 , 150 , and 180 of the study . Quality of life was assessed at the study start and end using the 36-Item Short-Form Health Survey ( SF-36 ) question naire . Blood pressure and heart rate were assessed , and adverse events ( AEs ) were recorded . Both groups received individually tailored diet and exercise programs . RESULTS Forty-six patients ( age range , 14 - 18 years ) with a BMI > 95th percentile for age were included ( sibutramine group , n = 23 [ 14 females , 9 males ] ; placebo group , n = 23 [ 12 females , 11 males ] ) . Twenty-one patients in the sibutramine group and 19 patients in the placebo group completed the 6-month trial . Using the intent-to-treat data , weight ( mean [ SD ] ) in the sibutramine group changed from 92.5 ( 14.6 ) kg to 85.7 ( 14.4 ) kg , for a net weight loss of 7.3 kg ( 95 % CI 4.6 - 9.9 ) , a waist circumference loss of 8.0 cm ( 95 % CI , 4.7 - 11.3 ) , and a % BMI loss of 9.2 % ( 95 % CI , 6.9 - 11.6 ) . In the placebo group , weight changed from 98.9 ( 22.7 ) kg to 94.6 ( 22.5 ) kg , a weight loss of 4.3 kg ( 95 % CI , 1.7 - 6.9 ) , a waist circumference loss of 3.8 cm ( 95 % CI , 0.7 - 7.0 ) , and a % BMI loss of 5.2 % ( 95 % CI , 2.4 - 7.9 ) ( P < 0.05 for all intragroup comparisons ; P > 0.05 for the intergroup comparisons ) . Mean ( SD ) scores on the SF-36 scale in the sibutramine group changed from 78.0 ( 13.3 ) at baseline to 84.8 ( 7.4 ) at study end ( P < 0.05 ) ; the respective values in the placebo group were 82.8 ( 10.3 ) and 87.3 ( 7.6 ) ( P < 0.05 ) . At base-line , systolic blood pressure ( SBP ) was 116.7 ( 5.9 ) mm Hg in the sibutramine group and 118.3 ( 7.6 ) mm Hg in the placebo group ; at end point , the respective SBPs were 112.4 ( 9.6 ) mm Hg and 112.6 ( 6.5 ) mm Hg . At baseline , diastolic blood pressure ( DBP ) was 78.9 ( 4.5 ) mm Hg in the sibutramine group and 79.5 ( 5.2 ) mm Hg in the placebo group ; at end point , the respective DBPs were 73.5 ( 6.3 ) mm Hg and 76.6 ( 6.2 ) mm Hg . At baseline , heart rate was 76.3 ( 6.4 ) beats/min in the sibutramine group and 81.1 ( 9.5 ) beats/min in the placebo group ; at end point , the respective findings were 79.8 ( 8.8 ) beats/min and 77.6 ( 8.6 ) beats/min ( P > 0.05 for all preceding intergroup comparisons ) . One patient in the sibutramine group had increased blood pressure ( at month 3 ) and 3 had increased heart rate ( at months 1 , 2 , and 4 ) ; 2 patients receiving placebo had increased blood pressure ( month 3 ) and 2 had increased heart rate ( at months 1 and 3 ) . These changes disappeared in 1 week and did not require treatment or trial suspension . Additionally , in the sibutramine group , 3 patients experienced 4 mild AEs : headache , dry mouth , headache with nausea , and headache with weakness and paleness ( P > 0.05 ) . In the placebo group , 3 patients experienced 4 mild AEs : 2 cases of headache , as well as 1 case of headache with somnolence and 1 case of headache with dry mouth ( P > 0.05 ) . CONCLUSION Sibutramine 10 mg QD in addition to diet and exercise was effective and generally well tolerated in this population of obese Mexican adolescents OBJECTIVE To determine whether regular aerobic exercise improves symptoms of sleep-disordered breathing in overweight children , as has been shown in adults . RESEARCH METHODS AND PROCEDURES Healthy but overweight ( BMI > or = 85th percentile ) 7- to 11-year-old children were recruited from public schools for a r and omized controlled trial of exercise effects on diabetes risk . One hundred children ( 53 % black , 41 % male ) were r and omly assigned to a control group ( n = 27 ) , a low-dose exercise group ( n = 36 ) , or a high-dose exercise group ( n = 37 ) . Exercise groups underwent a 13 + /- 1.5 week after-school program that provided 20 or 40 minutes per day of aerobic exercise ( average heart rate = 164 beats per minute ) . Group changes were compared on BMI z-score and four Pediatric Sleep Question naire scales : Snoring , Sleepiness , Behavior , and a summary scale , Sleep-Related Breathing Disorders . Analyses were adjusted for age . RESULTS Both the high-dose and low-dose exercise groups improved more than the control group on the Snoring scale . The high-dose exercise group improved more than the low-dose exercise and control groups on the summary scale . No group differences were found for changes on Sleepiness , Behavior , or BMI z-score . At baseline , 25 % screened positive for sleep-disordered breathing ; half improved to a negative screen after intervention . DISCUSSION Regular vigorous exercise can improve snoring , a symptom of sleep-disordered breathing , in overweight children . Aerobic exercise programs may be valuable for prevention and treatment of sleep-disordered breathing in overweight children Aims : To evaluate effects of a low energy diet , with or without strength training , on blood lipid profile in obese children . Methods : Eighty two obese children were enrolled into a six week dietary programme , and were r and omly allocated to a training group or a non-training group . The training group underwent regular exercise sessions with emphasis on strength training . Results : Height increased significantly , with a non-significant reduction in body mass index . Fat free mass increased significantly in the training group . Serum total cholesterol was significantly reduced in both groups . The LDL : HDL ratio significantly decreased in the training group . Conclusion : Results support the potentially beneficial effects of both diet and physical training . Further and longer term evaluation of such programmes is required OBJECTIVE To evaluate the efficacy of orlistat to enhance weight loss in obese adolescents . METHODS The study was a 6-month r and omized , double-blind , placebo-controlled trial to compare the effects of orlistat ( 120 mg orally 3 times a day ) and placebo on reduction of body mass index ( BMI ) . Forty adolescents between 14 and 18 years of age with a mean BMI of 40 kg/m2 entered the protocol between December 2002 and February 2003 . Study subjects stayed overnight in the General Clinical Research Center , during which dietary records were review ed and lifestyle recommendations were given . The study participants received either orlistat ( 120 mg orally 3 times a day ) or placebo and were assessed monthly for 6 months . At 0 , 3 , and 6 months , fasting laboratory tests were performed . The primary end point was the change in BMI from baseline to 6 months . Secondary outcomes included changes in weight , lean body mass , and results of blood chemistry studies . RESULTS No statistically significant difference was noted between the 2 study groups for decrease in BMI from baseline to 6 months ( P = 0.39 ) . The decrease in BMI within the orlistat group ( -1.3 + /- 1.6 kg/m2 ; P = 0.04 ) and within the placebo group ( -0.8 + /- 3.0 kg/m2 ; P = 0.02 ) , however , was statistically significant . Laboratory measurements did not differ between the 2 groups . In comparison with the placebo group , the orlistat group had increased adverse events , primarily gastrointestinal symptoms and findings . CONCLUSION In this study of obese adolescents , orlistat did not significantly reduce BMI in comparison with placebo at 6 months Background . Obesity has become the most common pediatric chronic disease in the modern era . Early prevention and treatment of childhood and adolescent obesity is m and ated . Surprisingly , however , only a minor fraction of obese children participate in weight reduction interventions , and the longer-term effects of these weight-reduction interventions among children have not been eluci date d. Objective . To examine prospect ively the short- and long-term effects of a 3-month , combined dietary-behavioral-physical activity intervention on anthropometric measures , body composition , dietary and leisure-time habits , fitness , and lipid profiles among obese children . Methods . In this r and omized prospect i ve study , 24 obese subjects completed the 3-month intervention and were compared with 22 obese , age- and gender-matched , control subjects . Results . At 3 months , there were significant differences in changes in body weight ( −2.8 ± 2.3 kg vs 1.2 ± 2.2 kg ) , BMI ( −1.7 ± 1.1 kg/m2 vs −0.2 ± 1.0 kg/m2 ) , body fat percentage ( from skinfold tests ; −3.3 ± 2.6 % vs 1.4 ± 4.7 % ) , serum total cholesterol level ( −24.6 ± 15.1 mg/dL vs 0.8 ± 18.7 mg/dL ) , low-density lipoprotein cholesterol level ( −23.3 ± 15.2 mg/dL vs −3.7 ± 17.3 mg/dL ) , and fitness ( 215 ± 107 seconds vs 50 ± 116 seconds ) in the intervention group versus the control group . After a 1-year follow-up period , there were significant differences between the intervention group ( n = 20 ) and the control group ( n = 20 ) in body weight ( 0.6 ± 6.0 kg vs 5.3 ± 2.7 kg ) , BMI ( −1.7 ± 2.3 kg/m2 vs 0.6 ± 0.9 kg/m2 ) , and body fat percentage . There was a significant increase in leisure-time physical activity among the intervention participants , compared with a decrease among the control subjects . Conclusions . Our data demonstrate the short- and longer-term beneficial effects of a combined dietary-behavioral-physical activity intervention among obese children . These results highlight the importance of multidisciplinary programs for the treatment of childhood obesity and emphasize their encouraging long-term effects Objectives : To reduce gain in body mass index ( BMI ) in overweight/mildly obese children in the primary care setting . Design : R and omized controlled trial ( RCT ) nested within a baseline cross-sectional BMI survey . Setting : Twenty nine general practice s , Melbourne , Australia . Participants : ( 1 ) BMI survey : 2112 children visiting their general practitioner ( GP ) April – December 2002 ; ( 2 ) RCT : individually r and omized overweight/mildly obese ( BMI z-score < 3.0 ) children aged 5 years 0 months–9 years 11 months ( 82 intervention , 81 control).Intervention : Four st and ard GP consultations over 12 weeks , targeting change in nutrition , physical activity and sedentary behaviour , supported by purpose - design ed family material s . Main outcome measures : Primary : BMI at 9 and 15 months post-r and omization . Secondary : Parent-reported child nutrition , physical activity and health status ; child-reported health status , body satisfaction and appearance/self-worth . Results : Attrition was 10 % . The adjusted mean difference ( intervention – control ) in BMI was −0.2 kg/m2 ( 95 % CI : −0.6 to 0.1 ; P=0.25 ) at 9 months and −0.0 kg/m2 ( 95 % CI : −0.5 to 0.5 ; P=1.00 ) at 15 months . There was a relative improvement in nutrition scores in the intervention arm at both 9 and 15 months . There was weak evidence of an increase in daily physical activity in the intervention arm . Health status and body image were similar in the trial arms . Conclusions : This intervention did not result in a sustained BMI reduction , despite the improvement in parent-reported nutrition . Brief individualized solution-focused approaches may not be an effective approach to childhood overweight . Alternatively , this intervention may not have been intensive enough or the GP training may have been insufficient ; however , increasing either would have significant cost and re source implication s at a population level OBJECTIVE To assess the effects of reducing television viewing and computer use on children 's body mass index ( BMI ) as a risk factor for the development of overweight in young children . DESIGN R and omized controlled clinical trial . SETTING University children 's hospital . PARTICIPANTS Seventy children aged 4 to 7 years whose BMI was at or above the 75th BMI percentile for age and sex . INTERVENTIONS Children were r and omized to an intervention to reduce their television viewing and computer use by 50 % vs a monitoring control group that did not reduce television viewing or computer use . MAIN OUTCOME MEASURES Age- and sex-st and ardized BMI ( z BMI ) , television viewing , energy intake , and physical activity were monitored every 6 months during 2 years . RESULTS Children r and omized to the intervention group showed greater reductions in targeted sedentary behavior ( P < .001 ) , z BMI ( P < .05 ) , and energy intake ( P < .05 ) compared with the monitoring control group . Socioeconomic status moderated z BMI change ( P = .01 ) , with the experimental intervention working better among families of low socioeconomic status . Changes in targeted sedentary behavior mediated changes in z BMI ( P < .05 ) . The change in television viewing was related to the change in energy intake ( P < .001 ) but not to the change in physical activity ( P = .37 ) . CONCLUSIONS Reducing television viewing and computer use may have an important role in preventing obesity and in lowering BMI in young children , and these changes may be related more to changes in energy intake than to changes in physical activity CONTEXT Childhood obesity is now considered to be an epidemic . Drug therapy in this age group remains a topic of research . OBJECTIVE The objective of this study was to examine the effect of treatment with sibutramine ( 10 mg ) on body composition and energy expenditure in obese adolescents . DESIGN The study was conducted as a r and omized , double-blind , placebo-controlled trial . SETTING The study was set in an obesity research center . PATIENTS The patients were 24 obese adolescents ( age 12 - 17 yr , 11 boys ) ; four patients withdrew . INTERVENTION Intervention was sibutramine ( Meridia ) or placebo in combination with an energy-restricted diet and exercise plan for 12 wk , followed by an identical , but medication-free , treatment period ( follow-up ) . MAIN OUTCOME MEASURE Change in body mass index ( BMI ) sd score ( BMI -SDS ) was the principal measure of efficacy . Body composition and total energy expenditure were measured by stable isotopes and further calculated according to the four-component model , using underwater weighing and dual x-ray absorptiometry . Basal metabolic rate ( BMR ) was measured by ventilated hood and adjusted for sex and body composition ( BMRadj ) . RESULTS After intervention , the decrease in BMI -SDS was comparable in both groups . During follow-up , BMI further decreased in the placebo group but stabilized in the sibutramine group . Changes in the percentage of fat mass were not different between both groups . BMRadj decreased in the placebo group and remained constant in the sibutramine group . During follow-up , BMRadj decreased in the sibutramine group and increased in the placebo group . Changes in total energy expenditure were not significantly different . CONCLUSION The effect of sibutramine on BMI -SDS was not significant . Sibutramine may diminish the decrease in BMRadj associated with energy restriction in obese adolescents The effectiveness of the adolescent obesity intervention SHAPEDOWN was evaluated for 15 months through a r and omized experimental design study . Test groups ( no. = 37 ) participating in the intervention were compared with a no-treatment control group ( no. = 29 ) at four sites in northern California . The program employs a variety of cognitive , behavioral , and affective techniques adapted to make successive small modifications in diet , exercise , communication , and affect that are sustainable . Very-low-calorie or restrictive diets are avoided in the program . Parents are instructed on strategies for supporting their adolescents ' weight-loss efforts . Participation in the group application of the program was associated with significant improvement in relative weight , weight-related behavior , depression , and knowledge of weight management concepts at post-treatment and at 1-year follow-up . Self-esteem increased significantly regardless of condition . Change in relative weight for the test group was -9.9 + /- 14.9 % ( mean + /- st and ard deviation ) and for the control group was -0.10 + /- 13.2 % . At month 15 of the study period , weight change in the test group compared with the controls was -5.15 kg . For all subject variables examined in the test group , mean change in relative weight at 1-year follow-up was negative , suggesting that none of the characteristics examined contraindicate program participation among obese adolescents seeking care . Drop-out rate was 16 % . The study suggests that the program produces significant long-term outcomes in obese adolescents and is transferable to a variety of setting OBJECTIVE This study evaluates the post-treatment and short-term follow-up efficacy of , as well as participant satisfaction for , a 4-month behavioral weight control program for overweight adolescents initiated in a primary care setting and extended through telephone and mail contact . RESEARCH METHODS AND PROCEDURES 44 overweight adolescents were r and omly assigned to either a multiple component behavioral weight control intervention ( Healthy Habits [ HH ] ; n = 23 ) or a single session of physician weight counseling ( typical care [ TC ] ; n = 21 ) . Weight , height , dietary intake , physical activity , sedentary behavior , and problematic weight-related and eating behaviors and beliefs were assessed before treatment , after the 4-month treatment , and at 3-month follow-up . Participant satisfaction and behavioral skills use were measured . RESULTS HH adolescents evidence d better change in body mass index z scores to post-treatment than TC adolescents . Body mass index z scores changed similarly in the conditions from post-treatment through follow-up . Behavioral skills use was higher among HH than TC adolescents , and higher behavioral skills use was related to better weight outcome . Energy intake , percentage of calories from fat , physical activity , sedentary behavior , and problematic weight-related or eating behaviors/beliefs did not differ by condition or significantly change over time independent of condition . The behavioral intervention evidence d good feasibility and participant satisfaction . DISCUSSION A telephone- and mail-based behavioral intervention initiated in primary care result ed in better weight control efficacy relative to care typically provided to overweight adolescents . Innovative and efficacious weight control intervention delivery approaches could decrease provider and participant burden and improve dissemination to the increasing population of overweight youth OBJECTIVES The present study aim ed to assess the effect of a 6-month exercise program in obese children on flow-mediated vasodilation ( FMD ) carotid intima-media thickness ( IMT ) and cardiovascular risk factors ( RF ) . BACKGROUND Childhood obesity contributes to adult obesity and subsequent cardiovascular disease . Physical inactivity is a major RF for obesity , endothelial dysfunction , and elevated carotid IMT , culminating in early atherosclerotic disease . METHODS Sixty-seven obese subjects ( age 14.7 + /- 2.2 years ) were r and omly assigned to 6 months ' exercise or non-exercise protocol . We examined the influence of exercises ( 1 h , 3 times/week ) on FMD , IMT , and cardiovascular risk profile . RESULTS Compared with lean control subjects , obese children demonstrated at baseline significantly impaired FMD ( 4.09 + /- 1.76 % vs. 10.65 + /- 1.95 % , p < 0.001 ) , increased IMT ( 0.48 + /- 0.08 mm vs. 0.37 + /- 0.05 mm , p < 0.001 ) , and a number of obesity-related cardiovascular RF . Significant improvements were observed in the exercise group for IMT ( 0.44 + /- 0.08 mm , p = 0.012 , -6.3 % ) and FMD ( 7.71 + /- 2.53 % , p < 0.001 , + 127 % ) . This improvement correlated with reduced RF , such as body mass index st and ard deviation scores , body fat mass , waist/hip ratio , ambulatory systolic blood pressure , fasting insulin , triglycerides , low-density lipoprotein/high-density lipoprotein ratio , and low-degree inflammation ( C-reactive protein , fibrinogen ) . CONCLUSIONS The present study documented increased IMT , impaired endothelial function , and various elevated cardiovascular RF in young obese subjects . Regular exercise over 6 months restores endothelial function and improves carotid IMT associated with an improved cardiovascular risk profile in obese children This study investigated the effectiveness of cognitive self-management training as an adjunct to the behavioural management of childhood obesity . Twenty-seven overweight children aged 7 - 13 years were r and omly assigned to either behavioural management plus relaxation placebo or a combined behavioural-cognitive self-management approach . Evaluations following the eight treatment sessions revealed a significant reduction in percentage overweight for children in both experimental groups and improvements were maintained at 3- and 6-month follow-ups . Both conditions were also effective in reducing the number of high-risk foods consumed . No difference in outcome was found between treatments at the post-treatment assessment or 3- and 6-month follow-ups . Although a reduction in percentage overweight of around 9 % was found for both procedures , subjects in general remained considerably overweight Hyperinsulinemia and insulin resistance are common features of obesity in humans and experimental animals . It has been demonstrated that metformin , an antihyperglycemic agent , decreases hyperinsulinemia and insulin resistance leading to decreased adiposity in obese and non-insulin-dependent diabetes mellitus ( NIDDM ) adults . To evaluate the antiobesity effect of metformin , we conducted a r and omized double-blind placebo controlled trial in 24 hyperinsulinemic nondiabetic obese adolescents ( body mass index [ BMI ] > 30 kg/m(2 ) ) . All subjects were placed on a low-calorie ( 1,500 kcal for women and 1,800 kcal for men ) meal plan . After an initial 1-week lead-in period , 12 subjects ( mean + /- SE for age and BMI , 15.6 + /- 0.4 and 41.2 + /- 1.8 , respectively ) received metformin ( 850 mg twice daily ) for 8 weeks , and 12 subjects ( mean + /- SE for age and BMI , 15.7 + /- 0.5 and 40.8 + /- 1.4 , respectively ) received placebo . Compared to the placebo group , the metformin group had greater weight loss ( 6.5 % + /- 0.8 % v 3.8 + /- 0.4 % , P < .01 ) , greater decrease in body fat ( P < .001 ) , greater increase in fat-free mass to body fat ratio ( P < .005 ) , and greater attenuation of area under the curve ( AUC ) insulin response to an oral glucose tolerance test ( P < .001 ) . This was associated with enhanced insulin sensitivity , as determined by the fasting plasma glucose : insulin , 2-hour glucose : insulin , and AUC glucose : AUC insulin ratios , in the metformin group compared to controls ( P < .01 ) . This corresponded to a significant reduction in plasma leptin ( P < .005 ) , cholesterol , triglycerides , and free fatty acid ( FFA ) levels ( P < .05 ) only in the metformin-treated subjects . Combined metformin treatment and low-calorie diet had a significant antiobesity effect in hyperinsulinemic obese adolescents compared to a low-calorie diet alone STUDY OBJECTIVE To evaluate the effect of family therapy on childhood obesity . DESIGN Clinical trial . One year follow-up . SETTING Referral from school after screening . PARTICIPANTS Of 1774 children ( aged 10 to 11 ) , screened for obesity , 44 obese children were divided into two treatment groups . In an untreated control group of 50 obese children , screened in the same manner , body mass index ( BMI ) values were recorded twice , at 10 to 11 and at 14 years of age . INTERVENTION Both treatment groups received comparable dietary counseling and medical checkups for a period of 14 to 18 months , while one of the groups also received family therapy . RESULTS At the 1-year follow-up , when the children were 14 years of age , intention-to-treat analyses were made of the weight and height data for 39 of 44 children in the two treatment groups and for 48 of the 50 control children . The increase of BMI in the family therapy group was less than in the conventional treatment group at the end of treatment , and less than in the control group ( P = .04 and P = .02 , respectively ) . Moreover , mean BMI was significantly lower in the family therapy group than in the control group ( P < .05 ) , and the family therapy group also had fewer children with BMI > 30 than the control group ( P = .02 ) . The reduction of triceps , subscapular , and suprailiac skinfold thicknesses , expressed as percentages of the initial values , was significantly greater in the family therapy group than in the conventional treatment group ( P = .03 , P = .005 and P = .002 , respectively ) , and their physical fitness was significantly better ( P < .05 ) . CONCLUSIONS Family therapy seems to be effective in preventing progression to severe obesity during adolescence if the treatment starts at 10 to 11 years of age BACKGROUND . Parenting-skills training may be an effective age-appropriate child behavior-modification strategy to assist parents in addressing childhood overweight . OBJECTIVE . Our goal was to evaluate the relative effectiveness of parenting-skills training as a key strategy for the treatment of overweight children . DESIGN . The design consisted of an assessor-blinded , r and omized , controlled trial involving 111 ( 64 % female ) overweight , prepubertal children 6 to 9 years of age r and omly assigned to parenting-skills training plus intensive lifestyle education , parenting-skills training alone , or a 12-month wait-listed control . Height , BMI , and waist-circumference z score and metabolic profile were assessed at baseline , 6 months , and 12 months ( intention to treat ) . RESULTS . After 12 months , the BMI z score was reduced by ∼10 % with parenting-skills training plus intensive lifestyle education versus ∼5 % with parenting-skills training alone or wait-listing for intervention . Waist-circumference z score fell over 12 months in both intervention groups but not in the control group . There was a significant gender effect , with greater reduction in BMI and waist-circumference z scores in boys compared with girls . CONCLUSION . Parenting-skills training combined with promoting a healthy family lifestyle may be an effective approach to weight management in prepubertal children , particularly boys . Future studies should be powered to allow gender sub analysis OBJECTIVE We conducted a study to determine if wearing a pedometer affects weight , body mass index ( BMI ) , or mediators of physical activity among families . METHODS Eighty-seven families were r and omized to 1 of 3 treatments : pedometer plus education ( PE ) , pedometer ( P ) , or control ( C ) . Participants in the PE and P groups wore pedometers and were encouraged to walk 10,000 steps daily for 12 weeks . PE group participants attended 6 sessions on healthy eating and exercise . Participants were surveyed about their knowledge and attitudes about healthy eating and physical activity prior to r and omization , at the end of the intervention , and 9 months later . Their heights and weights were measured and BMI calculated . RESULTS Children 's BMI percentile decreased from baseline to end of intervention ( -0.18 % ) and at 9-month follow-up ( -0.08 % ) but did not differ by treatment . Children 's BMI percentile varied by parental obesity status ( average BMI percentile was 88.7 % for children of obese parents and 78.5 % for children of non-obese parents ) . Parents ' weight decreased slightly by intervention 's end ( 0.6 pounds ) and at 9 months ( 1.2 pounds ) , but change was similar among groups . Attitudes about their physical activity level relative to their peers improved significantly among children and parents wearing the pedometer . Self-efficacy improved for parents wearing the pedometer . Both children and parents felt the pedometer increased their activity level , but most were unlikely to wear it beyond the intervention . CONCLUSIONS The pedometer had little impact on the activity level , weight , or BMI of participants OBJECTIVE To determine whether pediatricians and dietitians can implement an office-based obesity prevention program using motivational interviewing as the primary intervention . DESIGN Nonr and omized clinical trial . Fifteen pediatricians belonging to Pediatric Research in Office Setting s , a national practice -based research network , and 5 registered dietitians were assigned to 1 of 3 groups : ( 1 ) control ; ( 2 ) minimal intervention ( pediatrician only ) ; or ( 3 ) intensive intervention ( pediatrician and registered dietitian ) . SETTING Primary care pediatric offices . PARTICIPANTS Ninety-one children presenting for well-child care visits met eligibility criteria of being aged 3 to 7 years and having a body mass index ( calculated as the weight in kilograms divided by the height in meters squared ) at the 85th percentile or greater but lower than the 95th percentile for the age or having a normal weight and a parent with a body mass index of 30 or greater . INTERVENTIONS Pediatricians and registered dietitians in the intervention groups received motivational interviewing training . Parents of children in the minimal intervention group received 1 motivational interviewing session from the physician , and parents of children in the intensive intervention group received 2 motivational interviewing sessions each from the pediatrician and the registered dietitian . MAIN OUTCOME MEASURE Change in the body mass index-for-age percentile . RESULTS At 6 months ' follow-up , there was a decrease of 0.6 , 1.9 , and 2.6 body mass index percentiles in the control , minimal , and intensive groups , respectively . The differences in body mass index percentile change between the 3 groups were nonsignificant ( P=.85 ) . The patient dropout rates were 2 ( 10 % ) , 13 ( 32 % ) , and 15 ( 50 % ) for the control , minimal , and intensive groups , respectively . Fifteen ( 94 % ) of the parents reported that the intervention helped them think about changing their family 's eating habits . CONCLUSIONS Motivational interviewing by pediatricians and dietitians is a promising office-based strategy for preventing childhood obesity . However , additional studies are needed to demonstrate the efficacy of this intervention in practice setting Adolescent obesity is becoming a health problem in both developed and developing countries . Antiobesity drug therapy is not currently indicated for the treatment of adolescent obesity and remains investigational at this time . The aim of this study was to determine the efficacy and safety of sibutramine in obese adolescents . A r and omized , double-blind , placebo-controlled trial , enrolling 60 adolescents , aged 14 - 17 yr , for 6 months was conducted . In the first month , all patients received placebo and a hypocaloric diet plus exercise orientation . For the next 6 months , participants received either sibutramine or placebo . Patients assigned to sibutramine group lost an average of 10.3 + /- 6.6 kg , and patients in placebo group lost 2.4 + /- 2.5 kg ( P < 0.001 ) . The mean body mass index reduction was significantly greater in the sibutramine group ( 3.6 + /- 2.5 kg/m(2 ) ) than in the placebo group ( 0.9 + /- 0.9 kg/m(2 ) ; P < 0.001 ) . No participant withdrew because of adverse events , and no difference in blood pressure or heart rate was noted between groups . There were no changes in echocardiographic parameters . In conclusion , sibutramine plus diet and exercise induced significantly more weight loss in obese adolescents BACKGROUND General practitioners ( GPs ) could make an important contribution to management of childhood overweight . However , there are no efficacy data to support this , and the feasibility of this approach is unknown . OBJECTIVES To determine if GPs and families can be recruited to a r and omized controlled trial ( RCT ) , and if GPs can successfully deliver an intervention to families with overweight/obese 5- to 9-year-old children . METHODS A convenience sample of 34 GPs from 29 family medical practice s attended training sessions on management of childhood overweight . Practice staff trained in child anthropometry conducted a cross-sectional body mass index ( BMI ) survey of 5- to 9-year-old children attending these practice s. The intervention focused on achievable goals in nutrition , physical activity and sedentary behaviour , and was delivered in four solution-focused behaviour change consultations over 12 weeks . RESULTS General practitioners were recruited from across the sociodemographic spectrum . All attended at least two of the three education sessions and were retained throughout the trial . Practice staff weighed and measured 2112 children in the BMI survey , of whom 28 % were overweight/obese ( 17.5 % overweight , 10.5 % obese ) , with children drawn from all sociodemographic quintiles . Of the eligible overweight/obese children , 163 ( 40 % ) were recruited and retained in the LEAP RCT ; 96 % of intervention families attended at least their first consultation . CONCLUSIONS Many families are willing to tackle childhood overweight with their GP . In addition , GPs and families can participate successfully in the careful trials that are needed to determine whether an individualized , family-based primary care approach is beneficial , harmful or ineffective Background : Since obesity affects children 's health and social integration , treatment concepts with long-term efficiency are necessary . Methods : We analyzed changes of st and ard deviation score of body mass index ( SDS- BMI ) quarterly in the first year and once a year during the next 3 years in all obese children participating in the 1-year outpatient intervention program ‘ Obeldicks ’ , which was based on physical exercise , nutrition education and behavior therapy . All analyses were performed on the intention-to-treat approach . Results : One hundred and thirty-one children ( 77 % ) of the 170 children ( mean age 10.5 years , 51 % female , mean BMI 26.9 kg/m2 , mean SDS- BMI 2.54 ) attending the ‘ Obeldicks ’ intervention program reduced their overweight at the end of intervention ( mean SDS- BMI reduction 0.41 ) and 122 ( 66 % ) 3 years after end of intervention ( mean SDS- BMI reduction 0.48 ) . The reduction of overweight was independent of the child 's gender , age and parental age and BMI . Reduction of 0.33 SDS- BMI in the first 3 months was the best predictor for long-term success ( 95 % predictive value ) . Conclusions : Participating in the 1-year outpatient obesity intervention program ‘ Obeldicks ’ was associated with a decrease of overweight , which was sustained 3 years after the end of intervention . Reduction of overweight in the first 3 months of the intervention was highly predictive for long-term success

The field test of the new instrument showed good criterion validity . Participants found it useful in translating evidence from RCTs to practice . Conclusion A new instrument for the critical appraisal of RCTs of NPs was developed and tested . The instrument is distinct from other available assessment instruments for RCTs of NPs in its systematic development and validation .

Background The efficacy of natural products ( NPs ) is being evaluated using r and omized controlled trials ( RCTs ) with increasing frequency , yet a search of the literature did not identify a widely accepted critical appraisal instrument developed specifically for use with NPs . The purpose of this project was to develop and evaluate a critical appraisal instrument that is sufficiently rigorous to be used in evaluating RCTs of conventional medicines , and also has a section specific for use with single entity NPs , including herbs and natural source d chemicals .

Although r and omised trials are important for evidence -based medicine , little is known about their overall characteristics . We assessed the epidemiology and reporting of method ological details for all 519 PubMed -indexed r and omised trials published in December , 2000 ( 383 [ 74 % ] parallel-group , 116 [ 22 % ] crossover ) . 482 ( 93 % ) were published in specialty journals . A median of 80 participants ( 10th-90th percentile 25 - 369 ) were recruited for parallel-group trials . 309 ( 60 % ) were blinded . Power calculation , primary outcomes , r and om sequence generation , allocation concealment , and h and ling of attrition were each adequately described in less than half of publications . The small sample sizes are worrying , and poor reporting of method ological characteristics will prevent reliable quality assessment of many published trials When reading a clinical research article , the clinician must judge if the reported findings and conclusions are valid before applying them to patient care . This concern is legitimate given the wide range of study validity in the clinical literature . In this article , the authors present many validity markers that signify the quality of the information reported from a study , such as authors hip , bias , confounding , statistics , r and omization , controls , blinding , and the logical framework of scientific investigations The statistical adequacy of all papers published in the period 1976 - 80 describing clinical trials of five non-steroidal anti-inflammatory and two analgesic drugs introduced into the UK market in 1978 and 1979 has been assessed using a checklist of simple criteria . Most trials were reported to be r and omised and double-blind . Trial design s were less satisfactory in other important respects ; the sample size of most trials was inadequate to demonstrate superiority of the new drug compared with an active control therapy . The period of treatment assessment was short in view of the likelihood of prolonged prescription of drugs in these classes . It is suggested that licensing authorities should dem and higher st and ards of clinical trial evidence offered in support of new drugs Recent empirical evidence supports the importance of adequate r and omization in controlled trials . Trials with inadequate allocation concealment have been associated with larger treatment effects compared with trials in which authors reported adequate allocation concealment . While that provides empirical evidence of bias being interjected into trials , trial investigators rarely document the sensitive details of subverting the intended purpose of r and omization . This article relates anonymous accounts run the gamut from simple to intricate operations , from transillumination of envelopes to search ing for code in the office files of the principal investigator . They indicate that deciphering is something more frequent than a rate occurrence . These accounts prompt some method ological recommendations to help prevent deciphering . R and omized controlled trials appear to annoy human nature -- if properly conducted , indeed they should In the r and omized , placebo-controlled , physician-blinded Canadian cooperative trial of cyclophosphamide and plasma exchange , neither active treatment regimens ( group I : IV cyclophosphamide and prednisone ; group II : weekly plasma exchange , oral cyclophosphamide , and prednisone ) were superior to placebo ( group III : sham plasma exchange and placebo medications ) using the blinded , evaluating neurologists ' assessment s of disease course ( primary analysis ) . All patients were examined by both a blinded and an unblinded neurologist at each assessment in this trial . We compared the blinded and unblinded neurologists ' judgment of treatment response and analyzed the clinical behavior of patients who correctly guessed their treatment . The unblinded ( but not the blinded ) neurologists ' scores demonstrated an apparent treatment benefit at 6 , 12 , and 24 months for the group II patients ( not group I or placebo ; p < 0.05 , two-tailed ) . There were no significant differences in the time to treatment failure or in the proportions of patients improved , stable , or worse between the group II and group III patients who correctly guessed their treatment assignments and those who did not . Physician blinding prevented an erroneous conclusion about treatment efficacy ( false positive , type 1 error ) A system has been constructed to evaluate the design , implementation , and analysis of r and omized control trials ( RCT ) . The degree of quadruple blinding ( the r and omization process , the physicians and patients as to therapy , and the physicians as to ongoing results ) is considered to be the most important aspect of any trial . The analytic techniques are scored with the same emphasis as is placed on the control of bias in the planning and implementation of the studies . Description of the patient and treatment material s and the measurement of various controls of quality have less weight . An index of quality of a RCT is proposed with its pros and cons . If published papers were to approximate these principles , there would be a marked improvement in the quality of r and omized control trials . Finally , a reasonable st and ard design and conduct of trials will facilitate the interpretation of those with conflicting results and help in making valid combinations of undersized trials BACKGROUND The interpretation of the results of r and omized controlled trials ( RCTs ) has traditionally emphasized statistical significance rather than clinical importance . Our aim was to assess the quality of reporting of factors related to clinical importance in a sample of published RCTs . METHODS A r and om sample of 27 ( of a total of 266 ) RCTs published in 5 major medical journals over a 1-year period were review ed by 4 independent review ers for factors considered important in the interpretation of the clinical importance of study results : identification of a clearly defined primary outcome , reporting of the expected difference between groups used in the calculation of sample size ( the delta value ) and whether it was based on the minimal clinical ly important difference of the intervention , the statistical significance of the results , presentation of pertinent confidence intervals , and the authors ' interpretation of the clinical importance of the results . RESULTS Twenty-two of 27 ( 81 % ) articles explicitly reported a single primary outcome . Of the 20 articles that included a sample size calculation , 18 ( 90 % ) reported a delta value . Two of the 18 ( 11 % ) articles explicitly stated that the delta value was chosen to reflect the minimal clinical ly important difference of the intervention . For the primary outcomes , confidence intervals surrounding the point estimates of the efficacy of the interventions were reported in 11 of 27 ( 41 % ) studies . The study results were interpreted from the perspective of clinical importance in 20 of 27 ( 74 % ) of the articles . Of these 20 reports , 5 ( 25 % ) provided justification for their clinical interpretation of the results . INTERPRETATION Authors of RCTs published in major general medical and internal medicine journals do not consistently provide their own interpretation of the clinical importance of their results , and they often do not provide sufficient information to allow readers to make their own interpretation BACKGROUND Traditional and largely qualitative review s of evidence are now giving way to much more structured systematic overviews that use a quantitative method to calculate the overall effect of treatment . The latter approach is dependent on the quality of primary studies , which may introduce bias if they are of poor method ologic quality . OBJECTIVE To test the hypothesis that the inclusion of poor- quality trials in meta-analyses would bias the conclusions and produce incorrect estimates of treatment effect . METHODS An overview of r and omized trials of antiestrogen therapy in subfertile men with oligospermia was performed to test the hypothesis . Data sources included online search ing of MEDLINE and Science Citation Index data bases between 1966 and 1994 , scanning the bibliography of known primary studies and review articles , and contacting experts in the field . After independent , blind assessment , nine of 149 originally identified studies met the inclusion criteria and were selected . We assessed study quality independently . Outcome data from each study were pooled and statistically summarized . RESULTS There was a marginal improvement in pregnancy rate with antiestrogen treatment ( odds ratio , 1.6 ; 95 % confidence interval , 0.9 to 2.6 ) . Sensitivity analyses on the basis of method ologic quality demonstrated that poor- quality studies produced a positive effect with treatment , whereas no benefit was observed with high- quality studies . CONCLUSION The results of a meta- analysis are influenced by the quality of the primary studies included . Method ologically , poor studies tend to exaggerate the overall estimate of treatment effect and may lead to incorrect inferences Systematic Review Series Series Editors : Cynthia Mulrow , MD , MSc Deborah Cook , MD , MSc The last article in this series outlined methods with which to search the literature for studies on the clinical question that generates a systematic review [ 1 ] . Herein , we discuss the subsequent steps of selecting and appraising studies for a review . Both of these steps involve important judgments that can influence the results of a review . In selecting studies , review ers judge the relevance of the studies to the review question . In appraising studies , review ers judge numerous features of design and analysis . Some of these judgments are easy to make ; others are more difficult and prone to error . To be confident in their decisions , review ers should use methods that are reliable ( the results do not change if the procedure is repeated ) , impartial ( not influenced by the study results ) , and explicit ( unambiguous ) [ 2 ] . These strategies for selection and appraisal are sensible , and they distinguish most systematic review s from most narrative review s. However , evidence to support the importance of some of the methods we suggest is either scant or conflicting ; readers are referred to the original research on these approaches for more details . Selecting Studies for Systematic Review s If review ers perform a comprehensive search of the literature using the methods described previously in this series [ 1 ] , they will probably have assembled a large sample of articles . This sample will include most ( ideally , all ) studies that are relevant to the review question ( that is , the sensitivity of the search will be high ) . Inevitably , because such a wide net is cast , articles not pertinent to the clinical question will be retrieved ( that is , the specificity of the search will be modest ) . Thus , the review ers ' next task is to sort through all of the potentially relevant articles and select those that will be included in the review . To do so , review ers adopt several of the tactics listed in Table 1 and Table 2 for planning and executing the selection process ( in effect , improving the specificity of the search ) ; these tactics are described below . Table 1 . Planning Study Selection Table 2 . Strategies for Selecting and Appraising Studies Begin with a Well-Built Clinical Question Review ers should ensure that the question for review includes the four elements of a well-built clinical question [ 3 , 4 ] : the patients of interest , the main interventions under investigation , the comparison interventions , and the clinical outcomes of interest . By including these four elements , review ers can better focus the selection process . Choose Selection Criteria That Fit the Clinical Question Consider a systematic review of the effectiveness of a drug treatment ( for example , a proton-pump inhibitor ) for patients with a particular disorder ( such as esophageal reflux ) . Review ers need to decide whether to include studies of patients with any symptoms of reflux , only those with classic symptoms , or only those in whom definitive diagnostic tests have confirmed the presence of reflux . In addition , review ers might choose to include studies of patients with different comorbid conditions ; patients from different demographic or geographic or cultural background s ; or patients from different health systems , such as inpatient or community population s. Similarly , review ers should use selection criteria that reflect the main and comparison interventions of interest . In our esophageal reflux example , review ers would need to decide whether to include studies of a particular drug or studies of all agents in that drug 's class and whether to include studies of any dose and regimen or only studies with a specific regimen . For the comparison interventions , the review ers would decide whether to include studies that compare the experimental drug with alternate treatments ( such as antacids or histamine-2-receptor antagonists ) , with placebo , or with both . For the clinical outcomes , review ers have analogous tasks of defining the outcomes and translating them into criteria . In our example , the review ers would start by listing each clinical outcome ( for example , whether the outcome was endoscopic or clinical and whether it focused on cure or persistence ) and then decide whether to include studies that reported any outcome or only those with certain clinical ly important outcomes ( such as improvement in symptoms at 1 year ) . After thoroughly considering each element of the review question , review ers compile a set of explicit selection criteria . When these criteria are not explicit , the results of the review are more prone to error [ 5 , 6 ] . Reporting the selection criteria used in a review is extremely important to readers because the criteria indicate the relevance of the review to the readers ' clinical practice . Specify the Types of Study Design To Be Included After creating selection criteria that appropriately reflect the review question , review ers should consider which study design s to include . Ideally , review ers choose study design s that are most likely to produce valid results . For example , to answer questions about therapy or harm , review ers may want to include r and omized trials [ 7 ] because they provide more accurate estimates of benefit or harm than do cohort studies , casecontrol studies , and case series [ 8 ] . In reality , however , r and omized trials may not be conducted to address questions of harm [ 9 ] . Therefore , review ers need to consider which study design s are likely to be available to answer their question ; this information may necessitate modification of originally conceptualized selection criteria to incorporate observational ( nonexperimental ) studies . Specify Criteria Related to Type and Form of Publication Review ers also need to consider issues related to type and form of publication . Ideally , all of the relevant studies would be published as peer- review ed journal articles . However , some completed studies may be published only as abstract s , in non-peer- review ed form , or not at all . Review ers decide whether to include these incompletely reported studies when planning their literature search . By including all articles in various stages of publication and subjecting them to rigorous critical appraisal , review ers minimize the threat of publication bias ( the preferential reporting of studies with positive results ) [ 10 - 12 ] , which could generate misleading review s. Other studies may be reported more than once . To avoid over-representing duplicate studies in the review , investigators should plan to look for and exclude duplicate publications [ 13 ] . Finally , because studies may be published in different language s and because excluding studies published in different language s may bias the results of review s [ 14 , 15 ] , articles should be included , as appropriate , regardless of the language of publication ( translating as necessary ) . Limited time and re sources , however , may preclude such an approach . Construct and Pretest Selection Forms After deciding on selection criteria , review ers can prepare customized forms that contain checklists of the selection criteria ( Figure 1 ) . Using these forms can simplify the selection process , increase reliability , and provide a record of the judgments made about each study . After drafting form prototypes , review ers pretest these forms for clarity , ease of application , and reliability . To pretest the forms , two or more independent review ers typically apply them to a r and om sample of studies identified by the literature search . Review ers compare their results to identify sources of ambiguity and then revise the forms accordingly . If the revisions are substantial , this process may need to be repeated before the forms can be used . Figure 1 . Example of a form that might be developed for the selection of studies for a systematic review evaluating the efficacy of -blockers for secondary prevention of variceal bleeding . Write a Detailed Protocol Having a selection protocol as part of a larger protocol for the entire review helps review ers in two ways . First , it provides a document that explicitly states the review question and the selection criteria , making the process accountable . Review ers can later return to the protocol for guidance in resolving disagreements about article selection . Second , the selection protocol identifies what work will be done , by whom , in what manner , when , and for what reason ; thus , it provides a mode of communication within the review team . When review ers have a very large sample of studies from which to select , they can simplify this task by review ing all of the titles , then the abstract s , and then the full articles , excluding studies that do not meet one or more selection criteria at each step . In doing so , review ers should record ( on the selection forms ) the reasons for exclusion . After review ers have selected studies for the systematic review , they will move to the next task of critical appraisal . This procedure also requires careful planning . Appraising Studies for Systematic Review s Review ers appraise the studies selected for review with three objectives in mind : 1 ) to underst and the validity of the studies , 2 ) to uncover reasons for differences among study results other than chance , and 3 ) to provide readers with sufficient information with which to judge for themselves the applicability of the systematic review to their clinical practice . To achieve these goals , review ers use the strategies outlined in Table 2 and Table 3 to carefully reexamine many important features of the primary studies . Table 3 . Planning Study Appraisal Examine Important Clinical Features Although the selection criteria for a systematic review define the population , interventions , and outcomes of interest , the appraisal process involves a detailed assessment of the patients ( for example , high , medium , or low risk ) , the study interventions ( for example , frequency , degree , and duration ) , and the outcome measurements ( for example , definitions and degree of surveillance ) A check list is described which helps the systematic assessment of reports of therapeutic trials , particularly the aspects that need to be considered in assessing their validity . The check list was used to examine 141 reports of therapeutic trials published in four British non-specialist journals in the first six months of 1966 and of 1969 . Of these reports 51 % were found to be acceptable and a further 16 % probably acceptable ; 33 % were considered unacceptable because they lacked one or more of the features required in a valid report . The check list has been found useful in assessing cl aims made for drugs and other therapeutic measures on the basis of published reports The purpose of this project was to conduct a systematic review to identify instruments design ed to evaluate the quality of r and omized controlled trials ( RCTs ) of natural health products ( NHPs ) . Instruments were examined for inclusion of items assessing methods , identity and content of the NHP , generalizability of results and instructions for use . Online data bases , websites , textbooks and reference lists were search ed to identify instruments . Relevance assessment and data extraction of articles were completed by two investigators and disagreements were settled by the third investigator . Data were analyzed using descriptive statistics . Of the 4442 citations identified , 29 were potentially relevant with 16 meeting the criteria for inclusion . None of the instruments stated they were vali date d ; content in the four areas of interest varied considerably . The most common items included r and omization sequence generation ( 100 % ) , blinding ( 100 % ) , allocation concealment ( 75 % ) and participant flow ( 75 % ) . Only nine of the NHP instruments included at least one item to appraise the specific content of the NHP . The CONSORT Statement for Herbal Interventions most closely addressed the four areas of interest ; however , this instrument was specific for herbs . There is a need for the development of a vali date d instrument for assessment of the quality of RCTs that would be useful for herbs as well as other NHPs BACKGROUND AND PURPOSE Several studies have shown that the quality of reporting of trials throughout medicine is variable and often poor . We report on the quality of the final reports of r and omized controlled trials ( RCTs ) of drug therapies assessed in acute stroke . METHODS English- language reports published up to the end of 1996 relating to completed RCTs in acute stroke were identified from electronic search es of the Cochrane Stroke Review Group data base of stroke trials and the Cochrane Controlled Trials Register ( CD-ROM issue 1 , 1997 , of the Cochrane Library ) . Report quality was assessed with the 33 criteria of the CONSORT statement and 53 additional factors relevant to acute stroke or trials in general . Trial quality was also assessed with a 7-point scale . RESULTS Up to 1996 , 114 RCTs were published which involved 20 536 patients ( median , 80 ; range , 16 to 1267 per trial ) ; 39 ( 35.5 % ) of these were published in Stroke . The median total report quality was 40/86 ( range , 15 to 61 ) for all criteria and 19/33 ( range , 9 to 29 ) for the CONSORT criteria alone . Although adequate information was given in the introduction and discussion sections of most reports , insufficient details were given on methods , assignment of patients to treatment groups , statistical analyses , the prevalence of risk factors , and assessment of outcomes . Report quality has improved between 1956 and 1996 ( Spearman correlation coefficient [ rs ] , 0.575 ; 95 % confidence interval [ CI ] , 0 . 439 to 0.685 ) and was superior in large trials ( rs=0.434 ; 95 % CI , 0 . 274 to 0.571 ) . Although report quality was related to trial quality ( rs=0.675 ; 95 % CI , 0.563 to 0.763 ) , it was not related to journal impact factor ( rs=0.170 ; 95 % CI , -0.015 to 0.344 ) . Trials with a positive outcome tended to be less well reported than those with a neutral or negative outcome ( rs=-0.192 ; 95 % CI , -0.351 to -0.011 ) . CONCLUSIONS The overall quality of study reports for parallel group RCTs in acute stroke is poor but appears to be improving with time and in parallel with an increase in trial size . Reports often lack detailed information on the methods of r and omization , concealment of allocation , and statistical analysis , all factors which can , if undertaken poorly , affect trial results and validity . It is vital that future trials are adequately reported ; we believe that authors should follow the CONSORT guidelines and that referees and editors should ensure this happens We analysed 113 reports published in 1980 in a sample of medical journals to relate features of study design to the magnitude of gains attributed to new therapies over old . Overall we rated 87 per cent of new therapies as improvements over st and ard therapies . The mean gain ( measured by the Mann-Whitney statistic ) was relatively constant across study design s , except for non-r and omized controlled trials with sequential assignment to therapy , which showed a significantly higher likelihood that a patient would do better on the innovation than on st and ard therapy ( p = 0.004 ) . R and omized controlled trials that did not use a double-blind design had a higher likelihood of showing a gain for the innovation than did double-blind trials ( p = 0.02 ) . Any evaluation of an innovation may include both bias and the true efficacy of the new therapy , therefore we may consider making adjustments for the average bias associated with a study design . When interpreting an evaluation of a new therapy , readers should consider the impact of the following average adjustments to the Mann-Whitney statistic : for trials with non-r and om sequential assignment a decrease of 0.15 , for non-double-blind r and omized controlled trials a decrease of 0.11 CONTEXT Diagrams of the flow of participants through a clinical trial are recommended in the Consoli date d St and ards for Reporting of Trials ( CONSORT ) statement , but it is unclear whether such flow diagrams improve the quality of trial reports . OBJECTIVE To examine the information contributed by flow diagrams and the completeness of reporting overall in reports of r and omized controlled trials ( RCTs ) published in 5 general and internal medicine journals . DESIGN AND SETTING Analysis of 270 reports of RCTs published in 1998 in the Annals of Internal Medicine ( AIM ; n = 19 ) , BMJ ( n = 42 ) , JAMA ( n = 45 ) , The Lancet ( n = 81 ) , and The New Engl and Journal of Medicine ( NEJM ; n = 83 ) . MAIN OUTCOME MEASURES Proportion of reports that included a flow diagram , information provided in flow diagrams , and completeness of reporting about flow of participants overall in flow diagrams or text . RESULTS A total of 139 reports ( 51.5 % ) of RCTs included a flow diagram , but this varied widely among journals ( AIM , 21.0 % ; BMJ , 38.1 % ; JAMA , 80.0 % ; The Lancet , 93.8 % ; and NEJM , 8.4 % ) . Diagrams generally provided useful information , but only 73 ( 52.5 % ) included the number of participants who received allocated interventions and only 32 ( 23.0 % ) included the number of participants included in the analysis . In logistic regression analysis , overall completeness of reporting about flow of study participants was associated with publication of a flow diagram . CONCLUSIONS Flow diagrams are associated with improved quality of reporting of r and omized controlled trials . However , the structure of current flow diagrams is less than ideal . We propose a revised flow diagram that includes all important counts through the stages of parallel group trials AIMS To test the hypothesis that the quality of reporting of orthodontic clinical trials is insufficient to allow readers to assess the validity of the trial . DESIGN A retrospective observational study . SETTING The American Journal of Orthodontics and Dentofacial Orthopedics ( AJODO ) , the British Journal of Orthodontics ( BJO ) and European Journal of Orthodontics ( EJO ) . DATA SOURCE Clinical trials published between 1989 and 1998 . METHOD A h and search was performed to identify all clinical trials . The concealment of allocation , whether the trial was r and omized , double blind , and whether there was a description of withdrawals and dropouts was recorded . RESULTS One hundred and fifty-five trial reports were identified of which 4 ( 2.6 % ) were adequately concealed , 85 ( 54.8 % ) were described as being r and omized , 10 ( 6.5 % ) as double-blind , and 44 ( 28.4 % ) gave a description of withdrawals and drop-outs from the trial . The type of r and omization was considered appropriate in 78 ( 50.3 % ) reports and in 57 ( 36.8 % ) reports the level of blinding was considered appropriate . When assessed for the risk of bias in the reported trials,(1 ) one trial ( 0.6 % ) had a low risk of bias , 17 ( 11 % ) a moderate risk , and 137 ( 88.4 % ) a high risk . CONCLUSIONS In general the quality of reporting orthodontic clinical trials was insufficient to allow readers to assess the validity of the trials . Reporting of clinical trials could be improved by orthodontic journals adopting the CONSORT statement(2,)(3 ) to ensure that all relevant information is provided The " Consoli date d St and ards of Reporting Trials " ( CONSORT ) was developed to improve the suboptimal reporting of r and omized controlled trials ( RCTs ) . However , little is known about the quality of reporting since this publication . We undertook an observational study to determine the quality of reporting key method ological factors in RCTs since the publication of the CONSORT statement and if a journal policy to promote adherence to the CONSORT checklist was associated with superior reporting . We recorded the reporting of 11 key method ological factors in 105 RCTs from 29 medical journals published subsequent to the CONSORT statement . We examined the quality of reporting in relation to whether a journal was a " CONSORT promoter " as defined by inclusion of the CONSORT checklist in a journal 's " information to authors " section or a requirement that authors , manuscript review ers , or copy editors complete the CONSORT checklist . Multivariate analysis controlled for journal impact factor , study outcome , and time of publication . Six of the 11 method ological factors were reported < 50 % of the time . The number of method ological factors reported was greater in CONSORT promoters than in journals not promoting CONSORT in both unadjusted ( 6.0 and 5.1 , respectively , p-value = 0.03 ) and adjusted ( 6.4 and 4.8 of the 11 method ological factors , respectively , p-value = 0.0001 ) analyses . While journals that promote CONSORT demonstrate superior reporting of RCTs , persistent inadequacies in reporting remain . Until these inadequacies are resolved health-care providers will remain limited in their ability to make informed inferences about the validity of the studies upon which they base their clinical practice CONTEXT The evaluation of the method ologic quality of r and omized controlled trials ( RCTs ) is central to evidence -based health care . Important method ologic detail may , however , be omitted from published reports , and the quality of reporting is therefore often used as a proxy measure for method ologic quality . We examined the relationship between reporting quality and method ologic quality of published RCTs . METHODS Study of 60 reports of placebo-controlled trials published in English- language journals from 1985 to 1997 . Reporting quality was measured using a 25-item scale based on the 1996 issue of the Consoli date d St and ards of Reporting Trials ( CONSORT ) . Concealment of allocation , appropriate blinding , and analysis according to the intention-to-treat principle were indicators of method ologic quality . Method ologic quality was compared between groups of trials defined by reporting quality scores of low , intermediate , and high . Reporting quality scores were compared between groups defined by high and low method ologic quality . RESULTS Among 23 trials of low reporting quality ( median score , 9 [ range , 3.5 - 10.5 ] ) , allocation concealment was unclear for all but 1 trial , but there were 16 trials ( 70 % ) with adequate blinding and 9 trials ( 39 % ) that had been analyzed according to the intention-to-treat principle . Among 18 trials of high reporting quality ( median score , 18 [ range 16.5 - 22.0 ] ) , there were 8 trials ( 44 % ) with adequate allocation concealment , 16 trials ( 89 % ) with adequate blinding , and 13 trials ( 72 % ) analyzed according to the intention-to-treat principle . The median reporting score was 15.0 for the 33 trials that were analyzed according to intention-to-treat principle and 14.5 for the 14 trials with on-treatment analyses ( P = .67 ) . CONCLUSIONS Similar quality of reporting may hide important differences in method ologic quality , and well-conducted trials may be reported badly . A clear distinction should be made between these 2 dimensions of the quality of RCTs Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity Two check lists are used routinely in the statistical assessment of manuscripts su bmi tted to the " BMJ . " One is for papers of a general nature and the other specifically for reports on clinical trials . Each check list includes questions on the design , conduct , analysis , and presentation of studies , and answers to these contribute to the overall statistical evaluation . Only a small proportion of su bmi tted papers are assessed statistically , and these are selected at the refereeing or editorial stage . Examination of the use of the check lists showed that most papers contained statistical failings , many of which could easily be remedied . It is recommended that the check lists should be used by statistical referees , editorial staff , and authors and also during the design stage of studies Physicians are often faced with conflicting recommendations from therapeutic studies . An evaluation form is proposed to facilitate the evaluation of the quality of therapeutic studies and the result ing treatment or management recommendations in any area of medicine . Twelve major topics for evaluation include sample size determination , r and omization , selection of control group(s ) , " blinding , " and support for treatment recommendations . Emphasis is placed on study design and performance rather than data analysis . Thirty-four primary criteria based on accepted research st and ards are design ated as most important , and examples from the literature are provided to illustrate their use . The form provides a comprehensive set of well-accepted st and ards of research in a format that encourages detailed , consistent , and thoughtful evaluation of therapeutic studies . The evaluation form is recommended as a tool for physicians who wish to develop and exercise skill in evaluating therapeutic studies BACKGROUND / AIMS Electronic search es on data bases for r and omised clinical trials and controlled clinical trials do not identify as many trials as h and search es , and trial reporting may be flawed . The aims were to identify all fully reported r and omised clinical trials in the Journal of Hepatology and to make a qualitative assessment of the reporting . METHODS The publications were identified by systematic ally h and search ing the full text of the journal and search ing MEDLINE . Central dimensions of trial quality were used to assess the reporting quality of the trials . RESULTS R and omised clinical trials represented 8.4 % of the original articles ( 171/2028 ) . Ten original articles ( 0.5 % ) could not be classified . A search on MEDLINE identified 81.3 % of the r and omised clinical trials , i.e. , 139 out of the 171 identified by the h and search . A total of 166 r and omised clinical trials could be quality assessed . Forty-seven ( 28.3 % ) of them reported adequate generation of allocation sequence ; 22 ( 13.3 % ) adequate allocation concealment ; 95 ( 57.2 % ) allowed intention-to-treat analysis with only a few losses to follow-up ; 50 ( 30.1 % ) were double-blind ; 33 ( 19.9 % ) reported sample -size calculations ; 13 trials ( 7.8 % ) employed the crossover design ; and the median number of subjects per intervention arm in parallel group trials was 19 subjects ( interquartile range : 11 - 31 ; range : 5 - 519 ) . The quality of reporting was significantly better in regular issue articles than in supplement articles . CONCLUSIONS Many important r and omised clinical trials are published in the Journal of Hepatology , but there seems to be ample room for improvement of quality of reporting We devised 33 rules for the evaluation of r and om control trials ( RCT ) and used them to assess 56 RCTs listed in Index Medicus during 1980–82 on antibiotic prophylaxis of surgical wound infection . We asked 15 questions about design and conduct , 10 about analysis and 8 about presentation . Out of a maximum score of 100 only 16 papers scored over 70 , the highest being 89 and the lowest 34 . Defects in presentation were not common , and 17 papers scored over 90 per cent . Defects in analysis included the incorrect use of statistical tests and ignoring the Type II error in ‘ negative ’ trials ; only 13 papers scored over 70 per cent . Defects in design and conduct included transgressions of ethical principles , inappropriate regimens , ill‐defined end points and biased r and omization or assessment ; only 20 papers scored over 70 per cent . We conclude that there is room for improvement in the performance of RCT and that the application of the 33 rules would be helpful not only to research ers but also to editors and referees of scientific journals , and to their readers Guidelines are proposed for the reporting of clinical trials . These are meant to be used for both authors and journal editors . Specific proposals are made for : reporting the population under study , actual therapy used , describing the study design , accounting of patients , follow-up statistics , and describing the quality control of the data . Nonr and omized studies require special discussion . Such studies potentially have substantial biases which can lead to incorrect conclusions . Six areas of biases arising in nonr and omized studies are pointed out which should require a discussion in an acceptable published paper . The presentation of statistical results and the reporting of early studies present unusually difficult problems . Guidelines are presented for statistical analyses which , although simple to implement in practice , are not generally used . A proposal is made for the publication of early results of a study which require that the authors agree to follow and periodically report on their trial to the journal editor . If the early conclusions change with additional follow-up , the editor should notify its readers . The adoption of these guidelines can be an important force in raising the scientific level of the reporting of clinical trials Evidence shows that the quality of r and omized clinical trials ( RCTs ) affects estimates of intervention efficacy , which is significantly exaggerated in low- quality trials . The present study examines the quality of all 235 RCTs published in HEPATOLOGY from the initiation in 1981 through August 1998 . Quality was assessed by means of a vali date d 5-point scale and separate quality components associated with empirical evidence of bias . Only 26 % of all RCTs reported sample size calculations , 52 % adequate generation of the allocation sequence , 34 % adequate allocation concealment and 34 % double-blinding . The median quality score of all trials was 3 points ( range , 1 - 5 points ) . Multiple logistic regression analysis explored the association between quality and therapeutic areas , number of centers , external funding , year of publication , and country of origin . High- quality trials were most likely to investigate portal hypertension ( odds ratio [ OR ] : 2.4 ; 95 % CI : 1.1 - 5.5 ; P = .03 ) , be multicentered ( OR : 3.4 ; 95 % CI : 1.3 - 8.9 ; P = .01 ) , sponsored by public organizations ( OR : 4.2 ; 95 % CI : 2.1 - 8.6 ; P = .0001 ) , or the drug and device industry ( OR : 4.7 ; 95 % CI : 2.2 - 10.2 ; P = .0001 ) compared with other therapeutic areas , single-center trials , and trials with no external funding . Quality did not improve with time and was not associated with country of origin . The main conclusions are that the quality of RCTs in HEPATOLOGY needs improvement and that the probability of high quality increased with the number of centers involved and external funding As the sciences of emergency medicine and acute care medicine develop , it becomes imperative for research ers in these fields to accurately and completely report the methodology of their investigations . It is only through complete reporting that other investigators can critically examine , replicate , or exp and on the results of an investigation . The purpose of our study was to compare the completeness of methodology reporting in three acute care journals , Annals of Emergency Medicine , Critical Care Medicine , and Journal of Trauma . Thirty-eight criteria characteristics necessary for the replication of a clinical trial were identified and grouped into ten categories . The categories were experimental design , recruitment and exclusion of subjects , selection of study sample , subject allocation , therapeutic regimen , blindness , outcome criteria , analysis of confounders , withdrawal of subjects , and statistical analysis . All prospect i ve , interventional , controlled trials appearing in these journals from January 1980 to June 1983 were identified . A total of 45 trials were found . Each trial was read independently by two review ers to determine whether each of the 38 criteria was clearly reported , not clearly reported , or not applicable . Disagreements were resolved by a third reader ( adjudicator ) . The results are reported as the mean proportion of items clearly reported + /- st and ard deviation : Annals of Emergency Medicine ( n = 16 ) , 0.39 + /- 0.10 ; Journal of Trauma ( n = 18 ) , 0.33 + /- 0.14 ; and Critical Care Medicine ( n = 11 ) , 0.32 + /- 0.09 . A one-way analysis of variance found no statistically significant difference between journals with respect to these proportions ( P = .25 ) . ( ABSTRACT TRUNCATED AT 250 WORDS The methodology of r and omized control trials ( RCTs ) of the primary treatment of early breast cancer has been review ed using a quantitative method . Sixty-three RCTs comparing various treatment modalities tested on over 34,000 patients and reported in 119 papers were evaluated according to a st and ardized scoring system . A percentage score was developed to assess the internal validity of a study ( referring to the quality of its design and execution ) and its external validity ( referring to presentation of information required to determine its generalizability ) . An overall score was also calculated as the combination of the two . The mean overall score for the 63 RCTs was 50 % ( 95 % confidence interval [ CI ] = 46 % to 54 % ) with small and nonstatistically significant differences between types of trial . The most common method ologic deficiencies encountered in these studies were related to the r and omization process ( only 27 of the 63 RCTs adopted a truly blinded procedure ) , the h and ling of withdrawals ( only 26 RCTs included all patients in the analyses ) , the description of the follow-up schedule ( only 12 RCTs reported adequately ) , the report of side effects ( adequate information given in 33 RCTs ) , and the description of the patient population ( satisfactory in 29 RCTs ) . Telephone calls to the principal investigators improved the quality scores by seven points on a scale of 100 , indicating that some of the deficiencies lay in reporting rather than performance . There was evidence that quality has improved over time and that the increasing tendency of involving a biostatistician in the research team was positively associated with the improvement of the internal validity but not with the external A stepwise method for the assessment of reports of drug trials was used to determine the validity of drug reports published in The Canadian Medical Association Journal during the five-year period , January 1 , 1956 , to December 31 , 1960 . The method is simple and consists of applying four criteria : ( 1 ) the presence of adequate controls ; ( 2 ) r and omization of treatments ; ( 3 ) objective assessment of drug effects ; and ( 4 ) statistical analysis of results . If these criteria were absent , the assessment was stopped , and the report was felt to be invalid . A total of 203 articles were review ed and 11 were found to fulfil these criteria . During the same period of time there were 93 additional case reports of drug effects , 39 of which described the effectiveness of a drug without there being adequate controls . The remainder of the case reports described drug toxicities WHICH events should be counted in a r and omized clinical trial , and when they are counted , which treatment should be blamed ? That a controversy exists is clear from reading " Letters " columns after p ... THE R AND OMIZED controlled trial ( RCT ) , more than any other methodology , can have a powerful and immediate impact on patient care . Ideally , the report of such an evaluation needs to convey to the reader relevant information concerning the design , conduct , analysis , and generalizability of the trial . This information should provide the reader with the ability to make informed judgments regarding the internal and external validity of the trial . Accurate and complete reporting also benefits editors and review ers in their deliberations regarding su bmi tted manuscripts . For RCTs to ultimately benefit patients , the published report should be of the highest possible st and ard In a survey of 62 clinical trials published in four dermatology journals , recommended methodology was reported 41 % of the time . Of the 62 trials , 31 were open drug trials and 27 were controlled trials . Forty-one percent of 13 recommended method ologic items were reported in these articles . The rate of reporting for these items ranged from 3 % for power and method of r and omization to 76 % for loss to follow-up and the use of a control group . There were no differences among journals in reporting methods used . Investigators and editors are encouraged to improve the reporting and use of recommended methodology in clinical trials published in the dermatologic literature Herbal products are becoming increasingly mainstream . This is not simply a comment on their popularity , but on the level and rigor of scientific research and acceptance by clinical investigators , as well as the attention being paid to these therapeutic options by government bodies . A recent trial published in the Journal of the American Medical Association ( JAMA ) evaluating St. John 's wort for depression demonstrates this shift.1 Several features of this trial are noteworthy . Not only was the trial of rigorous design and published in a highly reputed journal , but it was completed by a group of high profile and experienced US psychiatric research ers who are generally associated with research ing pharmaceuticals . In the past , the quality of trials involving herbal products and other alternative treatment options for psychiatric and other disorders has been criticized.2 Criticisms have included failing to account for biases and confounders , using nonst and ardized products and poor study design . However , in the last 5 years , MEDLINE ( www.ncbi.nlm.nih.gov/ PubMed ) has indexed over 50 r and omized controlled trials ( RCTs ) investigating complementary medicines for treating mental disorders , suggesting that an increasing number of alternative approaches are being tested using what is approaching gold st and ard methods . This number is likely an underestimate because MEDLINE search strategies , even those devised by experts , can fail to locate a significant number of relevant trials.3 It is also well recognized that MEDLINE does not index all relevant journals in the area of complementary medicines.4 The Cochrane Controlled Trials Register of the Cochrane Library ( www.cochranelibrary.com ) , which lists clinical trials that have been identified through regular search ers of MEDLINE , EMBASE and h and search es of clinical journals , is considered an authoritative source of RCTs .5 For illustrative purpose s only , a selection of RCTs from the Cochrane Library of herbal products used for psychiatric indications is listed in Table 1.1,6,7,8,9,10,11,12,13 Table 1 Considering that the amount of good- quality research regarding herbals in psychiatric disorders appears to be exp and ing steadily , treatment review s , unless up date d regularly , quickly become out date d and serve a limited purpose . Such review s are also not particularly useful for making individual patient treatment decisions ; they tend not to address specific clinical questions adequately , but rather , provide the reader with a general awareness of the topic . As such , this paper is not intended to comprehensively review the benefits and risks of herbal products commonly used for psychiatric disorders . Recent examples of such review s can be found elsewhere.14,15,16,17 Instead , the purpose of this review is to present the steps involved in taking an evidence -based approach to clinical decision making regarding the use of herbal products in psychiatry . The reader will be oriented to the evidence -based process using examples of herbal product use for mental disorders . Methods and tools that facilitate rapid access to the best clinical research about herbal products will be presented . In addition , special issues concerning herbal therapies that differ from the evaluation of pharmaceutical products will be introduced and discussed The aim of this short paper is to make it easier for authors , refcrccs , cditors and , ultimately , rcadcrs to assess the quality of controlled trials mounted to compare alternative forms of care . The guidelines set out below are based on checklists publishcd in other journals ( e.g. the British Medical Journal 1987 ) , and schemes suggested for assessing the quality of published r and omized controlled trials ( Mahon & Daniel 1964 ; Mosteller et uf . 1980 ; McMastcr University Department of Clinical Epidemiology and Biostatistics 1981 ; Chalmers et al. 1981 ; Der Simonian et ul . 1982 ; Zelen 1983 ; Emcrson et ul . 1984 ; Thacker 1985 ; Meinert 1986 ) . The rationale for paying attention to aspects of study design and reporting is discussed in these and other publications included in the bibliography ( see Grant & Chalmers 1985 ; Chalmers 1989 ) . A list of 28 reasonable questions to ask in respect of reports of controlled trials is presented in Table 1 . Not all of these questions are relevant to all trials . Ncvertheless , cvidence that investigators have paid appropriate attention to these guidelines is likely to improve the chances that a trial report su bmi tted to this Journal will be accepted for publication . R and omized , controlled trials ( RCTs ) of herbal interventions often inadequately describe important aspects of their methods ( 1 - 4 ) . Although the quality of reporting of these trials may be improving with time , many still lack important information , particularly about the composition of the herbal intervention ( 4 , 5 ) . Crude herbal drugs are natural products and their chemical composition varies depending on several factors , such as geographic source of the plant material , climate in which it was grown , and time of harvest . Commercially available herbal medicinal products also vary in their content and concentration of chemical constituents from batch to batch and when products containing the same herbal ingredient are compared among manufacturers ( 6 - 14 ) . Even when herbal products are st and ardized for content of known active or marker compounds to achieve more consistent pharmaceutical quality , there is variation in the concentrations of other constituents . These variations can result in differences in pharmacologic activity in vitro ( 15 ) and in bioavailability in humans ( 16 ) . Mindful of these issues , we elaborated on the 22-item checklist of the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement ( 17 ) to help authors and editors improve reporting of RCTs of herbal interventions . Methods We developed these reporting recommendations in 3 phases that included premeeting item generation , a consensus meeting , and postmeeting feedback . The individuals who participated are listed in the Appendix . To generate items , 1 investigator conducted telephone interviews of 16 participants with expertise in the method and reporting of RCTs ( 5 participants ) , pharmacognosy ( 4 participants ) , herbal medicinal products ( 5 participants ) , medical statistics ( 1 participant ) , and herbal product manufacturing ( 1 participant ) . The investigator asked participants to suggest revisions to existing CONSORT checklist items and also to additional items required for reporting trials of herbal interventions . He asked participants to nominate revisions or new items on the basis of empirical evidence that not reporting the item would bias estimates of treatment effect . When no empirical evidence was available , commonsense reasoning was acceptable . After completing all telephone calls , the investigator thematically grouped items and circulated them by e-mail to each participant for review . Fourteen participants attended the consensus meeting . The meeting began with a review of the premeeting checklist item suggestions . We emphasized minimizing item elaborations and additions and basing elaborations on evidence whenever possible . Each item suggestion was presented and followed by debate for its inclusion , deletion , or modification . This process was repeated until all items were review ed and a consensus emerged . After the consensus meeting , we circulated a draft summary report to all participants to ensure that it accurately represented decisions made during the consensus meeting . We then circulated the report to the wider CONSORT Group for input and revised it on the basis of their suggestions . Ethical approval was obtained from The University of Toronto Health Sciences Ethics Review Committee on 23 January 2004 . Financial support for the consensus meeting was provided by the Canadian Institutes of Health Research . The funding body had no role in the design , conduct , or analysis of this study and did not influence the decision to su bmi t the manuscript for publication . All research ers are independent of the funders . Results The group did not recommend any new CONSORT checklist items or modifications in the CONSORT flow diagram . We did , however , elaborate on 9 of the 22 CONSORT checklist items to enhance their relevance to trials of herbal interventions ( Table , Figure ; Appendix Table ) , including minor recommendations for 8 items ( item 1 [ title and abstract ] , item 2 [ background ] , item 3 [ participants ] , item 6 [ outcomes ] , item 15 [ baseline data ] , item 20 [ interpretation ] , item 21 [ generalizability ] , and item 22 [ overall evidence ] ) and detailed recommendations for 1 item ( item 4 [ interventions ] ) . Table . Proposed Elaboration of CONSORT Checklist Item 4 for Reporting R and omized , Controlled Trials of Herbal Medicine Interventions Figure . The high-pressure liquid chromatography chemical fingerprint for the extract of Ginkgo biloba L Appendix Table . Proposed Elaborations of CONSORT Items for R and omized , Controlled Trials of Herbal Medicine Interventions The Table shows the detailed recommendations for item 4 and an example of good reporting related to each recommendation . These recommendations begin with the words where applicable to indicate that all information suggested may not be applicable to every type of herbal medicine intervention . For example , an herbal medicinal product comprising crude herbal material ( for example , leaves and stems ) simply prepared as a tea or decoction does not require description of the type and concentration of solvent used and the ratio of herbal drug to extract ( item 4B.3 ) . Also , not every herbal medicine intervention will have a finished product or extract name or manufacturer ( item 4A.2 ) , but instead may be made by the investigators specifically for the study . In such circumstances , all methods used in preparing and formulating the product must be reported . Similarly , item 4F is not required for herbal interventions when the practitioner is not a part of the intervention . With these exceptions , we recommend that all information shown in the Table be reported for all herbal interventions . Discussion We developed recommendations to be used in conjunction with the existing CONSORT checklist when reporting RCTs of herbal interventions . In particular , we thought it imperative that reports of RCTs provide clear and complete descriptions of the herbal intervention . We think that our recommendations might also be relevant for reporting herbal interventions in other research design s , whether pre clinical ( for example , in vivo or in vitro ) or clinical ( for example , N of 1 trials ) , and refer interested readers to a detailed explanatory document that further describes each of our recommendations and provides additional examples of good reporting ( 22 ) . We hope that authors find our recommendations instructive and that journals will endorse their use and modify their instructions to authors accordingly Wound-care journals contain abundant reports of trials , but not all report a satisfactory methodology . Systematic review s of wound-care trials have highlighted many areas for improvement , and the National Institute for Clinical Excellence ( NICE ) guidelines recommend that primary research in the field of pressure ulcer prevention should adhere more closely to current method ological st and ards in terms of conduct and reporting . The CONSORT tool was developed to help achieve these improvements in the design and reporting of r and omised controlled trials ( RCTs ) A R AND OMIZED controlled trial ( RCT ) is the most reliable method of assessing the efficacy of health care interventions .1,2Reports of RCTs should provide readers with adequate information about what went on in the design , execution , analysis , and interpretation of the trial . Such reports will help readers judge the validity of the trial . There have been several investigations evaluating how RCTs are reported . In an early study , Mahon and Daniel3 review ed 203 reports of drug trials published between 1956 and 1960 in theCanadian Medical Association Journal . Only 11 reports ( 5.4 % ) fulfilled their criteria of a valid report . In a review of 45 trials published during 1985 in three leading general medical journals , Pocock and colleagues4reported that a statement about sample size was only mentioned in five ( 11.1 % ) of the reports , that only six ( 13.3 % ) made use of confidence intervals , and that the statistical analyses tended Objective : The quality of original clinical trial publications pertaining to the use of oral antifungal agents to treat onychomycosis was evaluated using predetermined criteria . Methods : The list of studies included in this analysis was determined by conducting a search in Medline . For each clinical trial , two independent review ers each determined a composite score by evaluating a list of criteria that were felt to represent a good study , for example , r and omization and blinding , prior sample size calculated , and treatment regimen clearly explained . A citation count was performed to determine whether higher- quality papers were cited more often than lower- quality papers . Results : Forty-five studies were included in this quality analysis of study design . Of these , 27 were considered to be “ high quality ” ( score greater than or equal to 11 out of 20 ) . A significant correlation coefficient of 0.997 was found between the two review ers ( P < 0.00001 ) . Higher- quality papers were cited significantly more often than lower- quality papers ( P = 0.03 ) . Conclusion : The scale that we use to evaluate the quality of onychomycosis studies has high interrater reliability . According to this scale , many published studies ( 18 out of 45 ) pertaining to treatments for onychomycosis do not meet the criteria required to be considered “ high quality . ” SommaireObjectif : Évaluation de la qualité des publications initiales relatives aux essais cliniques sur l’usage d’agents antifongiques oraux , au moyen de critères prédéterminés . Méthodes : La liste des études considérées dans cette analyse a été tirée de la base de données Medline . Deux examinateurs indépendants ont déterminé chacun le score composite de chaque essai clinique en tenant compte d’une liste de critères qui définiraient une bonne étude . Par exemple , la r and omisation , l’insu , le calcul de la taille de l’échantillon et l’explication claire du schema thérapeutique . Un compte des références a été fait au préalable pour voir si les travaux de haute qualité étaient cités plus que les travaux de moindre qualité . Résultats : L’analyse de la qualité de la méthodologie a porté sur 45 études . Parmi ces études , 27 ont été considérées de « haute qualité » ( score supérieur ou égal à 11 sur 20 ) . Un coefficient de corrélation élevé de 0,997 a été trouvé entre les deux examinateurs ( P < 0,00001 ) . Les travaux de haute qualité ont été cités plus fréquemment que les travaux de moindre qualité ( P = 0,03 ) . Conclusion : L’échelle que nous avons adoptée dans l’évaluation de la qualité des études sur l’onychomycose présente un coefficient d’objectivité élevé . Selon cette échelle , un gr and nombre d’études publiées ( 18 sur 45 ) sur le traitement des onychomycoses ne répondent pas aux critères requis pour étre considérées de « haute qualite » In making treatment decisions , doctors and patients must take into account relevant r and omised controlled trials ( RCTs ) and systematic review s. Relevance depends on external validity ( or generalisability)--ie , whether the results can be reasonably applied to a definable group of patients in a particular clinical setting in routine practice . There is concern among clinicians that external validity is often poor , particularly for some pharmaceutical industry trials , a perception that has led to underuse of treatments that are effective . Yet research ers , funding agencies , ethics committees , the pharmaceutical industry , medical journals , and governmental regulators alike all neglect external validity , leaving clinicians to make judgments . However , reporting of the determinants of external validity in trial publications and systematic review s is usually inadequate . This review discusses those determinants , presents a checklist for clinicians , and makes recommendations for greater consideration of external validity in the design and reporting of RCTs OBJECTIVE To appraise systematic ally the study design and quality of reporting of r and omized controlled trials ( RCT ) on systemic lupus erythematosus ( SLE ) and to identify potential defects and biases . METHODS RCT with at least 5 patients with SLE were retrieved from MEDLINE , EMBASE , and the Cochrane Library . We analyzed study design , quality of reporting , and trial results . RESULTS Ninety-four trial reports ( 37 on lupus nephritis ) were eligible with 2,257 SLE patients ( n = 795 in lupus nephritis trials ) . Median sample size was 28 patients . Fifty-one trials ( 54.3 % ) were double blind , but only 31 ( 33.0 % ) mentioned the r and omization mode , only 19 ( 20.2 % ) described allocation concealment , and only 7 ( 7.5 % ) were adequately powered . Sixty-three trials ( 67 % ) described adequately reasons for withdrawals . Nephritis trials had on average longer followup ( p = 0.001 ) and were less likely to be double blind ( p < 0.001 ) , to describe reasons for withdrawals [ both overall ( p = 0.008 ) and per arm ( p = 0.009 ) ] and to involve a comparison against placebo or no treatment ( p < 0.001 ) . Larger trials scored higher on several quality characteristics . Significant efficacy or trend for efficacy was cl aim ed in 72 reports ( 76.6 % ) and this was even more common in trials published in 1999 - 2002 ( 89.5 % ) . Significant efficacy was found more frequently in trials that clearly specified withdrawals per arm ( p = 0.001 ) and outcomes ( p = 0.001 ) and used intention-to-treat analyses ( p = 0.03 ) . Besides outcome specification , no other quality variables seemed to improve significantly over time . CONCLUSION Several aspects of the design and reporting of RCT on SLE can be improved . Larger , adequately powered , and accurately reported trials are needed PURPOSE To critically appraise therapeutic innovations tested in r and omized controlled trials ( RCTs ) in multiple myeloma from 1966 - 1998 . DESIGN We performed a comprehensive search to identify published RCTs in multiple myeloma . Quality dimensions of the design , conduct , analysis and reporting of each trial were assessed . RESULTS We identified 136 RCTs reported in 114 papers . Overall , therapeutic efforts in multiple myeloma result ed in a 5 % absolute gain in five-year survival at a cost of a 0.35 % increase in treatment related deaths . Hence on average a patient enrolled in a RCT in myeloma is 14 ( 5/35 ) times more likely to be helped than harmed . However , when the RCTs were critically appraised for key quality dimensions of trials ' conduct , we found that only 7 % ) of the trials ( 10 of 136 ) were analyzed according to intention-to-treat ( ITT ) , 9 % ( 12 of 136 ) reported a power analysis ( beta error ) , 32 % ( 35 of 111 ) adequately concealed treatment allocation , 78 % ( 106 of 136 ) provided a detailed description of patient withdrawals , and 83 % ) ( 19 of 22 ) of the double blind RCTs had appropriately described methodology . CONCLUSIONS Therapeutic innovations tested through RCTs have improved the outcomes of patients with multiple myeloma . However , the quality of RCT reporting and methodology in multiple myeloma could be substantially improved . Most therapeutic strategies in multiple myeloma are based on modest quality , low power evidence . Despite these shortcomings our findings suggest patients may often clinical ly benefit from enrollment in clinical trials when available . Patients on average received modest benefit from innovative therapies tested in RCTs at little additional risk of side effects The criteria and scoring method for a system to evaluate the quality of r and omized control trials ( RCTs ) in dental research based on published reports is presented . This sytem is based on one devised for evaluation of RCTs in medicine . Items assessed in this system include r and omization and blinding procedures , subject selection criteria , treatment protocol s , and statistical analyses . Assessing the quality of RCTs can contribute to improved study design , implementation and reporting by investigators , and evaluation of reports by referees and editors of scientific journals OBJECTIVES To determine the relationship between the quality of articles and whether they were published in a supplement or in the parent journal . DATA SOURCES AND STUDY SELECTION All r and omized control trials of drug therapies in adults published in the American Journal of Cardiology , the American Journal of Medicine and the American Heart Journal from January 1990 and obtained in November 1992 by means of a MEDLINE search . A total of 318 abstract s appeared to meet our inclusion criteria , and these articles were obtained and review ed in further detail . An additional 76 were excluded . DATA EXTRACTION Three review ers who were " blinded " and thus unaware of supplement status independently assessed the quality of each of the remaining 242 articles according to a st and ard quality scoring system . DATA SYNTHESIS Overall , 67 ( 27.7 % ) of the articles were published in journal supplements . Article quality scores ranged from 4.2 % to 87.5 % , with a mean ( + /- SD ) score of 37.2 % + /- 13.1 % . Quality scores were lower in articles published in journal supplements than in those published in the parent journal ( t[240 ] = 2.61 , P = .01 ) . The mean quality score for articles published in journal supplements was 33.6 % + /- 12.8 % compared with a score of 38.5 % + /- 13.1 % for articles published in the parent journal . Supplement articles included in their final analysis a smaller proportion of the patients initially r and omized ( t[75 ] = 2.8 , P = .007 ) . CONCLUSION Our findings suggest that r and omized control trials published in journal supplements are generally of inferior quality compared with articles published in the parent journal . The review process surrounding the publication of journal supplements should be consistent with that of the parent journal In this first article of a series on controlled clinical trials in emergency medicine , an overview of the structure of such studies and the relevant issues related to study design , data generation , statistical analysis , and reporting are presented . The importance of precise patient selection , r and omization and stratification , blinding , and equivalent therapeutic intervention in study design has been discussed . In addition , precise outcome and measurement criteria , assessor qualifications , deficiencies in data , appropriate sample -size selection , and reporting are also presented . Although an idealized framework for the conduct and analysis of a controlled clinical trial is provided , it should be appreciated that design and analytical compromises may at times be difficult to avoid in clinical research . Future articles in this series will discuss r and omization in clinical trials , alternatives to r and omization , beta error and sample -size determination , the statistical and analytical issues related to imperfections in the execution of a trial , and issues related to the reporting of clinical trials Abstract Of 32 reports of anticoagulant therapy for acute myocardial infa rct ion , appraised to ascertain the maintenance of eight method ologic st and ards that affect the scientific comparability of t The ability of a small-scale r and om-control clinical trial comprising less than 500 patients to disclose clinical ly important differences between treatment groups depends on the event rate in the control group . The high rate of wound infection after abdominal operations has attracted many trials of methods of antibiotic prophylaxis . We review ed all of the pertinent English literature recorded in Index Medicus in 1980 and 1981 . We examined 45 articles for defects in design , analysis , and presentation . Of the 45 articles , 25 reported statistically significant differences between treatment groups and 20 , no significant differences . Unsatisfactory methods of r and omization were used in four trials , ethics were question able in 22 , statistical methods were incorrect in 31 , and presentation was inadequate in 40 . We concluded that there is room for improvement in the conduct of clinical trials The purpose s of this study were to develop an instrument to assess the validity of r and omized controlled trials and to report on the differences in the validity of r and omized controlled trials between two podiatric medical journals and a mainstream medical journal . The study demonstrated that after adequate training , there can be agreement among review ers evaluating the quality of published r and omized controlled trials using an established instrument and guidelines . The results of the study indicate that r and omized controlled trials published in podiatric medical journals are less credible than those published in a mainstream medical journal Background The authors evaluated the quality of clinical trials published in four anesthesia journals during the 20-yr period from 1981–2000 . Methods Trials published in four major anesthesia journals during the periods 1981–1985 , 1991–1995 , and the first 6 months of 2000 were grouped according to journal and year . Using r and om number tables , four trials were selected from all of the eligible clinical trials in each journal in each year for the periods 1981–1985 and 1991–1995 , and five trials were selected from all of the trials in each journal in the first 6 months of 2000 . Methods and results sections from the 160 trials from 1981–1985 and 1991–1995 were r and omly ordered and distributed to three of the authors for blinded review of the quality of the study design according to 10 predetermined criteria ( weighted equally , maximum score of 10 ) : informed consent and ethics approval , eligibility criteria , sample size calculation , r and om allocation , method of r and omization , blind assessment of outcome , adverse outcomes , statistical analysis , type I error , and type II error . After these trials were evaluated , 20 trials from the first 6 months of 2000 were r and omly ordered , distributed , and evaluated as described . Results The mean ( ± SD ) analysis scores pooled for the four journals increased from 5.5 ± 1.4 in 1981–1985 to 7.0 ± 1.1 in 1991–1995 ( P < 0.00001 ) and to 7.8 ± 1.5 in 2000 . For 7 of the 10 criteria , the percentage of trials from the four journals that fulfilled the criteria increased significantly between 1981–1985 and 1991–1995 . During the 20-yr period , the reporting of sample size calculation and method of r and omization increased threefold to fourfold , whereas the frequency of type I statistical errors remained unchanged . Conclusion Although the quality of clinical trials in four major anesthesia journals has increased steadily during the past two decades , specific areas of trial methodology require further attention The aim of this study was to develop a quality of study tool rate the method ological quality of individual primary r and omized controlled trials ( RCTs ) to be included in a meta- analysis . A Delphi-technique using several rounds of questions to seek consensus , among trialists , on criteria important in a RCT was used . Eight trialists formed the Delphi panel . The developed quality of study tool consisted of 53 items in 15 dimensions . The tool was tested for reliability and validity . Unlike many other quality assessment tools , the developed tool may be used to rate numerically each primary study . This is important in review s or in meta-analyses where one objective may be to ascertain whether those studies of a higher quality exhibit different results to review ing studies of lower quality . The tool needs further testing OBJECTIVES R and omized controlled trials offer the best chance for valid treatment comparisons , yet most trials are of poor quality . This may reflect a lack of awareness of the requirements for conducting and reporting this type of research . If so , then citation of methodology references might indicate knowledge of how to conduct these studies and vice versa . Our study tests the hypothesis that the method ologic quality of published trials is related to citation of methodology references . STUDY DESIGN We performed a h and search of the American Journal of Obstetrics and Gynecology , the British Journal of Obstetrics and Gynaecology , the Journal of Obstetrics and Gynaecology , and Obstetrics and Gynecology to identify all r and omized controlled trials published in 1990 and 1991 ( N = 206 ) . We review ed the reference lists of all reports of r and omized controlled trials and evaluated the adequacy of r and omization methods by accepted criteria . RESULTS Most reports ( 81.6 % ) cited no methodology text or article . Although lack of any methodology reference was not significantly related to failure to report an adequate r and om method of sequence generation , this was highly related ( p < 0.001 ) to failure to report adequate allocation concealment . Scanning the reference list of reports took a mean of 16 seconds and identified most poorly done trials . CONCLUSIONS Investigators who conduct r and omized controlled trials should be thoroughly familiar with this type of research or should get expert help . Poorly done trials are wasteful and often misleading

WIDER IMPLICATION S In a general IVF population , GnRH antagonists are associated with lower ongoing pregnancy rates when compared to long protocol agonists , but also with lower OHSS rates . Thus st and ard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization . In couples with PCOS and poor responders , GnRH antagonists do not seem to compromise ongoing pregnancy rates and are associated with less OHSS and therefore could be considered as st and ard treatment

BACKGROUND Most review s of IVF ovarian stimulation protocol s have insufficiently accounted for various patient population s , such as ovulatory women , women with polycystic ovary syndrome ( PCOS ) or women with poor ovarian response , and have included studies in which the agonist or antagonist was not the only variable between the compared study arms . OBJECTIVE AND RATIONALE The aim of the current study was to compare GnRH antagonist protocol s versus st and ard long agonist protocol s in couples undergoing IVF or ICSI , while accounting for various patient population s and treatment schedules .

PURPOSE To compare outcome following in vitro fertilization-embryo transfer ( IVF-ET ) using controlled ovarian hyperstimulation ( COH ) regimens using either the gonadotropin-releasing hormone ( GnRH ) agonist leuprolide acetate vs the GnRH antagonist ganirelix . METHODS Women needing IVF for conception were r and omly assigned to 300 IU of gonadotropins with ganirelix used in the follicular phase when a follicle with a 14 mm average diameter was attained vs a regimen using leuprolide acetate from the mid-luteal phase of the previous cycle . RESULTS There were no differences found in clinical , ongoing , delivered pregnancy rates or implantation rates between groups . CONCLUSIONS The use of GnRH antagonists do not seem to reduce IVF outcome compared to using GnRH agonists in COH regimens OBJECTIVE To compare the efficacy of the long GnRH agonist and the fixed GnRH antagonist protocol s in IVF poor responders . STUDY DESIGN This was a r and omized controlled trial performed in the Iakentro IVF centre , Thessaloniki , from January 2007 to December 2011 , concerning women characterised as poor responders after having 0 - 4 oocytes retrieved at a previous IVF cycle . They were assigned at r and om , using sealed envelopes , to either a long GnRH agonist protocol ( group I ) or a GnRH antagonist protocol ( group II ) . RESULTS Overall 364 women fulfilled the inclusion criteria and were allocated to the two groups : finally 330 participated in our trial . Of these , 162 were treated with the long GnRH agonist protocol ( group I ) , and 168 with the fixed GnRH antagonist protocol ( group II ) . Numbers of embryos transferred and implantation rates were similar between the two groups ( P = NS ) . The overall cancellation rate was higher in the antagonist group compared to the agonist group , but the difference was not significant ( 22.15 % vs. 15.2 % , P = NS ) . Although clinical pregnancy rates per transfer cycle were not different between the two groups ( 42.3 % vs. 33.1 % , P = NS ) , the clinical pregnancy rate per cycle initiated was significantly higher in the agonist compared to the antagonist group ( 35.8 % vs. 25.6 % , P=0.03 ) . CONCLUSIONS Although long GnRH agonist and fixed GnRH antagonist protocol s seem to have comparable pregnancy rates per transfer in poor responders undergoing IVF , the higher cancellation rate observed in the antagonist group suggests the long GnRH agonist protocol as the first choice for ovarian stimulation in these patients Objective To study if luteal E2 pre-treatment before GnRH antagonist protocol improves IVF/ICSI outcomes compared with st and ard long GnRH agonist protocol . Design A prospect i ve , r and omized and controlled study . Setting ART center of a state public hospitalPatient(s)Two hundred twenty infertile women underwent IVF/ICSI treatments . Intervention(s ) Participants received oral Estradiol Valerate 4 mg/day preceding the IVF cycle from day 21 until day 2 of next cycle before GnRH antagonist protocol ( E2 pre-treatment group n = 109 ) or received st and ard long GnRH agonist protocol as control group ( n = 111).Main outcome measure(s)Number of oocytes collected , MII oocytes , fertilization , implantation , live birth and early pregnancy rate , and hormone profiles . Result (s)E2 pre-treatment exerted a significant suppressive effect on FSH but not LH secretion compared with basal FSH and LH levels . In E2 pre-treatment group serum LH level was significantly higher during COH and serum P was also significantly higher on the day of HCG injection compared with control group . Five patients from E2 pre-treatment group had elevated LH at all time ( ≥10 IU/L ) and also a concomitantly high P ( > 1 ng/mL ) . Two of the five women achieved pregnancy but had early pregnancy loss . Overall , IVF/ICSI outcomes such as implantation , clinical pregnancy and live birth rates were similar between E2 pre-treatment and control groups . Conclusion (s)Luteal E2 pre-treatment before GnRH antagonist protocol significantly increases serum LH level and incidence rate of premature LH but no significant effect is observed on implantation , clinical pregnancy , live birth and early pregnancy loss rates compared with long GnRH agonist protocol . However , more studies in large numbers of cycles are needed to confirm that increased serum LH level by E2 pre-treatment during COH has no negative effect on the IVF/ICSI outcomes OBJECTIVE To evaluate whether the incidence of luteinizing hormone ( LH ) rise is reduced by using a flexible compared with a fixed day-6 protocol of GnRH antagonist administration . DESIGN R and omized controlled trial . SETTING Tertiary university hospital . PATIENT(S ) Patients undergoing in vitro fertilization ( n = 146 ) . INTERVENTION(S ) Ovarian stimulation was performed using recombinant FSH and GnRH antagonists . GnRH antagonist cetrorelix ( 0.25 mg/d ) was started either on day 6 of stimulation ( fixed group ) or when LH was > 10 IU/L , and /or a follicle with mean diameter > 12 mm was present , and /or serum E(2 ) was > 150 pg/mL. Patient monitoring was initiated on day 3 of stimulation . MAIN OUTCOME MEASURE(S ) Incidence of LH rise . RESULT ( S ) No statistically significant difference was observed between the flexible and fixed groups regarding the incidence of LH rise , which was lower in the flexible group ( 11.0 % vs. 15.1 % , difference -4.1 % , 95 % confidence interval -15.4 % to + 7.1 % ) . No LH surges were observed in any of the patients studied . CONCLUSION ( S ) Flexible antagonist administration from day 3 onward does not appear to reduce the incidence of LH rises compared with fixed antagonist administration on day 6 of stimulation Purpose To evaluate the results of gonadotropin-releasing hormone agonist ( GnRHa ) and gonadotropin-releasing hormone antagonist ( GnRHant ) use in two demographically matched groups of normoresponder in-vitro fertilisation or intracytoplasmic sperm injection ( IVF/ICSI ) patients in a prospect i ve study . Methods We r and omised 93 patients undergoing IVF/ICSI between May 2005 and August 2006 . Patients with IVF indications were included except for those with polycystic ovary syndrome or azoospermia , women older than 38 years and those with follicle-stimulating hormone ( FSH ) ≥10 IU/ml . Patients were stimulated with st and ard 225 IU recombinant FSH . In Group I ( n=45 ) a daily dose of GnRHant cetrorelix acetate 0.25 mg was administered when follicles reached a diameter of ≥14 mm . Group II ( n=48 ) patients were desensitised with the GnRHa , leuprolide acetate , in a long protocol . Human chorionic gonadotropin ( hCG ) was administered when at least three follicles of 18 mm in diameter were observed . Oocyte retrieval was scheduled 36 hours following hCG administration and embryos were transferred on day 3 after oocyte retrieval . Results The two groups were homogenous for age , infertility duration , basal FSH and serum oestradiol ( E2 ) ( P=0.537 , P=0.911 , P=0.103 and P=0.733 , respectively ) . In Group II ( the GnRHa group ) more antral follicles ( P<0.001 ) , a longer induction duration ( P=0.017 ) and higher peak E2 levels ( P<0.001 ) were observed . No differences were observed in the number of oocytes retrieved ( P=0.749 ) , embryos achieved and transferred ( P=0.677 ) , or fertilisation rates ( P=0.839 ) between the two groups . There was no statistically significant difference between groups in clinical pregnancy rates , cycle cancellation and ovarian hyperstimulation ( P=0.437 , P=0.109 and P=0.415 , respectively ) . Conclusion GnRHant and GnRHa provide comparable results in normoresponder patients , while GnRHant allows a greater flexibility in their treatment BACKGROUND The specific role of LH in folliculogenesis and oocyte maturation is unclear . GnRH antagonists , when administered in the late follicular phase , induce a sharp decrease in serum LH which may be detrimental for IVF outcome . This study was performed to evaluate whether the replacement of GnRH agonist ( triptorelin ) by a GnRH antagonist ( ganirelix ; NV Organon ) in oocyte donation cycles has any impact on pregnancy and implantation rates . METHODS A total of 148 donor IVF cycles was r and omly assigned to use either a GnRH antagonist daily administered from the 8th day of stimulation ( group I ) or a GnRH agonist long protocol ( group II ) for the ovarian stimulation of their donors . The primary endpoints were the pregnancy and the implantation rates . RESULTS The clinical pregnancy rate per transfer ( 39.72 % , 29/73 versus 41.33 % , 31/75 ) based on transvaginal scan findings at 7 weeks of gestation , the implantation rate ( 23.9 versus 25.4 % ) and the first trimester abortion rate ( 10.34 versus 12.90 % ) were similar in the two groups . CONCLUSION In oocyte donation cycles the replacement of GnRH agonist by a GnRH antagonist appears to have no impact on the pregnancy and implantation rates when its administration starts on day 8 of stimulation Objective To evaluate the effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase ( MDP-EL ) in comparison with st and ard GnRH agonist luteal long protocol ( LP ) in each non-obese and obese polycystic ovary syndrome ( PCOS ) women undergoing IVF . Methods Two hundred eleven infertile women with PCOS were recruited and r and omized to undergo either GnRH antagonist MDP-EL ( antagonist group ) or st and ard GnRH agonist luteal LP ( agonist group ) . IVF cycle outcomes were compared between the two groups . Results Total dose and days of recombinant human follicle stimulating hormone ( rhFSH ) administered were significantly fewer in the antagonist group than in the agonist group . Incidence of severe ovarian hyperstimulation syndrome was significantly lower in the antagonist group . However , IVF and pregnancy outcomes were similar in the two groups . When all subjects were divided into non-obese and obese subgroups , in non-obese PCOS subgroup , IVF and pregnancy outcomes were comparable in the antagonist and agonist groups but total dose and days of rhFSH were also significantly fewer in the antagonist group . Similar findings were also observed in obese PCOS subgroup . Conclusion GnRH antagonist MDP-EL is at least as effective as GnRH agonist LP and may be a more patient-friendly alternative in controlled ovarian stimulation for PCOS patients undergoing IVF , independent of body mass index OBJECTIVE To compare the effects of oral contraceptive ( OC ) pill pretreatment in recombinant FSH/GnRH-antagonist versus recombinant FSH/GnRH-agonist stimulation in in vitro fertilization ( IVF ) patients , and to evaluate optimization of retrieval day . DESIGN Prospect i ve , r and omized , multicenter study . SETTING Private practice and university centers . PATIENT(S ) Eighty patients undergoing IVF who met the appropriate inclusion criteria . INTERVENTION(S ) Four study centers recruited 80 patients . The OC regimen began on cycle days 2 to 4 and was discontinued on a Sunday after 14 to 28 days . The recombinant FSH regimen was begun on the following Friday . The GnRH-agonist group was treated with a long protocol ; the GnRH-antagonist was initiated when the lead follicle reached 12 to 14 mm . When two follicles had reached 16 to 18 mm , hCG was administered . MAIN OUTCOME MEASURE(S ) The primary outcome measures were the number of cumulus-oocyte complexes , day of the week for oocyte retrieval , and total dose and days of stimulation of recombinant FSH . Secondary efficacy variables included pregnancy and implantation rate ; serum E(2 ) levels on stimulation day 1 ; serum E(2 ) , P , and LH levels on the day of hCG administration ; follicle size on day 6 and day of hCG administration ; the total days of GnRH-analogue treatment ; total days on OC ; total days from end of OC to oocyte retrieval ; and the cycle cancellation rate . RESULT ( S ) Patient outcomes were similar for the days of stimulation , total dose of gonadotropin used , two-pronuclei embryos , pregnancy ( 44.4 % GnRH-antagonist vs. 45.0 % GnRH-agonist , P=.86 ) and implantation rates ( 22.2 % GnRH-antagonist vs. 26.4 % GnRH-agonist , P=.71 ) . Oral contraceptive cycle scheduling result ed in 78 % and 90 % of retrievals performed Monday through Friday for GnRH-antagonist and GnRH-agonist . A one day delay in OC discontinuation and recombinant FSH start would result in over 90 % of oocyte retrievals occurring Monday through Friday in both groups . CONCLUSION ( S ) The OC pretreatment in recombinant FSH/GnRH-antagonist protocol s provides a patient-friendly regimen and can be optimized for weekday retrievals . No difference was seen in number of 2PN embryos , cryopreserved embryos , embryos transferred , implantation and pregnancy rates between the two stimulation protocol Objective We compared the assisted reproductive technology ( ART ) outcomes among infertile women with polycystic ovary syndrome ( PCOS ) treated with IVM , conventional IVF , GnRH agonist , and GnRH antagonist cycles . Methods The prospect i ve study included a total of 67 cycles in 61 infertile women with PCOS . The women with PCOS were r and omized into three IVF protocol s : IVM/IVF with FSH and hCG priming with immature oocyte retrieval 38 hours later ( group A , 14 cycles ) , GnRH agonist long protocol ( group B , 14 cycles ) , and GnRH antagonist multi-dose flexible protocol ( group C , 39 cycles ) . IVF outcomes , such as clinical pregnancy rate ( CPR ) , implantation rate ( IR ) , miscarriage rate ( MR ) , and live birth rate ( LBR ) , were compared among the three groups . Results Age , BMI , and basal FSH and LH levels did not differ among the three groups . The number of retrieved oocytes and 2 pronucleus embryos was significantly lower in group A compared with groups B and C. The CPR , IR , MR , and LBR per embryo transfer showed no differences among the three groups . There was no incidence of ovarian hyperstimulation syndrome in group A. Conclusion The IR , MR , and LBR in the IVM cycles were comparable to those of the GnRH agonist and GnRH antagonist cycles . The IVM protocol , FSH and hCG priming with oocyte retrieval 38 hours later , is an effective ART option that is comparable with conventional IVF for infertile women with PCOS Background This large prospect i ve , r and omized study was design ed to compare the “ mild ” protocol with clomiphene citrate , low-dose gonadotropins and a GnRH-antagonist ( CC/Gn/GnRH-ant protocol ) with the “ long ” protocol with a GnRH-agonist and high-dose Gn for the controlled ovarian hyperstimulation ( COH ) of patients with expected poor ovarian responsiveness undergoing IVF . Material s and Methods A total of 695 women with clinical , endocrine and ultrasound characteristics suggesting a low ovarian reserve and a poor responsiveness to COH were recruited and r and omly assigned to receive the CC/Gn/GnRH-ant “ mild ” protocol ( mild group , n = 355 ) or the “ long ” protocol with high-dose Gn ( long group , n = 340 ) . Results The “ mild ” stimulation led to significantly shorter follicular phase , lower consumption of exogenous Gn and lower peak estradiol level than the “ long ” regimen . With the “ long ” protocol , significantly less cycles were cancelled due to the lack of ovarian response ; further , it obtained significantly more oocytes , more mature oocytes , more embryos , and a thicker endometrium . As for the final IVF outcome , however , the two stimulation regimens obtained comparable implantation rate , clinical pregnancy rate , and ongoing pregnancy rate at 12 weeks . Conclusions In conclusion , the “ mild ” CC/Gn/GnRH-ant stimulation protocol is a valid alternative to the long protocol with high Gn dose as it obtains a comparable success rate and requires significantly less medications , with an obvious economical advantage BACKGROUND Patients with polycystic ovary syndrome ( PCOS ) may need a longer period of pituitary downregulation to suppress the elevated serum LH and and rogen levels effectively during IVF treatment using the GnRH agonist long protocol . We proposed a stimulation protocol incorporating Diane-35 and GnRH antagonist ( Diane/cetrorelix protocol ) and compared it with the GnRH agonist long protocol for PCOS patients . METHODS Part I of the study was an observational pilot study to evaluate the hormonal change as a result of the Diane/cetrorelix protocol ( n = 26 ) . Part II of the study was a prospect i ve r and omized study comparing the Diane/cetrorelix protocol ( n = 25 ) and the GnRH agonist long protocol ( n = 24 ) . In the Diane/cetrorelix protocol , patients were pre-treated with three cycles of Diane-35 , followed by 0.25 mg of cetrorelix on cycle day 3 . From day 4 , cetrorelix and gonadotrophin were administered concomitantly until the day of HCG injection . RESULTS Serum LH , estradiol and testosterone levels were suppressed comparably in both protocol s at the start of gonadotrophin administration . Serum LH was suppressed at constant levels without a premature LH surge in the Diane/cetrorelix protocol . The clinical results for both protocol s were comparable , with significantly fewer days of injection , lower amounts of gonadotrophin used and lower estradiol levels on the day of HCG injection following the Diane/cetrorelix protocol . Furthermore , there was no significant difference in clinical pregnancy outcome between the two stimulation protocol s. CONCLUSIONS The Diane/cetrorelix protocol has a similar pregnancy outcome to the GnRH agonist long protocol for women with PCOS undergoing IVF treatment Aim . To compare the clinical pregnancy rate in recipients of oocytes from donors treated with leuprorelin + human menopausal gonadotropins ( hMG ) with that obtained when the donors were treated with ganirelix + recombinant follicle-stimulating hormone ( rFSH ) . The secondary aim was to compare the donors ' response to the two treatments . Method . A prospect i ve , r and omized , comparative study was conducted between January 2005 and November 2006 in a private hospital . Donors were r and omized to receive a long protocol of leuprorelin + hMG ( group DI ) or ganirelix + rFSH ( group DII ) . Their respective recipients were r and omized to group RI or group RII , respectively . Results . The characteristics of the donors were similar in both groups . More cycles were cancelled in group DI than in group DII ( 28.1 % vs. 2.5 % ; p < 0.05 ) . Compared with donors in group DII , the donors in group DI required a significantly higher dose of gonadotropins ( 2794 ± 957 U vs. 1777 ± 1043 U ; p < 0.05 ) and more days of stimulation ( 11.7 ± 2.3 vs. 9.5 ± 1.5 ; p < 0.05 ) ; they also yielded fewer oocytes ( 15.0 ± 6.1 vs. 17.9 ± 8.6 ; p < 0.05 ) . There were no differences in the characteristics of the recipients , in the fertilization rate or in the number of embryos transferred . The quality of transferred embryos was better in group RI ( 8.0 ± 1.2 vs. 7.5 ± 1.6 ; p < 0.05 ) , and this group also achieved a better pregnancy rate per embryo transfer than did group RII ( 62.3 % vs. 48.4 % ; p < 0.05 ) . Conclusions . Treating oocyte donors with leuprorelin + hMG produces among recipients a greater probability of clinical pregnancy per embryo transfer than when donors are treated with ganirelix + rFSH ; however , more cycles are cancelled and the former treatment is more unpleasant for donors STUDY QUESTION Is the risk of severe ovarian hyperstimulation syndrome ( OHSS ) similar in a short GnRH antagonist and long GnRH agonist protocol in first cycle IVF/ICSI patients less than 40 years of age ? . SUMMARY ANSWER There is an increased risk of severe OHSS in the long GnRH agonist group compared with the short GnRH antagonist protocol . WHAT IS KNOWN ALREADY ? : In the most recent Cochrane review , the GnRH antagonist protocol was associated with a similar live birth rate ( LBR ) , a similar on-going pregnancy rate ( OPR ) , and a lower incidence of OHSS ( odds ratio ( OR ) = 0.43 95 % confidence interval ( CI ) : 0.33 - 0.57 ) compared with the traditional GnRH agonist protocol . Previous trials comparing the two protocol s mainly included selected patient population s , a limited number of patients and the applied OHSS criteria differed , making direct comparisons difficult . In two recent large meta-analyses , no significant differences in LBR ( OR = 0.86 ; 95 % CI : 0.72 - 1.02 ) or in the incidence of severe OHSS were reported , while others found a lower LBR ( OR = 0.82 ; 95 % CI : 0.68 - 0.97 ) and a reduced risk of severe OHSS using the GnRH antagonist protocol ( OR = 0.60 ; 95 % CI : 0.40 - 0.88 ) . STUDY DESIGN , SIZE , DURATION Phase IV , dual-centre , open-label , RCT including 1050 women allocated to either short GnRH antagonist or long GnRH agonist protocol in a 1:1 ratio and enrolled over a 5-year period using a web-based concealed r and omization code . This is a superiority study design ed to detect a difference in severe OHSS , the primary outcome , between the two groups with a power of 80 % and stratified for age , assisted reproductive technology ( ART ) clinic and planned fertilization procedure ( IVF/ICSI ) . The secondary aims were to compare rates of mild and moderate OHSS , positive plasma (p)-hCG , on-going pregnancy and live birth between the two arms . None of the women had undergone previous ART treatment . PARTICIPANTS / MATERIAL S , SETTING , METHODS All infertile women referred for their first IVF/ICSI at two public fertility clinics , less than 40 years of age and with no uterine malformations were asked to participate . A total of 1099 subjects were r and omized , including women with poor ovarian reserve , polycystic ovary syndrome and irregular cycles . A total of 49 women withdrew their consent , thus 1050 subjects were allocated to the GnRH antagonist ( n = 534 ) and agonist protocol ( n = 516 ) , respectively . In total 1023 women started recombinant human follitropin-β ( rFSH ) stimulation , 528 in the GnRH antagonist group and 495 in the GnRH agonist group . All subjects were given a fixed rFSH dose of 150 IU or 225 IU according to age ≤36 years or > 36 years , with the option to adjust dose at stimulation day 6 . Clinical OHSS parameters were collected at oocyte retrieval , and Days 3 and 14 post-transfer . On-going pregnancy was determined by transvaginal ultrasonography at gestational weeks 7 - 9 . In the intention-to-treat ( ITT ) analysis for reproductive outcomes , 1050 subjects were included . For the ITT analyses on OHSS 1023 subjects who started gonadotrophin stimulation were included . MAIN RESULTS AND THE ROLE OF CHANCE The incidence of severe OHSS [ 5.1 % ( 27/528 ) versus 8.9 % ( 44/495 ) ( difference in proportion percentage point ( Δpp ) = -3.8pp ; 95 % CI : -7.1 to -0.4 ; P = 0.02 ) ] and moderate OHSS [ 10.2 % ( 54/528 ) versus 15.6 % ( 77/495 ) ( Δpp = -5.3pp ; 95 % CI : -9.6 to -1.0 ; P = 0.01 ) ] was significantly lower in the GnRH antagonist group compared with the agonist group , respectively . In the GnRH antagonist and agonist group , respectively , 4.7 % ( 25/528 ) versus 8.5 % ( 42/495 ) women were seen by a physician due to OHSS ( P = 0.01 ) , and 1.7 % ( 9/528 ) versus 3.6 % ( 18/495 ) were admitted to hospital due to OHSS ( P = 0.06 ) . No women had ascites-puncture in the GnRH antagonist group versus 2.0 % ( 10/495 ) in the GnRH agonist group ( P < 0.01 ) . LBRs were 22.8 % ( 122/534 ) versus 23.8 % ( 123/516 ) ( Δpp = -1.0pp ; 95 % CI : -6.3 to 4.3 ; P = 0.70 ) and OPRs were 24.9 % ( 133/528 ) versus 26.2 % ( 135/516 ) ( Δpp = -1.3pp ; 95 % CI : -6.7 to 4.2 ; P = 0.64 ) per r and omized subject in the GnRH antagonist versus agonist group , with a mean number of 1.1 versus 1.2 embryos transferred in the two groups . Pregnancy rates ( PR ) per r and omized subject , per started gonadotrophin stimulation and per embryo transfer were all similar in the two groups . LIMITATIONS , REASONS FOR CAUTION A possible limitation is the duration of the trial , with new methods , such as ' freeze all ' and ' GnRH agonist triggering ' , being developed during the trial , the new methods were sought avoided , however a total number of 32 women had ' freeze all ' and ' GnRH agonist triggering ' was performed in three cases . Ultrasonic measurements were performed by different physicians and inter-observer bias may be present . Measures of anti-Mullerian hormone and antral follicle count , to estimate ovarian reserve and thus predict risk of OHSS , were not performed . Finally , the physicians were not blinded to GnRH treatment group after r and omization . WIDER IMPLICATION S OF THE FINDINGS The short GnRH antagonist protocol should be the protocol of choice for patients undergoing their first ART cycle in females < 40 years of age including both low and high responders when an age-dependent initially fixed gonadotrophin dose is used , as an increased risk of severe OHSS and the associated complications is seen in the long GnRH agonist group and as PRs and LBRs are similar in the two groups . Patients at risk of OHSS particularly benefit from the short GnRH antagonist treatment as GnRH agonist triggering can be used . STUDY FUNDING /COMPETING INTERESTS An unrestricted research grant is funded by Merck Sharp & Dohme Corp. , a subsidiary of Merck & Co. , Inc. , Kenilworth , NJ , USA ( MSD ) . The funders had no influence on the data collection , analyses or conclusions of the study . No conflict of interests to declare . TRIAL REGISTRATION NUMBER EudraCT # : 2008 - 005452 - 24 . Clinical Trial.gov : NCT00756028 . Trial registration date : 18 September 2008 . Date of first patient 's enrolment : 14 January 2009 We performed a r and omized trial to compare IVF outcomes in 54 poor responder patients undergoing a microdose leuprolide acetate ( LA ) protocol or a GnRH antagonist protocol incorporating a luteal phase E(2 ) patch and GnRH antagonist in the preceding menstrual cycle . Cancellation rates , number of oocytes retrieved , clinical pregnancy rates ( PR ) , and ongoing PRs were similar between the two groups This study evaluates the efficacy of a stimulation protocol with clomiphene citrate (CC)/human menopausal gonadotropin (hMG)/cetrorelix and its effects on oocyte quality and endometrium . One hundred and twenty couples with male-factor infertility who were about to undergo their first intracytoplasmic sperm injection cycles were r and omized into two groups . Sixty women were stimulated with the CC/hMG/cetrorelix protocol ( cetrorelix group ) and 60 received the buserelin long protocol ( buserelin group ) . Fewer oocytes were recovered in the cetrorelix group than in the buserelin group ( mean ± st and ard deviation ( SD ) : 11.1 ± 4.0 vs. 17.3 ± 5.8 , p < 0.001 ) ; however , the percentages of metaphase II , metaphase I and germinal vesicle oocytes were similar between the two groups . Serum estradiol level was significantly lower in the cetrorelix than in the buserelin group ( mean ± SD : 2600.58 ± 1189.11 vs. 3293.46 ± 1221.49 pg/ml , p = 0.006 ) , but the endometrial thickness was similar . The implantation rates ( 19.2 % vs. 17.7 % ) and the pregnancy rates ( 41.7 % vs. 40.0 % ) were similar between groups . The ampoules ( mean ± SD : 18.9 ± 3.0 vs. 38.9 ± 12.2 , p < 0.001 ) and injections ( mean ± SD : 6.8 ± 1.1 vs. 15.7 ± 3.1 , p < 0.001 ) of gonadotropin used were significantly lower in the cetrorelix group than in the buserelin group . No patients in either group developed a premature luteinizing hormone surge . The present study found no statistically significant difference between the two treatment modalities with regard to pregnancy rates BACKGROUND The aim of this study was to assess the non-inferiority of an oral contraceptive (OC)-pretreated cetrorelix regimen and a buserelin regimen in IVF/ICSI patients treated with r-hFSH in terms of total number of oocytes retrieved . METHODS Multicentre , r and omized study . One hundred and eighty two patients were r and omized to receive cetrorelix with OC pretreatment ( n = 91 ) or to receive buserelin ( n = 91 ) . The cetrorelix group started with daily OCs on cycle day 5 and continued for 21 - 28 days . Cetrorelix ( 0.25 mg ) was given daily from stimulation day 6 up to and including the day of r-hCG administration . The buserelin group started with buserelin ( 500 microg/day ) for at least 10 days until down-regulation was achieved , after which the dose was reduced to daily 200 microg up to and including the day of r-hCG administration . r-hFSH was started in both groups on a Friday , in the cetrorelix group 5 days after the last OC pill intake . Both regimens were followed by a st and ard IVF or ICSI procedure . The primary efficacy endpoint was the number of oocytes retrieved per patient . RESULTS Number of oocytes , cancellation rates , r-hFSH requirements , number of oocyte retrievals during the weekend or public holiday and number of pregnancies were similar in both groups . Both treatment regimens were well tolerated . CONCLUSIONS Cetrorelix pretreated with OCs result ed in similar number of oocytes retrieved compared with a long buserelin protocol . Both regimens were well tolerated and allowed scheduling of the oocyte retrieval , with only small number of retrievals falling on a weekend or public holiday Purpose To evaluate the efficacy of GnRH antagonist in comparison with the GnRH agonist protocol in OCP pretreated polycystic ovary syndrome ( PCOs ) patients undergoing their first ART cycle . Material s and methods Prospect i ve r and omized controlled trial . University-based tertiary fertility center . Ninety-five PCOs patients under 35 years of age , with primary infertility were r and omized to an ovarian stimulation protocol consisting of either . GnRh antagonist ( study group ) or GnRH agonist ( control group ) after pretreatment with OCP . Coasting or GnRH agonist Trigger was used when estradiol level ≥3,000 pgr/ml in the control and study group , respectively . Both groups received 800 mg vaginal progesterone and 4 mg oral estradiol valerate for luteal phase support . Results There was no statistically significant difference in the age , body mass index , basal FSH , duration of infertility , the number of oocytes retrieved , the number of embryos transferred , Serum E2 levels on day of trigger , fertilization rate , chemical and clinical pregnancy rates between the two groups . None of the patients in the study group developed ovarian hyperstimulation syndrome ( OHSS ) compared with 22.2 % of patients in the control group . Total duration of treatment and the number of HMG ampoules used were lower in the study group . Conclusion Antagonist protocol and GnRH agonist trigger for ovulation whenever necessary has a similar cycle outcome to the GnRH-agonist protocol in OCP pretreated PCOs patients , with significantly reduced risk of OHSS Background : General concern is that the pregnancy rate is higher with GnRH-agonist as a protocol of pituitary suppression . GnRH-antagonist protocol provides a shorter period of administration and an easy flexible protocol . Objective : In this study , the outcomes of GnRH agonist and antagonist in ICSI cycles are compared in normo responder patients . Material s and Methods : In this r and omized clinical trial , 300 normoresponders undergoing ICSI were r and omly divided to GnRh agonist ( n=150 ) and GnRh antagonist ( n=150 ) groups . The main outcome measurements were chemical , clinical and ongoing pregnancy rates ( PR ) . Results : The mean duration of stimulation were 9.6±1.6 and 8.2±1.6 days in agonist and antagonist groups respectively ( p=0.001 ) . The mean number of MII oocyte retrieved in agonist and antagonist groups were 7.7±4.0 and 6.9±4.3 respectively ( p=0.03 ) . There was no significant difference between two groups regarding mean number of gonadotrophin ampoules , follicles , occytes , total embryos and good quality embryos , OHSS incidence , and abortion rate . Chemical pregnancy rate was 35.3 % in agonist and 39.3 % in antagonist group . Clinical pregnancy rate was 35.3 % in agonist and 34 % in antagonist group . Ongoing pregnancy rate was 45 ( 31.3 % ) in agonist and 44 ( 29.3 % ) in antagonist group . There was no significant difference between two groups in pregnancy rates . Conclusion : In this study antagonist protocol was shown to be an easy , safe and friendly protocol in Iranian normoresponder patients , having similar outcomes with st and ard agonist protocol but shorter period of stimulation OBJECTIVE To determine which protocol s work better between cetrorelix and long protocol s in older patients in a r and omized controlled study . DESIGN A controlled r and omized study in a single private IVF center . SETTING Infertile women referred to a private IVF center . PATIENT(S ) Five hundred sixty-four women 40 years or older undergoing IVF . INTERVENTION(S ) At their first IVF cycle , the women were r and omized into two study groups using a computer-generated number sequence : 281 cases were treated with the cetrorelix protocol , and 283 patients were treated with a long protocol for controlled ovarian hyperstimulation . MAIN OUTCOME MEASURE(S ) Days of stimulation , E(2 ) on the day of hCG administration , amount of FSH administered , number of oocytes yielded , number of embryos obtained , pregnancy rate , and implantation rate . RESULT ( S ) Patients treated with the long protocol showed a significantly higher number of oocytes retrieved and a higher pregnancy rate for both the cycle and transfer with respect to the cetrorelix protocol patients . The other parameter evaluated did not show any statistically significant differences . CONCLUSION ( S ) Our study showed that the long protocol performed better in older women than the cetrorelix protocol and that the GnRH antagonist may be detrimental in older women Background . The aim of this study was to evaluate the response to treatment in a group of patients undergoing IVF and r and omised to receive GnRH-antagonist or the GnRH-agonist . The endpoints were the pattern of follicular growth , the maturity of the oocytes collected , the embryo quality and the pregnancy outcome . Methods . A total of 136 patients undergoing IVF were included . Sixty-seven patients were allocated to the GnRH antagonist and 69 patients to the GnRH agonist . GnRH antagonist was administered when the leading follicle reached a diameter of 12–14 mm . GnRH agonist was administered in a long luteal protocol . Results . The mean numbers of oocytes retrieved and mature oocytes were significantly higher in the agonist than in the antagonist group ( p < 0.02 and p < 0.01 , respectively ) . Embryo quality , implantation rate , clinical pregnancy rates , ongoing pregnancy rate and miscarriage rate were similar in both groups . Conclusions . Better follicular growth and oocyte maturation are achieved with GnRH agonist treatment . However , both regimens seem to have similar efficacy in terms of implantation and pregnancy rates . Further studies clarifying the effect of the GnRH antagonist on ovarian function are needed , as well as a clear definition of the best period of the follicular phase for the GnRH antagonist administration OBJECTIVE To compare cycle outcomes after scheduling with the st and ard long protocol versus the use of oral contraceptive pills ( OCPs ) in patients undergoing GnRH antagonist cycles . DESIGN Prospect i ve , r and omized , controlled trial . SETTING University-affiliated private assisted reproduction center . PATIENT(S ) Regularly cycling women aged ≤38 years with fewer than three previous IVF attempts were enrolled . Previous low responses to controlled ovarian hyperstimulation , ovarian surgery , or polycystic ovary were exclusion criteria . INTERVENTION(S ) One hundred fifteen patients received OCP ( 0.030 ethinyl E(2)/0.15 desogestrel ) for 12 - 16 days , and controlled ovarian hyperstimulation was started on day 5 after OCP treatment ; similarly , 113 patients received the long protocol from day 20 - 22 of the previous cycle . MAIN OUTCOME MEASURE(S ) The primary outcome was ongoing pregnancy rate ; secondary outcome variables were clinical pregnancy rate , live birth rate , implantation rate , and miscarriage rate . RESULT ( S ) Patients receiving the GnRH antagonist treatment showed a lower peak serum E(2 ) ( 1,334 vs. 1,823 pg/mL ) but similar peak serum PE ( 0.58 vs. 0.65 ng/mL ) , lower duration of the stimulation ( 10.3 vs. 11.4 days ) with similar FSH consumption ( 1,613 vs. 1,807 IU ) , and ovarian response ( 10.2 vs. 11.7 oocytes ) . No differences were observed in the fertilization rates ( 68.1 % vs. 64.8 % ) , total number of embryos obtained ( 5.9 vs. 6.2 ) , mean number of embryos transferred ( 1.8 vs. 1.8 ) , implantation rate ( 36 % vs. 39 % ) , miscarriage rate ( 8.9 % vs. 17 % ) , ongoing pregnancy rate ( 47.8 % vs. 53.9 % ) , or live birth rate ( 44.3 % vs. 47 % ) . CONCLUSION ( S ) Comparable outcomes can be obtained using OCP containing 0.030 ethinyl E(2)/0.15 desogestrel to schedule patients undergoing the antagonist protocol BACKGROUND Women with polycystic ovary syndrome ( PCOS ) are at risk of developing ovarian hyperstimulation syndrome ( OHSS ) during ovarian stimulation . Use of GnRH antagonist in the general subfertile population is associated with lower incidence of OHSS than agonists and similar probability of live birth but it is unclear if this is true for patients with PCOS . Our aim was to compare the flexible GnRH antagonist and GnRH agonist long protocol s in patients with PCOS undergoing IVF ( primary end-point : ongoing pregnancy rate per patient r and omized ) . METHODS In this r and omised controlled trial ( RCT ) , 220 patients with PCOS were r and omly allocated in two groups : long GnRH agonist down-regulation protocol ( n = 110 ) and flexible GnRH antagonist protocol ( n = 110 ) . RESULTS No differences were observed in ongoing pregnancy rates [ 50.9 versus 47.3 % , difference 3.6 % , 95 % confidence interval ( CI ) : -9.6 to + 16.8 % ] in the agonist and antagonist protocol s , respectively . Incidence of OHSS Grade II was lower in the antagonist compared with agonist group ( 40.0 versus 60.0 % , difference -20.0 % , 95 % CI : -7.1 to -32.9 % , P < 0.01 ) . Duration of stimulation ( 10 versus 12 days , difference 2 days , 95 % CI : + 1 to + 2 , P < 0.001 ) and total gonadotrophin required ( 1575 versus 1850 IU , difference -275 IU , 95 % CI : -25 to -400 , P < 0.05 ) were also lower in the antagonist compared with agonist protocol . CONCLUSIONS The current RCT suggests that the flexible GnRH antagonist protocol is associated with a similar ongoing pregnancy rate , lower incidence of OHSS grade II , lower gonadotrophin requirement and shorter duration of stimulation , compared with GnRH agonist . The GnRH antagonist might be the treatment choice for patients with PCOS undergoing IVF . The study was registered at clinical trials.gov . ID : NCT00417144 Purpose : To examine the efficacy of low-dose hCG using a GnRH antagonist protocol . Methods : Prospect i ve r and omized study was performed at the Kyono Ladies Clinic . One hundred ninety-two women ( < 40 –years old , <3 previous cycles ) were r and omly assigned to GnRH agonist ( buserelin ) long protocol ( LP , n = 66 ) , GnRH antagonist ( cetrorelix ) with no low-dose hCG protocol ( NhCGP , n = 63 ) , or GnRH antagonist with low-dose hCG protocol ( hCGP , n = 63 ) . Results : The hCGP was associated with reduced total amounts of FSH , increased oocyte maturation rate , high- quality day 3 embryos rate , and number of frozen embryos . Ovarian hyperstimulation syndrome ( OHSS ) tended to be lower in the GnRH antagonist protocol . Pregnancy and implantation rates did not differ significantly between study groups . Conclusions : Daily low-dose hCG supplementation in the late follicular phase could improve the outcome in FSH based-GnRH antagonist protocol . This protocol , however , does require further modifications , including determination of the optimal doses for hCG and gonadotropin pretreatment Objective To investigate the effectiveness of GnRH antagonist multiple-dose protocol ( MDP ) with oral contraceptive pill ( OCP ) pretreatment in poor responders undergoing IVF/ICSI , compared with GnRH antagonist MDP without OCP pretreatment and GnRH agonist low-dose long protocol ( LP ) . Methods A total of 120 poor responders were r and omized into three groups according to controlled ovarian stimulation ( COS ) options ; GnRH antagonist MDP after OCP pretreatment ( group 1 ) , GnRH antagonist MDP without OCP pretreatment ( group 2 ) or GnRH agonist luteal low-dose LP without OCP pretreatment ( group 3 ) . Patients allocated in group 1 were pretreated with OCP for 21days in the cycle preceding COS , and ovarian stimulation using recombinant human FSH ( rhFSH ) was started 5 days after discontinuation of OCP . Results There were no differences in patients ' characteristics among three groups . Total dose and days of rhFSH used for COS were significantly higher in group 3 than in group 1 or 2 . The numbers of mature oocytes , fertilized oocytes and grade I , II embryos were significantly lower in group 2 than in group 1 or 3 . There were no significant differences in the clinical pregnancy rate and implantation rate among three groups . Conclusion GnRH antagonist MDP with OCP pretreatment is at least as effective as GnRH agonist low-dose LP in poor responders and can benefit the poor responders by reducing the amount and duration of FSH required for follicular maturation BACKGROUND To test whether ovarian stimulation for in-vitro fertilization ( IVF ) affects oocyte quality and thus chromosome segregation behaviour during meiosis and early embryo development , preimplantation genetic screening of embryos was employed in a prospect i ve , r and omized controlled trial , comparing two ovarian stimulation regimens . METHODS Infertile patients under 38 years of age were r and omly assigned to undergo a mild stimulation regimen using gonadotrophin-releasing hormone ( GnRH ) antagonist co-treatment ( 67 patients ) , which does not disrupt secondary follicle recruitment , or a conventional high-dose exogenous gonadotrophin regimen and GnRH agonist co-treatment ( 44 patients ) . Following IVF , embryos were biopsied at the eight-cell stage and the copy number of 10 chromosomes was analysed in 1 or 2 blastomeres . RESULTS The study was terminated prematurely , after an unplanned interim analysis ( which included 61 % of the planned number of patients ) found a lower embryo aneuploidy rate following mild stimulation . Compared with conventional stimulation , significantly fewer oocytes and embryos were obtained following mild stimulation ( P < 0.01 and < 0.05 , respectively ) . Consequently , both regimens generated on average a similar number ( 1.8 ) of chromosomally normal embryos . Differences in rates of mosaic embryos suggest an effect of ovarian stimulation on mitotic segregation errors . CONCLUSIONS Future ovarian stimulation strategies should avoid maximizing oocyte yield , but aim at generating a sufficient number of chromosomally normal embryos by reduced interference with ovarian physiology OBJECTIVE To determine whether there are any differences in the incidence of ovarian hyperstimulation syndrome ( OHSS ) and implantation rates in high-risk patients undergoing IVF using a protocol consisting of GnRH agonist trigger after cotreatment with GnRH antagonist or hCG trigger after dual pituitary suppression protocol . DESIGN Prospect i ve r and omized controlled trial . SETTING University-based tertiary fertility center . PATIENT(S ) Sixty-six patients under 40 years of age with polycystic ovarian syndrome , polycystic ovarian morphology , or previous high response undergoing IVF . INTERVENTION(S ) Patients were r and omized to an ovarian stimulation protocol consisting of either GnRH agonist trigger after cotreatment with GnRH antagonist ( study group ) or hCG trigger after dual pituitary suppression with a GnRH agonist ( control group ) . Both groups received luteal phase and early pregnancy supplementation with IM progesterone ( P ) , and patients in the study group also received E(2 ) patches and their doses were adjusted according to the serum levels . MAIN OUTCOME MEASURE(S ) Incidence of OHSS and implantation rate . RESULT ( S ) None of the patients in the study group developed any form of OHSS compared with 31 % ( 10/32 ) of the patients in the control group . There were no significant differences in the implantation ( 22/61 [ 36.0 % ] vs. 20/64 [ 31.0 % ] ) , clinical pregnancy ( 17/30 [ 56.7 % ] vs. 15/29 [ 51.7 % ] ) , and ongoing pregnancy rates ( 16/30 [ 53.3 % ] vs. 14/29 [ 48.3 % ] ) between the study and control groups , respectively . CONCLUSION ( S ) The use of a protocol consisting of GnRH agonist trigger after GnRH antagonist cotreatment combined with adequate luteal phase and early pregnancy E(2 ) and P supplementation reduces the risk of OHSS in high-risk patients undergoing IVF without affecting implantation rate Background The selection of developmentally competent human gametes may increase the efficiency of assisted reproduction . Spermatozoa and oocytes are usually assessed according to morphological criteria . Oocyte morphology can be affected by the age , genetic characteristics , and factors related to controlled ovarian stimulation . However , there is a lack of evidence in the literature concerning the effect of gonadotropin-releasing hormone ( GnRH ) analogues , either agonists or antagonists , on oocyte morphology . The aim of this r and omized study was to investigate whether the prevalence of oocyte dysmorphism is influenced by the type of pituitary suppression used in ovarian stimulation . Methods A total of 64 patients in the first intracytoplasmic sperm injection ( ICSI ) cycle were prospect ively r and omized to receive treatment with either a GnRH agonist with a long-term protocol ( n : 32 ) or a GnRH antagonist with a multi-dose protocol ( n : 32 ) . Before being subjected to ICSI , the oocytes at metaphase II from both groups were morphologically analyzed under an inverted light microscope at 400x magnification . The oocytes were classified as follows : normal or with cytoplasmic dysmorphism , extracytoplasmic dysmorphism , or both . The number of dysmorphic oocytes per total number of oocytes was analyzed . Results Out of a total of 681 oocytes , 189 ( 27.8 % ) were morphologically normal , 220 ( 32.3 % ) showed cytoplasmic dysmorphism , 124 ( 18.2 % ) showed extracytoplasmic alterations , and 148 ( 21.7 % ) exhibited both types of dysmorphism . No significant difference in oocyte dysmorphism was observed between the agonist- and antagonist-treated groups ( P ≫ 0.05 ) . Analysis for each dysmorphism revealed that the most common conditions were alterations in polar body shape ( 31.3 % ) and the presence of diffuse cytoplasmic granulations ( 22.8 % ) , refractile bodies ( 18.5 % ) and central cytoplasmic granulations ( 13.6 % ) . There was no significant difference among individual oocyte dysmorphisms in the agonist- and antagonist-treated groups ( P ≫ 0.05 ) . Conclusions Our r and omized data indicate that in terms of the quality of oocyte morphology , there is no difference between the antagonist multi-dose protocol and the long-term agonist protocol . If a GnRH analogue used for pituitary suppression in IVF cycles influences the prevalence of oocyte dysmorphisms , there does not appear to be a difference between the use of an agonist as opposed to an antagonist BACKGROUND In view of the current debate concerning possible differences in efficacy between the two GnRH analogues used in IVF stimulated cycles , the current study aim ed to explore whether progesterone control in the late follicular phase differs when GnRH antagonist is used as compared with GnRH agonist , and if so , to what extent the progesterone rise affects the probability of pregnancy . METHODS Overall 190 patients were r and omized : 94 in the GnRH-agonist group and 96 in the GnRH-antagonist group . The GnRH-agonist long protocol started on Day 21 of the preceding cycle with intranasal buserelin ( 600 mg per day ) . The GnRH-antagonist protocol started on Day 6 of the stimulation with ganirelix or cetrorelix ( each 0.25 mg ) . All blood sample s were analysed with the Elecsys analyzer . An intention-to-treat analysis was applied . RESULTS A progesterone rise > 1.5 ng/ml was noticed in 23.0 % of the antagonist group , comparable with 24.1 % incidence within the agonist group . Per patient r and omized , delivery rates were also comparable : 28.1 % in the antagonist group and 24.5 % in the agonist group ( odds ratio = 1.21 , 95 % confidence interval : 0.63 - 2.31 , P= 0.56 ) . However , there was a reduction in delivery rates when progesterone exceeded the threshold of 1.5 ng/ml , both in the agonist group ( 9.5 versus 31.8 % , P= 0.03 ) and in the antagonist group ( 14.3 versus 34.3 % , P= 0.07 ) . CONCLUSIONS Although the incidence of a progesterone rise was similar between the two analogues , our findings reconfirm previous observations that insufficient progesterone control ( > 1.5 ng/ml ) on the day of ovulation triggering is related to poor delivery rates in both protocol s. The current study has shown that the reproductive outcomes with the two GnRH analogues are comparable . Possible modes of action to circumvent late follicular progesterone rise should be explored . TRIAL REGISTRATION NUMBER NCT01191710 Gonadotrophin-releasing hormone agonists ( GnRHa ) are routinely used in IVF programmes to prevent an unwanted LH surge and consequent ovulation . Despite its widespread use in IVF , a convincing dose recommendation for GnRHa in IVF does not exist . In our opinion , the lowest possible dose of GnRHa should be used . Thus , we performed a prospect i ve , r and omized , double-blind , placebo-controlled study to determine the minimal daily dose of triptorelin acetate needed to suppress a premature LH surge during IVF treatment in a long protocol . A total of 240 women ( 60 in each group ) was r and omized to either placebo or to one of three doses of triptorelin , i.e. 15 , 50 or 100 microg daily . Ovarian stimulation was performed with two or three ampoules of FSH daily . A premature LH surge occurred in 23 % of placebo-treated patients , but in none of the triptorelin acetate-treated patients . There were significantly more oocytes and embryos in the 50 and 100 microg triptorelin groups . There was no dose relationship in rates of either implantation , pregnancy , ongoing pregnancy , live birth or baby take-home . In this study we showed that daily administration of 15 microg triptorelin is sufficient to prevent a premature LH surge , and that 50 microg is equivalent to 100 microg in terms of IVF results Objective To compare the IVF/ICSI outcomes of the long GnRH agonist and the fixed GnRH antagonist protocol in women with PCOS . Design R and omized controlled trial . Setting Baskent University Department of Obstetrics and Gynecology . Patients Three hundred women with PCOS . Interventions IVF/ICSI following the long GnRH agonist down-regulation or the fixed GnRH antagonist protocol s . Main outcome measures Ongoing pregnancy rates . Results Ongoing pregnancy rates were 36.4 % in the OCP + GnRH agonist group and 35.9 % in the OCP + GnRH antagonist group ( p > 0.05 ) . Progesterone levels on the day of hCG ( 0.76 ± 0.71 vs. 0.58 ± 0.50 ) , endometrial thickness on the day of hCG ( 11.57 ± 2.50 vs. 10.50 ± 2.01 ) , total gonadotropin used ( 1388.71 ± 482.39 vs. 1253.25 ± 415.81 ) , and duration of COH ( 9.07 ± 1.96 vs. 8.39 ± 1.75 ) were significantly lower in the OCP + GnRH antagonist group . Conclusion The OCP + long GnRH agonist and the OCP + fixed GnRH antagonist protocol s yield similar ongoing pregnancy rates in women with PCOS . Although this study consisting three hundred patients , seems to be large enough in a single center , we were not able to reach to the actual size of power analysis which was approximately 3,000 BACKGROUND This r and omized controlled trial was design ed to assess the impact of oral contraceptive ( OC ) scheduling with a GnRH antagonist ( ganirelix ) regimen on the ovarian response of women undergoing recombinant FSH ( rFSH ) stimulation for IVF , compared with a non-scheduled ganirelix regimen and a long GnRH agonist ( nafarelin ) protocol . METHODS A total of 110 women was treated with an OC and ganirelix , 111 with ganirelix alone and 111 with nafarelin . The OC ( containing 30 microg ethinylestradiol/150 microg desogestrel ) was taken for 14 - 28 days and stopped 2 days prior to the start of rFSH treatment . Primary efficiency parameters were the number of cumulus-oocyte complexes ( per attempt ) and the number of grade 1 or 2 embryos ( per attempt ) . RESULTS In terms of follicular growth and hormone profiles , the OC-scheduled antagonist regimen mimicked the agonist regimen rather than the ( non-scheduled ) GnRH antagonist regimen . In the OC-scheduled GnRH antagonist group and the nafarelin group ( versus the non-scheduled antagonist group ) , pituitary suppression was more profound at the start of stimulation ( P < or = 0.001 ) , there was a slower start of follicular growth ( P < or = 0.001 ) , longer stimulation was required ( 11.7 and 10.3 days respectively versus 9.4 ; P < or = 0.001 ) , and more rFSH was used ( 2667 and 2222 IU versus 1966 IU ; P < or = 0.001 ) . In the three groups , the number of oocytes was similar ( 13.1 , 12.9 and 11.5 respectively ; not significant ) as well as the number of good quality embryos ( 5.1 , 5.7 and 5.0 respectively ; not significant ) . CONCLUSION OC treatment prior to the rFSH/ganirelix regimen can be successfully applied to schedule patients , although more days of stimulation and more rFSH are required than with a non-scheduled GnRH antagonist regimen Background : Since increased LH in the early follicular phase in PCOS patients especially in GnRH antagonist protocol could be associated with reduced oocyte quality and pregnancy and impared implantation . The current study was conducted to determine ART outcomes in GnRH antagonist protocol ( flexible ) and long GnRH agonist protocol and compare them with adding GnRH antagonist in GnRH antagonist ( flexible ) protocol during early follicular phase in patients with polycystic ovary syndrome undergoing ICSI . Methods : In this r and omized clinical trial , 150 patients with polycystic ovary syndrome undergoing ICSI were enrolled from 2012 to 2014 and r and omly assigned to receive either GnRH antagonist protocol during early and late follicular phase or GnRH antagonist protocol ( flexible ) or long GnRH agonist protocol . The clinical and laboratory pregnancy in three groups was determined and compared . In this context , the chi-square and Fisher 's exact test and ANOVA were used for data analysis . Statistical significance was defined as p<0.05 . Results : There was no statistically significant difference with respect to chemical pregnancy and clinical pregnancy between the three groups . Also , other indices such as number and quality of oocytes and embryos were alike . Conclusion : Totally , according to our results , GnRH antagonist protocol during early and late follicular phase and GnRH antagonist protocol ( flexible ) and long GnRH agonist protocol in patients with polycystic ovary syndrome undergoing ICSI are similarly effective and use of each one based on patients ' condition and physicians ' opinion could be considered BACKGROUND The aim of this study was to define the minimal effective dose of antide ( Iturelix ) to prevent premature luteinizing hormone ( LH ) surges in in vitro fertilization ( IVF ) patients . METHODS In a prospect i ve , single centre study , 144 IVF/ICSI patients were stimulated with r-hFSH from cycle day 2 and from cycle day 6 onwards , cotreated with daily 2 mg/2 ml ( n=30 ) , 1 mg/ml ( n=30 ) , 0.5 mg/ml ( n=31 ) , 0.5 mg/0.5 ml ( n=23 ) and 0.25 mg/ml ( n=30 ) GnRH antagonist ( antide ) . Serum sample s were taken three times daily during antide administration to assess antide and hormone levels . The minimal effective dose was defined as the lowest dose group with < 2 LH surges ( LH > 12.4 IU/l and progesterone > 2 ng/ml ) . RESULTS Serum antide levels , mean LH and E2 levels per day and their area under the curves were dose-related to antide . The bioavailability of antide almost doubled after dilution in larger volumes . Pre-injection LH levels gradually increased during GnRH antagonist treatment . LH surges occurred in the lowest dose groups 0.5 mg/ml ( 3.2 % ) , 0.5 mg/0.5 ml ( 6.7 % ) and 0.25 mg/ml ( 13.3 % ) . Hence , 0.5 mg/ml is considered to be the minimal effective dose . Antide was overall well tolerated and safe . CONCLUSIONS 0.5 mg/ml antide is the minimal effective dose to prevent an untimely LH surge in IVF patients stimulated with r-hFSH A multicentre , open-label , r and omized study of the gonadotrophin-releasing hormone ( GnRH ) antagonist ganirelix ( Orgalutran((R))/Antagon((TM ) ) ) was performed in women undergoing ovarian stimulation with recombinant FSH ( rFSH : Puregon((R ) ) ) . The study was design ed as a non-inferiority study using a long protocol of buserelin ( intranasal ) and rFSH as a reference treatment . A total of 730 subjects was r and omized in a treatment ratio of 2:1 ( ganirelix : buserelin ) using an interactive voice response system which stratified for age , type of infertility and planned fertilization procedure [ IVF or intracytoplasmic sperm injection ( ICSI ) ] . The median duration of GnRH analogue treatment was 5 days in the ganirelix group and 26 days in the buserelin group , whereas the median total rFSH dose was 1500 IU and 1800 IU respectively . In addition , in the ganirelix group the mean duration of stimulation was 1 day shorter . During ganirelix treatment the incidence of LH rises ( LH > /=10 IU/l ) was 2.8 % versus 1.3 % during rFSH stimulation in the buserelin group . On the day of triggering ovulation by human chorionic gonadotrophin ( HCG ) , the mean number of follicles > /=11 mm diameter was 10.7 and 11.8 , and the median serum oestradiol concentrations were 1190 pg/ml and 1700 pg/ml in the ganirelix and buserelin groups respectively . The mean number of oocytes per retrieval was 9.1 and 10.4 respectively , whereas the mean number of good quality embryos was 3.3 and 3.5 respectively . The fertilization rate was equal in both groups ( 62.1 % ) , and the same mean number of embryos ( 2.2 ) was replaced . The mean implantation rates were 15.7 % and 21.8 % , and the ongoing pregnancy rates per attempt were 20.3 % and 25.7 % in the ganirelix and buserelin groups respectively . Evaluation of all safety data indicated that the ganirelix regimen was safe and well tolerated . The overall incidence of ovarian hyperstimulation syndrome was 2.4 % in the ganirelix group and 5.9 % in the reference group . The results of this study support a safe , short and convenient treatment regimen of ganirelix , result ing in a good clinical outcome for patients undergoing ovarian stimulation for IVF or ICSI Background : Given the controversies regarding the effectiveness of gonadotropin-releasing hormone ( GnRH ) antagonists in prevention of ovarian hyper stimulation syndrome stimulation , this study was design ed to compare GnRH agonist protocol with GnRH antagonist protocol in patients who were c and i date for assisted reproductive techniques ( ARTs ) . Material s and Methods : This investigation was performed on 136 patients who were r and omly allocated to two groups of GnRH agonist and GnRH antagonist . In the first group stimulation was performed by administration of Buserelin , and in the second group , it was performed by giving Cetrorelix . Then patients were compared regarding results of ovarian stimulation , pregnancy outcomes and rate of ovarian hyper stimulation syndrome ( OHSS ) . Results : There were not significant differences between 2 groups regarding the ovarian stimulation , pregnancy outcomes and rate of OHSS ( P value > 0.05 ) . Conclusion : Administration of GnRH antagonists in ovarian stimulation will be a reasonable option to GnRH agonists in assessment reproduction treatment ; however , further studies are suggested OBJECTIVE To confirm the value of a single dose of 3 mg of cetrorelix in preventing the occurrence of premature LH surges . DESIGN Multicenter r and omized , prospect i ve study . SETTING Reproductive medicine units . PATIENT(S ) Infertile patients undergoing ovarian stimulation for IVF-ET . INTERVENTION(S ) A single dose of 3 mg of cetrorelix ( Cetrotide ; ASTA Medica , Frankfurt , Germany ) ( 115 patients ) was administered in the late follicular phase . A depot preparation of triptorelin ( Decapeptyl ; Ipsen-Biotech , Paris , France ) was chosen as a control agent ( 39 patients ) . Ovarian stimulation was conducted with hMG ( Menogon ; Ferring , Kiel , Germany ) . MAIN OUTCOME MEASURE(S ) Premature LH surges ( LH level > 10 IU/L ) , progesterone level greater than 1 ng/L , and IVF results . RESULT ( S ) No LH surge occurred after cetrorelix administration . The patients in the cetrorelix group had a lower number of oocytes and embryos . The percentage of mature oocytes and fertilization rates were similar in both groups , and the pregnancy rates were not statistically different . The length of stimulation , number of hMG ampules administered , and occurrence of the ovarian hyperstimulation syndrome were lower in the cetrorelix group . Tolerance of cetrorelix was excellent . CONCLUSION ( S ) A cetrorelix single-dose protocol prevented LH surges in all patients studied . It compares favorably to the " long protocol " and could be a protocol of choice in IVF-ET BACKGROUND The optimal time for GnRH antagonist initiation is still debatable . The purpose of the current r and omized controlled trial is to provide endocrine and follicular data during ovarian stimulation for IVF in patients with polycystic ovarian syndrome ( PCOS ) treated either with a long GnRH agonist scheme or a fixed day-1 GnRH antagonist protocol . METHODS R and omized patients in both groups ( antagonist : n = 26 ; long agonist : n = 52 ) received oral contraceptive pill treatment for three weeks and a starting dose of 150 IU of follitropin beta . The primary outcome was E(2 ) level on Day 5 of stimulation , while secondary outcomes were follicular development , LH during ovarian stimulation and progesterone levels . RESULTS Significantly more follicles on days 5 , 7 and 8 of stimulation , significantly higher estradiol ( E(2 ) ) levels on days 1 , 3 , 5 , 7 and 8 and significantly higher progesterone levels on days 1 , 5 and 8 of stimulation were observed in the antagonist when compared with the agonist group . E(2 ) was approximately twice as high in the antagonist when compared with the agonist group on day 5 of stimulation ( 432 versus 204 pg ml(-1 ) , P lt ; 0.001 ) . These differences were accompanied by significantly lower LH levels on days 3 and 5 and significantly higher LH levels on days 1 , 7 and 8 of stimulation in the antagonist when compared with the agonist group . CONCLUSIONS In PCOS patients undergoing IVF , initiation of GnRH antagonist concomitantly with recombinant FSH is associated with an earlier follicular growth and a different hormonal environment during the follicular phase when compared with the long agonist protocol OBJECTIVE To determine the efficiency of a single-dose and a multiple-dose protocol for GnRH antagonist administration . DESIGN R and omized clinical trial . SETTING University hospital , tertiary medical center . PATIENT(S ) Sixty-one patients undergoing controlled ovarian stimulation ( COS ) and IVF/ICSI . INTERVENTION(S ) COS with either a multiple-dose ( MD ) or a single-dose ( SD ) protocol for GnRH antagonist ( cetrorelix ) administration , or with a long protocol ( LP ) for GnRH agonist ( buserelin ) administration , followed by oocyte retrieval , IVF/ICSI , and embryo transfer . MAIN OUTCOME MEASURE(S ) Follicular development and serum levels of E2 and LH . RESULT ( S ) The SD protocol for cetrorelix was associated with a more reduced level of follicular development , lower levels of serum estradiol on the day of HCG administration , and a more reduced number of zygotes than the LP for buserelin . The pregnancy and implantation rates did not differ significantly for the three study groups . CONCLUSION ( S ) The MD and SD GnRH antagonist protocol s were effective for preventing LH surge and appear to elicit an equivalent pregnancy rate to that corresponding to a LP GnRH agonist . In terms of follicular development , the SD protocol requires further modification , including flexible scheduling or possibly a small reduction of the dosage of the administered cetrorelix The aim of this prospect i ve study was to evaluate the efficacy of gonadotrophin-releasing hormone antagonist ( GnRH ) in comparison with the st and ard long protocol in poor-responder patients . Sixty patients with poor ovarian response in previous treatment cycles were r and omized into two groups : group A ( n = 30 ) was stimulated with a st and ard long protocol , and group B ( n = 30 ) received GnRH antagonist . Vaginal ultrasound was performed to evaluate ovarian response . There was a significantly reduced duration of ovarian stimulation ( 9.8 + /- 0.8 versus 14.6 + /- 1.2 , P = 0.001 ) in group B in comparison with group A , and a reduced number of ampoules was used in group B ( 49.3 + /- 4.3 versus 72.6 + /- 6.8 , P = 0.0001 ) . In group B , the number of oocytes retrieved was significantly higher than in group A ( 5.6 + /- 1.6 versus 4.3 + /- 2.2 , P = 0.02 ) and there was an increased number of follicles with a diameter > 15 mm at human chorionic gonadotrophin administration in group B ( P = 0.0001 ) . Fewer cycles were cancelled with the use of an antagonist protocol . Five pregnancies ( 17 % for embryo transfer ) were obtained with GnRH antagonist protocol and two ( 7 % for embryo transfer ) with GnRH agonist protocol This prospect i ve r and omized study compared the effectiveness of a flexible single-dose gonadotrophin-releasing hormone ( GnRH ) antagonist ( cetrorelix ) and a single-dose long GnRH agonist ( goserelin ) protocol for ovarian stimulation in IVF/intracytoplasmic sperm injection ( ICSI ) cycles . All patients from the waiting list were successively included in the study , pre-programmed with an oral contraceptive , and r and omized into goserelin and cetrorelix groups . Depending on the date on which their menstrual period started , patients took oral contraceptives for one or two cycles . Ultimately , 236 patients in the first group received a single dose of depot preparation of goserelin and 224 patients received a single 3 mg dose of cetrorelix in the late follicular phase , when the mean follicle diameter exceeded 12 mm . The mean number of ampoules of FSH and the duration of stimulation was statistically significantly lower in the cetrorelix group than in the goserelin group ( 25.9 versus 34.5 , and 9.6 versus 12.2 days , P < 0.01 ) . The mean number of oocytes retrieved was similar ( 6.7 + /- 4.5 versus 7.2 + /- 4.6 , NS ) . Similar results were observed in fertilization rates , blastulation rates and blastocyst transfer rates in both groups . Clinical pregnancy and delivery rates per cycle were higher in the goserelin group ( 34.3 and 30.1 % ) than in the cetrorelix group ( 31.9 and 28.3 % ) , but the differences were not statistically significant . The flexible single-dose GnRH antagonist protocol is an advantageous alternative to the long GnRH agonist protocol , with similar efficacy , shorter duration , a significant reduction in the number of FSH ampoules used and without the menopause-like effects of the GnRH antagonist In this prospect i ve and r and omized study , 188 patients received the luteinizing hormone-releasing hormone ( LHRH ) antagonist cetrorelix , and 85 patients the LHRH agonist buserelin to prevent endogenous luteinizing hormone ( LH ) surges during ovarian stimulation in in-vitro fertilization (IVF)/intracytoplasmic sperm injection ( ICSI ) cycles . Ultimately , 181 patients ( 96.3 % ) in the cetrorelix group , and 77 ( 90.6 % ) in the buserelin group , reached the day of the human chorionic gonadotrophin ( HCG ) injection . The mean number of human menopausal gonadotrophin ( HMG ) ampoules administered and the mean number of stimulation days with HMG were significantly less in the cetrorelix group than in the buserelin group ( P < 0.01 ) . A rise in LH and progesterone concentrations was observed in three of the 188 patients ( 1.6 % ) who received cetrorelix . On the day of the HCG administration , more follicles of a small diameter ( 11 - 14 mm ) were observed in the buserelin group than in the cetrorelix group ( P = 0 . 02 ) and the mean serum oestradiol concentration was significantly higher in patients who received buserelin than in those who received cetrorelix ( P < 0.01 ) . Similar results were observed in fertilization , cleavage and pregnancy rates in the two groups . In conclusion , the use of the LHRH antagonists might be considered more advantageous because of the short-term application needed to inhibit gonadotrophin secretion , so allowing a reduction in the treatment time in a clinical ly significant manner OBJECTIVE To compare the efficacy of the long GnRH agonist vs. the short GnRH agonist vs. the GnRH antagonist regimens in poor responders undergoing IVF . DESIGN R and omized controlled trial . SETTING Tertiary referral fertility units . PATIENT(S ) Women with previous poor ovarian response undergoing IVF . INTERVENTION(S ) One hundred eleven women were r and omized to the long GnRH agonist , short agonist , and antagonist regimens . MAIN OUTCOME MEASURE(S ) The primary outcome was the number of oocytes retrieved . Secondary outcome measures were gonadotropin consumption , duration of stimulation , cycle cancellation rate , mature oocytes retrieved , fertilization rate , cycles reaching ET , and clinical and ongoing pregnancy rates . RESULT ( S ) Number of oocytes retrieved was significantly higher with long GnRH agonist compared with the short agonist regimen ( 4.42 ± 3.06 vs. 2.71 ± 1.60 ) , while there was no significant difference between long agonist and antagonist regimens ( 4.42 ± 3.06 vs. 3.30 ± 2.91 ) . Duration of stimulation and total gonadotropin dose were significantly higher with long agonist compared with short agonist and antagonist regimens . The ongoing pregnancy rate was 8.1 % with long and short agonist regimens and 16.2 % with the antagonist regimen . CONCLUSION ( S ) Long GnRH agonist and antagonist regimens offer a suitable choice for poor responders , whereas the short agonist regimen may be less effective because of fewer eggs retrieved OBJECTIVE Evaluate the effectiveness of a new ovarian stimulation ( OS ) protocol before IVF . DESIGN Prospect i ve clinical r and omized trial . SETTING Private centers . PATIENT(S ) Three hundred and twenty-three intended-to-treat women c and i date s for IVF . INTERVENTION(S ) Patients were divided into three groups and administered the following treatments : group A , recombinant hFSH from day 3 until follicles reached 13 - 14 mm , when recombinant hFSH was lowered to 75 IU daily and daily injections of 200 IU of hCG and a GnRH antagonist were administered until final maturation ; group B , recombinant hFSH and a GnRH antagonist ; group C , recombinant hFSH and a GnRH agonist . MAIN OUTCOME MEASURE(S ) Primary outcome was the number of mature oocytes . Secondary outcomes included average initial and total recombinant hFSH dosage , serum E2 level on day of ovulation , number of oocytes retrieved , fertilization , number of top- quality embryos , endometrial thickness , implantation rate , pregnancy rate ( PR ) , and incidence of ovarian hyperstimulation syndrome ( OHSS ) . RESULT ( S ) The numbers of oocytes retrieved , mature oocytes , fertilization , top- quality embryos , and embryos transferred were comparable in all groups . Implantation rate , PR , and incidence of OHSS were also comparable . The total dose of recombinant hFSH was significantly lower in group A ( 1,674.7 + /- 59.4 IU , vs. 2,197.9 + /- 77.8 IU in group B and 2,156.7 + /- 80.9 IU in group C ) . CONCLUSION ( S ) This new OS protocol permits follicles and oocytes to fully develop , helps generate top- quality embryos , avoids premature ovulation , establishes clinical pregnancies , reduces administration of recombinant hFSH , minimizes costs , and does not increase the chances of OHSS An open label , r and omized , multi-centre study was performed to compare cetrorelix and leuprolide acetate for prevention of premature LH surge and to assess whether patients treated with cetrorelix benefit from addition of recombinant human (r-h)LH . Normo-ovulatory women ( n = 74 ) undergoing ovarian stimulation prior to intracytoplasmic sperm injection were treated with leuprolide acetate ( n = 25 ) before ovarian stimulation with recombinant human FSH ( r-hFSH ) or with cetrorelix 3 mg on stimulation day 7 ( with ( n = 25 ) or without ( n = 24 ) r-hLH 150 IU on days 7 - 10 ) . The main outcome measures were the number of metaphase II ( MII ) oocytes retrieved ; secondary efficacy end-points ; adverse events ( AE ) and other safety measures . There were no significant differences between groups for MII oocytes retrieved , duration of stimulation , total r-hFSH dose and pregnancy rates . The group treated with cetrorelix alone had a significantly lower concentration of oestradiol per follicle compared with the other groups . The majority of AE were mild to moderate in severity . Cetrorelix and leuprolide acetate appear to have comparable efficacy and safety , although cetrorelix has the advantage of typically requiring only one injection Abstract Purpose This prospect i ve study evaluated the efficacy of gonadotropin-releasing hormone ( GnRH ) antagonist protocol in comparison with the GnRH agonist protocol in the first cycle of assisted reproductive technique ( ART ) . Methods We r and omized 235 patients undergoing ART for the first time . The first group was stimulated with a st and ard long protocol and the second group stimulated with GnRH antagonis . Results There was no statistically significant difference in the age , infertility cause , basal FSH , BMI , the number of oocytes retrieved , number of M2 oocytes , embryo obtained and endometrial thickness between the two groups . But Serum estradiol , consumption of gonadotropins and ovarian hyperstimulation syndrome were significantly lower in the antagonist protocol . Cancellation rate of embryo transfer due to poor- quality embryo in the antagonist protocol was higher , but it was not significant . There was no significant difference in the clinical pregnancy and ongoing pregnancy between the two groups . Conclusion GnRH-antagonist is an effective , safe , and well-tolerated alternative to agonist in the first cycle of ART BACKGROUND Mild in-vitro fertilisation ( IVF ) treatment might lessen both patients ' discomfort and multiple births , with their associated risks . We aim ed to test the hypothesis that mild IVF treatment can achieve the same chance of a pregnancy result ing in term livebirth within 1 year compared with st and ard treatment , and can also reduce patients ' discomfort , multiple pregnancies , and costs . METHODS We did a r and omised , non-inferiority effectiveness trial . 404 patients were r and omly assigned to undergo either mild treatment ( mild ovarian stimulation with gonadotropin-releasing hormone [ GnRH ] antagonist co-treatment combined with single embryo transfer ) or a st and ard treatment ( stimulation with a GnRH agonist long- protocol and transfer of two embryos ) . Primary endpoints were proportion of cumulative pregnancies leading to term livebirth within 1 year after r and omisation ( with a non-inferiority threshold of -12.5 % ) , total costs per couple up to 6 weeks after expected date of delivery , and overall discomfort for patients . Analysis was by intention to treat . This trial is registered as an International St and ard R and omised Clinical Trial , number IS RCT N35766970 . FINDINGS The proportions of cumulative pregnancies that result ed in term livebirth after 1 year were 43.4 % with mild treatment and 44.7 % with st and ard treatment ( absolute number of patients = 86 for both groups ) . The lower limit of the one-sided 95 % CI was -9.8 % . The proportion of couples with multiple pregnancy outcomes was 0.5 % with mild IVF treatment versus 13.1 % ( p<0.0001 ) with st and ard treatment , and mean total costs were 8333 euros and 10745 euros , respectively ( difference 2412 euros , 95 % CI 703 - 4131 ) . There were no significant differences between the groups in the anxiety , depression , physical discomfort , or sleep quality of the mother . INTERPRETATION Over 1 year of treatment , cumulative rates of term livebirths and patients ' discomfort are much the same for mild ovarian stimulation with single embryos transferred and for st and ard stimulation with two embryos transferred . However , a mild IVF treatment protocol can substantially reduce multiple pregnancy rates and overall costs Purpose Embryological and clinical efficacy of gonadotropin-releasing hormone ( GnRH ) antagonist and agonist stimulation protocol s in non-obese women with polycystic ovarian syndrome ( PCOS ) were compared . Methods A prospect i ve r and omized study . Setting : Medical University Hospital . Patients : 70 infertile PCOS patients ; 33 in GnRH antagonist and 37 in GnRH agonist group . Results Similar mature metaphase II oocyte rate ( 76 % vs. 76 % ) was observed in both protocol s. Optimal pronuclear morphology zygotes dominated in both groups ( 64 % vs. 66 % ) . Transferred embryo quality did not differ in both protocol s. No significant differences between both protocol s were found in delivery rate ( p = 0.481 ) , pregnancy rate ( p = 0.810 ) , multiple pregnancy rate ( p = 0.501 ) , miscarriage rate ( p = 0.154 ) , fertilization rate ( p = 0.388 ) and implantation rate ( p = 1.000 ) . Duration of stimulation and total follicle-stimulating hormone ( FSH ) dose were significantly lower in GnRH antagonist protocol ( p = 0.0005 ) . Conclusions GnRH antagonist and agonist protocol s in non-obese PCOS patients yield similar embryological and clinical outcomes . Shorter duration of treatment and lower FSH requirement in GnRH antagonist group may be financially beneficial and therefore attractive for patients OBJECTIVE To investigate the outcomes of intracytoplasmic sperm injection ( ICSI ) cycles after controlled ovarian hyperstimulation ( COH ) with GnRH antagonist or GnRH agonist ( GnRH-a ) in mild-to-moderate endometriosis and endometrioma . DESIGN Prospect i ve r and omize trial . SETTING A private IVF center . PATIENT(S ) A total of 246 ICSI cycles in 246 patients were divided into three groups : women with mild-to-moderate endometriosis ( n = 98 ) ; women who had ovarian surgery for endometrioma ( n = 81 ) ; women with endometrioma and no history of previous surgery ( n = 67 ) . INTERVENTION(S ) Patients in each group were r and omized to COH with either triptrolein or cetrorelix . MAIN OUTCOME MEASURE(S ) Clinical parameters , characteristics of COH , and ICSI results were analyzed . RESULT ( S ) Outcomes of COH with both GnRH antagonist and GnRH-a were similar in patients with mild-to-moderate endometriosis . Implantation rates were 15.9 % vs. 22.6 % and clinical pregnancy rates were 27.5 % vs. 39 % with GnRH antagonist and GnRH-a protocol s , respectively , in patients who had ovarian surgery for endometrioma . Implantation rates were 12.5 % vs. 14.8 % and clinical pregnancy rates were 20.5 % vs. 24.2 % with GnRH antagonist and GnRH-a protocol s , respectively , in patients with endometrioma and no history of ovarian surgery . CONCLUSION ( S ) Considering the implantation and clinical pregnancy rates , COH with both GnRH antagonist and GnRH-a protocol s may be equally effective in patients with mild-to-moderate endometriosis and endometrioma who did and did not undergo ovarian surgery Objective To investigate the efficacy of gonadotropin releasing hormone antagonist ( GnRH ) in poor responders undergoing in vitro fertilization . Study design Ninety-six patients with poor ovarian response in previous treatment cycles were prospect ively r and omized into two groups . Forty-four patients were stimulated with GnRH antagonist multidose protocol and 45 patients received a st and ard long agonist protocol . Ovarian response was evaluated by transvaginal ultrasound and hormonal parameters . Cycle characteristics and treatment outcomes were statistically compared between groups . Results There was significantly reduced duration of stimulation and consumption of gonadotrophins in the antagonist group when compared to the agonist group . The estradiol concentrations on the day of human chorionic gonadotropin ( hCG ) injection , the number of oocytes retrieved , and the number of embryos transferred were similar for both groups . In the antagonist group , eight ( 18.1 % ) ongoing pregnancies were achieved and in the agonist group , ten ( 22.2 % ) clinical pregnancies were achieved but the difference was not statistically significant . Conclusion The present study was not powered to detect clinical ly relevant differences between two protocol s in outcomes such as pregnancy rate , with confidence Extending the FSH window for multifollicular development by administering FSH from the midfollicular phase onward constitutes a novel mild protocol for ovarian stimulation for in vitro fertilization ( IVF ) based on the physiology of single dominant follicle selection in normo-ovulatory women . We compared outcomes from this protocol with two other stimulation protocol s. One hundred and forty-two normo-ovulatory patients with an indication for IVF ( or IVF/ICSI ) were r and omized to a GnRH agonist long protocol ( group A ; n = 45 ) or one of two GnRH antagonist protocol s commencing recombinant FSH on cycle d 2 ( group B ; n = 48 ) or cycle d 5 ( group C ; n = 49 ) . A fixed dose ( 150 IU/d ) of rFSH was used for ovarian stimulation , and GnRH antagonist cotreatment was initiated on the day when the leading follicle reached 14 mm diameter . Group C showed a shorter duration of stimulation ( median duration , 11 , 9 , and 8 d for groups A , B , and C , respectively ; P < 0.001 ) , reflected in a significantly lower total dose of rFSH used ( median amount of rFSH , 1650 , 1350 , and 1200 IU for groups A , B , and C , respectively ; P < 0.001 ) . In group C more cycles were cancelled during the stimulation phase due to insufficient response , result ing in a lower percentage of oocyte retrievals ( 84 % , 73 % , and 63 % for groups A , B , and C ; P = 0.02 ) . However , women in group C obtained better quality embryos ( percentage of embryo score of 1 for best embryo , 29 % , 37 % , and 61 % for groups A , B , and C , respectively ; P = 0.008 ) , result ing in more transfers per oocyte retrieval ( 68 % , 71 % , and 90 % for groups A , B , and C , respectively ; P = 0.04 ) . After profound ovarian stimulation ( groups A and B ) only 7 % of the patients who retrieved four oocytes or less conceived , whereas after mild stimulation ( group C ) 67 % of these patients conceived ( P < 0.01 ) . Overall , no differences were found among the three groups comparing pregnancy rate per started IVF cycle . In conclusion , application of the described mild ovarian stimulation protocol result ed in pregnancy rates per started IVF cycle similar to those observed after profound stimulation with GnRH agonist cotreatment despite shorter stimulation and a 27 % reduction in exogenous FSH . A higher cancellation rate before oocyte retrieval was compensated by improved embryo quality concomitant with a higher chance of undergoing embryo transfer . A relatively low number of oocytes retrieved after mild ovarian stimulation distinctly differs from the pathological reduction in the number of oocytes retrieved after profound ovarian stimulation ( poor response ) associated with poor IVF outcome . The relatively small number of oocytes obtained after mild ovarian stimulation may represent the best of the cohort in a given cycle OBJECTIVE To assess the efficacy , safety , and local tolerance of ganirelix acetate for the inhibition of premature luteinizing hormone ( LH ) surges in women undergoing controlled ovarian hyperstimulation ( COH ) . DESIGN Phase III , multicenter , open-label r and omized trial . SETTING In vitro fertilization ( IVF ) centers in North America . PATIENT(S ) Healthy female partners ( n = 313 ) in subfertile couples for whom COH and IVF or intracytoplasmic sperm injection were indicated . INTERVENTION(S ) Patients were r and omized to receive one COH cycle with ganirelix or the reference treatment , a long protocol of leuprolide acetate in conjunction with follitropin-beta for injection . OUTCOME MEASURE(S ) Number of oocytes retrieved , pregnancy rates , endocrine variables , and safety variables . RESULT ( S ) The mean number of oocytes retrieved per attempt was 11.6 in the ganirelix group and 14.1 in the leuprolide group . Fertilization rates were 62.4 % and 61.9 % in the ganirelix and leuprolide groups , respectively , and implantation rates were 21.1 % and 26.1 % . Clinical and ongoing pregnancy rates per attempt were 35.4 % and 30.8 % in the ganirelix group and 38.4 % and 36.4 % in the leuprolide acetate group . Fewer moderate and severe injection site reactions were reported with ganirelix ( 11.9 % and 0.6 % ) than with leuprolide ( 24.4 % and 1.1 % ) . CONCLUSION ( S ) Ganirelix is effective , safe , and well tolerated . Compared with leuprolide acetate , ganirelix therapy has a shorter duration and fewer injections but produces a similar pregnancy rate The aim of this study was to determine whether follicular oestradiol and vascular endothelial growth factor ( VEGF ) concentrations in women with polycystic ovarian syndrome ( PCOS ) differ according to the use of gonadotrophin-releasing hormone ( GnRH ) antagonists or GnRH agonists . Furthermore , the effect of follicular oestradiol and VEGF concentrations on oocyte and embryo quality was investigated . In this prospect i ve clinical study , 20 women with PCOS undergoing intracytoplasmic sperm injection for male factor infertility were included using a GnRH antagonist or a GnRH agonist protocol . In each follicle , oestradiol and VEGF concentrations were determined . In the GnRH antagonist group 254 follicles and in the GnRH agonist group 245 follicles , were aspirated . Fewer metaphase II ( MII ) and more immature and degenerative oocytes were registered in the GnRH antagonist group . Follicular oestradiol and VEGF were lower in the GnRH antagonist group ( P = 0.014 and P < 0.001 , respectively ) . Moreover , higher oestradiol concentrations were related to embryos of higher quality ( P = 0.037 ) . It is concluded that GnRH antagonists decrease follicular oestradiol and VEGF concentrations and the number of retrieved MII oocytes in women with PCOS OBJECTIVE Testing the ability to program IVF GnRH-antagonist cycles to avoid weekend oocyte retrieval . STUDY DESIGN Preliminary r and omized clinical trial . Patients presenting an indication for IVF or IVF-ICSI were assigned into either the Treatment Group - GnRH antagonist protocol , programmed to start stimulatory agents on a Friday , with oral 2 mg estradiol valerate twice a day from the 2nd day of cycle until the first Friday to follow , or to the Control Group - long luteal GnRH agonist protocol . RESULTS The performance of 27 Treatment Group patients and 24 Control Group patients was analyzed . Cycle dynamics were not clinical ly or statistically different except for a significant difference in the number of follicles measuring ≥18 mm on hCG administration day . There were no differences in the number of aspirated ova , fertilization rates , embryo quality or number of embryos to be transferred . Pregnancy rate was 41.7 % in the Treatment Group and 50 % in the Control Group ( P>0.5 ) . Only one patient assigned to the Treatment Group had a weekend retrieval . CONCLUSIONS Preliminary results demonstrate no compromise related to follicular estrogen programming in a GnRH antagonist protocol and provide reassurance regarding the ability to achieve programming goals OBJECTIVE To determine whether the use of luteal phase vaginal E(2 ) supplementation improves clinical pregnancy rates in patients undergoing IVF treatment . DESIGN Prospect i ve r and omized controlled trial . SETTING University-based tertiary fertility center . PATIENT(S ) One hundred sixty-six patients undergoing their first cycle of IVF treatment . INTERVENTION(S ) Patients underwent three different protocol s for controlled ovarian hyperstimulation for IVF treatment with long GnRH agonist suppression , use of GnRH antagonist , or a microdose GnRH agonist protocol . Luteal phase support was in the form of IM P. Patients r and omized into the study group ( n = 84 ) received E(2 ) supplementation in the form of vaginal estrace 2 mg twice a day starting on the day of ET . Patients r and omized to the control group ( n = 82 ) received no E(2 ) supplementation . MAIN OUTCOME MEASURE(S ) Clinical pregnancy rates . RESULT ( S ) There were no significant differences in the implantation ( 56/210 [ 26.7 % ] vs. 64/203 [ 31.5 % ] ) , clinical pregnancy ( 42/84 [ 50 % ] vs. 52/82 [ 63.4 % ] ) , and ongoing pregnancy rates ( 40/84 [ 47.6 % ] vs. 46/82 [ 56.1 % ] ) between the study and control groups , respectively . In the subgroup of patients who used the long GnRH agonist suppression protocol , there was a lower clinical pregnancy rate in the study group compared with the control group ( 27/55 [ 49.1 % ] vs. 42/59 [ 71.2 % ] ) . There were , however , no differences in clinical pregnancy rates between the two groups in patients who used either the GnRH antagonist or microdose GnRH agonist protocol s. CONCLUSION ( S ) The addition of vaginal E(2 ) supplementation to routine P supplementation for luteal support does not improve the probability of conception after IVF treatment Purpose This study aims to verify if luteal estradiol pre-treatment improves IVF/ICSI outcomes in a GnRH antagonist protocol as compared with a micro dose GnRH agonist protocol in poor-responding patients . Methods A total of 116 IVF/ICSI cycles were included in this prospect i ve r and omized single blind clinical trial . The selected women were r and omly assigned to receive an estradiol pre-treatment in a GnRH antagonist protocol ( daily oral Estradiol Valerate 4 mg preceding the IVF cycle from the 21st day until the first day of the next cycle ) or in oral contraceptive pill micro dose GnRH agonist protocol . Results The patients in the luteal estradiol protocol required more days of stimulation ( 10.9 ± 1.6 vs. 10.2 ± 1.8 ) and a greater gonadotropin requirement ( 3,247.8 ± 634.6 vs. 2,994.8 ± 611 IU ) , yet similar numbers of oocytes were retrieved and fertilized . There was no significant difference between the two groups in terms of the implantation rates ( 9.8 vs. 7.9 % ) and the clinical pregnancy rates per transfer ( 16.3 vs. 15.6 % ) . Conclusion This study demonstrates that the use of estradiol during a preceding luteal phase in a GnRH antagonist protocol can provide similar IVF outcomes when compared to a micro dose GnRH agonist protocol Gonadotropin-releasing hormone ( GnRH ) antagonists for controlled ovarian stimulation ( COS ) were only recently introduced into China . The efficacy and safety of the GnRH antagonist ganirelix was assessed in a multicenter , controlled , open-label study , in which Chinese women were r and omized to either ganirelix ( n = 113 ) or a long GnRH agonist protocol of triptorelin ( n = 120 ) . The primary end point was the amount of recombinant follicle-stimulating hormone ( rFSH ) required to meet the human chorionic gonadotropin criterion ( three follicles ≥17 mm ) . The amount of rFSH needed was significantly lower for ganirelix ( 1272 IU ) vs. triptorelin ( 1416 IU ; P < 0.001 ) . Ongoing pregnancy rates per started cycle were 39.8 % ( ganirelix ) and 39.2 % ( triptorelin ) . Although both treatments were well tolerated , cancellation due to risk of ovarian hyperstimulation syndrome ( OHSS ) was less frequent with ganirelix ( 1.8 % ) than triptorelin ( 7.5 % ) ( P = 0.06 ) . Less rFSH was needed in the ganirelix protocol than the long GnRH agonist protocol , with fewer reported cases of OHSS and similar pregnancy rates The purpose of this prospect i ve r and omized study was to compare stimulation characteristics and IVF outcomes of the st and ard long GnRH agonist protocol for ovarian stimulation with a modified GnRH antagonist protocol . Starting GnRH antagonist in a flexible protocol according to the size of the leading follicle , with simultaneous augmentation of 75 IU recombinant FSH , failed to increase clinical pregnancy rates This multicentre , r and omized study was performed to assess the efficacy and safety of 0.25 mg ganirelix ( Orgalutran , Antagon ) treatment , using triptorelin ( Decapeptyl ) in a long protocol as a reference treatment . In total , 236 subjects were r and omized to treatment with ganirelix ( 0.25 mg , s.c . ) and 119 to triptorelin ( 0.1 mg , s.c . ) treatment ( treatment ratio 2:1 ) . Treatment with ganirelix started on day 6 of stimulation , whereas treatment with triptorelin started on menstrual cycle day 21 to 24 of the previous cycle ( i.e. the midluteal phase ) . The ganirelix regimen was on average 17 days shorter ( 9 versus 26 days ) compared to the triptorelin regimen . The median total dose of recombinant FSH ( Puregon ) used was 450 IU less ( 1350 versus 1800 IU ) in the ganirelix protocol . The initial follicular growth was faster and , consequently , oestradiol concentrations were higher in the ganirelix group . On the day of human chorionic gonadotrophin ( HCG ) , the mean number of follicles > or = 11 mm was 10.1 and 10.7 and the median serum oestradiol concentration was 1090 and 1370 pg/ml in the ganirelix and triptorelin groups respectively . Per attempt , 7.9 and 9.6 oocytes ( mean ) were retrieved in the ganirelix and triptorelin groups respectively . The fertilization rates ( 64.0 % ganirelix and 64.9 % triptorelin ) and the mean number of good quality embryos ( 2.7 and 2.9 ) were comparable in both treatment groups . The implantation rate was identical ( 22.9 % ) . The ongoing pregnancy rate per attempt was 31.0 and 33.9 % in the ganirelix and triptorelin groups respectively . The ganirelix regimen showed an improved local tolerance in that the percentage of subjects with at least one local skin reaction was 2-fold lower than in the triptorelin group ( 11.9 versus 24.1 % ) . Taking all data together , it may be concluded that ganirelix offers a new treatment regimen in ovarian stimulation that is short , safe and well-tolerated , optimizing convenience for the patient BACKGROUND The aim of this study was to investigate the effect of GnRH antagonists ( GnRH-ant ) on follicular fluid vascular endothelial growth factor ( FF VEGF ) . METHODS Sixty women undergoing assisted reproduction were r and omised ( computer-generated r and omisation list ) and assigned to two different GnRH analogue regimens : GnRH agonist ( GnRH-a ) ( Group A ; n = 30 ) and GnRH-ant ( Group B ; n = 30 ) . RESULTS Mean ( + /-S.D. ) FF VEGF concentrations were 1598+/-612 pg/mL and 2906+/-1558 pg/mL for Groups A and B , respectively ( p < 0.001 ) . In the women treated with GnRH-ant , we found a statistically significant reduction in serum LH levels ( 1.72+/-0.74 IU/L in Group A versus 0.93+/-0.43 IU/L in Group B , p < 0.001 ) , in serum oestradiol ( E2 ) levels ( 1562.1+/-410.7 pg/mL in Group A versus 1214.67+/-779.9 pg/mL in Group B , p < 0.05 ) , in FF E2 levels ( 1146+/-593 ng/mL in Group A versus 621+/-435 ng/mL in Group B , p < 0.05 ) , and in FF and rostenedione levels ( 136+/-55 ng/mL in Group A versus 78+/-31 ng/mL in Group B , p < 0.001 ) , as well as a reduction in the number of pregnancies , though not statistically significant ( 23.3 % in Group A versus 16.6 % in Group B ) . CONCLUSION The increase in FF VEGF levels in women treated with GnRH-ant might be explained by a suppression of LH and E2 levels In a first feasibility study , the efficacy and safety of a single dose of recombinant long-acting FSH ( FSH-CTP ) were investigated in in vitro fertilization ( IVF ) patients undergoing controlled ovarian stimulation with a flexible GnRH antagonist protocol . Eligible subjects were r and omized to receive a single dose of 120 micro g ( n = 25 ) , 180 microg ( n = 24 ) , or 240 microg ( n = 25 ) corifollitropin alfa ( FSH-CTP ) or to start daily fixed doses of 150 IU recombinant FSH ( rFSH ) ( n = 24 , reference ) . Subjects who received a single dose of FSH-CTP continued 1 wk after injection ( treatment d 8) with fixed daily doses of 150 IU rFSH ( Puregon/Follistim ) until the day of triggering final oocyte maturation . The terminal half-life of FSH-CTP was , on average , 65 h and dose independent . Cycle cancellation before human chorionic gonadotropin ( hCG ) administration occurred in only three subjects treated with FSH-CTP . The median duration of stimulation was 10.0 d in each FSH-CTP group and 9.0 d in the daily rFSH group . The total number of follicles at least 11 mm at stimulation d 8 and at the day of hCG administration tended to increase with dose of FSH-CTP , although a significant dose-response relationship was revealed only for the number of follicles at least 15 mm on the day of hCG ( P = 0.03 ) . Serum estradiol levels and inhibin-B levels were not significantly different between the four groups on d 8 and on the day of hCG . In total , 12 subjects ( 17.6 % ) in the FSH-CTP groups and two subjects ( 8.3 % ) in the rFSH group experienced a premature LH rise ( defined as LH > or= 10 IU/liter ) before the start of the GnRH antagonist ( P value not significant between groups ) . This relatively high incidence of women demonstrating an early LH rise in the FSH-CTP groups may be related to the higher initial rises of serum estradiol and the use of a flexible GnRH antagonist protocol . The mean number of oocytes recovered per started cycle was higher in FSH-CTP-treated subjects compared with rFSH-treated subjects ( significant at P = 0.03 for the 240- microg FSH-CTP group ) , but no difference could be noted between the number of good quality embryos ( range of means , 3.8 - 4.8 per attempt ) , and equal numbers of embryos were available for embryo transfer . In summary , FSH-CTP appeared to be a potent inducer of multiple follicular growth ; additional research will be needed to select the optimal FSH-CTP dose and treatment time interval This prospect i ve r and omized study was performed to compare the efficacy of GnRH antagonist multiple-dose protocol ( MDP ) with or without oral contraceptive pill ( OCP ) pretreatment and GnRH agonist low-dose long protocol ( LP ) in 82 patients undergoing IVF/intracytoplasmic sperm injection ( ICSI ) . GnRH antagonist MDP with OCP pretreatment was at least as effective as GnRH agonist low-dose LP in low responders , and can benefit the low responders by reducing the amount of FSH and the number of days of stimulation required for follicular maturation OBJECTIVE To compare the outcome of using gonadotropin-releasing hormone ( GnRH ) antagonists versus agonists in women with polycystic ovary disease ( PCOD ) who underwent controlled ovarian hyperstimulation ( COH ) for assisted reproductive techniques ( ART ) . STUDY DESIGN A total of 129 patients with PCOD were r and omly allocated to undergo COH with a GnRH antagonist ( 59 patients ) and GnRH agonist ( leuprolide acetate ) ( 70 patients ) to prevent a premature luteinizing hormone ( LH ) surge . Assisted fertilization following oocyte retrieval and embryo transfer was performed . RESULTS None of the cycles were cancelled due to a premature LH surge . There was no significant difference between the antagonist and agonist arms in the number of gonadotropin ampules consumed per cycle . However , in the antagonist arm a shorter duration of ovarian stimulation was recorded as compared to the agonist arm . Although similar numbers of oocytes was retrieved from both groups of patients , the quality of the oocytes , as measured by metaphase 2/total oocyte ratio , was lower in the antagonist arm as compared to the agonist arm . Pregnancy rates were 57.6 % and 58.5 % in the antagonist and agonist arms , respectively ( p > 0.05 ) . Implantation rates were not different ( 34.0 % and 34.6 % , respectively ) . The frequency of ovarian hyperstimulation syndrome also did not differ between the treatment groups ( 5 % and 7.1 % , respectively ) . CONCLUSION The size of our study , on a specific subgroup of patients , does not allow a reliable conclusion regarding ART outcome following the use of a GnRH antagonist versus agonist . Nevertheless , the protocol with the antagonist gave results that were as good as those of the protocol with the agonist in this PCOD patient population Due to inherent differences between gonadotrophin-releasing hormone ( GnRH ) antagonists and agonists , their late effect on ovarian steroidal production during the luteal phase of IVF cycles may differ . The aim of this study was to characterize and compare the luteal phase hormonal profile after the use of GnRH antagonists or agonists in ovarian stimulation protocol s for IVF , in non-conception cycles , to avoid the effect of human chorionic gonadotrophin ( HCG ) during the luteal phase in conception cycles . Seventy-eight normo-ovulatory patients < 35 years old , undergoing IVF due to male or tubal infertility were r and omly allocated either to a GnRH antagonist ( study group ) or GnRH agonist treatment ( control group ) . Similar st and ard luteal support was given to all patients , using vaginal micronized progesterone . In non-conception cycles , no statistically significant differences were found comparing luteal phase . oestradiol or progesterone levels in the study and control groups . No statistically significant differences were found comparing the hormonal profile dynamics , the mid-luteal ( HCG day + 8) oestradiol/progesterone ratio and the percentage of mid-luteal oestradiol decline between the study and control groups . In conclusion , similar characteristics and dynamics of luteal phase oestradiol and progesterone were demonstrated comparing ovarian stimulation for IVF using GnRH agonist or antagonists , under similar luteal support OBJECTIVE To assess safety and efficacy of cetrorelix utilisation in controlled ovarian stimulation ( COS ) . STUDY DESIGN Phase III , r and omized , single center study of 131 patients undergoing COS and IVF with or without ICSI , in a University affiliated Hospital . Sixty-six patients were allocated to the protocol with antagonist and 65 to the agonist protocol arm . The Student 's t-test , the Mann-Whitney test and the chi-square test were applied as required , using SPSS for Windows with a two-sided 5 % significance level . RESULTS The mean ( + /-S.D. ) duration of stimulation was 9.5+/-1.7 days in the antagonist group and 10.6+/-2.1 days in the agonist group ( P=0.02 ) . The mean ( + /-S.D. ) duration of suppression was 4.6+/-1.3 days in the antagonist group and 27.3+/-5.2 days in the agonist group ( P<0.0001 ) . No significant differences were noted in other outcome measures : amount of rFSH required , estradiol level on hCG day , number of follicles > or=15 mm and endometrial thickness on oocyte retrieval day , number of oocytes retrieved , fertilization rate and number of OHS cases . Clinical pregnancy rates per-attempt and per-transfer were 15.1 % and 17.0 % in the antagonist group and 16.9 % and 20.0 % in the agonist group ( P=0.79 and 0.71 , respectively ) . CONCLUSIONS GnRH antagonists are an effective , safe and well tolerated alternative to agonists for COS BACKGROUND This is the first published report of a prospect i ve , r and omized , controlled trial comparing a fixed , multi-dose GnRH antagonist protocol with a long GnRH agonist protocol in poor responders undergoing IVF . METHODS Sixty-six poor responders were r and omized into two groups : the study group received 0.25 mg of cetrorelix daily starting on day 6 of stimulation ; the control group received 600 microg of buserelin acetate daily starting in the mid-luteal phase of the preceding cycle . Both groups were given a fixed dose of recombinant FSH ( 300 IU daily ) for stimulation . RESULTS There were no significant differences in the cycle cancellation rates , duration of stimulation , consumption of gonadotrophins , and mean numbers of mature follicles , oocytes and embryos obtained . The implantation rates were similar , but the number of embryos transferred was significantly higher for the antagonist group ( 2.32 + /- 0.58 versus 1.50 + /- 0.83 ; P = 0.01 ) . The pregnancy rates were also higher in the antagonist group , but the difference was not statistically significant . CONCLUSION A fixed multi-dose GnRH antagonist protocol is feasible for patients who are poor responders on a long agonist protocol ; however , our study failed to demonstrate an overall improvement in ovarian responsiveness . Clinical outcomes may be improved by developing more flexible antagonist regimens , an approach that requires further evaluation OBJECTIVE Assess the efficiency of estradiol programming in In Vitro Fertilization ( IVF ) with antagonists by comparing with classical long luteal agonist protocol . PATIENTS AND METHODS It is a prospect i ve r and omized study , comparing 426 cycles in the arm estradiol antagonist with 412 cycles in the arm long agonist . Estradiol 4 mg/day begins on the 25th day of the previous cycle and continues during the menses until the first day of the stimulation which is from Thursday to Sunday whatever the beginning of the menses . The luteal protocol use Decapeptyl 0,1 mg which begins on the 20th day of the previous cycle . RESULTS Our two population s are similar . No pick-up has been done on Sunday . We have got significantly less oocytes and embryos in estradiol-antagonist ( 6,8+/-5,3 vs 7,6+/-5,7 ) and ( 3,7+/-3,2 vs 4,1+/-3,6 ) respectively . The ongoing pregnancy rate is comparable in the two groups : 28,6 % for estradiol antagonist 27,9 % for agonist for the whole population and 37 % vs 34,8 % respectively when at least one top embryo was transferred . DISCUSSION AND CONCLUSION Programming antagonist cycles with estradiol allows the organization of the center ; it is easy to implement and seems to give results as good as a long agonist protocol AIM Gonadotropin-releasing hormone ( GnRH ) antagonists have reduced the incidence of severe ovarian hyper stimulation syndrome ( OHSS ) and rate of hospitalization due to severe OHSS , especially in polycystic ovarian syndrome ( PCOS ) patients . The present study aim ed to compare the outcomes of patients with PCOS undergoing controlled ovarian hyperstimulation ( COH ) with GnRH agonist versus GnRH antagonist protocol s for assisted reproduction cycles . METHODS The present clinical trial compared GnRH antagonist ( cetrorelix ) and GnRH agonist ( buserelin ) protocol s during COH of 112 infertile PCOS patients entering assisted reproduction cycles . The primary outcome measure was pregnancy occurrence . Basal characteristics of the participants , stimulation cycle responses , pregnancy outcomes , incidence of OHSS and types of OHSS were considered in both groups . RESULTS Regarding chemical and clinical pregnancy rates , the number of retrieved oocytes was significantly higher and OHSS was significantly lower in the antagonist group . Follicle stimulating hormone ( FSH ) , luteinizing hormone ( LH ) levels , number of follicles , number of follicles > 18 mm , relative frequency of mature oocytes , number and days of gonadotropin injections , day of human chorionic gonadotropin ( HCG ) administration , estradiol level and abortion were similar between the two groups . CONCLUSION GnRH antagonists are more effective , safe and a well tolerated alternative to agonists for assisted reproduction cycles in PCOS patients . GnRH antagonists are associated with a reduction in the incidence of OHSS in these patients

Significance Real-world evidence suggests that low-frequency rTMS using a figure-8 coil may be an effective therapy for the treatment of drug-resistant epilepsy in pediatric patients .

Objective To perform a systematic review and meta- analysis of real-world evidence for the use of low-frequency repetitive transcranial magnetic stimulation ( rTMS ) in the treatment of drug-resistant epilepsy .

To study the antiepileptic effects of rTMS in patients with refractory epilepsy and malformations of cortical development in a r and omized , double‐blind , sham‐controlled trial Repetitive transcranial magnetic stimulation ( rTMS ) is an emerging non-pharmacological approach to treating many brain-based disorders . rTMS uses electromagnetic coils to stimulate areas of the brain non-invasively . Deep transcranial magnetic stimulation ( dTMS ) with the Brainsway H1-coil system specifically is a type of rTMS indicated for treating patients with major depressive disorder ( MDD ) who are resistant to medication . The unique H1-coil design of this device is able to stimulate neuronal pathways that lie deeper in the targeted brain areas than those reached by conventional rTMS coils . dTMS is considered to be low-risk and well tolerated , making it a viable treatment option for people who have not responded to medication or psychotherapy trials for their depression . R and omized , sham-control studies have demonstrated that dTMS produces significantly greater improvement in depressive symptoms than sham dTMS treatment in patients with major depression that has not responded to antidepressant medication . In this paper , we will review the methodology for treating major depression with dTMS using an H1-coil We evaluated the effect of low-frequency repetitive transcranial magnetic stimulation ( rTMS ) on seizure frequency in adult patients with medically intractable extratemporal lobe epilepsy ( ETLE ) . Seven patients with medically intractable ETLE received low-frequency rTMS at 0.9 Hz , basically two sets of 15 min stimulation per day for five days in a week , with the stimulus intensity of 90 % of resting motor threshold ( RMT ) . The number of seizures during two weeks before and after the stimulation of one week was compared . Furthermore , RMT and active motor threshold ( AMT ) were measured before and after rTMS for each daily session . After low-frequency rTMS of one week , the frequency of all seizure types , complex partial seizures ( CPSs ) and simple partial seizures was reduced by 19.1 , 35.9 and 7.4 % , respectively . The patients with smaller difference between RMT and AMT before rTMS had higher reduction rate of CPSs . A favorable tendency of seizure reduction , though not statistically significant , during two weeks after low-frequency rTMS was demonstrated in medically intractable ETLE patients . As far as CPSs are concerned , smaller decrease of motor threshold by voluntary muscle contraction was associated with better response to rTMS PURPOSE To evaluate the number of seizures and interictal epileptiform discharges ( IEDs ) in patients with focal neocortical epilepsy before , during and after rTMS . METHODS Twelve patients ( seven men and five women , mean age 29.3+/-15.8 years ) were studied . An open-label study with baseline ( 4 weeks ) , intervention ( 2 weeks ) and follow-up ( 8 weeks ) periods was carried out . Repetitive transcranial magnetic stimulation ( rTMS ) with 900 pulses , intensity of 120 % motor resting threshold and 0.5Hz frequency was used . A 120 channel EEG was recorded ; an electrical source analysis of IEDs with Variable Resolution Electromagnetic Tomography ( VARETA ) was performed . The number of seizures per week and IEDs per minute were measured and compared in the three periods . RESULTS During the basal period the mean seizure frequency was 2.25 per week ; in the intervention period it decreased to 0.66 per week ( F=2.825 ; p=0.0036 ) which corresponds to a 71 % reduction . In the follow-up period the mean frequency was 1.14 seizures per week , that is , a 50 % reduction in the number of seizures . In the visual EEG analysis , the baseline IED frequency was 11.9+/-8.3events/min ; it decreased to 9.3+/-7.9 during 2 weeks of rTMS with a further reduction to 8.2+/-6.6 in the follow-up period . These differences however were not significant ( p=0.190 ) . CONCLUSION We conclude that 2 weeks of rTMS at 0.5Hz with a figure-of-eight coil placed over the epileptic focus , determined with VARETA , decreases the number of seizures in patients with focal epilepsy , without reduction in IEDs PURPOSE To assess the effectiveness of slow repetitive transcranial magnetic stimulation ( rTMS ) as an adjunctive treatment for drug-resistant epilepsy . METHODS Forty-three patients with drug-resistant epilepsy from eight Italian Centers underwent a r and omized , double-blind , sham-controlled , crossover study on the clinical and EEG effects of slow rTMS . The stimulus frequency was 0.3 Hz . One thous and stimuli per day were given at the resting motor threshold intensity for 5 consecutive days , with a round coil at the vertex . RESULTS " Active " rTMS was no better than placebo for seizure reduction . However , it decreased interictal EEG epileptiform abnormalities significantly ( p < 0.05 ) in one-third of the patients , which supports a detectable biologic effect . No correlation linked the rTMS effects on seizure frequency to syndrome or anatomic classification , seizure type , EEG changes , or resting motor threshold ( an index of motor cortex excitability ) . CONCLUSIONS Although the antiepileptic action was not significant ( p > 0.05 ) , the individual EEG reactivity to " active " rTMS may be encouraging for the development of more-powerful , noninvasive neuromodulatory strategies OBJECTIVE To evaluate the antiepileptic effect of low-frequency rTMS ( repetitive transcranial magnetic stimulation ) in the patients with intractable epilepsy . METHODS We enrolled 35 patients with localization-related epilepsy who had experienced at least one complex partial seizure or a secondarily generalized seizure per week on a constant antiepileptic drug regimen over an 8-week period . rTMS was administered using a Rapid(2 ) magnetic stimulator with an air-cooled coil at 0.5Hz for 5 consecutive days at 100 % of rMT ( resting motor threshold ) . Patients were divided into a focal stimulation group with a localized epileptic focus , or a non-focal stimulation group with a non-localized or multifocal epileptic focus . These two groups were then r and omly subdivided into four subgroups depending on the total number of stimulations administered , i.e. , 3000 pulse and 1500 pulse subgroups . Weekly seizure frequencies were determined for 8 weeks before and after rTMS . To compare the number of interictal spikes before and after rTMS , EEG was recorded twice before ( 1st day ) and after rTMS ( 5th day ) . RESULTS Mean weekly seizure frequency was non-significantly decreased after rTMS ( 8.4 - ->6.8/week , -13.9 % ) . Longer stimulation subgroups ( 3000 pulses , -23.0 % ) tended to have fewer seizures than shorter stimulation subgroups ( 1500 pulses , -3.0 % ) , without statistical significance . TMS stimulation site and structural brain lesions did not influence seizure outcome . However , interictal spikes significantly decreased ( -54.9 % , P=0.012 ) after rTMS and they totally disappeared in 6 patients ( 17.1 % , 6/35 ) . CONCLUSIONS Low-frequency rTMS reduced interictal spikes , but its effect on seizure outcome was not significant . Focal stimulation for a longer duration tended to further reduce seizure frequency . SIGNIFICANCE These findings may help clinicians to further investigate the therapeutic potential of the rTMS for patients with intractable epilepsy Publisher Summary Based on the findings that the effects of repetitive transcranial magnetic stimulation ( rTMS ) last beyond the period of stimulation itself , therapeutical antiepileptic potential of low-frequency rTMS was hypothesized . This chapter presents an interim analysis of an ongoing placebo-controlled trial . The results are discussed on the bases of the existing rTMS literature regarding the treatment of epilepsies in humans . The results presented in this chapter are interim analyses of the first crossover placebo-controlled investigation on the antiepileptic efficacy of low-frequency rTMS . Although a significant difference to placebo could not be demonstrated in this patient group , the data seem to be in line with the results of the first open pilot study on nine patients who showed reduction in seizure frequency within a similar range over a 4-week period . The results were supplemented by a case report on a patient with focal dysplasia by another group : biweekly treatment with 100 stimuli at 0.5 Hz and 95 % motor threshold intensity using an unfocal coil placed over the area of dysplasia reduced seizure frequency by 70 % over a 4-weeks period of treatment PURPOSE This study was design ed to evaluate the therapeutic effect of low-frequency repetitive transcranial magnetic stimulation ( rTMS ) on patients with refractory partial epilepsy . METHODS Sixty-four patients with refractory focal epilepsy were screened and 60 patients were r and omly divided into two groups by stimulation intensity : 90 % ( group 1 ) or 20 % ( group 2 ) of resting motor threshold ( rMT ) . Seizure frequency and interictal EEG epileptic discharges were compared between the baseline and follow-up periods . KEY FINDINGS Seizures significantly decreased following 2-weeks high intensity ( 90 % rMT ) rTMS treatment compared with baseline level ( p < 0.05 ) . rTMS also decreased interictal epilepsy discharges and improved the scales of Symptom Checklist-90 significantly ( p < 0.05 ) . Seizures and spikes in the follow-up period in the patients who received low intensity ( 20 % rMT ) rTMS did not show any difference compared with baseline data ( p > 0.05 , respectively ) . SIGNIFICANCE Low-frequency high intensity rTMS ( 90 % rMT ) delivered into the epileptogenic zone had a significant antiepileptic effect on patients with refractory partial seizures . rTMS treatment can also reduce the interictal epileptic discharge frequency and improve the psychological condition of these patients Rapid-rate transcranial magnetic stimulation ( rTMS ) allows for the noninvasive examination of the cerebral cortex . Recent studies have begun to investigate whether rTMS may be therapeutic for the treatment of depression . In the present study , the authors report on the safety and efficacy of rTMS in treating 50 patients with refractory depression . Overall , there were 21 responders ( 42 % ) . Interestingly , 56 % of the young patients responded , but only 23 % of the elderly patients responded to rTMS . Overall , rTMS was well tolerated in all patients . Specifically , no patient developed a new onset of seizures during rTMS . The authors discuss the extant literature on rTMS for the treatment of depression along with future areas of research Objective To perform a controlled trial of transcranial magnetic stimulation ( TMS ) . Methods Twenty-four patients with localization-related epilepsy were r and omized to blinded active or placebo stimulation . Weekly seizure frequency was compared for 8 weeks before and after 1 week of 1-Hz TMS for 15 minutes twice daily . Results When the 8-week baseline and post-stimulation periods were compared , active patients had a mean seizure frequency reduction of 0.045 ± 0.13 and sham-stimulated control subjects −0.004 ± 0.20 . Over 2 weeks , actively treated patients had a mean reduction in weekly seizure frequency of 0.16 ± 0.18 and sham-stimulated control subjects 0.01 ± 0.24 . Neither difference was significant . Conclusion The effect of TMS on seizure frequency was mild and short lived Seventeen refractory partial epilepsy patients were enrolled in an open-label study to evaluate the antiepileptic effect of low-frequency repetitive transcranial magnetic stimulation ( rTMS ) . Seven of the patients had not obtained seizure-free status after epileptogenic focus resection surgery before they were enrolled in the study . All patients were treated with low-frequency rTMS which included 3 sessions per day ( 0.5 Hz , 90 % RMT and 500 pulses each session ) and lasted for 2 weeks . Seizure frequency , seizure days and epileptic discharges in the EEG obtained before , during and after stimulation were compared . The psychological conditions of all individual patients were evaluated with Symptom Checklist-90 ( SCL-90 ) before and after rTMS treatment . Mean seizure frequencies per week significantly decreased in the following 4-week rTMS treatment period compared with the pretreatment period ( 14.09 vs. 5.63 , p < 0.05 , mean reduction of 60.02 % in seizure frequency ) . Mean seizure days per week during the treatment period and the post-treatment period were lower than that of the pretreatment period ( 5.18 vs. 2.99 p < 0.05 , mean reduction of 42.5 % in seizure days ) . Mean epileptic discharges in the EEG decreased significantly during the treatment period compared to that of the pre-treatment period ( 78.60 vs. 66.09 , p < 0.05 , mean reduction of 15.9 % in epileptic spikes discharges ) in all 17 patients . Fourteen patients completed the test of Symptom Checklist-90 effectively . The scales of Global Severity Index , Depression , Anxiety , Phobic anxiety , Paranoid ideation , Psychoticism , Somatization , Obsession-compulsion , Interpersonal sensitivity , Hostility in patients decreased respectively at the post-treatment periods compared with those of the pre-treatment periods ( P < 0.05 ) . Low-frequency rTMS may have a significant antiepileptic effect in patients with refractory partial epilepsy . Additionally , our results indicate rTMS treatment can improve the psychological condition of these patients OBJECTIVE Determine the efficacy and side effects of low-frequency repetitive transcranial magnetic stimulation ( rTMS ) to treat refractory neocortical epilepsy and study differences in effect between a figure-8 and round coil type . METHODS This single-center r and omized sham-controlled crossover trial ( NCT01745952 on Clinical Trials.gov ) included 11 patients with well-defined focal epilepsy . rTMS ( 0.5 Hz ) was targeted to the focus during three treatment conditions consisting of 1,500 stimulations/day for 10 weekdays at 90 % of resting motor threshold ( rMT ) followed by a 10-week observation period . Patients were r and omized for the order in which the figure-8 , round , and sham coil were used . Outcome assessors and patients were blinded to the type of coil used . The primary outcome measure was the percentage of seizure reduction after active rTMS treatment . Other outcome measures were responder rate , quality of life , and side effects . RESULTS There was no difference between a figure-8 and round coil . None of the patients achieved an overall 50 % seizure reduction . One patient responded during 1 month after treatment with either active coil , followed by a significant increase in seizure frequency . Another patient had a fourfold increase in seizure frequency during rTMS treatment . SIGNIFICANCE This study provides evidence that rTMS is on average not effective for reducing seizure frequency . No difference in effectiveness between the different coil types was observed . It can , however , exacerbate seizures during treatment and lead to a rebound in seizure frequency after an initial reduction

This systematic review found insufficient evidence to state whether or not there were additional effects by adding PFMT to other active treatments when compared with the same active treatment alone for urinary incontinence ( SUI , UUI or MUI ) in women . Also , none of the included trials reported data on adverse events associated with the PFMT regimen , thereby making it very difficult to evaluate the safety of PFMT

BACKGROUND Pelvic floor muscle training ( PFMT ) is a first-line conservative treatment for urinary incontinence in women . Other active treatments include : physical therapies ( e.g. vaginal cones ) ; behavioural therapies ( e.g. bladder training ) ; electrical or magnetic stimulation ; mechanical devices ( e.g. continence pessaries ) ; drug therapies ( e.g. anticholinergics ( solifenacin , oxybutynin , etc . ) and duloxetine ) ; and surgical interventions including sling procedures and colposuspension . This systematic review evaluated the effects of adding PFMT to any other active treatment for urinary incontinence in women OBJECTIVES To compare the effects of pelvic floor muscle training combined with another active treatment versus the same active treatment alone in the management of women with urinary incontinence .

CONTEXT Pelvic floor electrical stimulation ( PFES ) has been shown to be effective for stress incontinence . However , its role in a multicomponent behavioral training program has not been defined . OBJECTIVE To determine if PFES increases efficacy of behavioral training for community-dwelling women with stress incontinence . DESIGN AND SETTING Prospect i ve r and omized controlled trial conducted from October 1 , 1995 , through May 1 , 2001 , at a university-based outpatient continence clinic in the United States . PATIENTS Volunteer sample of 200 ambulatory , nondemented , community-dwelling women aged 40 to 78 years with stress or mixed incontinence with stress as the predominant pattern ; stratified by race , type of incontinence ( stress only vs mixed ) , and severity ( frequency of episodes ) . INTERVENTIONS Patients were r and omly assigned to 8 weeks ( 4 visits ) of behavioral training , 8 weeks ( 4 visits ) of the behavioral training plus home PFES , or 8 weeks of self-administered behavioral treatment using a self-help booklet ( control condition ) . MAIN OUTCOME MEASURES Primary outcome was percentage reduction in the number of incontinent episodes as documented in bladder diaries . Secondary outcomes were patient satisfaction and changes in quality of life . RESULTS Intention-to-treat analysis showed that incontinence was reduced a mean of 68.6 % with behavioral training , 71.9 % with behavioral training plus PFES , and 52.5 % with the self-help booklet ( P = .005 ) . In comparison with the self-help booklet , behavioral training ( P = .02 ) and behavioral training plus PFES ( P = .002 ) were significantly more effective , but they were not significantly different from each other ( P = .60 ) . The PFES group had significantly better patient self-perception of outcome ( P<.001 ) and satisfaction with progress ( P = .02 ) . Significant improvements were seen across all 3 groups on the Incontinence Impact Question naire but with no between-group differences . CONCLUSIONS Treatment with PFES did not increase effectiveness of a comprehensive behavioral program for women with stress incontinence . A self-help booklet reduced incontinence and improved quality of life but not as much as the clinic-based programs In a prospect i ve r and omized study the efficiacy of physical therapy in female stress incontinence could be verified . The greatest success rate was achieved by medical gymnastics , whereas the perineal electrical stimulation should be used as supporting measure like a biofeedback mechanism because of its low effective intensity . Despite of the good therapeutic success ( 51.5 % ) with lasting effects no objective criteria to the use of physical therapy in female stress incontinence were found Purpose This study assessed the benefit of adding behavioural modification to darifenacin treatment for overactive bladder ( OAB ) . Material s and methods The ABLE trial was a r and omised , open-label , parallel-group , multicentre study of 12 weeks of darifenacin treatment [ with voluntary up-titration from 7.5 mg once daily ( qd ) to 15 mg qd at week 2 ] alone or in combination with a Behavioural Modification Programme ( BMP ) for men and women with dry or wet OAB . Efficacy was assessed as the change in the number ( per day ) of micturitions ( primary variable ) , urge urinary incontinence ( UUI ) episodes , urgency episodes , pads used and nocturnal voids . Health-related quality of life ( HRQoL ) was also evaluated . Tolerability and safety assessment s included adverse events and the number of discontinuations . Results Of 592 patients screened , 395 were r and omised , 190 to darifenacin alone and 205 to darifenacin + BMP . At baseline , the majority of subjects were dry ( mean 2.8 and three UUI episodes per day in the darifenacin and darifenacin + BMP groups respectively ) . At study end , darifenacin alone and darifenacin + BMP both produced significant reductions from baseline in median numbers of micturitions , UUI episodes , urgency episodes and nocturnal voids ( all p < 0.05 ) , but not in the number of pads used . HRQoL also improved . There were no significant differences between treatment groups in efficacy or HRQoL variables . Conclusions Darifenacin treatment provides a degree of normalisation of micturition variables and improvement in HRQoL that can not be further enhanced by behavioural therapy of the type used in this study . Whether behavioural modification would add benefit over darifenacin treatment in patients with more pronounced incontinence problems remains to be determined The objectives of this paper were to assess the quality of life of community-living women with urinary incontinence according to age , symptom group , amount of leakage , and duration , by use of the Sickness Impact Profile ( SIP ) . Thirty-six women aged between 40 and 60 years and 40 women aged 70 years or more were r and omly selected from the clients attending an incontinence clinic and interviewed using the SIP question naire . Urge and stress incontinence subgroups were defined by means of a symptom question naire . Total , psychosocial , and physical dysfunctions were moderate ( 8 % , 7 % , and 8 % respectively ) in general , but major differences were found when age and symptom groups were analysed . Urge symptoms were associated with more impairment than symptoms of stress incontinence . The elderly women with symptoms of stress incontinence were relatively little affected , while their younger counterparts were severely affected , especially in the categories of emotional behavior and recreation and pastimes . We conclude that urinary incontinence in women adversely affects quality of life to a significant degree ; the extent depends on the nature of incontinence and the age of the person The purpose of this study was to explore changes in psychological distress associated with behavioral treatment and drug treatment for urge incontinence in community-dwelling older women . Participants were 197 ambulatory , nondemented women ( aged 55 years or older ) with persistent urge urinary incontinence . Participants were patients in a r and omized clinical trial comparing biofeedback-assisted behavioral treatment , drug treatment with oxybutynin chloride , and a placebo-control condition . Psychological distress was measured before and after treatment using the Hopkins Symptom Checklist ( SCL-90-R ) . Multivariate and univariate analyses of variance showed that the two treatment groups and the control group had similar significant improvements on the nine subscales and the global severity index . Analysis of individual SCL-90-R subscale scores revealed trends suggesting that behavioral treatment tended to produce the largest improvements . The reductions of distress were not correlated consistently with reduction of incontinence . The results of this study showed that psychological distress was significantly reduced after treatment , regardless of the type of treatment ABSTRACT Objective To determine the efficacy of stress urinary incontinence treatments adding pelvic floor muscle training to vaginal electrical stimulation . Methods Forty-eight women with stress urinary incontinence were r and omized into 2 groups : 24 underwent isolated vaginal electrical stimulation , and 24 vaginal electrical stimulation plus pelvic floor muscle training . History , physical examination , voiding diary , perineum strength test , and urodynamic study were assessed . Comparisons were made for adherence to treatment , muscle strength improvement , urinary symptoms , and degree of satisfaction immediately , 12 and 96 months after treatment . Results Patients ' degree of satisfaction on vaginal electrical stimulation , and on vaginal electrical stimulation plus pelvic floor muscle training immediately , 12 and 96 months post treatment , were , respectively : 88.2 % versus 88.9 % 64.7 % versus 61.1 % and 42.9 % versus 28.6 % ( p>0.05 ) . Conclusion Vaginal electrical stimulation associated to pelvic floor muscle training did not show better results than vaginal electrical stimulation alone Introduction and hypothesisThe aim of the study was to determine whether successful incontinence pessary fitting or pessary size can be predicted by specific POPQ measurements in women without advanced pelvic organ prolapse . Methods In a multicenter study , women with stress urinary incontinence ( SUI ) and POPQ stage ≤2 were r and omized to three treatment arms : ( 1 ) incontinence pessary , ( 2 ) behavioral therapy , or ( 3 ) both . This study evaluates incontinence pessary size , POPQ measures , and successful fitting in the 266 women assigned to treatment arms 1 and 3 . Results Two hundred thirty-five women ( 92 % ) were successfully fitted with an incontinence ring ( n = 122 ) or dish ( n = 113 ) . Hysterectomy , genital hiatus ( GH ) , and GH/total vaginal length ( TVL ) ratios did not predict unsuccessful fitting ( p > 0.05 ) . However , mean TVL was greater in women successfully fitted ( 9.6 vs. 8.8 cm , p < 0.01 ) . Final pessary diameter was not predicted by TVL , point D , or point C ( p > 0.05 ) . Conclusions The vast majority of women with SUI can be successfully fitted with an incontinence pessary , but specific POPQ measures were not helpful in determining incontinence pessary size A r and omized controlled trial was carried out to evaluate the extent to which a program of reinforced pelvic floor muscle exercises ( PFME ) reduces urinary incontinence 1 year after delivery . Two hundred and thirty women who were incontinent 3 months postpartum were r and omized to either a control group doing st and ard postnatal pelvic floor muscle exercises ( n=117 ) or to an intervention group ( n=113 ) who saw a physiotherapist for instruction at approximately 3 , 4 , 6 and 9 months postpartum . Results collected 12 months after delivery included prevalence and frequency of incontinence and PFME , sexual satisfaction , perineometry measurements and pad tests . Twenty-six ( 22 % ) of the control group and 59 ( 52 % ) of the intervention group withdrew before the final assessment . The prevalence of incontinence was significantly less in the intervention group than in the control group ( 50 % versus 76%,P=0.0003 ) , and this group also did significantly more PFME . There were no significant differences between the groups as regards sexual satisfaction , perineometry measurements or pad test results Objective : To evaluate a new pattern of electrical of electrical stimulation as a treatment for stress incontinence . Design : A r and omized , double-blind , controlled trial . Setting : The study took place on three clinical sites . Subjects : Patients ( n= 27 ) with urodynamically proven stress incontinence recruited via consultant referral . Interventions : Patients were r and omly allocated to one of two groups : the new pattern of stimulation or sham stimulation . Main outcome measures : Patients were assessed pre , mid and post treatment using : perineometry , digital assessment and pad testing . The following were only used pre and post treatment : seven-day frequency/ volume chart , SF-36 , the Incontinence Impact Question naire and the Urogenital Distress Inventory . Results : No significant between-group differences were highlighted except when quality of life was assessed with the Urogenital Distress Inventory ( p= 0.01 ) . A significant reduction in scores was observed in the stimulation group ( p= 0.03 ) However , improvements were seen in both the strength and endurance characteristics of the pelvic floor musculature , although these changes were not translated into a reduction in symptoms . Conclusion : Although promising , the improvement in pelvic floor function did not result in a reduction in symptoms in all patients . Further research is required to investigate the effects of the new stimulation in combination with pelvic floor exercises and to compare the new stimulation pattern with existing forms of electrical stimulation PURPOSE We tested whether individualized drug therapy enhanced with behavioral training would result in better outcomes than individualized drug therapy alone . MATERIAL S AND METHODS Participants were community dwelling women with urge predominant incontinence . Using a r and omized clinical trial design women were r and omized to 8 weeks ( 4 visits ) of drug therapy alone ( 32 ) or drug therapy plus behavioral training ( 32 ) . Drug therapy was individually titrated , extended release oxybutynin with proactive management of side effects . Behavioral training included pelvic floor muscle training and urge suppression techniques . The primary outcome measure was reduction in frequency of incontinence episodes on bladder diary at 8 weeks ( with followup at 6 and 12 months ) . Secondary outcomes included patient satisfaction , global perception of improvement , Urogenital Distress Inventory and Incontinence Impact Question naire . RESULTS In intent to treat analysis frequency of incontinence was reduced a mean of 88.5 % in the drug alone group and 78.3 % in the combined therapy group ( p = 0.16 ) . Outcomes were not significantly different between the groups in the analysis of completers ( 91.5 % vs 86.2 % , p = 0.34 ) , or in either analysis at 6 or 12 months . The groups also did not differ significantly on secondary outcomes at any point . Participants in the drug alone group tended to be taking higher doses of oxybutynin at 8 weeks but the final dose did not differ significantly between the groups . Based on a conditional power calculation the trial was stopped early for futility . CONCLUSIONS When drug therapy is implemented with frequent individualized dose titration , daily bladder diaries and careful management of side effects , initiating concurrent behavioral training does not enhance outcomes for urge incontinence in women OBJECTIVES We previously reported high rates of urinary incontinence among gynecologic cancer survivors and aim ed to evaluate the effectiveness of a simple intervention for treatment of urinary incontinence in this population . METHODS We recruited 40 gynecologic cancer survivors who reported urinary incontinence on a vali date d question naire . Women were r and omized to either pelvic floor muscle training/behavioral therapy ( treatment group ) or usual care ( control group ) . The primary outcome measure , assessed at 12 weeks post intervention , was a 40 % difference in the vali date d Patient Global Impression of Improvement ( PGI-I ) score . Fisher 's exact test was used to identify differences between groups for frequency data ; two- sample t-test was conducted for continuous measurements . RESULTS Mean age of this cohort was 57 ( range : 37 - 79 ) . The majority of the survivors had uterine cancer ( 60 % ) , 18 % had received radiation therapy , 95 % had received surgical therapy , and 35 % had received chemotherapy . At three months , 80 % of the treatment and 40 % of the control group reported that their urinary incontinence was " much better " or " very much better " as evaluated by the Patient Global Impression of Improvement scale ( p=0.02 ) . Brink 's scores were significantly improved in the treatment group as compared to those of the controls ( p<0.0001 ) . Treatment group adherence was high ; the treatment group performed exercises with an average of 22 days/month . CONCLUSIONS Urinary incontinence negatively affects quality of life , and despite a high prevalence among gynecologic cancer survivors , it is often under-assessed and undertreated . We found a simple intervention that included pelvic floor muscle training and behavioral therapy , which significantly improved cancer survivor 's urinary incontinence In the United Kingdom regular urinary incontinence affects over 2000000 women and costs the NHS about pounds sterling70 million a year on aids and appliances . The assessment and treatment services lack a coherent plan for its recognition and treatment , and where and from whom care is best received is debated.1 Few of the current management strategies ( pelvic exercises , appliances , drugs , and surgery ) have been the subject of well design ed r and omised controlled trials in primary care , and few studies have reported long term results .2 3 4 Thus lack of evidence combined with poorly trained primary care physicians and nurses has meant that fewer than one in three patients are recognised and fewer still are appropriately managed.1 In 1991 we reported the results Many women in Japan have lived with urinary incontinence ( UI ) . These women are not willing to visit the hospital with their problem of incontinence . Even if the women consent to a hospital visit , continence education is often very limited and patients may immediately stop looking for further treatment . Programs of effective education are needed . The Continence Efficacy Intervention Program ( CEIP ) was developed for patients and was design ed to circumvent many of the obstacles common to stopping exercise . In this study , a r and omized trial was conducted to compare the effectiveness of this program to conventional intervention on exercise continuity . This report describes the study design , intervention program , and outcomes . Subjects were 48 women with stress urinary incontinence ( SUI ) : the mean age was 53.5 , the mean weight was 56.6 kg , and the average prevalent year was 6.5 years . The CEIP phone interviews improved exercise continuity and urine loss symptom . Findings suggest that this intervention program is effective and readily available to the community-residing women with SUI Objective The objective of this study was to determine if differences exist in pelvic symptom distress and impact on women r and omized to pessary versus behavioral therapy for treatment of stress urinary incontinence ( SUI ) . Methods Change in symptom and condition-specific health-related quality -of-life ( HRQOL ) measures were compared between pessary and behavioral groups 3 months after r and omization in the Ambulatory Treatments for Leakage Associated With Stress Incontinence trial . Four hundred forty-six women with symptoms of SUI were r and omized to continence pessary , behavioral therapy ( pelvic floor muscle training and continence strategies ) or combination therapy . Vali date d measures utilized included urinary , prolapse , and colorectal scales of the Pelvic Floor Distress Inventory ; urinary , prolapse , and colorectal scales of the Pelvic Floor Impact Question naire ; and Stress and Urge scales of the Question naire for Urinary Incontinence Diagnosis . Student t test and analysis of variance were used to compare scores within and between groups . Results Mean age of participants was 49.8 ( SD , 11.9 ) years ; 84 % were white , and 10 % were African American . One hundred forty-nine were r and omized to pessary , and 146 to behavioral therapy . Baseline symptoms and HRQOL scores were significantly reduced within treatment arms at 3 months after r and omization , but there was no statistically significant difference between groups . Conclusions There was no difference in pelvic floor symptom bother and HRQOL between the pessary and behavioral therapy arms in women undergoing conservative treatment for SUI . Individualized preference issues should be considered in the approach to the nonsurgical treatment of SUI The objective of this study was to compare the short-term effectiveness of rehabilitation treatment with a st and ard drug treatment for urge urinary incontinence ( UUI ) . The study design includes parallel clinical trial in an outpatient urogynecologic clinic setting . The subjects were 44 women who suffered from UUI and who were systematic ally assigned to a rehabilitation group ( REH ) ( N=24 ) or a medication group ( MED ) ( N=20 ) . The intervention for REH was consisted of five visits during a 3-month period of pelvic floor muscle training and behavioral training , whereas for MED was extended release oxybutynin at 5 mg/day , for 3 months . The urinary symptoms considered were frequency of voiding per day and night ( freq/day and freq/night ) , number of incontinent episodes per week based on a bladder diary , and data based on the Incontinence Quality of Life Instrument ( I-QoL ) . In the within-group comparison , both groups had improved significantly over time with respect to urinary symptoms and I-QoL ( p<0.01 ) . In addition , there was a significant group – time interaction effect on freq/day . While REH improved during the 3-month follow-up period , the MED group deteriorated to mean baseline value ( p<0.01 ) . A significant negative association was found between the urinary symptoms and the I-QoL at the end of follow-up ( rp=−0.35 to −0.62 , p<0.05 ) . Three months after the intervention , both groups maintained the achievements of the intervention period . In addition , the REH group demonstrated additional improvement in mean freq/day while the condition of MED patients deteriorated to baseline values The aim of this study was to assess the usefulness of pelvic floor exercises in the treatment of urinary incontinence in women and to analyse the factors which determine a successful outcome . The study involved 66 women who had reported ' genuine stress incontinence ' to their general practitioner . They were assigned at r and om to the treatment or control group . The treatment group received instructions in pelvic floor exercises from a general practitioner . The control group received no therapy . At the start of the trial the severity of the patients ' incontinence was assessed objective ly . This assessment was repeated after three months and patients were also asked for their own perception of whether their incontinence had improved . After the three months ' evaluation the patients in the control group were also given instructions in pelvic floor exercises . After another three months they were assessed in the same way . About 60 % of the patients in the treatment group were dry or mildly incontinent after three months compared with only one patient in the control group ; the mean weekly frequency of incontinence episodes fell from 17 to five in the treatment group but remained virtually unchanged in the control group ; and about 85 % of the women in the treatment group felt that their incontinence had improved or was cured compared with no one in the control group . These results were later corroborated by those for the control group . The most important factor in the success of the treatment was the patients ' motivation , as demonstrated by their adherence to the daily exercises . ( ABSTRACT TRUNCATED AT 250 WORDS Abstract Objective : To compare the effect of pelvic floor exercises , electrical stimulation , vaginal cones , and no treatment for genuine stress incontinence . Design : Stratified , single blind , r and omised controlled trial . Setting : Multicentre . Participants : 107 women with clinical ly and urodynamically proved genuine stress incontinence . Mean ( range ) age was 49.5 ( 24 - 70 ) years , and mean ( range ) duration of symptoms 10.8 ( 1 - 45 ) years . Interventions : Pelvic floor exercise ( n=25 ) comprised 8 - 12 contractions 3 times a day and exercise in groups with skilled physical therapists once a week . The electrical stimulation group ( n=25 ) used vaginal intermittent stimulation with the MS 106 Twin at 50 Hz 30 minutes a day . The vaginal cones group ( n=27 ) used cones for 20 minutes a day . The untreated control group ( n=30 ) was offered the use of a continence guard . Muscle strength was measured by vaginal squeeze pressure once a month . Main outcome measures : Pad test with st and ardised bladder volume , and self report of severity . Results : Improvement in muscle strength was significantly greater ( P=0.03 ) after pelvic floor exercises ( 11.0 cm H2O ( 95 % confidence interval 7.7 to 14.3 ) before v 19.2 cm H2O ( 15.3 to 23.1 ) after ) than either electrical stimulation ( 14.8 cm H2O ( 10.9 to 18.7 ) v 18.6 cm H2O ( 13.3 to 23.9 ) ) or vaginal cones ( 11.8 cm H2O ( 8.5 to 15.1 ) v 15.4 cm H2O ( 11.1 to 19.7 ) ) . Reduction in leakage on pad test was greater in the exercise group ( −30.2 g ; −43.3 to 16.9 ) than in the electrical stimulation group ( −7.4 g ; −20.9 to 6.1 ) and the vaginal cones group ( −14.7 g ; −27.6 to −1.8 ) . On completion of the trial one participant in the control group , 14 in the pelvic floor exercise group , three in the electrical stimulation group , and two in the vaginal cones group no longer considered themselves as having a problem . Conclusion : Training of the pelvic floor muscles is superior to electrical stimulation and vaginal cones in the treatment of genuine stress incontinence Background Behavioral intervention outcomes for urinary incontinence ( UI ) depend on active patient participation . Objective The purpose of this study was to describe adherence to behavioral interventions ( pelvic-floor muscle [ PFM ] exercises , UI prevention strategies , and delayed voiding ) , patient-perceived exercise barriers , and predictors of exercise adherence in women with urge-predominant UI . Design This was a prospect ively planned secondary data analysis from a 2-stage , multicenter , r and omized clinical trial . Patients and Intervention Three hundred seven women with urge-predominant UI were r and omly assigned to receive either 10 weeks of drug therapy only or 10 weeks of drug therapy combined with a behavioral intervention for UI . One hundred fifty-four participants who received the combined intervention were included in this analysis . Measurements Pelvic-floor muscle exercise adherence and exercise barriers were assessed during the intervention phase and 1 year afterward . Adherence to UI prevention strategies and delayed voiding were assessed during the intervention only . Results During intervention , 81 % of women exercised at least 5 to 6 days per week , and 87 % performed at least 30 PFM contractions per day . Ninety-two percent of the women used the urge suppression strategy successfully . At the 12-month follow-up , only 32 % of the women exercised at least 5 to 6 days per week , and 56 % performed 15 or more PFM contractions on the days they exercised . The most persistent PFM exercise barriers were difficulty remembering to exercise and finding time to exercise . Similarly , difficulty finding time to exercise persisted as a predictor of PFM exercise adherence over time . Limitations Co-administration of medication for UI may have influenced adherence . Conclusions Most women adhered to exercise during supervised intervention ; however , adherence declined over the long term . Interventions to help women remember to exercise and to integrate PFM exercises and UI prevention strategies into daily life may be useful to promote long-term adherence AIMS The objectives of this study were ( 1 ) to determine the effect of training on pelvic floor muscle strength ; ( 2 ) to determine whether changes in pelvic floor muscle strength correlate with changes in continence ; and ( 3 ) to determine whether demographic characteristics , clinical incontinence severity indices , or urodynamic measures predict response to pelvic floor muscle training . METHODS One hundred thirty-four women with urinary incontinence ( 95=genuine stress incontinence [ GSI ] ; 19=detrusor instability [ DI ] ; 20=mixed incontinence [ GSI+DI ] ) were r and omized to pelvic floor muscle training ( n=67 ) or bladder training ( n=67 ) . Urinary diaries , urodynamic evaluation , and vaginal pressure measurements by using balloon manometry were performed at baseline and after 12 weeks of therapy . Primary outcome measures consisted of incontinent episodes per week and vaginal pressure measurements . RESULTS Both treatment groups had a reduction in incontinent episodes ( P</=0.004 ) . Vaginal pressures increased more with pelvic floor muscle training than with bladder training ( P=0.0003 ) . Other than a weak correlation between a reduction in incontinent episodes/week and an increase in maximum sustained vaginal pressure in women with GSI ( r=0.32 , P=0.04 ) , there were no significant correlations between increases in pelvic floor muscle strength and improvement in continence status . There were no significant correlations between baseline demographic characteristics , clinical incontinence severity , or urodynamic measures and increases in vaginal pressure or improvement in clinical severity after pelvic floor muscle training . CONCLUSIONS Pelvic floor muscle training improves continence and increases vaginal pressure measurements , but the direct correlations between these alterations are weak . A woman 's response to behavioral treatment does not depend on her demographic characteristics , clinical incontinence severity , urodynamic measures , or initial pelvic floor muscle strength OBJECTIVE To compare the effect of individual pelvic floor muscle training with and without biofeedback in women with urodynamic stress incontinence METHODS The study was a single , blind , r and omized trial . All women completed 6 months of pelvic floor muscle training comprising three sets of ten contractions three times per day , supervised by a physical therapist . One group trained with a biofeedback apparatus at home , the other without biofeedback . The primary outcome measures were pad test with st and ardized bladder volume and self‐report of severity . RESULTS A total of 103 women were r and omized , and data from 94 women were analyzed . Mean age ( range ) was 46.6 ( 30–70 ) years , and mean ( range ) duration of symptoms was 9.7 ( 1–25 ) years . Seventy women had urodynamic stress incontinence alone , and 24 women reported additional urge symptoms . Women training with and without biofeedback showed a statistically significant reduction in leakage on pad test ( P < .01 ) after 6 months of pelvic floor muscle training . Objective cure ( 2 g or less of leakage ) in the total group was 58 % in women training with and 46 % in women training without biofeedback , and in the subgroup of women with urodynamic stress incontinence alone , 69 % in women training with and 50 % in women training without biofeedback . There was no statistically significant difference between the groups posttreatment in any outcome measure . CONCLUSION Cure rate was high , and the reduction in urinary leakage after treatment was statistically significant in both groups . However , there was no statistically significant difference in the effect of individual pelvic floor muscle training with and without biofeedback Purpose To assess the effects of the combination of pelvic floor rehabilitation and intravaginal estriol administration on stress urinary incontinence ( SUI ) , urogenital atrophy and recurrent urinary tract infections in postmenopausal women . Methods Two-hundred-six postmenopausal women with urogenital aging symptoms were enrolled in this prospect i ve r and omized controlled study . Patients were r and omly divided into two groups and each group consisted of 103 women . Subjects in the treatment group received intravaginal estriol ovules , such as 1 ovule ( 1 mg ) once daily for 2 weeks and then 2 ovules once weekly for a total of 6 months as maintenance therapy plus pelvic floor rehabilitation . Subjects in the control group received only intravaginal estriol in a similar regimen . We evaluated urogenital symptomatology , urine cultures , colposcopic findings , urethral cytologic findings , urethral pressure profiles and urethrocystometry before , as well as after 6 months of treatment . Results After therapy , the symptoms and signs of urogenital atrophy significantly improved in both groups . 61/83 ( 73.49 % ) of the treated patients , and only 10/103 ( 9.71 % ) of the control patients referred a subjective improvement of their incontinence . In the patients treated by combination therapy with estriol plus pelvic floor rehabilitation , we observed significant improvements of colposcopic findings , and there were statistically significant increases in mean maximum urethral pressure ( MUP ) , in mean urethral closure pressure ( MUCP ) , as well as in the abdominal pressure transmission ratio to the proximal urethra ( PTR ) . Conclusions Our results showed that combination therapy with estriol plus pelvic floor rehabilitation was effective and should be considered as a first-line treatment for symptoms of urogenital aging in postmenopausal women OBJECTIVE : To identify factors that may predict success and satisfaction in women undergoing nonsurgical therapy for stress urinary incontinence . METHODS : Baseline demographic and clinical characteristics of women participating in a multicenter r and omized trial of pessary , behavioral , or combined therapy for stress urinary incontinence were evaluated for potential predictors of success and satisfaction . Success and satisfaction outcomes were assessed at 3 months and included the Patient Global Impression of Improvement , stress incontinence subscale of the Pelvic Floor Distress Inventory , and Patient Satisfaction Question naire . Logistic regression was performed to identify predictors , adjusting for treatment and other important clinical covariates . Adjusted odds ratios ( ORs ) , 95 % confidence intervals ( CIs ) , and associated P values are presented . RESULTS : Four hundred forty-six women were r and omized . College education or more and no previous urinary incontinence surgery predicted success based on the stress subscale of the Pelvic Floor Distress Inventory ( adjusted OR 1.61 , 95 % CI 1.01–2.55 , P=.04 and adjusted OR 3.15 , 95 % CI 1.04- 9.53 , P=.04 , respectively ) . Menopausal status predicted success using the Patient Global Impression of Improvement ( adjusted OR 2.52 postmenopausal compared with premenopausal , 95 % CI 1.29–4.95 ; adjusted OR 1.32 unsure menopausal status compared with premenopausal , 95 % CI 0.65–2.66 ; P=.03 across all three groups ) . Fewer than 14 incontinence episodes per week predicted satisfaction with the Patient Satisfaction Question naire ( adjusted OR 1.97 , 95 % CI 1.21–3.19 ; P=.01 ) . These predictors did not differ across the three treatment groups . CONCLUSION : Menopause , higher education , no previous urinary incontinence surgery , and lower incontinence frequency were found to be predictors of success and satisfaction with nonsurgical therapy for stress urinary incontinence . This information may help better-align provider and patient expectations with nonsurgical treatment outcomes . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00270998 . LEVEL OF EVIDENCE : Introduction and hypothesisThe goal was to identify correlates of patient satisfaction with drug and behavioral treatments for urge-predominant incontinence , which may help tailor treatments to improve satisfaction . Methods Planned secondary analysis of a multi-center , clinical trial r and omizing 307 women to 10 weeks of tolterodine alone or combined with behavioral training . Satisfaction was measured using the Patient Satisfaction Question ( PSQ ) . Potential correlates included baseline demographics , incontinence characteristics and prior treatments , history and physical parameters , expectations of treatment success , and outcome variables including the Global Perception of Improvement ( GPI ) and Urogenital Distress Inventory ( UDI ) . Results After multivariable analysis , every 10-point increase in UDI change score increased odds of satisfaction by 11 % ( OR 1.11 ; 1.04–1.19 ) . Odds of satisfaction increased among women reporting “ much better ” on the GPI ( OR 13.8 ; 4.94–38.60 ) . Conclusions Treatment satisfaction for women with urge-predominant incontinence was associated with patient-related outcomes reflecting impression of improvement and bother from incontinence-related symptoms OBJECTIVE To evaluate the psychometric properties of the Pelvic Floor Distress Inventory ( PFDI ) and the Pelvic Floor Impact Question naire ( PFIQ ) . METHODS The PFDI and PFIQ are based on the structure and content of two previously vali date d question naires ( the Urinary Distress Inventory [ UDI ] and the Incontinence Impact Question naire [ IIQ ] ) and have additional questions regarding pelvic organ prolapse and colorectal dysfunction . The PFDI assesses symptom distress in women with pelvic floor disorders and has 3 scales : UDI ( 28 items ) , Colorectal-anal Distress Inventory ( 17 items ) , and Pelvic Organ Prolapse Distress Inventory ( 16 items ) . The PFIQ assesses life impact and also has 3 scales : IIQ , Colorectal-anal Impact Question naire , and the Pelvic Organ Prolapse Impact Question naire ( 31 items each ) . One hundred women with pelvic floor symptoms were enrolled and completed both the PFDI and PFIQ at baseline and again 1 week later . Patients underwent a comprehensive evaluation that included a structured history , Pelvic Organ Prolapse Quantitation , and a 1-week prospect i ve bowel/bladder diary . Patients with urinary incontinence and stage III or IV pelvic organ prolapse also had a urodynamic evaluation . RESULTS Each scale of the PFDI and PFIQ proved to be internally consistent ( alphas : PFDI.82-.89 ; PFIQ.96-.97 ) and reproducible ( interclass correlations : PFDI.86-.87 ; PFIQ.77-.92 ) . Both the UDI and the IIQ significantly correlated with the number of urinary incontinence episodes per week ( rho = .26 , P < .05 ; rho = .46 , P < .0001 , respectively ) and the number of pads used per week ( rho = .26 , P < .05 ; rho = .40 , P < .0001 , respectively ) . The Pelvic Organ Prolapse Distress Inventory and the Pelvic Organ Prolapse Impact Question naire significantly correlated with the stage of prolapse ( rho = .32 and rho = .33 , P < .01 each ) , and the Colorectal-anal Distress Inventory and Colorectal-anal Impact Question naire significantly correlated with the number of fecal incontinence episodes per month ( rho = .49 , P < .0001 and rho = .30 , P < .01 ) and a diagnosis of defecatory dysfunction ( rho = .47 , P < .0001 and rho = .29 , P < .01 ) . The total time taken to complete both instruments averaged 23 minutes ( range , 9 - 55 ) . CONCLUSION The PFDI and the PFIQ are reliable , valid , condition-specific quality of life instruments for women with pelvic floor disorders OBJECTIVES To evaluate the effectiveness of pelvic floor muscle ( PFM ) and fitness exercises in reducing urine leakage in elderly women with stress urinary incontinence ( UI ) . DESIGN R and omized , crossover , follow-up trial . SETTING Urban community in Japan . PARTICIPANTS Seventy women aged 70 and older who reported urine leakage one or more times per month ; 35 were r and omly assigned to intervention and the other 35 to control . INTERVENTION The intervention group attended an exercise class aim ed at enhancing PFMs and fitness . Duration of the exercise was 60 minutes per session twice a week for 3 months . After 3 months of exercise , the intervention group was followed for 1 year . MEASUREMENTS Body mass index ( BMI ) , urine leakage , walking speed , and muscle strength were measured at baseline , after the intervention , and at follow-up . RESULTS In the intervention group , maximum walking speed and adductor muscle strength increased significantly after the intervention ; there were no significant changes in the control group . After 3 months of exercise , 54.5 % of the intervention group and 9.4 % of the control group reported being continent . Within the cured group of UI , a significantly higher proportion had decreased their BMI at 3 months ( P=.03 ) and increased walking speed at 3 ( P=.04 ) and 12 ( P=.047 ) months . CONCLUSION Decrease in BMI and increase in walking speed may contribute to the treatment of UI , although the data do not support a positive correlation between strengthening of adductor muscle and improvement of UI , which needs more research Regular urinary incontinence affects one in six adult women . However , for the majority , good continence services are difficult to access and few primary care-based assessment and treatment facilities are available . A large r and omised trial of assessment and treatment in primary care using a trained nurse was conducted in Somerset in 1990 . This report summarises the methods and results of the initial study and reports the four-year follow-up results . The results show that 70 per cent of women will gain long lasting benefit . This model of service provision will also benefit secondary care specialist services by ensuring that patients are appropriately managed in primary care before any possible referral Introduction and hypothesisThe objective of this study was to examine the effects of drug therapy alone and combined with behavioral therapy on urgency and 24-voiding frequency in women with urge-predominant incontinence and to identify predictors of change . Methods A planned analysis of data from a multi-site , r and omized , controlled trial ( N = 307 ) . Bladder diaries were used to document voids , incontinence , and urgency severity . Results Urgency scores decreased significantly within both treatment groups , but changes did not differ between groups ( p = 0.30 ) . Improvement in urgency was associated with greater baseline urgency ( p < 0.0001 ) and black ethnicity ( p = 0.03 ) . Voiding frequency increased with drug alone and decreased slightly with combined therapy ( p = 0.009 ) , and improvement was associated with combined treatment ( p < 0.0001 ) , higher baseline frequency ( p < 0.0001 ) , and lower baseline incontinence episode frequency ( p = 0.001 ) . Conclusions Although combined drug and behavioral therapy does not appear to improve urgency more than drug alone , it result ed in better outcomes on voiding frequency Introduction and hypothesisThe aim of this study was to assess whether bladder training ( BT ) combined with high-intensity pelvic floor muscle training ( BT + PFMT ) results in better outcomes in the short term than BT alone on female urinary incontinence ( UI ) . Methods We r and omly assigned 108 women with diagnoses of stress UI ( SUI , n = 50 ) , urgency UI ( UUI , n = 16 ) , or mixed UI ( MUI , n = 42 ) to 6 weeks of BT + PFMT or BT alone ( control group ) . The primary outcome measure was self-reported improvement . Secondary outcome measures were UI severity , symptom distress , quality of life ( QOL ) , mean number of UI episodes and micturitions per day , and pelvic floor muscle strength and endurance ( PFME ) . Results Overall and in the SUI and MUI subgroups , significantly more patients in the BT + PFMT group reported cured and improved symptoms . Overall and in SUI patients , the BT + PFMT group also improved to significantly greater degree in UI severity , symptom distress , QOL , daily UI episodes , and PFME . The only parameter showing more improvement in patients with UUI was QOL , and UI severity in patients with MUI ( p < 0.05 ) . There were no other significant differences between the two study groups in overall and subgroup analysis ( p > 0.05 ) . Conclusions High-intensity PFMT combined with BT is more effective than BT alone in the short term for treating UI or SUI . It appears that the combination therapy may also lead to greater benefits for patients with UUI and MUI . Based on the results of this study , further studies with larger sample sizes ( for UUI ) and long-term follow-ups are warranted OBJECTIVE We sought to estimate the minimum important difference ( MID ) for the Urinary Distress Inventory ( UDI ) , UDI-stress subscale of the Pelvic Floor Distress Inventory , and Urinary Impact Question naire ( UIQ ) of the Pelvic Floor Impact Question naire . STUDY DESIGN We calculated MID using anchor- and distribution-based approaches from a r and omized trial for nonsurgical stress incontinence treatment . Anchors included a global impression of change , incontinence episodes from a urinary diary , and the Incontinence Severity Index . Effect size and st and ard error of measurement were the distribution methods used . RESULTS Anchor-based MIDs ranged from -22.4 to -6.4 points for the UDI , -16.5 to -4.6 points for the UDI-stress , and -17.0 to -6.5 points for the UIQ . These data were supported by 2 distribution-based estimates . CONCLUSION Reasonable estimates of MID are 11 , 8 , and 16 points for the UDI , UDI-stress subscale , and UIQ , respectively . Statistically significant improvements that meet these thresholds should be considered clinical ly important The purpose of this study was to compare the effect of three conservative interventions : pelvic floor muscle training , bladder training , or both , on urodynamic parameters in women with urinary incontinence . Two hundred four women with genuine stress incontinence ( GSI ) or detrusor instability with or without GSI ( DI + /- GSI ) participated in a two-site trial comparing pelvic floor muscle training , bladder training , or both . Patients were stratified based on severity of urinary incontinence , urodynamic diagnosis , and treatment site , then r and omized to a treatment group . All women underwent a comprehensive st and ardized evaluation including multi-channel urodynamics at the initial assessment and at the end of 12 weeks of therapy . Analysis of covariance was used to detect differences among treatment groups on urodynamic parameters . Post-treatment evaluations were available for 181 women . No differences were found among treatments on the following measurements : maximum urethral closure pressure , mean urethral closure pressure , maximum Kegel urethral closure pressure , mean Kegel urethral closure pressure , functional urethral length , pressure transmission ratios , straining urethral axis , first sensation to void , maximum cystometric capacity , and the MCC minus FSV . The effect of treatment did not differ by urodynamic diagnosis . Behavioral therapy had no effect on commonly measured urodynamic parameters . The mechanism by which clinical improvement occurs remains unknown . Neurourol . Urodynam . 18:427 - 436 , 1999 OBJECTIVE The purpose of this study was to assess the construct validity of two global assessment questions , the Patient Global Impression of Severity and of Improvement , in female patients with stress urinary incontinence . STUDY DESIGN This was a secondary analysis of data from two double-blind , placebo-controlled studies that evaluated duloxetine for the treatment of predominant stress urinary incontinence in the United States ( n = 1133 patients ) . Assessment variables included incontinence episode frequency , the Incontinence Quality of Life Question naire results , fixed volume ( 400 mL ) stress pad test results , and the Patient Global Impression of Improvement and of Severity question results . RESULTS Spearman correlation coefficients were 0.36 , 0.20 , and -0.50 among the Patient Global Impression of Severity question and incontinence episode frequency , stress pad test , and Incontinence Quality of Life Question naire results , respectively ( all P < .0001 ) . Mean incontinence episode frequency and median stress pad test results increased and mean Incontinence Quality of Life Question naire results decreased with increasing Patient Global Impression of Severity question severity levels . Similarly , significant ( P < .0001 ) correlations were observed between the Patient Global Impression of Improvement question response categories and the three independent measures of improvement in stress urinary incontinence ( 0.49 , 0.33 , and -0.43 with incontinence episode frequency , stress pad test , and Incontinence Quality of Life Question naire results , respectively ) . As with the Patient Global Impression of Severity question , differences in mean changes for Incontinence Quality of Life Question naire and median percent changes for incontinence episode frequency and stress pad test among the Patient Global Impression of Improvement question response categories were highly significant ( P < .0001 ) . These relationships indicate appropriate and significant associations between the Patient Global Impression of Severity and of Improvement questions and the three independent measures of stress urinary incontinence severity and improvement , respectively . CONCLUSION The Patient Global Impression of Severity and of Improvement question responses were correlated significantly with incontinence episode frequency , stress pad test , and Incontinence Quality of Life Question naire measures , which established the construct validity of these two global assessment questions for baseline severity and treatment response , respectively OBJECTIVE To compare sexual function in women with urinary incontinence and pelvic organ prolapse and to determine the effects of therapy on sexual function . METHODS 343 community‐dwelling women older than 45 years with urinary incontinence or advanced prolapse were recruited into a multi‐armed clinical trial . Women with incontinence were stratified to receive estrogen therapy , behavioral therapy , or surgical therapy . Women with prolapse were enrolled in a r and omized surgical trial . All women completed a st and ardized urogynecologic evaluation and a sexual function question naire at baseline and after therapy . RESULTS Women with prolapse or detrusor instability were more likely to cite pelvic floor symptoms as a reason for sexual inactivity than were women with other conditions . One third of patients with prolapse reported that their pelvic floor condition affected their ability to have sexual relations “ moderately ” or “ greatly ” significantly more than did other groups . Patients with genuine stress incontinence who underwent surgical or behavioral therapy were less likely to report being worried about urine leakage during intercourse after therapy than at baseline . After surgery , women with prolapse were less likely to report that their symptoms affected their ability to have sexual relations compared with baseline . Overall sexual satisfaction was the same at baseline and remained unchanged in all therapeutic groups at 6 months . CONCLUSION Prolapse is more likely than urinary incontinence to result in sexual inactivity and to be perceived as affecting sexual relations . However , overall sexual satisfaction appears to be independent of diagnosis of or therapy for urinary incontinence or prolapse PURPOSE We primarily compared the effectiveness of combined pelvic floor muscle training ( PFMT ) and duloxetine with imitation PFMT and placebo for 12 weeks in women with stress urinary incontinence ( SUI ) . In addition , we compared the effectiveness of combined treatment with single treatments , single treatments with each other and single treatments with no treatment . MATERIAL S AND METHODS This blinded , doubly controlled , r and omized trial enrolled 201 women 18 to 75 years old with SUI at 17 incontinence centers in the Netherl and s , United Kingdom and United States . Women averaged 2 or more incontinence episodes daily and were r and omized to 1 of 4 combinations of 80 mg duloxetine daily , placebo , PFMT and imitation PFMT , including combined treatment ( in 52 ) , no active treatment ( in 47 ) , PFMT only ( in 50 ) and duloxetine only ( in 52 ) . The primary efficacy measure was incontinence episode frequency . Other efficacy variables included the number of continence pads used and the Incontinence Quality of Life question naire score . RESULTS The intent to treat population incontinence episode frequency analysis demonstrated the superiority of duloxetine with or without PFMT compared with no treatment or with PFMT alone . However , pad and Incontinence Quality of Life analyses suggested greater improvement with combined treatment than single treatment . A completer population analysis demonstrated the efficacy of duloxetine with or without PFMT and suggested combined treatment was more effective than either treatment alone . CONCLUSIONS The data support significant efficacy of combined PFMT and duloxetine in the treatment of women with SUI . We hypothesize that complementary modes of action of duloxetine and PFMT may result in an additive effect of combined treatment Objective : To investigate and compare the effectiveness of various treatment protocol s for the treatment of women with idiopathic detrusor overactivity . Design : Prospect i ve , r and omized controlled trial . Setting : Departments of Physiotherapy and Rehabilitation and Obstetrics and Gynaecology , Hacettepe University . Subjects : Forty-six subjects were r and omized to three groups . Interventions : The first group received only pharmacotherapy , the second group received only physiotherapy and in the third group pharmacotherapy was combined with physiotherapy ( combined therapy group ) . Main measures : All patients were evaluated at the beginning and at the end of treatment . Assessment parameters were maximum cystometric capacity , electromyographic activity of pelvic floor muscles , voiding diary parameters , the amount of urine leakage and the quality of life score . Results : The maximum cystometric capacity and the electromyographic activity of pelvic floor muscles increased significantly and the number of voids/day and incontinence episodes/day , and the amount of urine leakage reduced significantly ( P < 0.05 ) in both physiotherapy and combined therapy groups while there was no significant difference in the pharmacotherapy group . After treatment , the number of voids/day increased by 0.3 ± 3.4 in the pharmacotherapy group ( P > 0.05 ) and decreased by 5.1 ± 5.5 and 4.7 ± 5.6 in the physiotherapy and combined therapy groups , respectively ( P < 0.05 ) . Statistically significant improvements were observed in all groups according to the number of voids/night and the quality of life scores at the end of the treatment . Conclusion : The physiotherapy protocol we introduced in the present study with or without anticholinergic therapy has a substantial positive impact on the treatment of female patients with idiopathic detrusor overactivity OBJECTIVE : To compare the effectiveness of a continence pessary to evidence -based behavioral therapy for stress incontinence and to assess whether combined pessary and behavioral therapy is superior to single-modality therapy . METHODS : This was a multisite , r and omized clinical trial ( Ambulatory Treatments for Leakage Associated with Stress Incontinence [ ATLAS ] ) that r and omly assigned 446 women with stress incontinence to pessary , behavioral therapy , or combined treatment . Primary outcome measures , at 3 months , were Patient Global Impression of Improvement and the stress incontinence subscale of the Pelvic Floor Distress Inventory . A priori , to be considered clinical ly superior , combination therapy had to be better than both single-modality therapies . Outcome measures were repeated at 6 and 12 months . Primary analyses used an intention-to-treat approach . RESULTS : At 3 months , scores from 40 % of the pessary group and 49 % of the behavioral group were “ much better ” or “ very much better ” on the Patient Global Impression of Improvement ( P=.10 ) . Compared with the pessary group , more women in the behavioral group reported having no bothersome incontinence symptoms ( 49 % compared with 33 % , P=.006 ) and treatment satisfaction ( 75 % compared with 63 % , P=.02 ) . Combination therapy was significantly better than pessary as shown on the Patient Global Impression of Improvement ( 53 % , P=.02 ) and Pelvic Floor Distress Inventory ( 44 % , P=.05 ) but not better than behavioral therapy ; it was therefore not superior to single-modality therapy . Group differences were not sustained to 12 months on any measure , and patient satisfaction remained above 50 % for all treatment groups . CONCLUSION : Behavioral therapy result ed in greater patient satisfaction and fewer bothersome incontinence symptoms than pessary at 3 months , but differences did not persist to 12 months . Combination therapy was not superior to single-modality therapy . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00270998 . LEVEL OF EVIDENCE : OBJECTIVE We compared the efficacy of bladder training , pelvic muscle exercise with biofeedback-assisted instruction , and combination therapy , on urinary incontinence in women . The primary hypothesis was that combination therapy would be the most effective in reducing incontinent episodes . STUDY DESIGN A r and omized clinical trial with three treatment groups was conducted in gynecologic practice s at two university medical centers . Two hundred and four women diagnosed with genuine stress incontinence ( n = 145 ) and /or detrusor instability ( n = 59 ) received a 12-week intervention program ( 6 weekly office visits and 6 weeks of mail/telephone contact ) with immediate and 3-month follow-up . Outcome variables included number of incontinent episodes , quality of life , perceived improvement , and satisfaction . Data analyses consisted of analysis of covariance using baseline values as covariates and chi2 tests . RESULTS The combination therapy group had significantly fewer incontinent episodes , better quality of life , and greater treatment satisfaction immediately after treatment . No differences among groups were observed 3 months later . Women with genuine stress incontinence had greater improvement in life impact , and those with detrusor instability had less symptom distress at the immediate follow-up ; otherwise , no differences were noted by diagnosis , incontinence severity , or treatment site . CONCLUSIONS Combination therapy had the greatest immediate efficacy in the management of female urinary incontinence regardless of urodynamic diagnosis . However , each of the 3 interventions had similar effects 3 months after treatment . Results suggest that the specific treatment may not be as important as having a structured intervention program with education , counseling , and frequent patient contact OBJECTIVE The objective of the study was to describe the prevalence , risk factors , and impact of urinary incontinence and other pelvic floor disorders among Asian-American women . STUDY DESIGN This was a population -based cohort study of older women r and omly selected from age and race strata . RESULTS Weekly urinary incontinence was reported by 65 of 345 Asian women ( 18 % ) , with stress and urge incontinence being approximately equally common . In multivariate analysis , higher body mass index ( greater than 25 kg/m2 ) was associated with both stress incontinence ( odds ratio 4.90 , 95 % confidence interval 1.76 to 13.68 ) and urge incontinence ( odds ratio 2.49 , 95 % confidence interval 1.01 to 6.16 ) in Asians . Hysterectomy was a significant risk factor for stress incontinence ( odds ratio 2.79 , 95 % confidence interval 1.03 to 7.54 ) . Only 34 % of Asian women with weekly urinary incontinence reported ever having sought treatment . Pelvic floor exercises were the most common form of treatment , being used by 29 % of Asian women with weekly incontinence . Asians were less likely then white women to report anal incontinence ( 21 % versus 29 % , P = .007 ) , although this difference became nonsignificant after adjusting for differences in risk factors . CONCLUSION Asian women share some risk factors for stress and urge urinary incontinence with white women . Urinary incontinence is associated with anal incontinence among Asian women The aims of this study were to compare " subjective " measures of severity of urinary incontinence to similar " objective " measures , establish their statistical correlation , and determine the effect of specific urodynamic diagnosis on such correlations . Baseline data was available from 265 women entered into a clinical trial study ing pharmacologic and behavioral interventions for urinary incontinence . The " subjective " measures of incontinence were obtained by patient recall during history taking and included : the number of incontinent episodes in 1 week , the number of perineal pads used during 1 week , and the number of clothing changes required due to wetness . The " objective " measures of severity included : the number of incontinent episodes per week as recorded on a 7-day diary , the number of perineal pads used per week , also recorded on a diary , and the amount of fluid lost during a st and ardized pad test . Analysis consisted of Pearson correlations and linear regressions to determine equations for the prediction of objective measurement on the basis of the corresponding subjective measure . Significant positive correlations were seen between " subjective " and " objective " measurements for the comparisons of number of weekly incontinent episodes ( R = 0.63 ) , and for the weekly number of pads used ( R = 0.81 ) . The comparison between the number of clothing changes and the amount of fluid lost during pad testing was also significantly but less strongly correlated ( R = 0.24 ) . For the correlations between subjective and objective determinations of urinary incontinent episodes and for those between clothing changes and pad testing , the urodynamic diagnosis had no effect on the correlation coefficients , but did have a statistically significant effect on the intercept . ( ABSTRACT TRUNCATED AT 250 WORDS Stress urinary incontinence is a common problem among women of all ages but may resolve with pelvic floor reeducation in many cases . Compliance to a regimen of pelvic floor muscle exercises is poor and many devices have been produced to make exercising these muscles more effective and interesting . This article describes a study in which two such devices -- vaginal cones and pressure biofeedback -- were compared with pelvic floor exercises alone . The results show that there is no statistically significant difference between the three modalities ; all treatments produced significant improvement in symptoms and quality of life scores To determine whether participants in the behavior enhances drug reduction of incontinence ( BE-DRI ) trial experienced reduction in the frequency of nocturia and /or nocturnal leakage during treatment with antimuscarinic phamacotherapy with or without additional behavioral therapy . We analyzed urinary diary data relating to nocturia and nocturnal incontinence before and after 8 weeks of study treatment in the BE-DRI trial , in which patients were r and omly assigned to receive drug therapy with tolterodine tartrate extended-release capsules 4 mg alone or in combination with behavioral training . Chi-square tests assessed whether nocturia and nocturnal incontinence prevalence varied by treatment arm and paired t tests assessed the change in mean frequency of nocturia and nocturnal leakage . Among 305 women , 210 ( 69 % ) had an average of at least one nocturia episode at baseline . There were small but statistically significant differences ( p < 0.001 ) in mean nocturia frequency and nocturnal incontinence frequency with both treatments after 8 weeks , but no significant difference between study treatment groups . Among these urge incontinent women , tolterodine with or without supervised behavioral therapy had little impact on either nocturic frequency or nocturnal incontinence OBJECTIVES To report on the further development of the Incontinence Quality of Life Instrument ( I-QOL ) , a self-report quality of life measure specific to urinary incontinence ( UI ) , including its measurement model , responsiveness , and effect size . METHODS Incontinent female patients ( 141 with stress , 147 with mixed UI ) completed the I-QOL and comparative measures at screening , pretreatment , and four subsequent follow-up visits during participation in a multicenter , double-blind , placebo-controlled , r and omized trial assessing the efficacy of duloxetine . Psychometric testing followed st and ardized procedures . RESULTS Factor analysis confirmed an overall score and three subscale scores ( avoidance and limiting behaviors , psychosocial impacts , and social embarrassment ) . All scores were internally consistent ( alpha = 0.87 to 0.93 ) and reproducible ( ICC = 0.87 to 0.91 ) . The pattern of previously reported correlations with the Short-Form 36-item Health Survey and Psychological Well-Being Schedule were confirmed . Responsiveness statistics using changes in the independent measures of stress test pad weight , number of incontinent episodes , and patient global impression of improvement ranged from 0.4 to 0.8 . Minimally important changes ranged from 2 % to 5 % in association with these measures and effect sizes . CONCLUSIONS In a clinical trial , the I-QOL proved to be valid , reproducible , and responsive to treatment for UI in women BACKGROUND Women with urge urinary incontinence are commonly treated with antimuscarinic medications , but many discontinue therapy . OBJECTIVE To determine whether combining antimuscarinic drug therapy with supervised behavioral training , compared with drug therapy alone , improves the ability of women with urge incontinence to achieve clinical ly important reductions in incontinence episodes and to sustain these improvements after discontinuing drug therapy . DESIGN 2-stage , multicenter , r and omized clinical trial conducted from July 2004 to January 2006 . SETTING 9 university-affiliated outpatient clinics . PATIENTS 307 women with urge-predominant incontinence . INTERVENTION 10 weeks of open-label , extended-release tolterodine alone ( n = 153 ) or combined with behavioral training ( n = 154 ) , followed by discontinuation of therapy and follow-up at 8 months . MEASUREMENTS The primary outcome , measured at 8 months , was no receipt of drugs or other therapy for urge incontinence and a 70 % or greater reduction in frequency of incontinence episodes . Secondary outcomes were reduction in incontinence , self-reported satisfaction and improvement , and scores on vali date d question naires measuring symptom distress and bother and health-related quality of life . Study staff who performed outcome evaluations , but not participants and interventionists , were blinded to group assignment . RESULTS 237 participants completed the trial . According to life-table estimates , the rate of successful discontinuation of therapy at 8 months was the same in the combination therapy and drug therapy alone groups ( 41 % in both groups ; difference , 0 percentage points [ 95 % CI , -12 to 12 percentage points ] ) . A higher proportion of participants who received combination therapy than drug therapy alone achieved a 70 % or greater reduction in incontinence at 10 weeks ( 69 % vs. 58 % ; difference , 11 percentage points [ CI , -0.3 to 22.1 percentage points ] ) . Combination therapy yielded better outcomes over time on the Urogenital Distress Inventory and the Overactive Bladder Question naire ( both P < 0.001 ) at both time points for patient satisfaction and perceived improvement but not health-related quality of life . Adverse events were uncommon ( 12 events in 6 participants [ 3 in each group ] ) . LIMITATIONS Behavioral therapy components ( daily bladder diary and recommendations for fluid management ) in the group receiving drug therapy alone may have attenuated between-group differences . Assigned treatment was completed by 68 % of participants , whereas 8-month outcome status was assessed on 77 % . CONCLUSION The addition of behavioral training to drug therapy may reduce incontinence frequency during active treatment but does not improve the ability to discontinue drug therapy and maintain improvement in urinary incontinence . Combination therapy has a beneficial effect on patient satisfaction , perceived improvement , and reduction of other bladder symptoms AIMS A longitudinal r and omized controlled trial ( RCT ) was conducted to evaluate the effectiveness of physiotherapeutic pelvic floor muscle exercise ( PFME ) therapy supplemented with a health education program to promote long-term adherence among women with stress , mixed , and urge urinary incontinence ( UI ) . METHODS Women ( n = 129 ) were evaluated by their general practitioner ( GP ) and r and omized in either the control group ( PFME therapy alone ) or one of the three experimental groups ( PFME therapy with one of the three health education program versions ) . Therapy consisted of 9 - 18 individual 30 min sessions with a specialized physiotherapist , over 14 - 22 weeks . Outcome measures were weekly frequency of wet episodes and adherence behavior . Women were assessed up to 1 year after therapy . RESULTS The health education program had no additional impact to individual contact during PFME therapy on treatment outcome , nor on adherence . However , the individual physiotherapeutic treatment protocol was very effective in reducing weekly frequency of wet episodes from 23 to 8 times a week immediately after therapy , and effects were maintained during the 1-year follow-up period . Adherence was very high ; most women followed the behavioral advice on average 6 days/week at posttest and still 4 - 5 days 1 year after therapy . Results were not different between incontinence types . Women who had relatively frequent wet episodes before and 1 year after therapy had higher adherence levels compared to women who had fewer weekly losses . CONCLUSIONS Results suggest that a st and ardized protocol checklist for physiotherapists covering all treatment aspects of PFME therapy , may optimize long-term treatment outcome and adherence behavior among patients , and outshines the addition of a health education program OBJECTIVE To compare pelvic floor exercises and vaginal weight cones in the treatment of genuine stress incontinence . STUDY DESIGN R and omised controlled trial . METHODS Sixty ambulatory and fit white women ( mean age 56 years ) with urinary stress incontinence , treated by a single physiotherapist as out patients during twelve weeks . Thirty women were allocated to a weekly session of pelvic floor exercises . Thirty were allocated to using cones , they were seen every two weeks . OUTCOME MEASURES Objective : stress test , vaginal squeezing capacity . Subjective : urinary diary , visual analogue scales . RESULTS Characteristics of both study groups were comparable . Unfortunately , there was an early withdrawal of fourteen ( 47 % ) women in the group treated with cones , and none in the other group . Therefore the pelvic floor exercise group was compared not only with the group intended to be treated with cones , but also with the selected group that only received cone therapy . No statistically significantly differences in outcome measures were found between the groups : 53 % in the group assigned to pelvic floor exercises and 57 % into the group assigned to cones , of which 50 % in the group actually treated with cones , considered themselves as cured or improved to a significant degree . Long-term follow-up was not possible as all cone users refused continued exercises with cones once the twelve weeks had ended . CONCLUSION Pelvic floor exercises and cones are equally effective in the treatment of genuine stress incontinence . Cones are cost and time saving . However , the low patient compliance with the cones importantly limits its clinical applicability , especially in the long run . Therefore , we do not recommend the use of cones OBJECTIVE To assess a st and ardized and simple educational intervention in overactive bladder ( OAB ) patients to improve compliance with anticholinergic medication , increase the use of concomitant behavioral treatments , and improve patients ' perception of bladder symptoms . MATERIAL S AND METHODS This is a 16-week open-label r and omized trial of tolterodine combined with an education intervention for the experimental group versus tolterodine alone ( no intervention ) for the control group . The setting was in family medicine and urology clinics in Ontario . The participants were male and female adults with OAB symptoms . Both groups received tolterodine prescriptions . The intervention patients received printed information and an explanation about OAB , medication use , and behavioral treatments ( kegel exercise , bladder stretching , fluid regulation ) . The primary outcomes were medication compliance and persistence at 16 weeks . Secondary outcomes were use of behavioral treatments and self-reported severity of symptoms . RESULTS More patients in the intervention group ( experimental ) purchased their prescriptions ( p<0.05 ) . Compliance rate was greater for the intervention group ( 39 % ) , versus the control group ( 31 % ) at 16 weeks although the difference was not significant ( p>0.05 ) . Significantly more patients started and /or continued non-drug treatments in the intervention group ( 82 % ) compared to the control group ( 53 % ) ( p<0.05 ) . Furthermore , more patients in this group reported improvement in severity of bladder symptoms ( p<0.05 ) . CONCLUSIONS The simple education intervention result ed in a greater , but not significant , increase in compliance with medication compared to the control group . It also result ed in a significantly increased use of behavior modification therapies and better self-perception of treatment outcome OBJECTIVE To assess the efficacy of physiotherapeutic treatment modalities in women with proven bladder overactivity . METHODS One hundred and twelve women received ambulatory urodynamics . Based on both urodynamic variables of ambulatory cystometry ( ACM ) and the micturition diary , the Detrusor Activity Index ( DAI ) for each patient was calculated . After r and omization , 68 women with a DAI > or = 0.50 were defined as having proven bladder overactivity . In a single blinded RCT patients were r and omized over four treatment groups , i.e. lower urinary tract exercises ( LUTE ) ; office- and home-based functional electrostimulation ( FES ) ; office-based FES and LUTE ; no treatment . Patients treated received nine treatment sessions , once weekly . The primary outcome variable was the DAI , measured before r and omization and , as soon as possible within a maximum of 14 days after the end of the study period . RESULTS Intention to treat analysis in the group of 68 patients showed a statistically significant decrease of DAI-scores in the FES group ( p=0.032 ) in comparison with no treatment , while this decrease was not statistically significant in the LUTE group ( p=0.105 ) and the LUTE+FES group ( p=0.672 ) . CONCLUSIONS Our conclusion is that , based on the DAI , in the homogeneous set of 68 patients , only FES seemed to be effective In 69 patients on chronic haemodialysis , blood sample d r and omly during dialysis was analyzed for carboxyhaemoglobin ( COHb ) . The median value was 1.40 % ( range 0.9 - 2.3 ) in non-smoking patients and ( 1.4 - 7.5 ) in smokers . In non-smokers treated with erythropoietin ( EPO ) correlation was found between COHb and the weekly EPO dose ( r = 0.57 , p = 0.007 ) . In smoking patients not given EPO , the COHb correlated well with the number of cigarettes smoked ( r = 0.84 , p = 0.003 ) . The COHb values did not correlate to the haemoglobin values . It is concluded that COHb levels in uraemic non-smokers are elevated because of increased endogenous CO production from the enhanced erythrocyte turnover . As even low COHb levels may negatively influence the oxygen status of the uraemic patient , the addition of exogenous CO from cigarette smoking should be avoided We aim ed to study the impact of conservative non-pharmacological , non-surgical management on quality of life in elderly incontinent patients . Community-dwelling patients age 60 years or older were r and omized to receive immediate or delayed conservative management . A number of questions relating to quality of life were administered at admission and then at 2 , 4 , 8 and 12 months . By 4 months , incontinence was cured in 25 % and improved in 63 % of patients . The frequency and severity of incontinence was reduced ( p < 0.001 ) , and deferment time was improved ( p < 0.01 ) . There were statistically significant improvements in subjective quality of life measures at 4 and 12 months involving depression ( p < 0.001 ) , isolation ( p < 0.03 ) , embarrassment ( p < 0.001 ) , laundry ( p < 0.001 ) and smell ( p < 0.02 ) when comparing these variables with initial assessment . This effect did not appear to be a placebo effect as evidence d by comparison with the delayed intervention group , and was sustained over 12 months . There are significant short- and long-term benefits to the quality of life of older patients with incontinence when treated by conservative measures . Intervention studies should measure and report quality of life as an outcome variable CONTEXT Although behavioral therapy has been shown to improve postoperative recovery of continence , there have been no controlled trials of behavioral therapy for postprostatectomy incontinence persisting more than 1 year . OBJECTIVE To evaluate the effectiveness of behavioral therapy for reducing persistent postprostatectomy incontinence and to determine whether the technologies of biofeedback and pelvic floor electrical stimulation enhance the effectiveness of behavioral therapy . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve r and omized controlled trial involving 208 community-dwelling men aged 51 through 84 years with incontinence persisting 1 to 17 years after radical prostatectomy was conducted at a university and 2 Veterans Affairs continence clinics ( 2003 - 2008 ) and included a 1-year follow-up after active treatment . Twenty-four percent of the men were African American ; 75 % , white . INTERVENTIONS After stratification by type and frequency of incontinence , participants were r and omized to 1 of 3 groups : 8 weeks of behavioral therapy ( pelvic floor muscle training and bladder control strategies ) ; behavioral therapy plus in-office , dual-channel electromyograph biofeedback and daily home pelvic floor electrical stimulation at 20 Hz , current up to 100 mA ( behavior plus ) ; or delayed treatment , which served as the control group . MAIN OUTCOME MEASURE Percentage reduction in mean number of incontinence episodes after 8 weeks of treatment as documented in 7-day bladder diaries . RESULTS Mean incontinence episodes decreased from 28 to 13 per week ( 55 % reduction ; 95 % confidence interval [ CI ] , 44%-66 % ) after behavioral therapy and from 26 to 12 ( 51 % reduction ; 95 % CI , 37%-65 % ) after behavior plus therapy . Both reductions were significantly greater than the reduction from 25 to 21 ( 24 % reduction ; 95 % CI , 10%-39 % ) observed among controls ( P = .001 for both treatment groups ) . However , there was no significant difference in incontinence reduction between the treatment groups ( P = .69 ) . Improvements were durable to 12 months in the active treatment groups : 50 % reduction ( 95 % CI , 39.8%-61.1 % ; 13.5 episodes per week ) in the behavioral group and 59 % reduction ( 95 % CI , 45.0%-73.1 % ; 9.1 episodes per week ) in the behavior plus group ( P = .32 ) . CONCLUSIONS Among patients with postprostatectomy incontinence for at least 1 year , 8 weeks of behavioral therapy , compared with a delayed-treatment control , result ed in fewer incontinence episodes . The addition of biofeedback and pelvic floor electrical stimulation did not result in greater effectiveness . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00212264 Background : Urinary incontinence is an annoying , uncomfortable and unpleasant condition affecting the elderly . The problem of bedwetting and other urinary complaints are common in rest homes . Objective : Our study aim ed to determine the efficiency of bladder training and Kegel exercises for older women living in a rest home . Methods : This is an experimental prospect i ve research study . Through a r and omization process , 25 women were included in the treatment group , and another 25 were included in the control group . Participants were living in a rest home for women aged older than 65 years with urinary complaints . The pretreatment interview form , Quality of Life Scale , Mini-Mental Test , Rankin Scale , daily urinary forms and pad tests were administered to the treatment and control groups . Bladder training and Kegel exercises were given to the treatment group for 6–8 weeks . The second evaluation was performed 8 weeks after treatment , and the last evaluation was carried out 6 months after treatment . Results : The average age of the treatment group was 78.88 ± 4.80 years , and the average age of the control group 79.44 ± 5.32 years . Urgency , frequency and nocturia were common complaints . Pretreatment , 8-week and 6-month evaluations revealed that the amount of urinary incontinence with urgency , frequency and nocturia complaints statistically and significantly decreased in the treatment group compared to the control group . In the pad test results , a statistically significant decrease was observed in the treatment group compared to the control group . A significant increase in pelvic floor strength was observed in the treatment group compared to the control group upon all evaluations . Conclusion : Behavioral therapy can be used easily as an effective treatment for urinary incontinence in elderly women living at a rest home

Although several studies examined the effects of PHT on oral health , none have studied those of the newer generation of AEDs .

OBJECTIVE Long-term use of phenytoin ( PHT ) causes gingival hyperplasia ; however , little is known about the oral side effects of other antiepileptic drugs ( AEDs ) . Through a systematic review of the literature , we explored the effects of AEDs on the oral health of patients with epilepsy .

The role of folic acid ( 5mg/day ) in combination with oral hygiene measures ( group II ) vis-a-vis oral hygiene measures alone ( group I ) in prevention of phenytoin-induced gingival overgrowth was investigated in a one-year follow-up study on sixty , 8 - 13-year-old epileptic children receiving phenytoin . The allocation of the children to the two groups was done alternately . In these children , at baseline , plaque ( Silness & Löe ) , gingivitis ( Löe & Silness ) and probing depths of gingival sulcus were recorded . These parameters were re-evaluated at 3-monthly intervals when gingival overgrowth was also recorded ( Modified Harris & Ewalt Index ) . It was seen that , after a period of one year , gingival overgrowth occurred in 60 and 50 percent children of groups I & II respectively and its development , too , was delayed in group II . More cases ( 93 percent ) in group II exhibited minimal overgrowth as against 78 percent in group I. The study concluded that systemic folic acid prescribed along with phenytoin delays the onset and reduces the incidence and severity of gingival overgrowth induced by phenytoin Summary Fifty-four out- patients with epilepsy who had been taking phenytoin for more than one year were examined for gingival hyperplasia . Approximately 76 % of patients showed either mild or no gingival hyperplasia . Lesion severity was then compared statistically to phenytoin dosage and drug concentrations as well as to other clinical and laboratory parameters . There was a tendency for gingival hypertrophy to be associated with both increasing dosage of phenytoin per unit of body weight and the duration of phenytoin administration . All patients followed had a statistically significant progressive trend to increasing gingival hyperplasia with higher total and free phenytoin concentration BACKGROUND More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy , but why this happens and whether it can be predicted are unknown . We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures . METHODS We prospect ively studied 525 patients ( age , 9 to 93 years ) who were given a diagnosis , treated , and followed up at a single center between 1984 and 1997 . Epilepsy was classified as idiopathic ( with a presumed genetic basis ) , symptomatic ( result ing from a structural abnormality ) , or cryptogenic ( result ing from an unknown underlying cause ) . Patients were considered to be seizure-free if they had not had any seizures for at least one year . RESULTS Among the 525 patients , 333 ( 63 percent ) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped . The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy ( 40 percent vs. 26 percent , P=0.004 ) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer ( 51 percent vs. 29 percent , P<0.001 ) . The seizure-free rate was similar in patients who were treated with a single established drug ( 67 percent ) and patients who were treated with a single new drug ( 69 percent ) . Among 470 previously untreated patients , 222 ( 47 percent ) became seizure-free during treatment with their first antiepileptic drug and 67 ( 14 percent ) became seizure-free during treatment with a second or third drug . In 12 patients ( 3 percent ) epilepsy was controlled by treatment with two drugs . Among patients who had no response to the first drug , the percentage who subsequently became seizure-free was smaller ( 11 percent ) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects ( 41 percent ) or an idiosyncratic reaction ( 55 percent ) . CONCLUSIONS Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy

Because 30 % to 50 % of patients with PE present with echocardiographic evidence of RV dysfunction , the administration of a thrombolytic treatment toallof them would have significant implication s. The arguments for thrombolysis in such patients are essentially the following:(1)RVdysfunctionisastrong prognostic factor in patients with acute PE ; ( 2 ) the ability of thrombolytic agents to improve pulmonary reperfusion and enhanceRVfunction should translate into clinical benefit ; and ( 3 ) results of several studies have suggestedabeneficialeffectof thrombolysis in patients with acute PE and RV dysfunction .

A LTHOUGH THE MORtality rate for those with acute PE is low , certain patients are at high risk . Therefore , optimal management strategies should rely on risk stratification rather than “ one-size-fits-all ” treatment . In high-risk patients , the use of aggressive treatment could be justified . Despite the lack of definitive evidence , massive PE associated with cardiogenic shock , given the high mortality rate , is a widely accepted indication for thrombolysis . At the other extreme , the risks of thrombolysis are not justified in patients with an anatomically small PE that causes no elevation in RV afterload . The mortality rate for these patients is low , with most patients dying from underlying conditions rather than from PE .

Treatment with heparin or streptokinase was allocated r and omly to 30 patients with life-threatening pulmonary embolism verified by angiography . Treatment was given for 72 hours and pulmonary angiography was repeated . There was significantly greater ( P < 0·001 ) evidence of thrombolysis in those patients treated with streptokinase compared with those treated with heparin . The reduction of systolic and mean pulmonary arterial pressures was also significantly greater ( P < 0·05 and P < 0·02 respectively ) in the streptokinase group . Seven patients failed to complete 72 hours of the trial treatment : five successfully underwent pulmonary embolectomy . Six of these “ failures ” had initial pulmonary angiographic scores of 24 or more and systemic systolic blood pressure recordings of 100 mm Hg or less . Patients with these features should probably be considered for pulmonary embolectomy as the initial treatment . A febrile reaction commonly occurred in the streptokinase group ; otherwise side effects were no more common than in the heparin group Dissolution of pulmonary emboli with heparin and urokinase is ascribed , respectively , to anticoagulation and fibrinolysis . Since truly independent assessment of these effects in man is lacking , we administered each drug alone . Fibrinogen and plasminogen plasma levels and the resolution of pulmonary emboli were measured in three r and omized groups of 10 patients each : groups A and C infused with small repeated doses of urokinase and a large single dose of urokinase , respectively , and group B who received heparin . After 6 h of treatment , fibrinogen fell in all the groups , while , after 12 h , remained equally reduced in groups A and B and declined further in group C. Plasminogen behaved similarly . Up to 60 h , statistical analysis showed that these effects were related to timing and amounts of urokinase and heparin infusion . These observations suggest that heparin may induce a lytic state . As to signs of pulmonary emboli resolution , no differences between groups were found in lung perfusion and gas exchange recovery at any time ( from 1 day to 1 year ) and in pulmonary artery pressure reduction at 1 week . The greater angiographic and scintigraphic recovery observed with urokinase , versus heparin alone , after 1 day of treatment in the Urokinase Pulmonary Embolism Trial may be ascribed to a synergistic effect with urokinase of heparin administered during the diagnostic work-out . The indications of heparin and urokinase should be evaluated in the light of these results BACKGROUND The role of echocardiographic right ventricular ( RV ) dysfunction in predicting clinical outcome in clinical ly stable patients with pulmonary embolism ( PE ) is undefined . In this study , we assessed the prevalence and clinical outcome of normotensive patients with RV dysfunction among a broad spectrum of PE patients . METHODS AND RESULTS This prospect i ve clinical outcome study included cohort of 209 consecutive patients ( age , 65+/-15 years ) with documented PE . Acute RV dysfunction was diagnosed in the presence of > /=1 of the following : RV dilatation ( without hypertrophy ) , paradox septal systolic motion , and Doppler evidence of pulmonary hypertension . Four groups were identified : 28 patients presenting with shock or cardiac arrest ( 13 % ) , 19 hypotensive patients without shock ( 9 % ) , 65 normotensive patients with echocardiographic RV dysfunction ( 31 % ) , and 97 normotensive patients without RV dysfunction ( 47 % ) . Among normotensive patients with RV dysfunction , 6 ( 10 % ) developed PE-related shock after admission : 3 of these patients died , and 3 were successfully treated with thrombolytic agents . In comparison , none of the 97 normotensive patients without RV dysfunction developed shock or died as a result of PE . CONCLUSIONS A significant proportion ( 31 % ) of normotensive patients with acute PE presents with RV dysfunction ; these patients with latent hemodynamic impairment have a 10 % rate of PE-related shock and 5 % in-hospital mortality and may require aggressive therapeutic strategies . Conversely , normotensive patients without echocardiographic RV dysfunction have a benign short-term prognosis . Thus , early detection of echocardiographic RV dysfunction is of major importance in the risk stratification of normotensive patients with acute PE BACKGROUND The effect of alteplase versus heparin in pulmonary embolism has not been studied extensively with serial pulmonary angiograms . OBJECTIVES The aim of this r and omized , open trial was to evaluate the efficacy and safety of alteplase followed by heparin , versus heparin alone , in 36 patients with angiographically documented pulmonary embolism . METHODS Twenty patients were allocated r and omly to a 2-h infusion of alteplase ( 10 mg bolus , then 90 mg over 2 h ) followed by heparin ; the other 16 patients were given intravenous heparin at a continuous infusion rate of 1,750 IU/h . RESULTS The vascular obstruction , assessed by the Miller index at pulmonary angiography , decreased significantly in alteplase-treated patients ( p less than 0.01 ) from a baseline of 28.3 + /- 2.9 to a value of 24.8 + /- 5.2 2 h after the start of infusion ; in the heparin group there was no change ( from 25.3 + /- 5.3 to 25.2 + /- 5.4 ) . Mean pulmonary artery pressure decreased significantly from a baseline of 30.2 + /- 7.8 mm Hg to 21.4 + /- 6.7 in the alteplase group and increased in the heparin group ( from 22.3 + /- 10.5 to 24.8 + /- 11.2 mm Hg ) . For a subset of patients , lung scans were performed at baseline and on days 7 and 30 . There were no differences between the two groups in the follow-up lung scans , but there were significant decreases from the baseline values . Bleeding occurred in 14 of 20 alteplase-treated patients and in 6 of 16 in the heparin group ( p = NS ) . There were three major bleeding episodes in the alteplase group and two in the heparin group . Two patients died after fibrinolysis ( one of acute renal failure after cardiac tamponade and one of cardiac arrest after cerebral hemorrhage ) and one patient in the heparin group died of recurrent pulmonary embolism . CONCLUSIONS Alteplase result ed in a greater and faster improvement of the angiographic and hemodynamic variables compared with heparin . However , the high frequency of bleeding observed with alteplase in this trial suggests that patients should be carefully selected before thrombolytic therapy is given BACKGROUND Pulmonary embolism is a potentially fatal disorder . Information about the outcome of clinical ly recognized pulmonary embolism is sparse , particularly given that new treatments for more seriously ill patients are now available . METHODS We prospect ively followed 399 patients with pulmonary embolism diagnosed by lung scanning and pulmonary angiography , who were enrolled in a multicenter diagnostic trial . We review ed all hospitalizations , all new investigations of pulmonary embolism , and all deaths among the patients within one year of diagnosis . RESULTS Of the 399 patients , 375 ( 94 percent ) received treatment for pulmonary embolism , usually conventional anticoagulation . Only 10 patients ( 2.5 percent ) died of pulmonary embolism ; 9 of them had clinical ly suspected recurrent pulmonary embolism . Clinical ly apparent pulmonary embolism recurred in 33 patients ( 8.3 percent ) , of whom 45 percent died during follow-up . Ninety-five patients with pulmonary embolism ( 23.8 percent ) died within one year . The conditions associated with these deaths were cancer ( relative risk , 3.8 ; 95 percent confidence interval , 2.3 to 6.4 ) , left-sided congestive heart failure ( relative risk , 2.7 ; 95 percent confidence interval , 1.5 to 4.6 ) , and chronic lung disease ( relative risk , 2.2 ; 95 percent confidence interval , 1.2 to 4.0 ) . The most frequent causes of death in patients with pulmonary embolism were cancer ( in 34.7 percent ) , infection ( 22.1 percent ) , and cardiac disease ( 16.8 percent ) . CONCLUSIONS When properly diagnosed and treated , clinical ly apparent pulmonary embolism was an uncommon cause of death , and it recurred in only a small minority of patients . Most deaths were due to underlying diseases . Patients with pulmonary embolism who had cancer , congestive heart failure , or chronic lung disease had a higher risk of dying within one year than did other patients with pulmonary embolism STUDY OBJECTIVES To assess the potential benefit of thrombolysis in patients with massive pulmonary embolism ( PE ) with stable hemodynamics and right ventricular dysfunction . DESIGN Retrospective , cohort study . SETTING University-based , tertiary referral medical center . PATIENTS One hundred fifty-three consecutive patients with massive PE from January 1992 to December 1997 treated with heparin or thrombolysis . MEASUREMENTS AND RESULTS Massive PE was confirmed by perfusion lung scan or pulmonary angiography . Right ventricular dysfunction was assessed by echocardiography ( right ventricular/left ventricular [ RV/LV ] diastolic diameter ratio > 0.6 ) in all patients . In order to study a homogeneous population , 64 patients treated with thrombolysis ( group 1 ) were matched on baseline RV/LV diameter ratio to 64 patients treated with heparin ( group 2 ) . Perfusion lung scan was repeated at day 7 to day 10 . Mean relative improvement in perfusion lung scans was higher in group 1 than group 2 ( 54 % vs 42 % , respectively ) . PE recurrences were the same in both groups ( 4.7 % ; n = 3 ) . There were no bleeding complications and no deaths in group 2 . Conversely , in group 1 , 15.6 % ( n = 10 ) of patients suffered from bleeding ( 4.7 % ; n = 3 with intracranial bleeding ) and 6.25 % ( n = 4 ) of them died . CONCLUSIONS The results of this monocenter registry do not support the indication for thrombolysis in patients suffering from massive PE with stable hemodynamics and right ventricular dysfunction . Appropriate therapy in such patients still remains unknown . Further prospect i ve r and omized trials should be performed To test the efficacy of thrombolytic therapy in massive pulmonary embolism , we conducted a prospect i ve r and omized controlled trial . Eight patients were r and omized to receive either 1,500,000 IU of streptokinase in 1 hour through a peripheral vein followed by heparin or heparin alone . All patients had major risk factors for deep vein thrombosis ( DVT ) and were considered to have high clinical suspicion for pulmonary embolism ( PE ) . At baseline all patients had a similar degree of systemic arterial hypotension , pulmonary arterial hypertension , and right ventricular dysfunction . The time of onset of cardiogenic shock in both groups was comparable ( 2.25 ±0.5 hours in the streptokinase group and 1.75 ±0.96 hours in the heparin group ) . The four patients who were r and omized to streptokinase improved in the first hour after treatment , survived , and in 2 years of follow-up are without pulmonary arterial hypertension . All four patients treated with heparin alone died from 1 to 3 hours after arrival at the emergency room ( p=0.02 ) . Post-thrombolytic therapy the diagnosis of PE was sustained in the streptokinase group by high probability V/Q lung scans and proven DVT . A necropsy study performed in three patients in the heparin group showed massive pulmonary embolism and right ventricular myocardial infa rct ion , without significant coronary arterial obstruction . The results indicate that thrombolytic therapy reduces the mortality rate of massive acute pulmonary embolism Experiments in animals have demonstrated that recombinant tissue plasminogen activator ( rt-PA ) produces continuing thrombolysis after it is cleared from the circulation and that thrombolysis is both increased and accelerated , and bleeding is reduced when rt-PA is administered over a short period . In previous studies in patients with thrombotic disease , rt-PA has been shown to be an effective thrombolytic agent when administered by continuous infusion over a period between 90 minutes and 8 hours . To determine whether a short course regimen of rt-PA can achieve thrombolysis , a double-blind r and omized trial has been conducted in which patients with objective ly established acute symptomatic pulmonary embolism who were receiving heparin were allocated to either a 2-minute infusion of rt-PA at a dose of 0.6 mg/kg ( 33 patients ) or saline placebo ( 25 patients ) . Perfusion lung scanning was used to assess the change in pulmonary perfusion at 24 hours and seven days post- study drug administration . Thirty-four percent of the rt-PA patients had a greater than 50 percent resolution in the perfusion defect at 24 hours compared to 12 percent of placebo patients ( p = 0.026 ) . At 24 hours , the mean relative improvement in the perfusion defect was 37.0 percent in rt-PA treated patients compared to 18.8 percent in the placebo group ( p = 0.017 ) . By day 7 , no difference in lung scan resolution was detected between the groups . There were no major bleeds in either group nor were there any differences in transfusion requirements between groups . Minor bleeding occurred in 15 of the rt-PA patients mainly at angiogram-catheter insertion and venipuncture sites . These results suggest that a bolus regimen of rt-PA produces accelerated thrombolysis and provides an alternative and convenient approach to thrombolytic therapy in patients with pulmonary embolism Treatment with streptokinase or heparin was allocated r and omly to 20 patients with major pulmonary embolism verified by angiography . In addition , 4 patients treated with streptokinase and 1 patient treated with heparin were included in the trial prior to the start of treatment . Streptokinase of heparin was given for 72 hours and pulmonary angiography was repeated . The angiographic evidence of thrombolysis was significantly greater ( p less than 0.01 ) in the 14 patients treated with streptokinase than in the 11 treated with heparin . In the heparin group , 1 patient died from massive embolism 15 hours after the start of treatment . In another patient who died 4 weeks later from cerebral glibolastoma , persistent massive embolism contributed to the fatal outcome . In the streptokinase group , 1 patient with a metastatic pulmonary carcinoma died 3 weeks after the start of treatment from gangrene of both legs following thrombotic occlusion of the inferior vena cava . Bleeding was more common after treatment with streptokinase than with heparin , but was not a serious problem in any patient . It is concluded that patients with life-threatening pulmonary embolism should be offered the benefits of streptokinase STUDY OBJECTIVE To determine the efficacy of a corticosteroid in reducing the short-term mortality of patients with severe alcoholic hepatitis . DESIGN R and omized , double-blind , placebo-controlled multicenter trial . SETTING Four university teaching hospitals . PATIENTS We enrolled 66 patients with alcoholic hepatitis and either spontaneous hepatic encephalopathy or a discriminant function value greater than 32 , calculated using the formula : 4.6 ( prothrombin time - control time ) + serum bilirubin [ in mumol/L]/17.1 . Fifty-nine patients ( 89 % ) completed the study . Two patients withdrew from the trial . The other 64 patients were hospitalized for the duration of the trial ; however , treatment was discontinued in 5 patients because of potential drug toxicity . INTERVENTIONS Patients were r and omly assigned to receive either methylprednisolone ( 32 mg ) or placebo within 7 days of admission . Treatment was given for 28 days . The doses were then tapered over 2 weeks and discontinued . MEASUREMENTS AND MAIN RESULTS The endpoint of the study was death . Of the 31 recipients of placebo , 11 ( 35 % ) died within 28 days of r and omization compared with 2 ( 6 % ) of the 35 patients given methylprednisolone ( P = 0.006 ) . The 95 % CI for the difference in mortality was 12 % to 70 % . In the patients with spontaneous hepatic encephalopathy at entry , 9 of 19 recipients of placebo died ( 47 % ) compared with 1 ( 7 % ) of the 14 patients given methylprednisolone ( P = 0.02 ) . The 95 % CI for the difference in mortality was 14 % to 66 % . The Cox proportional hazards regression model showed the advantage of methylprednisolone over placebo after adjustment for other potentially important prognostic variables ( P = 0.004 ) . CONCLUSIONS Methylprednisolone therapy decreases short-term mortality in patients with severe alcoholic hepatitis manifested either by spontaneous hepatic encephalopathy or a markedly elevated discriminant function value Data from a non-r and omised study have hinted that in patients with acute pulmonary embolism ( PE ) , thrombolysis followed by heparin more rapidly reverses right-ventricular dysfunction and restores pulmonary tissue perfusion than does heparin alone . We have pursued this idea in a r and omised protocol . 46 haemodynamically stable patients were r and omised to recombinant tissue plasminogen activator ( alteplase , rt-PA ) 100 mg over 2 h followed by intravenous heparin and 55 to heparin alone . Right-ventricular wall motion was assessed qualitatively , and right-ventricular end diastolic area was estimated by planimetry from echocardiograms at baseline and at 3 and 24 hours . Pulmonary perfusion scans were obtained at baseline and 24 hours . In 39 % of rt-PA patients but in only 17 % of heparin alone patients right-ventricular wall motion at 24 hours had improved from baseline and in 2 % and 17 % , respectively , it worsened ( p = 0.005 ) . rt-PA patients also had a significant decrease in right-ventricular end-diastolic area during the 24 hours after r and omisation and a significant absolute improvement in pulmonary perfusion ( 14.6 % vs 1.5 % ) . No clinical episodes of recurrent PE were noted among rt-PA patients , but there were 2 fatal and 3 non-fatal clinical ly suspected recurrent PEs within 14 days in patients r and omised to heparin alone . rt-PA rapidly improves right-ventricular function and pulmonary perfusion among patients with PE and may lead to a lower rate of adverse clinical outcomes

Material incentives may also be more effective than motivational education at improving return for tuberculin skin test results ( low quality evidence ) , but may be no more effective than peer counselling , or structured education at improving continuation or completion of prophylaxis ( low quality evidence ) . There is limited evidence to support the use of material incentives to improve return rates for tuberculosis diagnostic test results and adherence to antituberculosis preventive therapy .

BACKGROUND Patient adherence to medications , particularly for conditions requiring prolonged treatment such as tuberculosis , is frequently less than ideal , and can result in poor treatment outcomes . Material incentives ( given as cash , vouchers and tokens ) , have been used to improve adherence . OBJECTIVES To assess the effects of material incentives in people undergoing diagnostic testing , or receiving prophylactic or curative therapy , for tuberculosis .

Objective To determine the effectiveness of the provision of whole food to enhance completion of treatment for tuberculosis . Design Parallel group r and omised controlled trial . Setting Three primary care clinics in Dili , Timor-Leste . Participants 270 adults aged ≥18 with previously untreated newly diagnosed pulmonary tuberculosis . Main outcome measures Completion of treatment ( including cure ) . Secondary outcomes included adherence to treatment , weight gain , and clearance of sputum smears . Outcomes were assessed remotely , blinded to allocation status . Interventions Participants started st and ard tuberculosis treatment and were r and omly assigned to intervention ( nutritious , culturally appropriate daily meal ( weeks 1 - 8 ) and food package ( weeks 9 - 32 ) ( n=137 ) or control ( nutritional advice , n=133 ) groups . R and omisation sequence was computer generated with allocation concealment by sequentially numbered , opaque , sealed envelopes . Results Most patients with tuberculosis were poor , malnourished men living close to the clinics ; 265/270 ( 98 % ) contributed to the analysis . The intervention had no significant beneficial or harmful impact on the outcome of treatment ( 76 % v 78 % completion , P=0.7 ) or adherence ( 93 % for both groups , P=0.7 ) but did lead to improved weight gain at the end of treatment ( 10.1 % v 7.5 % improvement , P=0.04 ) . Itch was more common in the intervention group ( 21 % v 9 % , P<0.01 ) . In a subgroup analysis of patients with positive results on sputum smears , there were clinical ly important improvements in one month sputum clearance ( 85 % v 67 % , P=0.13 ) and completion of treatment ( 78 % v 68 % , P=0.3 ) . Conclusion Provision of food did not improve outcomes with tuberculosis treatment in these patients in Timor-Leste . Further studies in different setting s and measuring different outcomes are required . Trial registration Clinical Trials NCT0019256 BACKGROUND Drug users are at increased risk for latent tuberculosis infection ( LTBI ) and also at increased risk for noncompletion of medication regimens for treatment of LTBI or tuberculosis disease . Directly observed therapy ( DOT ) provided by outreach workers , the use of incentives , or both have been suggested as a means to increase adherence . OBJECTIVE To compare the independent and combined effects of monetary incentives and outreach worker provision of DOT for LTBI treatment in a sample of active drug users . METHODS The research design was a r and omized controlled trial in a community outreach program setting . Participants consisted of a volunteer sample of 163 active injection drug and crack cocaine users placed on twice weekly DOT . Condition 1 of the interventions consisted of provision of DOT by an outreach worker at a location chosen by the participant ( active outreach ) and a $ 5 per visit incentive . Condition 2 was comprised of active outreach with no monetary incentive , and Condition 3 , provision of DOT at the study community site and a $ 5 per visit incentive . The main outcome measures were percentage of medication taken as prescribed and completion of medication regimen . RESULTS The percentage of prescribed medication taken was higher for those who received incentives , either with ( 71 % ) or without ( 68 % ) active outreach , compared to those who received active outreach alone ( 13 % ) . Only 4 % of participants assigned to Condition 2 completed treatment , compared to 53 % of Condition 1 participants , and 60 % of Condition 3 participants . CONCLUSIONS Monetary incentives were clearly superior to active outreach . Active outreach in combination with monetary incentives did not increase adherence over incentives alone SETTING Few studies have examined strategies for optimizing adherence to latent tuberculosis infection ( LTBI ) treatment programs in homeless population s. OBJECTIVES 1 ) To compare the effectiveness of an intervention program employing nurse case management and incentives ( NCMI ) vs. a control program with st and ard care and incentives on completion of LTBI treatment ; and 2 ) to compare the impact of the two programs on tuberculosis ( TB ) knowledge among participants . DESIGN A prospect i ve , two-group site-r and omized design conducted among 520 homeless adults residing in the Skid Row region of Los Angeles from 1998 to 2003 , assessing completion rates of a 6-month isoniazid ( INH ) treatment program and change in TB knowledge . RESULTS Using intent-to-treat analysis , 62 % of participants in the intervention program , compared with 39 % of controls , completed the full 6-month course of LTBI treatment with INH . Logistic regression modeling revealed that intervention participants had three times greater odds of completing INH treatment than controls . TB knowledge improved in both programs , but the increase was greater among the intervention participants ( P < 0.001 ) . CONCLUSIONS Nurse case management combined with education , incentives , and tracking dramatically improves both adherence to LTBI treatment and TB knowledge in homeless persons compared to a st and ard approach of outreach and incentives OBJECTIVES To test 2 interventions to improve adherence to isoniazid preventive therapy for tuberculosis in homeless adults . We compared ( 1 ) biweekly directly observed preventive therapy using a $ 5 monetary incentive and ( 2 ) biweekly directly observed preventive therapy using a peer health adviser , with ( 3 ) usual care at the tuberculosis clinic . METHODS R and omized controlled trial in tuberculosis-infected homeless adults . Outcomes were completion of 6 months of isoniazid treatment and number of months of isoniazid dispensed . RESULTS A total of 118 subjects were r and omized to the 3 arms of the study . Completion in the monetary incentive arm was significantly better than in the peer health adviser arm ( P = .01 ) and the usual care arm ( P = .04 ) , by log-rank test . Overall , 19 subjects ( 44 % ) in the monetary incentive arm completed preventive therapy compared with 7 ( 19 % ) in the peer health adviser arm ( P = .02 ) and 10 ( 26 % ) in the usual care arm ( P = .11 ) . The median number of months of isoniazid dispensed was 5 in the monetary incentive arm vs 2 months in the peer health adviser arm ( P = .005 ) and 2 months in the usual care arm ( P = .04 ) . In multivariate analysis , independent predictors of completion were being in the monetary incentive arm ( odds ratio , 2.57 ; 95 % CI , 1.11 - 5.94 ) and residence in a hotel or other stable housing at entry into the study vs residence on the street or in a shelter at entry ( odds ratio , 2.33 ; 95 % CI , 1.00 - 5.47 ) . CONCLUSIONS A $ 5 biweekly cash incentive improved adherence to tuberculosis preventive therapy compared with a peer intervention or usual care . Living in a hotel or apartment at the start of treatment also predicted the completion of therapy Background : The efficacy of a nurse case-managed intervention was evaluated in sub sample s of participants with one of the following characteristics : female gender , African American ethnicity , recruited from a homeless shelter , a history of military service , lifetime injection drug use , daily alcohol and drug use , poor physical health , and a history of poor mental health . Objective : To determine whether a vali date d nurse case-managed intervention with incentives and tracking would improve adherence to latent tuberculosis infection treatment in sub sample s of homeless persons with characteristics previously identified in the literature as predictive of nonadherence . Methods : A prospect i ve 2-group site-r and omized design was conducted with 520 homeless adults residing in 12 homeless shelters and residential recovery sites in the Skid Row region of Los Angeles from 1998 to 2003 . Results : Daily drug users , participants with a history of injection drug use , daily alcohol users , and persons who were not of African American race or ethnicity had particularly poor completion rates , even in the nurse case-managed intervention program ( 48 % , 55 % , 54 % , and 50 % , respectively ) . However , the intervention achieved a 91 % completion rate for homeless shelter residents and significantly improved latent tuberculosis infection treatment adherence in 9 of 12 subgroups tested ( odds ratios = 2.51 - 10.41 ) , including daily alcohol and drug users , when potential confounders were controlled using logistic regression analysis . Discussion : Nurse case management with incentives appears to be a good foundation for increasing adherence to 6-month isoniazid treatment in a variety of homeless subgroups and , in particular , for sheltered homeless population s. However , additional social-structural and environmental strategies are needed to address those at greatest risk of nonadherence The design , logic , and results of a two-year health education study directed at i m proving rates of patient adherence to antituberculosis medical regimens are presented . An incentive scheme to reward positive health behaviors plus targeted educational coun seling sessions was implemented in a r and omized clinical controlled trial . The 205 subjects who participated in the study are categorized according to patients with active tuberculosis ( n = 88 ) or preventive patients with no evidence of active disease ( n = 117 ) . Patients in each of these groups were r and omly assigned to a special intervention ( SI ) group or a usual care ( UC ) control group and were followed monthly throughout their treatment program . While SI patients with active tuberculosis demonstrated higher levels of ap pointment-keeping behavior and mean percent of medication taken compared to UC patients , no statistically significant differences between the two groups were found . Pre ventive therapy patients assigned to the SI group , however , were significantly more likely than UC patients to remain in care during their 12-month regimen ( 64 % vs 47 % ; p = .003 ) . Furthermore , SI patients had significantly higher levels of adherence to their medical regimen compared to UC patients ( 68 % vs 38 % ; p < .001 ) . These results demonstrate the positive effects of a structured health education program on the i m provement of continuity of care and adherence behavior among patients with tuberculosis . This study was funded by the Centers for Disease Control through contract # 200 - 85 - 0835 . The assistance of the Project Clerk , Sook Hee Treadwell , the Project Health Educators , Magda Fischer , Jennifer Adams , Nancy Murray , Fred Dominguez , and the clinic staff and patients who participated in this project are gratefully acknowledged . 1 . US Department of Health and Human Services , Public Health Service : The 1990 Health Objectives for the Nation : A Midcourse Review . Office of Disease Prevention and Health Promotion , 1986 . 2 . Centers for Disease Control . Tuberculosis — Provisional data —United States , 1986 . MMWR 36 : 254 - 255 , 1987 . 3 . Centers for Disease Control . Tuberculosis . Final Data —United States , 1986 . MMWR 36 : 817 - 820 , 1988 . 4 . County of Los Angeles , Department of Health Services , Public Health Programs : Communicable Disease Morbidity Report , County of Los Angeles , 1986 . 5 . Kopanoff DE , Snider DE , Johnson M : Recurrent tuberculosis : Why do patients develop disease again ? A United States Public Health Service Cooperative Survey . Am J Public Health 78 : 30 - 33 , 1988 . 6 . American Thoracic Society : Treatment of tuberculosis and tuberculosis infection in adults and children . Am Rev Respir Dis 134 : 355 - 363 , 1986 . 7 . Haynes RB : Introduction , in RB Haynes , DW Taylor , DL Sackett . ( eds ) : Compliance in Health Care . Baltimore , Johns Hopkins University Press , 1979 , pp 1 - 7 . 8 . Sackett DL , Haynes RB , editor : Compliance with Therapeutic Regimens . Baltimore , Johns Hopkins University Press , 1976 . 9 . Haynes RB , Taylor DW , Sackett DL , ed : Compliance in Health Care . Baltimore , Johns Hopkins University Press , 1979 . 10 . Meichenbaum D , Turk DC : Facilitating Treatment Adherence : A Practitioner 's Guidebook . Plenum Press , New York , 1987 . 11 . Addington WW : Patient compliance : The most serious remaining problem in the control of tuberculosis in the United States . Chest 76 (supp):741 - 743 , 1979 . 12 . Report of the Committee : A Strategic Plan for the Elimination of Tuberculosis in the United States . US Department of Health and Human Services , Centers for Disease Control , May 1988 . 13 . Comstock GW : New data on preventive treatment with isoniazid . Annals of Internal Medicine 98:663 - 665 , 1983 . 14 . Cross FS , Long MW , Banner AS , Snider DE Jr : Rifampin-isoniazid therapy of alcoholics and nonalcoholic tuberculosis patients in a U.S. Public Health Service cooperative trial . Am Rev Respir Dis 122:349 - 353 , 1980 . 15 . Snider DE Jr , . Improving Patient Compliance in Tuberculosis Treatment Programs . Atlanta , U.S. Department of Health and Human Services , Public Health Service , Centers for Disease Control , 1985 . 16 . Green LW , Kreuter MW , Deeds SG , Partridge KB : Health Education Planning : A Diagnostic Approach . Palo Alto , CA , Mayfield Publishing Company , 1980 . 17 . Hochbaum GM , Public Participation in Medical Science Programs : A Sociopsy chological Study . Washington , DC , United States Government Printing Office , PHS Publication No. 572 , 1958 . 18 . Rosenstock IM : What research in motivation suggests for public health . Am J Public Health 50:295 - 302 , 1960 . 19 . Becker MH : The health belief model and personal health behavior . Health Educ Monographs 2:324 - 473 , 1974 . 20 . Becker MH : Sociobehavioral determinants of compliance , in DL Sackett , RB Haynes ( eds ) : Compliance with Therapeutic Regimens . Baltimore , Johns Hopkins University Press , 1976 , pp 40 - 50 . 21 . Janz NK , Becker MH : The health belief model : A decade later . Health Education Quarterly 11:1 - 47 , 1984 . 22 . Sackett DL : Priorities and methods for future research , in DL Sackett , RB Haynes ( eds ) : Compliance with Therapeutic Regimens . Baltimore , Johns Hopkins University Press , 1976 , pp 169 - 189 . 23 . Dunbar JM , Stunkard AJ : Adherence to diet and drug regimen , in Levy RI , Rifkind B , Dennis B , Ernst N ( eds ) : Nutrition , Lipids , and Coronary Heart Disease . New York , Raven Press , 1979 , pp 391 - 423 . 24 . Svarstad BL : Physician-patient communication and patient conformity with medical advice , in Mechanie D ( ed ) : The Growth of Bureaucratic Medicine . New York , John Wiley and Sons , 1976 , pp 220 - 238 . 25 . Colcher IS , Bass JW : Penicillin treatment of streptococcal pharyngitis : A comparison of schedules and the role of specific counselling . JAMA 222:657 - 659 , 1972 . 26 . Sharpe TR , Mikeal RL : Patient compliance with antibiotic regimens . Am J Hospital Pharm 31:479 - 484 , 1974 . 27 . Swain MA , Steckel SB : Influencing adherence among hypertensives . Res Nursing and Health 4:213 - 222 , 1981 . 28 . Levine DM , Green LW , Russell RP , Morisky DE , Chwalow J , Benson P : Compliance in hypertension management : What the physician can do . Practical Cardiology 5:151- 160 , 1979 . 29 . DiMatteo MR , DiNicola DD , Achieving Patient Compliance : The Psychology of the Medical Practitioner 's Role . New York , Pergamon Press , 1982 . 30 . Eraker SA , Kirscht JP , Becker MH : Underst and ing and improving patient compli ance . Ann Intern Med 100:258 - 268 , 1984 . 31 . Waitzkin H , Stoeckle JD : Information control and the micro-politics of health care . Soc Sci Med 10:263 - 276 , 1976 . 32 . Minkler M : The use of incentives in family planning programmes : A study of com peting theories regarding their influence on attitude change . Int J Health Educ 19 (supplement):1 - 11 , 1976 . 33 . Sbarbaro JA : Compliance : Inducements and enforcements . Chest 76 ( supp ) : 750- 756 , 1979 . 34 . Snider DE Jr , And ers HM , Pozsik CJ : Incentives to take up health services . Lancet 2:812 , 1986 . 35 . Hull CH , Nie NH . Survival : Life Table Analysis . SPSS Up date 7 - 9 , McGraw-Hill , New York , 1981 PURPOSE Assess the costs and cost-effectiveness of an incentive-based tuberculosis ( TB ) program design ed to promote adolescents ' compliance with treatment for latent TB infection ( LTBI ) . METHODS R and omized controlled trial . Adolescents between the ages of 11 and 19 years who were referred to one of two participating clinics after being screened for TB and receiving a positive diagnosis indicating LTBI ( n = 794 ) were assigned to one of four groups : usual care , peer counseling , contingency contracting , and combined peer counseling/contingency contracting . Primary outcome variables were completion of isoniazid preventive therapy ( IPT ) , total treatment costs , and lifetime TB-related costs per quality -adjusted life year ( QALY ) in each of the four study groups ( three treatment , one control ) . Cost effectiveness was evaluated using a five-stage Markov model and a Monte Carlo simulation with 10,000 trials . RESULTS Average costs were 199 dollars for usual care ( UC ) , 277 dollars for peer counseling ( PC ) , 326 dollars for contingency contracting ( CC ) , and 341 dollars for PC + CC combined . The differences among these groups were all significant at the p = .001 level . Only the PC + CC group improved the rate of IPT completion ( 83.8 % ) relative to usual care ( 75.9 % ) ( p = .051 ) , with an overall incremental CE ratio of 209 dollars per QALY relative to usual care . CONCLUSION Incentives combined with peer counseling are a cost-effective strategy for helping adolescents to complete care when combined with peer counseling PURPOSE To determine the effect of several interventions on adherence to tuberculosis preventive therapy . METHODS We conducted a r and omized trial with a factorial design comparing strategies for improving adherence to isoniazid preventive therapy in 300 injection drug users with reactive tuberculin tests and no evidence of active tuberculosis . Patients were assigned to receive directly observed isoniazid preventive therapy twice weekly ( Supervised group , n = 99 ) , daily self-administered isoniazid with peer counseling and education ( Peer group , n = 101 ) , or routine care ( Routine group , n = 100 ) . Patients within each arm were also r and omly assigned to receive an immediate or deferred monthly $ 10 stipend for maintaining adherence . The endpoints of the trial were completing 6 months of treatment , pill-taking as measured by self-report or observation , isoniazid metabolites present in urine , and bottle opening as determined by electronic monitors in a subset of patients . RESULTS Completion of therapy was 80 % for patients in the Supervised group , 78 % in the Peer group , and 79 % in the Routine group ( P = 0.70 ) . Completion was 83 % ( 125 of 150 ) among patients receiving immediate incentives versus 75 % ( 112 of 150 ) among patients with deferred incentives ( P = 0.09 ) . The proportion of patients who were observed or reported taking at least 80 % of their doses was 82 % for the Supervised arm of the study , compared with 71 % for the Peer arm and 90 % for the Routine arm . The proportion of patients who took 100 % of doses was 77 % for the Supervised arm ( by observation ) , 6 % for the Peer arm ( by report ) , and 10 % for the Routine arm ( by report ; P < 0.001 ) . Direct observation showed the median proportion of doses taken by the Supervised group was 100 % , while electronic monitoring in a subset of patients showed the Peer group ( n = 27 ) took 57 % of prescribed doses and the Routine group ( n = 32 ) took 49 % ( P < 0.001 ) . Patients in the Routine arm overreported adherence by twofold when data from electronic monitoring were used as a gold st and ard . There were no significant differences in electronically monitored adherence by type of incentive . CONCLUSION Adherence to isoniazid preventive therapy by injection drug users is best with supervised care . Peer counseling improves adherence over routine care , as measured by electronic monitoring of pill caps , and patients receiving peer counseling more accurately reported their adherence . More widespread use of supervised care could contribute to reductions in tuberculosis rates among drug users and possibly other high-risk groups BACKGROUND Adherence to treatment of persons with latent tuberculosis infection after release from jail has been poor . METHODS A r and omized controlled trial was conducted at the San Francisco City and County Jail , San Francisco , Calif. Subjects undergoing therapy for latent tuberculosis infection who spoke either English or Spanish were r and omly allocated to receive education every 2 weeks while in jail ; an incentive if they went to the San Francisco County Tuberculosis Clinic within 1 month of release ; or usual care . The main outcome measures were completion of a visit to the tuberculosis clinic within 1 month of release and completion of therapy . RESULTS Of 558 inmates enrolled , 325 were released before completion of therapy . Subjects in either intervention group were significantly more likely to complete a first visit than were control subjects ( education group , 37 % ; incentive group , 37 % ; and controls , 24 % ) ( adjusted odds ratio based on pooled results for the education and incentive groups , 1.85 ; 95 % confidence interval , 1.04 - 3.28 ; P = .02 ) . Those in the education group were twice as likely to complete therapy compared with controls ( adjusted odds ratio , 2.2 ; 95 % confidence interval , 1.04 - 4.72 ; P = .04 ) . Of those who went to the tuberculosis clinic after release , subjects in the education group were more likely to complete therapy ( education group , 65 % [ 24/37 ] ; incentive group , 33 % [ 14/42 ] ; and control group , 48 % [ 12/25 ] ; P = .02 ) . CONCLUSIONS Education or the promise of an incentive improved initial follow-up . Education was superior to an incentive for the completion of therapy . Fairly modest strategies provided in jail can improve adherence . Further links between jail health services and community care should be explored BACKGROUND In a prior study , we reported that monetary incentives were effective in increasing return for tuberculosis ( TB ) skin test reading . The purpose of this study was to compare the effects of monetary versus nonmonetary incentives and a theory-based educational intervention on return for TB skin test reading in a sample of newly recruited active injection and crack cocaine users , and to determine the prevalence of TB infection in this sample . METHODS Active injection drug and /or crack cocaine users ( n = 1,078 ) , recruited using street outreach techniques , were skin tested for TB . They were r and omly assigned to 1 of 5 experimental treatment conditions : $ 10 cash , grocery store coupons , bus tokens/fast-food coupons , motivational education , or usual encouragement to return . Nonmonetary incentives had a $ 10 value , and all incentives were provided at return for skin test reading . RESULTS Ninety-five percent of those who received $ 10 returned for skin test reading compared to 86 % of those who received grocery store coupons and 83 % of those who received either bus tokens or fast-food coupons . In contrast , only 47 % of those who received the educational session and only 49 % of those who received usual encouragement returned for skin test reading . The prevalence of a positive tuberculin test was 21 % , and was similar for crack cocaine and injection drug users . CONCLUSIONS Nonmonetary and monetary incentives dramatically increased the return rate for TB skin test reading among drug users who are at high risk of TB infection . Nonmonetary incentives were somewhat less effective than monetary incentives OBJECTIVES Activation of latent tuberculosis infection into tuberculosis disease ( TB ) , the primary killer among infectious diseases worldwide , can be prevented with six months of anti-TB medication . A large percentage of adolescents started on medication , however , fail to complete their treatment . The authors developed and tested the effects of innovative educational strategies on infected adolescents at two health centers serving ethnically diverse population s. METHODS The authors used a r and omized experimental four-group design to assess the independent and combined effects of peer counseling and a participant-parent contingency contract intervention . RESULTS A total of 794 adolescents were recruited into the study , for a 79 % participation rate . The overall rate of treatment completion was 79.8 % . Self-efficacy for medication-taking behavior at post-test correlated strongly with completion of care ( R = 0.367 , p = 0.002 ) . Participants r and omized to the peer counseling groups demonstrated significantly greater improvements in self-efficacy and mastery than the usual care control group . Based on the study results , continuing education seminars and workshops were implemented for TB control staff at the two health clinics and for all TB Control Division staff at the Los Angeles County Health Department . Educational material s and a training manual for enhancing completion of treatment of latent TB infection through tailored educational approaches were developed and disseminated to the clinics . CONCLUSIONS Health education and incentives are helpful adjuncts to the completion of treatment for latent tuberculosis infection in adolescents INTRODUCTION Wasting is the cardinal feature of tuberculosis , but not much documentary evidence supporting food supplements exists . This study was done to assess the effects of food supplements on body weight , physical function , quality of life and treatment outcomes in patients with tuberculosis and wasting . METHODS The study was conducted in 30 Anganwadi centres of 16 villages in the catchment area of Pinnamaneni Siddhartha Institute of Medical Sciences and Research Foundation and the Gannavaram Directly Observed Treatment Short Course chemotherapy centre from August 2005 to December 2005 . A total of 100 patients participated in the study . Patients who were started on anti-tubercular therapy within the previous two weeks were r and omly assigned to either the control or the food supplement group . At the end of three months , their body weight was measured and physical function and quality of life were assessed . Treatment outcomes were assessed at the one-year follow-up for both groups . RESULTS Patients who received supplements had a significant increase in body weight ( 8.6 percent versus 2.6 percent , p-value less than 0.001 ) and maximum grip strength ( p-value less than 0.001 ) , a higher sputum conversion rate ( p-value is 0.039 ) , a higher treatment completion rate ( p-value is 0.031 ) and improvements in the quality of life scores . CONCLUSION Intake of food supplements result ed in a definitive increase in body weight and physical function in our study sample . Improvements can be observed in all areas , including psychologically , physiologically , socially and in the treatment outcomes OBJECTIVE To determine the most effective strategy to encourage adherence with tuberculosis test reading in a high-risk population . Design . Prospect i ve r and omized controlled trial . SETTING / PARTICIPANTS Consecutive sample of 627 children ages 1 to 12 years due for a tuberculosis ( TB ) test in an urban children 's hospital outpatient department . One child per family was enrolled . INTERVENTION All families received education regarding the importance of skin testing for TB and the need for follow-up , and written and verbal instructions regarding test reading . Families were r and omly assigned to one of five strategies for follow-up TB test reading at 48 to 72 hours : 1 ) routine verbal and written instructions , 2 ) reminder phone call , 3 ) transportation tokens and toy on return , 4 ) withholding of school forms until time of reading and need to repeat TB test if not timely read , 5 ) parents taught to read in duration with nurse home visit . Those who did not have tests read at 48 to 72 hours by a trained professional were phoned 1 week later . RESULTS The five groups did not differ with regard to TB risk factor score , maternal education , transportation source , or perceived importance of TB testing . Before the study the follow-up rate of TB test reading by a trained professional was 45 % . Reading rates in this study were 58 % , 70 % , 67 % , 70 % , and 72 % for groups 1 to 5 , respectively . In group 4 , only 39 % had school forms to be completed and their adherence rate was 84 % ( 53/63 ) . Compared to group 1 , the only statistically significant improvement was in group 4 , especially for those who needed school forms completed , and in group 5 . Those not adhering in groups 1 to 4 did not differ from returnees with regard to TB risk factors , maternal education , transportation , or perceived importance of testing . The most common reasons for failing to return included forgetfulness , transportation , and time constraints . Group 5 was stopped early because of difficulty with nurse visits ( N = 98 ) . When told of the nurse visit , 9 % ( 9/98 ) families could not find a time for the visit . Seventeen percent ( 17/98 ) were visited but the child was not home , and 7 % ( 7/98 ) were not visited because of a nurse scheduling problem . CONCLUSIONS In a high-risk population , adherence with TB test reading is poor . However , education and return of school forms at reading time can significantly improve adherence . Although requiring larger investment in re sources , visiting nurses may also aid in test reading OBJECTIVES This study assessed the independent and combined effects of different levels of monetary incentives and a theory-based educational intervention on return for tuberculosis ( TB ) skin test reading in a sample of active injection drug and crack cocaine users . Prevalence of TB infection in this sample was also determined . METHODS Active or recent drug users ( n = 1004 ) , recruited via street outreach techniques , were skin tested for TB . They were r and omly assigned to 1 of 2 levels of monetary incentive ( $ 5 and $ 10 ) provided at return for skin test reading , alone or in combination with a brief motivational education session . RESULTS More than 90 % of those who received $ 10 returned for skin test reading , in comparison with 85 % of those who received $ 5 and 33 % of those who received no monetary incentive . The education session had no impact on return for skin test reading . The prevalence of a positive tuberculin test was 18.3 % . CONCLUSIONS Monetary incentives dramatically increase the return rate for TB skin test reading among drug users who are at high risk of TB infection BACKGROUND Adherence to tuberculosis evaluation is poor in a high-risk population such as the homeless . OBJECTIVE To test two interventions aim ed at improving adherence to tuberculosis evaluation and to identify predictors of adherence . METHODS We conducted a r and omized clinical trial in shelters and food lines in the inner city of San Francisco , Calif. We r and omized 244 eligible subjects infected with tuberculosis to ( 1 ) peer health adviser ( assistance by a peer [ n = 83 ] ) , ( 2 ) monetary incentive ( $ 5 payment [ n = 82 ] ) , or ( 3 ) usual care ( referral slips and bus tokens only [ n = 79 ] ) . The primary outcome of the study was adherence to a first follow-up appointment at the tuberculosis clinic , where subjects were evaluated for active tuberculosis and the need for isoniazid prophylaxis . RESULTS Of the subjects assigned to a monetary incentive , 69 ( 84 % ) completed their first follow-up appointment , compared with 62 subjects ( 75 % ) assigned to a peer health adviser and 42 subjects ( 53 % ) assigned to usual care . Adherence was higher in the monetary incentive and peer health adviser groups than in the usual care group ( P < .001 and P = .004 , respectively ) . Patients not using intravenous drugs and patients 50 years of age or older were more likely to adhere to a first follow-up appointment ( odds ratios [ 95 % confidence intervals ] , 2.5 [ 1.3 to 5.0 ] and 3.3 [ 1.2 to 8.8 ] , respectively ) . Among the 173 tuberculosis-infected subjects who completed their appointment , isoniazid therapy was started for 72 individuals , and three cases of active tuberculosis were identified . CONCLUSION A monetary incentive or a peer health adviser is effective in improving adherence to a first follow-up appointment in homeless individuals infected with tuberculosis . A monetary incentive appears to be superior . Intravenous drug users and young individuals are at high risk for poor adherence to referral SETTING Intravenous drug users ( IDUs ) represent a high risk group for dual human immunodeficiency virus ( HIV ) and tuberculosis ( TB ) infection . Screening with TB skin testing has therefore been suggested in this group . Subjects ' compliance for returning to have TB skin test results read is a major problem . In the setting of a needle exchange program we evaluated the role of financial incentives to increase compliance . METHODS We evaluated the role of giving a small financial incentive of Can $ 5 to subjects if they returned to have their purified protein derivative ( PPD ) skin test read . IDUs who had previously been skin-tested were compared with IDUs drawn from a similar population who , prospect ively , were offered a financial incentive . RESULTS During the initial period 558 subjects were evaluated and no incentive was offered . During the second phase of the study 549 IDUs were assessed but were also offered Can $ 5 if they returned to have their skin test read . Use of incentives increased compliance from 43 % to 78 % ( P = 0.001 ) . During the same period three active cases of TB were also diagnosed . CONCLUSIONS We suggest that use of financial incentives can increase the return of IDUs to have their skin tests read . Further studies are required to assess the efficacy of follow-up interventions , especially the use of isoniazid chemoprophylaxis

In terms of safety , gemcitabine plus anti-angiogenesis therapy did not increase the rate of grade 3 - 4 common adverse effects except for hypertension . Conclusions : Although gemcitabine plus anti-angiogenesis therapy might prolong the progression-free survival in locally advanced or metastatic pancreatic cancer , these successful results did not translate into a significant improvement in the overall survival or change in the clinical guidelines

Purpose : Pancreatic cancer is a common digestive neoplasm with a high fatality rate . We performed this systematic review and meta- analysis of clinical r and omized phase III trials to explore the efficacy and safety of gemcitabine plus anti-angiogenesis therapy versus gemcitabine monotherapy for locally advanced or metastatic pancreatic cancer .

Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor . Recent advances in conventional chemotherapy and the development of novel ‘ molecular ’ treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies . This r and omised study in pancreatic cancer compares marimastat ( orally administered matrix metalloproteinase inhibitor ) in combination with gemcitabine to gemcitabine alone . Two hundred and thirty-nine patients with unresectable pancreatic cancer were r and omised to receive gemcitabine ( 1000 mg m−2 ) in combination with either marimastat or placebo . The primary end-point was survival . Objective tumour response and duration of response , time to treatment failure and disease progression , quality of life and safety were also assessed . There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo ( P=0.95 log-rank test ) . Median survival times were 165.5 and 164 days and 1-year survival was 18 % and 17 % respectively . There were no significant differences in overall response rates ( 11 and 16 % respectively ) , progression-free survival ( P=0.68 log-rank test ) or time to treatment failure ( P=0.70 log-rank test ) between the treatment arms . The gemcitabine and marimastat combination was well tolerated with only 2.5 % of patients withdrawn due to presumed marimastat toxicity . Grade 3 or 4 musculoskeletal toxicities were reported in only 4 % of the marimastat treated patients , although 59 % of marimastat treated patients reported some musculoskeletal events . The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer . The combination of marimastat with gemcitabine was well tolerated . Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified Gemcitabine is a key drug for the treatment of pancreatic cancer ; however , with its limitation in clinical benefits , the development of another potent therapeutic is necessary . Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis , and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide ( elpamotide ) . Based on the promising results of this phase I trial , a multicenter , r and omized , placebo‐controlled , double‐blind phase II/III clinical trial has been carried out for pancreatic cancer . The eligibility criteria included locally advanced or metastatic pancreatic cancer . Patients were assigned to either the Active group ( elpamotide + gemcitabine ) or Placebo group ( placebo + gemcitabine ) in a 2:1 ratio by the dynamic allocation method . The primary endpoint was overall survival . The Harrington – Fleming test was applied to the statistical analysis in this study to evaluate the time‐lagged effect of immunotherapy appropriately . A total of 153 patients ( Active group , n = 100 ; Placebo group , n = 53 ) were included in the analysis . No statistically significant differences were found between the two groups in the prolongation of overall survival ( Harrington – Fleming P‐value , 0.918 ; log – rank P‐value , 0.897 ; hazard ratio , 0.87 , 95 % confidence interval [ CI ] , 0.486–1.557 ) . Median survival time was 8.36 months ( 95 % CI , 7.46–10.18 ) for the Active group and 8.54 months ( 95 % CI , 7.33–10.84 ) for the Placebo group . The toxicity observed in both groups was manageable . Combination therapy of elpamotide with gemcitabine was well tolerated . Despite the lack of benefit in overall survival , subgroup analysis suggested that the patients who experienced severe injection site reaction , such as ulceration and erosion , might have better survival BACKGROUND To investigate whether addition of cetuximab to st and ard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer , specifically whether the rate of disease-free survival ( DFS ) at 18 months ( primary end point ) exceeds the previously reported 35 % of gemcitabine alone . PATIENTS AND METHODS Prospect i ve , open-label , multicenter , nonr and omized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008 . Gemcitabine and cetuximab were administered for 24 weeks . Secondary end points included overall survival ( OS ) and toxic effect . RESULTS Seventy-three patients received cetuximab . Median DFS was 10.0 [ 95 % confidence interval ( CI ) 8.9 - 13.6 ] months and the DFS rate at month 18 of 27.1 % ( 16.7%-37.6 % ) was inferior to 35 % . Median OS was 22.4 ( 18.2 - 27.9 ) months . Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 ( median 14.7 versus 8.3 months , P = 0.073 ) and wild-type versus mutated K-Ras ( median 11.5 versus 9.3 months , P = 0.57 ) . Grade 3/4 toxic effects included neutropenia ( 11.0 % ) , thrombopenia ( 7 % ) , skin toxic effect ( 7 % ) and allergic reactions ( 7 % ) . CONCLUSION Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients . Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed PURPOSE To evaluate , in a phase 2 study , the safety and efficacy of induction gemcitabine , oxaliplatin , and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer ( BRPC or LAPC , respectively ) . METHODS AND MATERIAL S Patients received gemcitabine and oxaliplatin chemotherapy repeated every 14 days for 6 cycles , combined with weekly cetuximab . Patients were then restaged ; " downstaged " patients with resectable disease underwent attempted resection . Remaining patients were treated with chemoradiation consisting of intensity modulated radiation therapy ( 54 Gy ) and concurrent capecitabine ; patients with borderline resectable disease or better at restaging underwent attempted resection . RESULTS A total of 39 patients were enrolled , of whom 37 were evaluable . Protocol treatment was generally well tolerated . Median follow-up for all patients was 11.9 months . Overall , 29.7 % of patients underwent R0 surgical resection ( 69.2 % of patients with BRPC ; 8.3 % of patients with LAPC ) . Overall 6-month progression-free survival ( PFS ) was 62 % , and median PFS was 10.4 months . Median overall survival ( OS ) was 11.8 months . In patients with LAPC , median OS was 9.3 months ; in patients with BRPC , median OS was 24.1 months . In the group of patients who underwent R0 resection ( all of which were R0 resections ) , median survival had not yet been reached at the time of analysis . CONCLUSIONS This regimen was well tolerated in patients with BRPC or LAPC , and almost one-third of patients underwent R0 resection . Although OS for the entire cohort was comparable to that in historical controls , PFS and OS in patients with BRPC and /or who underwent R0 resection was markedly improved Purpose Considering promising results in phase II studies , a r and omized phase III trial was design ed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease ( ED ) small-cell lung cancer ( SCLC ) . Patients and Methods Treatment-naive patients with ED-SCLC were r and omly assigned to receive either cisplatin plus etoposide ( arm A ) or the same regimen with bevacizumab ( arm B ) for a maximum of six courses . In the absence of progression , patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses . The primary end point was overall survival ( OS ) . Results Two hundred four patients were r and omly assigned and considered in intent-to-treat analyses ( 103 patients in arm A and 101 patients in arm B ) . At a median follow-up of 34.9 months in arm A and arm B , median OS times were 8.9 and 9.8 months , and 1-year survival rates were 25 % and 37 % ( hazard ratio , 0.78 ; 95 % CI , 0.58 to 1.06 ; P = .113 ) , respectively . A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen ( hazard ratio , 0.60 ; 95 % CI , 0.40 to 0.91 ; P = .011 ) . Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B , respectively ( P = .030 ) . Regarding hematologic toxicity , no statistically significant differences were observed ; for nonhematologic toxicity , only hypertension was more frequent in arm B ( grade 3 or 4 , 1.0 % v 6.3 % in arms A v B , respectively ; P = .057 ) . Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival , which , however , did not translate into a statistically significant increase in OS . Further research with novel antiangiogenic agents , particularly in the maintenance setting , is warranted Background : We aim ed to identify molecular epidermal growth factor receptor ( EGFR ) tissue biomarkers in pancreatic cancer ( PC ) patients treated with the anti-EGFR agent erlotinib within the phase 3 r and omised AIO-PK0104 study . Methods : AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC ; primary study end point was the time-to-treatment failure after first- and second-line therapy ( TTF2 ) . Translational analyses were performed for KRAS exon 2 mutations , EGFR expression , PTEN expression , the EGFR intron 1 and exon 13 R497 K polymorphism ( PM ) . Biomarker data were correlated with TTF , overall survival ( OS ) and skin rash . Results : Archival tumour tissue was available from 208 ( 74 % ) of the r and omised patients . The KRAS mutations were found in 70 % ( 121 out of 173 ) of patients and exclusively occurred in codon 12 . The EGFR overexpression was detected in 89 out of 181 patients ( 49 % ) by immunohistochemistry ( IHC ) , and 77 out of 166 patients ( 46 % ) had an EGFR gene amplification by fluorescence in-situ hybridisation ( FISH ) ; 30 out of 171 patients ( 18 % ) had a loss of PTEN expression , which was associated with an inferior TTF1 ( first-line therapy ; HR 0.61 , P=0.02 ) and TTF2 ( HR 0.66 , P=0.04 ) . The KRAS wild-type status was associated with improved OS ( HR 1.68 , P=0.005 ) ; no significant OS correlation was found for EGFR – IHC ( HR 0.96 ) , EGFR – FISH ( HR 1.22 ) , PTEN – IHC ( HR 0.77 ) , intron 1 ( HR 0.91 ) or exon 13 R497 K PM ( HR 0.83 ) . None of the six biomarkers correlated with the occurrence of skin rash . Conclusion : The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study ; it remains to be defined whether this association is prognostic or predictive BACKGROUND Axitinib is a potent , selective inhibitor of vascular endothelial growth factor ( VEGF ) receptors 1 , 2 , and 3 . A r and omised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients . On the basis of these results , we aim ed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial . METHODS In this double-blind , placebo-controlled , phase 3 study , eligible patients had metastatic or locally advanced pancreatic adenocarcinoma , no uncontrolled hypertension or venous thrombosis , and Eastern Cooperative Oncology Group performance status 0 or 1 . Patients , stratified by disease extent ( metastatic vs locally advanced ) , were r and omly assigned ( 1:1 ) to receive gemcitabine 1000 mg/m(2 ) intravenously on days 1 , 8 , and 15 every 28 days plus either axitinib or placebo . Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day , which could be dose-titrated up to 10 mg twice daily if well tolerated . A central ised r and omisation procedure was used to assign patients to each treatment group , with r and omised permuted blocks within strata . Patients , investigators , and the trial sponsor were masked to treatment assignments . The primary endpoint was overall survival . All efficacy analyses were done in all patients assigned to treatment groups for whom data were available ; safety and treatment administration and compliance assessment s were based on treatment received . This study is registered at Clinical Trials.gov , number NCT00471146 . FINDINGS Between July 27 , 2007 , and Oct 31 , 2008 , 632 patients were enrolled and assigned to treatment groups ( 316 axitinib , 316 placebo ) . At an interim analysis in January , 2009 , the independent data monitoring committee concluded that the futility boundary had been crossed . Median overall survival was 8·5 months ( 95 % CI 6·9 - 9·5 ) for gemcitabine plus axitinib ( n=314 , data missing for two patients ) and 8·3 months ( 6·9 - 10·3 ) for gemcitabine plus placebo ( n=316 ; hazard ratio 1·014 , 95 % CI 0·786 - 1·309 ; one-sided p=0·5436 ) . The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension ( 20 [ 7 % ] and 5 [ 2 % ] events , respectively ) , abdominal pain ( 20 [ 7 % ] and 17 [ 6 % ] ) , fatigue ( 27 [ 9 % ] and 21 [ 7 % ] ) , and anorexia ( 19 [ 6 % ] and 11 [ 4 % ] ) . INTERPRETATION The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer . These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease . FUNDING Pfizer Purpose The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of pre clinical evidence of synergy between these drugs . According to our phase I study , the combination of capecitabine and everolimus is safe and feasible , with potential activity in pancreatic cancer patients . Methods Patients with advanced adenocarcinoma of the pancreas were enrolled . Eligible patients had a WHO performance status 0–2 and adequate hepatic and renal functions . The treatment regimen consisted of capecitabine 1000 mg/m2 BID day 1–14 and everolimus 10 mg daily ( 5 mg BID ) in a continuous 21-day schedule . Tumor assessment was performed with CT-scan every three cycles . Primary endpoint was response rate ( RR ) according to RECIST 1.0 . Secondary endpoints were progression-free survival , overall survival and 1-year survival rate . Results In total , 31 patients were enrolled . Median ( range ) treatment duration with everolimus was 76 days ( 1–431 ) . Principal grade 3/4 toxicities were hyperglycemia ( 45 % ) , h and -foot syndrome ( 16 % ) , diarrhea ( 6 % ) and mucositis ( 3 % ) . Prominent grade 1/2 toxicities were anemia ( 81 % ) , rash ( 65 % ) , mucositis ( 58 % ) and fatigue ( 55 % ) . RR was 6 % . Ten patients ( 32 % ) had stable disease result ing in a disease control rate of 38 % . Median overall survival was 8.9 months ( 95 % CI 4.6–13.1 ) . Progression-free survival was 3.6 months ( 95 % CI 1.9–5.3 ) . Conclusions The oral regimen with the combination of capecitabine and everolimus is a moderately active treatment for patients with advanced pancreatic cancer , with an acceptable toxicity profile at the applied dose level PURPOSE The combination of gemcitabine plus bevacizumab produced a 21 % response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer . These encouraging data led Cancer and Leukemia Group B ( CALGB ) to conduct a double-blind , placebo-controlled , r and omized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients . PATIENTS AND METHODS Eligible patients had no prior therapy for advanced disease , Eastern Cooperative Oncology Group ( ECOG ) performance status 0 to 2 , no tumor invasion of adjacent organs , and no increased bleeding risk . The primary end point was overall survival . Patients were stratified by performance status , extent of disease , and prior radiotherapy . Patients received gemcitabine at 1,000 mg/m(2 ) over 30 minutes on days 1 , 8 , and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days . RESULTS Between June 2004 and April 2006 , 602 patients were enrolled onto the study and 535 were treated . Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo ( P = .95 ) . Median progression-free survival was 3.8 and 2.9 months , respectively ( P = .07 ) . Overall response rates were 13 % and 10 % , respectively . Patients with a performance status of 0 , 1 , and 2 survived a median of 7.9 , 4.8 , and 2.4 months , respectively . The only statistically significant differences in grade s 3 and 4 toxicity occurred for hypertension ( 10 % v 3 % ; P < .001 ) and proteinuria ( 5 % v 1 % ; P = .002 ) ; venous thrombosis grade > or = 3 was equivalent in both arms ( 14 % and 15 % , respectively ) . CONCLUSION The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients BACKGROUND The RAF-MEK-ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations . A phase II r and omized trial was design ed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer . METHODS Locally advanced or metastatic pancreatic adenocarcinoma patients were r and omized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400 mg bid ( arm A ) or without sorafenib ( arm B ) . RESULTS One hundred and fourteen patients were enrolled ; of these , 43 ( 74.6 % ) patients progressed in arm A and 44 ( 82.4 % ) in arm B. Median progression-free survival was 4.3 months ( 95 % CI : 2.7 - 6.5 ) and 4.5 months ( 95 % CI : 2.5 - 5.2 ) , respectively ( HR=0.92 ; 95 % CI : 0.62 - 1.35 ) . Median overall survival was 7.5 ( 95 % CI : 5.6 - 9.7 ) and 8.3 months ( 95 % CI : 6.2 - 8.7 ) , respectively ( HR=0.95 ; 95 % CI : 0.62 - 1.48 ) . Response rates were 3.4 % in arm A and 3.6 % in arm B. CONCLUSIONS Sorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients , and therefore should not be assessed in phase III trials PURPOSE Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies . Pre clinical and early clinical evidence has supported targeting the epidermal growth factor receptor ( EGFR ) signaling pathway in patients with pancreas cancer . This trial was conducted to evaluate the contribution of an EGFR-targeted agent to st and ard gemcitabine therapy . Cetuximab is a monoclonal antibody against the lig and -binding domain of the receptor . PATIENTS AND METHODS Patients with unresectable locally advanced or metastatic pancreatic adenocarcinoma were r and omly assigned to receive gemcitabine alone or gemcitabine plus cetuximab . The primary end point was overall survival . Secondary end points included progression-free survival , time to treatment failure , objective response , and toxicity . RESULTS A total of 745 eligible patients were accrued . No significant difference was seen between the two arms of the study with respect to the median survival time ( 6.3 months for the gemcitabine plus cetuximab arm v 5.9 months for the gemcitabine alone arm ; hazard ratio = 1.06 ; 95 % CI , 0.91 to 1.23 ; P = .23 , one-sided ) . Objective responses and progression-free survival were similar in both arms of the study . Although time to treatment failure was longer in patients on gemcitabine plus cetuximab ( P = .006 ) , the difference in length of treatment was only 2 weeks longer in the combination arm . Among patients who were studied for tumoral EGFR expression , 90 % were positive , with no treatment benefit detected in this patient subset . CONCLUSION In patients with advanced pancreas cancer , the anti-EGFR monoclonal antibody cetuximab did not improve the outcome compared with patients treated with gemcitabine alone . Alternate targets other than EGFR should be evaluated for new drug development BACKGROUND Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways . A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer ( APC ) patients . The BAYPAN study was a multicentric , placebo-controlled , double-blind , r and omized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC . PATIENTS AND METHODS The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma , no prior therapy for advanced disease and a performance status of zero to two . The primary end point was progression-free survival ( PFS ) . The patients received gemcitabine 1000 mg/m(2 ) i.v . , weekly seven times followed by 1 rest week , then weekly three times every 4 weeks plus sorafenib 200 mg or placebo , two tablets p.o . , twice daily continuously . RESULTS Between December 2006 and September 2009 , 104 patients were enrolled on the study ( 52 pts in each arm ) and 102 patients were treated . The median and the 6-month PFS were 5.7 months and 48 % for gemcitabine/placebo and 3.8 months and 33 % for gemcitabine/sorafenib ( P = 0.902 , stratified log-rank test ) , respectively . The median overall survivals were 9.2 and 8 months , respectively ( P = 0.231 , log-rank test ) . The overall response rates were similar ( 19 and 23 % , respectively ) . CONCLUSION The addition of sorafenib to gemcitabine does not improve PFS in APC patients Objective Little progress has been made in the treatment of pancreatic cancer ( PC ) . This study evaluated the clinical activity of gemcitabine , oxaliplatin , and cetuximab ( GOC ) in patients with locally advanced or metastatic PC . Methods The study primary endpoint was progression-free survival ( PFS ) . Eligible , chemotherapy-naive PC patients were treated with gemcitabine ( 1000 mg/m2 over 100 min ) on day 1 , oxaliplatin ( 100 mg/m2 ) on day 2 , every 2 weeks , and weekly cetuximab , ( loading dose of 400 mg/m2 on cycle 1 day 1 and 250 mg/m2 thereafter ) . It was expected that GOC treatment would extend the median PFS from 5.8 to 7.54 months , a relative increase of 30 % , compared with gemcitabine and oxaliplatin ( historical control ) . Results A total of 41 evaluable patients were enrolled . The overall response rate was 24 % . Median PFS time was 6.9 months and median overall survival ( OS ) was 11.3 months . Patients with locally advanced disease had longer median PFS ( 12.4 vs. 4.7 mo ) and OS ( 15.7 vs. 6.4 mo ) compared with patients with metastatic disease . The most common grade 3 to 4 toxicities included neutropenia ( 32 % ) , infection ( with normal or grade 1 to 2 neutropenia , in 24 % ) , neuropathy ( 17 % ) , fatigue ( 15 % ) , and rash ( 7 % ) . Five patients ( 12 % ) discontinued study treatment without evidence of progression . Rash was not a significant prognostic factor affecting PFS or OS . Conclusions GOC is a feasible combination with an acceptable toxicity profile . However , GOC did not significantly extend PFS in the overall patient population to consider it for further development BACKGROUND Pancreatic ductal adenocarcinoma ( PDAC ) is one of the most common malignant tumours and is still associated with a poor prognosis in advanced disease . To improve the st and ard therapy with gemcitabine , we initiated a prospect i ve r and omised phase-II trial with gemcitabine ( GEM ) versus gemcitabine plus sunitinib ( SUNGEM ) based on data of in vitro trials and phase-I data for the combination treatment . The rational of adding sunitinib was its putative antiangiogenic mechanism of action . METHODS A total of 106 eligible patients with locally advanced , unresectable or metastatic PDAC without previous system therapy were r and omised to receive GEM at a dosage of 1.000mg/m(2 ) d1 , 8 , 15 q28 versus a combination of SUNGEM at a dosage of GEM 1.000mg/m(2 ) d1 + 8 and sunitinib 50 mg p.o . d1 - 14 , q21d . The primary end-point was progression free survival ( PFS ) , secondary end-points were overall survival ( OS ) , toxicity and overall response rate ( ORR ) . RESULTS The confirmatory analysis of PFS was based on the intend-to-treat ( ITT ) population ( N=106 ) . The median PFS was 13.3 weeks ( 95 % confidence interval ( 95%-CI ) : 10.4 - 18.1 weeks ) for GEM and 11.6 weeks for SUNGEM ( 95%-CI : 7.0 - 18.0 weeks ; p=0.78 one-sided log-rank ) . The ORR was 6.1 % ( 95%-CI : 0.7 - 20.2 % ) for GEM and for 7.1 % ( 95%-CI : 0.9 - 23.5 % ) for SUNGEM ( p=0.87 ) . The median time to progression ( TTP ) was 14.0 weeks ( 95%-CI : 12.4 - 22.3 weeks ) for GEM and 18.0 weeks ( 95%-CI : 11.3 - 19.3 weeks ) for SUNGEM ( p=0.60 ; two-sided log-rank ) . The median OS was 36.7 weeks ( 95%-CI : 20.6 - 49.0 weeks ) for the GEM arm and 30.4 weeks ( 95%-CI : 18.1 - 37.6 weeks ) for the SUNGEM ( p=0.78 , one-sided log-rank ) . In regard to toxicities , suspected SAEs were reported in 53.7 % in the GEM arm and 71.2 % in the SUNGEM arm . Grade 3 and 4 neutropenia was statistically significantly higher in the SUNGEM arm with 48.1 % versus 27.8 % in the GEM arm ( p=0.045 , two sided log-rank ) . CONCLUSIONS The combination SUNGEM was not sufficient superior in locally advanced or metastatic PDAC compared to GEM alone in regard to efficacy but was associated with more toxicity PURPOSE Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996 . Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 ( HER1/EGFR ) and this is associated with a worse prognosis . We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable , locally advanced , or metastatic pancreatic cancer . PATIENTS AND METHODS Patients were r and omly assigned 1:1 to receive st and ard gemcitabine plus erlotinib ( 100 or 150 mg/d orally ) or gemcitabine plus placebo in a double-blind , international phase III trial . The primary end point was overall survival . RESULTS A total of 569 patients were r and omly assigned . Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio ( HR ) of 0.82 ( 95 % CI , 0.69 to 0.99 ; P = .038 , adjusted for stratification factors ; median 6.24 months v 5.91 months ) . One-year survival was also greater with erlotinib plus gemcitabine ( 23 % v 17 % ; P = .023 ) . Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 ( 95 % CI , 0.64 to 0.92 ; P = .004 ) . Objective response rates were not significantly different between the arms , although more patients on erlotinib had disease stabilization . There was a higher incidence of some adverse events with erlotinib plus gemcitabine , but most were grade 1 or 2 . CONCLUSION To our knowledge , this r and omized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine . The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d Objective We retrospectively compared the efficacy and toxicity of gemcitabine combination with capecitabine or erlotinib in unresectable pancreatic cancer to know whether the combination with cytotoxic and target agent has more benefit comparing to combination of cytotoxic agents . Methods Fifty-three patients with unresectable pancreatic cancer , treated with gemcitabine and capecitabine ( GC ) or gemcitabine and erlotinib ( GE ) as first line between October 2006 and July 2010 , were review ed . In GC group , patients were treated with gemcitabine 1,000 mg/m2 on days 1 , 8 , and capecitabine 1,300 mg/m2 bid was administered on days 1–14 , repeated every 21 days . In GE group , gemcitabine was given at 1,000 mg/m2 I.V for 30 min on days 1,8,15 , and erlotinib was taken orally at 100 mg through days 1–28 , repeated every 28 days . Results Response rate was similar , 23.5 % in GE and 21.1 % in GC , but GC had better disease control rate with 73.7 % than GE with 52.9 % . GC also showed longer PFS and OS ( 5.37 and 14.43 months ) than GE ( 2.63 and 6.23 months ) ( p = 0.032 for PFS and 0.002 for OS ) . In toxicity profiles , GC had more hematologic toxicities and GE had more non-hematologic toxicities . Conclusions The combination with cytotoxic agents seems to have better efficacy and clinical outcome than combination with cytotoxic agent and target agent . The new combination should be developed for the treatment for advanced pancreatic cancer Objective AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer ( PC ) : a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine . Methods 281 patients with PC were r and omly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib . In case of treatment failure ( eg , disease progression or toxicity ) , patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib . The primary study endpoint was time to treatment failure ( TTF ) after 1st- and 2nd-line therapy ( TTF2 ; non-inferiority design ) . KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the r and omised patients . Results Of the 274 eligible patients , 43 had locally advanced and 231 had metastatic disease ; 140 ( 51 % ) received 2nd-line chemotherapy . Median TTF2 was estimated with 4.2 months in both arms ; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine , respectively ( HR 1.02 , p=0.90 ) . TTF for 1st-line therapy ( TTF1 ) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib ( 3.2 vs 2.2 months ; HR 0.69 , p=0.0034 ) . Skin rash was associated with both TTF2 ( rash grade 0/1/2–4:2.9/4.3/6.7 months , p<0.0001 ) and survival ( 3.4/7.0/9.6 months , p<0.0001 ) . Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy . A KRAS wild-type status ( 52/173 patients , 30 % ) was associated with an improved overall survival ( HR 1.68 , p=0.005 ) . Conclusion Both treatment strategies are feasible and demonstrated comparable efficacy ; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib . Trial registration number This study was registered at Clinical Trials.gov , number NCT00440167 . Significance of this study What is already known on this subject ? Gemcitabine-based chemotherapy remains an international st and ard of care for patients with non-resectable , advanced pancreatic cancer ( PC ) . Anti-EGFR treatment with the tyrosine kinase inhibitor erlotinib , as well as chemotherapy intensification by application of the FOLFIRINOX regimen , both significantly improved overall survival in r and omised phase 3 trials . The optimal ( sequential ) regimen for the use of gemcitabine , erlotinib and the oral fluoropyrimidine capecitabine remains unclear in advanced PC . Molecular predictors for the efficacy of anti-EGFR treatments in PC have not been defined up to now . What are the new findings ? The sequential use of gemcitabine , erlotinib and capecitabine is safe and equally effective in PC ; gemcitabine appears to be more effective in 1st- and 2nd-line therapy than capecitabine and therefore remains the preferred combination partner for erlotinib . Skin rash is strongly correlated with efficacy outcome measures in PC patients treated with erlotinib . KRAS wild-type status appears to be associated with improved overall survival in patients treated with erlotinib in this AIO study . Significance of this study How might it impact on clinical practice in the foreseeable future ? The benefit of adding erlotinib to chemotherapy is restricted to patients that experience skin rash during treatment ; non-rash patients are characterised by a very poor outcome and need to be offered novel treatment strategies . Second-line salvage chemotherapy is effective and safe in selected PC patients . KRAS could serve as the first biomarker for improved survival in erlotinib-treated patients ; the predictive value of KRAS for erlotinib efficacy remains to be defined prospect ively

The EORTC-QLQ-C30 and MY24 have undergone the most comprehensive psychometric validation . Reliable , valid and responsive tools exist for this purpose , but may miss issues important to patients .

INTRODUCTION Treatment advances in multiple myeloma have increased expected survival from months to years for some patients .

When a r and omized trial ( NMSG 4/90 ) comparing treatment with melphalan/prednisone to melphalan/prednisone + interferon α‐2b in newly diagnosed multiple myeloma was inititated in 1990 , a quality ‐of‐life assessment was integrated into the study . We used the question naire ( QLQ‐C30 ) developed by the European Organization of Research and Treatment of Cancer ( EORTC ) Study Group on Quality of Life . The QLQ‐C30 incorporates five functional scales , three symptom scales , a global health and quality ‐of‐life scale and some single symptom measures . The question naire was completed prior to treatment and after 1 , 6 , 12 , 24 , 36 and 48 months . 524 ( 90.2 % ) of 581 patients enrolled in the NMSG 4/90 completed the first question naire , and 484 ( 83.3 % ) completed all question naires given to them . All but one of the scales met the minimum criteria of reliability ( Cronbach ’s alpha ≥0.70 ) . Validity was shown by ( 1 ) the ability of the scales to discriminate clearly between patients differing in clinical status as defined by pre‐treatment W.H.O. performance index and Durie & Salmon stage , and ( 2 ) the sensitivity to changes in objective disease status ( response and relapse ) . This is the first report of the measurement of health‐related quality of life in a prospect i ve clinical trial in multiple myeloma . The results demonstrate that the QLQ‐C30 is a reliable and valid instrument for the measurement of quality of life in these patients . The data will be used for a cost – utility analysis of the results of the NMSG 4/90 trial Measurement of health-related quality of life was integrated into a r and omized trial ( NMSG 4/90 ) comparing melphalan/prednisone to melphalan/prednisone + interferon alpha-2b in newly diagnosed multiple myeloma . One of the aims of the study was to assess the prognostic significance of quality -of-life scores , using the EORTC QLQ-C30 question naire . Univariate analysis showed a highly significant association with survival from the start of therapy for physical functioning as well as role and cognitive functioning , global quality of life , fatigue and pain . In multivariate analysis , physical functioning and W.H.O. performance status were independent prognostic factors ( P values = 0.001 for both ) when analysed in a Cox regression model with the somatic variables beta-2 microglobulin , skeletal disease and age . The best prediction for survival from the start of therapy was obtained by combining the beta-2 microglobulin and physical functioning scores in a variable consisting of three risk factor levels with an estimated median survival of 17 , 29 and 49 months , respectively . At a 12 months l and mark analysis , the relative risk for patients with physical functioning score 0 - 20 v 80 - 100 was 5.63 ( 99 % CI 2.76 - 11.49 ) , whereas the relative risk for patients without an objective response to chemotherapy compared to those with at least a minor response was 2.32 ( 99 % CI 1.44 - 3.74 ) . Quality -of-life assessment may be an independent and valuable addition to the known prognostic factors in multiple myeloma Patients who undergo hematopoietic SCT ( HSCT ) often experience physical and psychological problems , even long after treatment has been completed . This study was performed to evaluate the effects of a 12-week outpatient physical exercise ( PE ) program , incorporating aerobic and strength exercises , as compared with a usual care control condition on patients ’ physical performance and psychosocial well-being . Patients who had completed HSCT up to 6 months earlier were r and omly assigned to a supervised PE program ( n=64 ) or a usual care control group ( n=67 ) . Primary outcomes were quantified physical performance and self-reported physical functioning . Secondary outcomes were body composition measurement , quantified walking activity and patient-reported outcomes ( physical activity , fatigue and health-related quality of life ) . Assessment s were at baseline , immediately after program completion and at 3-month follow-up . Significant intervention effects were observed at both posttreatment and follow-up on physical performance measures . No other outcomes yielded statistically significant group differences . PE should be considered in the management of HSCT recipients to improve physical performance after discharge from the hospital . Further research is needed to determine how the program can be enhanced so that improved physical performance also translates into improved physical and psychosocial functioning in daily life Few studies have evaluated long-term health-related quality of life ( HRQL ) in patients during auto-SCT . This prospect i ve study examined HRQL in 96 eligible patients before , during and up to 3 years after auto-SCT . The aim of the study was to make a comprehensive assessment of the frequency and severity of different symptoms in patients undergoing auto-SCT . The European Organization for Treatment and Research of Cancer Quality of Life Question naire ( EORTC QLQ C-30 ) was administered 13 times . The second week during treatment was the period when patients had the lowest HRQL regarding both total quality of life and function and symptom scales . The patients recovered quickly and just two months after transplantation the baseline values were restored . Three years after transplantation most of the items in the question naire had stabilized , except role function and dyspnea , which had improved . There were significant differences between multiple myeloma ( MM ) and lymphoma patients ’ physical function , quality of life , fatigue and pain during week 2 . At the 3-year follow-up , lymphoma patients indicated a better HRQL than MM patients . The quick recovery of patients after transplantation suggests that treatment is well tolerated ; however , the supportive care could be improved at week 2 , especially for the lymphoma patients AIM The aim of this study was to compare the effect of two methods of rehabilitation after stem cell transplantation on health and quality of life . BACKGROUND Stem cell transplantation is routinely used in the treatment of haematological malignancy . However , it is an intensive treatment often associated with deterioration in wellbeing and the need for prolonged recovery . METHODS During a 14-month data collection period ( August 2005 to October 2006 ) , patients who had had a stem cell transplant ( n = 58 ) were r and omly allocated to either a healthcare professional-led rehabilitation programme or a self-managed rehabilitation programme . The primary outcome measure , physical functioning as measured by the 36-item Short Form Health Survey , was recorded at baseline and 6 months after r and omization . Secondary health and quality of life measures included the seven other dimensions of the 36-item Short Form Health Survey , General Health Question naire , Graham and Longman Quality of Life Scale and a Shuttle Walk Test . FINDINGS There was no difference in change in Short Form 36 physical functioning scores between the two groups at follow-up ( mean difference 0.19 points , 95 % confidence interval 10.77 - 11.16 ) . No evidence of a difference between the two modes of rehabilitation was observed for any of the trial outcomes . CONCLUSION One approach for providing a flexible service may be for staff and individual patients to work together , selecting from a series of specified options a programme with the appropriate content and duration to meet that individual 's needs PURPOSE To investigate the effect of recombinant human erythropoietin ( epoetin beta ) on anemia , transfusion need , and quality of life ( QOL ) in severely anemic patients with low- grade non-Hodgkin 's lymphoma ( NHL ) , chronic lymphocytic leukemia ( CLL ) , or multiple myeloma ( MM ) . PATIENTS AND METHODS Transfusion-dependent patients with NHL ( n = 106 ) , CLL ( n = 126 ) , or MM ( n = 117 ) and a low serum erythropoietin concentration were r and omized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks . Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival ( hemoglobin [ Hb ] > 8.5 g/dL ) between weeks 5 to 16 . Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need . QOL was assessed by the Functional Assessment of Cancer Therapy scale . RESULTS Transfusion-free ( P = .0012 ) survival and transfusion- and severe anemia-free survival ( P = .0001 ) were significantly greater in the epoetin beta group versus placebo ( Wald chi(2 ) test ) , giving a relative risk reduction of 43 % and 51 % , respectively . The response rate was 67 % and 27 % in the epoetin beta versus the placebo group , respectively ( P < .0001 ) . After 12 and 16 weeks of treatment , QOL significantly improved in the epoetin beta group compared with placebo ( P < .05 ) ; this improvement correlated with an increase in Hb concentration ( > or = 2 g/dL ) . A target Hb that could be generally recommended could not be identified . CONCLUSION Many severely anemic and transfusion-dependent patients with advanced MM , NHL , and CLL and a low performance status benefited from epoetin therapy , with elimination of severe anemia and transfusion need , and improvement in QOL Health‐related quality of life ( HRQL ) was prospect ively measured during the phase III APEX trial of bortezomib versus dexamethasone in relapsed multiple myeloma patients . The European Organisation for Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire – Core ( QLQ‐C30 ) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity ( NTX ) side‐effects question naires were administered at baseline and every 6 weeks up to 42 weeks . Patients receiving bortezomib ( 1·3 mg/m2 , days 1 , 4 , 8 and 11 for eight 3‐week cycles , then days 1 , 8 , 15 and 22 for three 5‐week cycles ; n = 296 ) demonstrated significantly better mean Global Health Status over the study versus patients receiving dexamethasone ( 40 mg/d , days 1–4 , 9–12 , and 17–20 for four 5‐week cycles , then days 1–4 only for five 4‐week cycles ; n = 302 ) , plus significantly better physical health , role , cognitive , and emotional functioning scores , lower dyspnoea and sleep symptom scores , and better NTX question naire score , using multiple imputation to account for missing data . Results were similar using available‐ data analyses . Sensitivity analyses suggested that improved HRQL with bortezomib is at least partially explained by improved survival . These results show that bortezomib was associated with significantly better multidimensional HRQL compared with dexamethasone , consistent with the better clinical outcomes seen with bortezomib OBJECTIVES Without clear guidelines , clinicians and health care providers are often uncertain how to interpret ( quality of life ) QOL scores . To facilitate the interpretation , QOL scores of multiple myeloma patients at diagnosis were compared with the scores of a reference population , and the clinical significance of QOL score differences and of changes in scores over time was assessed . METHODS Data from two prospect i ve Nordic Myeloma Study Group trials ( 221 patients < 60 yr treated with high dose chemotherapy , and 203 patients > 60 yr treated with melphalan and prednisone ) were analysed . The EORTC QLQ-C30 question naire was used . The results were compared with the scores of an age- and gender-adjusted Norwegian reference population ( n = 3000 ) , using a regressional approach . The magnitude of the observed differences and of score changes during follow-up was estimated as effect size [ score difference ( SD ) ] and according to a subjective rating system as small , moderate or large . RESULTS At diagnosis , the most distressing problems were pain and fatigue , reduced physical functioning , limitations in role functioning and reduced overall QOL . These differences from the reference population were statistically significant ( P < 0.001 ) , and large or moderate according to the rating systems . After the start of treatment , small to moderate improvement in mean QOL scores were observed for most domains . CONCLUSION Comparison with a reference population eases the interpretation of QOL scores and prevents overestimation of symptoms and underestimation of subjective treatment response . The agreement between the two methods to evaluate the meaning of differences and changes in QOL scores was good Purpose To report the experience of using the SEIQoL-DW for the measurement of quality of life with patients with advanced COPD and consider its feasibility , acceptability and appropriateness for a Phase III r and omised controlled trial ( RCT ) . Methods The SEIQoL-DW was administered according to its instructions within a Phase II RCT 3–5 times per patient , across 13 patients and the process audio-recorded . Quantitative and qualitative criteria were used to assess feasibility , acceptability and appropriateness . Qualitative analysis of the transcripts and fieldwork notes was conducted using Framework Analysis . Results The SEIQoL-DW steps ( of identifying five quality of life cues , rating their functioning and importance ) were completed at 48/51 interviews . However , some respondents were overwhelmed by the scripted introduction , experienced difficulty with cue identification , and focused only on certain types of cues ( Step 1 ) ; some had difficulty interpreting and rating the concept of Step 2 ; and some had difficulty interpreting ‘ importance ’ and manipulating the SEIQoL-DW disc ( Step 3 ) . Conclusions Patients with advanced COPD were able to complete the SEIQoL-DW but analysis of its administration identified practical and conceptual concerns which question the validity of the results obtained . Suggestions for the development of the SEIQoL-DW and future feasibility studies are given Longitudinal data of neurocognitive functions and quality of life ( QOL ) were obtained for a cohort of 25 patients followed before transplant and through the first year after haematopoietic stem cell transplantation ( SCT ) . A battery of neuropsychological tests and two self-report question naires were used to assess neurocognitive functions , QOL and psychological functioning . In comparison to normative data , up to one-fourth of the patients experienced impaired functioning on several cognitive domains before SCT . R and om regression modelling revealed a slight improvement in the mean group scores of memory tasks over time , especially for younger patients . Impairment in neurocognitive functions was positively related to depression and anger at baseline , and to the emotional functioning scale at follow-up . These preliminary results emphasize the significance of a pre-treatment assessment and the need of a large baseline sample in future longitudinal studies to overcome the expected dropout rate of more than 50 % OBJECTIVES To investigate the subjective well-being of patients with newly diagnosed multiple myeloma who were treated in a t and em transplantation programme . METHODS Fifty-one patients participated in the prospect i ve , longitudinal question naire study . The EORTC QLQ-C30 and the EuroQol-5D were administered 2 wk after completion of vincristine , adriamycin and dexamethason/vincristine , adriamycin and methyl prednison ( VAD/VAMP ) chemotherapy , both at hospital discharge after treatment with high-dose melphalan ( HDM ) and 1 month after this hospital discharge , at hospital admission , at the day of hospital discharge for peripheral stem cell transplantation ( PSCT ) and at 6 and 12 months following discharge after PSCT . RESULTS Overall , patients ' functioning improved during treatment and follow-up , with significant decreases shortly following PSCT . Shortly after HDM and PSCT , patients reported a considerable increase in levels of soreness in the mouth ( + 26/+36 points on a scale ranging form 0 to 100 ; P < 0.01 ) , change of taste ( + 23/+21 points ; P < 0.05/NS ) , nausea/vomiting ( + 26/+27 points ; P < 0.01/ < 0.05 ) , appetite loss ( + 40/+43 points ; P < 0.001 ) and diarrhoea ( + 25/+36 points ; P < 0.01 ) . However , none of these symptoms persisted during follow-up . CONCLUSION The intensive treatment programme was subjectively being well tolerated by the majority of patients . The duration of declined quality of life after administration of HDM seemed to be short . The duration of subjective recovery after PSCT remained uncertain , but in any case was present at the 6 month follow-up . Together with the rather good results in survival , the evaluation of quality of life invites further exploration of double transplantations in multiple myeloma BACKGROUND Compared with placebo , prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma . However , because of toxicity associated with long-term bisphosphonate treatment , establishing the lowest effective dose is important . This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma . METHODS This double-blind , r and omised , phase 3 trial was undertaken at 37 clinics in Denmark , Norway , and Sweden . Patients with multiple myeloma who were starting antimyeloma treatment were r and omly assigned in a 1:1 ratio to receive one of two doses of pamidronate ( 30 mg or 90 mg ) given by intravenous infusion once a month for at least 3 years . R and omisation was done by use of a central , computerised minimisation system . Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer ( EORTC ) QLQ-C30 question naire ( scale 0 - 100 ) . All patients who returned question naires at 12 months and were still on study treatment were included in the analysis of the primary endpoint . This study is registered with Clinical Trials.gov , number NCT00376883 . FINDINGS From January , 2001 , until August , 2005 , 504 patients were r and omly assigned to pamidronate 30 mg or 90 mg ( 252 in each group ) . 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis . Mean physical function at 12 months was 66 points ( 95 % CI 62·9 - 70·0 ) in the 90 mg group and 68 points ( 64·6 - 71·4 ) in the 30 mg group ( 95 % CI of difference -6·6 to 3·3 ; p=0·52 ) . Median time to first skeletal-related event in patients who had such an event was 9·2 months ( 8·1 - 10·7 ) in the 90 mg group and 10·2 months ( 7·3 - 14·0 ) in the 30 mg group ( p=0·63 ) . In a retrospective analysis , eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group . INTERPRETATION Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma . FUNDING Nordic Cancer Union and Novartis Healthcare OBJECTIVE The aim was to prospect ively measure quality of life in patients with malignant blood disorders following stem cell transplantation ( SCT ) using an individualized and a st and ardized measure . METHODS Twenty-two consecutive patients were assessed before and one year following SCT , using a generic and disease-related version of the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting ( SEIQoL-DW ) and the EORTC QLQ-C30 . Results of the QLQ-C30 were compared with Swedish norm values . RESULTS A majority of the patients reported concerns related to health before as well as one year after SCT , recorded by both instruments . Mean scores produced by the SEIQoL-DW , and four scales of the EORTC QLQ-C30 , showed a change over time , indicating improved quality of life one year after SCT . In comparison with Swedish norm values for the EORTC QLQ-C30 , SCT recipients reported a worse functioning . CONCLUSIONS In addition to well-known disease and treatment-related problems , areas not typically included in st and ardized instruments were nominated in the disease-related SEIQoL-DW . Such areas included positive aspects , e.g. a changed view of life and oneself . The results support the use of the generic and disease-related SEIQoL-DW to achieve a comprehensive picture of patient 's clinical situation under treatment or when recovering from illness Background Precisely defining the different applications of patient-reported outcome measures ( PROs ) in clinical practice can be difficult . This is because the intervention is complex and varies amongst different studies in terms of the type of PRO used , how the PRO is fed back , and to whom it is fed back . Methods A theory-driven approach is used to describe six different applications of PROs in clinical practice . The evidence for the impact of these applications on the process and outcomes of care are summarised . Possible explanations for the limited impact of PROs on patient management are then discussed and directions for future research are highlighted . Results The applications of PROs in clinical practice include screening tools , monitoring tools , as a method of promoting patient-centred care , as a decision aid , as a method of facilitating communication amongst multidisciplinary teams ( MDTs ) , and as a means of monitoring the quality of patient care . Evidence from r and omised controlled trials suggests that the use of PROs in clinical practice is valuable in improving the discussion and detection of HRQoL problems but has less of an impact on how clinicians manage patient problems or on subsequent patient outcomes . Many of the reasons for this may lie in the ways in which PROs fit ( or do not fit ) into the routine ways in which patients and clinicians communicate with each other , how clinicians make decisions , and how healthcare as a whole is organised . Conclusions Future research needs to identify ways in with PROs can be better incorporated into the routine care of patients by combining qualitative and quantitative methods and adopting appropriate trial design Health-related quality of life ( HRQOL ) in leukemia and lymphoma patients treated with high-dose chemotherapy followed by allogeneic ( SCT ) and autologous ( ASCT ) stem cell transplantation or receiving combination chemotherapy ( CT ) was prospect ively assessed by the EORTC QLQ-C30 and compared with reference data from a general population sample . One year after transplant , the SCT group had functional scores which were close to population values except for lower social ( P < 0.0001 ) and role function ( P = 0.0004 ) . More symptoms and problems were reported , especially appetite loss ( P = 0.001 ) and financial difficulties ( P = 0.0001 ) . The ASCT patients reported a less than optimal HRQOL relative to the population 1 year post transplant . Cognitive , physical , role , and social function , dyspnoea , financial difficulties and global quality of life were most impaired ( P < 0.001 ) . in the ct group , physical , role and social function , dyspnoea and financial difficulties were impaired 1 year after start of chemotherapy , compared with the general population ( P < 0.001 ) . the eortc qlq-c30 was supplemented by a high-dose chemotherapy module , the hdc-19 , at the 1-year assessment , but no consistent differences were found across groups . fifteen to 34 % of the patients expressed fears of relapse and worries about future health , while 24–30 % indicated no participation in sexual activities The aim of this study was to evaluate to what extent the quality of life ( QOL ) of young patients with chronic myelocytic leukemia ( CML ) was affected by treatment with interferon ( IF ) and intensive chemotherapy . In a main study performed by The Swedish CML Group , aim ing at reduction of the malignant pH+ cell clone by treatment with hydroxyurea and IF followed by ABMT , QOL was evaluated with VAS scales and the Life Ingredient Profile in 44 % of the patients . The intensive treatment did not lead to intolerable suffering or protracted reduction in QOL . However , 80 % of the patients were on sick leave during the first year of treatment PURPOSE To compare the effects of pegylated interferon-alpha2b ( P-IFN ) and interferon-alpha2b ( IFN ) on quality of life ( QoL ) and toxicity in patients with multiple myeloma maintained on a steady dose of IFN . PATIENTS AND METHODS Consenting , eligible myeloma patients on IFN maintenance therapy for at least 6 weeks were r and omly ( 1:1 ) allocated to receive P-IFN for 3 months followed by IFN for 3 months , or to continue with IFN for 3 months followed by P-IFN for 3 months ( cross-over design ) . Patients were assessed for toxicity and QoL. Dose of P-IFN was equivalent to IFN . RESULTS The study enrolled 60 patients . At enrollment , 35 patients were in complete remission , 20 in partial remission and 5 were minimal responders . P-IFN was associated with significantly better global QoL score ( mean difference 8.4 ; P = 0.0002 ) . There was a significant improvement in functional scales -- physical ( P = 0.03 ) , emotional ( P = 0.04 ) , social ( P = 0.0008 ) with P-IFN . Fatigue ( P = 0.0003 ) , pain ( P = 0.02 ) and appetite loss ( P = 0.003 ) symptom scales were less in patients while on P-IFN . There were no statistically significant differences between treatment arms in QoL as measured by QLQ-MY24 . CONCLUSION These data suggest that patients on P-IFN have a better QoL. Dose escalation studies are warranted to investigate potential impact on survival In a population -based study , the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age ( risk ratio : 1.62 ; confidence interval [ CI ] 1.22–2.15 ; p=0.001 ) . A study of health-related quality of life ( HRQoL ) was integrated in the trial , using the EORTC QLQ-C30 question naire . Of the 274 patients receiving intensive therapy 221 ( 81 % ) were compared to 113 ( 94 % ) of 120 patients receiving conventional melphalan-prednisone treatment . Prior to treatment , there were no statistically significant differences in any HRQoL score between the two groups . One month after the start of induction chemotherapy , the patients on intensive treatment had more sleep disturbance than the control patients . At 6 mo , corresponding to a mean of 52 d after high-dose melphalan , the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss . At 12 and 24 mo , the HRQoL was similar to that of the control patients . At 36 mo , there was a trend toward less fatigue , pain , nausea , and appetite loss in the intensive-treatment group . Thus , the 18 mo of prolonged survival seem to be associated with a good health-related quality of life . Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase , this treatment modality must be regarded as an important step forward in the care of multiple myeloma PURPOSE / OBJECTIVES To examine the patterns of fatigue , physical activity , health status , and quality of life before and after high-dose chemotherapy and hematopoietic stem cell transplantation ( HSCT ) and to examine the feasibility of obtaining real-time fatigue and physical activity data . DESIGN Prospect i ve , repeated measures . SETTING Two midwestern academic medical centers . SAMPLE Convenience sample of autologous or allogeneic patients undergoing HSCT ( N = 20 baseline , N = 17 post-transplant ) . METHODS Subjects were assessed over a five-day period before and after HSCT for a total of 10 days . Subjects rated fatigue intensity three times daily and wore a wrist actigraph to measure physical activity . At the end of both five-day periods , subjects completed measures of perceived health status ( European Organization for Research and Treatment of Cancer Quality of Life Question naire-Core 30 ) and life satisfaction Quality of Life Index ) . MAIN RESEARCH VARIABLES Fatigue , physical activity , perceived health status , and quality of life . FINDINGS Study results indicate that fatigue significantly increased and physical activity decreased following high-dose chemotherapy and HSCT . The decline coincided with diminished physical , emotional , role , and cognitive functioning . The symptoms that patients experienced ( i.e. , fatigue , pain , nausea and vomiting , sleep disturbances , appetite loss , and diarrhea ) increased during the acute post-transplant period . No significant changes in life satisfaction were found . CONCLUSIONS The study findings suggest that patients receiving high-dose chemotherapy followed by HSCT experience increased fatigue , reduced physical activity , diminished functioning , and poorer quality of life immediately after transplant . Findings demonstrate that real-time fatigue and physical activity data can feasibly be collected in acutely ill patients . IMPLICATION S FOR NURSING Patients undergoing HSCT require considerable supportive nursing care immediately following transplant . Clinicians and research ers need to strive for effective symptom management to improve the likelihood of successful outcomes PURPOSE Bortezomib , a boronic acid dipeptide , has been recently introduced as a new approach to treating multiple myeloma ( MM ) . The goal of this work was to evaluate the added value of patient-reported outcomes ( PRO ) in the interpretation of bortezomib clinical trial outcomes . PATIENTS AND METHODS Two hundred two patients with relapsed , refractory MM were treated with bortezomib as part of the SUMMIT ( Study of Uncontrolled Multiple Myeloma Managed with Proteasome Inhibition Therapy ) study . Patients were administered the following four PRO measures at several time points : the European Organisation for Research and Treatment of Cancer ( EORTC ) core Quality of Life Question naire ( QLQ-C30 ) and the myeloma-specific module ( QLQ-MY24 ) , the Functional Assessment of Chronic Illness Therapy ( FACIT ) Fatigue scale , and the Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group ( GOG ) Neurotoxicity ( Ntx ) scale . Minimal important difference ( MID ) thresholds were used to define patients as improved , stable , or worsened . A survival analysis was conducted to assess the predictive power of PRO data . RESULTS For the total population , there was a positive change between baseline and best end point . Consistent with the clinical responses , change in PRO scores showed statistically significant differences between response groups with PRO improvement in patients with complete response ( CR ) or partial response ( PR ) , mostly stable scores in patients with minor response or no change , and deterioration in most scores for patients with progressive disease . Change in scores for neuropathy-related symptoms was reasonably stable . In contrast , fatigue scores significantly improved for patients with CR or PR . When various MID thresholds were applied , the proportion of improved patients exceeded 35 % for several domains within all change group definitions . Moreover , survival analysis results demonstrated the additional prognostic information PRO data can provide to supplement clinical data . CONCLUSION This study demonstrated the complementary value for PRO assessment s in further interpreting clinical response , the impact of adverse effects , and patient prognosis in clinical trials BACKGROUND & AIMS Multiple myeloma ( MM ) ranks among the most frequent blood cancers in adults . Optimal treatment consists of high-dose chemotherapy and autologous stem cell transplantation . Health-related quality of life ( HRQoL ) is reduced before , during , and after therapy . Several HRQoL items are associated with nutritional health , e.g. , nausea/vomiting , appetite loss and fatigue . It is unknown whether nutritional status in MM is affected by treatment . Hence we assessed nutritional status before , during and ( 1/2 ) year after treatment-start . METHODS We applied anthropometry ( height , weight , h and -grip strength , triceps skinfold ) and plasma concentrations of biomarkers to assess nutritional status . HRQoL was determined with the EORTC QLQ-C30 question naire . RESULTS The anthropometrical parameters all decreased ( p<0.05 ) during treatment , but were restored at the end of the observation period . Albumin and the fat-soluble vitamins D and E followed a similar pattern , whereas transferrin and vitamin A were unchanged ( p>0.05 ) . Interestingly , markers of thyroid function declined and remained low ( p<0.05 ) even 6 months after start of therapy . Nutrition-associated symptoms used as markers of HRQoL worsened during therapy , but returned to pre-therapy levels . CONCLUSION Intensive therapy in MM is associated with a decline in both nutritional status and health-related quality of life High-dose melphalan and autologous hematopoietic stem cell transplantation ( HSCT ) is a st and ard treatment for myeloma , but very little is known about the psychosocial or quality -of-life difficulties that these patients encounter during treatment . Data regarding older patients is particularly scarce . Using a prospect i ve design , this investigation evaluated 94 patients at stem cell collection and again after high-dose therapy and transplantation . Outcomes included quality -of-life ( FACT-BMT ) and psychosocial adjustment ( ie , Brief Symptom Inventory , Impact of Events Scale , and Satisfaction with Life Scale ) . Findings were compared with age- and sex-adjusted population norms and with transplantation patient norms . At stem cell collection , physical deficits were common , with most patients scoring 1 st and ard deviation below population norms for physical well-being ( 70.2 % ) and functional well-being ( 57.5 % ) , and many reporting at least moderate fatigue ( 94.7 % ) and pain ( 39.4 % ) . Clinical ly meaningful levels of anxiety ( 39.4 % ) , depression ( 40.4 % ) , and cancer-related distress ( 37.0 % ) were evident in a notable proportion of patients . After transplantation , there was a worsening of transplant-related concerns ( P < .05 ) , depression ( P < .05 ) , and life-satisfaction ( P < .001 ) ; however , pain improved ( P < .01 ) , and social functioning was well preserved . Overall , the declines in functioning after transplantation were less pronounced than anticipated . Older patients were not more compromised than younger ones ; in multivariate analyses , they reported better overall quality of life ( P < .01 ) and less depression ( P < .05 ) before transplantation . Our findings emphasize the importance of early screening and intervention PURPOSE To examine the effects on process of care and patient well-being , of the regular collection and use of health-related quality -of-life ( HRQL ) data in oncology practice . PATIENTS AND METHODS In a prospect i ve study with repeated measures involving 28 oncologists , 286 cancer patients were r and omly assigned to either the intervention group ( regular completion of European Organization for Research and Treatment of Cancer-Core Quality of Life Question naire version 3.0 , and Hospital Anxiety and Depression Scale on touch-screen computers in clinic and feedback of results to physicians ) ; attention-control group ( completion of question naires , but no feedback ) ; or control group ( no HRQL measurement in clinic before encounters ) . Primary outcomes were patient HRQL over time , measured by the Functional Assessment of Cancer Therapy-General question naire , physician-patient communication , and clinical management , measured by content analysis of tape-recorded encounters . Analysis employed mixed-effects modeling and multiple regression . RESULTS Patients in the intervention and attention-control groups had better HRQL than the control group ( P = .006 and P = .01 , respectively ) , but the intervention and attention-control groups were not significantly different ( P = .80 ) . A positive effect on emotional well-being was associated with feedback of data ( P = .008 ) , but not with instrument completion ( P = .12 ) . A larger proportion of intervention patients showed clinical ly meaningful improvement in HRQL . More frequent discussion of chronic nonspecific symptoms ( P = .03 ) was found in the intervention group , without prolonging encounters . There was no detectable effect on patient management ( P = .60 ) . In the intervention patients , HRQL improvement was associated with explicit use of HRQL data ( P = .016 ) , discussion of pain , and role function ( P = .046 ) . CONCLUSION Routine assessment of cancer patients ' HRQL had an impact on physician-patient communication and result ed in benefits for some patients , who had better HRQL and emotional functioning