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Our systematic review confirms that international recommendations on exercise for knee osteoarthritis also apply to subjects aged 70 - 80 years .

BACKGROUND Rheumatologic and geriatric scholarly organisations recommendations for the management of hip and knee osteoarthritis , which emphasise the usefulness of non-pharmacological therapies , are not scaled according to patient 's age and physical condition . We conducted a systematic review of clinical trials on exercise and weight loss in hip and knee osteoarthritis in very old patients .

OBJECTIVE To evaluate the effect of aquatic exercise and education on fall risk factors in older adults with hip osteoarthritis ( OA ) . METHOD Seventy-nine adults , 65 years of age or older with hip OA and at least 1 fall risk factor , were r and omly assigned to 1 of 3 groups : aquatics and education ( AE ; aquatic exercise twice a wk with once-a-wk group education ) , aquatics only ( A ; 2 wk aquatic exercise ) and control ( C ; usual activity ) . Balance , falls efficacy , dual-task function , functional performance ( chair st and s ) , and walking performance were measured pre- and postintervention or control period . RESULTS There was a significant improvement in fall risk factors ( full-factorial MANCOVA , baseline values as covariates ; p = .038 ) ; AE improved in falls efficacy compared with C and in functional performance compared with A and C. CONCLUSION The combination of aquatic exercise and education was effective in improving fall risk factors in older adults with arthritis OBJECTIVE To examine effects of activity strategy training ( AST ) , a structured rehabilitation program taught by occupational therapists and design ed to teach adaptive strategies for symptom control and engagement in physical activity ( PA ) . METHODS A r and omized controlled pilot trial was conducted at 4 sites ( 3 senior housing facilities and 1 senior center ) in southeastern , lower Michigan . Fifty-four older adults with hip or knee osteoarthritis ( mean + /- SD age 75.3+/-7.1 years ) participated . At each site , older adults were r and omly assigned to 1 of 2 programs : exercise plus AST ( Ex + AST ) or exercise plus health education ( Ex + Ed ) . The programs involved 8 sessions over 4 weeks with 2 followup sessions over a 6-month period , and were conducted concurrently within each site . Pain , total PA and PA intensity ( measured objective ly by actigraphy and subjectively by the Community Healthy Activities Model Program for Seniors question naire ) , arthritis self-efficacy , and physical function were assessed at baseline and posttest . RESULTS At posttest , participants who received Ex + AST had significantly higher levels of objective peak PA ( P=0.02 ) compared with participants who received Ex + Ed . Although not statistically significant , participants in Ex + AST tended to have larger pain decreases , increased total objective and subjective PA , and increased physical function . No effects were found for arthritis self-efficacy . CONCLUSION Although participants were involved in identical exercise programs , participants who received AST tended to have larger increases in PA at posttest compared with participants who received health education . Future studies will be needed to examine larger sample s and long-term effects of AST OBJECTIVE The Arthritis , Diet , and Activity Promotion Trial ( ADAPT ) was a r and omized , single-blind clinical trial lasting 18 months that was design ed to determine whether long-term exercise and dietary weight loss are more effective , either separately or in combination , than usual care in improving physical function , pain , and mobility in older overweight and obese adults with knee osteoarthritis ( OA ) . METHODS Three hundred sixteen community-dwelling overweight and obese adults ages 60 years and older , with a body mass index of > or = 28 kg/m(2 ) , knee pain , radiographic evidence of knee OA , and self-reported physical disability , were r and omized into healthy lifestyle ( control ) , diet only , exercise only , and diet plus exercise groups . The primary outcome was self-reported physical function as measured with the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Secondary outcomes included weight loss , 6-minute walk distance , stair-climb time , WOMAC pain and stiffness scores , and joint space width . RESULTS Of the 316 r and omized participants , 252 ( 80 % ) completed the study . Adherence was as follows : for healthy lifestyle , 73 % ; for diet only , 72 % ; for exercise only , 60 % ; and for diet plus exercise , 64 % . In the diet plus exercise group , significant improvements in self-reported physical function ( P < 0.05 ) , 6-minute walk distance ( P < 0.05 ) , stair-climb time ( P < 0.05 ) , and knee pain ( P < 0.05 ) relative to the healthy lifestyle group were observed . In the exercise group , a significant improvement in the 6-minute walk distance ( P < 0.05 ) was observed . The diet-only group was not significantly different from the healthy lifestyle group for any of the functional or mobility measures . The weight-loss groups lost significantly ( P < 0.05 ) more body weight ( for diet , 4.9 % ; for diet plus exercise , 5.7 % ) than did the healthy lifestyle group ( 1.2 % ) . Finally , changes in joint space width were not different between the groups . CONCLUSION The combination of modest weight loss plus moderate exercise provides better overall improvements in self-reported measures of function and pain and in performance measures of mobility in older overweight and obese adults with knee OA compared with either intervention alone OBJECTIVE To evaluate the effects of st and ardized western acupuncture and physiotherapy on pain and functional ability in patients with severe osteoarthritic knee pain awaiting knee arthroplasty . METHODS Three-arm , assessor-blind , r and omized controlled trial . PARTICIPANTS 181 patients awaiting knee arthroplasty . INTERVENTIONS acupuncture for 6 weeks ; physiotherapy for 6 weeks ; st and ardized advice . MAIN OUTCOME MEASURES Oxford Knee Score question naire ( OKS ) ( primary ) ; 50 m timed walk , and duration of hospital stay following knee arthroplasty . RESULTS There was no baseline difference between groups . At 7 weeks , there was a 10 % reduction in OKS in the acupuncture group which was a significant difference between the acupuncture and the control group : Mean ( s.d . ) acupuncture 36.8 ( 7.20 ) ; physiotherapy 39.2 ( 8.22 ) ; control 40.3 ( 8.48 ) ( P = 0.0497 ) . These effects were no longer present at 12 weeks . There was a trend ( P = 0.0984 ) towards a shorter in-patient stay of 1 day for the physiotherapy group [ mean 6.50 days ( s.d . 2.0 ) ] compared with the acupuncture group [ mean 7.77 days ( s.d . 3.96 ) ] . CONCLUSIONS We have demonstrated that patients with severe knee osteoarthritis can achieve a short-term reduction in OKS when treated with acupuncture . However , we failed to demonstrate any other clinical ly or statically significant effects between the groups . Both interventions can be delivered effectively in an out-patient group setting at a district general hospital . Further study is needed to evaluate the combined effects of these treatments BACKGROUND Although weight loss reduces risk for comorbid diseases , many observational studies suggest that weight loss is associated with increased mortality risk , leading to reluctance by clinicians to consider weight reduction as a strategy to maintain health and independence in older adults . However , whether the observed weight loss is intentional is difficult to determine and may not accurately represent the mortality risk associated with intentional weight reduction . Data from the Arthritis , Diet , and Activity Promotion Trial ( ADAPT ) were used to determine whether r and omization to a weight reduction program was associated with total mortality in overweight/obese older adults . METHODS ADAPT ( n = 318 ; mean age 69 + /- 6 years , body mass index 34 + /- 5 kg/m2 , 72 % female ) assessed the influence of weight loss ( achieved through dietary counseling and lifestyle modification ) and /or exercise on function in overweight/obese older adults with knee osteoarthritis . ADAPT ended in December 1999 . Participant vital was ascertained status through December 2006 using the National Death and Social Security Indexes . RESULTS The mortality rate for those r and omized to the 18-month weight loss intervention ( n = 159 , mean weight loss = -4.8 kg , 15 deaths ) was lower than that for those not r and omized to the weight loss intervention ( n = 159 , mean weight loss = -1.4 kg , 30 deaths ; hazard rate ratio = 0.5 , 95 % confidence interval 0.3 - 1.0 ) . Results were not appreciably changed when analyses were stratified by age , gender , baseline weight status , or magnitude of weight loss . CONCLUSIONS In older adults , intentional weight loss was not associated with increased total mortality and may reduce mortality risk . Observational studies of weight loss , especially when intentionality can not be rigorously established , may be misleading with respect to the effect of weight loss on mortality PURPOSE This study assessed the impact of a low cost , multicomponent physical activity intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of a facility-based multiple-component training program followed by home-based adherence ( n = 80 ) to a wait list control group ( n = 70 ) . Assessment s were conducted at baseline and at 2 and 6 months following r and omization . The training program consisted of range of motion , resistance training , aerobic walking , and education-group problem solving regarding self-efficacy for exercise and exercise adherence . All training group participants developed individualized plans for posttraining adherence . RESULTS Relative to the persons in the control group , individuals who participated in the exercise program experienced a statistically significant improvement in exercise efficacy , a 48.5 % increase in exercise adherence , and a 13.3 % increase in 6-min distance walk that were accompanied by significant decreases in lower extremity stiffness at 2 and 6 months . Program participants also experienced a significant decrease in lower extremity pain and a borderline significant improvement in efficacy to adhere to exercise over time at 6 months ( p = .052 ) . In contrast , persons in the control group deteriorated over time on the efficacy and adherence measures and showed no change on the other measures . No adverse health effects were encountered . IMPLICATION S These benefits indicate that this low-cost intervention may hold great promise as one of a growing number of public health intervention strategies for older adults in the United States with osteoarthritis OBJECTIVE To compare the preoperative effects of multidimensional l and -based and pool-based exercise programs for people awaiting joint replacement surgery of the hip or knee . DESIGN R and omized , single-blind , before-after trial . SETTING Physiotherapy gymnasium and hydrotherapy pool . PARTICIPANTS Patients awaiting elective hip or knee joint replacement surgery . INTERVENTIONS L and -based ( n=40 ) or pool-based exercise program ( n=42 ) . Each 6-week program included an education session , twice-weekly exercise classes , and an occupational therapy home assessment . MAIN OUTCOME MEASURES Participants were assessed immediately before and after the 6-week intervention , then 8 weeks later . Primary outcomes were pain and self-reported function ( Western Ontario and McMaster Universities Osteoarthritis Index ) and patient global assessment . Secondary outcomes were performance-based measures ( timed walk and chair st and ) and psychosocial status ( Medical Outcomes Study 36-Item Short-Form Health Survey mental component score ) . Pain was also measured before and after each exercise class on a 7-point verbal rating scale . RESULTS Although both interventions were effective in reducing pain and improving function , there were no postintervention differences between the groups for the primary and secondary outcomes . However , the pool-based group had less pain immediately after the exercise classes . CONCLUSIONS While our multidimensional exercise-based interventions appeared to be effective in reducing disability in those awaiting joint replacement surgery of the hip or knee , there were no large differences in the postintervention effects of the interventions . However , pool-based exercise appeared to have a more favorable effect on pain immediately after the exercise classes BACKGROUND People with osteoarthritis ( OA ) of the knee experience pain and deconditioning that lead to disability . This study challenged the clinical belief that repetitive lower extremity exercise is not indicated in persons with knee OA . The effects of high-intensity and low-intensity stationary cycling on functional status , gait , overall and acute pain , and aerobic capacity were examined . METHODS Thirty-nine adults ( 71+/-6.9 years old ) with complaints of knee pain and diagnosis of OA were r and omized to either a high-intensity ( 70 % heart rate reserve [ HRR ] ) or low-intensity ( 40 % HRR ) exercise group for 10 weeks of stationary cycling . Participants cycled for 25 minutes , 3 times per week . Before and after the exercise intervention they completed the Arthritis Impact Measurement Scale 2 for overall pain assessment , underwent timed chair rise , 6-minute walk test , gait , and grade d exercise treadmill tests . Acute pain was reported daily with a visual analog scale and the Western Ontario and McMaster Universities Osteoarthritis Index scale . RESULTS Analysis of variance revealed that participants in both groups significantly improved in the timed chair rise , in the 6-minute walk test , in the range of walking speeds , in the amount of overall pain relief , and in aerobic capacity . No differences between groups were found . Daily pain reports suggested that cycling did not increase acute pain in either group . CONCLUSIONS Cycling may be considered as an alternative exercise modality for patients with knee OA . Low-intensity cycling was as effective as high-intensity cycling in improving function and gait , decreasing pain , and increasing aerobic capacity Lifestyle interventions have result ed in weight loss or improved physical fitness among individuals with obesity , which may lead to improved physical function . This prospect i ve investigation involved participants in the Action for Health in Diabetes ( Look AHEAD ) trial who reported knee pain at baseline ( n = 2,203 ) . The purpose s of this investigation were to determine whether an Intensive Lifestyle Intervention ( ILI ) condition result ed in improvement in self-reported physical function from baseline to 12 months vs. a Diabetes Support and Education ( DSE ) condition , and whether changes in weight or fitness mediated the effect of the ILI . Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) pain , stiffness , and physical function subscales , and WOMAC summary score . ILI participants exhibited greater adjusted mean weight loss ( s.e . ) vs. DSE participants ( -9.02 kg ( 0.48 ) vs. -0.78 kg ( 0.49 ) ; P < 0.001 ) ) . ILI participants also demonstrated more favorable change in WOMAC summary scores vs. DSE participants ( β ( s.e . ) = -1.81 ( 0.63 ) ; P = 0.004 ) . Multiple regression mediation analyses revealed that weight loss was a mediator of the effect of the ILI intervention on change in WOMAC pain , function , and summary scores ( P < 0.001 ) . In separate analyses , increased fitness also mediated the effect of the ILI intervention upon WOMAC summary score ( P < 0.001 ) . The ILI condition result ed in significant improvement in physical function among overweight and obese adults with diabetes and knee pain . The ILI condition also result ed in significant weight loss and improved fitness , which are possible mechanisms through which the ILI condition improved physical function OBJECTIVE This 8 week r and omized , double blind clinical trial compared the effect of a combined home based progressive exercise program and treatment with the nonsteroidal medication oxaprozin to treatment with oxaprozin alone on pain and physical functioning in older community dwelling patients with unilateral knee osteoarthritis ( OA ) . METHODS Efficacy variables measured before and after 8 weeks included ( 1 ) pain using the Western Ontario McMaster ( WOMAC ) pain , physical disability , and stiffness subscales and a 10 point visual analog scale ( VAS ) before and after self-paced walking ( SPW ) and stepping ( SPS ) functional tasks ; ( 2 ) physical function using the time to complete a self-paced 40 m walk ( SPW ) and 20 cycles of 2 steps ( SPS ) : ( 3 ) physical activity level using the Physical Activity Scale for Elderly ( PASE ) ; ( 4 ) clinical measures of knee functioning ( range of motion ) . One hundred seventy-nine men and women ( mean age 74 + /- 6 yrs ) with radiographic evidence of mild/moderate medial compartment OA were r and omized to either a progressive home based knee exercise program ( n = 88 ) or a control program ( n = 89 ) . All patients were given oxaprozin 1,200 mg per os daily . RESULTS We observed significant reduction from baseline in activity related pain ( VAS ) ; and improvement in SPW and SPS test time , passive range of motion , and PASE after 8 weeks in both groups . These changes were significantly greater ( p < 0.05 ) in the exercise versus sham group . CONCLUSION Addition of a progressive exercise program to nonsteroidal antiinflammatory therapy in patients with knee OA can improve measures of activity and activity related pain more than medication alone OBJECTIVE To determine whether gains in functioning observed immediately following participation in an 8-week program of supervised fitness walking for patients with knee osteoarthritis were sustained at 1-year followup . METHODS Twenty-nine ( 61.1 % ) of 47 original intervention program patients and 23 ( 51.1 % ) of 45 original control patients were interviewed by telephone at 1-year followup . Patients completed the Arthritis Impact Measurement Scales physical activity , arthritis impact , pain , medication use , and general health perceptions subscales , as well as a separate visual analog pain scale and measures of perceived self-efficacy to cope with arthritis pain and other symptoms . RESULTS Adherence to walking was low , and there were no statistically significant differences between intervention and control patients at one year . CONCLUSIONS The failure of intervention patients to maintain regular walking result ed in loss of functional benefits that were observed at 8 weeks in the original study . Long-term adherence to walking is critical to maintenance of initial gains in functional outcomes OBJECTIVE To compare the effects of a hydrotherapy resistance exercise programme with a gym based resistance exercise programme on strength and function in the treatment of osteoarthritis ( OA ) . DESIGN Single blind , three arm , r and omised controlled trial . SUBJECTS 105 community living participants aged 50 years and over with clinical OA of the hip or knee . METHODS Participants were r and omised into one of three groups : hydrotherapy ( n = 35 ) , gym ( n = 35 ) , or control ( n = 35 ) . The two exercising groups had three exercise sessions a week for six weeks . At six weeks an independent physiotherapist unaware of the treatment allocation performed all outcome assessment s ( muscle strength dynamometry , six minute walk test , WOMAC OA Index , total drugs , SF-12 quality of life , Adelaide Activities Profile , and the Arthritis Self-Efficacy Scale ) . RESULTS In the gym group both left and right quadriceps significantly increased in strength compared with the control group , and right quadriceps strength was also significantly better than in the hydrotherapy group . The hydrotherapy group increased left quadriceps strength only at follow up , and this was significantly different from the control group . The hydrotherapy group was significantly different from the control group for distance walked and the physical component of the SF-12 . The gym group was significantly different from the control group for walk speed and self efficacy satisfaction . Compliance rates were similar for both exercise groups , with 84 % of hydrotherapy and 75 % of gym sessions attended . There were no differences in drug use between groups over the study period . CONCLUSION Functional gains were achieved with both exercise programmes compared with the control group OBJECTIVE Physical function and body composition in older obese adults with knee osteoarthritis ( OA ) were examined after intensive weight loss . RESEARCH METHODS AND PROCEDURES Older obese adults ( n = 87 ; > or = 60 years ; BMI > or = 30.0 kg/m2 ) with symptomatic knee OA and difficulty with daily activities were recruited for a 6-month trial . Participants were r and omized into either a weight stable ( WS ) or weight loss ( WL ) program . Participants in WL ( 10 % weight loss goal ) were prescribed a 1000 kcal/d energy deficit diet with exercise 3 d/wk . WS participants attended health information sessions . Body composition and physical function ( Western Ontario and McMaster University Osteoarthritis Index , 6-minute walking distance , and stair climb time ) were assessed at baseline and 6 months . Statistical analysis included univariate analysis of covariance on 6-month measurements using baseline values as covariates . Associations between physical function and body composition were performed . RESULTS Body weight decreased 8.7 + /- 0.8 % in WL and 0.0 + /- 0.7 % in WS . Body fat and fat-free mass were lower for WL than WS at 6 months ( estimated means : fat = 38.1 + /- 0.4 % vs. 40.9 + /- 0.4 % , respectively ; fat-free mass = 56.7 + /- 0.4 vs. 58.8 + /- 0.4 kg , respectively ) . WL had better function than WS , with lower Western Ontario and McMaster University Osteoarthritis Index scores , greater 6-minute walk distance , and faster stair climb time ( p < 0.05 ) . Changes in function were associated with weight loss in the entire cohort . DISCUSSION An intensive weight loss intervention incorporating energy deficit diet and exercise training improves physical function in older obese adults with knee OA . Greater improvements in function were observed in those with the most weight loss OBJECTIVE To determine whether Tai Chi or hydrotherapy classes for individuals with chronic symptomatic hip or knee osteoarthritis ( OA ) result in measurable clinical benefits . METHODS A r and omized controlled trial was conducted among 152 older persons with chronic symptomatic hip or knee OA . Participants were r and omly allocated for 12 weeks to hydrotherapy classes ( n = 55 ) , Tai Chi classes ( n = 56 ) , or a waiting list control group ( n = 41 ) . Outcomes were assessed 12 and 24 weeks after r and omization and included pain and physical function ( Western Ontario and McMaster Universities Osteoarthritis Index ) , general health status ( Medical Outcomes Study Short Form 12 Health Survey [ SF-12 ] , version 2 ) , psychological well-being , and physical performance ( Up and Go test , 50-foot walk time , timed stair climb ) . RESULTS At 12 weeks , compared with controls , participants allocated to hydrotherapy classes demonstrated mean improvements ( 95 % confidence interval ) of 6.5 ( 0.4 , 12.7 ) and 10.5 ( 3.6 , 14.5 ) for pain and physical function scores ( range 0 - 100 ) , respectively , whereas participants allocated to Tai Chi classes demonstrated improvements of 5.2 ( -0.8 , 11.1 ) and 9.7 ( 2.8 , 16.7 ) , respectively . Both class allocations achieved significant improvements in the SF-12 physical component summary score , but only allocation to hydrotherapy achieved significant improvements in the physical performance measures . All significant improvements were sustained at 24 weeks . In this almost exclusively white sample , class attendance was higher for hydrotherapy , with 81 % attending at least half of the available 24 classes , compared with 61 % for Tai Chi . CONCLUSION Access to either hydrotherapy or Tai Chi classes can provide large and sustained improvements in physical function for many older , sedentary individuals with chronic hip or knee OA PURPOSE We present final outcomes from the multiple-component Fit and Strong ! intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of this exercise and behavior-change program followed by home-based reinforcement ( n=115 ) with a wait list control ( n=100 ) at 2 , 6 , and 12 months . Fit and Strong ! combined flexibility , aerobic walking , and resistance training with education and group problem solving to enhance self-efficacy for exercise and maintenance of physical activity . All participants developed individualized plans for long-term maintenance . RESULTS Relative to controls , treatment participants experienced statistically significant improvements in self-efficacy for exercise ( p=.001 ) , minutes of exercise per week ( p=.000 ) , and lower extremity stiffness ( p=.018 ) at 2 months . These benefits were maintained at 6 months and were accompanied by increased self-efficacy for adherence to exercise over time ( p=.001 ) , reduced pain ( p=.040 ) , and a marginally significant increase in self-efficacy for arthritis pain management ( p=.052 ) . Despite a substantially smaller sample size at 12 months , significant treatment-group effects were maintained on self-efficacy for exercise ( p=.006 ) and minutes of exercise per week ( p=.001 ) , accompanied by marginally significant reductions in lower extremity stiffness ( p=.056 ) and pain ( p=.066 ) . No adverse health effects were seen . Effect sizes for self-efficacy for exercise and for maintenance of physical activity were 0.798 and 0.713 , and 0.905 and 0.669 , respectively , in the treatment group at 6 and 12 months . IMPLICATION S This consistent pattern of benefits indicates that this low-cost intervention is efficacious for older adults with lower extremity osteoarthritis A group of 120 patients with rheumatoid arthritis or osteoarthritis volunteered to be subjects for this study of aerobic versus nonaerobic exercise . Patients were stratified by diagnosis and r and omized into an exercise program of aerobic walking , aerobic aquatics , or nonaerobic range of motion ( controls ) . The retention rate for the 12-week program was 83 % . Exercise tolerance , disease-related measures , and self-reported health status were assessed . The aquatics and walking exercise groups showed significant improvement over the control group in aerobic capacity , 50-foot walking time , depression , anxiety , and physical activity after the 12-week exercise program . There were no significant between-group group differences in the change scores for flexibility , number of clinical ly active joints , duration of morning stiffness , or grip strength . Our findings document the feasibility and efficacy of conditioning exercise for people who have rheumatoid arthritis or osteoarthritis OBJECTIVE To assess the effect of a program of supervised fitness walking and patient education on functional status , pain , and use of medication in patients with osteoarthritis of the knee . DESIGN An 8-week r and omized , controlled trial . SETTING Inpatient and outpatient services of an orthopedic hospital in an academic medical center . PATIENTS A total of 102 patients with a documented diagnosis of primary osteoarthritis of one or both knees participated in the study . Data were obtained on 47 of 51 intervention patients and 45 of 51 control patients . INTERVENTIONS An 8-week program of supervised fitness walking and patient education or st and ard routine medical care . MEASUREMENTS Patients were evaluated and outcomes assessed before and after the intervention using a 6-minute test of walking distance and scores on the physical activity , arthritis impact , pain , and medication subscales of the Arthritis Impact Measurement Scale ( AIMS ) . RESULTS Patients r and omly assigned to the walking program had a 70-meter increase in walking distance relative to their baseline assessment , which represents an improvement of 18.4 % ( 95 % Cl , 9.8 % to 27.0 % ) . In contrast , controls showed a 17-meter decrease in walking distance relative to their baseline assessment ( P less than 0.001 ) . Improvements in functional status as measured by the AIMS physical activity subscale were also observed in the walking group but not in the control group ( P less than 0.001 ) ; patients assigned to the walking program improved 39 % ( Cl , 15.6 % to 60.4 % ) . Although changes in scores on the arthritis impact subscale were similar in the two groups ( P = 0.093 ) , the walking group experienced a decrease in arthritis pain of 27 % ( Cl , 9.6 % to 41.4 % ) ( P = 0.003 ) . Medication use was less frequent in the walking group than in the control group at the post-test ( P = 0.08 ) . CONCLUSIONS A program of supervised fitness walking and patient education can improve functional status without worsening pain or exacerbating arthritis-related symptoms in patients with osteoarthritis of the knee OBJECTIVE To investigate physical function in patients with severe osteoarthritis ( OA ) of the knees during and after a general physical training program . DESIGN R and omized control trial , blinded observer , follow-up at 3 months and 1 year . SETTING Outpatient clinic . PATIENTS Consecutive sample of 25 patients ( 3 men , 22 women ) with OA of the knees according to the criteria of the American College of Rheumatology ( ACR ) . Two patients ( 8 % ) failed to complete the study . There were no withdrawals for adverse effects . INTERVENTION Twelve patients received training in groups of 6 , twice a week for 3 months . Training focused on general fitness , balance , coordination , stretching , and lower extremity muscle strength , and included a daily home exercise program . MAIN OUTCOME MEASURES Muscle strength across the knee ( extension and flexion ) , Algofunctional Index ( AFI ) , pain ( 0 to 10 point scale ) , walking speed , clinical findings . RESULTS Patients participated in 96 of 96 assessment s ( 100 % ) and in 218 of 280 training sessions ( 77.9 % ) . From baseline to 3 months , isokinetic quadriceps strength ( 30 degrees/sec ) improved 20 % ( confidence interval [ CI ] 2alpha = .05 , 8 % to 50 % ) in the least affected leg ; isometric strength improved 21 % . By 1 year , AFI had decreased 3.8 points ( CI2alpha = .05 , 1.0 to 7.0 ) , pain had decreased 2.0 points ( CI2alpha = 05 , 0.0 to 4.0 ) , and walking speed had increased 13 % ( CI2alpha = .05 , 4 % to 23 % ) . There was an increase in the frequency of palpable joint effusions ( p < .01 ) on the most affected side . Frequency of crepitus decreased on the least affected side ( p < .01 ) . CONCLUSIONS General physical training appears to be beneficial to patients with OA of the knee . As shown by the high compliance and low dropout frequency , such a program is feasible even in patients with severe OA of the knee OBJECTIVE To investigate the efficacy of a water-based exercise program specifically targeting balance to reduce falls risk and improve measures of balance and physical function in older adults with osteoarthritis ( OA ) . DESIGN R and omized controlled trial . SETTING Community . PARTICIPANTS Persons ( N=39 ; mean±SD age , 74±6y ; 26 women ) with mild to moderate OA and at risk for falling met study criteria , were measured at baseline , and were r and omly assigned to the intervention ( n=23 ) and control groups ( n=16 ) . INTERVENTIONS Water-based program ( 12wk , twice weekly ; intervention group ) or a time-matched computer training program ( control group ) . MAIN OUTCOME MEASURE The primary outcome was the short-form Physiological Profile Assessment ( PPA ) . Secondary outcomes included the Step Test , Timed Up and Go Test , Western Ontario and McMaster Universities OA Index ( Likert 3.0 version ) , Arthritis Impact Measurement Scales 2 , and Activity-specific Balance Confidence Scale . RESULTS No statistically significant between-group differences were found for any outcome measured ( n=35 ; 4 lost to follow-up ) . Within-group analysis indicated that Step Test results improved significantly in both groups ( mean change : control group , left leg , 2.07 ; 95 % confidence interval , 3.19-.95 ; P=.002 ; intervention group , 2.14 ; 95 % confidence interval , 3.20 - 1.08 ; P=.000 ) . Two PPA item scores ( reaction time , contrast sensitivity ) improved significantly ( 86.83 ; 95 % confidence interval , 9.86 - 163.79 ; P=.03 ; 1.43 ; 95 % confidence interval , 2.35-.50 ; P=.005 , respectively ) in the control group , result ing in a lower falls risk score . CONCLUSIONS Water-based exercise did not reduce falls risk in our sample compared with attending a computer skills training class . Our study is , to our knowledge , the first to compare water-based exercise in this population with a control group that attended a time-dose-equivalent seated community-based activity . Whether gaining computer skills and going out into the community twice weekly is adequate stimulus to reduce falls risk in people with OA requires further investigation

The effects of cigarette smoke are dose-dependent and are influenced by the presence of other toxic substances and hormonal status . Individual sensitivity , dose , time and type of exposure also play a role in the impact of smoke constituents on human fertility . All stages of reproductive functions are targets of cigarette smoke toxicants .

BACKGROUND Cigarette smoking is associated with lower fecundity rates , adverse reproductive outcomes and a higher risk of IVF failures . Over the last few decades , prevalence of smoking among women of reproductive age has increased . This review focuses on current knowledge of the potential effects of smoke toxicants on all reproductive stages and the consequences of smoke exposure on reproductive functions . RESULTS Cigarette smoke contains several thous and components ( e.g. nicotine , polycyclic aromatic hydrocarbons and cadmium ) with diverse effects .

OBJECTIVE To assess the association between recent cigarette smoking ( CS ) in female and male partners and assisted reproduction technology ( ART ) outcomes . DESIGN Cohort prospect i ve study . SETTING University ART program in Chile . PATIENT(S ) One hundred sixty-six couples seeking pregnancy through ART . INTERVENTION(S ) Follicular fluid ( FF ) and serum cotinine concentrations were measured in female partners . Self-reported CS data were collected through personal interviews . MAIN OUTCOME MEASURE(S ) The association between female recent smoking , assessed by FF and serum cotinine concentrations , and ART outcomes , such as number of ova retrieved and implantation rates , and the association between self-reported male recent smoking and live birth rates . RESULT ( S ) A significant age-adjusted association between increased FF cotinine level and decreased number of ova retrieved was found . The male partner 's smoking habit significantly decreased the live birth rate from 21.1 % to 7.8 % . Serum cotinine concentrations paralleled those of FF . CONCLUSION ( S ) The hypothesis of a detrimental effect of recent female smoking over implantation rates is rejected . However , recent male smoking is associated with significantly decreased live birth rates even after adjusting for confounders . Female recent smoking was significantly associated with decreased number of retrieved ova Several studies published within the past 10 years indicate that smoking reduces fecundity , but not all studies have found this effect , and smoking cessation is not used routinely in infertility treatment in Europe . The present study was design ed to examine male and female smoking at the start of a couple 's waiting time to a planned pregnancy . Two types of sample s were used : population -based sample s of women aged 25 - 44 years who were r and omly selected in different countries from census registers and electoral rolls , in which the unit of analysis was the couple ; and pregnancy-based sample s of pregnant women ( at least 20 weeks ' pregnant ) who were consecutively recruited during prenatal care visits , in which the unit of analysis was a pregnancy . More than 4,000 couples were included in each sample , and 10 different regions in Europe took part in data collection . The data were collected between August 1991 and February 1993 by personal interview in all population -based sample s and in all but three regions of the pregnancy sample , where self-administered question naires were used . The results based on the population sample showed a remarkably coherent association between female smoking and subfecundity in each individual country and in all countries together , both with the first pregnancy ( odds ratio ( OR ) = 1.7 , 95 % confidence interval ( CI ) 1.3 - 2.1 , at the upper level of exposure ) and during the most recent waiting time to pregnancy ( OR = 1.6 , 95 % CI 1.3 - 2.1 ) . Results based on the pregnancy sample were similar ( OR = 1.7 , 95 % CI 1.3 - 2.3 ) . No significant association was found with male smoking ( in the population sample , OR = 0.9 , 95 % CI 0.7 - 1.1 ( first pregnancy ) and OR = 1.0 , 95 % CI 0.9 - 1.3 ( most recent waiting time ) ; in the pregnancy sample , OR = 0.9 , 95 % CI 0.7 - 1.1 ) . The fecundity distribution among smokers appeared to be shifted toward longer waiting times without a change in the shape of the distribution . Women who have difficulty conceiving should try to stop smoking or to reduce their smoking to less than 10 cigarettes per day The electromechanical activity of the uterus was studied in 18 healthy women ( mean age 38.3+/-14.2 SD years ; 8 were nulliparous , 10 multiparous ) aim ing at characterizing a normal electrohysterogram . Two monopolar silver-silver chloride electrodes were applied to the uterine and one to the cervical mucosa . The uterine pressure was measured by a water-perfused tube connected to a pressure transducer . Monophasic , negatively deflected slow waves or pacesetter potentials ( PPs ) were recorded from the 2 uterine electrodes . They had regular rhythm and exhibited the same frequency , amplitude and velocity of conduction by the 2 electrodes . The PPs were followed r and omly by bursts of action potentials ( APs ) . The APs and not the PPs were associated with uterine pressure rise . PPs from the cervix were registered only occasionally . The occurrence of the electric activity is believed to depend on the smooth muscle fibers content which is high in the uterine body and meagre in the cervix . The APs seem to have contractile activity which might act to sweep away the uterine secretions . According to the uterocervical reflex , the cervix dilates upon uterine contractions . A normal electrohysterogram could be characterized . It might show a different pattern in the various uterine pathologic conditions and may thus represent an investigative tool in the diagnosis of such disorders OBJECTIVE To evaluate the predictive value of serial uterine artery Doppler ultrasound for embryo implantation in in-vitro fertilization (IVF)-intracytoplasmic sperm injection ( ICSI ) cycles . METHODS This was a prospect i ve observational study at the VU University Medical Center , Amsterdam . Patients with an indication for IVF or IVF-ICSI according to departmental protocol underwent controlled ovarian hyperstimulation followed by IVF or IVF-ICSI and embryo transfer and had serial Doppler ultrasound performed during this treatment cycle . Patient and cycle characteristics , number of conceptions and ongoing pregnancies and pulsatility index ( PI ) of both uterine arteries on different cycle days were assessed and results were compared between patients who conceived and those who did not . RESULTS Of the 102 patients enrolled into the study , 83 underwent embryo transfer . Of these , 41 became pregnant and 42 did not ( Group 1 ) . Of the 41 pregnancies , 30 were ongoing ( Group 2 ) and 11 miscarried ( Group 3 ) . Between Groups 1 , 2 and 3 , linear regression revealed no significant difference between any of the variables examined except in the quality of transferred embryos . There was no significant difference in the mean PI of the left and right uterine arteries on any day of the cycle , or in the change in PI during the cycle . Receiver-operating characteristics curves derived to determine the performance of PI to predict pregnancy outcome supported our findings that the uterine artery PI is not a suitable marker for identifying patients with implantation failure . Multivariate analysis showed no relationship between pregnancy and PI between groups , but it did show a relationship between pregnancy and some patient and cycle characteristics . CONCLUSION In an unselected group of patients undergoing IVF or IVF-ICSI and embryo transfer , serial Doppler ultrasound examination of the uterine artery does not discriminate between cycles result ing in ongoing pregnancy , miscarriage and no pregnancy The authors earlier conducted a retrospective study of time to pregnancy among a group of pregnant women in Minnesota , in order to investigate the relation between cigarette smoking and fecundability . Further analysis of these data shows that women who had been exposed as children to cigarette smokers had increased fertility . This finding lacks biologic plausibility . However , the authors found a similar association in a group of North Carolina women whose fecundability had been measured prospect ively . Furthermore , both groups showed an apparent dose-response effect . The authors briefly describe this unexpected finding so that it might be more fully explored in other studies OBJECTIVE To study acute hemodynamic alterations in the fetal-placental maternal system immediately after maternal exposure to nicotine . METHODS This is a noncontrolled experimental study involving 21 pregnant smoking women , r and omly selected , with uncomplicated pregnancies and without risk factors for fetal heart disease . Patients underwent ultrasound and fetal echocardiography before and after smoking a cigarette . They were asked to abstain from smoking for 12 hours before the study . The mean nicotine content of the cigarettes used in the study was 0.5 mg of nicotine and 6 mg of carbon monoxide . RESULTS The average number of cigarettes smoked per a day prior to the study was 9.67 . Gestational age ranged between 18 and 36 weeks . The mean maternal heart rate was elevated ( P<0.001 ) as was the mean fetal heart rate ( P=0.044 ) . Maternal systolic blood pressure ( P=0.004 ) and diastolic blood pressure ( P=0.033 ) were also elevated after smoking . A decrease occurred in the systolic/diastolic ratio in the right uterine artery ( P=0.014 ) and in the left uterine artery ( P=0.039 ) . The other hemodynamic variables remained unchanged . CONCLUSION Cigarette smoking can cause changes in physiologic variables of fetal-placental circulation , but it does not change fetal cardiac function , in the dose of nicotine and its components used in this study . The decrease in systolic/diastolic ratio in the uterine arteries is probably related to a dose-dependent nicotine pattern BACKGROUND Smoking has been reported to promote infertility . The zona pellucida plays an important role in fertilization and implantation . We report , for the first time , the effect of cigarette smoking on zona pellucida thickness of oocytes and embryos as one of the factors that may interfere with fertility . METHODS This study comprised 169 women , grouped according to their smoking habits : 31 active smokers , whose husb and s do not smoke ; 44 active smokers , whose husb and s smoke ; 65 passive smokers , because of smoking husb and s and 29 non-smokers ( women and husb and s ) . Zona pellucida thickness was measured prospect ively on printed photos of 903 oocytes and 456 embryos . RESULTS The zona pellucida thickness of oocytes and embryos of non-smoking women was significantly thinner than those of active and passive smokers . However , no significant differences were observed in the natural ability of the zona pellucida to become thinner after 48 h in culture . CONCLUSIONS Our study demonstrates that active and passive cigarette smoking increases the zona pellucida thickness of oocytes and embryos . Our findings also show that active and passive smoking has no significant effect on the thinning mechanism of the zona pellucida , which implies that it is independent of the initial zona pellucida thickness Objectives The ratio of trans-3′hydroxycotinine/cotinine ( 3HC/COT ) is a marker of CYP2A6 activity , an important determinant of nicotine metabolism . This analysis sought to conduct a combined genetic epidemiologic and pharmacogenetic investigation of the 3HC/COT ratio in plasma and urine . Methods One hundred and thirty-nine twin pairs [ 110 monozygotic and 29 dizygotic ] underwent a 30-min infusion of stable isotope-labelled nicotine and its major metabolite , cotinine , followed by an 8-h in-hospital stay . Blood and urine sample s were taken at regular intervals for analysis of nicotine , cotinine , and metabolites . DNA was genotyped to confirm zygosity and for variation in the gene for the primary nicotine metabolic enzyme , CYP2A6 ( variants genotyped : * 1B , * 1 × 2 , * 2 , * 4 , * 9 , * 12 ) . Univariate biometric analyses quantified genetic and environmental influences on each measure in the presence and absence of covariates , including measured CYP2A6 genotype . Results There was a substantial amount of variation in the free 3HC/COT ratio in plasma ( 6 h postinfusion ) attributable to additive genetic influences ( 67.4 % , 95 % confidence interval=55.9–76.2 % ) . The heritability estimate was reduced to 61.0 and 49.4 % , respectively , after taking into account the effect of covariates and CYP2A6 genotype . In urine ( collected over 8 h ) , the estimated amount of variation in the 3HC/COT ratio attributable to additive genetic influences was smaller ( 47.2 % , 95 % confidence interval=0–67.2 % ) and decreased to 44.6 and 42.0 % after accounting for covariates and genotype . Conclusion Additive genetic factors are prominent in determining variation in plasma 3HC/COT but less so in determining variation in urine 3HC/COT In the present study we investigated the effect of a woman 's smoking status on the quality of the oocyte , zygote , and on day 3 pre-embryo , as well as the likelihood of achieving an ongoing pregnancy at 8 weeks . Smokers presented a higher number of nonfertilized oocytes than nonsmokers ( 20.1 % vs. 10.8 % of fertilization failure ) , by comparable clinical pregnancy rate for smokers ( 40.8 % ; 28/72 ) and for nonsmokers ( 39.2 % ; 23/58 ) OBJECTIVE To search for a possible correlation between an effective marker of smoking and uterine and placental resistance during pregnancy . STUDY DESIGN A prospect i ve study was conducted at the Intercommunal Hospital Center of Montreuil , France : 81 healthy pregnant women underwent uterine and placental Doppler and cotidin blood assay , the best current test for smoking . RESULTS This study shows a significative increase of utero-placental vascular resistances according with increased cotidine levels . CONCLUSIONS The previously observed association between smoking and perinatal events most likely involves vascular resistance of uterus and placenta The research was design ed to compare the effect of cadmium and p-nonylphenol on the increase of uterine weight and to study the related mechanisms . It provided basic evidence for us to underst and the possible different mechanisms among different EEDs . In this study , both ovaries of 60 Wistar rats ( 28 days age ) were ectomized , and after 21 days recovery , the rats were r and omly assigned into six groups and exposed to cadmium ( 0.12 , 1.20mg/kg ) , NP ( 100 , 200mg/kg ) , control ( sterile PBS ) , and positive control ( 17beta-estradiol ) per day for 3 days , respectively , then related indexes were detected . The results showed that the increase of uterine weight induced by cadmium was accompanied by the increase of the thickness of luminal epithelium cell and endometrium but the decrease of nuclear/cytoplasm of luminal epithelium cell and endometrium , while the increase of uterine weight induced by p-nonylphenol was accompanied by the increase of the thickness of luminal epithelium cell , endometrium , and myometrium but the decrease of nuclear/cytoplasm of luminal epithelium cell and endometrium . Cadmium could inhibit the positive expression of PCNA while p-nonylphenol prompted it . Exposure to cadmium and NP both could also stimulate phosphorylation of ERK mitogen-activated protein kinases , implying that this signal pathway had an effect on the increase of the uterine weight induced by cadmium and p-nonylphenol . The results indicate that cadmium may induce the increase of uterine weight , which is accompanied with toxic effect on endometrium , while NP 's effect of the increase of uterine weight is due to cell proliferation of endometrium , the mechanisms of which are the same as estrogen , but they may both activate ERK signal pathway Animal studies have suggested that fertility may be impaired by transplacental exposures , but little is known about human prenatal exposures and subsequent adult reproduction . A possible relation between prenatal exposure to cigarette smoking and adult fecundability in women was explored , with the use of data from a prospect i ve study of 221 North Carolina couples . These couples were recruited during 1983 - 1985 , at the time they stopped using birth control in order to become pregnant . The relative fecundability of exposed compared with unexposed women was estimated by applying a discrete-time proportional probabilities model to the cycle-by-cycle conception rates . Women with prenatal exposure to their mother 's cigarette smoking had reduced fecundability . The fecundability ratio associated with prenatal exposure to mother 's smoking , adjusted for age , frequency of intercourse , current smoking status , age at menarche , and childhood exposure to cigarette smoking , was 0.5 ( 95 % confidence interval 0.4 - 0.8 ) . This association was not changed by further adjustment for other possible confounding variables , including educational level , reproductive history , body weight , and consumption of alcohol and caffeine . Thus , women whose mothers smoked while pregnant with them may be on average substantially less fecund than women whose mothers did not smoke during pregnancy OBJECTIVE To assess a " stage-of-change " oriented smoking cessation intervention for infertile and pregnant women , compared with st and ard of care . DESIGN R and omized controlled trial . SETTING Three university teaching hospitals in Hamilton , Ontario , Canada . PATIENT(S ) Infertile women at their first visit to a tertiary referral infertility clinic ( n = 94 ) and new patients seeking pre-natal care ( n = 110 ) who had smoked > /= 3 cigarettes in the past six months . INTERVENTION(S ) A three to five minute scripted intervention and booklet specific to the woman 's " stage-of-change " in the smoking continuum , versus st and ard of care . Exhaled carbon-monoxide ( CO ) monitoring was used to vali date exposure in both groups . MAIN OUTCOME MEASURE(S ) Delta " stage-of-change " and rate of maintained cessation at 12 months post follow-up . RESULT ( S ) Intervention and control were similarly effective for infertile women : the rate of maintained cessation rose significantly from 4 % to 24 % over twelve months , with a mean delta " stage-of-change " 0.28 . In prenatal women , neither approach was effective . Maintained cessation did not significantly change from 0 to 12 months ( 19 % to 18 % ) . Mean delta " stage-of-change " declined by -0.62 . CONCLUSION ( S ) For infertile women , basic information describing the impact of smoking on fertility , along with exhaled CO monitoring and a more intensive intervention were both highly effective . In pregnant women neither approach was beneficial , with some evidence of post-partum relapse OBJECTIVE [ 1 ] To examine the effects of body mass index ( BMI ) , age , cigarette smoking , cause of infertility , and use of oral contraceptives on baseline serum testosterone ( T ) , and [ 2 ] to examine associations between baseline serum T and IVF outcomes such as pre-hCG serum E(2 ) , number of oocytes retrieved , oocyte fertilization rate , and pregnancy outcome in regularly cycling women . DESIGN Prospect i ve , cohort study . SETTING Three IVF programs in eastern Massachusetts . PATIENT(S ) Four hundred twenty-five regularly cycling women planning to undergo IVF . Women with polycystic ovary syndrome , ovulatory infertility , or irregular cycles were excluded from this study . INTERVENTION(S ) Collection of epidemiological data and baseline serum in women undergoing IVF . MAIN OUTCOME MEASURE(S ) Baseline serum total T , sex hormone binding globulin ( SHBG ) , and calculation of free and rogen index . RESULT ( S ) Body mass index > 26 kg/m(2 ) was associated with a significant increase in serum T ( P<.01 ) and free and rogen index ( P<.0001 ) . Serum T decreased significantly throughout the fourth decade of life ( P<.03 ) . A history of cigarette smoking > 10 pack years was associated with increased serum T ( P<.01 ) . A diagnosis of endometriosis was associated with decreased serum T. Serum T correlated positively with pre-hCG serum E(2 ) and number of oocytes retrieved . However , serum T did not significantly influence fertilization or pregnancy rates . CONCLUSION ( S ) In cycling infertile women , increasing BMI and cigarette smoking are associated with increased serum T. Advancing age and endometriosis are associated with decreased serum To investigate the possible consequences of uterine contractions ( UC ) as visualized by ultrasound ( US ) on in-vitro fertilization (IVF)-embryo transfer outcome , we studied prospect ively 209 infertile women undergoing 220 cycles of controlled ovarian stimulation . Inclusion criteria were age < or = 38 years , a morphologically normal uterus , and at least three good quality embryos transferred . Just before embryo transfer , women underwent 5 min digital recordings of the uterus using US image analysis software for UC assessment . Plasma progesterone and oestradiol concentrations were measured . Four groups were defined according to UC frequency : < or = 3.0 ( n = 53 ) , 3.1 - 4.0 ( n = 50 ) , 4.1 - 5.0 ( n = 43 ) , and > 5.0 ( n = 74 ) UC/min respectively . Patients , controlled ovarian hyperstimulation and embryology characteristics were comparable in all groups . A stepwise decrease in clinical and ongoing pregnancy rates as well as in implantation rates occurred from the lowest to the highest UC frequency groups ( 53 , 36 , 21 ; 46 , 32 , 20 ; 23 , 19 , 10 ; and 14 , 11 , 4 % ; P < 0.001 ) . Plasma progesterone and UC frequency were negatively correlated ( r = -0.34 , P < 0.001 ) . Direction of UC did not affect embryo transfer outcome . As this study was controlled strictly for confounding variables and UC were assessed objective ly by a computerized system , its results indicate that high frequency UC on the day of embryo transfer hinder IVF-embryo transfer outcome , possibly by expelling embryos out of the uterine cavity . The negative correlation between UC frequency and progesterone concentrations supports the uterine relaxing properties of progesterone The effect of short-term nicotine consumption on endothelin-1 ( ET-1 ) levels was studied in 10 male healthy smokers . Volunteers smoked in r and om order on 3 separate days a low-tar cigarette or a high-tar cigarette , or were studied without having smoked ( no-cigarette experiment ) . ET-1 , corticotropin , and cortisol levels , heart rate , and blood pressure were determined before and 1 , 3 , 5 , 10 , 20 , and 30 minutes after smoking . In contrast to results obtained after smoking a low-tar cigarette or not smoking , smoking a high-tar cigarette result ed in a significant increase in ET-1 levels within 10 minutes , followed by an increase in corticotropin levels within 20 minutes after smoking . Thirty minutes after smoking , cortisol levels were higher after a high-tar cigarette compared with a low-tar cigarette or no smoking . Increases in heart rate and systolic blood pressure were likewise higher after smoking a high-tar cigarette than after smoking a low-tar cigarette . In conclusion , it is tempting to speculate that ET-1 may indeed act as the long- search ed-for link between vasopressin and corticotropin-releasing hormone ( CRH ) and thus play an essential role in the stimulation of the hypothalamic-pituitary-adrenal axis . In addition , these results suggest that the increase in the level of ET-1 , a powerful vasoconstrictor and mitogen , may play an important part in the disease mechanisms of atherosclerosis arising from smoking The non-pregnant uterus shows different patterns of contractility during the menstrual cycle . A renewed interest in uterine contractility has result ed from reports of non-invasive ultrasound ( US ) based studies . To clarify the changes in uterine contractility occurring throughout the menstrual cycle , we prospect ively studied uterine contractions ( UC ) at six representative stages with US and intrauterine pressure ( IUP ) based approaches in 30 cycling volunteers . Results showed UC frequency could be measured by either US or IUP . UC amplitude and resting pressure tone could only be assessed by IUP . Conversely , direction of UC displacement could only be assessed by US . UC frequency increased at mid-cycle and decreased throughout the luteal phase suggesting oestradiol and progesterone exert positive and negative actions on uterine contractility , respectively . UC amplitude increased throughout the menstrual cycle to maximum values in the late luteal phase . Retro grade UC were most frequent at mid-cycle and convergent ( ' opposing ' ) UC predominated during the luteal phase . While the former pattern ensures sperm transport , the latter may facilitate embryo implantation . In conclusion , UC changes throughout the menstrual cycle assessed by US and IUP emphasize the hormonal dependence of uterine contractility . Although UC patterns favouring sperm transport appear regulated by oestradiol , uterine quiescence and the dominance of convergent UC prevailing at the time of implantation are linked to progesterone . These data will serve to identify and treat possible dyskinetic changes in uterine contractility , particularly in women suffering from infertility , endometriosis , and dysmenorrhea Serial ultrasound biometry and Doppler flow velocity waveform analysis were used to measure the effects of maternal smoking in a prospect i ve study of 535 pregnancies . Smoking was associated with significant reductions in maternal weight gain , birthweights and placental weights . Decreased fetal biparietal diameter measurements were observed in pregnancies of smoking women ; this effect was maximal at 24 weeks ' gestation , was restricted to male fetuses and was not associated with altered head circumferences after birth . Umbilical artery and uteroplacental systolic/diastolic ratios were similar in pregnancies of smoking and non-smoking women , indicating that the effects of smoking on placental vascular resistance are periodic rather than continuous . The findings of this study confirm the need for studies of fetal growth to include prenatal measurements obtained by high resolution ultrasound imaging , rather than relying on findings obtainable by examination of the infant after birth The objective of this study was to examine the associations between active and passive smoking in different periods of pregnancy and changing smoking habits during pregnancy , with low birthweight and preterm birth . The study was embedded in the Generation R Study , a population -based prospect i ve cohort study from early fetal life onwards in Rotterdam , The Netherl and s. Active and passive smoking were assessed by question naires in early , mid- and late pregnancy . Analyses were based on 7098 pregnant women and their children . Active smoking until pregnancy was ascertained and was not associated with low birthweight and preterm birth . Continued active smoking after pregnancy was also recorded and was associated with low birthweight ( adjusted odds ratio 1.75 [ 95 % CI 1.20 , 2.56 ] ) and preterm birth ( adjusted odds ratio 1.36 [ 95 % CI 1.04 , 1.78 ] ) . The strongest associations were found for active maternal smoking in late pregnancy . Passive maternal smoking in late pregnancy was associated with continuously measured birthweight ( P for trend < 0.001 ) . For all active smoking categories in early pregnancy , quitting smoking was associated with a higher birthweight than continuing to smoke . Tendencies towards smaller non-significant beneficial effects on mean birthweight were found for reducing the number of cigarettes without quitting completely . This study shows that active and passive smoking in late pregnancy are associated with adverse effects on weight and gestational age at birth . Smoking in early pregnancy only , seems not to affect fetal growth adversely . Health care strategies for pregnant women should be aim ed at quitting smoking completely rather than reducing the number of cigarettes BACKGROUND No information exists in the literature regarding the factors affecting the blood flow towards the endometrial and subendometrial regions during IVF treatment . METHODS We examined the effect of women 's age , their smoking habits , their type of infertility ( i.e. primary or secondary ) and parity , causes of infertility and serum estradiol ( E2 ) concentration on endometrial and subendometrial blood flows as measured by a three-dimensional ( 3D ) power Doppler ultrasound during IVF treatment . All patients received a st and ard long protocol of ovarian stimulation and serum E2 concentration was determined on the day of hCG . 3D ultrasound examination with power Doppler was performed on the day of oocyte collection to determine vascularization index ( VI ) , flow index ( FI ) and vascularization flow index ( VFI ) of endometrial and subendometrial regions . RESULTS The age of women , their smoking habits , their types of infertility and parity and causes of infertility had no effect on the endometrial and subendometrial 3D power Doppler flow indices . There was a negative correlation between serum E(2 ) concentration and endometrial FI ( r = -0.109 ; P = 0.006 ) . CONCLUSIONS Endometrial blood flow in IVF treatment was negatively affected by serum E2 concentration only The objective of this study was to evaluate the effect of sub-acute exposure to inhaled benzo(a)pyrene ( BaP ) on testicular steroidogenesis and epididymal function in Fisher 344 rats . Animals were assigned r and omly to two control groups and one experimental group for each exposure regimen . Treatment consisted of sub-acute exposure of rats via inhalation to 25 , 75 , and 100 microg BaP/m(3 ) , 4 h daily for 10 days . Control animals were either exposed to carbon black ( CB ; sham ) to control for inert BaP carrier or they remained unexposed ( UNC ) . Blood sample s were collected immediately after the cessation of exposures ( time 0 ) and at 24 , 48 , and 72 h post-cessation of exposure , to assess the effect of bioavailable BaP on systemic testosterone and luteinizing hormone ( LH ) concentrations by radioimmunoassay ( RIA ) . Progressive sperm motility of stored sperm ( cauda epididymal sperm ) was determined microscopically , while density of stored sperm was determined by hemocytometric counting . Progressive motility of stored sperm was reduced in rats exposed to 75 and 100 microg BaP/m(3 ) compared with their counterparts that were exposed to 25 microg BaP/m(3 ) or controls . Plasma testosterone concentrations declined as a result of exposure of rats to 75 microg BaP/m(3 ) from 0 to 48 h post-termination of exposure compared with controls ( P<0.05 ; treatment x time interaction ) . This decrease was followed subsequently by a compensatory increase in the plasma concentrations of this steroid at 72 h post-cessation of exposures compared with previous time periods and controls ( P<0.05 ) . Increases in the mean plasma LH concentrations were observed in rats exposed to 75 microg BaP/m(3 ) compared with controls , throughout the time periods studied ( P<0.05 ; treatment x time interaction ) . These data suggest that sub-acute exposure to inhaled BaP contributes to reduced testosterone concentrations and consequently impaired epididymal function of exposed animals OBJECTIVE To determine the relationship between cigarette smoking and primary female infertility . DESIGN Retrospective , case-control study . SETTING Population -based and r and omly selected from eight geographic areas in the United States . PARTICIPANTS Women , 20 to 54 years of age , who were r and omly selected to serve as the control group of the Cancer and Steroid Hormone Study were used for this study . Within this group , there were 483 women who were classified as having experienced primary infertility and 2,231 women eligible to serve as controls . Primary infertility , defined as 24 consecutive months of unprotected intercourse without conception , was documented from a calendar of each women 's reproductive and contraceptive history . RESULTS Smoking one pack of cigarettes per day ( odds ratio = 1.36 ) and starting to smoke before 18 years of age ( odds ratio = 1.30 ) were significantly associated with increased risk of infertility . Life table and proportional hazards analysis indicated that smoking did not significantly increase the time required to conceive among infertile women . CONCLUSIONS Number of cigarettes smoked and age when the women began smoking contributed to infertility in this study . It is reasonable , therefore , to recommend that women stop smoking when they are attempting to become pregnant OBJECTIVE To evaluate whether endometrial parameters by three-dimensional ultrasonography and power Doppler angiography ( 3D US-PDA ) can predict in vitro fertilization/intracytoplasmic sperm injection ( IVF/ICSI ) outcome . DESIGN Prospect i ve clinical study . SETTING Assisted reproduction unit in a referral hospital . PATIENT(S ) Eighty women who underwent IVF cycles . INTERVENTION(S ) Endometrial 3D US-PDA evaluated by VOCAL software ( plane C and 9 degrees of rotational steps ) . MAIN OUTCOME MEASURE(S ) Endometrial pattern , endometrial thickness ( ET ) , endometrial volume ( EV ) , and PDA indexes of vascularization index ( VI ) , flow index ( FI ) , and vascularization flow index ( VFI ) were measured on the day of human chorionic gonadotropin ( hCG ) administration . These measurements were related to IVF/ICSI and embryo transfer outcome . RESULT ( S ) In the pregnant group , EV , VI , FI , and FVI but not triple-line pattern and ET were statistically significantly higher . The area under receiver operating characteristic ( ROC ) curve was statistically significant for EV ( 0.746 ) , VI ( 0.724 ) , FI ( 0.828 ) , and VFI ( 0.800 ) when no grade 1 embryos or only one were transferred ( 43 cycles , 14 pregnancies ) but not when two or three grade 1 embryos were transferred . Moreover , these parameters were statistically significant in predicting a normal pregnancy outcome ( no early pregnancy loss ) but were not related to multiple pregnancies . CONCLUSION ( S ) In IVF/ICSI cycles , 3D US-PDA is useful for evaluating endometrial receptivity . Endometrial volume and 3D power Doppler indexes are statistically significant in predicting the cycle outcome when one grade 1 or no grade 1 embryos are transferred , which could be helpful data in a single-embryo transfer policy BACKGROUND Smoking by both male and female partners may play a significant role in the success rates of assisted reproductive technologies . The objective of this 5-year prospect i ve study was to investigate the influence of cigarette smoking by the wife , husb and , and couple at various time points ( e.g. lifetime , week prior , or during the procedures ) on different biological parameters of IVF and gamete intra-Fallopian transfer ( GIFT ) . METHODS AND RESULTS A total of 221 couples , aged > 20 years , of Caucasian , Black , Asian or Hispanic descent were recruited from seven infertility clinics located in Southern California . Couples ( i.e. either female or male or both ) who ever smoked compared with non-smokers , had adjusted relative risks ( RR ) of 2.41 ( 95 % CI 1.07 - 5.45 , P = 0.03 ) of not achieving a pregnancy , and 3.76 ( 95 % CI 1.40 - 10.03 , P < 0.01 ) of not having a live birth delivery , while adjusting for potential confounders . For couples who smoked for > 5 years , there was an adjusted RR = 4.27 of not achieving a pregnancy ( 95 % CI l.53 - 11.97 , P = 0.01 ) . The number of oocytes retrieved decreased by 40 % for couples ( smokers , n = 6 ) and by 46 % for men who smoked during the week of the visit for IVF or GIFT . Women who smoked in their lifetime had adjusted risks of 2.71 of not achieving a pregnancy ( 95 % CI 1.37 - 5.35 , P < 0.01 ) , and 2.51 ( 95 % CI 1.11 - 5.67 , P < 0.03 ) of not having a live birth delivery . CONCLUSIONS There is compelling evidence that couples should be made aware that smoking years before undergoing IVF and GIFT can impact treatment outcome . This study may also provide insight into the timing and effects of male and female smoking on natural reproduction

Modest weight loss generated preferential loss of VAT , but with greater weight loss this effect was attenuated . The method of weight loss was not an influence with one exception . Very-low-calorie diets ( VLCDs ) provided exceptional short-term ( < 4 weeks ) preferential VAT loss . Conclusions : Visceral adipose tissue is lost preferentially with modest weight loss , but the effect is attenuated with greater weight loss . Acute caloric restriction , using VLCD , produces early preferential loss of VAT . These observations may help to explain the metabolic benefits of modest weight loss

Background : Visceral adipose tissue ( VAT ) is associated with greater obesity-related metabolic disturbance . Many studies have reported preferential loss of VAT with weight loss . Objective : This systematic review looks for factors associated with preferential loss of VAT relative to subcutaneous abdominal fat ( SAT ) during weight loss .

This study examined the effects of aerobic exercise without weight loss , a hypocaloric high monounsaturated fat diet , and diet plus exercise ( D+E ) on total abdominal and visceral fat loss in obese postmenopausal women with type 2 diabetes . Thirty-three postmenopausal women ( body mass index , 34.6 + /- 1.9 kg/m(2 ) ) were assigned to one of three interventions : a hypocaloric high monounsaturated fat diet alone , exercise alone ( EX ) , and D+E for 14 wk . Aerobic capacity , body composition , abdominal fat distribution ( magnetic resonance imaging ) , glucose tolerance , and insulin sensitivity were measured pre- and postintervention . Body weight ( approximately 4.5 kg ) and percent body fat ( approximately 5 % ) were decreased ( P < 0.05 ) with the D and D+E intervention , whereas only percent body fat ( approximately 2.3 % ) decreased with EX . Total abdominal fat and sc adipose tissue ( SAT ) were reduced with the D and D+E interventions ( P < 0.05 ) , whereas visceral adipose tissue ( VAT ) decreased with the D+E and EX intervention , but not with the D intervention . EX result ed in a reduction in total abdominal fat , VAT , and SAT ( P < 0.05 ) despite the lack of weight loss . The reductions in total abdominal fat and SAT explained 32.7 % and 9.7 % , respectively , of the variability in the changes in fasting glucose levels , whereas the reductions in VAT explained 15.9 % of the changes in fasting insulin levels ( P < 0.05 ) . In conclusion , modest weight loss , through either D or D+E , result ed in similar improvements in total abdominal fat , SAT , and glycemic status in postmenopausal women with type 2 diabetes ; however , the addition of exercise to diet is necessary for VAT loss . These data demonstrate the importance of exercise in the treatment of women with type 2 diabetes Background —C-reactive protein ( CRP ) has been proposed as an independent risk factor for cardiovascular disease and has been positively associated with body weight and body fatness . We examined the hypothesis that weight loss would reduce plasma CRP levels in obese postmenopausal women . Methods and Results —In a sample of 61 obese ( body mass index , 35.6±5.0 kg/m2 ) , postmenopausal women ( age , 56.4±5.2 years ) , we found that plasma CRP levels were positively associated with dual x-ray absorptiometry – measured total body fatness ( r = 0.36 , P < 0.005 ) and CT-measured intra-abdominal body fat area ( r = 0.30 , P < 0.02 ) . Significant correlations were also found between plasma CRP and triglyceride levels ( r = 0.33 , P < 0.009 ) and glucose disposal measured by the hyperinsulinemic-euglycemic clamp technique ( r = −0.29 , P < 0.03 ) . Twenty-five of the 61 women tested at baseline completed a weight loss protocol . The average weight loss was 14.5±6.2 kg ( −15.6 % , P < 0.0001 ) , with losses of 10.4±5.4 kg fat mass ( −25.0 % , P < 0.0001 ) and 2.8±1.4 kg fat-free mass ( −6.0 % , P < 0.0001 ) . Visceral and subcutaneous fat areas were reduced by −36.4 % and −23.7 % , respectively ( P < 0.0001 ) . Plasma CRP levels were significantly reduced by weight loss : average −32.3 % , from 3.06 ( + 0.69 , −1.29 ) to 1.63 ( + 0.70 , −0.75 ) & mgr;g/mL ( P < 0.0001 , medians and interquartile differences ) . Changes in body weight and in total body fat mass were both positively associated with plasma CRP level reductions . Conclusions —Adiposity was a significant predictor of plasma CRP in postmenopausal women on a cross-sectional basis . Moreover , caloric restriction – induced weight loss decreased plasma CRP levels . Weight loss may represent an important intervention to reduce CRP levels , which may mediate part of its cardioprotective effects in obese postmenopausal women The effects of energy restriction ( diet ) in combination with either aerobic ( DA ) or resistance exercise ( DR ) on adipose tissue ( AT ) distribution were evaluated in 24 obese women ( DA , n = 10 ; DR , n = 14 ) . AT distribution was measured by magnetic resonance imaging ( MRI ) . Comparison between groups demonstrated that the relative losses observed for body weight , subcutaneous AT ( SAT ) , and visceral AT ( VAT ) volume were not significantly different ( P > 0.05 ) . A significant reduction in the volume ratio of VAT to SAT was observed for both groups ( P < 0.01 ) . Comparison of arm , abdomen and torso , and lower-body regions revealed that the regional mobilization of SAT was not significantly different between groups ( P > 0.05 ) and that for both groups there was a preferential mobilization of SAT from the abdominal region ( P < 0.05 ) . Within the VAT depot , significant reductions were observed for both intraperitoneal and extraperitoneal AT ( P < 0.01 ) . These findings suggest that the combination of moderate energy restriction and either resistance or aerobic exercise induces significant reductions in VAT and SAT , with a preferential loss of VAT , and are thus effective means of reducing total and upper-body obesity in obese women BACKGROUND Dietary fat has been reported to influence insulin sensitivity . OBJECTIVE The objective of the study was to determine how identical weight loss ( target : loss of 8 % of body weight over 3 - 6 mo ) in women taking orlistat or placebo combined with a hypocaloric diet influences body composition and insulin sensitivity . DESIGN Forty-seven obese women [ body mass index ( in kg/m(2 ) ) : 32.1 + /- 0.4 ] were r and omly assigned to receive either orlistat ( 120 mg 3 times daily ; n = 23 ) or placebo ( n = 24 ) with a hypocaloric diet . Whole-body insulin sensitivity ( insulin clamp technique ) , serum fatty acids , and body composition ( magnetic resonance imaging ) were measured before and after weight loss . RESULTS The groups did not differ significantly at baseline with respect to age , body weight , intraabdominal and subcutaneous fat volumes , or insulin sensitivity . Weight loss did not differ significantly between the orlistat ( 7.3 + /- 0.2 kg , or 8.3 + /- 0.1 % ) and placebo ( 7.4 + /- 0.2 kg , or 8.2 + /- 0.1 % ) groups . Insulin sensitivity improved significantly ( P < 0.001 ) and similarly after weight loss in the orlistat ( from 4.0 + /- 0.3 to 5.1 + /- 0.3 mg x kg fat-free mass(-1 ) x min(-1 ) ) and placebo ( from 4.4 + /- 0.4 to 5.4 + /- 0.4 mg x kg fat-free mass(-1 ) x min(-1 ) ) groups . Intraabdominal fat and subcutaneous fat decreased significantly in both groups , but the ratio of the 2 decreased significantly only in the orlistat group . The proportion of dihomo-gamma-linolenic acid ( 20:3n-6 ) in serum phospholipids was inversely related to insulin sensitivity both before ( r = -0.48 , P < 0.001 ) and after ( r = -0.46 , P < 0.001 ) weight loss , but it did not change significantly in either group . CONCLUSIONS Weight loss rather than inhibition of fat absorption enhances insulin sensitivity . A decrease in fat absorption by orlistat appears to favorably influence the ratio between intraabdominal and subcutaneous fat , which suggests that exogenous fat or its composition influences fat distribution OBJECTIVE Moderate weight loss is recommended for overweight and obese patients with type 2 diabetes , and conjunctive use of weight loss medication has been advocated . The current study examined weight loss-dependent and -independent effects of the intestinal lipase inhibitor orlistat at 6 months of treatment , using behavioral intervention ( Int ) combined with r and omized , double-blinded , placebo (P)-controlled treatment with orlistat ( O ) . RESEARCH DESIGN AND METHODS Metabolic control , insulin sensitivity ( IS ) , regional fat distribution , and fat content in liver and muscle were measured in 39 volunteers with type 2 diabetes in whom all antidiabetic medication was withdrawn 1 month preceding r and omization . Weight loss was equivalent in the Int+O and Int+P groups , respectively ( -10.3 + /- 1.3 vs. -8.9 + /- 1.1 % ) , and there were identical decreases in visceral adipose tissue ( VAT ) , fat mass ( FM ) , thigh adiposity , and hepatic steatosis . RESULTS Weight loss result ed in substantial improvement ( P < 0.001 ) in HbA(1c ) ( -1.6 + /- 0.3 vs. -1.0 + /- 0.4 % ; NS between groups ) . IS improved significantly more with orlistat ( Delta2.2 + /- 0.4 vs. Delta1.2 + /- 0.4 mg . min(-1 ) . kg(-1 ) fat-free mass [ FFM ] ; P < 0.05 ) , and plasma free fatty acid ( FFA ) levels were strongly correlated with IS ( r = 0.56 ; P < 0.001 ) . Orlistat caused greater reductions in fasting plasma FFA ( Delta-154 + /- 22 vs. Delta-51 + /- 33 micro mol/l ; P < 0.05 ) , insulin-suppressed FFA ( Delta-119 + /- 23 vs. Delta-87 + /- 34 micro mol/l ; P < 0.05 ) , and fasting plasma glucose ( FPG ; -62 + /- 9 vs. -32 + /- 8 mg/dl ; P = 0.02 ) . Changes in HbA(1c ) were correlated with DeltaIS ( r = -0.41 ; P < 0.01 ) but not with weight loss per se . CONCLUSIONS At equivalent weight loss , conjunctive use of orlistat result ed in greater improvement in FFA levels and IS Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome ( PCOS ) . Dietary-induced weight loss and the administration of insulin-lowering drugs , such as metformin , are usually followed by improved hyper and rogenism and related clinical abnormalities . This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight , fat distribution , the glucose-insulin system , and hormones in a group of 20 obese PCOS women [ body mass index ( BMI ) > 28 kg/m2 ] with the abdominal phenotype ( waist to hip ratio > 0.80 ) , and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS . At baseline , we measured sex hormone , sex hormone-binding globulin ( SHBG ) , and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography ( CT ) at the L4-L5 level , to measure sc adipose tissue area ( SAT ) and visceral adipose tissue area . All women were then given a low-calorie diet ( 1,200 - 1,400 kcal/day ) alone for one month , after which anthropometric parameters and CT scan were newly measured . While continuing dietary treatment , PCOS women and obese controls were subsequently placed , in a r and om order , on metformin ( 850 mg/os , twice daily ) ( 12 and 8 , respectively ) or placebo ( 8 and 12 , respectively ) , according to a double-blind design , for the following 6 months . Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment . During the treatment period , 3 women of the control group ( all treated with placebo ) were excluded because of noncompliance ; and 2 PCOS women , both treated with metformin , were also excluded because they became pregnant . Therefore , the women cohort available for final statistical analysis included 18 PCOS ( 10 treated with metformin and 8 with placebo ) and 17 control women ( 8 treated with metformin and 9 with placebo ) . The treatment was well tolerated . In the PCOS group , metformin therapy improved hirsutism and menstrual cycles significantly more than placebo . Baseline anthropometric and CT parameters were similar in all groups . Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups , without any significant effect on CT scan parameters . In both PCOS and control women , however , metformin treatment reduced body weight and BMI significantly more than placebo . Changes in the waist-to-hip ratio values were similar in PCOS women and controls , regardless of pharmacological treatment . Metformin treatment significantly decreased SAT values in both PCOS and control groups , although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment . On the contrary , visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups , but only in the former was the effect of metformin treatment significantly higher than that of placebo . Fasting insulin significantly decreased in both PCOS women and controls , regardless of treatment , whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin . Neither metformin or placebo significantly modified the levels of LH , FSH , dehydroepi and rosterone sulphate , and progesterone in any group , whereas testosterone concentrations decreased only in PCOS women treated with metformin . SHBG concentrations remained unchanged in all PCOS women ; whereas in the control group , they significantly increased after both metformin and placebo . Leptin levels decreased only during metformin treatment in both PCOS and control groups . ( ABSTRACT TRUNCATED In a previous study we were the first to describe a negative correlation between circulating ghrelin concentrations and and rogen levels in human plasma , suggesting an interaction between ghrelin and the endocrine regulation of reproductive physiology . We now investigated a potential direct regulatory influence of circulating and rogens on plasma ghrelin levels . Fourteen obese women with polycystic ovary syndrome ( PCOS ) on a hypocaloric diet were r and omly assigned to treatment groups ( open-labeled design ) , receiving either placebo ( no.= 7 ) or the anti and rogen flutamide ( no.=7 ) for 6 months . Anthropometry , visceral ( VAT ) and subcutaneous ( SAT ) adipose tissue ( quantified by computerized tomography ) , plasma hormone levels , insulin sensitivity indexes ( Quantitative Insulin-Sensitivity Check Index-QUICKI ) and Homeostatic Model Assessment applied to the oral glucose tolerance test ( HOMAOGTT ) were evaluated at baseline and at the end of the study . Body weight decreased and insulin resistance indexes improved in both groups . A tendency toward a greater loss of VAT was observed in the flutamide group . Only in the flutamide group was a significant reduction of and rogens levels observed . Plasma ghrelin levels significantly increased following treatment with flutamide , while ghrelin remained unchanged in the placebo group . We observed a negative correlation between changes of ghrelin levels and changes of and rogen plasma concentration in the flutamide-treated group . In the same group a positive correlation was found between plasma ghrelin changes and insulin sensitivity as expressed by HOMAOGTT . Analysis in a multiple regression model , however , showed that plasma ghrelin changes were mainly due to changes of and rogen levels rather than improved insulin sensitivity . We , therefore , conclude that and rogens are independent modulators of circulating ghrelin concentrations We tested the hypothesis that reductions in total body and abdominal visceral fat with energy restriction would be associated with increases in cardiovagal baroreflex sensitivity ( BRS ) in overweight/obese older men . To address this , overweight/obese ( 25 < or = body mass index < or = 35 kg/m(2 ) ) young ( OB-Y , n = 10 , age = 32.9 + /- 2.3 yr ) and older ( OB-O , n = 6 , age = 60 + /- 2.7 yr ) men underwent 3 mo of energy restriction at a level design ed to reduce body weight by 5 - 10 % . Cardiovagal BRS ( modified Oxford technique ) , body composition ( dual-energy X-ray absorptiometry ) , and abdominal fat distribution ( computed tomography ) were measured in the overweight/obese men before weight loss and after 4 wk of weight stability at their reduced weight and compared with a group of nonobese young men ( NO-Y , n = 13 , age = 21.1 + /- 1.0 yr ) . Before weight loss , cardiovagal BRS was approximately 35 % and approximately 60 % lower ( P < 0.05 ) in the OB-Y and OB-O compared with NO-Y. Body weight ( -7.8 + /- 1.1 vs. -7.3 + /- 0.7 kg ) , total fat mass ( -4.1 + /- 1.0 vs. -4.4 + /- 0.8 kg ) , and abdominal visceral fat ( -27.6 + /- 6.9 vs. -43.5 + /- 10.1 cm(2 ) ) were reduced ( all P < 0.05 ) after weight loss , but the magnitude of reduction did not differ ( all P > 0.05 ) between OB-Y and OB-O , respectively . Cardiovagal BRS increased ( 11.5 + /- 1.9 vs. 18.5 + /- 2.6 ms/mmHg and 6.7 + /- 1.2 vs. 12.8 + /- 4.2 ms/mmHg ) after weight loss ( both P < 0.05 ) in OB-Y and OB-O , respectively . After weight loss , cardiovagal BRS in the obese/overweight young and older men was approximately 105 % and approximately 73 % ( P > 0.05 ) of NO-Y ( 17.5 + /- 2.2 ms/mmHg ) . Therefore , the results of this study indicate that weight loss increases the sensitivity of the cardiovagal baroreflex in overweight/obese young and older men In 1997 , the World Health Organization published a l and mark document recognizing obesity as a worldwide disease that poses a serious threat to public health ( 1 ) . Persons who are overweight or obese have substantially increased risk for morbidity from numerous chronic disorders , such as diabetes ( 2 , 3 ) , hypertension ( 4 , 5 ) , and cardiovascular disease ( 6 , 7 ) . Obesity-related health risk is greater when excess fat is deposited in the abdomen region because this phenotype is a stronger predictor of cardiovascular disease and type 2 diabetes mellitus than general obesity is ( 8 - 11 ) . This may be partially explained by excess accumulation of visceral fat , an independent correlate of insulin resistance ( 9 - 11 ) and dyslipidemia ( 8 , 9 ) . These observations highlight the need to identify appropriate treatment strategies to prevent and reduce obesity and suggest that the effectiveness of these treatments would be enhanced if abdominal obesity , particularly visceral fat , was substantially reduced . Diet restriction remains the most common method of obesity reduction ( 12 ) . Despite the observation that low levels of physical activity are a major cause of obesity ( 13 ) , increased physical activity alone is not thought to be a useful strategy for obesity reduction . Some reports have suggested that physical activity in obese adults results in only modest weight loss ( approximately 1 to 2 kg ) independent of the effects of diet restriction ( 14 ) . However , these conclusions are drawn from studies in which individual energy intake and expenditure were not rigorously controlled or accurately measured ( 15 - 17 ) . Moreover , in most studies , the negative energy balance induced by exercise was modest enough that substantial weight loss was not expected ( 15 - 17 ) . Currently , no compelling evidence supports the observation that exercise alone is not a useful method for reducing total or abdominal obesity . It is well known that a single exercise session is associated with a significant improvement in insulin-stimulated glucose uptake ( 18 , 19 ) . It is also clear that weight loss is associated with an improvement in insulin action ( 20 - 24 ) . It is unclear , however , whether regular exercise improves glucose metabolism after the short-term effects of exercise and changes in body fat distribution are considered . Segal and colleagues ( 25 ) controlled for the confounding effect of the last exercise session and body composition changes and found that exercise had no independent effect on insulin sensitivity ( 25 ) . Given the established importance of insulin resistance as an antecedent to both cardiovascular disease and type 2 diabetes mellitus ( 26 ) , it is important to clarify whether exercise improves insulin action independent of fat loss . We performed a r and omized , controlled trial to determine the independent effect of diet-induced or exercise-induced weight loss on obesity and insulin resistance in moderately obese men . We also evaluated whether exercise without weight loss was associated with reductions in abdominal obesity and insulin resistance . Methods Participants Participants were recruited from Kingston , Ontario , Canada , a typical suburban region , through the general media . We selected men with a body mass index greater than 27 kg/m2 and a waist circumference greater than 100 cm whose weight had been stable ( 2 kg ) for 6 months before study entry . Participants were nonsmokers who consumed an average of fewer than two alcoholic beverages per day , had a sedentary lifestyle , and took no medications known to affect the principal outcome measures . All participants had a preparticipation medical examination that included screening for normal glucose tolerance and plasma lipid profile . A computer program was used to r and omly assign eligible men to one of the following four groups : control , diet-induced weight loss , exercise-induced weight loss , and exercise without weight loss ( Figure 1 ) . Of the 101 participants who were r and omly assigned to groups , 34 chose not to participate because they were dissatisfied with their assigned group , 5 were diabetic or dyslipidemic , and 3 were relocated because of job transfers . Those who chose not to participate and those who completed the trial were similar with regard to anthropometric variables . In addition , those who completed the trial were similar to those who did not in each group ( P > 0.10 ) . Baseline characteristics among groups were similar for all participants ( Table 1 ) . All participants gave fully informed written consent . The study was conducted in accordance with the ethical guidelines of Queen 's University . The participants did not receive monetary compensation . Figure 1 . Flow of participants through the study . Table 1 . Selected Anthropometric , Magnetic Resonance Imaging , and Metabolic Variables before Treatment and 3 Months after Treatment Diet and Exercise Regimen During the baseline period , daily energy requirements for all participants were determined by estimating resting energy expenditure and multiplying the obtained value by a factor of 1.5 ( 27 ) . All participants followed a weight maintenance diet ( 55 % to 60 % carbohydrate , 15 % to 20 % protein , and 20 % to 25 % fat ) for a 4- to 5-week baseline period . During this period , body weight was monitored to determine the accuracy of the prescribed energy requirement , which was adjusted accordingly to maintain body weight . Controls were asked to maintain body weight throughout the 12-week treatment period . Participants in the diet-induced weight loss group were asked to reduce the isocaloric diet by 700 kcal/d during the treatment period to achieve a weekly weight loss of approximately 0.6 kg . To lose the same amount of weight , participants in the exercise-induced weight loss group were asked to maintain the isocaloric diet for the duration of the treatment period and to perform exercise that expended 700 kcal/d . Participants assigned to exercise without weight loss were asked to maintain body weight . Therefore , they consumed enough calories to compensate for the energy expended during the daily exercise sessions ( approximately 700 kcal ) . At the end of the treatment period , isocaloric requirements were determined and prescribed for a 2-week weight stabilization period . All participants were free-living and consumed self-selected foods . No vitamins or other nutritional supplements were prescribed . Each person participated in a series of weekly 1-hour seminars in which a dietitian taught proper food selection and preparation . Participants were told that the composition of the maintenance and energy-reduced diets should be approximately 55 % to 60 % carbohydrate , 15 % to 20 % protein , and 20 % to 25 % fat . Participants kept and analyzed daily , detailed food records for the duration of the study period ( approximately 20 weeks ) ; the study dietitian also review ed these records . For the 2-week period during which doubly labeled water measurements were acquired ( weeks 6 and 7 ) , the diet records were analyzed by using a computerized program ( Food Processor , Esha Research , Salem , Oregon ) . Participants in both exercise groups performed daily exercise ( brisk walking or light jogging ) on a motorized treadmill for the duration of the 12-week trial . The length of each exercise session was determined by the time required to expend 700 kcal . Participants were asked to exercise at an intensity not greater than 70 % of their peak oxygen uptake ( Vo 2 ) ( approximately 80 % of maximal heart rate ) . Energy expenditure was determined by using the heart rate and oxygen consumption data that were obtained from the pretreatment grade d exercise test and were adjusted according to the results of two subsequent tests performed at weeks 4 and 8 . During each session , heart rate was monitored every 5 minutes by using an automated heart rate monitor ( Polar Oy , Kempele , Finl and ) . All exercise sessions were by appointment and were supervised . Peak Vo 2 was determined by using a grade d treadmill test and st and ard open-circuit spirometry techniques ( SensorMedics , Yorba Linda , California ) . Energy Expenditure Total energy expenditure for 14 days was measured by using a two-point doubly labeled water method ( 28 ) . Deuterium enrichment was analyzed by using a 903 deuterium dual-inlet isotope ratio mass spectrometer ( VG Isogas , Cheshire , United Kingdom ) . Oxygen-18 was determined by using a SIRA 12 isotope ratio mass spectrometer ( VG Isogas ) . Total energy expenditure was calculated by using the DeWeir formula ( 29 ) . After an overnight stay in the hospital , resting metabolic rate was measured at 7:00 a.m. by using indirect calorimetry with a modified mask system ( Teem 100 , Aerosport , Inc. , Ann Arbor , Michigan ) . Values were obtained for 30 minutes , and the last 25 minutes were used to determine resting metabolic rate . Resting systolic and diastolic blood pressure were measured when the participant was supine . Magnetic Resonance Imaging and Anthropometric Measurements Whole-body data from magnetic resonance imaging ( approximately 45 equidistant images ) were obtained with a General Electric 1.5-Tesla magnet ( Milwaukee , Wisconsin ) by using an established protocol described in detail elsewhere ( 30 ) . Once acquired , the data were transferred to a st and -alone work station ( Silicon Graphics , Mountain View , California ) for analysis with specially design ed computer software ( Tomovision , Inc. , Montreal , Canada ) , the procedures for which are described elsewhere ( 31 ) . For adipose tissue ( fat ) and skeletal muscle , volume units ( L ) were converted to mass units ( kg ) by multiplying the volumes by the assumed constant density for fat ( 0.92 kg/L ) and fat-free skeletal muscle ( 1.04 kg/L ) ( 32 ) . All anthropometric circumference measurements were obtained by using st and ard procedures described elsewhere ( 30 ) . Insulin Sensitivity and Glucose Tolerance Participants consumed a weight-maintenance diet consisting of at least 200 g of carbohydrate for a minimum of 4 days and were asked to avoid strenuous physical activity for 3 days before insulin The independent effects of weight loss and exercise on plasma leptin and total ( AT ) , subcutaneous ( SAT ) , and visceral ( VAT ) adipose tissue were investigated in 52 obese men . Subjects were r and omly assigned to four 12-wk protocol s : 1 ) control ( C , n = 8) , 2 ) diet-induced weight loss ( DWL , n = 14 ) , 3 ) exercise-induced weight loss ( EWL , n = 14 ) , and 4 ) exercise with weight maintenance ( EWS , n = 16 ) . Plasma leptin was unchanged in C ( from 7.8 + /- 1.3 to 7.7 + /- 1.0 ng/ml ) . Equivalent weight loss ( 7.5 kg ) decreased leptin significantly but similarly ( DWL , from 8.5 + /- 1.0 to 4.8 + /- 0.6 ng/ml ; EWL , from 10.1 + /- 1.0 to 5.0 + /- 0.6 ng/ml ) . Exercise in the absence of weight loss did not alter leptin levels ( from 10.1 + /- 1 . 3 to 9.2 + /- 1.2 ng/ml ) . Changes in leptin correlated with changes in AT and SAT ( both P < 0.05 ) but not in VAT . We conclude that reduction in adipose tissue after weight loss results in a collateral decrease in circulating leptin , and exercise , independent of its effects on weight loss , has no profound influence on leptin secretion OBJECTIVE : To test the effects on abdominal fat reduction of adding aerobic exercise training to a diet program and obesity phenotype in response to weight loss . DESIGN : A prospect i ve clinical trial with a 14-week weight-loss intervention design . SETTING AND PARTICIPANTS : In total , 209 overweight and obese women were assigned to four subgroups depending on type of treatment and the subject 's obesity phenotype : diet alone ( DA ) with intra-abdominal fat ( IF ) obesity ( ≥mean IF area ) , diet plus exercise ( DE ) with IF obesity , DA with abdominal subcutaneous fat ( ASF ) obesity ( < mean IF area ) and DE with ASF obesity . Abdominal fat areas were evaluated by CT scans , with values adjusted for selected variables . RESULTS : Values were adjusted for age , menopausal status and change in body weight and total fat mass . The IF reductions were significantly ( P<0.0001 ) greater in subjects with IF obesity phenotype ( −45.1 cm2 ) compared to the ASF obesity phenotype ( −22.2 cm2 ) . The ASF reductions were significantly ( P<0.001 ) greater for subjects with ASF obesity ( −74.5 cm2 ) compared to IF obesity ( −55.5 cm2 ) . For IF obesity , the IF reduction was significantly ( P<0.01 ) greater in the DE group ( −49.3 cm2 ) than in the DA group ( −37.8 cm2 ) . CONCLUSION : These results suggest that for individuals with IF obesity , the efficacy on reducing IF of adding aerobic exercise training to a diet-alone weight-reduction program is more prominent ( −49.3 cm2/−37.8 cm2=1.3 times ) compared with DA . Moreover , abdominal fat reduction was found to be modified by obesity phenotype in response to weight loss CONTEXT The increasing prevalence of obesity is a major public health concern . Physical activity may promote weight and body fat loss . OBJECTIVE To examine the effects of exercise on total and intra-abdominal body fat overall and by level of exercise . DESIGN R and omized controlled trial conducted from 1997 to 2001 . SETTING AND PARTICIPANTS A total of 173 sedentary , overweight ( body mass index > or = 24.0 and > 33 % body fat ) , postmenopausal women aged 50 to 75 years who were living in the Seattle , Wash , area . INTERVENTION Participants were r and omly assigned to an intervention consisting of exercise facility and home-based moderate-intensity exercise ( n = 87 ) or a stretching control group ( n = 86 ) . MAIN OUTCOME MEASURE Changes in body weight and waist and hip circumferences at 3 and 12 months ; total body , intra-abdominal , and subcutaneous abdominal fat at 12 months . RESULTS Twelve-month data were available for 168 women . Women in the exercise group participated in moderate-intensity sports/recreational activity for a mean ( SD ) of 3.5 ( 1.2 ) d/wk for 176 ( 91 ) min/wk . Walking was the most frequently reported activity . Exercisers showed statistically significant differences from controls in baseline to 12-month changes in body weight ( -1.4 kg ; 95 % confidence interval [ CI ] , -2.5 to -0.3 kg ) , total body fat ( -1.0 % ; 95 % CI , -1.6 % to -0.4 % ) , intra-abdominal fat ( -8.6 g/cm2 ; 95 % CI , -17.8 to 0.9 g/cm2 ) , and subcutaneous abdominal fat ( -28.8 g/cm2 ) ; 95 % CI , -47.5 to -10.0 g/cm2 ) . A significant dose response for greater body fat loss was observed with increasing duration of exercise . CONCLUSIONS Regular exercise such as brisk walking results in reduced body weight and body fat among overweight and obese postmenopausal women OBJECTIVE To evaluate the influence of a twice-weekly progressive resistance training ( PRT ) program , without a concomitant weight loss diet , on abdominal fat and insulin sensitivity in older men with type 2 diabetes . RESEARCH DESIGN AND METHODS Nine older men ( aged 66.6 + /- 3.1 ) with type 2 diabetes participated in a 16-week PRT supervised program ( 50 - 80 % of the one repetition maximum ) , for all main muscle groups . Basal glycemia , HbA(1c ) , diet , habitual physical activity , body composition , and upper/lower maximal strength were measured . Insulin sensitivity was determined according to Bergman 's minimal model procedure and abdominal fat was obtained by computed tomography . The measurements were taken 4 weeks before training ( -4 ) , immediately before training ( 0 ) , and at 8-week intervals ( i.e. , weeks 8 and 16 ) during the 16-week training period . RESULTS No significant variation was observed in any of the above selected parameters during the 4-week control period . After PRT , both leg and arm maximal strength increased significantly by 17.1 and 18.2 % , respectively . Visceral and subcutaneous abdominal fat decreased significantly by 10.3 % ( from 249.5 + /- 97.9 to 225.6 + /- 96.6 cm(3 ) , P < 0.01 ) and by 11.2 % ( from 356.0 + /- 127.5 to 308.6 + /- 118.8 cm(3 ) , P < 0.01 ) , respectively , while no changes were observed in body mass . PRT significantly increased insulin sensitivity by 46.3 % ( from 2.0 + /- 1.2 to 2.8 + /- 1.6 . 10(4 ) . min(-1 ) . muU(-1 ) . ml(-1 ) , P < 0.01 ) , whereas it significantly decreased ( -7.1 % , P < 0.05 ) fasting blood glucose ( from 146.6 + /- 28.3 to 135.0 + /- 29.3 mg/dl ) . Finally , a 15.5 % increase in energy intake ( from 2,287.1 + /- 354.7 to 2,619.0 + /- 472.1 kcal/day , P < 0.05 ) was observed . CONCLUSIONS Two sessions per week of PRT , without a concomitant weight loss diet , significantly improves insulin sensitivity and fasting glycemia and decreases abdominal fat in older men with type 2 diabetes OBJECTIVE To determine whether " low-intensity " exercise ( walking ) and " high-intensity " exercise ( aerobic dance ) , when added to a weight loss diet , have different effects on coronary heart disease ( CHD ) risk factors and physical fitness . RESEARCH METHODS AND PROCEDURES Ninety obese women were divided into diet only ( DO ) , diet plus walking ( DW ) , and diet plus aerobic dance ( DA ) groups . DXA was used to evaluate segmental body composition . Leg-extension strength and maximal oxygen uptake ( VO2max ) were the indicators of physical fitness . Blood pressure , lipoproteins , and fasting glucose were used as indices for CHD risk factors . These items were measured before and after a 14-week intervention period . RESULTS Whole-body plus all segmental fat masses were significantly reduced ( p < 0.001 ) . Reductions in whole-body and lower-limb fat- and bone-free masses were significantly less ( p < 0.01 ) in the DA group ( -1.5 and -0.1 kg , respectively ) compared with the DO ( -2.1 and -0.4 kg , respectively ) and DW ( -2.5 and -0.5 kg , respectively ) groups . Improvements in leg-extension strength and VO2max were significantly greater ( p < 0.05 ) in the DA group compared with the DO group . The CHD risk factors clearly improved ( p < 0.05 ) within each group . Reductions in low density lipoprotein-cholesterol and fasting glucose were significantly greater ( p < 0.05 ) in the DA group compared with the DO and DW groups . DISCUSSION Adding higher intensity aerobic dance to a weight-loss diet program may help maintain fat- and bone-free mass and may be more effective in improving CHD risk factors compared with low-intensity walking OBJECTIVE : To examine the influence of sex on whole body and regional subcutaneous , visceral , total adipose tissue ( AT ) , skeletal muscle ( SM ) , and lean tissue in response to weight loss induced by diet alone ( DO ) or the combination of diet and aerobic ( DA ) or resistance exercise ( DR ) . DESIGN : Sixty upper‐body obese men and women were r and omly assigned to one of three treatments : DO , DA , or DR . All tissues were measured using a whole body , magnetic resonance imaging protocol . RESULTS : Within each group reductions were observed for body weight ( ~11 kg ) , subcutaneous and visceral AT ( P<0.01 ) . After controlling for pretreatment differences in tissue size , reductions in total adiposity , total and regional subcutaneous and visceral adipose tissue were not different between sexes ( P>0.1 ) . Independent of sex , the reduction in visceral AT was greater than subcutaneous AT ( P<0.05 ) in response to DO and DA . With the exception of DA women , the reduction in abdominal subcutaneous AT was greater ( P<0.05 ) than lower‐body subcutaneous AT in response to diet and exercise , but not diet alone , in both sexes ( P>0.05 ) . Independent of sex , skeletal muscle mass was preserved within the exercise groups ( P>0.05 ) but not diet alone ( P<0.05 ) . Peak VO2 ( l/min ) improved in the DA groups as did muscular strength in the DR groups ( P<0.01 ) . CONCLUSIONS : These findings indicate that in response to diet or diet and exercise‐induced weight loss , reductions in total adiposity , subcutaneous and visceral adipose tissue distribution are not different in obese men and women . Independent of sex , the combination of diet and exercise results in a preservation of skeletal muscle mass , a preferential reduction of abdominal subcutaneous AT , and improved functional capacity by comparison to diet alone BACKGROUND AND AIM Little is known about the association between abdominal obesity and insulin sensitivity during rapid weight loss . We assessed the role of visceral and subcutaneous fat as determinants of insulin sensitivity during rapid weight loss in obese persons with the metabolic syndrome . METHODS AND RESULTS Twenty abdominally obese individuals [ 11 women and 9 men , body mass index ( BMI ) 35.8+/-3.5 kg/m2 ] with the metabolic syndrome underwent a very-low-calorie diet ( VLCD ) for nine weeks . At baseline , the computed tomography ( CT ) measured area of total ( r=-0.50 , p=0.033 ) and visceral fat tissue ( r=-0.48 , p=0.043 ) , but not that of subcutaneous fat tissue ( r=-0.34 , p=0.17 ) , correlated with insulin sensitivity as assessed by the quantitative insulin sensitivity check index after adjusting for sex and age . The 18 subjects who completed the study lost 14.8 kg during the VLCD . Total , visceral and subcutaneous abdominal fat tissue decreased by 22 % , 29 % and 17 % , respectively . The decrease in total ( r=-0.51 , p=0.035 ) and subcutaneous abdominal fat ( r=-0.57 , p=0.017 ) , but not visceral fat ( r=0.11 , p=0.68 ) , correlated with the increase in insulin sensitivity . Waist circumference did not offer any additional information concerning abdominal fat distribution or insulin sensitivity compared with that provided by BMI at baseline or after weight loss . The waist/hip ratio was not associated with the CT measures of abdominal fat distribution or insulin sensitivity . CONCLUSIONS Total abdominal fat may be more important than its compartmentalisation in abdominally obese individuals with the metabolic syndrome . In this subgroup of individuals with obesity , the measurement of waist circumference and the waist/hip ratio offered little additional information over that provided by BMI at baseline or after weight loss OBJECTIVES To determine the effects of equivalent diet- or exercise-induced weight loss and exercise without weight loss on subcutaneous fat , visceral fat , and insulin sensitivity in obese women . RESEARCH METHODS AND PROCEDURES Fifty-four premenopausal women with abdominal obesity [ waist circumference 110.1 + /- 5.8 cm ( mean + /- SD ) ] ( BMI 31.3 + /- 2.0 kg/m2 ) were r and omly assigned to one of four groups : diet weight loss ( n = 15 ) , exercise weight loss ( n = 17 ) , exercise without weight loss ( n = 12 ) , and a weight-stable control group ( n = 10 ) . All groups underwent a 14-week intervention . RESULTS Body weight decreased by approximately 6.5 % within both weight loss groups and was unchanged in the exercise without weight loss and control groups . In comparison with controls , cardiorespiratory fitness improved within the exercise groups only ( p < 0.01 ) . Reduction in total , abdominal , and abdominal subcutaneous fat within the exercise weight loss group was greater ( p < 0.001 ) than within all other groups . The reduction in total and abdominal fat within the diet weight loss and exercise without weight loss groups was greater than within controls ( p < 0.001 ) but not different from each other ( p > 0.05 ) . Visceral fat decreased within all treatment groups ( p < 0.008 ) , and these changes were not different from each other . In comparison with the control group , insulin sensitivity improved within the exercise weight loss group alone ( p < 0.001 ) . DISCUSSION Daily exercise without caloric restriction was associated with substantial reductions in total fat , abdominal fat , visceral fat , and insulin resistance in women . Exercise without weight loss was also associated with a substantial reduction in total and abdominal obesity Introduction The relation between insulin-leptin-visceral fat axis during weight loss has not been studied previously . Aims To evaluate the insulin , leptin , and abdominal adiposity relation during weight loss in patients with upper body obesity . Methodology Twenty volunteers ( 7 men , 13 women ) with mean age 50.6 ± 6.3 ( SD ) and upper body obesity ( weight 105.4 ± 12.3 kg , BMI 35.9 ± 2.5 kg/m 2 ) were recruited . Participants were enrolled in a one-arm clinical study using a calorie-deficient diet and an escalating dose regimen of sibutramine , starting with 5 mg daily and increasing in 5-mg increments to 20 mg per day . Body weight , insulin , leptin , glucose , lipids , abdominal computed tomography ( CT ) , and total body electrical conductance ( TOBEC ) were measured serially at weeks 0 , 4 , 8 , 12 , and 24 . Results Eighteen patients completed the 6-month study : one man and one woman discontinued because of adverse events . With diet and sibutramine , body weight was significantly and continuously reduced throughout the 6-month study . There was a 16.0 % ( p = 0.0001 ) reduction in body weight ( p < 0.001 ) and 22.5 % ( p = 0.0001 ) decrease in total body fat mass . Abdominal CT scans showed a 28.3 % ( p = 0.0001 ) reduction in total abdominal fat , a 26.0 % ( p = 0.0001 ) reduction in subcutaneous fat ( p < 0.001 ) , and a 31.0 % ( p = 0.0003 ) reduction in visceral fat ( p < 0.001 ) . There was a 32.0 % ( p = 0.0008 ) reduction in leptin levels and 37.9 % ( p = 0.0001 ) reduction in insulin levels between baseline and week 4 , but no further significant reduction in leptin and insulin levels was observed for the duration of the study . There was a significant correlation between insulin and leptin concentrations throughout the study ( p = 0.0001 ) . Leptin was presented as a function of insulin measured at the same time . Significant associations between visceral abdominal fat , subcutaneous fat , and leptin were also observed . Conclusion In this study , we found that leptin and insulin were related in weight loss . The data suggest that insulin may act as a strong regulator of leptin secretion during weight loss and that circulating leptin levels can be predicted by insulin level . Using sibutramine in conjunction with hypocaloric diet reduced body weight and decreased fat mass significantly . Visceral and subcutaneous abdominal fat depots were shown to decrease . Whether sibutramine exerts any selective reduction of visceral abdominal fat as opposed to total body fat mass will require further clinical investigation OBJECTIVE To evaluate the effects of an intense physical training program on abdominal fat distribution , glycemic control , and insulin sensitivity in patients with NIDDM and to determine whether branched-chain amino acid ( BCAA ) supplements influence these effects . RESEARCH DESIGN AND METHODS Twenty-four patients ( ages 45 ± 2 [ mean ± SE ] years , BMI 30.2 ± 0.9 kg/m2 , HbA1c 7.9 ± 0.3 % ) were r and omly assigned to four groups : training plus BCAA supplement ( n = 6 ) , training plus placebo ( n = 6 ) , sedentary plus BCAA supplement ( n = 6 ) , and sedentary plus placebo ( n = 6 ) . Physical training consisted of a supervised 45-min cycling exercise at 75 % of their oxygen uptake peak ( VO2 peak ) two times per week and an intermittent exercise one time per week for 2 months . RESULTS Patients who exercised increased their VO2 peak by 41 % and their insulin sensitivity by 46 % . Physical training significantly decreased abdominal fat evaluated by magnetic resonance imaging ( umbilicus ) , with a greater loss of visceral adipose tissue ( VAT ) ( 48 % ) in comparison with the loss of subcutaneous adipose tissue ( 18 % ) , but did not significantly affect body weight . The change in visceral abdominal fat was associated with the improvement in insulin sensitivity ( r = 0.84 , P = 0.001 ) . BCAA supplementation had no effect on abdominal fat and glucose metabolism . CONCLUSIONS Physical training result ed in an improvement in insulin sensitivity with concomitant loss of VAT and should be included in the treatment program for patients with NIDDM OBJECTIVE To analyze the relationship between visceral fat accumulation and resting energy expenditure in obese women and to evaluate the effects of a severe weight loss both on energy expenditure and on fat distribution . DESIGN Twelve premenopausal women , aged 19 - 50 years , undergoing adjustable silicone gastric b and ing ( ASGB ) for morbid obesity participated at the study . The patients were evaluated twice . The baseline evaluation was performed immediately before surgery . After surgery , a diet specifically developed for patients su bmi tted to gastric restriction ( 2.5 MJ/day ) was given to the patients . The second evaluation was performed 6 months after surgery . MEASUREMENTS Resting metabolic rate ( RMR ) was determined by indirect calorimetry . Total fat area ( TFA ) , visceral fat area ( VFA ) and subcutaneous fat area ( SFA ) were measured by abdominal computed tomography . Fat mass ( FM ) and fat free mass ( FFM ) were derived by bioelectrical impedance analysis . RESULTS At baseline , RMR was positively related to VFA ( r = 0.60 , P < 0.05 ) . ASGB induced a highly significant weight loss of 24.4 + /- 9.0 kg . This weight reduction was mainly due to a loss of FM ( 68.5 + /- 10.8 vs 48.5 + /- 9.2 kg , P < 0.001 ) , whereas FFM was only slightly reduced ( 52.6 + /- 4.0 vs 47.9 + /- 4.6 kg , P < 0.05 ) . The BMI reduction was positively related to the baseline BMI and FM values ( r = 0.61 , P < 0.05 and r = 0.55 , P < 0.05 , respectively ) . There was no significant correlation between the BMI reduction and the baseline variables of fat distribution , nor between the BMI reduction and the basal RMR . Weight loss was accompanied by modifications of fat distribution . In particular , the reduction of VFA after surgery was strictly related to the VFA values at baseline ( r = 0.91 , P < 0.001 ) . Weight loss induced a significant reduction of RMR ( 7.96 + /- 1.77 vs 6.57 + /- 6.90 MJ/day ; P < 0.01 ) . The reduction of the RMR observed with weight loss was significantly related to the FFM loss ( r = 0.63 , P < 0.05 ) , whereas no correlations were found between the changes of RMR and the FM loss . Regarding to fat distribution , the reduction of the RMR was significantly related to the visceral fat loss ( r = 0.57 , P < 0.05 ) , but not to the modifications of total or subcutaneous fat area . The independent contribution of the modifications of FFM , FM , and visceral fat to the changes of RMR was analyzed by multiple regression analysis . In this model , both FFM and visceral fat changes result ed independently related to the RMR . CONCLUSIONS ( 1 ) visceral fat accumulation was a significant predictor of RMR in the very obese woman ; ( 2 ) visceral obese women lost more visceral fat than subcutaneous ones ; ( 3 ) the reduction of the RMR observed during weight loss could partly be explained by a reduction of visceral fat mass BACKGROUND The majority of patients with coronary heart disease ( CHD ) are overweight . However , little weight loss occurs with participation in a st and ard cardiac rehabilitation ( CR ) program . METHODS Fifteen overweight patients ( average body mass index of 31.0 kg/m2 ) with CHD completed a 4-month exercise training program in a CR program . The exercise program consisted primarily of walking long duration ( 60 - 90 minutes per session ) 5 to 7 days per week at a relatively low intensity of 50 % to 60 % of peak VO2 . Measures of body composition by dual-energy x-ray absorptiometry , body fat distribution by computed tomography , plasma lipid-lipoprotein , glucose and insulin concentrations , and peak VO2 were obtained before and after the exercise intervention . Patients maintained an isocaloric diet throughout the study . RESULTS Patients had reductions in total body weight ( -4.6 kg ) , fat mass ( -3.6 kg ) , percent body fat ( -2.9 % ) , and waist circumference ( -5.6 cm ) ( all P < .001 ) while maintaining fat-free mass . Subcutaneous adipose tissue was reduced by 12 % ( P < .001 ) and visceral adipose tissue was lowered by 14 % ( P < .001 ) . There were favorable changes in the lipid-metabolic profile with reductions in triglyceride levels ( -23.7 % ) , total cholesterol/HDL-C ratio ( -14.3 % ) , and fasting insulin levels ( -22.3 % ) ( all P < .05 ) . Peak VO2 increased by 21.2 % ( P < .001 ) . CONCLUSIONS The present pilot study results suggest that a high caloric training exercise training program in the CR setting may be effective in promoting weight loss and improving coronary risk factors in overweight coronary patients . Although additional research with r and omized control patients is needed , this alternative to traditional CR may be considered to maximize weight loss as part of a secondary prevention program OBJECTIVE To compare the effects of testosterone enanthate ( TE ) , anabolic steroid ( AS ) or placebo ( PL ) on regional fat distribution and health risk factors in obese middle-aged men undergoing weight loss by dietary means . DESIGN R and omized , double-blind , placebo-controlled clinical trial , carried out for 9 months with primary assessment s at 3 month intervals . Due to adverse blood lipid changes , the AS group was switched from oral ox and rolone ( ASOX ) to parenteral n and rolone decaoate ( ASND ) after the 3 month assessment point . SUBJECTS Thirty healthy , obese men , aged 40 - 60 years , with serum testosterone ( T ) levels in the low-normal range ( 2 - 5 ng/mL ) . MAIN OUTCOME MEASURES Abdominal fat distribution and thigh muscle volume by CT scan , body composition by dual energy X-ray absorptiometry ( DEXA ) , insulin sensitivity by the Minimal Model method , blood lipids , blood chemistry , blood pressure , thyroid hormones and urological parameters . RESULTS After 3 months , there was a significantly greater decrease in subcutaneous ( SQ ) abdominal fat in the ASOX group compared to the TE and PL groups although body weight changes did not differ by treatment group . There was also a tendency for the ASOX group to exhibit greater losses in visceral fat , and the absolute level of visceral fat in this group was significantly lower at 3 months than in the TE and PL groups . There were significant main effects of treatment at 3 months on serum T and free T ( increased in the TE group and decreased in the ASOX group ) and on thyroid hormone parameters ( T4 and T3 resin uptake significantly decreased in the ASOX group compared with the other two groups ) . There was a significant decrease in HDL-C , and increase in LDL-C in the ASOX group , which led to their being switched to the parenteral n and rolone decanoate ( ASND ) after 3 months . ASND had opposite effects on visceral fat from ASOX , producing a significant increase from 3 to 9 months while continuing to decrease SQ abdominal fat . ASND treatment also decreased thigh muscle area , while ASOX treatment increased high muscle . ASND reversed the effects of ASOX on lipoproteins and thyroid hormones . The previously reported effect of T to decrease visceral fat was not observed , in fact , visceral fat in the TE group increased slightly from 3 to 9 months , although SQ fat continued to decrease . Neither TE nor AS treatment result ed in any change in urologic parameters . CONCLUSIONS Oral ox and rolone decreased SQ abdominal fat more than TE or weight loss alone and also tended to produce favorable changes in visceral fat . TE and ASND injections given every 2 weeks had similar effects to weight loss alone on regional body fat . Most of the beneficial effects observed on metabolic and cardiovascular risk factors were due to weight loss per se . These results suggest that SQ and visceral abdominal fat can be independently modulated by and rogens and that at least some anabolic steroids are capable of influencing abdominal fat The aim of this study was to evaluate the effects of sibutramine on body composition and fat distribution , insulin resistance , and serum adiponectin levels in obese women . A total of 28 obese , premenopausal women ( mean age , 34.5 + /- 13.7 years ; BMI , 31.00 + /- 4.10 kg/m2 ) was studied before and after 12-week-course of sibutramine ( 10mg/day ) . Sibutramine treatment reduced body mass index ( P < 0.05 ) and total body fat ( P < 0.05 ) . Abdominal subcutaneous and visceral fat areas ( ASFA and AVFA ) and mid-thigh low density muscle areas ( LDMA ) measured by computed-tomography decreased significantly ( all , P < 0.05 ) . Insulin resistance ( IR ) calculated from the homeostasis model assessment ( HOMA ) method decreased ( P < 0.05 ) and serum adiponectin levels increased significantly ( P < 0.05 ) . In our sequential data , the changes of fasting serum insulin levels and the HOMA-IR scores , serum free fatty acids and triglyceride levels , serum adiponectin levels and the mid-thigh LDMA preceded significant changes of body weight , total body fat , and abdominal fat distribution , suggesting sibutramine might improve insulin sensitivity directly by alterations of fatty acid metabolism or secondarily by increasing serum adiponectin levels . Conclusively , sibutramine improved fat distribution and insulin resistance , and increased serum adiponectin levels in Korean obese nondiabetic premenopausal women OBJECTIVE This study had two objectives . First , we examined whether the influence of diet combined with either aerobic ( DA ) ( n = 10 ) or resistance ( DR ) ( n = 10 ) exercise has effects on insulin and glucose levels that are different in obese men . Second , we tried to determine whether the combination of diet and exercise is associated with improvements in insulin and glucose levels that are greater than those associated with diet alone ( DO ) ( n = 9 ) . RESEARCH DESIGN AND METHODS Insulin and glucose levels were measured after an overnight fast and a 75-g oral glucose challenge ( OGTT ) . Visceral adipose tissue ( AT ) , subcutaneous AT , and skeletal muscle were measured by magnetic resonance imaging ( MRI ) before and after treatment ( 16 weeks ) . RESULTS Reductions in weight ( 12.4 + /- 3.8 kg ) and in visceral ( 37 + /- 15.1 % ) and subcutaneous AT ( 24.3 + /- 8.6 % ) were not different between treatments ( P > 0.05 ) . Skeletal muscle was maintained in the DA and DR groups but was reduced ( 7.3 + /- 2.8 % ) in the DO group ( P < 0.05 ) . Independent of treatment , fasting glucose and OGTT glucose did not change ( P > 0.05 ) . However , fasting insulin , OGTT insulin , and the insulin-to-glucose ratio decreased within all treatments ( P < 0.05 ) . Reductions in the OGTT insulin area under the curve were greater ( P < 0.05 ) within the DA ( 52 + /- 12 % ) and DR ( 42 + /- 17 % ) treatments than in the DO ( 20 + /- 15 % ) treatment . Collapsed across group , reductions in visceral AT were related to reductions in fasting and OGTT glucose ( P < 0.05 ) , whereas reductions in abdominal subcutaneous AT correlated with reductions in fasting insulin ( P < 0.05 ) . CONCLUSIONS Weight loss induced by diet and aerobic or resistance exercise has similar positive effects on lowering fasting and OGTT insulin values that are greater than those with diet alone . Because changes in glucose and insulin were related to reductions in visceral and abdominal subcutaneous AT , we conclude that reduction in abdominal obesity consequent to diet and exercise-induced weight loss is important for attaining improvements in plasma insulin levels , observations that strengthen the concept that abdominal obesity has an important role in mediating insulin resistance

The preponderance of evidence suggests a positive impact of PSPs on adherence , clinical and humanistic outcomes . Although less often measured , health care utilization and costs are also reduced following PSP implementation .

BACKGROUND Patient support programs ( PSPs ) , including medication management and counseling , have the potential to improve care in chronic disease states with complex therapies . Little is known about the program 's effects on improving clinical , adherence , humanistic , and cost outcomes . PURPOSE To conduct a targeted review describing medical conditions in which PSPs have been implemented ; support delivery components ( eg , face-to-face , phone , mail , and internet ) ; and outcomes associated with implementation .

BACKGROUND Cardiovascular disease ( CVD ) and diabetes account for one-third of the mortality difference between African American and white patients . We evaluated the effect of a CVD risk reduction intervention in African Americans with diabetes . METHODS We r and omized 359 African Americans with type 2 diabetes to receive usual care or a nurse telephone intervention . The 12-month intervention provided monthly self-management support and quarterly medication management facilitation . Co primary outcomes were changes in systolic blood pressure ( SBP ) , hemoglobin A1c ( HbA1c ) , and low-density lipoprotein cholesterol ( LDL-C ) over 12 months . We estimated between-intervention group differences over time using linear mixed-effects models . The secondary outcome was self-reported medication adherence . RESULTS The sample was 72 % female ; 49 % had low health literacy , and 37 % had annual income < $ 10,000 . Model-based estimates for mean baseline SBP , HbA1c , and LDL-C were 136.8 mm Hg ( 95 % CI 135.0 - 138.6 ) , 8.0 % ( 95 % CI 7.8 - 8.2 ) , and 99.1 mg/dL ( 95 % CI 94.7 - 103.5 ) , respectively . Intervention patients received 9.9 ( SD 3.0 ) intervention calls on average . Primary providers replied to 76 % of nurse medication management facilitation contacts , 18 % of these result ed in medication changes . There were no between-group differences over time for SBP ( P = .11 ) , HbA1c ( P = .66 ) , or LDL-C ( P = .79 ) . Intervention patients were more likely than those receiving usual care to report improved medication adherence ( odds ratio 4.4 , 95 % CI 1.8 - 10.6 , P = .0008 ) , but adherent patients did not exhibit relative improvement in primary outcomes . CONCLUSIONS This intervention improved self-reported medication adherence but not CVD risk factor control among African Americans with diabetes . Further research is needed to determine how to maximally impact CVD risk factors in African American patients Background — Even in high-performing health systems , some patients with diabetes mellitus have poor blood pressure ( BP ) control because of poor medication adherence and lack of medication intensification . We examined whether the Adherence and Intensification of Medications intervention , a pharmacist-led intervention combining elements found in efficacy studies to lower BP , improved BP among patients with diabetes mellitus with persistent hypertension and poor refill adherence or insufficient medication intensification in 2 high-performing health systems . Methods and Results — We conducted a prospect i ve , multisite cluster r and omized pragmatic trial with r and omization of 16 primary care teams at 5 medical centers ( 3 Veterans Affairs and 2 Kaiser Permanente ) to the Adherence and Intensification of Medications intervention or usual care . The primary outcome was relative change in systolic BP ( SBP ) , comparing 1797 intervention with 2303 control team patients , from 6 months preceding to 6 months after the 14-month intervention period . We examined shorter-term changes in SBP as a secondary outcome . The mean SBP decrease from 6 months before to 6 months after the intervention period was ≈9 mm Hg in both arms . Mean SBPs of eligible intervention patients were 2.4 mm Hg lower ( 95 % CI : −3.4 to −1.5 ; P<0.001 ) immediately after the intervention than those achieved by control patients . Conclusions — The Adherence and Intensification of Medications program more rapidly lowered SBPs among intervention patients , but usual-care patients achieved equally low SBP levels by 6 months after the intervention period . These findings show the importance of evaluating in different real-life clinical setting s programs found in efficacy trials to be effective before urging their widespread adoption in all setting s. Clinical Trial Registration — URL : http:// clinical trials.gov . Unique identifier : NCT00495794 Background : Diabetes mellitus ( DM ) requires continuous medical care , patients ’ self-management , education , and adherence to prescribed medication to reduce the risk of long-term complications . The aim of this study was to assess the benefits of an education program on diabetes , patient self-management , adherence to medication , anxiety , depression and glycemic control in type 2 diabetics in Saudi Arabia . Material s and Methods : This was a prospect i ve study , conducted among 104 diabetic patients at a major tertiary hospital in Riyadh , Saudi Arabia , between May 2011 and October 2012 . Education material s given to diabetic patients included pamphlets/h and outs written in Arabic , the national language . Special videotapes about DM were made and distributed to all participants . In addition , specific educational programs through the diabetes educators and one-on-one counseling sessions with the doctor were also arranged . Patients were interviewed using a structured interview schedule both during the baseline , and after 6 months of the program . The interview schedule included , socio-demographics , clinical characteristics , diabetes self-management , adherence to medication , anxiety , and depression . Glycemic control was considered poor , if hemoglobin A1c ( HbA1c ) was ≥ 7 % . Results : The mean age of the study population was 57.3 ± 14.4 years . Seventy one were males ( 68.3 % ) and 33 ( 31.7 % ) were females . After six months of the diabetes education program , there were significant improvements in patients ’ dietary plan ( P = 0.0001 ) , physical exercise ( P = 0.0001 ) , self-monitoring of blood glucose ( SMBG ) ( P = 0.0001 ) , HbA1c ( P = 0.04 ) , adherence to medication ( P = 0.007 ) , and depression ( P = 0.03 ) . Conclusions : Implementation of education programs on diabetes among type 2 diabetic patients is associated with better outcomes such as their dietary plan , physical exercise , SMBG , adherence to medication , HbA1c and depression AIM To compare the effectiveness of two methods of follow-up : short message service and telephone follow-up on type 2 diabetes adherence for three months . BACKGROUND Using telemedicine approaches may preserve appropriate blood glucose levels and may improve adherence to diabetes control recommendations in diabetic patients . DESIGN A quasi-experimental , two-group , pretest and post-test design was used in this study to evaluate the effectiveness of nurse 's follow-up via cellular phones and telephones . METHODS The sample consisted of 77 patients with type 2 diabetes that r and omly were assigned to two groups : telephone follow-up ( n = 39 ) and short message service ( n = 38 ) . Telephone interventions were applied by a research er for three months ; twice a week for the first month and every week for the second and third month . For three successive months , the short message service group that received messages about adherence to therapeutic regimen was examined . The data gathering instrument included data sheets - to record glycosylated haemoglobin - and the question naire related to adherence therapeutic regimen . Data gathering was carried out at the beginning of the study and after three and six months . The data were analysed using descriptive and inferential statistic methods with SPSS version 11.5 . RESULTS Results showed that both interventions had significant mean changes in glycosylated haemoglobin . For the telephone group ( p < 0.001 ) , a mean change of -0.93 and for the short message service group ( p < 0.001 ) , a mean change of -1.01 . There was no significant difference in diet adherence ( p = 0.000 ) , physical exercise ( p = 0.000 ) and medication taking ( p = 0.000 ) adherence in either groups . CONCLUSION Intervention using short message services of cellular phones and nurse-led-telephone follow-up improved HbA1c levels and adherence to diabetes therapeutic regimen for three months in type 2 diabetic patients . RELEVANCE TO CLINICAL PRACTICE Both of follow-up intervention uses in this study can decrease HbA1c levels and escalate adherence to diabetes control recommendations in people with type 2 diabetes for three months BACKGROUND Peripheral arterial disease patients are less likely than other high-risk patients to achieve ideal low-density lipoprotein ( LDL ) cholesterol levels . This r and omized controlled trial assessed whether a telephone counseling intervention , design ed to help peripheral arterial disease patients request more intensive cholesterol-lowering therapy from their physician , achieved lower LDL cholesterol levels than 2 control conditions . METHODS There were 355 peripheral arterial disease participants with baseline LDL cholesterol ≥70 mg/dL enrolled . The primary outcome was change in LDL cholesterol level at 12-month follow-up . There were 3 parallel arms : telephone counseling intervention , attention control condition , and usual care . The intervention consisted of patient-centered counseling , delivered every 6 weeks , encouraging participants to request increases in cholesterol-lowering therapy from their physician . The attention control condition consisted of telephone calls every 6 weeks providing information only . The usual care condition participated in baseline and follow-up testing . RESULTS At 12-month follow-up , participants in the intervention improved their LDL cholesterol level , compared with those in attention control ( -18.4 mg/dL vs -6.8 mg/dL , P=.010 ) but not compared with those in usual care ( -18.4 mg/dL vs -11.1 mg/dL , P=.208 ) . Intervention participants were more likely to start a cholesterol-lowering medication or increase their cholesterol-lowering medication dose than those in the attention control ( 54 % vs 18 % , P=.001 ) and usual care ( 54 % vs 31 % , P < .001 ) conditions . CONCLUSION Telephone counseling that helped peripheral arterial disease patients request more intensive cholesterol-lowering therapy from their physician achieved greater LDL cholesterol decreases than an attention control arm that provided health information alone AIMS To determine whether an extended pharmacy service would improve glycaemic control and cardiovascular risks in diabetic Muslims . METHODS Ambulatory literate adult diabetic Muslims with A1C > 7 % were r and omly assigned to either a study group ( usual care plus added pharmacist input , N=63 ) or a control group ( usual care only , N=67 ) . On four consecutive visits , at 2-month intervals , the study group met a pharmacist who educated and discussed with each patient regarding medication uses and diabetic treatment . This was accompanied by providing a diabetic pamphlet . Changes in A1C ( mg/dL ) , lipid parameters ( mg/dL ) , medication adherence ( % pill count ) and diabetic knowledge scores were measured . RESULTS There was no difference in A1C reduction between the study and the control groups ( -0.8 vs. -0.6 , p=0.56 ) . Total cholesterol and LDL-C improvements were greater in the study group than in the control group ( -31.6 vs. -1.2 , p=0.000 ; -15.0 vs. + 9.1 , p=0.002 , respectively ) . The percent pill count ( + 6.8 vs. -2.8 , p=0.004 ) and diabetic knowledge scores ( + 2.1 vs. + 0.6 , p=0.002 ) were increased in the study group but not in the control group . CONCLUSION The pharmacist ' s one-on-one education on diabetes accompanied by its pamphlet , in Muslim patients with diabetes did not affect glycaemic outcome but reduction in cardiovascular risks through lowering total cholesterol and LDL-C was found . The strategies may also improve diabetic knowledge and medication adherence We studied the effects of home telemonitoring in elderly patients with congestive heart failure ( CHF ) on mortality and rate of hospitalization , compliance with treatment , quality of life and costs of CHF management , by comparison with a group receiving usual care . Fifty-seven elderly CHF patients were r and omized to st and ard care or to home telemonitoring-based care and followed for 12 months . In the subjects who were monitored , weekly reports on their clinical status were obtained and their management was modified accordingly . Home telemonitoring was associated with improvements in the composite endpoint of mortality and rate of hospitalizations ( P = 0.006 ) , a better compliance with therapy , more frequent use of beta-blockers and statins , lower total cholesterol level and a better reported health perception score . The improved results with home telemonitoring in CHF were probably due to better compliance and to closer monitoring of the patients OBJECTIVE To examine the effect of a 12-month pharmaceutical care ( PC ) program on vascular risk in type 2 diabetes . RESEARCH DESIGN AND METHODS We recruited 198 community-based patients r and omized to PC or usual care . PC patients had face-to-face goal -directed medication and lifestyle counseling at baseline and at 6 and 12 months plus 6-weekly telephone assessment s and provision of other educational material . Clinical , biochemical , and medication-related data were sent regularly to each patient 's physician(s ) . The main outcome measure was change in HbA(1c ) . A diabetes-specific risk engine was used to estimate changes in 10-year coronary heart disease ( CHD ) and stroke risk in patients without a history of cardiovascular disease . RESULTS At total of 180 patients ( 91 % ) completed the study . Mean ( 95 % CI ) reductions were greater in PC case subjects ( n = 92 ) than control subjects ( n = 88 ) for HbA(1c ) ( -0.5 % [ 95 % CI -0.7 to -0.3 ] vs. 0 [ -0.2 to 0.2 ] ) and systolic ( -14 mmHg [ -19 to -9 ] vs. -7 [ -11 to -2 ] ) and diastolic ( -5 mmHg [ -8 to -3 ] vs. -2 [ -4 to 1 ] ) blood pressure ( P < or = 0.043 ) . The improvement in HbA(1c ) persisted after adjustment for baseline value and demographic and treatment-specific variables . The median ( interquartile range ) 10-year estimated risk of a first CHD event decreased in the PC case subjects ( 25.1 % [ 15.6 - 36.2 ] to 20.3 [ 14.6 - 30.2 ] ; n = 42 , P = 0.002 ) but not in the control subjects ( 26.1 % [ 17.2 - 39.4 ] vs. 26.4 [ 16.7 - 38.0 ] ; n = 52 , P = 0.17 ) . CONCLUSIONS A 12-month PC program in type 2 diabetes reduced glycemia and blood pressure . Pharmacist involvement contributed to improvement in HbA(1c ) independently of pharmacotherapeutic changes . PC could prove a valuable component of community-based multidisciplinary diabetes care OBJECTIVES We sought to identify whether home telemonitoring ( HTM ) improves outcomes compared with nurse telephone support ( NTS ) and usual care ( UC ) for patients with heart failure who are at high risk of hospitalization or death . BACKGROUND Heart failure is associated with a high rate of hospitalization and poor prognosis . Telemonitoring could help implement and maintain effective therapy and detect worsening heart failure and its cause promptly to prevent medical crises . METHODS Patients with a recent admission for heart failure and left ventricular ejection fraction ( LVEF ) < 40 % were assigned r and omly to HTM , NTS , or UC in a 2:2:1 ratio . HTM consisted of twice-daily patient self-measurement of weight , blood pressure , heart rate , and rhythm with automated devices linked to a cardiology center . The NTS consisted of specialist nurses who were available to patients by telephone . Primary care physicians delivered UC . The primary end point was days dead or hospitalized with NTS versus HTM at 240 days . RESULTS Of 426 patients r and omly assigned , 48 % were aged > 70 years , mean LVEF was 25 % ( SD , 8) and median plasma N-terminal pro-brain natriuretic peptide was 3,070 pg/ml ( interquartile range 1,285 to 6,749 pg/ml ) . During 240 days of follow-up , 19.5 % , 15.9 % , and 12.7 % of days were lost as the result of death or hospitalization for UC , NTS , and HTM , respectively ( no significant difference ) . The number of admissions and mortality were similar among patients r and omly assigned to NTS or HTM , but the mean duration of admissions was reduced by 6 days ( 95 % confidence interval 1 to 11 ) with HTM . Patients r and omly assigned to receive UC had higher one-year mortality ( 45 % ) than patients assigned to receive NTS ( 27 % ) or HTM ( 29 % ) ( p = 0.032 ) . CONCLUSIONS Further investigation and refinement of the application of HTM are warranted because it may be a valuable role for the management of selected patients with heart failure Objective Studies have demonstrated that hypertension remains inadequately managed throughout the world , with lack of adherence to BP-lowering medication being a major factor . The aim of the present study was to evaluate if a pharmaceutical care program could improve antihypertensive medication adherence and blood pressure control . Setting This study was conducted in a secondary care hypertension/dyslipidemia outpatient clinic in the university teaching hospital of Cova da Beira Hospital Centre , Covilhã , located in the Eastern Central Region of Portugal . Method This report evaluates the pharmacist ’s interventions during a prospect i ve r and omised controlled trial , from July 2009 to June 2010 . Patients with diagnosis of essential hypertension attending the clinic for routine follow-up were r and omly allocated either to a control group ( no pharmaceutical care ) or to an intervention group ( quarterly follow-up by a hospital pharmacist during a 9-month period ) . The pharmacist interventions , aim ed to increase medication adherence and blood pressure control , involved educational interventions and counselling tips directed to the patient . Main outcome measure Systolic blood pressure , diastolic blood pressure and blood pressure control ( according to JNC 7 guidelines ) assessed at the baseline visit and at the end of pharmaceutical care were the main outcome measures . Blood pressure measurements were performed by blinded nurses . Medication adherence was also evaluated , using a vali date d question naire at baseline and at the end of investigation . Results A total of 197 hypertensive patients were r and omly assigned to the study ( 99 in the control group and 98 in the intervention group ) . Although there were no significant differences ( P > 0.05 ) in both groups concerning mean age , gender , body mass index , and antihypertensive pharmacotherapy , blood pressure control was higher in the intervention group ( P = 0.005 ) at the end of the study . Significant lower systolic blood pressure ( −6.8 mmHg , P = 0.006 ) and diastolic blood pressure ( −2.9 mmHg , P = 0.020 ) levels were observed in the intervention group . Medication adherence was also significantly higher in the intervention group at the end of the study ( 74.5 % vs. 57.6 % , P = 0.012 ) . Conclusion Pharmacist intervention can significantly improve medication adherence and blood pressure control in patients treated with antihypertensive agents Context People with chronic conditions may need tailored , practical help for managing their conditions . Contribution This 12-month trial of assistance with managing systolic- dysfunction heart failure r and omly assigned 406 ethnically diverse adults from Harlem , New York , to usual care or nurse management . Nurses counseled nurse management patients about sodium intake , fluid buildup , medication adherence , and self-management of symptoms ; served as a bridge between patients and physicians ; and regularly called patients to discuss problems . Compared with usual care patients , nurse management patients had fewer hospitalizations and better functioning . Implication s Nurse management can improve some outcomes in ethnically diverse patients with systolic-dysfunction heart failure in ambulatory practice s. The Editors Heart failure disproportionately affects black and elderly people and is a leading cause of hospitalization among people 65 years of age or older ( 1 , 2 ) . Although effective therapies can improve functioning and survival in patients with systolic dysfunction , many patients may not be receiving the full benefit of existing knowledge ( 35 ) . Patients play a critical role in managing a chronic condition , such as heart failure . Patients may not realize that specific symptoms are related to heart failure or that adhering to medications and diet can reduce symptoms and life-threatening episodes ( 6 ) . Evidence -based guidelines for systolic dysfunction recommend that physicians not only offer patients effective therapies but also teach them the importance of adherence and self-monitoring ( 3 , 4 ) . Clinicians have fallen short in prescribing angiotensin-converting enzyme inhibitors and -blockers for patients with systolic dysfunction ( 5 , 7 , 8) . When prescribed , the doses have often been lower than those proven to convey greater benefits ( 3 , 9 ) . Clinicians have also documented counseling only a fraction of patients with heart failure about self-management ( 10 , 11 ) . System-related factors may also influence patients ' ability to obtain quality care ( 12 , 13 ) . Systematic review s of clinical behavior change have suggested that interventions targeted to specific problems are more likely to be successful ( 14 , 15 ) . On the basis of shortfalls identified in patient self-management and clinical care in Harlem , New York , a predominately nonwhite area , we tailored a nurse management intervention to address documented problems and evaluated its effectiveness in a r and omized , controlled trial . Our trial among primarily minority patients addresses important gaps in the literature . We targeted problems documented among patients with heart failure in Harlem , enrolled patients from ambulatory care practice s , r and omly assigned patients to either nurse management or usual care , and evaluated the patients ' subsequent health-related outcomes . We hypothesized that patients in the focused nurse management program would have fewer hospitalizations and report better functioning than patients in usual care . Methods Development of the Intervention During interviews with patients with heart failure at Mount Sinai Hospital , New York , New York , patients reported inadequate underst and ing of heart failure and their role in managing it ( 6 ) . Less than half of patients followed a very-low-salt diet , and only about one quarter weighed themselves daily . Regarding clinical management , medical records noted prescriptions for an angiotensin-converting enzyme inhibitor or hydralazinedinitrate combination in 82 % of 322 consecutive black patients with documented systolic dysfunction who were scheduled for visits at the general medicine clinic at Harlem Hospital from February 1995 through February 1997 . The prescribed doses , however , equaled or exceeded those found to be efficacious in clinical trials in only 26 % of these patients ( 3 ) . In design ing a nurse management intervention to address these problems , we built on a Stanford University program that evaluated primarily privately insured patients at Kaiser Permanente in northern California ( 16 , 17 ) . We adapted their question naire on the frequency of foods eaten to incorporate those that are common among African-American and Hispanic people in Harlem . Setting s and Recruitment All 4 hospitals in Harlem , the area 's major providers , collaborated in the trial : 1 large private academic medical center ( 1171 beds ) , 2 medium-sized municipal hospitals ( 286 beds and 363 beds ) , and 1 smaller private community hospital ( 200 beds ) . In 2000 , these hospitals had 521 , 267 , 218 , and 168 discharges for the heart failure diagnosis-related group ( code 127 ) , respectively . All are not-for-profit institutions . The trial had the following inclusion criteria : adults 18 years of age or older ; systolic dysfunction documented on a cardiac test ( echocardiography , radionuclide ventriculography , myocardial stress sestamibi or thallium stress testing , or left-heart catheterization ) ; English- language or Spanish- language speakers ; community-dwelling at enrollment ; and current patient in a general medicine , geriatrics , or cardiology clinic or office at a participating site . Exclusion criteria were medical conditions that prevented interaction with the nurse , including blindness , deafness , or cognitive impairment ; medical conditions requiring individualized management that might differ from st and ard protocol , namely pregnancy , renal dialysis , or terminal illness ; or procedures that corrected systolic dysfunction , such as heart transplantation . Of the 216 clinicians ( 209 physicians and 7 physicians ' assistants or nurse practitioners ) in participating practice s , 1 clinician declined permission to recruit his patients . The institutional review boards for each site approved the study . We identified patients with International Classification of Diseases , Ninth Revision , Clinical Modification ( ICD-9-CM ) , and diagnosis-related group codes on outpatient or inpatient billings for heart failure , March 1999 through February 2001 , who had at least 1 clinician visit to a participating practice and impaired systolic dysfunction . We defined impaired systolic dysfunction as a left ventricular ejection fraction less than 0.40 or moderately or severely reduced systolic dysfunction on echocardiography , radionuclide ventriculography , myocardial stress sestamibi or thallium stress testing , or left-heart catheterization . We obtained clinicians ' permission to recruit specific patients and sent each approved patient a letter from the site 's physician coordinator . Bilingual recruiters telephoned eligible patients or approached them at scheduled clinician appointments . The recruiter confirmed each patient 's eligibility , obtained written informed consent to participate in the study , conducted the baseline survey , and telephoned the project manager for the treatment group assignment . The recruiter conveyed the assignment to the patient and , for each nurse management patient , scheduled the in-person appointment with a nurse . We provided telephone service for 3 patients who did not have it so we could telephone patients in both treatment groups every 3 months for data on end points and so nurse management patients could participate in the intervention . R and omization and Treatment Groups The project 's statistician used a computer-generated , r and om-number sequence without blocking or stratification to central ly determine r and omization assignments and concealed treatment group assignments in sealed , opaque envelopes . Usual care patients received federal consumer guidelines for managing systolic dysfunction but no other intervention ( 18 ) . In the nurse management intervention , 1 of 3 trained registered nurses met once with each patient ( Table 1 ) . In counseling the patient , the nurse stressed the relationship among sodium intake ; fluid buildup ; and symptoms , such as shortness of breath . Nurses mailed patients the reports from the food-frequency question naire after each administration . The nurse also served as a bridge between the patient and the clinician ( Table 1 ) . A local clinical advisory committee implemented national evidence -based guidelines , and a committee of key clinicians from participating sites approved the protocol ( 3 , 4 ) . Nurses contacted patients ' clinicians to discuss specific medications and arranged any prescription changes and examinations ordered ( Table 1 ) . An internist monitored the nurses ' work , initially in weekly and then in biweekly meetings , and a cardiologist provided oversight and substituted for the internist at regular meetings , as necessary . Table 1 . Components of Nurse Management * One nurse who was bilingual in English and Spanish delivered the intervention primarily at the 2 municipal hospitals , a second bilingual nurse delivered the intervention primarily at the small community hospital , and the second and a third English- language speaking nurse delivered the intervention primarily at the academic center . All 3 nurses covered each other , especially for the follow-up telephone calls . Outcomes and Measurement To measure hospitalizations , we used billing data from the 4 participating hospitals . At quarterly telephone surveys , interviewers who were blinded to treatment assignment asked patients about hospitalizations at nonparticipating hospitals ; however , we present the analysis of billing data because they measure hospitalizations independent of possibly socially acceptable responses or survey nonresponse of the patients . For functional status , we used the generic Short Form-12 ( SF-12 ) physical component score and the condition-specific Minnesota Living with Heart Failure ( MLHF ) Question naire , with both scales administered at the quarterly interviews . We measured deaths recorded in the National Death Index plus deaths reported by patients ' families for patients with no subsequent billings . Since both nurse management and usual care involved only services delivered in routine practice , the study did not monitor adverse effects . As required by the OBJECTIVE The aim of this study was to determine whether the provision of further practice -based support by pharmacists will bring about improved outcomes for blood pressure ( BP ) control in middle-aged and elderly Nigerian hypertensive patients managed with combination diuretics ( amiloride hydrochloride 5 mg+hydrochlorothiazide 50 mg ) and /or methyl dopa at the primary care level . DESIGN AND SETTING This was a 1-year prospect i ve , r and omized cohort study of the out patients of a state comprehensive health centre in South-western Nigeria . Free primary health services including free drugs were provided for all patients . PATIENTS AND METHOD The study population comprised 51 Nigerian patients with uncomplicated hypertension aged 45 years or more , with a 0.2 - 3.0-year history of hypertension , registered at the Comprehensive Health Centre , Ife between October 2002 and March 2003 . They were invited into the pharmacist-managed hypertension clinic and followed for the study period . Participating pharmacists counselled for current medication , personalized goals of lifestyle modification stressing weight loss and /or increased activity , increased patient awareness by providing relevant education about hypertension and associated/related diseases , adjusted drug therapy to optimize effectiveness and minimize adverse events , utilized treatment schedules that enhanced patients ' adherence to therapy , and monitored treatment outcomes between enrollment and return visits . Patient satisfaction and the number of treatment failures within 6 months post enrollment were compared with retrospective data from our earlier study involving physician-managed patients under a similar setting . RESULTS Uncontrolled BP reduced from 92 to 36.2 % by 10.15+/-5.02 days after enrollment . Treatment failures were observed at 5.9 % of the total return visits ( n=184 ) within 6 months . CONCLUSION Pharmacist-managed hypertension clinics can improve BP control , reduce treatment failure and increase patient satisfaction BACKGROUND : Diabetes mellitus has become an international healthcare crisis that requires new approaches to prevent and treat it . The objective of this study was to evaluate the impact of pharmaceutical care on quality of life ( QOL ) in patients with type 2 diabetes mellitus . METHODS : A prospect i ve study on impact of pharmaceutical care on QOL in patients with type 2 diabetes mellitus was conducted in a private tertiary care teaching hospital in South India for a period of 8 months . Study was done on 120 eligible patients with type 2 diabetes mellitus enrolled r and omly in the intervention group ( with pharmaceutical care teachings ) or the control ( without drug related educations ) . The intervention group patients received pharmaceutical care through diabetes education , medication counseling , instructions on lifestyle that needed modifications ( necessary for better drug function ) and dietary regulations regarding their prescribed drugs , whereas the control group patients were deprived of any pharmaceutical care till the end of the study . The “ Audit of Diabetes Dependent Quality of Life ” st and ard question naire was used to assess the relevant parameters ( including : Fasting Blood Glucose , HbA1c , Body Mass Index ) and to evaluate the impact of the pharmaceutical care on the subjects . Data were analyzed using t-student test . RESULTS : The intervention group showed an improvement in the quality of life score from -2.156 ± 0.12 at the baseline to -1.41 ± 0.13 at the final interview ( p < 0.01 ) . The average HbA1c values decreased from 8.44 ± 0.29 % to 6.73 ± 0.21 % ( p < 0.01 ) . There was a significant decrease in the fasting blood glucose from 195.57 ± 10.10 mg/dl to 107.25 ± 3.70 mg/dl between the baseline and the final interview in the intervention group ( p < 0.01 ) . The findings in the diabetes treatment satisfaction score also changed in a similar pattern . CONCLUSIONS : The pharmaceutical care program was effective in improving the clinical outcome and the patients ’ QOL with type 2 diabetes mellitus OBJECTIVE The objective of the study was to evaluate the effectiveness of a single home-based educational intervention for patients admitted with heart failure . METHODS There were 106 patients : 42 in the intervention group and 64 in the control group . Patients were r and omly assigned to receive an intervention by nursing staff 1 week after discharge . Primary end points were readmissions , emergency department visits , deaths , costs , and quality of life . RESULTS During the 24-month follow-up , there were fewer mean emergency department visits in the intervention group than in the control group ( .68 vs 2.00 ; P = .000 ) , fewer unplanned readmissions ( .68 vs 1.71 ; P = .000 ) , and lower costs ( € 671.56 = $ 974.63 = GBP598.42 per person vs € 2,154.24 = $ 3,126.01 = GBP1,919.64 ; P = .001 ) . There was a trend toward fewer out-of-hospital deaths ( 14 [ 46.6 % ] vs 31 [ 55.3 % ] ; P = .45 ) and improvement in quality of life . CONCLUSION Patients with heart failure who receive a home-based educational intervention experience fewer emergency department visits and unplanned readmissions with lower healthcare costs Purpose Individualized patient care may help reduce the incidence of adverse drug events in systemic cancer therapy . This study was conducted to explore the feasibility and potential of additional pharmaceutical care for breast and ovarian cancer patients . Methods The study was design ed as a prospect i ve , multicentered cohort study with a control group . Ninety-eight breast or ovarian cancer patients were recruited from outpatient oncology clinics and primary care oncologists : initially into the control group receiving st and ard care and after implementation of pharmaceutical care into the intervention group consisting of additional patient counseling on the management of treatment-associated adverse events and optimization of supportive medication . Primary outcome was the complete response to the antiemetic prophylaxis . Secondary endpoints were the severity of nausea , frequency of emesis , health-related quality of life , and patient satisfaction with information on cancer treatment education . Results Forty-eight patients were included in the control group and 50 in the intervention group . Of the patients , 35.4 % in the control group and 76.0 % in the intervention group ( p < 0.001 ) had a complete response to the antiemetic prophylaxis . The severity of acute and delayed nausea was not reduced . The global health scale and two symptom scales ( nausea and vomiting , appetite loss ) of the EORTC QLQ-C30 question naire were positively affected by pharmaceutical care . Patient satisfaction with information was significantly higher in the intervention group . Conclusions Patients with breast and ovarian cancer seem to benefit from pharmaceutical care , as suggested by improved patient-reported outcomes such as emetic episodes , quality of life , and patient satisfaction after implementation Objective The purpose of the study was to assess the influence of pharmaceutical care on patients ’ knowledge , quality of life and blood pressure and to determine whether new type of pharmaceutical services changes the pharmacists ’ satisfaction and knowledge . Methods Community pharmacies were r and omly assigned to study and control group and pharmacists from both groups included patients with hypertension , who meet inclusion and exclusion criteria . Study group provided the pharmaceutical care ( education , pharmacotherapy monitoring , detecting and solving drug related problems ) for their patients , while the control group provided the st and ard pharmaceutical services ( dispensing medicines with or without counseling ) . At the beginning and the end of the study pharmacists and patients filled in the knowledge test . Pharmacists fulfilled also satisfaction question naire . Results Survey data were collected from 28 and 56 patients from community pharmacies in study and control group respectively . At the last meeting the normal blood pressure achieved 79 % and 55 % patients in study and control group , respectively ( p>0,05 ) . The pharmaceutical care improved patients ’ knowledge about disease . Pharmacists from study group , who provided pharmaceutical care , had higher level of pharmacotherapy knowledge and professional satisfaction than the control group . Conclusions Implementation of pharmaceutical care into the pharmacy practice benefits both , patients and pharmacists OBJECTIVE We compared the short-term efficacy of home telemonitoring coupled with active medication management by a nurse practitioner with a monthly care coordination telephone call on glycemic control in veterans with type 2 diabetes and entry A1C ≥7.5 % . RESEARCH DESIGN AND METHODS Veterans who received primary care at the VA Pittsburgh Healthcare System from June 2004 to December 2005 , who were taking oral hypoglycemic agents and /or insulin for ≥1 year , and who had A1C ≥7.5 % at enrollment were r and omly assigned to either active care management with home telemonitoring ( ACM+HT group , n = 73 ) or a monthly care coordination telephone call ( CC group , n = 77 ) . Both groups received monthly calls for diabetes education and self-management review . ACM+HT group participants transmitted blood glucose , blood pressure , and weight to a nurse practitioner using the Viterion 100 TeleHealth Monitor ; the nurse practitioner adjusted medications for glucose , blood pressure , and lipid control based on established American Diabetes Association targets . Measures were obtained at baseline , 3-month , and 6-month visits . RESULTS Baseline characteristics were similar in both groups , with mean A1C of 9.4 % ( CC group ) and 9.6 % ( ACM+HT group ) . Compared with the CC group , the ACM+HT group demonstrated significantly larger decreases in A1C at 3 months ( 1.7 vs. 0.7 % ) and 6 months ( 1.7 vs. 0.8 % ; P < 0.001 for each ) , with most improvement occurring by 3 months . CONCLUSIONS Compared with the CC group , the ACM+HT group demonstrated significantly greater reductions in A1C by 3 and 6 months . However , both interventions improved glycemic control in primary care patients with previously inadequate control Objectives To implement and assess hospital-based pharmaceutical care services for patients with asthma . Methods A prospect i ve , r and omized , controlled study was conducted in Shaab teaching hospital , Khartoum , Sudan . Patients were allocated r and omly either in the intervention group ( 60 ) or control group ( 40 ) patients . The drug therapy of asthma for the patients in the intervention group was review ed by a trained pharmacist , and interventions were suggested to the attending physicians for the identified problems . Intervention patients received comprehensive medication counselling and asthma education every 2 weeks , while the control group received the routine medical consultation and dispensing services . The outcome measures were recorded using structured forms at baseline and monitored during a follow-up of every two weeks for 6 months in both groups . Data were analyzed using SPSS version 13 , level of significance was p<0.05 . Results At the end of the study period the mean reduction in frequency of acute attacks ( 1.91 ; SD=0.18 vs. 1.0 ; SD=0.14 ; p=0.03 ) , nocturnal asthma symptoms ( 3.5 ; SD=0.3 vs. 1.1 ; SD=0.2 ; p=0.02 ) and frequency of using inhaled β2 agonists per week ( 19.9 ; SD= 2.1 vs. 3.3 ; SD=0.3 ; p=0.01 ) were significantly greater in the intervention group compared to control . A significant mean reduction ( p=0.002 ) in the days of sickness/week was in the intervention group , while in control group there was an increase in mean days of sickness/week . The intervention group showed a significant greater improvement in the score for assessing the inhalation technique ( p<0.001 ) , patient ’s knowledge about asthma ( p<0.001 ) , and its drug-therapy ( p=0.01 ) compared with control . Conclusion The present findings suggest that pharmacist ’s intervention can have positive impact on asthma-related outcomes in patients Background Improving adherence to ocular hypertension (OH)/glaucoma therapy is highly likely to prevent or reduce progression of optic nerve damage . The present study used a behaviour change counselling intervention to determine whether education and support was beneficial and cost-effective in improving adherence with glaucoma therapy . Methods A r and omised controlled trial with a 13-month recruitment and 8-month follow-up period was conducted . Patients with OH/glaucoma attending a glaucoma clinic and starting treatment with travoprost were approached . Participants were r and omised into two groups and adherence was measured over 8 months , using an electronic monitoring device ( Travalert ® dosing aid , TDA ) . The control group received st and ard clinical care , and the intervention group received a novel glaucoma education and motivational support package using behaviour change counselling . Cost-effectiveness framework analysis was used to estimate any potential cost benefit of improving adherence . Results Two hundred and eight patients were recruited ( 102 intervention , 106 control ) . No significant difference in mean adherence over the monitoring period was identified with 77.2 % ( CI , 73.0 , 81.4 ) for the control group and 74.8 % ( CI , 69.7 , 79.9 ) for the intervention group ( p = 0.47 ) . Similarly , there was no significant difference in percentage intraocular pressure reduction ; 27.6 % ( CI , 23.5 , 31.7 ) for the control group and 25.3 % ( CI , 21.06 , 29.54 ) for the intervention group ( p = 0.45 ) . Participants in the intervention group were more satisfied with information about glaucoma medication with a mean score of 14.47/17 ( CI , 13.85 , 15.0 ) compared with control group which was 8.51 ( CI , 7.72 , 9.30 ) . The mean intervention cost per patient was GB£10.35 ( < US$ 16 ) and not cost-effective . Conclusions Adherence with travoprost was high and not further increased by the intervention . Nevertheless , the study demonstrated that provision of information , tailored to the individual , was inexpensive and able to achieve high patient satisfaction with respect to information about glaucoma medication . Measurement of adherence remains problematic since awareness of study participation may cause a change in participant behaviour . Trial registration Current Controlled Trials , IS RCT N89683704 Objective To quantify the impact of a practical , hospital-based nurse-coordinated prevention programme on cardiovascular risk , integrated into the routine clinical care of patients discharged after an acute coronary syndrome , as compared with usual care only . Design RESPONSE ( R and omised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists ) was a r and omised clinical trial . Setting Multicentre trial in secondary and tertiary healthcare setting s. Participants 754 patients admitted for acute coronary syndrome . Intervention A nurse-coordinated prevention programme , consisting of four outpatient nurse clinic visits , focusing on healthy lifestyles , biometric risk factors and medication adherence , in addition to usual care . Main outcome measures The main outcome was 10-year cardiovascular mortality risk as estimated by Systematic Coronary Risk Evaluation at 12 months follow-up . Secondary outcomes included Framingham Coronary Risk Score at 12 months , in addition to changes in individual risk factors . Risk factor control was classified as ‘ poor ’ if 0 to 3 factors were on target , ‘ fair ’ if 4 to 6 factors were on target , and ‘ good ’ if 7 to 9 were on target . Results The mean Systematic Coronary Risk Evaluation at 12 months was 4.4 per cent ( SD 4.5 ) in the intervention group and 5.4 per cent ( SD 6.2 ) in the control group ( p=0.021 ) , representing a 17.4 % relative risk reduction . At 12 months , risk factor control classified as ‘ good ’ was achieved in 35 % of patients in the intervention group compared with 25 % in the control group ( p=0.003 ) . Attendance to the nurse-coordinated prevention programme was 92 % . In the intervention group , 86 rehospitalisations were observed against 132 in the control group ( relative risk reduction 34.8 % , p=0.023 ) . Conclusions The nurse-coordinated hospital-based prevention programme in addition to usual care is a practical , yet effective method for reduction of cardiovascular risk in patients with coronary disease . Our data suggest that the counselling component of the programme may lead to a reduction in hospital readmissions . Trial Registration trialregister.nl Identifier TC1290 OBJECTIVES To evaluate the efficacy of a healthcare education program for patients with hypertension . METHODS A multicenter , prospect i ve , cluster-r and omized trial was conducted . R and omization was by primary care center ; 18 of 36 urban primary care centers in Barcelona and its metropolitan area were r and omized to the intervention group ( IG ) and 18 to the control group ( CG ) . The study sample consisted of patients with hypertension ( n=996 ; 515 in the IG and 481 in the CG ) receiving outpatient treatment with antihypertensive drugs . The intervention consisted of personalized information by a trained nurse and written leaflets . Question naires on knowledge and awareness of hypertension and its medication , treatment adherence , healthy lifestyle habits , systolic and diastolic blood pressure , and body mass index were assessed at each visit , with a 12-month follow-up . An intention-to-treat analysis was applied . RESULTS Knowledge of hypertension increased by 27.8 % in the IG and by 18.5 % in the CG , while that of medication increased by 10.1 % in the IG and 5.5 % in the CG . Treatment adherence measured by the Morisky-Green test increased by 9.6 % ( 95 % CI : 5.5 - 13.6 ) in the IG and 8.8 % ( 95 % CI : 4.9 - 12.6 ) in the CG . There were no differences in adherence on the other tests used . No differences were observed between the IG and CG in clinical variables such as blood pressure or BMI at the end of the trial . CONCLUSIONS The educational intervention had no significant impact on patients ' adherence to the medication Background Most HIV treatment programs in re source -limited setting s utilize multiple facilitators of adherence and retention in care but there is little data on the efficacy of these methods . We performed an observational cohort analysis of a treatment program in Kenya to assess which program components promote adherence and retention in HIV care in East Africa . Methods Patients initiating ART at A.I.C. Kijabe Hospital were prospect ively enrolled in an observational study . Kijabe has an intensive program to promote adherence and retention in care during the first 6 months of ART that incorporates the following facilitators : home visits by community health workers , community based support groups , pharmacy counseling , and unannounced pill counts by clinicians . The primary endpoint was time to treatment failure , defined as a detectable HIV-1 viral load ; discontinuation of ART ; death ; or loss to follow-up . Time to treatment failure for each facilitator was calculated using Kaplan-Meier analysis . The relative effects of the facilitators were determined by the Cox Proportional Hazards Model . Results 301 patients were enrolled . Time to treatment failure was longer in patients participating in support groups ( 448 days vs. 337 days , P<0.001 ) , pharmacy counseling ( 480 days vs. 386 days , P = 0.002 ) , pill counts ( 482 days vs. 189 days , P<0.001 ) and home visits ( 485 days vs. 426 days , P = 0.024 ) . Better adherence was seen with support groups ( 89 % vs. 82 % , P = 0.05 ) and pill counts ( 89 % vs. 75 % , P = 0.02 ) . Multivariate analysis using the Cox Model found significant reductions in risk of treatment failure associated with pill counts ( HR = 0.19 , P<0.001 ) and support groups ( HR = 0.43 , P = 0.003 ) . Conclusion Unannounced pill counts by the clinician and community based support groups were associated with better long term treatment success and with better adherence BACKGROUND Few studies have examined the potential benefits of specialist nurse-led programs of care involving home and clinic-based follow-up to optimise the post-discharge management of chronic heart failure ( CHF ) . OBJECTIVE To determine the effectiveness of a hybrid program of clinic plus home-based intervention ( C+HBI ) in reducing recurrent hospitalisation in CHF patients . METHODS CHF patients with evidence of left ventricular systolic dysfunction admitted to two hospitals in Northern Engl and were assigned to a C+HBI lasting 6 months post-discharge ( n=58 ) or to usual , post-discharge care ( UC : n=48 ) via a cluster r and omization protocol . The co- primary endpoints were death or unplanned readmission ( event-free survival ) and rate of recurrent , all-cause readmission within 6 months of hospital discharge . RESULTS During study follow-up , more UC patients had an unplanned readmission for any cause ( 44 % vs. 22 % : P=0.019 , OR 1.95 95 % CI 1.10 - 3.48 ) whilst 7 ( 15 % ) versus 5 ( 9 % ) UC and C+HBI patients , respectively , died ( P = NS ) . Overall , 15 ( 26 % ) C+HBI versus 21 ( 44 % ) UC patients experienced a primary endpoint . C+HBI was associated with a non-significant , 45 % reduction in the risk of death or readmission when adjusting for potential confounders ( RR 0.55 , 95 % CI 0.28 - 1.08 : P=0.08 ) . Overall , C+HBI patients accumulated significantly fewer unplanned readmissions ( 15 vs. 45 : P<0.01 ) and days of recurrent hospital stay ( 108 vs. 459 days : P<0.01 ) . C+HBI was also associated with greater uptake of beta-blocker therapy ( 56 % vs. 18 % : P<0.001 ) and adherence to Na restrictions ( P<0.05 ) during 6-month follow-up . CONCLUSION This is the first r and omised study to specifically examine the impact of a hybrid , C+HBI program of care on hospital utilisation in patients with CHF . Its beneficial effects on recurrent readmission and event-free survival are consistent with those applying either a home or clinic-based approach Background This study describes the analysis of secondary outcomes from a previously published r and omised controlled trial , which assessed the effects of pharmaceutical care on medication adherence , persistence and bone turnover markers . The main focus of this manuscript is the effect of the provision of pharmaceutical care on these secondary outcomes , and details on the design of the intervention provided , the osteoporosis care plan and material s used to deliver the intervention . Objectives To evaluate the effects of pharmaceutical care on knowledge , quality of life ( QOL ) and satisfaction of postmenopausal osteoporotic women prescribed bisphosphonates , and their associating factors . Setting R and omised controlled trial , performed at an osteoporosis clinic of a tertiary hospital in Malaysia . Methods Postmenopausal women diagnosed with osteoporosis ( T-score ≤−2.5/lowtrauma fracture ) , just been prescribed weekly alendronate/risedronate were r and omly allocated to receive intervention or st and ard care ( controls ) . Intervention participants received a medication review , education on osteoporosis , risk factors , lifestyle modifications , goals of therapy , side effects and the importance of medication adherence at months 0 , 3 , 6 and 12 . Main outcomes measure Knowledge , QOL and satisfaction . Results A total of 198 postmenopausal osteoporotic women were recruited : intervention = 100 and control = 98 . Intervention participants reported significantly higher knowledge scores at months 3 ( 72.50 vs. 62.50 % ) , 6 ( 75.00 vs. 65.00 % ) and 12 ( 78.75 vs. 68.75 % ) compared to control participants . QOL scores were also lower ( which indicates better QOL ) at months 3 ( 29.33 vs. 38.41 ) , 6 ( 27.50 vs. 36.56 ) and 12 ( 27.53 vs. 37.56 ) compared to control participants . Similarly , satisfaction score was higher in intervention participants ( 93.67 vs. 84.83 % ) . More educated women , with back pain , who were provided pharmaceutical care had better knowledge levels . Similarly , older , more educated women , with previous falls and back pain tend to have poorer QOL , whilst women who exercised more frequently and were provided pharmaceutical care had better QOL . Satisfaction also increased as QOL increases and when provided pharmaceutical care . Conclusion The provision of pharmaceutical care improved knowledge , QOL and satisfaction in Malaysian postmenopausal osteoporotic women , showing that pharmacists have the potential to improve patients ’ overall bone health . Policymakers should consider placing a clinical pharmacist in the osteoporosis clinic to provide counselling to improve these outcomes Objective To assess the impact of an asthma educational program provided by a nurse combined with asthma counseling provided by a pharmacist on asthma knowledge , quality of life and clinical outcomes in Taiwanese patients with asthma . Setting All patients were recruited from Pulmonary Medicine outpatient clinic , the Tri-Service General Hospital , Taipei , Taiwan . Asthma education was given in three one-hour sessions offered during monthly clinic visits . Method A total of 91 asthma patients were r and omly assigned to a nurse-administered education program ( Group 1 ) , the education program with additional pharmacist counseling ( Group 2 ) , or a control group receiving routine care only ( control ) . Three question naires were used for assessment at months 0 , 3 and 6 . Outcomes were compared between groups to determine efficacy . Main Outcome Measure Asthma knowledge , health-related quality of life , and medication adherence were measured at baseline and 3 and 6 months after enrollment . Results A total of 104 patients were enrolled ; 91 completed the study . Knowledge scores of patients in Groups 1 and 2 increased significantly compared to control group . Both intervention groups showed significant increases in knowledge scores with longer follow-up . Group 2 showed a significant improvement in clinical symptoms between baseline ( month 0 ) and month 6 ( 4.99 vs. 4.21 , P = 0.008 ) . No significant differences in medication adherence were seen among groups . Conclusion Regular nurse-administered asthma education with additional pharmacist counseling improves asthma knowledge and clinical symptoms in asthma patients AIM This paper reports an evaluation of the effect of symptom management programmed on drug adherence , CD4 count and virus load and the quality of life of patients with HIV/AIDS . BACKGROUND Patients with HIV/AIDS have to face the long-term side effects caused by highly active antiretroviral therapy regimens . There has been little research to evaluate the influence of drug intervention side effects on self-care . METHODS Sixty-seven patients with HIV/AIDS were r and omly assigned to one-on-one teaching , group teaching , or control groups . All those in the one-on-one and group teaching groups attended a symptom management programme once a week , followed by 3 weeks of continuity and telephone counselling . Those in the control group were offered experimental intervention at the conclusion of data collection . The Customized Adherence Self-Report Question naire , CD4 count and virus load , and Quality of Life Index were used to evaluate the effectiveness of the symptom management programme before and at 3 months after the intervention . RESULTS Median differences on the Customized Adherence Self-Report Question naire , CD4 count and virus load , and quality of life in both experimental groups were statistically significantly better than in the control group . CONCLUSIONS The symptom management programme can increase self-care ability in managing medication side effects in patients with HIV/AIDS AIM The aim of this study was to investigate the impact of a pharmacist-led pharmaceutical care programme , involving optimization of drug treatment and intensive education and self-monitoring of patients with heart failure ( HF ) within the United Arab Emirates ( UAE ) , on a range of clinical and humanistic outcome measures . METHODS The study was a r and omized , controlled , longitudinal , prospect i ve clinical trial at Al-Ain Hospital , Al-Ain , UAE . Patients were recruited from the general medical wards and from cardiology and medical outpatient clinics . HF patients who fulfilled the entrance criteria , and had no exclusion criteria present , were identified for inclusion in the study . After recruitment , patients were r and omly assigned to one of two groups : intervention group or control group . Intervention patients received a structured pharmaceutical care service while control patients received traditional services . Patient follow-up took place when patients attended scheduled outpatient clinics ( every 3 months ) . A total of 104 patients in each group completed the trial ( 12 months ) . The patients were generally suffering from mild to moderate HF ( NYHA Class 1 , 29.5 % ; Class 2 , 50.5 % ; Class 3 , 16 % ; and Class 4 , 4 % ) . RESULTS Over the study period , intervention patients showed significant ( P < 0.05 ) improvements in a range of summary outcome measures [ AUC ( 95 % confidence limits ) ] including exercise tolerance [ 2-min walk test : 1607.2 ( 1474.9 , 1739.5 ) m.month in intervention patients vs. 1403.3 ( 1256.5 , 1549.8 ) in control patients ] , forced vital capacity [ 31.6 ( 30.8 , 32.4 ) l.month in the intervention patients vs. 27.8 ( 26.8 , 28.9 ) in control patients ] , health-related quality of life , as measured by the Minnesota living with heart failure question naire [ 463.5 ( 433.2 , 493.9 ) unit.month in intervention patients vs. 637.5 ( 597.2 , 677.7 ) in control patients ; a lower score in this measure indicates better health-related quality of life ] . The number of individual patients who reported adherence to prescribed medications was higher ( P < 0.05 ) in the intervention group ( 85 vs. 35 ) , as was adherence to lifestyle advice ( 75 vs. 29 ) at the final assessment ( 12 months ) . There was a tendency to have a higher incidence of casualty department visits by intervention patients , but a lower rate of hospitalization . CONCLUSIONS The research provides clear evidence that the delivery of pharmaceutical care to patients with HF can lead to significant clinical and humanistic benefits OBJECTIVE Compare the efficacy of a multicomponent social support intervention to st and ard-of-care counseling on medication adherence among HIV-infected patients initiating antiretroviral therapy . DESIGN R and omized controlled trial . Generalized estimating equations tested for differences in the percentage of participants achieving 90 % adherence . MAIN OUTCOME MEASURES Pill-taking , electronically monitored over 6 consecutive months ; plasma viral load ( VL ) , assessed at 3 and 6 months following initiation of therapy . RESULTS Of 226 participants who were r and omized and began the trial , 87 ( 38 % ) were lost to the study by 6 months . The proportion of adherent participants declined steadily over time , with no time by group interaction . Sustained adherence was associated with increased odds of achieving an undetectable VL ( OR=1.78 ; 95 % CI=1.01 , 3.13 ) . In intention-to-treat analyses , a larger proportion of the intervention group than the control group was adherent ( 40.15 % vs. 27.59 % , p=.02 ) and achieved an undetectable VL p=.04 ) . However , the majority of participants who remained on study experienced some reduction in VL ( > or=1-log drop or undetectable ) , regardless of experimental condition . CONCLUSION The multicomponent social support intervention significantly improved medication adherence over st and ard-of-care counseling ; evidence for improved virologic outcomes was inconsistent . Early discontinuation of care and treatment may be a greater threat to the health of HIV patients than imperfect medication-taking STUDY OBJECTIVES To determine changes in bone mineral density ( BMD ) and T scores of patients after 2 years of teriparatide therapy , and to determine the number of fractures that occurred during therapy . DESIGN Prospect i ve , observational study . SETTING Pharmacist-run teriparatide clinic in a private- practice endocrinology group . PATIENTS Sixty patients with osteoporosis who experienced fractures or adverse events while receiving antiresorptive therapy and were referred by the endocrinologists to the clinic between January 1 , 2002 , and January 1 , 2004 . INTERVENTION After a 1-hour counseling and training session with a clinical pharmacist , patients self-administered subcutaneous teriparatide 20 microg/day for the next 2 years . MEASUREMENTS AND MAIN RESULTS Primary outcome measures were dual x-ray absorptiometry-determined BMDs and T scores for the total hip , spine , and wrist at baseline and at 1 and 2 years . Patients ' BMDs for the hip significantly increased by 3.5 % at 1 year and by 3.9 % at 2 years . In addition , BMD for the spine significantly increased by 7.2 % at 1 year and 10.9 % at 2 years . In 56 ( 93 % ) patients , BMD for the spine increased after 2 years of treatment . For the wrist , BMD decreased by 0.75 % at 1 year and by 2.4 % at 2 years , but the change was only significant at 2 years ( p=0.011 ) . At both 1 and 2 years , T scores for the total hip and spine significantly improved from baseline ( p < or = 0.019 ) , whereas T scores for the wrist significantly declined after 2 years of therapy ( p<0.003 ) . No new fractures were documented in any of the patients . CONCLUSION In patients with osteoporosis , the use of teriparatide in a pharmacist-run clinic significantly increased BMD at the total hip and spinal sites and significantly decreased BMD in the wrist BACKGROUND The aim of the present study was to determine whether the addition of nurse case managers ( NCMs ) trained in motivational interviewing ( MI ) to usual care would result in improved outcomes in high-risk type 2 diabetes patients . METHODS A 2-year r and omized controlled pragmatic trial r and omized 545 patients to usual care control ( n=313 ) or those who received the intervention ( n=232 ) with additional practice -embedded NCM care , including MI-guided behavior change counseling . The NCMs received intensive MI training with ongoing fidelity assessment . RESULTS Systolic blood pressure ( SBP ) was better in the intervention than usual care group ( 131 ± 15 vs. 135 ± 18 mmHg , respectively ; P<0.05 ) . Improvements were seen in both the control and intervention groups in terms of HbA1c ( from 9.1 % to 8.0 % and from 8.8 % to 7.8 % , respectively ) , low-density lipoprotein ( LDL ; from 127 to 100 mg/dL and from 128 to 102 mg/dL , respectively ) , and diastolic blood pressure ( from 78 to 74 mmHg and from 80 to 74 mmHg , respectively ) . Depression symptom scores were better in the intervention group . The reduction in diabetes-related distress approached statistical significance . CONCLUSIONS The NCMs and MI improved SBP and complications screening . The large decrease in HbA1C and LDL in the control group may have obscured any further intervention effect . Although nurses prompted providers for medication titration , strategies to reduce provider clinical inertia may also be needed PURPOSE The effect of pharmaceutical care services for home care patients with heart failure on death and rehospitalization rates was studied . METHODS Eligible patients had to be at least 21 years old and included those with a primary or secondary diagnosis of heart failure who were referred to receive skilled nursing services . Patients were then r and omized to receive usual care or pharmaceutical care . Patients assigned to the usual care group received the services typically provided by the visiting nurses association , while patients in the pharmaceutical care group received usual care plus st and ardized services from a clinical pharmacist . Pharmaceutical care services consisted of an initial comprehensive in home medication assessment and two follow-up visits . Throughout the three-week intervention period , the clinical pharmacist accessed and review ed all pertinent physician notes and laboratory test values and interacted with prescribers on behalf of the patients as necessary . RESULTS A total of 154 patients met all criteria and participated in the study . The pharmacist made 79 specific therapy recommendations , 47 ( 60 % ) of which were related directly to drug therapy for heart failure or cardiovascular disease . Overall , 14 therapy recommendations were fully implemented , and 10 heart failure-specific recommendations were fully implemented . Patients for whom the pharmacist had made recommendations that were followed by the prescriber had a reduced rate of the composite primary endpoint , but this difference did not reach statistical significance . CONCLUSION A home-based pharmaceutical care model for recently hospitalized patients with heart failure did not significantly improve the combined rate of death or rehospitalization CONTEXT Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome ( HIV/AIDS ) is one of the world 's most challenging p and emics . For treatment with Highly Active Anti-Retroviral Therapy ( HAART ) to be effective , high rate of adherence is essential . AIM To demonstrate the effect of adherence counseling and text message reminders in improving patients ' adherence to HAART . SETTING S AND DESIGN A r and omized control trial among non-adherents was carried out in a tertiary hospital in Nigeria between March and July , 2011 . MATERIAL S AND METHODS A total of 104 patients : 45 males ( 43.3 % ) and 59 females ( 56.7 % ) participated in the study . They were r and omized into intervention and control groups . The intervention group received monthly adherence counseling and twice weekly short message reminders for four months , while the control group received only st and ard care . Self-reported adherence and CD4 + cell counts were measured pre- and post-intervention . STATISTICAL ANALYSIS USED Data was analysed using Statistical Package for Social Sciences ( SPSS ) version 18 . Risk rates , Chi-square , Mann-Whitney U test and Cohen 's effect size were calculated . Level of significance was set at P = 0.05 . RESULTS At post-intervention , 76.9 % of the intervention group and 55.8 % of the control group achieved adherence ( χ2 = 5.211 , P = 0.022 , RR = 0.75 ( 0.55 - 0.96 ) , Cohen 's w = 0.224 ) . Also , median CD4 + cell count of the intervention group increased from 193 cells/ml to 575.0 cells/ml against 131.0 cells/ml to 361.5 cells/ml in the control group ( P = 0.007 ) . CONCLUSION Adherence counseling and text message reminders improved adherence among HIV patients . Its adoption for HIV patient management is advocated OBJECTIVE To evaluate various strategies aim ed at improving adherence to antiretroviral therapy ( ART ) . METHODS Patients initiated on ART at Muhimbili National Hospital HIV clinic were r and omly assigned to either regular adherence counseling , regular counseling plus a calendar , or regular counseling and a treatment assistant . Patients were seen monthly ; during these meetings self-reported adherence to treatment was recorded . Disease progression was monitored clinical ly and immunologically . RESULTS Of the 621 patients r and omized , 312 received regular counseling only , 242 regular counseling and calendars , while 67 had treatment assistants in addition to regular counseling . The mean ( SD ) follow-up time was 14.5 ( 4.6 ) months . During follow-up 20 ( 3.2 % ) patients died , and 102 ( 16.4 % ) were lost to follow-up ; this was similar in all groups . In 94.8 % of all visits , patients reported to have adhered to treatment . In only 39 ( 0.7 % ) visits did patients report a < or = 95 % adherence . There were no differences in adherence ( P = 0.573 ) or differences in CD4 count and weight changes over time in the interventions . CONCLUSIONS Good adherence to ART is possible in re source constrained countries . Persistent adherence counseling in clinic setting s by itself may be effective in improving adherence to ART Objective . To study the efficacy of telephone and mail intervention in therapeutic compliance among patients with mild to moderate hypertension . Design . A prospect i ve controlled multicenter clinical trial . Setting . Eighty‐five primary care centers in Spain , with a duration of 6 months . Patients . A total of 636 patients with newly diagnosed or uncontrolled hypertension were included . Interventions . The patients were r and omized and distributed between the following groups : ( i ) control ( CG ) – under routine clinical management ; ( ii ) mail intervention ( MIG ) – received a mailed message reinforcing compliance and reminding of the visits ( 15 days , 2 and 4 months ) ; ( iii ) telephone intervention ( TIG ) – received a telephone call at 15 days , then at 7 and 15 weeks . Main outcome measure . Five visits were scheduled , with the measurement of blood pressure and counting of tablets . Compliers were defined as subjects showing 80–110 % drug consumption . Calculations were made of mean percentage compliance ( MPC ) and compliers , mean blood pressure and percentage controlled subjects . Results . Five hundred and thirty‐eight patients completed the study ( 261 males ) ; 85.5 % were compliers ( CI = 82.5–88.5 ; n = 460 ) . The MPC was 95.1±19.6 % ( CI = 93.28–96.92 ) . The CG consisted of 182 individuals , MIG = 172 and TIG = 184 . Compliers represented 69.2 % of the CG ( CI 62.5–75.9 % ) , 91.3 % ( CI = 87.1–95.5 ) of the MIG ( p = 0.0001 ) and 96.2 % of the TIG ( CI 93.5–98.9 % ) ; the final MPC was 89.6%±15 in CG , 96.6%±12 in MIG and 99.1±26.8 in TIG ( p = 0.0001 ) . The percentage of controlled subjects was 47.2 % in CG ( CI = 40–54.4 ) , 61.3 % in MIG ( CI = 54.1–68.5 % ) and 63.3 % in TIG ( CI = 56.4–70.2 % ) ( p<0.05 ) . Conclusions . TIG and MIG are effective measures for improving patient compliance in hypertension Abstract Low compliance with antihypertensive drug regimens is a major cause of failure to achieve adequate blood pressure control . A simple clinical interview can identify the noncompliant patient who is most likely to benefit from compliance-improving strategies . These strategies , many of which require a minimal amount of additional clinical effort , can be applied in sequence to help a substantial portion of uncontrolled hypertensives achieve goal blood pressures Low levels of statin adherence may compromise treatment outcomes . The aim of this study was to investigate whether nurse-led cardiovascular risk-factor counseling could improve statin adherence and lipid levels without increasing patients ' anxiety . Patients with indications for statin therapy for primary or secondary prevention of cardiovascular disease were r and omly assigned to receive routine care or extended care ( EC ) at baseline and at months 3 , 9 , and 18 . Patients in the EC group received a personalized risk-factor passport , showing modifiable and unmodifiable individual risk factors and a graphical presentation of their calculated absolute 10-year cardiovascular disease risk as well as the target risk that could be reached if all modifiable risk factors were optimally treated . Lipid levels were assessed at each visit . Carotid intima-media thickness was measured at baseline and at month 18 . Adherence , anxiety , quality of life , symptoms , and smoking status were assessed using a self-administered question naire at each visit . A total of 201 patients were included in the study . Statin adherence was significantly higher ( p < 0.01 ) and anxiety was significantly lower ( p < 0.01 ) in the EC group than in the routine care group . Low-density lipoprotein cholesterol was statistically significantly lower in the EC group than in the routine group ( 2.66 vs 3.00 mmol/L , respectively , p = 0.024 ) in primary prevention patients only . Intima-media thickness improved significantly from baseline ( p < 0.01 ) in all patients , irrespective of group assignment . In conclusion , cardiovascular risk-factor counseling result ed in improved lipid profiles in primary prevention patients and higher levels of adherence to statins and lower levels of anxiety in all patients Objective Elderly heart failure patients are at high risk of events . Available studies and systematic review s suggest that elderly patients benefit from disease management programmes ( DMPs ) . However , important questions remain open , including the optimal follow-up intensity and duration and whether such interventions are cost-effective during long-term follow-up and in different healthcare systems . The aim of this study was to determine the long-term efficacy of a hybrid DMP in consecutive older out patients . Methods Intervention consisted in combined hospital-based ( cardiologists and nurse-coordinators from two heart failure clinics ) and home-based ( patient 's general practitioner visits ) care . The components of the DMP were the following : discharge planning , education , therapy optimisation , improved communication , early attention to signs and symptoms . Intensive follow-up was based on scheduled hospital visits ( starting within 14 days of discharge ) , nurse 's phone call and home general practitioner visits . Results A group of 173 patients aged ≥70 years ( mean age 77 ± 6 years , 48 % women ) was r and omly assigned to DMP ( n = 86 ) or usual care ( n = 87 ) . At 2-year follow-up , a 36 % reduction in all-cause death and heart failure hospital admissions was observed in DMP vs. usual care . All-cause and heart failure admissions as well as the length of hospital stay were also reduced . DMP patients reported , compared to baseline , significant improvements in functional status , quality of life and β-blocker prescription rate . The intervention was cost-effective with a mean saving of & U20AC ; 982.04 per patient enrolled . Conclusions A hybrid DMP for elderly heart failure patients improves outcomes and is cost-effective over a long-term follow-up OBJECTIVE To investigated the effectiveness of an adherence intervention ( AIMS ) design ed to fit HIV-clinics ' routine care procedures . DESIGN Through block r and omization , patients were allocated to the intervention or control group . The study included 2 months baseline measurement , 3 months intervention , and 4 months follow-up . HIV-nurses delivered a minimal intervention ( " adherence sustaining " ) to patients scoring > 95 % adherence at baseline , and an intensive intervention ( " adherence improving " ) to patients with < 95 % adherence . Control participants received high- quality usual care . MAIN OUTCOME MEASURES Electronically monitored adherence and viral load . RESULTS 133 patients were included ( 67 control , 66 intervention ) , 60 % had < 95 % adherence at baseline , and 87 % ( 116/133 ) completed the trial . Intent-to-treat analyses showed that adherence improved significantly in the complete intervention sample . Subgroup analyses showed that this effect was caused by participants scoring < 95 % at baseline ( mean difference = 15.20 % ; p < .001 ) . These effects remained stable during follow-up . The number of patients with an undetectable viral load increased in the intervention group compared to the control group ( OR = 2.96 , p < .05 ) . Treatments effects on viral load were mediated by the improvements in adherence . CONCLUSIONS The AIMS -intervention was effective and can be integrated in routine clinical care for HIV-infected patients . Future research should study its (cost)effectiveness among more heterogeneous sample s and in setting s with variable levels of st and ard care STUDY OBJECTIVE To determine the relationship between poor adherence and self-efficacy or social support after a pharmacist intervention . DESIGN Post-hoc analysis of data from two r and omized controlled trials of physician-pharmacist collaborative interventions ( 6 and 9 mo , respectively ) to improve blood pressure control . SETTING Eleven university-affiliated primary care clinics . PATIENTS Five hundred eighty-four patients ( aged 21 - 85 yrs ) with uncontrolled primary hypertension ; 296 were in the intervention group and 288 were in the control group . INTERVENTION Pharmacists provided intensified hypertension management and drug adherence counseling to patients in the intervention group . MEASUREMENTS AND MAIN RESULTS Social support and self-efficacy question naires were administered at baseline and end-of- study visits . Patient adherence was monitored by using the Morisky self-reported adherence question naire . Self-reported adherence scores improved significantly in the control group ( p=0.0053 ) but not in the intervention group ; however , adherence at baseline in both groups was high . There were small , but significant , improvements in self-efficacy ( p<0.04 ) and social support ( p<0.05 ) scores in the intervention group but not the control group at the end of the study . Social support and , to a lesser extent , self-efficacy improved as a function of duration of study participation ( 9-mo vs 6-mo intervention ) , regardless of whether the patient received the intervention . Blood pressure control in both groups improved significantly at the end of the study ; however , mean blood pressure was significantly lower in the intervention group ( 129.7/76.6 mm Hg ) compared with the control group ( 140.8/78.9 mm Hg ; p<0.0001 for systolic , p=0.032 for diastolic ) . CONCLUSION Social support and self-efficacy improved significantly in the intervention group at the end of the pharmacist intervention . Drug adherence was correlated with self-efficacy even though drug adherence did not improve significantly in the intervention group . The fact that social support and self-efficacy improved as a function of duration of study participation suggests that participation in a research study may have had a positive influence on these measures . Even though the changes in social support , self-efficacy , and drug adherence were modest , there was significantly better blood pressure control in the intervention group compared with the control group . These findings indicate that changes in drug adherence , self-efficacy , or social support probably played a minor role in the blood pressure outcomes in these studies OBJECTIVES To demonstrate that pharmacists working with physicians and other providers in an ambulatory care setting can improve glucose , blood pressure , and lipid control for patients with type 2 diabetes and to report patient adherence to screening and general preventive measures . DESIGN Prospect i ve , r and omized , clinical practice study . SETTING Burlington , MA , between January 2001 and August 2003 . PATIENTS 164 patients patients with type 2 diabetes older than 18 years with glycosylated hemoglobin ( A1C ) greater than 8 % . INTERVENTION Pharmacist-patient clinic visits included obtaining a comprehensive medication review ; performing targeted physical assessment ; ordering laboratory tests ; review ing , modifying , and monitoring patients ' medication therapy and providing detailed counseling on all therapies ; facilitating self-monitoring of blood glucose ; and providing reinforcement of dietary guidelines and exercise . MAIN OUTCOME MEASURE Effect of clinical pharmacists working with physicians in an ambulatory setting on health measures ( e.g. , A1C , blood pressure , cholesterol ) of patients with diabetes . RESULTS Baseline characteristics were similar between the two groups . After 1 year , significant improvements occurred for A1C and low-density lipoprotein ( LDL ) cholesterol in the intervention group compared with the control group ( A1C , 7.7 % vs. 8.4 % ; LDL , 93.7 vs. 105.1 mg/dL ; P < 0.05 ) . Systolic blood pressure improved for all study patients without a difference between the two groups . Diastolic blood pressure improved significantly in the intervention group compared with the control group ( 73.4 mm Hg vs. 77.6 mm Hg , P < 0.05 ) . Significantly more intervention patients were screened for retinopathy , neuropathy , and microalbuminuria than control patients ( P < 0.05 ) . CONCLUSION For all indices measured , this study demonstrated that collaborative diabetes management with a clinical pharmacist can improve overall care BACKGROUND Poor adherence leads to a high rate of exacerbation and poor health-related quality of life ( HRQoL ) in patients with chronic obstructive pulmonary disease ( COPD ) . However , few strategies are acceptable and effective in improving medication adherence . We investigated whether pharmaceutical care by clinical pharmacists could reinforce medication adherence to reduce exacerbation and improve HRQoL. METHODS A r and omized controlled study was carried out at The First Affiliated Hospital of Guangzhou Medical University from February 2012 to January 2014 . Non-adherence patients were r and omly assigned to receive pharmaceutical care or to usual care . The pharmaceutical care consisted of individualized education and a series of telephone counseling for 6 months provided by clinical pharmacists . Medication adherence was measured by pill counts plus direct interview at 1- and 6-month pharmaceutical care and one-year follow-up . Severe exacerbations were defined as events that led to hospitalization for acute COPD attack . An interview was conducted to investigate hospital admissions and evaluate severe exacerbations at one-year follow-up . HRQoL was measured by St George 's Respiratory Question naire at 6 months . RESULTS At 6-month pharmaceutical care and one-year follow-up , the pharmaceutical care group exhibited higher medication adherence than the usual care group ( 73.4±11.1 vs. 55.7±11.9 , P=0.016 and 54.4±12.5 vs. 66.5±8.6 , P=0.039 , respectively ) . There are 60 acute exacerbations result ed in a hospital admission in the usual group while 37 ones in the pharmaceutical care group during one-year follow-up ( P=0.01 ) . Hospital admissions due to acute exacerbation in the pharmaceutical care group were 56.3 % less than the usual care group ( P=0.01 ) . There was a significant difference in the symptoms and impact subscales respectively at 6-month pharmaceutical care between two groups ( P=0.032 , P=0.018 ) . CONCLUSIONS Individualized pharmaceutical care improved medication adherence , reduced hospitalization and elevated HRQoL in patients with COPD Background : The relationship between patient adherence and treatment outcomes has been documented across chronic health conditions , but the evidence base for effective adherence interventions in human immunodeficiency virus ( HIV ) and acquired immune deficiency syndrome ( AIDS ) requires more rigorous research and reporting . Objectives : The aims of this study were to determine whether a tailored , nurse-delivered adherence intervention program-Client Adherence Profiling and Intervention Tailoring (CAP-IT)-improved adherence to HIV medications , compared with st and ard care , and to identify the relationship among adherence measures . Methods : A r and omized controlled trial ( RCT ) with repeated measures was used to test the efficacy of CAP-IT over a 6-month period . A convenience sample of 240 participants was recruited from a freest and ing public HIV/AIDS clinic in Houston , TX , that provides medical , psychological , and pharmaceutical services for over 5,000 clients . Study instruments and measures included demographics ; chart audit to capture CD4 count , viral load , and prescribed medications ; health literacy ; and five measures of adherence ( AIDS Clinical Trial Group-Revised Reasons for Missing Medications , Morisky Self-Report of Medication Non-Adherence , Pill Count , Medication Event Monitoring System [ MEMS ] caps , and Pharmacy Refill ) . Results : A logistic regression using generalized estimating equations method showed no significant differences over time on the five medication-adherence measures between the experimental and control groups . Little correlation was documented among the five different adherence measures , and there was minimal correlation with clinical markers . Discussion : It is unclear why the tailored adherence intervention was not efficacious in improving medication adherence . The findings suggest that these measures of medication adherence did not perform as expected and that , perhaps , they are not adequate measures of adherence . Effective and efficient adherence interventions are needed to address the barriers to medication adherence in HIV/AIDS Abstract The primary aim of this study was to test an intervention to support antiretroviral medication adherence among primarily low-income men and women with HIV . The study was a r and omized controlled trial ( Get Busy Living ) with participants assigned to treatment ( Motivational Interviewing [ MI ] ) and control groups . Participants were recruited from an HIV/AIDS clinic in Atlanta , Georgia , US . Of those referred to the study , 247 completed a baseline assessment and were enrolled with 125 r and omized to the intervention group and 122 to the control group . Participants were patients beginning antiretroviral therapy or changing to a new drug regimen . The intervention consisted of five MI sessions delivered by registered nurses in individual counselling sessions . Participants were paid for each session attended . The intervention sought to build confidence , reduce ambivalence and increase motivation for ART medication-taking . Medication adherence was measured by the Medication Event Monitoring System ( MEMS ® ) from the time of screening until the final follow-up conducted approximately 12 months following the baseline assessment . Participants in the intervention condition showed a trend towards having a higher mean percent of prescribed doses taken and a greater percent of doses taken on schedule when compared to the control group during the months following the intervention period . This effect was noted beginning at about the eighth month of the study period and was maintained until the final study month . Although the finding was weaker for overall percent of prescribed doses taken , the results for the percent of doses taken on schedule suggests that the MI intervention may be a useful approach for addressing specific aspects of medication adherence , such as adherrence to a specified dosing schedule STUDY OBJECTIVE To evaluate whether a simple pharmacist protocol , consisting of patient screening and cardiovascular risk stratification , identification and reminders about uncontrolled risk factors , and drug adherence support , can significantly reduce cardiovascular risk . DESIGN Prospect i ve , r and omized , controlled pilot study . SETTING Large primary care medical clinic in Saskatoon , Saskatchewan , Canada . PATIENTS One hundred seventy-six adult patients ( mean age 60 yrs ) who exhibited a 10-year Framingham risk score of 15 % or greater , or a coronary artery disease risk equivalent ( coronary artery disease , peripheral artery disease , cerebrovascular disease , or diabetes mellitus ) . INTERVENTION Eligible patients initially met with the pharmacist to receive general counselling about cardiovascular disease and were then r and omly assigned to receive ongoing follow-up by the pharmacist ( follow-up group [ 88 patients ] ) or to return to usual care ( single-contact group [ 88 patients ] ) for a minimum of 6 months . MEASUREMENTS AND MAIN RESULTS The primary end point was mean reduction in the 10-year Framingham risk score . Secondary end points included individual modifiable risk factors ( systolic and diastolic blood pressures ; total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol [ HDL ] , and triglyceride levels ; total cholesterol : HDL ratio ; and hemoglobin A(1c ) value ) , as well as statin utilization , initiation , and adherence rates . Baseline characteristics were similar across both groups . Neither the mean reduction in 10-year risk ( -2.68 for the follow-up group and -1.25 for the single-contact group , one-tailed p=0.098 ) nor individual risk factors were significantly different between groups . The proportion of patients exhibiting statin adherence of 80 % or greater did not significantly differ between groups at study end ( 73.1 % [ 57/78 ] and 80.0 % [ 52/65 ] , respectively , p=0.333 ) . However , 85.2 % ( 75/88 ) in the follow-up group continued with statin therapy at the end of the study compared with 67.0 % ( 59/88 ) in the single-contact group ( p=0.005 ) . Statin initiations were more frequent in the follow-up group than in the single-contact group ( 75.0 % [ 30/40 ) vs 48.9 % [ 22/45 ] , p=0.013 ) . CONCLUSION This simple cardiovascular care protocol for nonspecialist pharmacists did not result in a clear improvement to cardiovascular risk reduction success among patients in a primary care medical clinic . The intervention did , however , appear to improve statin utilization BACKGROUND Poor medication adherence is a significant problem in hypertensive African Americans . Although motivational interviewing ( MINT ) is effective for adoption and maintenance of health behaviors in patients with chronic diseases , its effect on medication adherence remains untested in this population . METHODS This r and omized controlled trial tested the effect of a practice -based MINT counseling vs. usual care ( UC ) on medication adherence and blood pressure ( BP ) in 190 hypertensive African Americans ( 88 % women ; mean age 54 years ) . Patients were recruited from two community-based primary care practice s in New York City . The primary outcome was adherence measured by electronic pill monitors ; the secondary outcome was within-patient change in office BP from baseline to 12 months . RESULTS Baseline adherence was similar in both groups ( 56.2 and 56.6 % for MINT and UC , respectively , P = 0.94 ) . Based on intent-to-treat analysis using mixed-effects regression , a significant time x group interaction with model-predicted posttreatment adherence rates of 43 and 57 % were found in the UC and MINT groups , respectively ( P = 0.027 ) , with a between-group difference of 14 % ( 95 % confidence interval , -0.2 to -27 % ) . The between-group difference in systolic and diastolic BP was -6.1 mm Hg ( P = 0.065 ) and -1.4 mm Hg ( P = 0.465 ) , respectively , in favor of the MINT group . CONCLUSIONS A practice -based MINT counseling led to steady maintenance of medication adherence over time , compared to significant decline in adherence for UC patients . This effect was associated with a modest , nonsignificant trend toward a net reduction in systolic BP in favor of the MINT group Background Medicine usage in Parkinson 's disease patients is often imperfect , in particular irregular timing of medication . The effect of informing Parkinson 's disease patients about the continuous dopaminergic hypothesis ( to encourage regular medicine intake ) on medication adherence and motor control was tested . Methods Patients were r and omised either to the active group ( receiving the intervention ) or control group ( no extra information ) . Antiparkinson medicine usage was monitored for 3 months before and after the intervention using electronic pill bottles which record the date and time of opening ( MEMS ® , Aardex , Switzerl and ) and data used to calculate the percentage of doses taken at correct time intervals . Results 43 patients ( 52 % ) were r and omised to active counselling , and 40 ( 48 % ) were controls ( st and ard management ) . The intervention effect ( difference in timing adherence pre- to post-intervention between the 2 groups ) was 13.4 % ( CI 5.1 to 21.7 ) , p = 0.002 . Parkinson motor scores did not change significantly ( active group 0.1 , CI -3.4 to 3.7 ) versus controls ( 4.5 , CI 1.6 to 7.1 ) , p = 0.06 . Conclusion Timing adherence , but not motor scores , improves by providing patients with extra information . Therapy timing is of potential importance in Parkinson 's disease management . Trial registration BACKGROUND Multiple studies demonstrate poor adherence to medication regimens prescribed for chronic illnesses , including osteoporosis , but few interventions have been proven to enhance adherence . We examined the effectiveness of a telephone-based counseling program rooted in motivational interviewing to improve adherence to a medication regimen for osteoporosis . METHODS We conducted a 1-year r and omized controlled clinical trial . Participants were recruited from a large pharmacy benefits program for Medicare beneficiaries . All potentially eligible individuals had been newly prescribed a medication for osteoporosis . Consenting participants were r and omized to a program of telephone-based counseling ( n = 1046 ) using a motivational interviewing framework or a control group ( n = 1041 ) that received mailed educational material s. Medication regimen adherence was the primary outcome compared across treatment arms and was measured as the median ( interquartile range ) medication possession ratio , calculated as the ratio of days with filled prescriptions to total days of follow-up . RESULTS The groups were balanced at baseline , with a mean age of 78 years ; 93.8 % were female . In an intention-to-treat analysis , median adherence was 49 % ( interquartile range , 7%-88 % ) in the intervention arm and 41 % ( 2%-86 % ) in the control arm ( P = .07 , Kruskal-Wallis test ) . There were no differences in self-reported fractures . CONCLUSION In this r and omized controlled trial , we did not find a statistically significant improvement in adherence to an osteoporosis medication regimen using a telephonic motivational interviewing intervention OBJECTIVE To evaluate HIV drug resistance ( HIVDR ) among Chinese patients with HIV receiving first-line highly active antiretroviral therapy ( HAART ) . METHODS Based on the WHO HIVDR surveys , a prospect i ve cohort study with 12-month follow-up was conducted to estimate the prevalence of HIV RNA<1000 copies/ml and HIVDR . RESULTS A total of 341 study subjects naïve to prior antiretroviral therapy ( ART ) were followed up for a median of 12.1 months . The overall mortality rate was 9.9 per 100 person-years . The median of CD4 counts increased from 182 cells/mm(3 ) at baseline to 268 cells/mm(3 ) at 12 months ( P<0.0001 ) . Of patients with plasma HIV-1 RNA concentrations ≥1000 copies/ml at 12 months , the proportions of resistance to non-nucleoside reverse transcriptase drugs , nucleoside/nucleotide reverse transcriptase inhibitors , and protease inhibitor drugs were 34.2 % , 23.7 % and 0 % , respectively . The overall proportion of HIV RNA<1000 copies/ml was 85.7 % at 12 months . Occupation of farmer ( AOR=0.3 , 95 % CI : 0.08 , 0.94 ; P=0.0393 ) and HAART counselling and instruction through telephone ( AOR=2.8 , 95 % CI : 1.4 , 5.6 ; P=0.0047 ) were significantly associated with HIV RNA<1000 copies/ml . CONCLUSION Our study demonstrated that the community-based ART had significant effects on viral suppression and immune recovery . HIVDR should be monitored in the long term to guide informed decisions on preventing HIVDR and choices of first- and second-line regimens Background : Few studies have reported the efficacy of collaborative care involving family physicians and community pharmacists for patients with dyslipidemia . Methods : We r and omly assigned clusters consisting of at least two physicians and at least four pharmacists to provide collaborative care or usual care . Under the collaborative care model , pharmacists counselled patients about their medications , requested laboratory tests , monitored the effectiveness and safety of medications and patients ’ adherence to therapy , and adjusted medication dosages . After 12 months of follow-up , we assessed changes in low-density lipoprotein ( LDL ) cholesterol ( the primary outcome ) , the proportion of patients reaching their target lipid levels and changes in other risk factors . Results : Fifteen clusters representing a total of 77 physicians and 108 pharmacists were initially recruited , and a total of 51 physicians and 49 pharmacists were included in the final analyses . The collaborative care teams followed a total of 108 patients , and the usual care teams followed a total of 117 patients . At baseline , mean LDL cholesterol level was higher in the collaborative care group ( 3.5 v. 3.2 mmol/L , p = 0.05 ) . During the study , patients in the collaborative care group were less likely to receive high-potency statins ( 11 % v. 40 % ) , had more visits with health care professionals and more laboratory tests , were more likely to have their lipid-lowering treatment changed and were more likely to report lifestyle changes . At 12 months , the crude incremental mean reduction in LDL cholesterol in the collaborative care group was −0.2 mmol/L ( 95 % confidence interval [ CI ] −0.3 to −0.1 ) , and the adjusted reduction was −0.05 ( 95 % CI −0.3 to 0.2 ) . The crude relative risk of achieving lipid targets for patients in the collaborative care group was 1.10 ( 95 % CI 0.95 to 1.26 ) , and the adjusted relative risk was 1.16 ( 95 % CI 1.01 to 1.34 ) . Interpretation : Collaborative care involving physicians and pharmacists had no significant clinical impact on lipid control in patients with dyslipidemia . International St and ard R and omized Controlled Trial register no. IS RCT N66345533

RESULT ( S ) Women with subserosal fibroids had no differences in their fertility outcomes compared with infertile controls with no myomas , and myomectomy did not change these outcomes compared with women with fibroids in situ . Women with intramural fibroids appear to have decreased fertility and increased pregnancy loss compared with women without such tumors , but study quality is poor . Myomectomy does not significantly increase the clinical pregnancy and live birth rates , but the data are scarce . Fibroids with a submucosal component led to decreased clinical pregnancy and implantation rates compared with infertile control subjects . Removal of submucous myomas appears likely to improve fertility . CONCLUSION ( S ) Fertility outcomes are decreased in women with submucosal fibroids , and removal seems to confer benefit . Subserosal fibroids do not affect fertility outcomes , and removal does not confer benefit . Intramural fibroids appear to decrease fertility , but the results of therapy are unclear .

OBJECTIVE To investigate the effect of fibroids on fertility and of myomectomy in improving outcomes .

Eleven women with a history of infertility and uterine leiomyomas underwent magnetic resonance ( MR ) imaging of the pelvis prior to myomectomy . Nine also underwent preoperative pelvic ultrasonography ( US ) , and ten underwent hysterosalpingography . All studies were interpreted prospect ively by independent observers . With each imaging modality , the location ( one of 11 anatomic segments ) , size , and appearance of detected uterine leiomyomas were determined and compared with surgical and histologic findings . Among the nine patients who underwent both MR and US , the sensitivity ( 85 % ) and accuracy ( 94 % ) of MR imaging for abnormal segments was significantly better than that of US ( sensitivity = 69 % , P = .015 ; accuracy = 87 % , P = .043 ) . For the ten patients who underwent both MR and hysterosalpingography , the sensitivity ( 91 % ) and accuracy ( 96 % ) of MR imaging was better than that of hysterosalpingography ( sensitivity = 18 % , P = .0005 ; accuracy = 72 % , P = .0005 ) . The specificities of the three modalities did not significantly differ ( 100 % , 97 % , and 98 % for MR , US , and hysterosalpingography , respectively ) . These data suggest that MR imaging is superior to US or hysterosalpingography for preoperatively locating uterine leiomyomas BACKGROUND Several studies have reported that the presence of intramural fibroids affects conception following IVF . We attempted to corroborate or refute the conclusions relating to IVF and leiomyomas of the aforementioned studies . METHODS Women with small intramural leiomyomata ( < or = 5 cm ) discovered on initial pelvic sonographic studies performed in preparation for IVF were prospect ively matched by age , with the next patient of the same age undergoing IVF who did not demonstrate fibroids ( controls ) . RESULTS Though no significant differences were found in outcome when comparing these two groups , there was a distinct trend for lower live delivery rates and higher miscarriage rates . CONCLUSIONS These data support the conclusions of the only other prospect i ve matched control study evaluating similar factors , i.e. that small intramural fibroids can negatively affect IVF outcome . Nevertheless , we think that a multicentre study should be conducted first before evaluating whether myomectomy improves outcome or not Objective To assess the usefulness of transabdominal sonohysterography in the diagnosis and evaluation of submucous myomas . Methods Fifty-two premenopausal women hospitalized for hysterectomy for benign gynecologic indications under-went preoperative conventional transvaginal sonography , transabdominal sonohysterography , and hysteroscopy . The results of the three techniques in terms of diagnosis , size , intracavitary growth , and location of the submucous myomas were compared with those revealed by direct inspection of the surgical specimens . Results Conventional transvaginal sonography for the diagnosis of submucous myomas had a sensitivity of 90 % and a specificity of 98 % ; the predictive values of abnormal and normal scans were 90 and 98 % , respectively . Transabdominal sonohysterography had sensitivity , specificity , and predictive values of 100 % , as did hysteroscopy . In all cases , the sonographic techniques measured tumor size more accurately than did hysteroscopy . The transabdominal sonohysterography measurements differed from direct evaluation by no more than 2 mm , and the hysteroscopic measurements were significantly different from those of the surgical specimens . The sonohysterographic evaluation of intrauterine growth was significantly more precise than that of the other techniques , differing from direct measurements by no more than 5–10 % . Conventional transvaginal sonography failed to localize three of 11 myomas ; hysteroscopy and transabdominal sonohysterography provided the exact location in all cases . Conclusion Transabdominal sonohysterography is the most accurate technique for detecting submucous myomas and evaluating their size , intracavitary growth , and location BACKGROUND There is no consensus as to whether uterine fibroids have any adverse effects on the outcomes of assisted reproduction treatment . This prospect i ve study compared implantation/pregnancy rates of women with and without fibroids undergoing IVF-embryo transfer and measured uterine blood flow indices of the fibroid group . METHODS Patients who had fibroids that , during transvaginal scanning , were found to be not distorting the endometrial lining were placed in the fibroid group , while patients with normal uteri were controls . Those with previous myomectomy or pedunculated subserosal fibroids only were excluded . All received a st and ard ovarian stimulation regimen . Doppler ultrasound examinations of uterine arteries were carried out in the fibroid group prior to oocyte retrieval . RESULTS Similar implantation/pregnancy rates , multiple pregnancy rates and pregnancy outcomes were noted in both groups . In the fibroid group , significantly lower pulsatility index ( PI ) and resistance index ( RI ) of the right uterine artery and the average of right and left uterine arteries were found in those failing to conceive than in those patients who subsequently conceived ( P < 0.001 ) . CONCLUSION The presence of fibroids not distorting the endometrial lining does not adversely affect implantation and pregnancy rates during IVF-embryo transfer . Significantly lower uterine artery PI and RI were found in non-pregnant women with fibroids than in their pregnant counterparts BACKGROUND Although uterine fibroids occur in 30 % of women and are associated with a degree of subfertility , the effect of intramural fibroids on the outcome of IVF or ICSI treatment has not been prospect ively studied . METHODS Data were prospect ively collected on 434 women undergoing IVF/ICSI in the assisted conception unit of an inner London teaching hospital . Patients were assessed for the presence of fibroids by transvaginal ultrasound and hysterosonography or hysteroscopy where appropriate . RESULTS During the study period , 112 women with ( study ) , and 322 women without ( controls ) , intramural fibroids were treated . Patients were similar regarding the cause and duration of their infertility , number of previous treatments , and basal serum FSH concentration . Women in the study group were on average 2 years older ( 36.4 versus 34.6 years ; P < 0.01 ) . There was no significant difference in the duration of ovarian stimulation or gonadotrophin requirement , number of follicles developed , oocytes collected , embryos available for transfer or replaced . When analysing only women with intramural fibroids of < or = 5 cm in size ( n = 106 ) pregnancy , implantation and ongoing pregnancy rates were significantly reduced : 23.3 , 11.9 and 15.1 respectively compared with 34.1 , 20.2 and 28.3 % in the control group ( P = 0.016 , P = 0.018 and P = 0.003 ) . The mean size of the largest fibroids was 2.3 cm ( 90 % range 2.1 - 2.5 cm ) . Logistic regression analysis demonstrated that the presence of intramural fibroids was one of the significant variables affecting the chance of an ongoing pregnancy , even after controlling for the number of embryos available for replacement and increasing age , particularly age > or = 40 years , odds ratio 0.46 ( CI 0.24 - 0.88 ; P = 0.019 ) . CONCLUSION This study demonstrated that an intramural fibroid halves the chances of an ongoing pregnancy following assisted conception This prospect i ve , controlled study was performed in order to evaluate whether the location of uterine fibroids may influence reproductive function in women and whether removal of the fibroid prior to conception may improve pregnancy rate and pregnancy maintenance . We examined 181 women affected by uterine fibroids who had been trying to conceive for at least 1 year without success . The main outcome measures were the pregnancy rate and the miscarriage rate . Among the patients who underwent myomectomy , the pregnancy rates obtained were 43.3 % in cases of submucosal , 56.5 % in cases of intramural , 40.0 % in cases of submucosal – intramural and 35.5 % in cases of intramural – subserosal uterine fibroids , respectively . Among the patients who did not undergo surgical treatment , the pregnancy rates obtained were 27.2 % in women with submucosal , 41.0 % in women with intramural , 15.0 % in women with submucosal – intramural and 21.43 % in women with intramural – subserosal uterine fibroids , respectively . Although the results were not statistically significant in the group of women with intramural and intramural – subserosal fibroids , this study confirms the important role of the position of the uterine fibroid in infertility as well as the importance of fibroids removal before the achievement of a pregnancy , to improve both the chances of fertilization and pregnancy maintenance OBJECTIVE To evaluate the role of sonohysterography for screening of the uterine cavity in patients with recurrent pregnancy loss . DESIGN Prospect i ve evaluation of sonohysterography , including comparison with available hysterosalpingography and hysteroscopy . SETTING University referral center . PATIENT(S ) Thirty-four reproductive-aged women with at least two consecutive pregnancy losses . INTERVENTION(S ) Sonohysterography was performed on all patients , using saline instilled through an endocervically placed balloon catheter with concurrent vaginal sonography . RESULT ( S ) Seventeen of 34 sonohysterograms ( 50.0 % ) demonstrated intrauterine abnormalities . Eighteen of 34 cases have undergone hysteroscopy or , in 1 case , laparoscopy . All confirmed the positive or negative sonohysterographic finding , result ing in a sensitivity and specificity of 100 % . Additionally , 100 % ( 12/12 ) of the defects were diagnosed accurately at sonohysterography when confirmed by surgery . Twenty-seven of 34 patients also had a hysterosalpingogram that demonstrated a 90.0 % sensitivity and 20.0 % specificity based on hysteroscopic findings , yet only 5 of 11 ( 45.5 % ) defects were diagnosed accurately at hysterosalpingography when compared with surgery . CONCLUSION ( S ) Sonohysterography is a highly sensitive , specific , and accurate screening tool for the evaluation of uterine cavitary defects associated with recurrent pregnancy loss and offers several advantages over hysterosalpingography The goal of this study was to assess the risk of adhesions after laparoscopic myomectomy . To this end our enquiry was based on observations with a prospect i ve collection of data . Between October 26 , 1990 and October 1 , 1996 , 45 patients underwent a second look after laparoscopic myomectomy . Seventy-two myomectomy sites were checked . The overall rate of postoperative adhesion was 35.6 % per patient . The rate of adhesions per myomectomy site was 16.7 % . The factors which influenced the occurrence of an adhesion on the myomectomy site were posterior location of the myoma and the existence of sutures . The rate of adhesions on the adnexa after laparoscopic myomectomy was 24.4 % . The factors which influenced the occurrence of adnexal adhesions were another surgical procedure carried out at the same time , the existence of adhesions prior to the operation and posterior location of the myoma . The rate of adhesions after laparoscopic myomectomy is low and the adhesions rarely involved the adnexa . We recommend that a second-look laparoscopy be carried out systematic ally after laparoscopic myomectomy in patients desiring pregnancy

Diverse psychosocial or psychological interventions do not significantly reduce the number of women who develop postnatal depression . The most promising intervention is the provision of intensive , professionally based postpartum support

OBJECTIVE To assess the effects of psychosocial and psychological interventions compared with usual antepartum , intrapartum , or postpartum care on the risk of postnatal depression .

OBJECTIVE This project aim ed to evaluate the impact of a home visiting programme that targeted families where the child , for environmental reasons , was at great risk of poor health and developmental outcomes . METHODOLOGY Women in the immediate postpartum period were recruited to a r and omized double-blind controlled trial on the basis of self-reported vulnerability factors and were r and omly assigned to receive either a structured programme of nurse home visiting , supported by a social worker and paediatrician ( n = 90 ) , or assigned to a comparison group receiving st and ard community child health services ( n = 91 ) . Parenting stress and maternal depression were measured at enrollment and at 6 weeks . Preventive health behaviour , service satisfaction and home environment outcomes were tested at 6 weeks , as were child health outcomes . RESULTS At six weeks , women receiving the home-based programme had significant reductions in postnatal depression screening scores as well as improvements in their experience of the parental role and improvement in the ability to maintain their own identity . Maternal-infant interactions were more likely to be positive , with significantly higher ( better ) scores in aspects of the home environment related to optimal development in children , particularly maternal-infant secure attachment . Intervention group mothers were significantly more satisfied with the community child health service . CONCLUSIONS This form of intervention for families is effective in promoting secure maternal-infant attachment , preventing maternal mood disorder and is welcomed by the families receiving it . These findings may predict long-term benefits for the healthy development of children otherwise at risk of a range of poor health and development outcomes BACKGROUND Women who have suffered one episode of postpartum-onset major depression ( PPMD ) comprise a high-risk group for subsequent episodes . We conducted a double-blind , r and omized clinical trial to test the efficacy of nortriptyline in the prevention of recurrent PPMD . METHOD Nondepressed women who had at least one past episode of PPMD ( Research Diagnostic Criteria ) were recruited during pregnancy . Subjects were r and omly assigned to nortriptyline or placebo . Treatment began immediately postpartum . Each subject was assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression and Research Diagnostic Criteria for recurrence of major depression . RESULTS No difference was found in the rate of recurrence in women treated with nortriptyline compared with those treated with placebo . Of 26 subjects who took nortriptyline preventively , 6 ( 0.23 , 95 % exact confidence interval [ CI ] = 0.09 to 0.44 ) suffered recurrences . Of 25 subjects who took placebo , 6 ( 0.24 , 95 % exact CI = 0.09 to 0.45 ) suffered recurrence ( Fisher exact p = 1.00 ) . CONCLUSION Nortriptyline did not confer additional preventive efficacy beyond that of placebo . The rate of recurrence of PPMD ( one fourth of women ) was unacceptably high OBJECTIVE Postpartum depression affects between 10 and 15 percent of new mothers . These mothers are apprehensive about recurrence after later births . This study tested the efficacy of antidepressant medication administered during the postpartum period to prevent a recurrence of postpartum depression among women who had suffered a previous episode . METHODS An open clinical trial was conducted at a university-based outpatient clinic treating pregnant and postpartum women with mood disorders . Study participants were 23 pregnant women who had at least one previous postpartum episode that fit DSM-III-R criteria for nonbipolar major depression without psychotic features . Postpartum monitoring for recurrence of depressive symptoms was compared with postpartum monitoring plus postbirth treatment with either the medication that had been effective for the previous episode or nortriptyline . The first dose was given within 24 hours of birth . The authors assessed recurrence of postpartum major depression by psychiatric examination and use of the Inventory to Diagnose Depression , a reliable self-report instrument . RESULTS A significantly greater proportion of the women who elected monitoring alone ( 62.5 percent ) suffered recurrence of major depression compared with the women who received monitoring plus medication ( 6.7 percent ) ( p = .0086 ) . CONCLUSIONS Prophylactic antidepressant treatment reduced the recurrence of postpartum major depression Abstract Objectives : To establish the relative cost effectiveness of postnatal support in the community in addition to the usual care provided by community midwives . Design : R and omised controlled trial with six month follow up . Setting : Recruitment in a university teaching hospital and care provided in women 's homes . Participants : 623 postnatal women allocated at r and om to intervention ( 311 ) or control ( 312 ) group . Intervention : Up to 10 home visits in the first postnatal month of up to three hours duration by a community postnatal support worker . Main outcome measure : General health status as measured by the SF-36 and risk of postnatal depression . Breast feeding rates , satisfaction with care , use of services , and personal costs . Results : At six weeks there was no significant improvement in health status among the women in the intervention group . At six weeks the mean total NHS costs were £ 635 for the intervention group and £ 456 for the control group ( P=0.001 ) . At six months figures were £ 815 and £ 639 ( P=0.001 ) . There were no differences between the groups in use of social services or personal costs . The women in the intervention group were very satisfied with the support worker visits . Conclusions : There was no health benefit of additional home visits by community postnatal support workers compared with traditional community midwifery visiting as measured by the SF-36 . There were no savings to the NHS over six months after the introduction of the community postnatal support worker service UNLABELLED Adverse childbirth experiences can evoke fear and overwhelming anxiety for some women and precipitate posttraumatic stress disorder . The objective of this study was to assess a midwife-led brief counseling intervention for postpartum women at risk of developing psychological trauma symptoms . METHOD Of 348 women screened for trauma symptoms , 103 met inclusion criteria and were r and omized into an intervention ( n = 50 ) or a control ( n = 53 ) group . The intervention group received face-to-face counseling within 72 hours of birth and again via telephone at 4 to 6 weeks postpartum . Main outcome measures were posttraumatic stress symptoms , depression , self-blame , and confidence about a future pregnancy . RESULTS At 3-month follow-up , intervention group women reported decreased trauma symptoms , low relative risk of depression , low relative risk of stress , and low feelings of self-blame . Confidence about a future pregnancy was higher for these women than for control group women . Three intervention group women compared with 9 control group women met the diagnostic criteria for posttraumatic stress disorder at 3 months postpartum , but this result was not statistically significant . DISCUSSION A high prevalence of postpartum depression and trauma symptoms occurred after childbirth . Although most women improved over time , the intervention markedly affected participants ' trajectory toward recovery compared with women who did not receive counseling . CONCLUSIONS A brief , midwife-led counseling intervention for women who report a distressing birth experience was effective in reducing symptoms of trauma , depression , stress , and feelings of self-blame . The intervention is within the scope of midwifery practice , caused no harm to participants , was perceived as helpful , and enhanced women 's confidence about a future pregnancy BACKGROUND Social support theory and observational risk factor studies suggest that increased antenatal psychosocial support could prevent post-natal depression . We used empirical knowledge of risk and protective factors for post-natal depression not employed previously in order to develop and evaluate an antenatal preventive intervention . METHODS We conducted a pragmatic r and omized controlled trial in antenatal clinics . We screened 1300 primiparous women and 400 screened positive , 69 screen-positive women were untraceable or not eligible . Of 292 women who completed baseline assessment , 209 consented to r and omization , of these 190 provided outcome data 3 months post-natally . ' Preparing for Parenthood ' , a structured antenatal risk factor reducing intervention design ed to increase social support and problem-solving skills , was compared with routine antenatal care only . We compared the percentage depressed at 3 months after childbirth using the self-completion General Health Question naire Depression scale and Edinburgh Post-natal Depression Scale ( EPDS ) , and the Schedules for Clinical Assessment in Neuropsychiatry a systematic clinical interview . RESULTS Assignment to the intervention group did not significantly impact on post-natal depression ( odds ratio for GHQ-Depression 1.22 ( 95 % CI 0.63 - 2.39 ) , P = 0.55 ) or on risk factors for depression . Forty-five per cent of the intervention group women attended sufficient sessions to be likely to benefit from intervention if effective . Attenders benefited no more than non-attenders . CONCLUSIONS Prevention services targeting post-natal depression should not implement antenatal support programmes on these lines until further research has demonstrated the feasibility and effectiveness of such methods . The development of novel , low cost interventions effective in reducing risk factors should be completed before further trial evaluation OBJECTIVES To investigate the effectiveness of a psychosocial intervention for the prevention of postnatal depression . DESIGN A controlled trial . METHOD Women expecting their first or second child and design ated as ' more vulnerable ' by the Leverton Question naire ( LQ ) or Crown Crisp Experiential Index ( CCEI ) were allocated to a preventive intervention ( N = 47 ) or control group ( N = 52 ) by expected date of delivery to provide groups expecting their babies around the same time . Women were assessed at 3 months postnatal . An additional group of women design ated as ' less vulnerable ' ( N = 88 ) were assessed to confirm the validity of the LQ as a vulnerability measure . RESULTS Question naire measures of mood in first-time mothers invited to the Preparation for Parenthood groups revealed significantly more positive mood than in the group receiving routine care . The median Edinburgh Postnatal Depression Scale ( EPDS ) score for those invited was 3 , compared to 8 for those not invited ( p < .005 ) . The diagnosis of depression using the Present State Examination revealed differences for both groups , though it reached statistical significance only with the first-time mothers . Only 19 % of the ' more vulnerable ' invited first-time mothers were ' borderline ' or ' cases ' at any time in the first 3 months postnatally compared to 39 % of those not invited . The Surviving Parenthood groups for second-time mothers were not successful . CONCLUSION Some depressions following childbirth can be prevented by brief interventions that can be incorporated with existing systems of antenatal classes and postnatal support groups BACKGROUND A prospect i ve epidemiology study evaluated the role of specific social and psychological variables in the prediction of depressive symptomatology and disorders following childbirth in a community sample . Measures of social support used previously in clinical ly depressed population s facilitated further comparison . METHODS Nulliparous pregnant women ( N = 507 ) were interviewed during pregnancy with the Interview Measure of Social Relationships ( IMSR ) and a context ual assessment of pregnancy-related support and adversity and 427 were followed up at 3 months postpartum with the 30-item GHQ , including six depression items . To establish the clinical representativeness of the GHQ , high GHQ scorers and a r and om sub sample of low scorers were interviewed using the SCAN . Regression models were developed using the GHQ Depression scale ( GHQ-D ) , the IMSR and other risk factor data . RESULTS GHQ-D after childbirth was predicted by lack of perceived support from members of the woman 's primary group and lack of support in relation to the event becoming pregnant ; this held even after controlling for antenatal depression , neuroticism , family and personal psychiatric history and adversity . Informant-rated deficits in provision of social support also predicted later depression . The size of the primary social network group previously found to be related to depression in women , did not predict depressive symptom development . CONCLUSION Predictors of depressive symptom development differ from predictors of recovery from clinical depression in women . Interventions should be design ed to reduce specific deficits in social support observed in particular study population OBJECTIVE To test whether critical incident stress debriefing after childbirth reduces the incidence of postnatal psychological disorders . DESIGN R and omised single-blind controlled trial stratified for parity and delivery mode . SETTING Two large maternity hospitals in Perth . PARTICIPANTS 1745 women who delivered healthy term infants between April 1996 and December 1997 ( 875 allocated to intervention and 870 to control group ) . INTERVENTION An individual , st and ardised debriefing session based on the principles of critical incident stress debriefing carried out within 72 hours of delivery . MAIN OUTCOME MEASURES Diagnosis of stress disorders or depression in the 12 months postpartum , using structured psychological interview and criteria of the Diagnostic and statistical manual of mental disorders , 4th edition . RESULTS Follow-up information was available for 1730 women ( 99.1 % ) , 482 of whom underwent psychological interview . There were no significant differences between control and intervention groups in scores on Impact of Events or Edinburgh Postnatal Depression Scales at 2 , 6 or 12 months postpartum , or in proportions of women who met diagnostic criteria for a stress disorder ( intervention , 0.6 % v control , 0.8 % ; P = 0.58 ) or major or minor depression ( intervention , 17.8 % v control , 18.2 % ; relative risk [ 95 % CI ] , 0.99 [ 0.87 - 1.11 ] ) during the postpartum year . Nor were there differences in median time to onset of depression ( intervention , 6 [ interquartile range , 4 - 9 ] weeks v control , 4 [ 3 - 8 ] weeks ; P = 0.84 ) , or duration of depression ( intervention , 24 [ 12 - 46 ] weeks v control , 22 [ 10 - 52 ] weeks ; P = 0.98 ) . CONCLUSIONS There is a high prevalence of depression in women during the first year after childbirth . A session of midwife-led , critical incident stress debriefing was not effective in preventing postnatal psychological disorders , but had no adverse effects BACKGROUND Recently enacted federal legislation m and ates insurance coverage of at least 48 hours of postpartum hospitalization , but most mothers and newborns in the United States will continue to go home before the third postpartum day . National guidelines recommend a follow-up visit on the third or fourth postpartum day , but scant evidence exists about whether home or clinic visits are more effective . METHODS We enrolled 1163 medically and socially low-risk mother-newborn pairs with uncomplicated delivery and r and omly assigned them to receive home visits by nurses or pediatric clinic visits by nurse practitioners or physicians on the third or fourth postpartum day . In contrast with the 20-minute pediatric clinic visits , the home visits were longer ( median : 70 minutes ) , included preventive counseling about the home environment , and included a physical examination of the mother . Clinical utilization and costs were studied using computerized data bases . Breastfeeding continuation , maternal depressive symptoms , and maternal satisfaction were assessed by means of telephone interviews at 2 weeks ' postpartum . RESULTS Comparing the 580 pairs in the home visit group and the 583 pairs in the pediatric clinic visit group , no significant differences occurred in clinical outcomes as measured by maternal or newborn rehospitalization within 10 days postpartum , maternal or newborn urgent clinic visits within 10 days postpartum , or breastfeeding discontinuation or maternal depressive symptoms at the 2-week interview . The same was true for a combined clinical outcome measure indicating whether a mother-newborn pair had any of the above outcomes . In contrast , higher proportions of mothers in the home visit group rated as excellent or very good the preventive advice delivered ( 80 % vs 44 % ) , the provider 's skills and abilities ( 87 % vs 63 % ) , the newborn 's posthospital care ( 87 % vs 59 % ) , and their own posthospital care ( 75 % vs 47 % ) . On average , a home visit cost $ 255 and a pediatric clinic visit cost $ 120 . CONCLUSIONS For low-risk mothers and newborns in this integrated health maintenance organization , home visits compared with pediatric clinic visits on the third or fourth postpartum hospital day were more costly , but were associated with equivalent clinical outcomes and markedly higher maternal satisfaction . This study had limited power to identify group differences in rehospitalization , and may not be generalizable to higher-risk population s without comparable access to integrated hospital and outpatient care BACKGROUND Women who are positive for thyroid antibodies in early gestation are prone to post-partum depression , apparently independent of thyroid dysfunction , as measured by serum levels of free thyroxine , free triodothyroxine and thyroid-stimulating hormone . This finding may be due to infrequent monitoring of thyroid function , because hyperthyroidism , hypothyroidism and combinations of both may occur post-partum . AIMS To test the hypothesis that stabilising thyroid function post-partum by administering daily thyroxine reduces the rate of occurrence and severity of associated depression . METHOD In a r and omised double-blind placebo-controlled trial , 100 microg of thyroxine or placebo was given daily to 446 thyroid-antibody-positive women ( 342 of whom were compliant ) from 6 weeks to 6 months post-partum , assessing their psychiatric and thyroid status at 4-weekly intervals . RESULTS There was no evidence that thyroxine had any effect on the occurrence of depression . The 6-month period prevalence of depression was similar to that reported previously . CONCLUSIONS The excess of depression in thyroid-antibody-positive women in the post-partum period is not corrected by daily administration of thyroxine Objectives To study whether proactive educational counselling , in addition to routine clinical care , reduces psychological morbidity and improves quality of life and client satisfaction among women who suffer suboptimal outcomes during childbirth BACKGROUND Although policymakers have suggested that improving continuity of midwifery can increase women 's satisfaction with care in childbirth , evidence based on r and omized controlled trials is lacking . New models of care , such as birth centers and team midwife care , try to increase the continuity of care and caregiver . The objective of this study was to evaluate the effect of a new team midwife care program in the st and ard clinic and hospital environment on satisfaction with antenatal , intrapartum , and postpartum care in low-risk women in early pregnancy . METHODS Women at Royal Women 's Hospital in Melbourne , Australia , were r and omly allocated to team midwife care ( n = 495 ) or st and ard care ( n = 505 ) at booking in early pregnancy . Doctors attended most women in st and ard care , and continuity of the caregiver was lacking . Satisfaction was measured by means of a postal question naire 2 months after the birth . RESULTS Team midwife care was associated with increased satisfaction , and the differences between the groups were most noticeable for antenatal care , less noticeable for intrapartum care , and least noticeable for postpartum care . The study found no differences between team midwife care and st and ard care in medical interventions or in women 's emotional well-being 2 months after the birth . CONCLUSION Conclusions about which components of team midwife care were most important to increased satisfaction with antenatal care were difficult to draw , but data suggest that satisfaction with intrapartum care was related to continuity of the caregiver OBJECTIVE The purpose of this study was to determine the effect of docosahexaenoic acid supplementation on plasma phospholipid docosahexaenoic acid content and indices of depression and information processing for women who breast-feed . STUDY DESIGN Mothers who planned to breast-feed their infants were assigned r and omly in a double-masked fashion to receive either docosahexaenoic acid ( approximately 200 mg/d ) or placebo for the first 4 months after the delivery . Major outcome variables included plasma phospholipid fatty acid patterns and scores on a self-rating question naire of current depression symptoms . A structured clinical interview of depression , scores on another self-rating question naire of depression symptoms , and a laboratory measure of information processing were obtained in subgroups of the total population . RESULTS Plasma phospholipid contents of docosahexaenoic acid at baseline were 3.15 + /- 0.78 and 3.31 + /- 0.70 ( mg/dL of total fatty acids ) in the docosahexaenoic acid and placebo groups , respectively . After 4 months , the plasma phospholipid docosahexaenoic acid content of the docosahexaenoic acid group was 8 % higher ( 3.40 + /- 0.97 mg/dL ) , whereas that of the placebo group was 31 % lower ( 2.27 + /- 0.87 mg/dL ) . Despite the higher plasma phospholipid docosahexaenoic acid content of the supplemented group after 4 months , there was no difference between groups in either self-rating or diagnostic measures of depression ; information processing scores of the two groups also did not differ . CONCLUSION Docosahexaenoic acid supplementation ( approximately 200 mg/d ) for 4 months after the delivery prevented the usual decline in plasma phospholipid docosahexaenoic acid content of women who breastfeed but did not influence self-ratings of depression , diagnostic measures of depression , or information processing This r and omized , controlled trial tested the hypothesis that women identified as more vulnerable to developing postnatal depression who attended two specific antenatal groups and one postnatal group have a reduced frequency of postnatal depression from 37 to 15 percent at 6 weeks , 12 weeks , and 6 months postpartum . A modified antenatal screening question naire was completed , and women identified as more vulnerable to postnatal depression were stratified by parity and r and omly allocated to receive extra support groups or to a control group . The Edinburgh Postnatal Depression Scale ( EPDS ) was used to detect postnatal depression . Attendance at the support groups was low , 31 percent overall . At six weeks , in the intervention group , 8 ( 13 % ) of 64 women scored high ( > 12 ) on the EPDS , compared with 11 ( 17 % ) controls . Similarly , at 12 weeks 7 ( 11 % ) of 63 versus 10 ( 15 % ) of 65 women scored higher than 12 , and at 6 months , 9 ( 15 % ) of 60 versus 6 ( 10 % ) of 64 women scored higher than 12 , indicating that the intervention did not reduce postnatal depression . It is possible that the method of applying the intervention , using groups separate from the st and ard antenatal classes , may have affected attendance . More research is required into ways of reaching and supporting women who may become depressed Objectives To determine the effect of postnatal administration of the long‐acting progestogen contraceptive , norethisterone enanthate , on postnatal depression and on serum hormone concentrations , and their association with depression Objectives To establish whether providing additional postnatal support during the early postnatal months influences women 's physical and psychological health and to identify health service benefits Objective To test the effectiveness of a prenatal intervention in reducing the incidence of postnatal depression Abstract Objective : To assess the effectiveness of a midwife led debriefing session during the postpartum hospital stay in reducing the prevalence of maternal depression at six months postpartum among women giving birth by caesarean section , forceps , or vacuum extraction . Design : R and omised controlled trial . Setting : Large maternity teaching hospital in Melbourne , Australia . Participants : 1041 women who had given birth by caesarean section ( n= 624 ) or with the use of forceps ( n= 353 ) or vacuum extraction ( n= 64 ) . Main outcome measures : Maternal depression ( score ≥13 on the Edinburgh postnatal depression scale ) and overall health status ( comparison of mean scores on SF-36 subscales ) measured by postal question naire at six months postpartum . Results : 917 ( 88 % ) of the women recruited responded to the outcome question naire . More women allocated to debriefing scored as depressed six months after birth than women allocated to usual postpartum care ( 81 ( 17 % ) v 65 ( 14 % ) ) , although this difference was not significant ( odds ratio=1.24 , 95 % confidence interval 0.87 to 1.77 ) . They were also more likely to report that depression had been a problem for them since the birth , but the difference was not significant ( 123 ( 28 % ) v 94 ( 22 % ) ; odds ratio=1.37 , 1.00 to 1.86 ) . Women allocated to debriefing had poorer health status on seven of the eight SF-36 subscales , although the difference was significant only for role functioning ( emotional ) : mean scores 73.32 v 78.98 , t= −2.31 , 95 % confidence interval −10.48 to −0.84 ) . Conclusions : Midwife led debriefing after operative birth is ineffective in reducing maternal morbidity at six months postpartum . The possibility that debriefing contributed to emotional health problems for some women can not be excluded A pretest-posttest experimental design with a convenience sample of 60 subjects was used to examine the effects of a relaxation with guided imagery protocol on anxiety , depression , and self-esteem in primiparas during the first 4 weeks of the postpartum period . The results showed that the experimental group had less anxiety and depression and greater self-esteem than did the control group at the end of the period . Positive correlations were obtained between anxiety and depression ; negative correlations between self-esteem and anxiety and depression . All findings were significant at the .05 level BACKGROUND Research is needed to evaluate the efficacy of prevention and treatment for post-partum depression . METHOD Subjects were screened with the Edinburgh Post-natal Depression Scale ( EPDS ) at the obstetric clinic . Mothers at risk ( N = 258 ) ( EPDS scores > or = 9 ) were r and omly assigned to a prevention/treatment group or a control group . The prevention group received one cognitive-behavioural prevention session during hospitalization . At 4 to 6 weeks post-partum , subjects were screened again with the EPDS , after drop-out rates ( refusals plus no return of the second EPDS ) of 25.4 % ( 33/130 ) in the intervention group and 10.9 % ( 14/128 ) in the control group . Mothers with probable depression ( EPDS scores > or = 11 ) were assessed using the Hamilton Depression Rating Scale ( HDRS ) and the Beck Depression Inventory ( BDI ) . Mothers with major depression continued in the treatment group ( N = 18 ) or in the control group ( N = 30 ) . Treated subjects received a cognitive-behavioural programme of between five and eight weekly home-visits . RESULTS Compared with the control group , women in the prevention group had significant reductions in the frequency of probable depression ( 30.2 % v. 48.2 % ) . Recovery rates based on HDRS scores of < 7 and BDI scores of < 4 were also significantly greater in the treated group than in the control group . CONCLUSIONS The study suggests that this programme for prevention and treatment of post-partum depression is reasonably well-accepted and efficacious Objectives To investigate whether a visit to a general practitioner one week after discharge results in less depression , increased breastfeeding rates , improved patient wellbeing , fewer physical problems and greater satisfaction with general practice care than the traditional six week postnatal check‐up OBJECTIVE Postpartum depression is a common feature of childbearing and is the cause of considerable morbidity . We have explored the possibility that clinical ly oriented care during labor may contribute to its occurrence . STUDY DESIGN Of 189 nulliparous women laboring in a familiar community hospital , 92 were allocated by r and omized , sealed envelopes to receive additional companionship from one of three volunteer labor companions recruited from the community . RESULTS The group receiving support attained higher self-esteem scores and lower postpartum depression and anxiety ratings 6 weeks after delivery . CONCLUSION In the clinical labor environment companionship modifies factors that contribute to the development of postnatal depression . We emphasize the importance of paying attention to the psychosocial environment in which labor takes place , to facilitate adaptation to parenthood OBJECTIVE To compare intensive and conventional therapy for severe fear of childbirth . METHODS In Finl and , 176 women who had fear of childbirth were r and omly assigned at the 26th gestational week to have either intensive therapy ( mean 3.8 ± 1.0 sessions with obstetrician and one with midwife ) or conventional therapy ( mean 2.0 ± 0.6 sessions ) , with follow‐up 3 months postpartum . Pregnancy‐related anxiety and concerns , satisfaction with childbirth , and puerperal depression were assessed with specific question naires . Power analysis , based on previous studies , showed that 74 women per group were necessary to show a 50 % reduction in cesarean rates . RESULTS Birth‐related concerns decreased in the intensive therapy group but increased in the conventional therapy group ( linear interaction between the group and birth‐concerns P = .022 ) . Labor was shorter in the intensive therapy group ( mean ± st and ard deviation 6.8 ± 3.8 hours ) compared with the conventional group ( 8.5 ± 4.8 hours , P = .039 ) . After intervention , 62 % of those originally requesting a cesarean ( n = 117 ) chose to deliver vaginally , equally in both groups . Cesarean was more frequent for those who refused to fill in the question naires than for those who completed them ( 57 % compared with 27 % , P = .001 ) . In the log‐linear model , parous women who had conventional therapy and refused to fill in the question naires chose a cesarean more often than expected ( st and ardized residual 2.54 , P = .011 ) . There were no differences between groups in satisfaction with childbirth or in puerperal depression . CONCLUSION Both kinds of therapy reduced unnecessary cesareans , more so in nulliparous and well‐motivated women . With intensive therapy , pregnancy‐ and birth‐related anxiety and concerns were reduced , and labors were shorter BACKGROUND Much postpartum physical and psychological morbidity is not addressed by present care , which tends to focus on routine examinations . We undertook a cluster r and omised controlled trial to assess community postnatal care that has been re design ed to identify and manage individual needs . METHODS We r and omly allocated 36 general practice clusters from the West Midl and s health region of the UK to intervention ( n=17 ) or control ( 19 ) care . Midwives from the practice s recruited women and provided care . 1087 ( 53 % ) of 2064 women were in practice s r and omly assigned to the intervention group , with 977 ( 47 % ) women in practice s assigned to the control group . Care was led by midwives , with no routine contact with general practitioners , and was extended to 3 months . Midwives used symptom checklists and the Edinburgh postnatal depression scale ( EPDS ) to identify health needs and guidelines for the management of these needs . Primary outcomes at 4 months were obtained by postal question naire and included the women 's short form 36 physical ( PCS ) and mental ( MCS ) component summary scores and the EPDS . Secondary outcomes were women 's views about care . Multilevel analysis accounted for possible cluster effects . FINDINGS 801 ( 77 % ) of 1087 women in the intervention group and 702 ( 76 % ) of 977 controls responded at 4 months . Women 's mental health measures were significantly better in the intervention group ( MCS , 3.03 [ 95 % CI 1.53 - 4.52 ] ; EPDS -1.92 [ -2.55 to -1.29 ] ; EPDS 13 + odds ratio 0.57 [ 0.43 - 0.76 ] ) than in controls , but the physical health score did not differ . INTERPRETATION Re design of care so that it is midwife-led , flexible , and tailored to needs , could help to improve women 's mental health and reduce probable depression at 4 months ' postpartum BACKGROUND Women who are traumatized after childbirth find that listening , support , counseling , underst and ing , and explanation are the most useful treatments . However , little evidence is available from r and omized trials of the relative efficacy of these treatments as a positive postnatal intervention . This study purpose was to examine if postnatal " debriefing " by midwives can reduce psychological morbidity after childbirth . METHOD A r and omized trial was conducted in a regional teaching hospital in northwest Engl and . One hundred and twenty postnatal primigravidas were allocated by sealed envelopes to receive the debriefing intervention ( n = 56 ) or not ( n = 58 ) . The main outcome measure was the Hospital Anxiety and Depression ( HAD ) scale administered by postal question naire 3 weeks after delivery . The proportion of women in each group with anxiety and depression scores of more than 10 points were compared , using odds ratios and 95 % confidence intervals . RESULTS Women who received the intervention were less likely to have high anxiety and depression scores after delivery when compared with the control group . CONCLUSIONS The support , counseling , underst and ing , and explanation given to women by midwives in the postnatal period provides benefits to psychological well-being . Maternity units have a responsibility to develop a service that offers all women the option of attending a session to discuss their labor OBJECTIVE To evaluate whether providing doulas during hospital-based labor affects mode of delivery , epidural use , breast-feeding , and postpartum perceptions of the birth , self-esteem , and depression . METHODS This was a r and omized study of nullipara enrollees in a group-model health maintenance organization who delivered in one of three health maintenance organization-managed hospitals ; 149 had doulas , and 165 had usual care . Study data were obtained from the mothers ' medical charts , study intake forms , and phone interviews conducted 4 - 6 weeks postpartum . RESULTS Women who had doulas had significantly less epidural use ( 54.4 % versus 66.1 % , P < .05 ) than women in the usual-care group . They also were significantly ( P < .05 ) more likely to rate the birth experience as good ( 82.5 % versus 67.4 % ) , to feel they coped very well with labor ( 46.8 % versus 28.3 % ) , and to feel labor had a very positive effect on their feelings as women ( 58.0 % versus 43.7 % ) and perception of their bodies ' strength and performance ( 58.0 % versus 41.0 % ) . The two groups did not differ significantly in rates of cesarean , vaginal , forceps , or vacuum delivery , oxytocin administration ; or breast-feeding , nor did they differ on the postpartum depression or self-esteem measures . CONCLUSION For this population and setting , labor support from doulas had a desirable effect on epidural use and women 's perceptions of birth , but did not alter need for operative deliveries A prospect i ve , r and omized , clinical trial was conducted to investigate whether a postpartum visit between a mother and her neonate 's future primary care provider combined with telephone access would improve health care utilization , enhance identification of the provider as a source of advice , increase maternal knowledge of infant care , and decrease maternal anxiety and depression . Of 251 mother-neonate pairs , 122 were r and omized to the control group and 129 to the intervention group . Outcome variables included health care utilization and results of maternal interviews . More mothers in the intervention group made a scheduled clinic visit in the first 30 days ( P = .003 ) , were more likely to seek some form of care at the clinic ( P = .006 ) , and tried to reach their physician by phone more often than the control group ( P less than .001 ) . There were no differences between the groups ' emergency room utilization , the percent who received immunizations by 90 days of age , maternal knowledge of infant care , maternal anxiety , or postpartum depression . The intervention succeeded in improving some measures of health care utilization and results suggest that the relationship between the mother and clinician was strengthened AIM The aim of the study was to investigate the effectiveness of informational support in reducing the Edinburgh Postnatal Depression Scale ( EPDS ) scores in Taiwan . METHODS Five hundred Taiwanese women were screened during the fourth week after giving birth and those with a score of over 10 on the EPDS were considered to be at risk of postnatal depression . Seventy postpartum women were r and omly allocated to the experimental or control group . Only those in the experimental group received informational support about postnatal depression during the sixth week postpartum . Two groups were assessed by the EPDS at 3 months postpartum to explore their depressive status . RESULTS Taiwanese women who received informational support about postnatal depression 6 weeks after giving birth experienced lower EPDS scores at 3 months postpartum than those who did not receive this information . CONCLUSIONS The findings suggest that informational support about postnatal depression given to women in the postnatal period may contribute to psychological well-being Objective : To evaluate the effectiveness of continuous midwifery care in reducing rates of postnatal depression in women with histories of depression . Methods : Fifty-one women from a sample of 98 pregnant women with histories of major depressive disorder were r and omly allocated , at antenatal booking , to continuous midwifery care . The remaining 47 women received st and ard maternity care . A total of 87 women ( 44 treatment , 43 control ) completed baseline assessment s ( after r and omization ) and outcome assessment s ( at 3 months postpartum ) . Results : Of the women allocated to continuous midwifery care , 88 % complied in full with their allocated treatment protocol . Forty-nine percent of women had an episode of illness in pregnancy ( DSM-III-R case of major or minor depression ) , 26 % developed a new episode of illness after antenatal booking , and 23 % were depressed in the first 3 months postpartum . There were no differences between treatment conditions in total rates , or rates within the context of social adversity , of antenatal depression , depressions which occurred post-booking , postnatal depression , and the duration of depressive episodes . Conclusions : While continuous midwifery care had no impact on psychiatric outcome , it was highly successful at engaging women in treatment and therefore has an important contribution to make in the care of child-bearing women with mental health problems OBJECTIVE This study investigated whether a preventive intervention based on the principles of interpersonal psychotherapy administered to pregnant women would reduce the risk of postpartum major depression . METHOD Thirty-seven pregnant women receiving public assistance who had at least one risk factor for postpartum depression were r and omly assigned to a four-session group intervention or to a treatment-as-usual condition . Thirty-five of the women completed the study . Structured diagnostic interviews were administered to assess for postpartum major depression . RESULTS Within 3 months after they gave birth , six ( 33 % ) of the 18 women in the treatment-as-usual condition had developed postpartum major depression , compared with none of the 17 women in the intervention condition . CONCLUSIONS A four-session interpersonal-therapy-oriented group intervention was successful in preventing the occurrence of major depression during a postpartum period of 3 months in a group of financially disadvantaged women OBJECTIVE Antenatal depression is a significant risk factor for postpartum depression , with a 10%-12 % prevalence in all pregnancies . Rates of depression are higher for pregnant women with chronic stressors , financial and housing problems , and inadequate social support . Despite the prevalence and associated family and infant morbidity , there are no controlled clinical treatment trials regarding this topic , to the authors ' knowledge . APA has identified treatment of depression during pregnancy as a priority for clinical guidelines . METHOD A 16-week bilingual controlled clinical trial compared a group receiving interpersonal psychotherapy for antepartum depression to a parenting education control program . Fifty outpatient antepartum women who met DSM-IV criteria for major depressive disorder were r and omly assigned to interpersonal psychotherapy or a didactic parenting education program . Thirty-eight women remained in the study and were included in the data analysis . Depressed mood was measured with the Edinburgh Postnatal Depression Scale , the Beck Depression Inventory , and the Hamilton Depression Rating Scale . The Clinical Global Impression ( CGI ) and the Hamilton depression scale measured recovery . RESULTS The interpersonal psychotherapy treatment group showed significant improvement compared to the parenting education control program on all three measures of mood at termination . Recovery criteria were met in 60 % of the women treated with interpersonal psychotherapy , according to a CGI score of < or = 2 . In addition , there was a significant correlation between maternal mood and mother-infant interaction . CONCLUSIONS Interpersonal psychotherapy is an effective method of antidepressant treatment during pregnancy and should be a first-line treatment in the hierarchy of treatment for antepartum depression

Immunohistochemistry-determined cell-of-origin , and BCL2 and BCL6 translocation status added no additional prognostic value . Half of the studies on gene expression profiling-determined cell-of-origin and MYC translocation status found that germinal center B-cell – like ( GCB ) and no translocation were associated with better overall survival ( OS ) whereas the remaining studies found no effect of these covariates .

Abstract We examined the additional prognostic value for survival of cell-of-origin , and MYC , BCL2 and BCL6 translocation status to that provided by the International Prognostic Index in newly-diagnosed diffuse large B-cell lymphoma ( DLBCL ) patients treated firstline with rituximab-containing immunochemotherapy .

Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items The survival of diffuse large B-cell lymphoma patients varies considerably , reflecting the molecular diversity of tumors . In view of the controversy whether cytologic features , immunohistochemical markers or gene expression signatures may capture this molecular diversity , we investigated which features provide prognostic information in a prospect i ve trial in the R-CHOP treatment era . Within the cohort of DLBCLs patients treated in the RICOVER-60 trial of the German High- Grade Lymphoma Study Group ( DSHNHL ) , we tested the prognostic impact of IB morphology in 949 patients . The expression of immunohistochemical markers CD5 , CD10 , BCL2 , BCL6 , human leukocyte antigen (HLA)-DR , interferon regulatory factor-4/multiple myeloma-1 ( IRF4/MUM1 ) , and Ki-67 was assessed in 506 patients . Expression of the immunohistochemical markers tested was of modest , if any , prognostic relevance . Moreover , the Hans algorithm using the expression patterns of CD10 , BCL6 , and interferon regulatory factor-4/multiple myeloma-1 failed to show prognostic significance in the entire cohort as well as in patient subgroups . IB morphology , however , emerged as a robust , significantly adverse prognostic factor in multivariate analysis , and its diagnosis showed a good reproducibility among expert hematopathologists . We conclude , therefore , that IB morphology in DLBCL is likely to capture some of the adverse molecular alterations that are currently not detectable in a routine diagnostic setting , and that its recognition has significant prognostic power BACKGROUND Dose intensification with a combination of cyclophosphamide , doxorubicin , vincristine , and prednisolone ( CHOP ) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks . We investigated whether this survival benefit from dose intensification persists in the presence of rituximab ( R-CHOP ) in all age groups . METHODS Patients ( aged ≥18 years ) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were r and omly assigned central ly in a one-to-one ratio , using minimisation , to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab ( R-CHOP-14 ) or eight cycles of R-CHOP every 21 days ( R-CHOP-21 ) . R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2 ) , doxorubicin 50 mg/m(2 ) , vincristine 1·4 mg/m(2 ) ( maximum dose 2 mg ) , and rituximab 375 mg/m(2 ) on day 1 , and oral prednisolone 40 mg/m(2 ) on days 1 - 5 , administered every 21 days for a total of eight cycles . R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2 ) , doxorubicin 50 mg/m(2 ) , vincristine 2 mg , rituximab 375 mg/m(2 ) on day 1 , and oral prednisolone 100 mg on days 1 - 5 , administered every 14 days for six cycles , followed by two further infusions of rituximab 375 mg/m(2 ) on day 1 every 14 days . The trial was not masked . The primary outcome was overall survival ( OS ) . This study is registered , number IS RCT N 16017947 . FINDINGS 1080 patients were assigned to R-CHOP-21 ( n=540 ) and R-CHOP-14 ( n=540 ) . With a median follow-up of 46 months ( IQR 35 - 57 ) , 2-year OS was 82·7 % ( 79·5 - 85·9 ) in the R-CHOP-14 group and 80·8 % ( 77·5 - 84·2 ) in the R-CHOP-21 ( st and ard ) group ( hazard ratio 0·90 , 95 % CI 0·70 - 1·15 ; p=0·3763 ) . No significant improvement was noted in 2-year progression-free survival ( R-CHOP-14 75·4 % , 71·8 - 79·1 , and R-CHOP-21 74·8 % , 71·0 - 78·4 ; 0·94 , 0·76 - 1·17 ; p=0·5907 ) . High international prognostic index , poor-prognosis molecular characteristics , and cell of origin were not predictive for benefit from either schedule . Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group ( 318 [ 60 % ] of 534 vs 167 [ 31 % ] of 534 ) , with no prophylactic use of recombinant human granulocyte-colony stimulating factor m and ated in this group , whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 ( 50 [ 9 % ] vs 28 [ 5 % ] ) ; other frequent grade 3 or 4 adverse events were febrile neutropenia ( 58 [ 11 % ] vs 28 [ 5 % ] ) and infection ( 125 [ 23 % ] vs 96 [ 18 % ] ) . Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups . INTERPRETATION R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma ; therefore , R-CHOP-21 remains the st and ard first-line treatment in patients with this haematological malignancy . No molecular or clinical subgroup benefited from dose intensification in this study . FUNDING Chugai Pharmaceutical , Cancer Research UK , National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust , and Institute of Cancer Research MYC rearrangements occur in 5 % to 10 % of diffuse large B-cell lymphomas ( DLBCL ) and confer an increased risk to cyclophosphamide , hydroxydaunorubicin , oncovin , and prednisone ( CHOP ) and rituximab (R)-CHOP treated patients . We investigated the prognostic relevance of MYC- , BCL2- and BCL6-rearrangements and protein expression in a prospect i ve r and omized trial . Paraffin-embedded tumor sample s from 442 de novo DLBCL treated within the RICOVER study of the German High- Grade Non-Hodgkin Lymphoma Study Group ( DSHNHL ) were investigated using immunohistochemistry and fluorescence in situ hybridization ( FISH ) to detect protein expression and breaks of MYC , BCL2 , and BCL6 . Rearrangements of MYC , BCL2 , and BCL6 were detected in 8.8 % , 13.5 % , and 28.7 % , respectively . Protein overexpression of MYC ( > 40 % ) was encountered in 31.8 % of tumors ; 79.6 % and 82.8 % of tumors expressed BCL2 and BCL6 , respectively . MYC translocations , MYChigh , BCL2high , and BCL6low protein expressions were associated with inferior survival . In multivariate Cox regression modeling , protein expression patterns of MYC , BCL2 and BCL6 , and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index ( IPI ) for overall survival and event-free survival . A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15 % of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP . Registered at http://www.cancer.gov/ clinical trials : RICOVER trial of the DSHNHL is NCT 00052936

We were unable to draw conclusions about the difference in adverse events between interventions , however recent studies suggest that pre-quit NRT does not increase adverse events . AUTHORS ' CONCLUSIONS Reducing cigarettes smoked before quit day and quitting abruptly , with no prior reduction , produced comparable quit rates , therefore patients can be given the choice to quit in either of these ways .

BACKGROUND The st and ard way to stop smoking is to quit abruptly on a design ated quit day . A number of smokers have tried unsuccessfully to quit this way . Reducing smoking before quitting could be an alternative approach to cessation . Before this method is adopted it is important to determine whether it is at least as successful as abrupt quitting . OBJECTIVES 1 . To compare the success of reducing smoking to quit and abrupt quitting interventions . 2 . To compare adverse events between arms in studies that used pharmacotherapy to aid reduction .

BACKGROUND New ways of improving the efficacy of nicotine therapy need to be explored . We tested whether starting nicotine polacrilex gum treatment 4 weeks before the quit date improved smoking abstinence rates compared with starting treatment on the quit date . METHODS An open r and omized trial of 314 daily smokers ( mean , 23.7 cigarettes/d ) enrolled through the Internet and by physicians in Switzerl and from November 2005 to January 2007 . In the precessation treatment group , participants received nicotine polacrilex gum ( 4 mg , unflavored ) by mail for 4 weeks before and 8 weeks after their target quit date , and they were instructed to decrease their cigarette consumption by half before quitting . In the usual care group , participants received the same nicotine gum for 8 weeks after their quit date and were instructed to quit abruptly . Instructions were limited to a booklet sent by mail and access to a smoking cessation Web site . Results are expressed as self-reported abstinence rates at the end of treatment and as biochemically verified smoking abstinence ( cotinine plus carbon monoxide ) after 12 months . RESULTS Eight weeks after the target quit date , self-reported 4-week abstinence rates were 41.6 % in the precessation treatment group and 44.4 % in the usual care group ( P = .61 ) . One year after the target quit date , biochemically verified 4-week smoking abstinence rates were 20.8 % in the precessation treatment group and 19.4 % in the usual care group ( P = .76 ) . CONCLUSION Starting nicotine gum treatment 4 weeks before the target quit date was no more effective than starting treatment on the quit date One hundred ten patients addicted to nicotine were subjected to either sudden or gradual withdrawal in the course of a smoking cessation programme . Eighty-two patients emerged from the treatment as non-smokers . In a follow-up after 1 year 70 % of these successful clients replied to an anonymous question naire . Concerning the relapse rate , no significant difference could be found between the two treatment groups , but patients who underwent slow withdrawal smoked significantly less when comparing their current consumption with that before the start of the therapy . Patients who underwent sudden stopping reached their original level of nicotine use again Two recommended quit methods in st and ard cessation programs involve either gradual reduction of smoking prior to complete abstinence ( " cut down " ) or abrupt abstinence from cigarettes ( " cold turkey " ) . This study examined the reported use , characteristics of users , and the impact of self-selected strategy choice on quitting success and relapse of adult smokers who reported quitting on their own . Data came from the first three waves of the International Tobacco Control Policy Evaluation 4-Country Survey ( ITC-4 ) . The ITC-4 is a r and om-digit-dialed telephone survey of a cohort of more than 8,000 adult smokers from the United Kingdom , the United States , Canada , and Australia , with a 75 % follow-up rate . The results indicated that 68.5 % of the smokers who had made a quit attempt between waves reported using the cold-turkey method . Of those who used the cold turkey method , 22 % and 27 % succeeded at Waves 2 and 3 , respectively , compared with the 12 % and 16 % , respectively , who used the cut-down method . Multivariate analyses revealed that cold-turkey users were more likely to be aged 25 - 39 years , male , from the United Kingdom , and smoking heavily , and had lower perceived dependence . Controlling for sociodemographic and known predictors of quitting including use of medications , we found that smokers who used the cold-turkey method to quit were almost twice as likely to abstain for a month or more in their attempt . Overall , we cautiously conclude that cold turkey should be the recommended strategy for smokers who want to quit on their own OBJECTIVE To evaluate the smoking cessation efficacy of nicotine patch therapy as an adjunct to low-intensity , primary care intervention . DESIGN R and omized , placebo-controlled , double-blind , multisite trial . SETTING S Twenty-one primary care sites in Nebraska . PATIENTS A total of 369 smokers of 20 or more cigarettes per day . INTERVENTION Two brief primary care visits for smoking intervention with 10 weeks of active or placebo-patch therapy . MAIN OUTCOME MEASURES Confirmed self-reported abstinence 3 , 6 , and 12 months after the quit day . RESULTS Compared with placebo control subjects , participants assigned nicotine patches had higher 3-month ( 23.4 % vs 11.4 % ; P < .01 ) and 6-month ( 18.5 % vs 10.3 % ; P < .05 ) abstinence rates . The 1-year abstinence rates for the active and placebo patch groups were 14.7 % and 8.7 % , respectively ( P = .07 ) . Of smokers aged 45 years and older , 9 ( 18.8 % ) of 48 using active patches compared with 0 of 31 using placebo patches achieved 12-month abstinence ( chi 2 = 6.56 ; P < .05 ) . Among those with high nicotine dependency scores ( Fagerstrom score > or = 7 ) , 1-year abstinence rates were significantly higher in the nicotine patch group ( 19.1 % ) compared with the placebo group ( 5.0 % ) ( chi 2 = 10.7 ; P = .001 ) . However , there was no significant difference in 1-year quit rates for participants with low Fagerstrom scores ( < 7 ) . CONCLUSIONS Nicotine patch therapy enhanced 6 month quit rates as an adjunct to brief primary care intervention . The highest quit rates were achieved by participants who specifically contacted the site to enroll in the study or to obtain a prescription for nicotine patches . Differences in participant selection factors may account , in part , for the lower smoking cessation rates associated with primary care intervention . Duration of counseling , patient age , and Fagerstrom scores may be important factors related to the long-term smoking cessation success of nicotine patch therapy Background The st and ard way to stop smoking is to stop abruptly on a quit day with no prior reduction in consumption of cigarettes . Many smokers feel that reduction is natural and if reduction programmes were offered , many more might take up treatment . Few trials of reduction versus abrupt cessation have been completed . Most are small , do not use pharmacotherapy , and do not meet the st and ards necessary to obtain a marketing authorisation for a pharmacotherapy . Design / Methods We will conduct a non-inferiority r and omised trial of rapid reduction versus st and ard abrupt cessation among smokers who want to stop smoking . In the reduction arm , participants will be advised to reduce smoking consumption by half in the first week and to 25 % of baseline in the second , leading up to a quit day at which participants will stop smoking completely . This will be assisted by nicotine patches and an acute form of nicotine replacement therapy . In the abrupt arm participants will use nicotine patches only , whilst smoking as normal , for two weeks prior to a quit day , at which they will also stop smoking completely . Smokers in either arm will have st and ard withdrawal orientated behavioural support programme with a combination of nicotine patches and acute nicotine replacement therapy post-cessation . Outcomes /Follow-upThe primary outcome of interest will be prolonged abstinence from smoking , with secondary trial outcomes of point prevalence , urges to smoke and withdrawal symptoms . Follow up will take place at 4 weeks , 8 weeks and 6 months post-quit day . Trial Registration Current Controlled Trials IS RCT The nicotinic antagonist mecamylamine was evaluated in a r and omized smoking cessation trial . Four groups of participants ( n = 20 per group ) received nicotine plus mecamylamine , nicotine alone , mecamylamine alone , or no drug for 4 weeks before cessation . After the quit-smoking date , all subjects received nicotine plus mecamylamine treatment for 6 weeks . Nicotine skin patches ( 21 mg/24 hr ) and mecamylamine capsules ( 2.5 - 5.0 mg twice per day ) were used . Precessation mecamylamine significantly prolonged the duration of continuous smoking abstinence ; abstinence rates at the end of treatment were 47.5 % with mecamylamine and 27.5 % without mecamylamine . Nicotine + mecamylamine reduced ad lib smoking , smoking satisfaction , and craving more than either drug alone . Moreover , the orthostatic decrease in blood pressure caused by mecamylamine was offset by nicotine . Mecamylamine before smoking cessation may be an effective adjunct to nicotine patch therapy The present study investigated whether treatment with the combination of denicotinized cigarettes and 21-mg nicotine patch for 2 weeks before a design ated quit date could lessen cravings for smoking , thereby helping smokers abstain from smoking . The study was a r and omized controlled clinical trial conducted at Roswell Park Cancer Institute , Buffalo , New York , in 2004 and 2005 . Patients included 98 adult heavy smokers ( using 20 or more cigarettes/day ) . Half of the subjects received 2 weeks of combination of denicotinized cigarettes ( Quest 3 ) and 21-mg nicotine patch for 2 weeks before the quit date . The remaining smokers were switched to light cigarettes ( Quest 1 ) during the 2 weeks before the quit date . After the quit date , all subjects received counseling for smoking cessation and were provided nicotine patches for up to 8 weeks after the quit date . Self-reported cravings for smoking , withdrawal symptoms , and smoking abstinence were measured at predetermined intervals using phone-based surveys and in clinical visits . The group that used denicotinized cigarettes and nicotine patch before quitting reported less frequent and less intense cravings for cigarettes in the 2 weeks before and after the design ated quit date . Self-reported withdrawal symptoms and quit rates did not differ significantly between the groups . The use of a denicotinized cigarette combined with the nicotine patch appears to lessen cravings to smoke in the immediate postcessation period . A larger , better-powered study is needed to test if this treatment combination has merit for increasing quit rates The study examined the occurrence of acute tobacco withdrawal symptoms among three methods of smoking cessation . Smokers were asked to smoke ad lib for 3 days and then r and omly assigned to one of three groups for the next 5 days : ( 1 ) total cigarette cessation ; ( 2 ) 50 % reduction of number of cigarettes ; or ( 3 ) reduction of nicotine yield of cigarettes . Of the 13 measures of tobacco withdrawal , six of the measures showed significant differences in severity of withdrawal symptoms between the total cessation group and partial reduction groups . There were no significant differences in severity of withdrawal between the two partial reduction groups This study compared the efficacy of 2 traditional methods of smoking cessation , gradual reduction and " cold turkey , " with a new approach involving variation in the intercigarette interval . One hundred twenty-eight participants quit smoking on a target date , after a 3-week period of ( a ) scheduled reduced smoking ( progressive increase in the intercigarette interval ) , ( b ) nonscheduled reduced smoking ( gradual reduction , no specific change in the intercigarette interval ) , ( c ) scheduled nonreduced smoking ( fixed intercigarette interval , no reductions in frequency ) , or ( c ) nonscheduled nonreduced smoking ( no change in intercigarette interval or smoking frequency ) . Participants also received cognitive-behavioral relapse prevention training . Abstinence at 1 year averaged 44 % , 18 % , 32 % , and 22 % for the 4 groups , respectively . Overall , the scheduled reduced group performed the best and the nonscheduled reduced group performed the worst . Both scheduled groups performed better than nonscheduled ones . Scheduled reduced smoking was associated with reduced tension , fatigue , urges to smoke , withdrawal symptoms , increased coping effort ( ratio of coping behavior to urges ) , and self-efficacy , suggesting an improved adaptation to nonsmoking and reduced vulnerability to relapse Two theoretical approaches to smoking cessation were compared . Participants were r and omly assigned either to ( a ) a traditional treatment program that used contingency contracting and that emphasized the necessity for absolute abstinence ( AA ) or to ( b ) a relapse-prevention ( RP ) treatment that focused on gradual acquisition of nonsmoking skills . It was hypothesized that participants in the RP treatment would be less successful initially but would have better maintenance skills and thus would relapse less during a 1-year follow-up period . Each program was evaluated in two formats : group-based treatment and self-help material s. Results indicated comparable 1-year abstinence rates for all treatments , although more participants dropped out of the self-help formats . Participants in the RP intervention were more likely to lapse sooner after quitting and were more likely to quit again during the 1-year maintenance period . Exploratory analyses of successful participants suggested that women were more successful in the RP program and that men had greater success with the AA approach Tobacco use is a major cause of cardiovascular , respiratory and oncological disease . Quitting smoking significantly benefits health , but for highly dependent smokers , unable to overcome their nicotine dependence , the concept of smoking reduction as a method of harm reduction is gaining ground . The University Hospital of Basle , Switzerl and , has run double-blind , placebo-controlled smoking cessation and smoking reduction studies : the CEASE trial evaluated the efficacy of the nicotine patch in achieving abstinence , and the Rosette study is evaluating the efficacy and tolerability of the nicotine oral inhaler in smokers who do not wish to quit . Smokers were instructed either to quit smoking ( CEASE ) or to reduce cigarette consumption by > 50 % ( Rosette ) . In both studies , success rates for active treatment versus placebo at 4 months demonstrated that nicotine replacement therapy ( NRT ) is effective in achieving both smoking cessation and reduction . Current approaches to smoking cessation and reduction at our clinic are discussed . Combination NRT rather than monotherapy is commonly used to achieve both smoking reduction and cessation . Treatment appears to be most effective if subjects are allowed to select their preferred NRT product . There are clear differences in patient population s aim ing to quit or reduce , the cessation population being more motivated . Smoking cessation remains the ultimate aim but , if unfeasible , a significant reduction in cigarette consumption is a valid goal Most smoking cessation programs advise abrupt rather than gradual cessation . We conducted a r and omized , controlled trial of gradual cessation ( n=297 ) vs. abrupt cessation ( n=299 ) vs. minimal treatment ( n=150 ) among smokers who wanted to quit now and preferred to quit gradually . Participants were recruited via newspaper and radio advertisements . The gradual and abrupt conditions received five phone calls ( total=90 min ) and the minimal treatment condition received two calls ( 25 min total ) . The gradual condition received nicotine lozenge ( via mail ) to reduce smoking prior to their quit date . After the quit day , all participants received lozenge . The primary outcome was prolonged abstinence from 2 weeks post-quit day through 6 months . Prior to the quit day , the gradual condition decreased cigarettes/day by 54 % , whereas the other two conditions decreased by 1 % and 5 % . Prolonged abstinence rates ( CO<10 ppm ) did not differ among gradual , abrupt and minimal treatment conditions ( 4 % , 7 % and 5 % ) , nor did 7-day point prevalence rates ( 7 % , 11 % and 11 % ) . Fewer smokers in the gradual condition ( 48 % ) made a quit attempt than in the abrupt ( 64 % ) or minimal ( 60 % ) conditions ( p<.001 ) . In the gradual condition , every week delay to the quit date increased the probability of lapsing by 19 % ( p<.001 ) . We conclude that among smokers who want to stop gradually in the near future , gradual cessation with nicotine pre-treatment does not produce higher quit rates than abrupt cessation . One liability of gradual reduction may be that it allows smokers to delay their quit date In the current study , 34 smokers were treated in a smoking cessation program that involved either a scheduled smoking procedure , or a minimal contact self-help treatment control . The interval smoking program consisted of baseline , cessation , and relapse prevention phases . During baseline , subjects self-monitored smoking and the total hours spent awake . During a 3-week cessation period , the scheduled smoking group progressively increased their intercigarette interval , thereby gradually reducing their total daily intake of nicotine . Smokers were expected to quit on a target date set at the end of this period . Cognitive behavioral interventions and relapse prevention training consisted of behavioral rehearsal of nonsmoking skills in a relapse prone environment . Control subjects were given the American Cancer Society " I Quit Kit " , and provided subsequent discussion of its use . The results showed that 53 % and 41 % of the scheduled smoking group was abstinent at the 6- and 12-month follow-up points , respectively . Controls averaged only 6 % for the same periods . Scheduled smoking may be a useful addition to a multicomponent treatment program and further study appears warranted to determine the saliency of the treatment features The effectiveness of nicotine gum in combination with a behavior modification program was studied . The nicotine dependence of participating smokers ( N = 322 ) was assessed . One hundred sixty-eight smokers were labeled as high nicotine dependent and 154 as moderate to low dependent . In a r and omized double-blind procedure , the high-dependent smokers were given gum containing 4 mg of nicotine ( 87 ) or 2 mg of nicotine ( 81 ) and the smokers with medium or low dependence were given gum containing 2 mg ( 76 ) or a placebo gum ( 78 ) . The smokers were also r and omized to familiarizing themselves with the medication a week before quit day ( 112 ) or to regular use , that is starting gum use on the quit day ( 122 ) . In the high-dependent group , sustained and chemically verified nonsmoking rates at 6 weeks , 1 year , and 2 years were , respectively , 60 % , 39 % , and 34 % in the subjects given the 4-mg dose compared with 41 % , 16 % , and 16 % for those using the 2-mg dose . In the group with medium or low dependence , the success rates at the same time periods were 70 % , 49 % , and 39 % for the subjects given the 2-mg dose and 38 % , 22 % , and 17 % for those given placebo gum . The differences in success rates were significant at least at the p < 0.02 % level for all comparisons . Familiarizing with the gum as compared with regular use gave fewer reports of side effects , 15 % vs 34 % , p < 0.001 . A trend toward better success rates at 6 weeks , although not statistically significant , was observed for the familiarization group , 61 % vs 52 % . The study shows that high nicotine-dependent smokers need higher doses of nicotine replacement , in this case the 4-mg dose rather than the 2-mg dose , whereas 2 mg is superior to placebo among less dependent smokers . These results compare favorably with those reported from the more recent nicotine patch therapy Abstract I f you want to stop smoking , any number of procedures can be recommended as effective temporarily . However , follow-up data for these methods are often lacking or disappointing ( Marston and McFall , 1971 ) . The two purpose s of this study were to ( a ) replicate and provide follow-up data for a promising method developed by Upper and Meredith ( 1970 ) , and ( b ) compare the success of those who set out to “ quit ” versus those trying merely to “ cut down ” . The method used is based on the theory that if smoking can be brought under the control of a single stimulus rather than the usual , multiple elicitors , then it can be more easily modified . The stimulus used in this particular approach was the buzz of a pocket timer AIMS To determine whether 2-week pre-treatment with transdermal nicotine influences withdrawal symptoms or success rate of subsequent smoking cessation using nicotine patches . DESIGN R and omized controlled trial . SETTING Smoking cessation clinic . PARTICIPANTS Healthy smokers ( n = 200 , 45 % female ) were allocated r and omly to either active nicotine-patch ( AP , 15 mg daily , n = 100 ) or placebo-patch ( PP , n = 100 ) pre-treatment . Baseline characteristics were well balanced except for daily cigarette consumption : mean ( + /- SD ) 23.1 ( 8) and 26.4 ( 11 ) for AP and PP groups , respectively ( P = 0.021 ) . INTERVENTION At the screening visit ( -2 weeks ) subjects were counselled and started pre-treatment with daily patches ( AP or PP ) . From the quit date ( week 0 ) onwards all subjects received active nicotine patches for 12 weeks ( 15 mg daily for 8 weeks , 10 and 5 mg daily for 2 weeks each ) and counselling . MEASUREMENTS Follow-up visits included measurement of exhaled carbon monoxide at the quit date , 2 , 6 , 10 and 26 weeks . Subjects documented daily cigarette consumption and severity of withdrawal symptoms ( Wisconsin scale ) from -2 weeks to week 2 . Outcome measures were withdrawal symptoms composite score and abstinence rates . FINDINGS There was no significant difference in withdrawal symptoms , but more subjects in the AP group were smoke-free during the 6-month study period . Overall sustained abstinence was documented in 17 % of subjects at 6 months ; 22 % and 12 % for AP and PP , respectively ( P = 0.03 ) . Retrospective subgroup analysis showed for subjects smoking > 16 cigarettes/day sustained cessation rates were 22 % and 9 % for AP and PP , respectively ( P = 0.01 ) . No difference in adverse event rates was observed . CONCLUSIONS Nicotine patch pre-treatment before cessation did not reduce early withdrawal symptoms but increased sustained abstinence rates at 6 months . The nicotine pre-treatment was equally effective in light and heavy smokers Objectives . Investigators planning studies employing group-r and omized design s need good estimates of the extra variation introduced as a result of correlated observations within units of assignment . We report intraclass correlation coefficients ( ICCs ) for a wide range of outcomes commonly employed in worksite studies and demonstrate analysis methods that can limit their deleterious impact . Methods . A sample of 11 , 711 employees of 24 firms recruited from the Minneapolis/St . Paul metropolitan area completed a mailed survey in the SUCCESS study , reporting on a broad array of outcomes . Applying mixed-model regression , we provide both crude and adjusted estimates of ICCs for 27 outcomes . Results . The crude ICCs were generally small , with a mean of .0163 and values ranging from 0 to .0650 . Adjustment for demographics reduced the ICCs for 25 of the 27 outcomes , and adjustment for additional individual-level covariates further reduced the ICCs for 23 of the 27 outcomes . Conclusions . Our results suggest that worksite-level ICCs for a variety of outcomes are generally small and can generally be reduced by adjustment for individual-level characteristics . Incorporating this information in planning worksite studies can improve sample size calculations to avoid underpowered studies

Based on low- or moderate- quality evidence using the GRADE approach and generally low risk of bias , the detection rate of CIN2 + or CIN3 + after two years does not appear to differ between immediate colposcopy and cytological surveillance in the absence of HPV testing , although women may default from follow-up . Immediate colposcopy probably leads to earlier detection of high- grade lesions , but also detects more clinical ly insignificant low- grade lesions .

BACKGROUND A significant number of women are diagnosed with minor cytological abnormalities on cervical screening . Many authorities recommend surveillance as spontaneous regression might occur . However , attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease . OBJECTIVES To assess the optimum management strategy for women with minor cervical cytological abnormalities ( atypical squamous cells of undetermined significance - ASCUS or low- grade squamous intra-epithelial lesions - LSIL ) at primary screening in the absence of HPV ( human papillomavirus ) DNA test .

Background Large numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities . Little is known about the psychological consequences of alternative management policies for these women . We compared , over 30-months , psychosocial outcomes of two policies : cytological surveillance ( repeat cervical cytology tests in primary care ) and a hospital-based colposcopy examination . Methods Women attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate . 3399 women , aged 20–59 years , with low- grade abnormal cytology , were r and omised to cytological surveillance ( six-monthly tests ; n = 1703 ) or initial colposcopy with biopsies and /or subsequent treatment based on colposcopic and histological findings ( n = 1696 ) . At 12 , 18 , 24 and 30-months post-recruitment , women completed the Hospital Anxiety and Depression Scale ( HADS ) . A subgroup ( n = 2354 ) completed the Impact of Event Scale ( IES ) six weeks after the colposcopy episode or first surveillance cytology test . Primary outcomes were percentages over the entire follow-up period of significant depression ( ≥8 ) and significant anxiety ( ≥11 ; “ 30-month percentages ” ) . Secondary outcomes were point prevalences of significant depression , significant anxiety and procedure-related distress ( ≥9 ) . Outcomes were compared between arms by calculating fully-adjusted odds ratios ( ORs ) for initial colposcopy versus cytological surveillance . Results There was no significant difference in 30-month percentages of significant depression ( OR = 0.99 , 95 % CI 0.80–1.21 ) or anxiety ( OR = 0.97 , 95 % CI 0.81–1.16 ) between arms . At the six-week assessment , anxiety and distress , but not depression , were significantly less common in the initial colposcopy arm ( anxiety : 7.9 % vs 13.4 % ; OR = 0.55 , 95 % CI 0.38–0.81 ; distress : 30.6 % vs 39.3 % , OR = 0.67 95 % CI 0.54–0.84 ) . Neither anxiety nor depression differed between arms at subsequent time-points . Conclusions There was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy . Policy-makers , clinicians , and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost . Trial Registration Controlled-Trials.com IS RCT N OBJECTIVE The success of cervical screening relies on women with abnormal cervical cytology attending for follow-up by colposcopy and related procedures . Failure to attend for colposcopy , however , is a common problem in many countries . The objective of this study was to identify factors associated with non-attendance at an initial colposcopy examination among women with low- grade abnormal cervical cytology . STUDY DESIGN A cohort study was conducted within one arm of a multi-centre population -based r and omised controlled trial nested within the UK NHS Cervical Screening Programmes . The trial recruited women aged 20 - 59 years with recent low- grade cervical cytology ; women r and omised to immediate referral for colposcopy were included in the current analysis ( n=2213 ) . At trial recruitment , women completed a socio-demographic and lifestyle question naire ; 1693 women in the colposcopy arm were also invited to complete a psychosocial question naire , including the Hospital Anxiety and Depression Scale . Women were sent up to two colposcopy appointments . A telephone number was provided to reschedule if necessary . Defaulters were defined as those who failed to attend after two appointments . Logistic regression methods were used to compute multivariate odds ratios ( OR ) to identify variables significantly associated with default . RESULTS 148 women defaulted ( 6.7 % , 95%CI 5.7 - 7.8 % ) . In multivariate analysis , risk of default was significantly raised in those not in paid employment ( OR=2.70 , 95%CI 1.64 - 4.43 ) and current smokers ( OR=1.62 , 95%CI 1.12 - 2.34 ) . Default risk deceased with increasing age and level of post-school education/training and was lower in women with children ( OR=0.59 , 95%CI 0.35 - 0.98 ) . Among the sub-group invited to complete psychosocial question naires , women who were not worried about having cervical cancer were significantly more likely to default ( multivariate OR=1.56 , 95%CI 1.04 - 2.35 ) . Anxiety and depression were not significantly associated with default . CONCLUSIONS Women at highest risk of default from colposcopy are younger , not in paid employment , smoke , lack post-school education , have not had children and are not worried about having cervical cancer . Findings such as these could inform the development of tools to predict the likelihood that an individual woman will default from follow-up . Interventions to minimise default also deserve consideration , but a better underst and ing of reasons for default is needed to inform intervention development OBJECTIVE To investigate the potential value of tree classifiers for the triage of high- grade squamous intraepithelial lesions . STUDY DESIGN The data set comprised 808 histologically confirmed cases having a complete range of the cytologic sample assessment s -- liquid-based cytology , reflex human papillomavirus ( HPV ) DNA test , E6/E7 HPV mRNA test , and p16 immunocytochemical examinations . Data include 488 histologically negative ( cervical intraepithelial neoplasia [ CIN ] 1 and below ) or clinical ly negative cases and 320 with histologic diagnosis of CIN 2 or worse . Cytologic diagnosis was made according to the criteria of the Bethesda System . Cases were classified in two groups according to histology : those with CIN 2 or worse and those with CIN 1 and below . Fifty percent were r and omly selected as a training set and the remaining were as a test set . RESULTS Application of tree classifier on the test set gave correct classification of 66.9 % for CIN 2 and above cases and 97.3 % for CIN 1 and below , producing overall accuracy of 91.5 % , outperforming cytologic diagnosis alone . CONCLUSION Application of tree classifiers , based on st and ard cytologic diagnosis and expression of studied biomarkers , produces improved classification results for cervical precancerous lesions and cancer diagnosis OBJECTIVE The detection of high- grade cervical intraepithelial neoplasia ( CIN ) amongst patients with low- grade cytology ( LSIL ) is challenging . This study evaluated the role of high-risk HPV ( HR-HPV ) DNA test and p16(INK4a ) immunostaining in identifying women with LSIL cytology at risk of harboring CIN2 or worse ( CIN2 + ) and the role of p16(INK4a ) in the triage of a population of HR-HPV positive LSIL . METHODS We conducted a prospect i ve study including women with LSIL cytology . Detection of HR-HPV was carried out by means of a polymerase chain reaction based assay . p16(INK4a ) immunostaining was performed using the Dako CINtec cytology kit . All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix . The endpoint was detection of a biopsy-confirmed CIN2 + . RESULTS A series of 126 women with LSIL cytology were included . HR-HPV test had sensitivity 75 % and specificity 64 % for an endpoint of CIN2 + . p16(INK4a ) had significantly higher specificity of 89 % ( p=0.0000 ) but low sensitivity of 42 % . The role of p16(INK4a ) immunostaining in the triage of LSIL positive for HR-HPV was also evaluated . p16(INK4a ) triage had 70 % positive predictive value ( PPV ) ; however , this was not significantly higher than the PPV ( 56 % ) of HR-HPV test alone ( p=0.4 ) . CONCLUSIONS The results indicate that HR-HPV or p16(INK4a ) can not be used as solitary markers for the assessment of LSIL . The addition of p16(INK4a ) immunostaining led to an increase in HR-HPV specificity ; however , the biomarker needs to be assessed further to establish its role as an adjunct test in the triage of LSIL Objectives To compare the effectiveness of punch biopsy and selective recall for treatment versus a policy of immediate treatment by large loop excision in the management of women with low grade abnormal cervical cytology referred for colposcopy . Design Multicentre individually r and omised controlled trial , nested within the NHS cervical screening programmes . Setting Grampian , Tayside , and Nottingham . Participants 1983 women , aged 20 - 59 , with cytology showing borderline nuclear abnormalities or mild dyskaryosis , October 1999-October 2002 . Interventions Immediate large loop excision or up to four targeted punch biopsies taken immediately with recall for treatment ( by large loop excision ) if these showed cervical intraepithelial neoplasia grade II or III or worse . Participants were followed for three years , concluding with an exit colposcopy . Main outcome measures Clinical end points : cumulative incidence of cervical intraepithelial neoplasia grade II or worse and grade III or worse at three years . Clinical ly significant anxiety and depression and self reported after effects assessed six weeks after colposcopy , biopsies , or large loop excision . Results 879 women ( 44 % ) had a normal transformation zone at colposcopy and had no further procedures at that time . Colposcopists were less likely to classify the transformation zone as abnormal when the allocation was large loop excision ( 603 ( 60 % ) in the biopsy and selective recall group ; 501 ( 51 % ) in the immediate large loop excision group ) . Of women r and omised to biopsy and recall , 157 ( 16 % ) required a second clinic visit for treatment . Specimens from almost 60 % ( n=296 ) of women who underwent immediate large loop excision showed no cervical intraepithelial neoplasia ( 31 % ; n=156 ) or showed cervical intraepithelial neoplasia grade I ( 28 % ; n=140 ) . The percentages of women diagnosed with grade II or worse up to and including the exit examination were 22 % ( n=216 ) in the biopsy and recall arm and 23 % ( n=228 ) in the immediate large loop excision arm . There was no significant difference between the arms in cumulative incidence of cervical intraepithelial neoplasia grade II or worse ( adjusted relative for risk large loop excision v biopsy 1.04 , 95 % confidence interval 0.86 to 1.25 ) or grade III or worse ( 1.03 , 0.79 to 1.34 ) . A greater proportion of disease was detected at initial investigation and less during follow-up and at exit in the immediate large loop excision arm , but time of detection did not differ significantly between arms . Levels of anxiety and depression and reported pain did not differ between arms . Higher proportions of women r and omised to large loop excision reported moderate or more severe bleeding and discharge . Conclusion A policy of targeted punch biopsies with subsequent treatment for cervical intraepithelial neoplasia grade II or III and cytological surveillance for grade I or less provides the best balance between benefits and harms for the management of women with low grade abnormal cytology referred for colposcopy . Immediate large loop excision results in overtreatment and more after effects and should not be recommended . Trial Registration IS RCT N 34841617 Objective It is well known that receipt of an initial abnormal cervical cytology test can trigger considerable anxiety among women . Less is known about the impact of follow-up by repeat cytology tests . We quantified prevalence , and identified predictors , of distress after repeat cytologic testing in women with a single low- grade test . Methods Within the framework of the TOMBOLA r and omized controlled trial of alternative managements , 844 women aged 20 to 59 years with a single routine cytology test showing borderline nuclear abnormalities ( BNA ; broadly equivalent to atypical squamous cells of undetermined significance ) were assigned to follow-up by repeat cytology in primary care ( the first test was due 6 months after the initial BNA result ) . Women completed sociodemographic and psychosocial question naires at recruitment and the Impact of Event Scale ( IES ) 6 weeks after their first follow-up cytology test . Factors associated with significant psychologic distress ( IES ≥ 9 ) were identified using logistic regression . Results The response rate was 74 % ( n = 621/844 ) . Of all the respondents , 39 % scored in the range for significant distress . Distress varied by follow-up cytology result : negative , 36 % ; BNA or mild dyskaryosis , 42 % ; other ( including high grade and inadequate ) , 55 % . After adjusting for the cytology result , risk of distress was significantly raised in women who had significant anxiety at recruitment , reported experiencing pain after the follow-up cytology , had children , or were dissatisfied with support they had received after their initial BNA test . Conclusions Substantial proportions of women experience surveillance-related psychologic distress after a follow-up cytology test , even when the result is negative . This is an important , albeit unintended , consequence of cervical screening . Strategies to alleviate this distress merit attention BACKGROUND Tests for the DNA of high-risk types of human papillomavirus ( HPV ) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse ( CIN3 + ) than does cytological testing , but the necessity of such testing in cervical screening has been debated . Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented . METHODS Women aged 29 - 56 years who were participating in the regular cervical screening programme in the Netherl and s were r and omly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only . After 5 years , combined cytological and HPV DNA testing were done in both groups . The primary outcome measure was the number of CIN3 + lesions detected . Analyses were done by intention to treat . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N20781131 . FINDINGS 8575 women in the intervention group and 8580 in the control group were recruited , followed up for sufficient time ( > or = 6.5 years ) , and met eligibility criteria for our analyses . More CIN3 + lesions were detected at baseline in the intervention group than in the control group ( 68/8575 vs 40/8580 , 70 % increase , 95 % CI 15 - 151 ; p=0.007 ) . The number of CIN3 + lesions detected in the subsequent round was lower in the intervention group than in the control group ( 24/8413 vs 54/8456 , 55 % decrease , 95 % CI 28 - 72 ; p=0.001 ) . The number of CIN3 + lesions over the two rounds did not differ between groups . INTERPRETATION The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3 + lesions . Earlier detection of such lesions could permit an extension of the screening interval Objective To estimate the cost effectiveness of alternative methods of managing low grade cervical cytological abnormalities detected at routine screening . Design Cost analysis within multicentre individually r and omised controlled trial . Setting Grampian , Tayside , and Nottingham . Participants 4201 women with low grade abnormalities . Interventions Cytological surveillance or referral to colposcopy for biopsy and recall if necessary or referral to colposcopy with immediate treatment based on colposcopic appearance . Main outcome measures Data on re source use collected from participants throughout the duration of the trial ( 36 months ) , enabling the estimation of both the direct ( health care ) and indirect ( time and travel ) costs of management . Quality of life assessed at recruitment and at 12 , 18 , 24 , and 30 months , using the EQ-5D instrument . Economic outcomes expressed as costs per case of cervical intraepithelial neoplasia ( grade II or worse ) detected , by trial arm , as confirmed at exit , and cost utility ratios ( cost per quality adjusted life year ( QALY ) gained ) for the three pairwise comparisons of trial arms . Results The mean three year discounted costs of surveillance , immediate treatment , and biopsy and recall were £ 150.20 ( € 177 , $ 249 ) , £ 240.30 ( € 283 , $ 415 ) , and £ 241.10 ( € 284 , $ 4000 ) , respectively , viewed from the health service perspective . From the social perspective , mean discounted costs were £ 204.40 ( € 241 , $ 339 ) , £ 339.90 ( € 440 , $ 563 ) , and £ 327.50 ( € 386 , $ 543 ) , respectively . Estimated at the means , the incremental cost effectiveness ratios indicated that immediate treatment was dominated by the other two management methods , although it did offer the lowest cost per case of cervical intraepithelial neoplasia detected and treated . The pronounced skews in the distributions indicated that probabilistic uncertainty analysis would offer more meaningful estimates of cost effectiveness . The observed differences in the cost effectiveness ratios between trial arms were not significant . Conclusion Judged within the time frame of the TOMBOLA evaluation , there is no compelling economic reason to favour any one follow-up method over either of the others . Trial Registration IS RCT N 34841617 Objectives To examine the effectiveness of cytological surveillance in primary care compared with immediate referral for colposcopic examination in women with low grade abnormal results on cervical cytology tests . Design Multicentre individually r and omised controlled trial . Setting NHS cervical screening programmes in Grampian , Tayside , and Nottingham . Participants 4439 women , aged 20 - 59 , with a cytology result showing borderline nuclear abnormalities or mild dyskaryosis , October 1999-October 2002 . Interventions Cytological screening every six months in primary care ( n=2223 ) or referral for colposcopy and related interventions ( n=2216 ) . All women were followed for three years , concluding with an exit appointment at which colposcopic examination was undertaken . Colposcopists assessing outcome at this appointment were blinded to r and omisation . Main outcome measures Primary end point : cumulative incidence of cervical intraepithelial neoplasia grade II or more severe disease . Other end points : cervical intraepithelial neoplasia grade III or worse , clinical ly significant anxiety and depression , other self reported after effects , and rates of non-attendance . Analysis was by intention to treat ; all those r and omised were included . Results The cumulative incidence of cervical intraepithelial neoplasia grade II or worse was 79 per 1000 person years in the colposcopy arm and 58 per 1000 person years in the cytological surveillance arm ( relative risk 1.37 , 95 % confidence interval 1.19 to 1.57 ) . This difference was less marked for cervical intraepithelial neoplasia grade III or more severe disease , but the incidence was still higher in the colposcopy arm ( relative risk 1.26 , 1.04 to 1.53 ) . Among women r and omised to immediate colposcopy , 79 % ( 74.9 % to 82.5 % ) of cases of cervical intraepithelial neoplasia grade II or worse were diagnosed at the time of the immediate colposcopy , while among women r and omised to cytological surveillance , 77 % ( 72.1 % to 81.2 % ) of cases were detected by surveillance cytology and related interventions . Similar proportions of women were anxious or depressed in the two arms . A higher proportion of women in the colposcopy arm reported after effects , and these were of longer duration and more severe . Non-attendance was low in both arms . Conclusion The more marked difference between the arms in the occurrence of cervical intraepithelial neoplasia grade II or worse than in the occurrence of grade III or worse can probably be accounted for by the spontaneous regression of some cases of grade II neoplasia . Compared with cytological surveillance , a policy of immediate colposcopy detects more cervical intraepithelial neoplasia grade II or worse , and some more grade III or worse , but might lead to overtreatment . Such a policy is associated with a higher rate of reported after effects , which are more severe and of longer duration than those associated with cytological surveillance . Trial registration IS RCT N 34841617 Background The grading of recommendation , assessment , development and evaluation ( GRADE ) approach is widely implemented in health technology assessment and guideline development organisations throughout the world . GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention , but is complex and therefore challenging to apply in a consistent manner . Methods We developed a checklist to guide the research er to extract the data required to make a GRADE assessment . We applied the checklist to 29 meta-analyses of r and omised controlled trials on the effectiveness of health care interventions . Two review ers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome . Results For most ( 70 % ) checklist items , there was good agreement between review ers . The main problems were for items relating to indirectness where considerable judgement is required . Conclusions There was consistent agreement between review ers on most items in the checklist . The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessment s , particularly for inexperienced users or in rapid review s without the re sources to conduct assessment s by two research ers independently OBJECTIVE To assess how the proportion of the cervical volume/length removed during treatment for cervical intraepithelial neoplasia ( CIN ) varies and whether this correlates to the pregnancy duration at delivery . METHODS The present prospect i ve observational study included 142 women undergoing CIN treatment at a university hospital during 2009 - 2013 . The pretreatment and post-treatment cervical dimensions and cone size were measured with magnetic resonance imaging , three-dimensional transvaginal ultrasonography , or two-dimensional transvaginal ultrasonography , and the correlation between pregnancy outcomes and the relative proportion of the cervix excised was assessed . RESULTS Pretreatment cervical volumes and cone volumes varied substantially ( range 11 - 40 cm(3 ) and 0.6 - 8 cm(3 ) , respectively ) . The proportion of the volume excised ranged from 2.2 % to 39.4 % . Sixteen ( 11 % ) women conceived following treatment ; 12 had a live birth ( seven at term , three preterm ) . The pregnancy duration at delivery was significantly correlated with the proportion of the cervical volume ( r=-0.9 ; P<0.001 ) and length ( r=-0.7 ; P=0.01 ) excised and the cone volume ( r=-0.6 ; P=0.04 ) . CONCLUSION The pretreatment cervical dimensions and the proportions of the volume/length excised vary substantially , and the latter correlates with the pregnancy duration . Assessment of the proportion excised might help to stratify women at risk who need intensive surveillance when pregnant BACKGROUND To investigate the natural history of HPV infection of the uterine cervix following a 10-year prospect i ve observational study . PATIENTS AND METHODS Three hundred and thirty women with cytological and colposcopic features of HPV infection + /- CIN 1 were recruited into the study . These women were followed up for a period of 10 years , during which time they had repeated colposcopic assessment s and cytological monitoring Those women with evidence of high- grade disease at any stage of follow-up were treated by Large Loop excision of the transformation zone ( LLETZ ) and excluded from the study . At the end of the surveillance period , 179 women with evidence of persistent HPV infection alone or in conjunction with low- grade disease underwent a shallow diagnostic LLETZ . In total , 51 women defaulted from follow-up . RESULTS Thirty-three per cent of the women with cytological and colposcopic features suggestive of persistent HPV infection alone during the 10-year follow-up period had histological evidence of CIN at the end of the study . Two thirds of this disease was grade d as CIN 2 or 3 . Nineteen per cent of the women with cytological and colposcopic features suggestive of persistent HPV infection and CIN 1 actually had high- grade CIN at histology ( CIN 2 and 3 ) . Only 6.1 % of the study population had normal histological findings . CONCLUSION The finding that a relatively large percentage of high- grade lesions might have been masked for anything up to a decade by a low- grade phenotype , coupled with the worrying percentage of defaulters from follow-up , indicate that an early decision for intervention ( diagnostic and /or therapeutic ) may be appropriate if a low- grade abnormality persists after a short surveillance period BACKGROUND The aim of the study was to compare the cost effectiveness of immediate diagnosis and treatment of mild dyskaryosis compared with the usual policy of cytological surveillance . METHODS A cost effectiveness analysis was carried out alongside a r and omized clinical trial . RESULTS Immediate diagnosis and treatment increased total costs by 50 per cent from 54.42 pounds per treated woman [ 95 per cent confidence interval ( CI ) 48.85 pounds-59.98 pounds ] in the surveillance group to 82.02 pounds per woman in the immediate diagnosis and treatment group with an incremental cost of 27.60 pounds ( 95 per cent CI 22.04 pounds-33.17 pounds ) . However , the number of cases of CIN III detected increased by 69 per cent for the policy of immediate diagnosis and treatment . This led to an average cost effectiveness ration of 180.18 pounds for the immediate diagnosis and treatment group and 199.94 pounds per case of CIN III detected for the surveillance group , with a marginal cost effectiveness ratio of 148.22 pounds ( 95 per cent CI 94.01 pounds-309.33 pounds ) for the immediate diagnosis and treatment group . CONCLUSION Immediate diagnosis and treatment increases the total cost of managing mildly dyskaryotic smears but this increased cost is offset by a sharp increase in the number of cases of CIN III detected Cervical screening reduces the risk of cervical cancer by detecting and treating cervical intraepithelial neoplasia ( CIN ) . The management of women with low- grade cervical abnormalities is controversial . Two management policies exist : repeat smears in primary care and colposcopy examination . It is not clear which of these is the more effective and efficient . There is also uncertainty as to the most effective and efficient management of women at colposcopy when an area of abnormality is seen on the cervix - immediate treatment or biopsy and selective recall for treatment if the biopsy result suggests this is necessary . The result of a human papillomavirus ( HPV ) test might assist in deciding the appropriate management of women with low- grade abnormalities . TOMBOLA , a pragmatic r and omised-controlled trial set within the cervical screening programmes in Scotl and and Engl and , addresses these three areas of uncertainty . Almost four and a half thous and women aged 20 - 59 with a low- grade cervical abnormality have been recruited and r and omised to either repeat smears or colposcopy examination . Women in the colposcopy arm of the trial are further r and omised to a policy of either immediate treatment or biopsy and selective recall for treatment if they have an abnormal transformation zone . Women are followed up to an exit examination at 3 years . HPV testing is undertaken at recruitment and at the exit examination . The primary endpoint is cumulative incidence of CIN2/3 . A range of other clinical , psychosocial and economic outcomes is being considered . This paper describes the design of the trial , and discusses the rationale underlying aspects of the design and the challenges faced in design ing and implementing the trial Abstract Objective : To compare the outcomes in women with mild and moderate dyskaryosis after increasing periods of surveillance and thereby to define a rational protocol for managing such women . Design - Prospect i ve study with r and omisation of women to one of four treatment groups , each with a different period of surveillance ; one group in which the women were given immediate treatment and three other groups in which the women were under surveillance for six , 12 , and 24 months . Setting : A dedicated colposcopy clinic in Aberdeen , Scotl and . Subjects : 902 women who presented with a mildly or moderately dyskaryotic smear for the first time . Interventions : Cytological and colposcopic examinations at intervals of six months until the allocated period of surveillance was completed , at which time biopsy was performed . Women with severe dyskaryosis were withdrawn from surveillance and a biopsy was performed . Main outcome measures - The histological findings after punch biopsy or large loop excision of the transformation zone , and the trends in cytological appearances of serial cervical smears . Results - 793 women completed the study . In all , 769 women had an adequate final smear , of which 197 were normal cytologically , 328 were still mildly or moderately dyskaryotic , and 244 were severely dyskaryotic . Seventeen of the 67 ( 25 % ) women with one repeat smear showing non-dyskaryosis had cervical intraepithelial neoplasia grade III compared with only one of the 31 ( 3 % ) women with no dyskaryosis in four repeat cervical smears ( P < 0.0001 ) . None of the women had invasive cancer . Of 158 women whose index smear showed mild dyskaryosis and who were allocated to the group under surveillance for two years , only 40 had not defaulted or still had dyskaryotic smears by the end of the two years . Conclusion : Cytological surveillance , although safe , is not an efficient strategy for managing women with mildly abnormal smears . Women with any degree of dyskaryosis in a smear should be referred for colpscopy Objectives This study aim ed to determine during 36 months of follow-up the ( 1 ) clinical outcomes and ( 2 ) influence of high-risk human papillomavirus ( HPV ) status on the risk of progression to cervical intraepithelial neoplasia 2 + ( CIN 2 + ) , among women with histologically proven CIN 1 . Material s and Methods This is an ad hoc analysis of women with CIN 1 within TOMBOLA , a r and omized trial of the management of women with low- grade cervical cytology . Women from the colposcopy arm with CIN 1 confirmed on punch biopsies and managed conservatively by cytology every 6 months in primary care were included . Sociodemographic data and a sample for HPV testing were collected at recruitment . Data on the sample women were extracted to calculate the cumulative incidence of CIN 2 + and the performance characteristics of the baseline HPV test . Detection of CIN 2 or worse ( CIN 2 + ) during follow-up or at exit colposcopy was analyzed . Results A total of 171 women were included . Their median age was 29 years . Fifty-two percent were high-risk HPV positive , 17 % were HPV-16 positive , and 11 % were HPV-18 positive . Overall , 21 women ( 12 % ) developed CIN 2 + , with a median time to detection of 25 months . Factors associated with progression to CIN 2 + were presence of HPV-18 ( relative risk = 3.04 ; 95 % CI = 1.09–8.44 ) and HPV-16 and /or HPV-18 at recruitment ( relative risk = 3.98 ; 95 % CI = 1.60–9.90 ) . The sensitivity and specificity of a combined HPV-16/HPV-18 test for the detection of CIN 2 + during 3 years were 58 % and 78 % , respectively . Conclusions Our results suggest that women with confirmed CIN 1 have low rates of progression to high- grade CIN within 3 years . Because the median time to progression was 25 months , conservative management could recommend the next repeat cytology at 2 years Objective To determine whether choice of colposcopy or six month cytological surveillance would be beneficial to women with mildly abnormal smears when compared with the national policy of six months surveillance in terms of psychological morbidity Objective To compare immediate and deferred treatment in women with cervical smears showing borderline nuclear abnormalities or mild dyskaryosis OBJECTIVE This study was undertaken to compare alternative strategies for the initial management of low- grade squamous intraepithelial lesion ( LSIL ) cytology . STUDY DESIGN A total of 1572 women with a community-based LSIL interpretation were r and omly assigned to immediate colposcopy , triage based on enrollment HPV DNA testing and liquid-based cytology at a colposcopy referral threshold of high- grade squamous intraepithelial lesion ( HSIL ) , or conservative management based on repeat cytology at a referral threshold of HSIL . All arms included 2 years of semiannual follow-up and colposcopy at exit . Loop electrosurgical excision procedure was offered to women with histologic diagnoses of cervical intraepithelial neoplasia ( CIN ) grade 2 or 3 at any visit or persistent CIN grade 1 at exit . The main study end point was 2-year cumulative diagnosis of CIN grade 3 . RESULTS The 2-year cumulative diagnosis of CIN grade 3 was approximately 15 % in all study arms . The HPV triage arm was closed early because more than 80 % of women were HPV positive , precluding efficient triage . The immediate colposcopy strategy yielded 55.9 % sensitivity for cumulative cases of CIN grade 3 diagnosed over 2 years . A conservative management strategy of repeat cytology at the HSIL threshold referred 18.8 % of women while detecting 48.4 % of cumulative CIN grade 3 . At lower cytology thresholds , sensitivity would improve but would ultimately yield unacceptably high referral rates . CONCLUSION LSIL cytology is best managed by colposcopy initially , because there was no useful triage strategy identified . Management of these patients , after colposcopy to rule out immediately overt CIN grade 2 or 3 , needs to be determined BACKGROUND Screening for cervical cancer based on testing for human papillomavirus ( HPV ) increases the sensitivity of detection of high- grade ( grade 2 or 3 ) cervical intraepithelial neoplasia , but whether this gain represents overdiagnosis or protection against future high- grade cervical epithelial neoplasia or cervical cancer is unknown . METHODS In a population -based screening program in Sweden , 12,527 women 32 to 38 years of age were r and omly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou ( Pap ) test ( intervention group ) or a Pap test alone ( control group ) . Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later , and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy . A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in r and omly selected women in the control group . Comprehensive registry data were used to follow the women for a mean of 4.1 years . The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated . RESULTS At enrollment , the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51 % greater ( 95 % confidence interval [ CI ] , 13 to 102 ) than the proportion of women in the control group who were found to have such lesions . At subsequent screening examinations , the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42 % less ( 95 % CI , 4 to 64 ) and the proportion with grade 3 lesions or cancer was 47 % less ( 95 % CI , 2 to 71 ) than the proportions of control women who were found to have such lesions . Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy . CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations . ( Clinical Trials.gov number , NCT00479375 [ Clinical Trials.gov ] . ) Please cite this paper as : Cotton S , Sharp L , Little J , Cruickshank M , Seth R , Smart L , Duncan I , Harrild K , Neal K , Waugh N , The TOMBOLA ( Trial Of Management of Borderline and Other Low‐ grade Abnormal smears ) Group . The role of human papillomavirus testing in the management of women with low‐ grade abnormalities : multicentre r and omised controlled trial . BJOG 2010 ; DOI : 10.1111/j.1471‐0528.2010.02519.x OBJECTIVES To develop a clinical decision support scoring system ( DSSS ) based on artificial neural networks ( ANN ) for personalised management of women with cervical abnormalities . METHODS We recruited women with cervical abnormalities and healthy controls that attended for opportunistic screening between 2006 and 2014 in 3 University Hospitals . We prospect ively collected detailed patient characteristics , the colposcopic impression and performed a series of biomarkers using a liquid-based cytology sample . These included HPV DNA typing , E6&E7 mRNA by NASBA or flow cytometry and p16INK4a immunostaining . We used ANNs to combine the cytology and biomarker results and develop a clinical DSSS with the aim to improve the diagnostic accuracy of tests and quantify the individual 's risk for different histological diagnoses . We used histology as the gold st and ard . RESULTS We analysed data from 2267 women that had complete or partial data set of clinical and molecular data during their initial or followup visits ( N=3565 ) . Accuracy parameters ( sensitivity , specificity , positive and negative predictive values ) were assessed for the cytological result and /or HPV status and for the DSSS . The ANN predicted with higher accuracy the chances of high- grade ( CIN2 + ) , low grade ( HPV/CIN1 ) and normal histology than cytology with or without HPV test . The sensitivity for prediction of CIN2 or worse was 93.0 % , specificity 99.2 % with high positive ( 93.3 % ) and negative ( 99.2 % ) predictive values . CONCLUSIONS The DSSS based on an ANN of multilayer perceptron ( MLP ) type , can predict with the highest accuracy the histological diagnosis in women with abnormalities at cytology when compared with the use of tests alone . A user-friendly software based on this technology could be used to guide clinician decision making towards a more personalised care

Conclusions Work-related outcomes are rarely reported in journal publication on r and omized , double blind , placebo-controlled trials of h and , hip or knee OA .

Background Osteoarthritis ( OA ) has a high prevalence in Western societies and can affect an individual ’s life in a number of domains , including work . In our experience , treatment trials on OA , however , rarely report work-related outcomes . Here we conducted a systematic review to assess the reporting of work-related outcomes in r and omized , double blind , placebo-controlled trials in OA .

Background The purpose of this study was to assess the effect of 8-weeks ingestion of a commercialized joint pain dietary supplement ( InstaflexTM Joint Support , Direct Digital , Charlotte , NC ) compared to placebo on joint pain , stiffness , and function in adults with self-reported joint pain . InstaflexTM is a joint pain supplement containing glucosamine sulfate , methylsufonlylmethane ( MSM ) , white willow bark extract ( 15 % salicin ) , ginger root concentrate , boswella serrata extract ( 65 % boswellic acid ) , turmeric root extract , cayenne , and hyaluronic acid . Methods Subjects included 100 men and women , ages 50 - 75 years , with a history ( > 3 months ) of joint pain , and were r and omized to Instaflex ™ or placebo ( 3 colored gel capsules per day for 8 weeks , double-blind administration ) . Subjects agreed to avoid the use of non-steroidal anti-inflammatory drugs ( NSAID ) and all other medications and supplements targeted for joint pain . Primary outcome measures were obtained pre- and post- study and included joint pain severity , stiffness , and function ( Western Ontario and McMaster Universities [ WOMAC ] ) , and secondary outcome measures included health-related quality of life ( Short Form 36 or SF-36 ) , systemic inflammation ( serum C-reactive protein and 9 plasma cytokines ) , and physical function ( 6-minute walk test ) . Joint pain symptom severity was assessed bi-weekly using a 12-point Likert visual scale ( 12-VS ) . Results Joint pain severity was significantly reduced in Instaflex ™ compared to placebo ( 8-week WOMAC , ↓37 % versus ↓16 % , respectively , interaction effect P = 0.025 ) , with group differences using the 12-VS emerging by week 4 of the study ( interaction effect , P = 0.0125 ) . Improvements in ability to perform daily activities and stiffness scores in Instaflex ™ compared to placebo were most evident for the 74 % of subjects reporting knee pain ( 8-week WOMAC function score , ↓39 % versus ↓14 % , respectively , interaction effect P = 0.027 ; stiffness score , ↓30 % versus ↓12 % , respectively , interaction effect P = 0.081 ) . Patterns of change in SF-36 , systemic inflammation biomarkers , and the 6-minute walk test did not differ significantly between groups during the 8-week study Conclusions Results from this r and omized , double blind , placebo-controlled community trial support the use of the Instaflex ™ dietary supplement in alleviating joint pain severity in middle-aged and older adults , with mitigation of difficulty performing daily activities most apparent in subjects with knee pain . Trial registration Clinical Trials.gov Identifier : Background The purpose of this study was to determine whether sedentary obese women with knee OA initiating an exercise and weight loss program may experience more beneficial changes in body composition , functional capacity , and /or markers of health following a higher protein diet compared to a higher carbohydrate diet with or without GCM supplementation . Methods Thirty sedentary women ( 54 ± 9 yrs , 163 ± 6 cm , 88.6 ± 13 kg , 46.1 ± 3 % fat , 33.3 ± 5 kg/m2 ) with clinical ly diagnosed knee OA participated in a 14-week exercise and weight loss program . Participants followed an isoenergenic low fat higher carbohydrate ( HC ) or higher protein ( HP ) diet while participating in a supervised 30-minute circuit resistance-training program three times per week for 14-weeks . In a r and omized and double blind manner , participants ingested supplements containing 1,500 mg/d of glucosamine ( as d-glucosamine HCL ) , 1,200 mg/d of chondroitin sulfate ( from chondroitin sulfate sodium ) , and 900 mg/d of methylsulfonylmethane or a placebo . At 0 , 10 , and 14-weeks , participants completed a battery of assessment s. Data were analyzed by MANOVA with repeated measures . Results Participants in both groups experienced significant reductions in body mass ( -2.4 ± 3 % ) , fat mass ( -6.0 ± 6 % ) , and body fat ( -3.5 ± 4 % ) with no significant changes in fat free mass or resting energy expenditure . Perception of knee pain ( -49 ± 39 % ) and knee stiffness ( -42 ± 37 % ) was decreased while maximal strength ( 12 % ) , muscular endurance ( 20 % ) , balance indices ( 7 % to 20 % ) , lipid levels (-8 % to -12 % ) , homeostasis model assessment for estimating insulin resistance ( -17 % ) , leptin ( -30 % ) , and measures of physical functioning ( 59 % ) , vitality ( 120 % ) , and social function ( 66 % ) were improved in both groups with no differences among groups . Functional aerobic capacity was increased to a greater degree for those in the HP and GCM groups while there were some trends suggesting that supplementation affected perceptions of knee pain ( p < 0.08 ) . Conclusions Circuit style resistance-training and weight loss improved functional capacity in women with knee OA . The type of diet and dietary supplementation of GCM provided marginal additive benefits .Trial Registration Clinical Trials.gov : The aim of this study was to investigate the effects of focused low-intensity pulsed ultrasound ( FLIPUS ) therapy on the functional and health status of patients with knee osteoarthritis ( KOA ) . A total of 106 subjects with bilateral KOA were r and omized sequentially into two groups . Group I received FLIPUS + diclofenac sodium , and group II received sham FLIPUS + diclofenac sodium . The therapeutic effects of the interventions were evaluated by measuring changes in VAS pain , the WOMAC scores , and the LI scores after 10 days of treatment as well as changes in LI and VAS at follow-up , 4 and 12 weeks later . In addition , changes in the range of motion , ambulation speed , and the SF-36 in each group were recorded after 10 days of treatment . Compared with those in group II , patients in group Ishowed significant improvements in VAS , WOMAC , LI , ambulation speed , and most items in the SF-36 after 10 days of treatment . In addition , patients in group I showed significant improvements in LI and VAS at follow-up . There were no FLIPUS-related adverse events during and after the interventions . In conclusion , FLIPUS is a safe and effective treatment modality for relieving pain and improving the functions and quality of life of patients with KOA Objectives : To estimate the effects of low level laser therapy in combination with a programme of exercises on pain , functionality , range of motion , muscular strength and quality of life in patients with osteoarthritis of the knee . Design : A r and omized double-blind placebo-controlled trial with sequential allocation of patients to different treatment groups . Setting : Special Rehabilitation Services . Subjects : Forty participants with knee osteoarthritis , 2–4 osteoarthritis degree , aged between 50 and 75 years and both genders . Intervention : Participants were r and omized into one of two groups : the laser group ( low level laser therapy dose of 3 J and exercises ) or placebo group ( placebo laser and exercises ) . Main measures : Pain was assessed using a visual analogue scale ( VAS ) , functionality using the Lequesne question naire , range of motion with a universal goniometer , muscular strength using a dynamometer , and activity using the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) question naire at three time points : ( T1 ) baseline , ( T2 ) after the end of laser therapy ( three weeks ) and ( T3 ) the end of the exercises ( 11 weeks ) . Results : When comparing groups , significant differences in the activity were also found ( P = 0.03 ) . No other significant differences ( P > 0.05 ) were observed in other variables . In intragroup analysis , participants in the laser group had significant improvement , relative to baseline , on pain ( P = 0.001 ) , range of motion ( P = 0.01 ) , functionality ( P = 0.001 ) and activity ( P < 0.001 ) . No significant improvement was seen in the placebo group . Conclusion : Our findings suggest that low level laser therapy when associated with exercises is effective in yielding pain relief , function and activity on patients with osteoarthritis of the knees Background Pharmacological treatment for osteoarthritis ( OA ) can be divided into two groups : symptom-modifying drugs and disease-modifying drugs . Symptom-modifying drugs are currently the prescription of choice for patients with OA , as disease-modifying drugs are not yet available in usual care . However , there has recently been a lot of debate about glucosamine sulphate ( GS ) , a biological agent that is thought to have both symptom-modifying and disease-modifying properties . This assumption has yet to be proved . The objective of this article is to present the design of a blind r and omised clinical trial that examines the long-term symptom-modifying and disease-modifying effectiveness of GS in patients with hip OA . This trial is ongoing and will finish in March 2006 . Methods / design Patients with hip OA meeting the ACR- criteria are r and omly allocated to either 1500 mg of oral GS or placebo for the duration of two years . The primary outcome measures , which are joint space narrowing ( JSN ) , and change in the pain and function score of the Western Ontario McMaster Universities Osteoarthritis index ( WOMAC ) , are determined at baseline and after two years of follow-up during the final assessment . Intermediate measures at three-month intervals throughout the trial are used to study secondary outcome measures . Secondary outcome measures are changes in WOMAC stiffness score , quality of life , medical consumption , side effects and differences in biomarker CTX-II The efficacy and safety of a once-daily extended-release formulation of tramadol hydrochloride ( tramadol ER ) was evaluated in patients with moderate to severe chronic pain of osteoarthritis ( OA ) . This was a r and omized , double-blind , placebo-controlled , parallel-group , 12-week study . Eligible patients with radiographically confirmed OA of the knee meeting the American College of Rheumatology diagnostic criteria , defined by knee pain and presence of osteophytes , plus at least age > 50 years , morning stiffness < 30 minutes in duration , and /or crepitus , entered a 2 - 7 day washout period during which all analgesics were discontinued . When pain at the index knee joint reached > or = 40 mm ( 0 - 100 mm VAS ) , patients were r and omized to tramadol ER or placebo . Tramadol ER was initiated at 100 mg QD and increased to 200 mg QD by the end of 1 week of treatment . After the first week , further increases to tramadol ER 300 mg or 400 mg QD were allowed . Outcome measures included Arthritis Pain Intensity Visual Analogue Scale ( VAS ) , Western Ontario and McMaster Universities Arthritis Scale ( WOMAC ) Pain , Stiffness , Physical Function VAS subscales , Patient and Physician Global Assessment of Therapy , Sleep , dropouts due to insufficient therapeutic effect , and adverse events . Two hundred forty-six patients were r and omized ( tramadol ER 124 , placebo 122 ) . There were no baseline differences between the two treatments . The mean age was 61 years , mean duration of OA 12.9 years , and the mean tramadol ER dose was 276 mg QD . All efficacy outcome measures favored tramadol ER over placebo . On the primary outcome variable of average change from baseline in Arthritis Pain Intensity VAS over 12 weeks , tramadol ER was superior to placebo ( least squares mean change from baseline : 30.4 mm vs. 17.7 mm , P < 0.001 ) . Significant differences from placebo were evident at week 1 , the first post-treatment visit . Similarly , outcomes on the WOMAC Pain , Stiffness and Physical Function subscales , the WOMAC Composite Scale , dropouts due to insufficient therapeutic effect , Patient and Physician Global Assessment of Therapy , and Sleep were all significantly better with tramadol ER than placebo ( P < 0.001 to < 0.05 ) . Treatment with tramadol ER results in statistically significant and clinical ly important and sustained improvements in pain , stiffness , physical function , global status , and sleep in patients with chronic pain . A once-a-day formulation of tramadol has the potential to provide patients increased control over the management of their pain , fewer interruptions in sleep and improved compliance We studied the efficacy and tolerability of glycosaminoglycan polysulfuric acid ( GAGPS ) in 80 patients with osteoarthritis ( OA ) of the knee . Patients received two series of five intra-articular injections , at 1-week intervals , of 25 mg ( 0.5 ml ) GAGPS into the knee in a double-blind , parallel , r and omized , placebo-controlled trial . There was an immediate decrease in pain after the injections of 43 % with GAGPS and 33 % with placebo ( P = 0.047 ) ( Jezek pain index ) . Pain relief of GAGPS vs placebo was not different at other intervals ( 10 , 14 , 22 , 26 weeks after start of treatment ) . At 6 weeks the Lequesne index decreased 20 % after GAGPS and 9 % after placebo ( P = 0.17 ) . At 10 weeks the Lequesne index decreased 24 % after GAGPS and 13 % after placebo ( P = 0.20 ) . The decrease in Lequesne index at 14 weeks was 31 % after GAGPS and 15 % after placebo ( P = 0.06 ) . The other measured parameters tended to be more favorably influenced by GAGPS than placebo . GAGPS was well tolerated , with associated mild adverse reactions in 8 % of cases . GAGPS may have a role as a symptomatic slow acting drug for OA . Further study appears appropriate Background Osteoarthritis of the knee is a major cause of disability among adults . Electro-acupuncture is considered a potentially useful treatment for osteoarthritis . The purpose of this study is to assess the efficacy of electro-acupuncture on pain control , pain perception , plasma cortisol and beta-endorphin levels , patient-perceived quality of life , and pain medication use in patients with chronic knee pain . Methods / design This study is a placebo-controlled , r and omized , double-blind , parallel design trial . One hundred sixty out- patients who are more than 50 years old and who have osteoarthritis of the knee will be recruited from the isl and of Mallorca , Spain . Each participant will be r and omly placed into one of two groups : ( sham ) electro-acupuncture non-insertion technique and real electro-acupuncture . Acupuncture treatments will be the Traditional Chinese Medicine type . The patients will be evaluated after a period of 1 month ( with two weekly sessions ) , 3 months ( with one monthly session ) , 6 months ( with one session every 45 days ) , and 1 year later with follow-up sessions at the end of the study ( with one session every 2 months).The primary outcomes will be based on the observed changes from the baseline of the visual analogue scale ( VAS ) and the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) for pain measured at 12 weeks after the end of treatment . Also to be included in the study are the possible changes in the secondary efficacy variables from baseline as assessed by the Short Form 36 version 2 health survey ( patient-perceived quality of life ) , patient plasma cortisol and beta-endorphin levels at the different treatment stages , the Goldberg Anxiety and Depression Scale , pain medication use , functional capacity and stiffness ( WOMAC subscales ) , and a VAS . These variables will be assessed at 1 month , 3 months , 6 months , and 1 year after study commencement . Discussion The findings from this study will help to determine whether electro-acupuncture is effective for chronic knee pain management in older people and whether electro-acupuncture can deliver results for the improvement of pain relief , stiffness , and disability . The study will therefore be a major step toward underst and ing the roles of the hypothalamic-pituitary-adrenal axis and the endogenous opioid system in the effectiveness of electro-acupuncture for chronic pain . Trial registration Clinical Trials.gov identifier NCT02299713 ( 11 Nov. 2014 ) ABSTRACT Objective : To compare the efficacy of rofecoxib and celecoxib for the treatment of knee or hip OA over 6 weeks . Methods : Two similarly design ed , multicenter , r and omized , double-blind , placebo-controlled studies . Patients were r and omly assigned 3:3:3:1 in Study 1 to once daily ( QD ) rofecoxib 12.5 mg ( N = 456 ) , rofecoxib 25 mg ( N = 459 ) , celecoxib 200 mg ( N = 456 ) , or placebo ( N = 150 ) and 3:3:1 in Study 2 to QD rofecoxib 25 mg ( N = 471 ) , celecoxib 200 mg ( N = 460 ) , or placebo ( N = 151 ) . There was no rofecoxib 12.5 mg arm in Study 2 . The primary outcome measure of both studies was pain at night over 6 weeks for rofecoxib 25 mg vs. celecoxib 200 mg . Efficacy comparisons with rofecoxib 12.5 mg in Study 1 were included as pre-specified study objectives but not as pre-specified study hypotheses . Secondary endpoints included Patient Global Assessment of Response to Therapy ( PGART ) over 6 weeks and over 1 week . Safety was evaluated through the assessment of spontaneously reported adverse experiences ( AEs ) , evaluation of vital signs , and laboratory data reported by investigators and patients . Results : For the primary endpoint , reduction in pain at night over 6 weeks in Study 1 was not significantly different between active treatments ; in Study 2 rofecoxib 25 mg significantly ( p = 0.023 ) reduced pain at night compared with celecoxib 200 mg over 6 weeks . For the secondary endpoints , in both studies , significantly ( p < 0.05 ) more patients treated with rofecoxib 25 mg than celecoxib 200 mg had a good or excellent PGART over 6 weeks , and over the first week ( p < 0.01 ) . In both studies , there were no significant differences between active medications in the incidence of reported overall , serious , or drug-related AEs . The reported AE rates with the active treatments were generally similar to those with placebo in the two studies . Conclusions : Rofecoxib 25 mg was significantly better than celecoxib 200 mg in relieving night pain at 6 weeks in one study ; this was not confirmed in the accompanying study Introduction Nonsteroidal anti-inflammatory drugs are recommended for the relief of pain associated with h and osteoarthritis ( OA ) but do not alter the underlying structural changes that contribute to impaired physical function . The current analysis examined the relationship of pain relief with measures of function and global rating of disease in patients with h and OA . Methods This was a combined analysis of 2 prospect i ve , r and omized , double-blind , 8-week , multicenter , parallel-group studies comparing diclofenac sodium 1 % gel with placebo gel ( vehicle ) in patients with radiographically confirmed mild to moderate h and OA . Patients ( n = 783 ) aged ≥ 40 years applied diclofenac sodium 1 % gel ( 2 g ) or vehicle to each h and 4 times daily for 8 weeks . Outcome measures included pain intensity assessed on a 100-mm Visual Analog Scale ( VAS ) ; the Australian/Canadian Osteoarthritis H and Index ( AUSCAN ) subscales for pain , stiffness , and physical function ( 100-mm VAS ) ; and a global rating of disease ( 100-mm VAS ) . Change in VAS pain intensity from baseline to week 8 was categorized ( < 0 % , 0%-<15 % , 15%-<30 % , 30%-<50 % , 50%-<70 % , and ≥ 70 % ) without regard to treatment and compared in each category with the mean change from baseline in each AUSCAN subindex and the global rating of disease . Pearson correlations between changes in outcome measures from baseline to week 8 were calculated . Results Changes in VAS pain intensity were accompanied by similar changes in AUSCAN scores and global rating of disease . Pearson correlations confirmed significant associations ( P < 0.001 ) between change in VAS pain intensity and changes in AUSCAN pain ( correlation coefficient [ r ] = 0.81 ) , AUSCAN function ( r = 0.75 ) , AUSCAN stiffness ( r = 0.66 ) , and global rating of disease ( r = 0.76 ) . Conclusions Pain relief correlated with improvements in physical function , stiffness , and global rating of disease in patients with h and OA , irrespective of treatment . This suggests that pain or anticipation of pain inhibits physical function and influences patient perception of disease severity in h and OA . These results also suggest that any intervention to relieve the pain of h and OA may improve function and patient perception of disease severity , despite the absence of a disease-modifying mechanism of action . Trial registration Clinical trials.gov NCT00171652 , NCT00171665 OBJECTIVE To assess the efficacy of a nonpharmacologic , noninvasive static magnetic device as adjunctive therapy for knee pain in patients with rheumatoid arthritis ( RA ) . DESIGN R and omized , double-blind , controlled , multisite clinical trial . SETTING An American and a Japanese academic medical center as well as 4 community rheumatology and orthopedics practice s. PATIENTS Cohort of 64 patients over age 18 years with rheumatoid arthritis and persistent knee pain , rated greater than 40/100 mm , despite appropriate use of medications . INTERVENTION Four blinded MagnaBloc ( with 4 steep field gradients ) or control devices ( with 1 steep field gradient ) were taped to a knee of each subject for 1 week . MAIN OUTCOME MEASURES The American College of Rheumatology recommended core set of disease activity measures for RA clinical trials and subjects ' assessment of treatment outcome . RESULTS Subjects r and omly assigned to the MagnaBloc ( n = 38 ) and control treatment groups ( n = 26 ) reported baseline pain levels of 63/100 mm and 61/100 mm , respectively . A greater reduction in reported pain in the MagnaBloc group was sustained through the 1-week follow-up ( 40.4 % vs 25.9 % ) and corroborated by twice daily pain diary results ( p < .0001 for each vs baseline ) . However , comparison between the 2 groups demonstrated a statistically insignificant difference ( p < .23 ) . Subjects in the MagnaBloc group reported an average decrease in their global assessment of disease activity of 33 % over 1 week , as compared with a 2 % decline in the control group ( p < .01 ) . After 1 week , 68 % of the MagnaBloc treatment group reported feeling better or much better , compared with 27 % of the control group , and 29 % and 65 % , respectively , reported feeling the same as before treatment ( p < .01 ) . CONCLUSIONS Both devices demonstrated statistically significant pain reduction in comparison to baseline , with concordance across multiple indices . However , a significant difference was not observed between the 2 treatment groups ( p < .23 ) . In future studies , the MagnaBloc treatment should be compared with a nonmagnetic placebo treatment to characterize further its therapeutic potential for treating RA . This study did eluci date methods for conducting clinical trials with magnetic devices Infrared ( IR ) therapy is used for pain relief in patients with knee osteoarthritis ( OA ) . However , IR 's effects on the cardiovascular system remain uncertain . Therefore , we investigated the local and systemic cardiovascular effects of monochromatic IR therapy on patients with knee OA in a double-blind , r and omized , placebo-controlled study . Seventy-one subjects with knee OA received one session of 40 min of active or placebo monochromatic IR treatment ( with power output of 6.24 W , wavelength of 890 nm , power density of 34.7 mW/cm2 for 40 min , total energy of 41.6 J/cm2 per knee per session ) over the knee joints . Heart rate , blood pressure , and knee arterial blood flow velocity were periodically assessed at the baseline , during , and after treatment . Data were analyzed by repeated-measure analysis of covariance . Compared to baseline , there were no statistically significant group x time interaction effects between the 2 groups for heart rate ( P = 0.160 ) , blood pressure ( systolic blood pressure : P = 0.861 ; diastolic blood pressure : P = 0.757 ) , or mean arterial blood flow velocity ( P = 0.769 ) in follow-up assessment s. The present study revealed that although there was no increase of knee arterial blood flow velocity , monochromatic IR therapy produced no detrimental systemic cardiovascular effects Objective . To assess the short-term efficacy and safety of two kinds of Traditional Chinese herbal patches , Fufang Nanxing Zhitong Gao ( FNZG ) and Shangshi Jietong Gao ( SJG ) , for painful knee osteoarthritis ( OA ) . Methods . Patients were r and omly enrolled in a double-blind , placebo-controlled study to receive FNZG ( n = 60 ) , SJG ( n = 60 ) , or placebo patch ( n = 30 ) for 7 days . Outcome measures included visual analogue scale ( VAS ) , Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) , and Traditional Chinese Medicine Syndrome Question naire ( TCMSQ ) subscale . Results . Although there was no significant difference among , three groups in short-term pain management , patients receiving FNZG got significant improvement in symptom of fear of coldness as compared with placebo patch ( P = 0.029 ) . The most common local adverse events of rash , itching , erythema , and slightly damaged skin were observed in 7 % of participants . Conclusions . FNZG may be a useful treatment for symptom of knee OA and merits long-term study in broader population Objectives : To present a pilot study of valerian to explore issues of feasibility and efficacy in studies of sedative herbs for arthritis-related sleep disturbance . Methods : Fifteen persons with arthritis and mild sleep disturbance were r and omized to receive 600 mg valerian ( Valeriana officinalis , n = 7 ) or placebo ( n = 8) for five nights . Results : Protocol adherence ( dosing and data collection ) was high . Allocation concealment was successful using a novel approach for matching the placebo on the distinctive odor of valerian . Nonsignificant differences between the groups were found on all sleep outcomes , measured by daily diaries and wrist actigraphy . Conclusion : The study methods were feasible , except for recruitment issues ( addressed in the discussion ) , and may guide the testing of other sedative herbs for persons with arthritis . Although efficacy outcomes were inconclusive due to the small sample size of this study , recent evidence from larger trials of valerian also does not support its efficacy OBJECTIVE To compare the analgesic efficacy and safety of nonprescription doses of naproxen sodium , ibuprofen , and placebo in patients with osteoarthritis ( OA ) of the knee . METHODS In 2 identical multicenter , r and omized , double-blind , placebo-controlled , multidose , parallel- design studies , patients aged > or = 25 years with OA were r and omized to daily doses of naproxen sodium 660 mg , naproxen sodium 440 mg ( patients > or = 65 years ) , ibuprofen 1200 mg , or placebo , for 7 days . RESULTS For investigator and patient assessment of knee joint pain , naproxen sodium ( 440/660 mg ) and ibuprofen were clinical ly effective at relieving pain compared with placebo ( n = 444 ) ; both treatments reduced the mean symptom score by 30 - 45 % , compared with a 20 - 25 % reduction with placebo . Naproxen sodium ( 440/660 mg ) significantly improved all 7 symptoms from baseline compared with placebo , while ibuprofen significantly improved 5 of the symptoms . For the subgroup of patients aged > or = 65 years ( n = 183 ) , naproxen sodium 440 mg was significantly superior to placebo in all symptoms except pain on weight-bearing ; ibuprofen only significantly reduced day pain . For daily diary evaluations , naproxen sodium and ibuprofen were effective in reducing all 6 symptoms ; there was a trend toward higher efficacy for night-time pain with naproxen sodium 440/660 mg compared with ibuprofen . There were no significant differences in adverse event reporting between groups . CONCLUSION Over-the-counter doses of naproxen sodium ( 440/660 mg ) and ibuprofen ( 1200 mg ) effectively relieve pain in patients with mild to moderate OA of the knee . Naproxen sodium provided more effective pain relief for most variables compared with placebo , and for night pain compared with ibuprofen . Efficacy was combined with good safety and tolerability BACKGROUND Arthroscopic partial meniscectomy is one of the most common orthopedic procedures , yet rigorous evidence of its efficacy is lacking . METHODS We conducted a multicenter , r and omized , double-blind , sham-controlled trial in 146 patients 35 to 65 years of age who had knee symptoms consistent with a degenerative medial meniscus tear and no knee osteoarthritis . Patients were r and omly assigned to arthroscopic partial meniscectomy or sham surgery . The primary outcomes were changes in the Lysholm and Western Ontario Meniscal Evaluation Tool ( WOMET ) scores ( each ranging from 0 to 100 , with lower scores indicating more severe symptoms ) and in knee pain after exercise ( rated on a scale from 0 to 10 , with 0 denoting no pain ) at 12 months after the procedure . RESULTS In the intention-to-treat analysis , there were no significant between-group differences in the change from baseline to 12 months in any primary outcome . The mean changes ( improvements ) in the primary outcome measures were as follows : Lysholm score , 21.7 points in the partial-meniscectomy group as compared with 23.3 points in the sham-surgery group ( between-group difference , -1.6 points ; 95 % confidence interval [ CI ] , -7.2 to 4.0 ) ; WOMET score , 24.6 and 27.1 points , respectively ( between-group difference , -2.5 points ; 95 % CI , -9.2 to 4.1 ) ; and score for knee pain after exercise , 3.1 and 3.3 points , respectively ( between-group difference , -0.1 ; 95 % CI , -0.9 to 0.7 ) . There were no significant differences between groups in the number of patients who required subsequent knee surgery ( two in the partial-meniscectomy group and five in the sham-surgery group ) or serious adverse events ( one and zero , respectively ) . CONCLUSIONS In this trial involving patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear , the outcomes after arthroscopic partial meniscectomy were no better than those after a sham surgical procedure . ( Funded by the Sigrid Juselius Foundation and others ; Clinical Trials.gov number , NCT00549172 . ) OBJECTIVE The aim of the trial was to assess the efficacy of chondroitin sulphate ( CS ) on symptomatic knee osteoarthritis ( OA ) associated to psoriasis . METHODS In this r and omized , double-blind , placebo (PBO)-controlled clinical trial 129 patients with symptomatic knee OA and concomitant psoriasis were r and omized into two groups receiving 800 mg daily of CS or PBO for 3 months . The primary efficacy outcome for knee OA was the Huskisson 's visual analogue scale ( VAS ) and for psoriasis was the Psoriasis Area and Severity Index ( PASI ) . Additionally , other secondary efficacy criteria for both conditions were assessed . RESULTS After 3 months of treatment , CS was more effective than PBO , relieving pain VAS ( CS -26.9+/-24.8 vs PBO -14.23+/-20.8 mm , P<0.01 ) , decreasing the Lequesne index ( CS -4.8+/-3.4 vs PBO -3.3+/-3.5 , P<0.05 ) and reducing the number of patients using acetaminophen as rescue medication ( CS 43 % vs PBO 64 % , P<0.05 ) . Regarding PASI , Overall Lesion Severity Scale and Physician 's Global Assessment of Change no statistically significant changes were detected in front of PBO . However , CS improved plantar psoriasis compared to PBO ( CS 87 % vs PBO 27 % , P<0.05 ) . Quality of life improved significantly in CS-treated patients according to the Short Form-36 health survey and the Dermatology Life Quality Index ( DLQI ) . CS tolerability was excellent . Adverse events were infrequent and evenly distributed among groups . The incidence of psoriatic flares did not increase after treatments . CONCLUSIONS This study confirms the efficacy and safety of CS as a symptomatic slow-acting drug in patients with knee OA and shows that CS improves plantar psoriasis . The use of CS could represent a special benefit in patients with both pathologies since non-steroidal anti-inflammatory drugs have been reported to induce or exacerbate psoriasis One thous and twenty-eight ( 1,028 ) patients with pain due to osteoarthritis ( OA ) of the knee were enrolled in this multicenter , r and omized , double-blind , parallel study design ed to assess the analgesic efficacy and safety of Tramadol Contramid OAD compared to placebo . An open-label phase was followed by a double-blind phase , in which a total of 646 patients were r and omized to double-blind treatment with placebo or Tramadol Contramid OAD . Patients were titrated to their optimal dose ( 200 mg or 300 mg ) , which was maintained for 12 weeks . An absolute mean reduction of 3.0+/-2.1 on a Pain Intensity Numerical Rating Scale ( PI-NRS ) was noted in the Tramadol Contramid OAD treatment group . The difference between active and placebo groups regarding this absolute mean reduction was statistically significant ( P<0.001 ) throughout the study . The responder analysis demonstrated that a significantly greater percentage of patients in the active treatment arm achieved a reduction of > or=1 and > or=2 points on the PI-NRS score by the end of the study ( P=0.035 ) . A significantly greater percentage of respondents in the Tramadol Contramid OAD group indicated improvement on both the Patient and Physician Global Impressions of Change ( P=0.0002 ) . Both the 200 mg and 300 mg doses contributed to the overall superiority of Tramadol Contramid OAD . The most frequent adverse events were consistent with the known side effects of tramadol and were generally mild to moderate in intensity . These results confirm that Tramadol Contramid OAD given once daily is an efficacious and safe treatment for pain due to OA Background Folklore remedies for pain and inflammation in rheumatoid arthritis include the application of magnets and copper to the skin . Despite the popular use of devices containing magnets or copper for this purpose , little research has been conducted to evaluate the efficacy of such treatments . Objective To investigate whether the practice of wearing magnetic wrists straps , or copper bracelets , offers any specific therapeutic benefit for patients with rheumatoid arthritis . Design R and omised double-blind placebo-controlled crossover trial . Methods 70 patients , aged 33 to 79 years and predominantly female ( n = 52 ) , with painful rheumatoid arthritis were recruited from general practice s within Yorkshire . Participants were r and omly allocated to wear four devices in a different order . Devices tested were : a st and ard ( 1502 to 2365 gauss ) magnetic wrist strap , a demagnetised ( < 20 gauss ) wrist strap , an attenuated ( 250 to 350 gauss ) magnetic wrist strap , and a copper bracelet . Devices were each worn for five weeks , with treatment phases being separated by one week wash-out periods . The primary outcome measured was pain using a 100 mm visual analogue scale . Secondary pain measures were the McGill Pain Question naire and tender joint count . Inflammation was assessed using C-reactive protein and plasma viscosity blood tests and by swollen joint count . Physical function was assessed using the Health Assessment Question naire ( Disability Index ) . Disease activity and medication use was also measured . Results 65 participants provided complete self-report outcome data for all devices , four participants provided partial data . Analysis of treatment outcomes did not reveal any statistically significant differences ( P>0.05 ) between the four devices in terms of their effects on pain , inflammation , physical function , disease activity , or medication use . Conclusions Wearing a magnetic wrist strap or a copper bracelet did not appear to have any meaningful therapeutic effect , beyond that of a placebo , for alleviating symptoms and combating disease activity in rheumatoid arthritis . Trial Registration Controlled-Trials.com IS RCT N51459023 IS RCT N51459023 OBJECTIVE To evaluate the structural effect of avocado/soybean unsaponifiables ( ASU ) in the treatment of patients with symptomatic osteoarthritis ( OA ) of the hip . METHODS Patients with regular painful primary OA of the hip ( European League Against Rheumatism 1980 criteria ) and a joint space still > or = 1 mm ( Kellgren grade 1 to 3 , assessed by an independent observer prior to inclusion ) entered a prospect i ve , multicenter , r and omized , parallel group , double-blind , placebo-controlled trial of 2 years duration . Patients had at least a 6-month history of regular pain and an algofunctional index ( AFI ) > or = 4 . The primary assessment criterion was a decrease of the joint space width ( JSW ) on plain anteroposterior radiographs of the pelvis performed in st and ing position , measured at the narrowest points by 2 independent readers , previously tested and selected and blinded to both the treatment and the time sequence . Secondary criteria were st and ard clinical outcome measurements ( AFI , pain on a visual analog scale , consumption of nonsteroidal antiinflammatory drugs and patient 's and investigator 's global assessment s ) . RESULTS One hundred sixty-three patients were included : 102 men and 61 women ( mean age 63.2 + /- 8.7 years ) . A total of 108 patients ( 72 men and 36 women ; mean age 64 + /- 7.9 years ) were radiologically evaluable at 23.7 + /- 2.6 months ( ASU group ; n = 55 ) and 23.7 + /- 3.2 months ( placebo group ; n = 53 ) . Overall comparison of the evolution of JSW showed no difference between the ASU and placebo groups , from 2.35 + /- 0.93 to 1.87 + /- 1.10 mm and from 2.5 + /- 0.94 to 1.9 + /- 1.33 mm , respectively ( intergroup P value at end point = 0.9 ) . When patients were divided into 2 subgroups according to the median value of the baseline JSW ( 2.45 mm ) , the joint space loss in the most severely affected subgroup of patients ( baseline JSW < or = median ) was significantly greater in the placebo group than in the ASU group : from 1.69 + /- 0.58 to 0.84 + /- 0.77 mm ( -0.86 + /- 0.62 mm ) and from 1.66 + /- 0.42 to 1.22 + /- 0.7 mm ( -0.43 + /- 0.51 mm ) , respectively ( P < 0.01 ) . The JSW decrease was identical , with no difference in ASU and placebo groups , in the less severely affected subgroup of patients ( baseline JSW > median ) . Clinical parameters in the 2 groups did not differ significantly throughout the study . CONCLUSION This pilot r and omized , double-blind , placebo-controlled trial failed to demonstrate a structural effect of ASU in hip OA . However , in a post-hoc analysis , ASU significantly reduced the progression of joint space loss as compared with placebo in the subgroup of patients with advanced joint space narrowing . These results suggest that ASU could have a structural effect but require confirmation in a larger placebo-controlled study in hip OA The aim of this study was to evaluate the utility of the American Pain Society ( APS ) question naire in the assessment of osteoarthritis ( OA ) pain and to determine the onset of action of celecoxib in the treatment of acute flare pain in patients with OA of the knee or hip . Pooled data from three pivotal , r and omized , double-blind , placebo-controlled , 12-week trials of patients with OA who exhibited a flare of disease activity after withdrawal of nonsteroidal anti-inflammatory drug or analgesic therapy were evaluated . Patients completed the APS Pain Measure Question naire , which evaluates pain intensity and quality of life , at baseline and daily for the first 7 days of therapy . In addition , patients underwent a range of st and ard OA assessment s to evaluate the analgesic efficacy of celecoxib up to 12 weeks . Three thous and two hundred fifty-eight patients were enrolled in the three studies , of whom 2041 completed the APS question naire ( 1010 received celecoxib , 513 received naproxen , and 518 received placebo ) . Within the first 24 hours , celecoxib at a dose of 200 or 400 mg/d significantly reduced the amount of acute pain experienced compared with placebo for four of the five measures , and statistical significance for the remaining parameter , “ pain in the last 24 hours , ” was achieved on day 2 . Celecoxib at a dose of 200 to 400 mg/d provided similar efficacy to naproxen at a dose of 1000 mg/d . The pain relief observed with celecoxib was maintained for the APS evaluation period . Long-term efficacy assessment s showed the efficacy of 200 mg/d of celecoxib to be continuous and maintained for at least the 12 weeks of the study and that it was equivalent to 400 mg/d of celecoxib and 1000 mg/d of naproxen . This study demonstrates that the APS question naire is a useful measure of pain and therapeutic response in OA . Celecoxib furthermore seems to be an effective acute and chronic analgesic in OA ABSTRACT Objective : This study evaluated the efficacy and safety of tramadol extended-release ( tramadol ER ) tablets once daily in subjects with osteoarthritis pain . Methods : This 12‐week , multicenter , r and omized , double-blind , placebo-controlled , parallel-group clinical trial included 1020 adults with osteoarthritis of the knee or hip and baseline pain intensity ≥ 40 on a 100‐mm pain visual analog scale ( 0 = no pain , 100 = extreme pain ) . Subjects took placebo or were titrated to a target dose of tramadol ER 100 , 200 , 300 , or 400 mg once daily . Main outcome measures : The co- primary efficacy variables were pain and physical function subscales of the WOMAC Osteoarthritis Index and subject global assessment of disease activity . Results : Mean changes in WOMAC Osteoarthritis Index pain and physical function subscales were significantly different between tramadol ER and placebo , overall ( p ≤ 0.021 ) and for each dose ( p ≤ 0.050 ) . However , the protocol -specified decision rule for the 3 co- primary endpoints was not satisfied because the overall comparison of subject global assessment of disease activity was not statistically significant ( p = 0.079 ) . All doses of tramadol ER once daily were more effective than placebo ( p ≤ 0.050 ) for WOMAC Osteoarthritis Index joint stiffness subscale , WOMAC Osteoarthritis Index composite score , pain intensity of the index joint , and daily pain intensity scores . Tramadol ER 200 and 300 mg were significantly more effective than placebo ( p ≤ 0.050 ) for subject global assessment of disease activity and pain intensity of non-index joints . Adverse events ( e.g. , constipation , dizziness , nausea , somnolence , headache ) occurred most often with tramadol ER 400 mg . Conclusions : Tramadol ER 100–300 mg once daily was associated with significant improvement in pain intensity and physical function , and was well tolerated , despite the use of a fixed-dose study design not reflective of usual clinical practice . Tramadol ER is a useful treatment option for patients with osteoarthritis pain OBJECTIVE To determine the efficacy of fluoroscopically guided corticosteroid injection for hip osteoarthritis ( OA ) in a r and omized , double-blind , placebo-controlled trial . METHODS Fifty-two patients with symptomatic hip OA were r and omly allocated to receive placebo ( 10 mg bipuvicaine , 2 ml saline ) ( n = 21 ) or corticosteroid treatment ( 10 mg bipuvicaine , 40 mg triamcinolone hexacetonide ) ( n = 31 ) . Patients were followed up for 1 , 2 , 3 , and 6 months . The primary outcome measure was the pain improvement response , defined as a 20 % decrease in the Western Ontario and McMaster Universities OA Index ( WOMAC ) pain score ( on 5 100-mm visual analog scales [ VAS ] ) ( WOMAC20 ) from baseline to 2 months postinjection . Secondary outcomes were a 50 % decrease in the WOMAC pain score ( WOMAC50 ) , changes in other WOMAC subscale scores , patient 's global assessment of health ( on a 100-mm VAS ) , and Short Form 36 ( SF-36 ) quality of life indices . Analyses were based on the intent-to-treat principle . RESULTS The mean WOMAC pain score fell 49.2 % ( decreasing from 310.1 mm to 157.4 mm ) at 2 months postinjection in patients receiving corticosteroid , compared with a decrease of 2.5 % ( from 314.3 mm to 306.5 mm ) in the placebo group ( P < 0.0001 ) . The proportion of WOMAC20 responders at 2 months ' followup was significantly higher in the corticosteroid group ( 67.7 % ) compared with the placebo group ( 23.8 % ) ( P = 0.004 ) ; similar proportions of WOMAC50 responders were observed between groups ( 61.3 % in the corticosteroid group versus 14.3 % in the placebo group ; P = 0.001 ) . Response differences were maintained at 3 months ' followup ( 58.1 % responders in the corticosteroid group versus 9.5 % responders in the placebo group ; P = 0.004 ) . Significant differences in the WOMAC stiffness and physical function scores ( P < 0.0001 ) , patient 's global health scores ( P = 0.005 ) , and SF-36 physical component scores ( P = 0.04 ) were observed , with patients in the corticosteroid group showing greater improvements . There were no differences in the frequency of adverse events between groups . CONCLUSION This placebo-controlled trial confirms that corticosteroid injection can be an effective treatment of pain in hip OA , with benefits lasting up to 3 months in many cases . Future studies should address questions related to the benefits of repeated steroid injection and the effects of this treatment on disease modification OBJECTIVE To determine whether or not N of 1 trials with diclofenac/misoprostol ( Arthrotec ) are superior and cost-effective compared with st and ard treatment in osteoarthritis ( OA ) . METHODS We r and omized subjects with OA who were " uncertain that nonsteroidal antiinflammatory drugs ( NSAID ) were helpful " to 2 different groups . One group received conventional treatment whereby they were told to stop their NSAID and to wait and see what happened . If necessary , treatment with other NSAID and all other usual OA treatment strategies were used . The other group received a series of crossover trials with diclofenac 50 mg and misoprostol 200 micro g twice a day or an identical placebo for 2 weeks each in a r and om double-blinded manner . Every 4 weeks they chose which treatment they preferred . By 3 months , if there was no clear preference , the N of 1 trials were discontinued . All trial participants were seen monthly for 3 months and at 6 months . All costs ( direct and indirect ) were collected for both groups . Costs of research -generated visits were not counted in the " conventional treatment " group . RESULTS Fifty-one subjects were r and omized ( stratified by most symptomatic OA area ) : 25 with knee , 7 with hip , and 19 with h and OA . Twenty-four were r and omized into the N of 1 group . There were no differences in the baseline and followup variables including age , income , education , past and current NSAID use , global assessment , Health Assessment Question naire ( HAQ ) , Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) , and Medical Outcome Study Short Form-36 ( SF-36 ) scores . In the N of 1 group , 11 patients preferred diclofenac in total ( of whom 7 did only one round , 2 did 2 rounds , and 2 did 3 rounds ) . None of the N of 1 patients preferred placebo and 11 had no preference ( 2 dropped out at baseline ) . At 6 months , 15 of 19 in " conventional therapy " and 17 of 21 in N of 1 were taking NSAID . That is , NSAID appeared to be effective in 81 % of N of 1 subjects and 79 % of conventionally treated patients , even though subjects were initially uncertain that their NSAID were helpful . The total OA-related costs in Canadian dollars per patient ( in 1996 ) for N of 1 treated patients at 6 months were : 551.66 dollars + /- 154.02 dollars ( SD ) versus 395.62 dollars + /- 226.87 dollars for controls , excluding 2 research visits for controls ( p < 0.009 ) . The HAQ pain and disability , WOMAC scales , and physician global assessment s improved more in the N of 1 group ( at greater cost ) , but no between-group differences in efficacy were seen , possibly due to small numbers . CONCLUSION N of 1 trials were time-consuming in these patients and are more expensive , but with slightly better outcomes . In addition , NSAID seem to be effective in a majority of subjects with OA who have been uncertain of their benefit OBJECTIVE To investigate if st and ardised powder made from rose-hip ( Rosa canina ) can reduce the symptom score in patients with rheumatoid arthritis . METHODS In a double-blind placebo-controlled trial , patients with rheumatoid arthritis ( RA ) according to ARA/ACR criteria were r and omised to treatment with capsulated rose-hip powder 5 g daily or matching placebo for 6 months at two outpatient clinics in Berlin and Copenhagen . Primary outcome variable was Health Assessment Question naire ( HAQ ) at 6 months , secondary outcome included DAS-28 , physician 's global evaluation of disease activity , RAQoL , SF-12 and concomitant pain medication . RESULTS In a total of 89 patients ( 90 % female , mean age 56.6 + 11.3 years , mean disease duration 12.8 + 9.6 years ) HAQ-DI in the rose-hip group improved by 0.105+/-0.346 , whereas in the placebo group it worsened by 0.039+/-0.253 ( p adjusted=0.032 ) . In the HAQ Patient Pain Scale no significant differences were observed between both groups . In the HAQ Patient Global Scale a trend was seen favouring rose-hip ( p=0.078 ) . The DAS-28 score yielded improvement in the rose-hip group of 0.89+/-1.32 and in the placebo group of 0.34+/-1.27 ( p=0.056 ) indicating moderate clinical relevance . The Physicians Global Scale demonstrated more improvement in the rose-hip compared to the placebo group ( p=0.012 ) . RAQoL and SF-12 physical score improved significantly in the rose-hip group compared to placebo , whereas SF-12 mental score remained unchanged . Intake of pain medication was not different between the groups . Per- protocol analysis confirmed these results . CONCLUSION The results indicate that patients with RA may benefit from additional treatment with rose hip powder PURPOSE To determine if rofecoxib 50 mg administered 1 hour preoperatively to patients undergoing arthroscopic knee surgery reduces postoperative pain , provides a narcotic-sparing effect , and reduces time spent in recovery . TYPE OF STUDY Prospect i ve , r and omized , double-blinded clinical trial . METHODS Fifty patients ( age range , 30 to 60 years ) undergoing knee arthroscopy under spinal anesthesia were r and omized to receive either 50 mg of rofecoxib or placebo 1 hour preoperatively . Postoperatively , pain was assessed in recovery , 8 hours postoperatively , and 24 hours postoperatively , using a 100-mm visual analog scale . Pain medication usage was monitored for 24 hours and time in recovery room was determined . Mann-Whitney tests determined significance between groups . RESULTS Patients in the rofecoxib group showed significantly lower pain scores at 8 and 24 hours postoperatively . They also showed a significant reduction in postoperative narcotic consumption . CONCLUSIONS Rofecoxib 50 mg as a single preoperative dose should be considered as part of a perioperative analgesic plan in arthroscopic knee surgery . LEVEL OF EVIDENCE Level I , Therapeutic Study ( r and omized controlled trial ) This double-blind , r and omized controlled study was conducted with the aim to investigate the effect of magnetic field therapy applied to the hip region on clinical and functional status in ankylosing spondylitis ( AS ) patients . Patients with AS ( n = 66 ) who were diagnosed according to modified New York criteria were enrolled in this study . Patients were r and omly divided in two groups . Participants were r and omly assigned to receive magnetic field therapy ( 2 Hz ) ( n = 35 ) , or placebo magnetic field therapy ( n = 31 ) each hip region for 20 min . Patients in each group were given heat pack and short-wave treatments applied to bilateral hip regions . Both groups had articular range of motion and stretching exercises and strengthening exercises for surrounding muscles for the hip region as well as breathing and postural exercises by the same physical therapist . These treatment protocol s were continued for a total of 15 sessions ( 1 session per day ) , and patients were examined by the same physician at months 1 , 3 and 6 . Visual analogue scale ( VAS ) pain , VAS fatigue , Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , Bath Ankylosing Spondylitis Functional Index ( BASFI ) , Bath Ankylosing Spondylitis Metrologic Index ( BASMI ) , DFI , Harris hip assessment index and Ankylosing Spondylitis Quality of Life scale ( ASQOL ) were obtained at the beginning of therapy and at month 1 , month 3 and month 6 for each patient . There were no significant differences between groups in the VAS pain , VAS fatigue , morning stiffness , BASDAI , BASFI , BASMI , DFI , Harris hip assessment index and ASQoL at baseline , month 1 , month 3 or month 6 ( p > 0.05 ) . Further r and omized , double-blind controlled studies are needed in order to establish the evidence level for the efficacy of modalities with known analgesic and anti-inflammatory action such as magnetotherapy , particularly in rheumatic disorders associated with chronic pain OBJECTIVE To perform a r and omized , double-blind , crossover clinical trial of diclofenac + misoprostol versus acetaminophen in ambulatory patients with osteoarthritis of the hip or knee . METHODS Patients in 12 ambulatory care setting s were eligible if they were age > 40 years and if they had Kellgren/Lawrence radiographic grade 2 - 4 osteoarthritis of the knee or hip and a score of > or = 30 mm on a 100-mm visual analog pain scale . Patients were r and omized to one of two groups , 75 mg diclofenac + 200 microg misoprostol twice daily or 1,000 mg acetaminophen 4 times daily ( each for 6 weeks ) , and were then crossed over to the other treatment for 6 weeks . A placebo was included in each treatment regimen to enable double blinding . The primary outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index and the visual analog pain scale of the Multidimensional Health Assessment Question naire . Safety was assessed using a st and ard form to review adverse events . RESULTS We enrolled 227 patients , of whom 218 provided data for the first treatment period and 181 provided data for both treatment periods . Significantly higher levels of improvement in the primary outcomes were seen for diclofenac + misoprostol than for acetaminophen ( P < 0.001 ) . Adverse events were more common when patients took diclofenac + misoprostol ( P = 0.046 ) . Diclofenac + misoprostol was rated as " better " or " much better " by 57 % of the 174 patients who provided such ratings for both treatment periods , while acetaminophen was rated as " better " or " much better " by 20 % of these patients , and 22 % reported no difference ( P < 0.001 ) . Differences favoring diclofenac + misoprostol over acetaminophen were greater in patients with more severe osteoarthritis according to baseline pain scores , radiographs , or number of involved joints . CONCLUSION Patients with osteoarthritis of the hip or knee had significantly greater improvements in pain scores over 6 weeks with diclofenac + misoprostol than with acetaminophen , although patients with mild osteoarthritis had similar improvements with both drugs . Acetaminophen was associated with fewer adverse events OBJECTIVE To assess the efficacy and safety of avocado/soybean unsaponifiables ( ASU ) in the treatment of patients with symptomatic osteoarthritis ( OA ) of the knee or hip , as well as the potential residual effects of ASU after stopping treatment , to determine whether ASU might be a symptomatic slow-acting drug for the treatment of OA . METHODS One hundred sixty-four patients with regular , painful , primary OA of the knee ( n = 114 ) or hip ( n = 50 ) entered a prospect i ve , r and omized , double-blind , placebo-controlled , parallel-group , multicenter trial with a 6-month treatment period and a 2-month posttreatment followup . A 15-day washout period for nonsteroidal antiinflammatory drugs ( NSAIDs ) preceded the study . Efficacy was judged according to 1 ) Lequesne 's functional index ( LFI ) and 2 ) pain on Huskisson 's visual analog scale ( VAS ; 100-mm scale ) , intake of NSAIDs/analgesics , and overall disability score ( by 100-mm VAS ) . RESULTS Eighty-five patients received ASU ; 79 received placebo . One hundred forty-four patients were evaluable at month 6 ( 75 taking ASU ; 69 taking placebo ) . The mean + /- SEM LFI score decreased from 9.7 + /- 0.3 to 6.8 + /- 0.4 in the ASU group and from 9.4 + /- 0.3 to 8.9 + /- 0.4 in the placebo group ( P < 0.001 for intergroup difference at month 6 ) . Pain decreased from 56.1 + /- 1.6 mm to 35.3 + /- 2.3 in the ASU group and from 56.1 + /- 1.8 mm to 45.7 + /- 2.6 in the placebo group ( P = 0.003 at month 6 ) . NSAID consumption was slightly lower in the ASU group . Fewer patients in the ASU group required NSAIDs ( 48 % , versus 63 % in the placebo group ; P = 0.054 ) . The success rate was 39 % in the ASU group and 18 % in the placebo group . Overall functional disability was significantly reduced in the ASU group . Improvement appeared more marked in patients with hip OA . A residual effect was observed at month 8 . Tolerance was good to excellent for most patients . CONCLUSION ASU treatment showed significant symptomatic efficacy over placebo in the treatment of OA , acting from month 2 and showing a persistent effect after the end of treatment Abstract Objective : To demonstrate that a fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg has comparable efficacy to celecoxib for knee osteoarthritis . Research design and methods : Two r and omized , double-blind , parallel-group , placebo-controlled , multicenter phase III studies ( PN400 - 307 and PN400 - 309 ) enrolled patients aged ≥50 years with symptomatic knee osteoarthritis . Following an osteoarthritis flare , patients received naproxen/esomeprazole magnesium twice daily , celecoxib 200 mg once daily , or placebo for 12 weeks . Clinical trial registration : NCT00664560 and NCT00665431 . Main outcome measures : Three co- primary efficacy endpoints were mean change from baseline to week 12 in Western Ontario and McMaster Osteoarthritis Index ( WOMAC ) pain and function subscales , and Patient Global Assessment of osteoarthritis using a visual analog scale ( PGA-VAS ) . Results : In Study 307 , 619 patients were r and omized and 614 treated . In Study 309 , 615 patients were r and omized and 610 treated . Both naproxen/esomeprazole magnesium and celecoxib were associated with improvements ( least squares mean change from baseline to week 12 ) in WOMAC pain ( Study 307 : −42.0 and −41.8 , respectively ; Study 309 : −44.2 and −42.9 , respectively ) , WOMAC function ( Study 307 : −36.4 and −36.3 , respectively ; Study 309 : −38.9 and −36.8 , respectively ) , and PGA-VAS ( Study 307 : 21.2 and 21.6 , respectively ; Study 309 : 29.0 and 25.6 , respectively ) . A prespecified non-inferiority margin of 10 mm between naproxen/esomeprazole magnesium and celecoxib was satisfied for each co- primary endpoint at week 12 in both studies . Significant improvements were observed with naproxen/esomeprazole magnesium versus placebo in both studies ( p < 0.05 ) . Celecoxib was significantly different from placebo in Study 307 ( p < 0.05 ) ; however , the improvements were not significant in Study 309 . Acetaminophen use and patient expectation of receiving active treatment ( 80 % probability ) may have contributed to a high placebo response observed . Conclusions : Naproxen/esomeprazole magnesium has comparable efficacy to celecoxib for the management of pain associated with osteoarthritis of the knee over 12 weeks OBJECTIVE To evaluate the association between pain intensity improvement and improvements in functionality and health status in patients with chronic osteoarthritis pain of the hip or knee . METHODS Data were obtained from a 12-week , r and omized , double-blind , placebo-controlled study of tramadol ER 100 mg , 200 mg , 300 mg , or 400 mg once daily . Patients reported pain intensity with a 100-mm visual analog scale ( 0 = no pain , 100 = extreme pain ) and functionality and health status with the disease-specific Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) question naire and the generic Short-Form-36 Health Survey ( SF-36 ) . Pain intensity improvement from baseline was categorized as < 0 % , 0 - 14 % , 15 - 29 % , 30 - 49 % , 50 - 69 % , and > or= 70 % , and mean changes in WOMAC and SF-36 scores were determined for patients in each category . RESULTS A total of 1011 patients received placebo ( n = 205 ) or tramadol ER 100 mg ( n = 202 ) , 200 mg ( n = 201 ) , 300 mg ( n = 201 ) , or 400 mg ( n = 202 ) . The degree of pain intensity improvement was correlated with the degree of improvement in WOMAC and SF-36 scores ; as little as 15 % reduction of pain intensity was associated with notable improvements in function and health status . Potential limitations included the lack of established thresholds to assess clinical ly meaningful changes in these outcomes . CONCLUSIONS Pain intensity improvement is associated with corresponding improvements in function and health status . While large improvements in pain intensity are associated with large improvements in health status and functionality , modest pain reductions are also associated with improvement of certain health status parameters The main goal of our study was to examine the effectiveness and safety of Fermathron plus , a specific br and of hyaluronic acid ( HA ) , in patients with mild to moderate knee osteoarthritis . In a r and omized , controlled , double-blind trial , 196 patients with symptomatic knee osteoarthritis ( mean age ± SD , 59.4 ± 9.9 years , Kellgren-Lawrence grade 1 - 3 ) were given either 3 weekly intra-articular injections of HA or saline ( placebo ) . Although pain and functional scores ( WOMAC scale ) improved significantly from baseline up to 6 months , HA was not superior to placebo at any follow-up ( VAS pain 50 m walking from 56.4 to 38.1 , P < .001 , and 58.2 to 39.6 , P < .001 , respectively ) . No subgroup analysis result ed in superior outcomes . No serious adverse events were noticed Objective : This 6-week , r and omized , double-blind , parallel-group study compared the analgesic efficacy , tolerability and safety of celecoxib , naproxen and placebo in African Americans with osteoarthritis ( OA ) of the knee . Methods : A total of 322 patients aged ≥ 45 years with OA of the knee in a flare state received 200 mg celecoxib orally once daily , 500 mg naproxen orally twice daily or placebo for 6 weeks . The primary endpoint was change from baseline in the Patient 's Assessment of Arthritis Pain . Results : Celecoxib was as effective as naproxen in reducing OA pain . Similar efficacy was observed in many of the secondary outcome measures . Celecoxib was well tolerated and demonstrated favorable upper gastro-intestinal tolerability . Improvements in outcome measures were numerically greater in the active treatment groups compared with the placebo group , but did not reach statistical significance . Conclusions : Celecoxib was as effective as naproxen in relieving OA pain in African Americans and was well tolerated . Few significant differences were observed between active treatments and placebo , possibly because of a strong placebo effect OBJECTIVE To examine the effects of extended release tramadol ( tramadol ER ) on reducing pain-related sleep disturbances ( PRSDs ) in patients ( 20 - 80 years ) with moderate to moderately severe pain with radiographically confirmed osteoarthritis ( OA ) of the knee or hip . METHODS A post hoc analysis of two 12-week , double-blind , placebo-controlled , r and omized , parallel-group studies was conducted . In Study A , patients ( n = 1,020 ) received tramadol ER 100 , 200 , 300 , or 400 mg , or placebo . In Study B ( n = 1,011 ) , patients received tramadol ER 100 , 200 , or 300 mg , or placebo . MAIN OUTCOME MEASURES PRSDs were evaluated using the Chronic Pain Sleep Inventory ( CPSI ) based on a 100-mm visual analog scale ( VAS ; 0 = very poor , 100 = excellent for the overall quality of sleep ) . RESULTS Significant improvements in CPSI scores from baseline were seen as early as week 1 in all tramadol ER groups and were maintained through the final visit for overall sleep quality compared with placebo ( all p < or = 0.022 ) . Compared with placebo , significant improvements in scores from baseline were seen beginning at week 1 for tramadol ER 200 and 300 mg and week 3 for tramadol ER 100 mg , and were maintained in all dose groups through the final visit , for being awakened by pain in the night and in the morning , and less trouble falling asleep due to pain ( all p < or = 0.046 ) . CONCLUSION In this post hoc analysis , a reduction in pain was associated with a significant reduction in PRSDs due to OA OBJECTIVE The aim of this study was to estimate the prevalence of frequent knee pain in radiographic , symptomatic and clinical ly defined knee OA in middle-aged and elderly patients and the proportion that seeks medical care . METHODS In 2007 a r and om sample of 10 000 56- to 84-year-old residents of Malmö , Sweden , were question ed about knee pain . We classified subjects reporting knee pain with a duration of at least 4 weeks as having frequent knee pain . A r and om sample of 1300 individuals with frequent knee pain and 650 without were invited for assessment by the ACR clinical knee OA criteria and for bilateral weight-bearing knee radiography . We considered a Kellgren-Lawrence grade ≥2 as radiographic knee OA and that in combination with frequent knee pain as symptomatic knee OA . By linkage with the Skåne Healthcare Register , we determined the proportion of subjects that had consulted for knee OA or pain . RESULTS The 10 000 subjects had a mean age of 70 years ( s.d . 7.6 ) , a mean BMI of 27.1 kg/m(2 ) and 62 % were women . The prevalence of frequent knee pain was 25.1 % ( 95 % CI 24.1 , 26.1 ) , higher in women and similar across age groups . The prevalence of radiographic knee OA was 25.4 % while 15.4 % had either symptomatic or clinical ly defined knee OA . Of these , 68.9 % consulted a physician for knee OA or pain during 2004 - 11 . CONCLUSION Fifteen per cent of middle-aged or elderly individuals have knee OA and symptoms . About one in three of those do not consult a physician . Inefficient care of OA and self-coping may be an explanation STUDY DESIGN R and omized , double-blind , placebo-controlled study . OBJECTIVES To examine the short-term therapeutic effects of monochromatic infrared energy ( MIRE ) on participants with knee osteoarthritis ( OA ) . Patients were assessed according to the International Classification of Functioning , Disability and Health . BACKGROUND MIRE is commonly used in therapy for patients with peripheral neuropathies . However , research has not focused intensively on the therapeutic effects of MIRE in patients with knee OA . METHODS This study enrolled 73 participants with knee OA . Participants received six 40-minute sessions of active or placebo MIRE treatment ( 890-nm wavelength ; power , 6.24 W ; energy density , 2.08 J/cm2/min ; total energy , 83.2 J/cm2 ) over the knee joints for 2 weeks . International Classification of Functioning , Disability and Health-related outcomes were collected weekly over 4 weeks using the Knee injury and Osteoarthritis Outcome Score , Lysholm Knee Scale , Hospital Anxiety and Depression Scale , Multidimensional Fatigue Inventory , Chronic Pain Grade question naire , World Health Organization Quality of Life-brief version , and OA Quality of Life Question naire . Data were analyzed by repeated- measures analysis of variance . RESULTS No statistically significant differences were found for the interaction of group by time for Knee injury and Osteoarthritis Outcome Score scores , including pain , other symptoms , function in daily living , function in sport and recreation , and knee-related quality of life . Scores on the Lysholm Knee Scale , Hospital Anxiety and Depression Scale , Multidimensional Fatigue Inventory , Chronic Pain Grade question naire , World Health Organization Quality of Life-brief version , and OA Quality of Life Question naire also showed no significant differences between the 2 groups at any of the 4 follow-up assessment s. CONCLUSION Short-term MIRE therapy provided no beneficial effects to body functions , activities , participation , and quality of life in patients with knee OA OBJECTIVE To compare the effects of intraarticular ( IA ) injections of glycosaminoglycan polysulfate ( GAGPS ) plus basic conservative treatment with the effects of placebo injections plus conservative treatment and with the effects of conservative treatment alone in patients with chronic patellofemoral pain syndrome ( PFPS ) . METHODS We treated 53 patients who presented with chronic PFPS in 1 knee , according to 1 of the 3 protocol s , in a prospect i ve , r and omized , double-blind study . Basic conservative treatment consisted of a 6-week program of quadriceps muscle exercise , elimination of symptom-producing activities , and oral doses of nonsteroidal antiinflammatory drugs . Physiologic saline served as placebo for injection . During the 6-week treatment period , 5 injections were given 1 week apart . Along with measurements of quadriceps strength , st and ardized subjective , functional , and clinical assessment s were performed at presentation , after 6 weeks of treatment , and after 6 months . RESULTS Results at 6 months indicated that IA injections of GAGPS or saline did not result in significant improvement beyond the good results achieved by the basic conservative treatment alone . More than two-thirds of the patients in each group experienced complete recovery . CONCLUSION Neither the GAGPS injections nor the physiologic saline injections are more effective than conservative therapy in the treatment of chronic PFPS . Restoration of normal quadriceps muscle function to the affected knee seems to be crucial in treating PFPS INTRODUCTION Incubation of blood with CrSO(4)-coated glass beads stimulates the synthesis of anti-inflammatory cytokines , such as interleukin-1 receptor antagonist ( IL-1ra ) , IL-4 , IL-10 , and IL-13 . As IL-1beta is thought to play a key role in the development of osteoarthritis ( OA ) , this product , also known as Orthokin , might be a viable treatment for symptomatic knee OA . The aim of the current study was to evaluate the efficacy of Orthokin for treatment of symptomatic knee OA in a r and omized , multicentre , double-blind , placebo-controlled trial . PATIENTS AND METHODS One hundred and sixty-seven patients received six intra-articular injections either with Orthokin or physiological saline . The primary efficacy objective consisted of 30 % superiority on the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) at 3 , 6 , 9 , and 12 months post-treatment . Additionally , the patients completed the visual analogue scale for pain , the Knee injury and Osteoarthritis Outcome Score ( KOOS ) and Knee Society Clinical Rating System . RESULTS Orthokin and placebo treatment result ed in similar improvements on the WOMAC ( 16.8 % vs 16.5 % , respectively ; n.s . ) . Orthokin result ed in significantly more improvement for KOOS symptom ( P = 0.002 ) and KOOS sport ( P = 0.042 ) parameters as compared to placebo treatment . For most other outcome parameters , Orthokin-treated patients consistently showed higher improvement compared to placebo-treated patients , although none of these differences were statistically significant . Two serious adverse events were observed in the Orthokin group : one patient with repeated severe inflammatory reactions of the knee joint within hours after the injection and one patient with septic arthritis which was attributed to the injection procedure rather than the product . CONCLUSION The statistically significant improvement of KOOS symptom and sport parameters together with the consistently higher , though non-statistically significant , improvement of most other parameters demonstrates that Orthokin clearly induces a biological response different from placebo treatment and warrant future investigations into the possible chondroprotective effect of Orthokin . However , in the current study the primary efficacy objective was not met and , therefore , the use of Orthokin currently can not yet be recommended for the treatment of OA Background Osteoarthritis ( OA ) is common and disabling among older patients around the world . Data exploring the prevalence and risk factors of OA are of paramount importance in establishing healthcare policies . However , few studies have evaluated these topics among Asian population s. Questions / purpose sThis study was conducted to determine the prevalence and risk factors of radiographic OA in the spine , shoulder , h and , hip , and knee in Koreans older than age 65 years . Methods A simple r and om sample ( N = 1118 ) was drawn from a roster of elderly individuals older than age 65 years in Seongnam . Of the 1118 invited subjects , 696 ( males = 298 , females = 398 ) participated in this study ( a response rate of 62 % ) . The mean age of respondents was 72 ± 5 years ( range , 65–91 years ) . Radiographs of the lumbar spine , shoulder , h and , hip , and knee were taken and afterward evaluated for radiographic OA . The Kellgren-Lawrence grading system was used for all mentioned joints , and radiographic OA was defined as Grade 2 changes or higher . The association of sex , aging , and obesity with OA in each of the mentioned joints was determined with the help of multivariate logistic regression . Results The highest prevalence of radiographic OA was seen in the spine ( number of subjects with OA/number of whole population = 462 of 696 [ 66 % ] ) followed by the h and ( 415 of 692 [ 60 % ] ) , knee ( 265 of 696 [ 38 % ] ) , shoulder ( 36 of 696 [ 5 % ] ) , and hip ( 15 of 686 [ 2 % ] ) . Female sex was associated with knee OA ( odds ratio [ OR ] , 5.7 ; 95 % confidence interval [ CI ] , 3.9–8.4 ; p < 0.001 ) and h and OA ( OR , 2.3 ; 95 % CI , 1.6–3.1 ; p < 0.001 ) , and male sex was associated with spine OA ( OR , 0.7 ; 95 % CI , 0.5–1.0 ; p = 0.025 ) . Aging was associated with radiographic OA in the spine , knee , and h and ( OR per 5-year increments , 1.3 [ 95 % CI , 1.1–1.6 ; p = 0.001 ] , 1.6 [ 95 % CI , 1.4–1.9 ; p < 0.001 ] , and 1.4 [ 95 % CI , 1.2–1.7 ; p < 0.001 ] ) , respectively ) but not associated with OA in the hip and shoulder . Obesity was associated with knee OA ( OR , 3.4 ; 95 % CI , 2.4–5.0 ; p < 0.001 ) and spine OA ( OR , 1.5 ; 95 % CI , 1.1–2.2 ; p = 0.014 ) but not with OA in other joints . Conclusions OA of the spine , h and , and knee is likely to become a major public health problem rather than shoulder and hip OA in Korea . Associations of demographic factors with radiographic OA differed among each joint , and that would be valuable information to assess the role and influence of risk factors of OA in various joints . Level of Evidence Level III , prognostic study Alternative and complementary therapeutic approaches , such as the use of a wide array of herbal , nutritional , and physical manipulations , are becoming popular for relieving symptoms of osteoarthritis ( OA ) . The present study evaluated the efficacy of soy protein ( SP ) supplementation in relieving the pain and discomfort associated with OA . One hundred and thirty-five free-living individuals ( 64 men and 71 women ) with diagnosed OA or with self-reported chronic knee joint pain not attributed to injury or rheumatoid arthritis were recruited for this double-blind , placebo-controlled , parallel design study . Study participants were assigned r and omly to consume 40 g of either supplemental SP or milk-based protein ( MP ) daily for 3 months . Pain , knee range of motion , and overall physical activity were evaluated prior to the start of treatment and monthly thereafter . Serum levels of glycoprotein 39 ( YKL-40 ) , a marker of cartilage degradation , and insulin-like growth factor-I ( IGF-I ) , a growth factor associated with cartilage synthesis , were assessed at baseline and at the end of the study . Overall , SP improved OA-associated symptoms such as range of motion and several factors associated with pain and quality of life in comparison to MP . However , these beneficial effects were mainly due to the effect of SP in men rather than women . Biochemical markers of cartilage metabolism further support the efficacy of SP in men as indicated by a significant increase in serum level of IGF-I and a significant decrease in serum level of YKL-40 compared to MP . This study is the first to provide evidence of possible beneficial effects of SP in the management of OA . Examining and verifying the long-term effects of SP on improving symptoms of OA , particularly in men , is warranted Osteoarthritis ( OA ) is a significant source of pain and disability . Current medical and surgical treatments can be costly and have serious side effects . The aim of this r and omized , double-blind , placebo-controlled trial was to investigate the tolerability and efficacy of BioCell Collagen ( BCC ) , a low molecular weight dietary supplement consisting of hydrolyzed chicken sternal cartilage extract , in the treatment of OA symptoms . Patients ( n = 80 ) in the study had physician-verified evidence of progressive OA in their hip and /or knee joint . Joint pain had been present for 3 months or longer at enrollment , and pain levels were 4 or higher at baseline as assessed by Physician Global Assessment scores . Subjects were divided into two groups and administered either 2 g of BCC or placebo for 70 days . Other outcome measurements included visual analogue scale ( VAS ) for pain and Western Ontario and McMaster Universities Arthritis Index ( WOMAC ) scores taken on days 1 , 35 , and 70 . The tolerability profile of the treatment group was comparable to that of the placebo . Intent-to-treat analysis showed that the treatment group , as compared to placebo , had a significant reduction of VAS pain on day 70 ( p < 0.001 ) and of WOMAC scores on both days 35 ( p = 0.017 ) and 70 ( p < 0.001 ) . The BCC group experienced a significant improvement in physical activities compared to the placebo group on days 35 ( p = 0.007 ) and 70 ( p < 0.001 ) . BCC was well tolerated and found to be effective in managing OA-associated symptoms over the study period , thereby improving patient 's activities of daily living . BCC can be considered a potential complement to current OA therapies OBJECTIVE To determine whether glucosamine sulfate has an effect on cartilage type II collagen degradation in patients with knee osteoarthritis ( OA ) . METHODS A r and omized , double blind , placebo controlled glucosamine discontinuation trial was conducted in 137 subjects with knee OA , who had had at least moderate relief of knee pain after starting glucosamine . Subjects were r and omized to glucosamine at pre study dose or placebo at an equivalent dose . Treatment was continued to Week 24 or disease flare , whichever occurred first . Serum and urine sample s were collected at Weeks 0 , 4 , 12 , and 24 or flare visit . Sample s were analyzed in triplicate for 2 type II collagen degradation biomarkers : C2C epitope ( COL2 - 3/4C(long ) ) and C1,2C epitope ( COL2 - 3/4C(short ) ) . The primary outcome was the mean change in serum and urine C1,2C/C2C ratio in the glucosamine and placebo groups from baseline to final ( flare or Week 24 ) visit . Linear regression analyses were conducted to adjust for potential confounders . Due to non-normal distributions , the data were log-transformed ( lnC1,2C/C2C ) . Secondary outcomes included comparison of mean change scores at final visit compared to baseline for serum and urine C1,2C and C2C in the 2 treatment groups and in Flare versus No-Flare groups . RESULTS Baseline and final visit sample s were available in 130 subjects for serum analysis and 126 subjects for urinalysis . No significant difference was seen between placebo and glucosamine groups in the serum C1,2C/C2C ratio , with a mean ( SD ) change from baseline to final visit of 0.8 ( 27.8 ) and -0.1 ( 1.8 ) , respectively ( mean difference 0.9 ; 95 % CI -6.0 , 7.7 , p = 0.80 ) . Similarly , no differences between treatment groups were seen for mean change in urine C1,2C/C2C ( p = 0.82 ) , or for mean change in C2C or C1,2C . In linear regression analysis , after adjustment for sex , radiographic severity , baseline lnC1,2C/C2C ratio , WOMAC function , and flare status , treatment was not a significant predictor of final serum or urine lnC1,2C/C2C ratio . When those who experienced flare were contrasted with those without flare , there was a nonsignificant trend toward a difference in mean baseline to final visit change score for serum C1,2C/C2C ratio ( p = 0.12 ) . In addition , in the multivariable linear regression analysis , flare status showed a borderline association with final visit serum lnC1,2C/C2C ratio ( p = 0.16 ) . CONCLUSION No statistically significant effect of glucosamine sulfate on type II collagen fragment levels in serum or urine was observed for knee OA over 6 months . Further research is necessary to eluci date which biopathologic systems , if any , are affected by glucosamine treatment . While collagen degradation products may be of value in predicting progression , at least as defined by clinical flare , a larger data set would be needed to prove this OBJECTIVE To identify changes in joint pain , stiffness , and functional ability in patients with knee osteoarthritis ( OA ) after use of a knee sleeve that prevents loss of body heat by the joint . METHODS Subjects with symptomatic knee OA ( n = 52 ) were r and omized to 2 treatment groups : verum sleeve ( specially fabricated to retain body heat ) or placebo sleeve ( st and ard cotton/elastane sleeve ) . Subjects wore the sleeve over the more painful OA knee for at least 12 hours daily for 4 weeks . Pain , stiffness , and functional impairment ( Western Ontario and McMaster Universities Osteoarthritis Index [ WOMAC ] ) in the index knee were measured at baseline and after 4 weeks of wear , after which sleeve use was discontinued . Telephone followup interviews were conducted 2 and 4 weeks later . RESULTS After 4 weeks of sleeve wear , subjects in the active treatment group reported a 16 % decrease in mean WOMAC pain score relative to baseline ( P = 0.001 ) . Those who wore the placebo sleeve reported a 9.7 % decrease from baseline ( P = 0.002 ) . The difference between treatment groups was not statistically significant ( P = 0.12 ) . However , it was found that the 12 subjects who believed correctly that they had received the verum sleeve reported a highly significant decrease in WOMAC pain score ( -27.5 % relative to baseline , P = 0.0001 ) . In comparison , subjects who received the verum sleeve but believed they had received the placebo sleeve exhibited only a marginally significant improvement in pain ( -13.0 % relative to baseline , P = 0.07 ) . In the placebo group , the modest improvement in pain scores appeared unrelated to the subject 's impression of the type of sleeve worn . CONCLUSION This pilot study was insufficiently powered to be a definitive trial of the heat-retaining sleeve . Given the magnitude of changes in knee pain in the active treatment group , heat retention merits further scientific investigation as a treatment modality for patients with knee OA Objective Our study was design ed to determine if transcutaneous-pulsed radiofrequency treatment ( TCPRFT ) was able to reduce the pain experienced by patients awaiting total knee joint replacement ( TKJR ) . We conducted a r and omized , double-blinded , placebo controlled trial of TCPRFT in patients referred for TKJR to our hospital 's Orthopedic Outpatient Clinic . Methods Patients on the waiting list for assessment for TKJR were invited to participate and were examined in the clinic if they satisfied the inclusion criteria . Patients were r and omized to receive active or sham TCPRFT . The alteration in pain and function of the treated knee after a single TCPRFT was assessed at examination at 1 and 4 weeks using visual analog pain score ( VAS ) at rest and after 20 and 400 m walks . Results The results of 50 patients showed a statistically significant reduction in VAS at 1 and 4 weeks compared with baseline in the group who received active treatment . We also demonstrated what is considered a clinical ly significant improvement in this group that became more pronounced at week 4 compared with week 1 and also more after a 400 m walk compared with a 20 m walk . Maximum improvement observed in group data was 19/100 VAS . Patients receiving sham treatment showed no statistically significant improvement . Discussion We believe this to be the first report of a controlled study of TCPRFT . This pilot study shows a benefit of the technique that justifies future research In this placebo-controlled double-blind trial in 30 patients suffering from disabling osteoarthritis of the h and , the long-term effect of periarticular injections of glycosaminoglycan polysulphate ( GAGPS ) on symptoms , h and function and life quality was investigated . The overall effect of the half-year follow-up was clinical ly good in 46 % of the GAGPS-treated cases , compared with 14 % of the controls . Significant differences in grip- and pinch strength were also found between the treatment groups . Significant differences were still seen at the one-year follow-up , as 13 patients ( 87 % ) in the GAGPS group reported improvement in their most restricted activity , compared with 6 ( 43 % ) of the controls . Nine periarticular injections of GAGPS over a period of 13 weeks gave a clinical ly good and long-lasting effect , with improved life quality for most of the patients Abstract Objective : To determine the efficacy , tolerability , and safety of duloxetine when added to oral nonsteroidal anti-inflammatory drugs ( NSAIDs ) in patients with osteoarthritis ( OA ) of the knee with pain of moderate or greater severity . Research design and methods : This was a 10-week r and omized , double-blind , flexible-dose ( duloxetine 60/120 mg/day ) , placebo-controlled trial that enrolled adult out patients who had persistent moderate pain ( ≥4 on a 0–10 numerical rating scale ) due to OA of the knee , despite , per protocol , having received optimized oral NSAID therapy ( specific drug , dose , and frequency at investigator discretion ) . Clinical trials registration : Trial registration : Clinical Trials.gov identifier : NCT01018680 . Main outcome measure : Patients entered daily pain ratings in a telephone-based diary . The primary efficacy outcome was the weekly mean of the daily average pain rating at week 8 . Safety outcomes were assessed during the entire 10-week study . Results : A total of 524 patients r and omly received duloxetine 60/120 mg/day ( N = 264 ) or placebo ( N = 260 ) . In total , 74 % of the patients completed the study . Mean age was 61 years ( SD 9.2 ) , 57 % were female , and 81 % were white . Duloxetine-treated patients had significantly greater pain reduction at week 8 ( p < 0.001 ) than placebo-treated patients . In addition , relative to placebo at week 8 , duloxetine-treated patients had significant improvements in physical function as measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( p < 0.001 ) , and Patient Global Impression of Improvement ( p < 0.001 ) . Compared to placebo , significantly more nausea , dry mouth , constipation , fatigue and decreased appetite were reported by patients taking duloxetine ( each p < 0.05 ) . Discontinuation due to adverse events occurred more commonly in the duloxetine group than the placebo group ( p = 0.03 ) . Conclusion : Duloxetine added to oral NSAID therapy provided additional significant pain reduction , improved function , and patient-rated impression of improvement . Adverse events were consistent with those seen in previous duloxetine trials . The short duration of the study may not reflect the longer term efficacy and safety of NSAID/duloxetine cotherapy Nonprescription doses of naproxen sodium , acetaminophen , and placebo were compared to determine their efficacy and safety in osteoarthritis of the knee . In two identical multicenter , r and omized , double-blind , placebo-controlled , multidose , parallel- design studies , patients with osteoarthritis aged ( mean ± SD ) 60.6 ± 12.8 years were r and omized to daily doses of 660 mg naproxen sodium ( 440 mg naproxen sodium in patients ≥65 years ) , 4000 mg acetaminophen , or placebo for 7 days . Naproxen sodium ( 440/660 mg ) provided significantly greater improvements in pain at rest , on passive motion , on weight-bearing , stiffness after rest ( morning ) , day and night pain compared with placebo , and significantly greater relief from resting pain than acetaminophen ( P < 0.05 ) . Acetaminophen provided significantly greater improvements in day pain compared with placebo . Daily evaluations showed naproxen sodium ( 440/660 mg ) provided superior pain relief to acetaminophen and was significantly better than acetaminophen at reducing difficulties experienced in walking several blocks and difficulties in bending , lifting , and stooping . Naproxen sodium ( 440/660 mg ) and acetaminophen ( 4000 mg ) were significantly more effective than placebo in improving mobility level , household tasks , and walking and bending . Patient and investigator evaluation scores were significantly higher in naproxen sodium and acetaminophen groups compared with placebo ; no differences were observed between active treatments . Naproxen sodium and acetaminophen had similar safety profiles to placebo . Nonprescription doses of naproxen sodium ( 440/660 mg ) effectively relieve pain and other symptoms of osteoarthritis . Naproxen sodium is an alternative in the initial treatment of osteoarthritis and may be preferred to acetaminophen as first-line therapy in patients with moderate or severe pain STUDY OBJECTIVE To evaluate the functional status of patients with signs and symptoms of osteoarthritis of the knee after treatment with celecoxib compared with placebo and naproxen . DESIGN Prospect i ve , r and omized , double-blind , parallel-group , 12-week trial . SETTING Multicenter study conducted at 71 sites in the United States and Canada . PATIENTS One thous and four patients with active osteoarthritis of the knee in a flare state . INTERVENTIONS Patients were assigned r and omly to one of five treatment groups : placebo ; celecoxib 50 mg twice/day , 100 mg twice/day , and 200 mg twice/day ; and naproxen 500 mg twice/day . MEASUREMENTS AND MAIN RESULTS The Western Ontario and McMaster Universities Osteoarthritis Index was used to measure functional status . At the end of the treatment period , patients in the four active treatment groups had significantly better functional status than those receiving placebo . Patients treated with celecoxib 100 mg twice/day had significantly better improvements in pain scores than those treated with placebo and naproxen . CONCLUSION Celecoxib was better than placebo and comparable with naproxen in improving aspects of functional status in patients with osteoarthritis OBJECTIVE To investigate the effects of short-term light therapy with 890-nm radiation on pain , physical activity , and postural stability in patients with knee osteoarthritis ( OA ) . DESIGN A double-blind , r and omized , placebo-controlled study . SETTING Rehabilitation clinic . PARTICIPANTS Women ( n=62 ) and men ( n=10 ) with a mean age of 61.2 years ( range , 40 - 88y ) . All patients fulfilled the combined clinical and radiographic criteria for knee OA as established by the American College of Rheumatology , and all had obtained a Kellgren-Lawrence score of 2 or more . INTERVENTIONS Participants received 6 sessions , lasting 40 minutes each , of active or placebo radiation treatment over the knee joints for 2 weeks ( wavelength , 890 nm ; radiant power output , 6.24W ; power density , 34.7mW/cm(2 ) for 40 minutes ; total energy , 41.6J/cm(2 ) per knee per session ) . MAIN OUTCOME MEASURES Participants were assessed weekly over 4 weeks using the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) for pain , stiffness , and physical function . Physical activity ( timed stair climbing , 10-m fast-speed walking , and chair-rising time ) and postural stability ( using the postural stability evaluation system ) were also assessed . The pain score on WOMAC was the primary outcome variable . Data were analyzed by repeated- measures analysis of covariance . RESULTS Compared with baseline , no significant improvement was observed between groups for pain ( P=.546 ) , stiffness ( P=.573 ) , or physical function ( P=.904 ) . No significant improvement was noted for physical activity including the 10-m fast-speed walking time ( P=.284 ) , stair-climbing time ( P=.202 ) , stair-descending time ( P=.468 ) , chair-rising time ( P=.499 ) , or postural stability ( P=.986 ) at the 4 follow-up assessment s. Follow-up assessment s were conducted after 1 week of treatment ( thus , after 3 treatments ) ; after 2 weeks of treatment ( thus , after 6 treatments ) ; and 1 and 2 weeks , respectively , after treatment was terminated . Although we found a significant time effect for the 10-m fast-speed walking time ( P<.001 ) in the 2 groups , and a significant group effect in the improvement of stair-climbing time in the treatment group ( P=.032 ) , the group × time interaction effects were not significant . CONCLUSIONS Short-term 890-nm radiation therapy for patients with knee OA provided no beneficial effect in improving pain , physical activity , and postural stability OBJECTIVE To evaluate the efficacy and safety of duloxetine in the treatment of chronic pain due to osteoarthritis of the knee . METHODS This was a 13-week , r and omized , double-blind , placebo-controlled trial in patients meeting American College of Rheumatology clinical and radiographic criteria for osteoarthritis of the knee . At baseline , patients were required to have a ≥ 4 weekly mean of the 24-hour average pain ratings . Patients were r and omized to either duloxetine 60 mg once daily ( QD ) or placebo . At week 7 , the duloxetine dosage was increased , in a blinded fashion , to 120-mg QD in patients reporting < 30 % pain reduction . The primary efficacy measure was Brief Pain Inventory ( BPI ) 24-hour average pain . Secondary efficacy measures included Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) ; Clinical Global Impressions of Severity ( CGI-S ) . Safety and tolerability was also assessed . RESULTS Of the total ( n = 256 ) patients , 111 ( 86.7 % ) in placebo group and 93 ( 72.7 % ) in duloxetine group completed the study . Patients treated with duloxetine had significantly ( P ≤ 0.001 ) greater improvement at all time points on BPI average pain and had significantly greater improvement on BPI pain severity ratings ( P ≤ 0.05 ) , WOMAC total ( P = 0.044 ) and physical functioning scores ( P = 0.016 ) , and CGI-S ( P = 0.009 ) at the study endpoint . Frequency of treatment-emergent nausea , constipation , and hyperhidrosis were significantly higher in the duloxetine group ( P ≤ 0.05 ) . Significantly more duloxetine-treated patients discontinued the trial because of adverse events ( P = 0.002 ) . CONCLUSIONS Treatment with duloxetine 60 mg to 120 mg QD was associated with significant pain reduction and improved function in patients with pain due to osteoarthritis of the knee Extracts from the seed of the African shea tree Vitellaria paradoxa C.F. Gaertn have been used traditionally for the treatment of arthritic conditions . However , little is known about the mechanisms by which benefit is conferred . This single-site , 15-week r and omized , double-blind , parallel , placebo-controlled study examined a range of biomarkers in 89 patients with osteoarthritis of the knees and /or hips to determine potential modes of action of SheaFlex70 , a triterpene-rich extract of Vitellaria paradoxa . In the group of participants with levels of osteoarthritis biomarkers in the upper quartile at baseline , there were significant decreases in inflammation and cartilage breakdown and trend level decreases in bone remodeling in the SheaFlex70 group versus placebo between commencement and completion of the study . Inflammation marker TNF-alpha fell 23.9 % vs 6 % ( treatment vs placebo ) , p = 0.041 . Cartilage degradation marker CTX-II fell 28.7 % vs an increase of 17.6 % ( treatment vs placebo ) , p = 0.018 . This marker also showed significant falls across the entire study group , 10.6 % vs an increase of 11.6 % , ( treatment vs placebo ) , p = 0.016 . Osteocalcin levels fell 9.2 % , p = 0.014 ( treatment ) vs 1.2 % , ns ( placebo ) , p = 0.096 ( treatment vs placebo ) . These findings indicate that in patients with the highest levels of osteoarthritis biomarkers , SheaFlex70 demonstrated multiple beneficial activities consistent with slowing the disease process

Toxicity consisted mainly of nausea and thrombotic events and was higher in combination therapy of chemotherapy and hormonal therapy and hormonal therapy and mTOR inhibitors compared to other therapies . Conclusion : Tamoxifen or a combination of tamoxifen and progestin should be the preferred choice when selecting second line hormonal treatment because the RRs are similar to first line progestin treatment and the toxicity is low .

Introduction : Hormonal therapy in endometrial cancer ( EC ) is used for patients who wish to preserve fertility and for patients with advanced or recurrent disease in a palliative setting . First line hormonal therapy consists of treatment with progestins , which has a response rate of 25 % in an unselected population . Treatment with anti-estrogens is an alternative hormonal therapy option , but there is limited data on the effect and side-effects of anti-estrogens in EC . Therefore , we performed a systematic review to investigate the response rate and toxicity of anti-estrogenic therapy in patients with endometrial cancer .

A multicenter phase II trial was conducted to define the activity of letrozole in postmenopausal women with recurrent or advanced endometrial carcinoma , who had no more than one prior line of progestins and never had chemotherapy ( except adjuvant ) . Archival paraffin-embedded tumor sample s were retrieved to determine the expression level of estrogen ( ER ) and progesterone receptor ( PgR ) , p53 , HER-2 , bcl-2 and PTEN protein , and phosphorylation status of protein kinase B ( PKB/Akt ) . Thirty-two eligible patients were treated with letrozole at 2.5 mg daily continuously , of whom 10 ( 31 % ) had prior progestins . Of the 28 patients evaluated for response , one complete and two partial responses were noted ; overall response was 9.4 % ( 95 % confidence interval 2–25 % ) . Eleven patients had stable disease for a median duration of 6.7 months ( range 3.7–19.3 months ) . Amongst 22 patients who had tumor blocks available , the proportion showing positive expression of the following markers includes : PgR ( 86 % ) , ER ( 86 % ) , PTEN ( 82 % ) , phosphorylated PKB/Akt ( 59 % ) , bcl-2 ( 45 % ) , p53 ( 32 % ) , and HER-2 ( 0 % ) . None of these markers correlated with response to letrozole or disease progression . In conclusion , letrozole is well tolerated but has little overall activity in this cohort of women with endometrial cancer Background We evaluated the efficacy and safety of the aromatase inhibitor exemestane in patients with advanced , persistent or recurrent endometrial carcinoma . Methods We performed an open-label one-arm , two-stage , phase II study of 25 mg of oral exemestane in 51 patients with advanced ( FIGO stage III-IV ) or relapsed endometrioid endometrial cancer . Patients were stratified into subsets of estrogen receptor ( ER ) positive and ER negative patients . Results Recruitment to the ER negative group was stopped prematurely after 12 patients due to slow accrual . In the ER positive patients , we observed an overall response rate of 10 % , and a lack of progression after 6 months in 35 % of the patients . No responses were registered in the ER negative patients , and all had progressive disease within 6 months . For the total group of patients , the median progression free survival ( PFS ) was 3.1 months ( 95 % CI : 2.0 - 4.1 ) . In the ER positive patients the median PFS was 3.8 months ( 95 % CI : 0.7 - 6.9 ) and in the ER negative patients it was 2.6 months ( 95 % CI : 2.1 - 3 - 1 ) . In the ER positive patients the median overall survival ( OS ) time was 13.3 months ( 95 % CI : 7.7 - 18.9 ) , in the ER negative patients the corresponding numbers were 6.1 months ( 95 % CI : 4.1 - 8.2 ) . Treatment with exemestane was well tolerated . Conclusion Treatment of estrogen positive advanced or recurrent endometrial cancer with exemestane , an aromatase inhibitor , result ed in a response rate of 10 % and lack of progression after 6 months in 35 % of the patients .Trial registration Trial identification number ( Clinical Trials.gov ) : NCT01965080.Nordic Society of Gynecological Oncology : NSGO – EC–0302.EudraCT number : 2004 - 001103 - 35 OBJECTIVES The objectives of this study were to estimate the clinical response rate and toxicity of daily tamoxifen combined with intermittent weekly medroxyprogesterone acetate ( MPA ) . METHODS This study reports the results of 61 patients with measurable advanced or recurrent endometrial carcinoma enrolled on this study to be treated with tamoxifen 40 mg p.o . daily plus alternating weekly cycles of MPA 200 mg p.o . daily . RESULTS One patient was excluded and two patients did not receive study treatment . The percent of patients responding ( 6 complete and 13 partial ) was 33 % ( 95 % confidence interval [ CI ] : 21 - 46 % ) among 58 eligible patients who received therapy . Median progression-free survival ( PFS ) was 3 months and median overall survival ( OS ) was 13 months . CONCLUSION The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma . Further investigation of this combination is appropriate Advanced uterine leiomyosarcoma ( ULMS ) is an incurable disease . A significant percentage of cases of ULMS express estrogen and /or progesterone receptors ( ER and /or PR ) . To the authors ' knowledge , the role of estrogen suppression in disease management is not known BACKGROUND Some endometrial cancers are hormonally dependent . A principal source of circulating estrogen is conversion of adrenal and rostenedione by aromatase . Anastrozole ( Arimidex ) is an oral nonsteroidal aromatase inhibitor which is active in recurrent breast cancer . This Phase II study was undertaken to evaluate anastrozole in recurrent endometrial carcinoma . METHODS Patients with advanced or recurrent endometrial cancer not curable with either surgery or radiation therapy and with measurable disease , a GOG ( Zubrod ) performance status of < or = 2 , no more than one prior hormonal therapy regimen , and no prior chemotherapy were eligible . Anastrozole was administered at a dose of 1 mg/day orally for at least 28 days . RESULTS Twenty-three patients were entered on this trial . On central pathology review , 9 of them had grade 2 and 14 had grade 3 tumors . One to 24 courses ( median : 1 ) of therapy were administered . Two partial responses were noted ( 9 % ; 90 % confidence interval 3 to 23 % ) . Two additional patients had short-term stable disease . With the exception of 1 case of venous thrombosis , the toxicity profile was mild . Median duration s of progression-free survival and overall survival are 1 and 6 months , respectively . CONCLUSIONS Anastrozole has minimal activity in an unselected population of patients with recurrent endometrial cancer Estrogen-only menopausal hormone therapy ( HT ) increases the risk of endometrial cancer , but less is known about the association with other types of HT . Using Cox proportional hazards regression , the authors examined the association of various types of HT with the risk of endometrial cancer among 115,474 postmenopausal women recruited into the European Prospect i ve Investigation into Cancer and Nutrition between 1992 and 2000 . After a mean follow-up period of 9 years , 601 incident cases of endometrial cancer were identified . In comparison with never users of HT , risk of endometrial cancer was increased among current users of estrogen-only HT ( hazard ratio ( HR ) = 2.52 , 95 % confidence interval ( CI ) : 1.77 , 3.57 ) , tibolone ( HR = 2.96 , 95 % CI : 1.67 , 5.26 ) , and , to a lesser extent , estrogen-plus-progestin HT ( HR = 1.41 , 95 % CI : 1.08 , 1.83 ) , although risks differed according to regimen and type of progestin constituent . The association of HT use with risk was stronger among women who were older , leaner , or had ever smoked cigarettes . The finding of a strong increased risk of endometrial cancer with estrogen-only HT and a weaker association with combined HT supports the hypothesis that progestins have an attenuating effect on endometrial cancer risk . The increased risk associated with tibolone use requires further investigation We have studied the response rates and survival of a group of 93 patients with Stage III or IV endometrial adenocarcinoma after r and om allocation to therapy with tamoxifen ( TAM ) 20 mg twice daily ( n = 45 ) or medroxyprogesterone acetate ( MPA ) 1 g/wk intramuscularly ( n = 48 ) . The patients were examined every 4 months . In the non-responders and in those who relapsed , combination therapy with TAM and MPA was given . Twenty-four of 45 ( 53.4 % ) responded to TAM alone , 27 of 48 ( 56.2 % ) responded to MPA alone . Of the responders 23 later relapsed in the TAM group and 24 in the MPA group and of these 14 ( 60.8 % ) and 15 ( 62.5 % ) , respectively , responded to the combination therapy . Of the original 21 non-responders to MPA alone , 10 responded to the combination ( 47.6 % ) and 11 ( 52.4 % ) did not ; the comparable figures for the TAM alone group were 13 ( 61.9 % ) and 8 ( 38.1 % ) , respectively . Survival rates were much higher in the differentiated than in the undifferentiated carcinomas . In conclusion , we feel that the efficacy , and the few side-effects of these drugs used alone and particularly when used in sequential combination , make them a very attractive treatment for advanced endometrial adenocarcinoma The author presents a hypothesis that the complex of endocrine and metabolic disturbances arising long before the development of endometrial carcinoma determines the biological peculiarities of the tumor , its clinical course , and the prognosis of the disease . On the basis of a prospect i ve study of 366 patients with endometrial carcinoma , the author postulates that there are two different pathogenetic types of endometrial carcinoma . The first pathogenetic type of the disease arises in women with obesity , hyperlipidemia , and signs of hyperestrogenism : anovulatory uterine bleeding , infertility , late onset of the menopause , and hyperplasia of the stroma of the ovaries and endometrium . The second pathogenetic type of the disease arises in women who have no signs stated above or these signs are not clearly defined . The frequency of the first pathogenetic type in the studied group of women was 65 % , whereas the frequency of the second type was 35 % . The peculiarities outlined above which are characteristic of the first pathogenetic type of the disease determine the development of highly and moderately differentiated tumors ( 82.3 % G1 and G2 ) , superficial invasion of the myometrium ( 69.4 % ) , high sensitivity to progestogens ( 80.2 % ) , and favorable prognosis ( 85.6 % 5-year survival rate ) . In patients who have the second pathogenetic type of endometrial cancer when endocrine and metabolic disturbances are absent or occult , poorly differentiated tumors arise ( 62.5 % G3 ) , a tendency to deep invasion of tumor into the myometrium is observed ( 65.7 % ) ; high frequency of metastatic spread into the pelvic lymph nodes ( 27.8 % ) ; decrease of sensitivity to progestogens ( 42.5 % ) ; and doubtful prognosis ( 58.8 % 5-year survival rate ) are noted We evaluated the therapeutic value of sequential cyclical hormonal therapy ( megestrol acetate , and tamoxifen citrate ) plus single-agent chemotherapy ( carboplatin ) in the outpatient management of advanced or recurrent endometrial cancer . Carboplatin ( 300 mg/m2 ) was administered every 4 weeks for six courses or until disease progression . In addition , patients alternated megestrol acetate ( 80 mg orally twice daily ) with tamoxifen citrate ( 20 mg orally twice daily ) every 3 weeks . Thirteen of 18 ( 72.2 % ) patients were considered evaluable . Four patients ( 30.8 % ) had a complete response , six ( 46.2 % ) had a partial response , one ( 7.7 % ) had stable disease , and two patients ( 15.4 % ) progressed . Six of seven patients with vaginal disease responded . The median progression-free interval was 14 months for complete responders . Two patients ( 15.4 % ) are alive with no evidence of disease at 41 and 59 months . Seven of 13 patients experienced a hematologic toxicity ( six grade 2 , one grade 3 ) ; all resolved within 2 weeks . Dose reduction of carboplatin to 200 mg/m2 was required in one patient . No other toxicities were encountered . The median survival for all patients is 11 months , and is 33 months for complete responders . We conclude that a regimen of carboplatin plus sequential hormonal therapy shows promise in this pilot study for the treatment of advanced or recurrent endometrial cancer PURPOSE Progestins represent the most widely used form of endocrine therapy in advanced or recurrent endometrial carcinoma . Based on encouraging response rates in breast cancer with high-dose megestrol acetate ( MA ) 800 mg/d , this phase II trial assessed response rates in patients with endometrial carcinoma treated with high-dose MA . PATIENTS AND METHODS Sixty-three patients with recurrent or advanced endometrial carcinoma were entered into this Gynecologic Oncology Group ( GOG ) study . Patients had either failed to respond to or were considered incurable with local therapy and had not received prior cytotoxic or hormonal therapy . MA 800 mg/d was administered orally in divided doses . St and ard GOG toxicity criteria were used . RESULTS Of 63 patients entered , 58 were assessable for toxicity and 54 for response . Of 13 responders ( 24 % ) , six ( 11 % ) had a complete and seven ( 13 % ) a partial response . Four of the responses lasted greater than 18 months . Twelve patients ( 22 % ) had stable disease . The response rate of patients with grade 1 or 2 lesions ( 11 of 30 , 37 % ) was significantly higher ( P = .02 ) than that of patients with more poorly differentiated tumors ( two of 24 , 8 % ) . There was no difference in response rates comparing advanced versus recurrent disease , cell type , including papillary serous lesions , site of disease , prior radiation , age , or weight . The median progression-free survival ( PFS ) and overall survival intervals were 2.5 and 7.6 months , respectively . Grade 3 weight gain ( > 20 % ) was seen in three patients and grade 3/4 hyperglycemia in three . Three deaths secondary to cardiovascular events were possibly related to therapy ; diabetes was also a contributing factor in all three cases . CONCLUSION High-dose MA is active in endometrial carcinoma , but appears to have no advantage over lower-dose progestins OBJECTIVES To estimate the objective response rate and toxicity associated with alternating megestrol acetate ( MA ) and tamoxifen citrate ( T ) in women with endometrial carcinoma . METHODS Consenting patients with measurable recurrent or advanced endometrial carcinoma were eligible if they had not received prior cytotoxic or hormonal treatment . MA 80 mg BID x 3 weeks alternating with T 20 mg BID x 3 weeks orally was given . RESULTS Of 61 patients entered , 56 eligible patients were evaluable for toxicity and response . Fifteen patients responded ( 12 complete , 3 partial ) for an overall response rate of 27 % ( 90 % Confidence Interval : 17 - 38 % ) . In 8 of 15 ( 53 % ) responders , response duration exceeded 20 months . The response rate was 38 % in patients with histologic grade 1 tumors ( n = 16 ) , 24 % in those with grade 2 disease ( n = 17 ) , and 22 % among patients with grade 3 disease ( n = 23 ) . Women less than or equal to 60 years ( n = 16 ) appear to have a better response rate than those > 60 years ( n = 40 ) , 44 % versus 20 % . The response rate in patients with extra pelvic disease ( n = 42 ) was 31 % as compared to 14 % in those with strictly pelvic and /or vaginal disease ( n = 14 ) . The median progression-free survival ( PFS ) was 2.7 months and median overall survival was 14.0 months . Two patients experienced a grade 4 thromboembolic event . Additional toxicities included one of each grade 3 gastrointestinal , grade 3 neurologic , and grade 3 genitourinary . CONCLUSION A regimen of alternating megestrol acetate and tamoxifen is active in treating endometrial cancer and may result in a prolonged complete response ( CR ) in some patients The aim of this study was to detect and analyze changes in hormone receptor ( HR ) status after treatment of operable breast cancer with neoadjuvant chemotherapy ( NCT ) . Patients were treated from 1982 to 2004 with different NCT combinations , mainly in successive prospect i ve phase II trials . HR status before and after NCT was retested and review ed in a blinded fashion by two pathologists , for 420 patients from a data base of 710 patients . Among these 420 tumors , 145 ( 35 % ) were HR negative and 275 ( 65 % ) were HR positive before NCT . The HR status had changed after treatment in 98 patients ( 23 % ) : 61 patients ( 42 % ) initially HR negative became HR positive . This HR-positive switch was significantly correlated with better overall survival ( OS ) , compared with patients with unchanged HR-negative tumors . Moreover , this HR-positive switch also had an effect on disease-free survival ( DFS ) . Conversely , 37 patients ( 13 % ) initially HR positive became HR negative after NCT . However , this group of previously positive patients still had a survival advantage for OS , but not for DFS . The Allred score was evaluated before and after chemotherapy . An increase in Allred score after NCT was significantly correlated with better DFS but not OS . It was previously shown , for other tumor parameters , that residual disease after NCT , rather than parameters evaluated on the initial biopsy , must be considered for patient prognosis . In this work , NCT induced variations in HR status in 23 % of patients . A positive switch in HR status after NCT could be an indicator of better prognosis for patient outcome Forty-six eligible women with metastatic endometrial cancer were r and omly allocated to receive monthly cycles of either CAF ( cyclophosphamide , adriamycin , 5-fluorouracil ) or CAF plus Provera 200 mg daily for 3 weeks followed cyclically by Tamoxifen 20 mg daily for 3 weeks . Overall response rates of 15 and 43 % were seen with CAF and CAF plus hormonal therapy . Using a multivariate analysis of the results , this difference is significant ( P value 0.05 ) . In 8 patients with operable endometrial cancer , negative estrogen receptor concentration ( ER less than 15 fmole/mg protein ) and Grade 3 disease , the clinical course was aggressive in 4 patients with systemic and local relapse . In 10 other similar patients ( negative ER and Grade 3 ) who received adjuvant cyclical hormonal therapy only 1 relapsed and the other 9 are disease-free for an average of more than 31 months . Sequential cyclical hormonal therapy with ER and progesterone receptor analysis has a place in the management of endometrial carcinoma OBJECTIVES To evaluate the activity and toxicity of danazol in advanced , recurrent , or persistent endometrial carcinoma . METHODS Eligible patients with advanced , recurrent , or persistent endometrial carcinoma not amenable to curative therapy were treated with danazol at a dose of 100 mg four times per day until disease progression or toxicity necessitated discontinuation . Eligibility criteria included the presence of measurable disease and no prior chemotherapy . Immunohistochemical analysis of metastatic tumor tissue for estrogen and progesterone receptors was required . RESULTS Twenty-five patients were enrolled and 3 were excluded . Six patients had tumors staining positive for both estrogen and progesterone receptors . There were no responders among 22 eligible patients . Six patients ( 27 % ) demonstrated stable disease as their best response . The median progression-free survival and overall survival were 1.9 and 14.4 months , respectively . A median total dose of 21.7 ( range : 1.4 to 67.2 ) of danazol was administered . Therapy was discontinued in 5 eligible patients due to toxicity . Four of these patients experienced hepatic toxicity . CONCLUSIONS Danazol has minimal activity in advanced , recurrent , or persistent endometrial carcinoma OBJECTIVES To determine the response , toxicities , and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced , or recurrent endometrial carcinoma . BACKGROUND Pre clinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy . METHODS We performed a r and omized phase II trial of intravenous temsirolimus 25 mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma . RESULTS There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis , with 5 episodes of deep venous thrombosis ( DVT ) and 2 pulmonary emboli . There were three responses observed in that arm ( 14 % ) . A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses ( 22 % ) . Response rates were similar in patients with prior chemotherapy ( 7 of 29 ; 24 % ) and those with no prior chemotherapy ( 4 of 21 ; 19 % ) . Two of four patients with clear cell carcinoma responded . CONCLUSIONS Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis . Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy Objective The aim of this study was to report the gynecologic safety findings from the Generations trial , a phase 3 study of the selective estrogen receptor modulator ( SERM ) , arzoxifene . Methods A predefined objective of the trial was to evaluate the effects of arzoxifene on the genital tract . Gynecologic examinations were performed yearly , and further gynecologic assessment , including endometrial biopsy , was performed in a predefined subset of women and in those who developed vaginal bleeding . Results Overall , 9,354 women were r and omized ( 4,678 to placebo , 4,676 to arzoxifene 20 mg/d ) . There were 13 adjudicated cases of endometrial cancer ( placebo , 4 cases ; arzoxifene , 9 cases : P = 0.165 ) and 6 cases of endometrial hyperplasia ( placebo , 2 cases ; arzoxifene , 4 cases ) . Endometrial thickness , assessed at 24- and 36-month transvaginal ultrasounds in a subset of women , increased slightly in women assigned to arzoxifene compared with baseline and women in placebo . At the last measurement , 3 ( 1.7 % ) women assigned to placebo and 21 ( 10.2 % ) assigned to arzoxifene had an endometrial thickness greater than 5 mm ( P < 0.001 for difference between treatment groups ) . Endometrial polyps were more common in women treated with arzoxifene ( n = 37 ) than in women treated with placebo ( n = 18 ; P < 0.05 ) . Vulvular and vaginal inflammation , including mycotic infections , and vaginal discharge were reported more frequently in women treated with arzoxifene than in women treated with placebo , as were urinary tract infections . Conclusions Gynecologic events were generally more common in women treated with arzoxifene than in women treated with placebo . The gynecologic effects of arzoxifene seem to differ from those of raloxifene , although both SERMs have a benzothiophene structure . Although all SERMs influence cells through the estrogen receptor , they need to be evaluated independently in terms of their effects on various tissues , including the genital tract To investigate the effect of adding tamoxifen to megestrol in the hormonal therapy for advanced endometrial cancer , 66 patients were entered in this study . Initially , 41 patients were r and omized to either the st and ard progestin therapy of megestrol or to the combination of megestrol and tamoxifen between October 1982 and October 1984 . The megestrol arm was terminated because of poor accrual and 25 patients were directly assigned to the combination arm . Among the 20 eligible cases on the megestrol arm , the response rate of 20 % consisted of 1 complete response and 3 partial responses . The response rate on the megestrol plus tamoxifen arm was 19 % with 1 ( 2 % ) complete response and 7 ( 17 % ) partial responses among 42 eligible cases . The median survival times were 12.0 months and 8.6 months , respectively . Only mild and moderate toxicities were observed on megestrol compared with more toxic complications observed on the combination of megestrol and tamoxifen , including a life-threatening case of pulmonary embolism . Although we could not carry out a comparative evaluation as intended , we conclude that the combination of megestrol and tamoxifen offers no clinical advantage over megestrol alone in the treatment of advanced endometrial carcinoma BACKGROUND Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women . At present , however , these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues . METHODS We studied the effect of raloxifene , a nonsteroidal benzothiophene , on bone mineral density , serum lipid concentrations , and endometrial thickness in 601 postmenopausal women . The women were r and omly assigned to receive 30 , 60 , or 150 mg of raloxifene or placebo daily for 24 months . RESULTS The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine , hip , and total body , whereas those receiving placebo had decreases in bone mineral density . For example , at 24 months , the mean ( + /-SE ) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine , 2.4+/-0.4 percent for the total hip , and 2.0+/-0.4 percent for the total body ( P<0.001 for all comparisons ) . Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups , whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change . Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study . The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo . CONCLUSIONS Daily therapy with raloxifene increases bone mineral density , lowers serum concentrations of total and low-density lipoprotein cholesterol , and does not stimulate the endometrium PURPOSE Progestins have definite activity against advanced or recurrent endometrial carcinoma . Both parenteral and oral progestins yield similar serum levels and response rates , which range from 18 % to 34 % . The one major study that used oral medroxyprogesterone acetate ( MPA ) noted a response rate at the lower end of the range ( 18 % ) and much poorer progression-free and overall survival times ( 4 and 10.5 months , respectively ) than previously reported . The present study sought to confirm this earlier study of oral MPA , to assess the importance of prognostic factors such as histologic grade and receptor levels , and to determine whether a higher dose of MPA would yield a higher response rate . PATIENTS AND METHODS Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were r and omized to receive oral MPA either 200 mg/d or 1 , 000 mg/d until unacceptable toxicity intervened or their disease progressed . RESULTS Among 145 patients receiving the low-dose regimen , there were 25 complete ( 17 % ) and 11 partial ( 8 % ) responses for an overall response rate of 25 % . The 154 patients receiving the high-dose regimen experienced 14 ( 9 % ) complete and 10 ( 6 % ) partial responses for an overall response rate of 15 % . Median duration s of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens , respectively . Median survival duration s were 11.1 months and 7.0 months , respectively . The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 ( 90 % confidence interval , 0.36 to 1.04 ) . Prognostic factors having a significant impact on the probability of response included initial performance status , age , histologic grade , and progesterone receptor concentration . Compliance with oral therapy was documented with serum levels 1 month after starting therapy , when possible . MPA levels were commensurate with the assigned dose and schedule . CONCLUSION Oral MPA is active against endometrial carcinoma . Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status . This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally . In fact , the trends suggest the opposite . The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma , particularly those lesions that are well-differentiated and /or progesterone receptor-positive ( > 50 fmol/mg cytosol protein ) . Patients with poorly differentiated and /or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8 % to 9 % response rate OBJECTIVES The goal of this study was to determine response rate and evaluate toxicity of LY353381 ( arzoxifene ) in patients with recurrent or advanced endometrial cancer ( EC ) . METHODS A phase II , open-labeled study with arzoxifene was performed at 13 centers . Patients with measurable recurrent/advanced EC not amenable to curative therapies were eligible if either the primary tumor or recurrent tumor was ER+ and /or PR+ . If receptor status could not be determined , patients with well or moderately well-differentiated EC were also permitted . Prior use of salvage chemotherapy was not allowed ; however , prior use of progestagens was permitted and patients were stratified by prior exposure to progestagen . Patients received 20 mg/day PO , and were treated for at least 8 weeks in the absence of disease progression or unacceptable toxicity . Efficacy was based on the frequency of complete ( CR ) and partial ( PR ) responses , and a 95 % confidence interval ( CI ) was calculated . The Kaplan-Meier method was used to analyze time to progression and duration of response . RESULTS From February 1999 through April 2001 , 37 patients were entered of whom 34 received treatment . Efficacy was evaluated for the 29 patients who received at least 4 weeks of therapy and at least one tumor response assessment . Safety was assessed in all 34 patients who received any drug . Thirty patients were defined as progestagen sensitive , and 4 patients were defined as progestagen failures . Twenty-six patients were ER+ , and 22 were PR+ . Nine ( 1 CR + 8 PR ) of 29 patients responded ( 31 % , CI 25 - 51 % ) , with a median duration of response of 13.9 months . All 9 responses occurred in progestagen-sensitive patients . Two additional patients ( one from each progestagen cohort ) had stable disease for > or=6 months . The median progression-free interval was 3.7 months ( CI 1.9 - 6.6 months ) for all 29 patients . Toxicity was minimal with no grade 3 - 4 toxic effects , and 9 patients had only grade 1 - 2 toxic effects ( 7 grade 1 , 2 grade 2 ) . Hot flashes were the most common toxic effect and , in all 3 reported cases , were grade 1 . CONCLUSIONS Arzoxifene has demonstrated a high response rate with the longest median duration of response reported in a phase II trial of this patient population . The ease of administration and extremely favorable toxicity profile make this an agent warranting further evaluation PURPOSE In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy , progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15 % and 25 % . Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy . The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma , who have not received systemic therapy , to warrant a phase III trial . PATIENTS AND METHODS Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed . RESULTS Three complete ( 4 % ) and four partial ( 6 % ) responses were observed for an overall response rate of 10 % ( 90 % confidence interval [ CI ] , 5.7 % to 17.9 % ) . Patients with tumors that were more anaplastic tended to respond less frequently . The median progression-free survival for all 68 eligible patients was 1.9 months ( 90 % CI , 1.7 to 3.2 months ) . The median survival was 8.8 months ( 90 % CI , 7.0 to 10.1 months ) . CONCLUSION Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease . Ongoing trials will assess the sequential use of tamoxifen and progestational agents

Results demonstrated that health status is a potentially important effect modifier as RCTs with higher baseline cholesterol , blood pressure and glycaemia demonstrated greater overall effectiveness , which was also found in studies where specific subgroup analyses were performed .

Plant-based diets rich in bioactive compounds such as polyphenols have been shown to positively modulate the risk of cardiometabolic ( CM ) diseases . The inter-individual variability in the response to these bioactives may affect the findings . This systematic review aim ed to summarize findings from existing r and omized clinical trials ( RCTs ) evaluating the effect of hydroxycinnamic acids ( HCAs ) on markers of CM health in humans .

Potatoes have the highest daily per capita consumption of all vegetables in the U.S. diet . Pigmented potatoes contain high concentrations of antioxidants , including phenolic acids , anthocyanins , and carotenoids . In a single-dose study six to eight microwaved potatoes with skins or a comparable amount of refined starch as cooked biscuits was given to eight normal fasting subjects ; repeated sample s of blood were taken over an 8 h period . Plasma antioxidant capacity was measured by ferric reducing antioxidant power ( FRAP ) . A 24 h urine was taken before and after each regimen . Urine antioxidant capacity due to polyphenol was measured by Folin reagent after correction for nonphenolic interferences with a solid phase ( Polyclar ) procedure . Potato caused an increase in plasma and urine antioxidant capacity , whereas refined potato starch caused a decrease in both ; that is , it acted as a pro-oxidant . In a crossover study 18 hypertensive subjects with an average BMI of 29 were given either six to eight small microwaved purple potatoes twice daily or no potatoes for 4 weeks and then given the other regimen for another 4 weeks . There was no significant effect of potato on fasting plasma glucose , lipids , or HbA1c . There was no significant body weight increase . Diastolic blood pressure significantly decreased 4.3 % , a 4 mm reduction . Systolic blood pressure decreased 3.5 % , a 5 mm reduction . This blood pressure drop occurred despite the fact that 14 of 18 subjects were taking antihypertensive drugs . This is the first study to investigate the effect of potatoes on blood pressure . Thus , purple potatoes are an effective hypotensive agent and lower the risk of heart disease and stroke in hypertensive subjects without weight gain The consumption of cocoa and dark chocolate is associated with a lower risk of CVD , and improvements in endothelial function may mediate this relationship . Less is known about the effects of cocoa/chocolate on the augmentation index ( AI ) , a measure of vascular stiffness and vascular tone in the peripheral arterioles . We enrolled thirty middle-aged , overweight adults in a r and omised , placebo-controlled , 4-week , cross-over study . During the active treatment ( cocoa ) period , the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage ( total cocoa = 22 g/d , total flavanols ( TF ) = 814 mg/d ) . Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar ( TF = 3 mg/d ) . Treatments were matched for total fat , saturated fat , carbohydrates and protein . The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6 % ( + 2 mm ) and basal blood flow volume by 22 % . Substantial decreases in the AI , a measure of arterial stiffness , were observed in only women . Flow-mediated dilation and the reactive hyperaemia index remained unchanged . The consumption of cocoa had no effect on fasting blood measures , while the control treatment increased fasting insulin concentration and insulin resistance ( P= 0·01 ) . Fasting blood pressure ( BP ) remained unchanged , although the acute consumption of cocoa increased resting BP by 4 mmHg . In summary , the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women Epidemiological studies indicate that habitual coffee consumption lowers the risk of diabetes and cardiovascular diseases . Postpr and ial hyperglycemia is a direct and independent risk factor for cardiovascular diseases . We previously demonstrated that coffee polyphenol ingestion increased secretion of Glucagon-like peptide 1 ( GLP-1 ) , which has been shown to exhibit anti-diabetic and cardiovascular effects . We hypothesized coffee polyphenol consumption may improve postpr and ial hyperglycemia and vascular endothelial function by increasing GLP-1 release and /or reducing oxidative stress . To examine this hypothesis , we conducted a r and omized , acute , crossover , intervention study in healthy male adults , measuring blood parameters and flow-mediated dilation ( FMD ) after ingestion of a meal with or without coffee polyphenol extract ( CPE ) . Nineteen subjects consumed a test meal with either a placebo- or CPE-containing beverage . Blood biomarkers and FMD were measured at fasting and up to 180 minutes postpr and ially . The CPE beverage led to a significantly lower peak postpr and ial increase in blood glucose and diacron-reactive oxygen metabolite , and significantly higher postpr and ial FMD than the placebo beverage . Postpr and ial blood GLP-1 increase tended to be higher after ingestion of the CPE beverage , compared with placebo . Subclass analysis revealed that the CPE beverage significantly improved postpr and ial blood GLP-1 response and reduced blood glucose increase in the subjects with a lower insulinogenic index . Correlation analysis showed postpr and ial FMD was negatively associated with blood glucose increase after ingestion of the CPE beverage . In conclusion , these results suggest that coffee polyphenol consumption improves postpr and ial hyperglycemia and vascular endothelial function , which is associated with increased GLP-1 secretion and decreased oxidative stress in healthy humans There is much epidemiological evidence suggesting a reduced risk of development of type 2 diabetes ( T2D ) in habitual coffee drinkers , however to date there have been few longer-term interventions , directly examining the effects of coffee intake on glucose and lipid metabolism . Previous studies may be confounded by inter-individual variation in caffeine metabolism . Specifically , the rs762551 SNP in the CYP1A2 gene has been demonstrated to influence caffeine metabolism , with carriers of the C allele considered to be of a ' slow ' metaboliser phenotype . This study investigated the effects of regular coffee intake on markers of glucose and lipid metabolism in coffee-naïve individuals , with novel analysis by rs762551 genotype . Participants were r and omised to either a coffee group ( n 19 ) who consumed four cups/d instant coffee for 12 weeks or a control group ( n 8) who remained coffee/caffeine free . Venous blood sample s were taken pre- and post-intervention . Primary analysis revealed no significant differences between groups . Analysis of the coffee group by genotype revealed several differences . Before coffee intake , the AC genotype ( ' slow ' caffeine metabolisers , n 9 ) displayed higher baseline glucose and NEFA than the AA genotype ( ' fast ' caffeine metabolisers , n 10 , P<0·05 ) . Post-intervention , reduced postpr and ial glycaemia and reduced NEFA suppression were observed in the AC genotype , with the opposite result observed in the AA genotype ( P<0·05 ) . These observed differences between genotypes warrant further investigation and indicate there may be no one-size-fits-all recommendation with regard to coffee drinking and T2D risk BACKGROUND Accumulating evidence suggests that certain dietary polyphenols have biological effects in the small intestine that alter the pattern of glucose uptake . Their effects , however , on glucose tolerance in humans are unknown . OBJECTIVE The objective was to investigate whether chlorogenic acids in coffee modulate glucose uptake and gastrointestinal hormone and insulin secretion in humans . DESIGN In a 3-way , r and omized , crossover study , 9 healthy fasted volunteers consumed 25 g glucose in either 400 mL water ( control ) or 400 mL caffeinated or decaffeinated coffee ( equivalent to 2.5 mmol chlorogenic acid/L ) . Blood sample s were taken frequently over the following 3 h. RESULTS Glucose and insulin concentrations tended to be higher in the first 30 min after caffeinated coffee consumption than after consumption of decaffeinated coffee or the control ( P < 0.05 for total and incremental area under the curve for glucose and insulin ) . Glucose-dependent insulinotropic polypeptide secretion decreased throughout the experimental period ( P < 0.005 ) , and glucagon-like peptide 1 secretion increased 0 - 120 min postpr and ially ( P < 0.01 ) after decaffeinated coffee consumption compared with the control . Glucose and insulin profiles were consistent with the known metabolic effects of caffeine . However , the gastrointestinal hormone profiles were consistent with delayed intestinal glucose absorption . CONCLUSIONS Differences in plasma glucose , insulin , and gastrointestinal hormone profiles further confirm the potent biological action of caffeine and suggest that chlorogenic acid might have an antagonistic effect on glucose transport . Therefore , a novel function of some dietary phenols in humans may be to attenuate intestinal glucose absorption rates and shift the site of glucose absorption to more distal parts of the intestine BACKGROUND AND OBJECTIVES Obesity has become a public health problem and is a cause of some preventable illnesses . Among several methods for treating obesity , the use of food supplements is highly common . A commonly used food supplement is green coffee bean extract . The objective of this study was to evaluate the efficacy of green coffee bean extract combined with an energy-restricted diet on the body composition and serum adipocytokines in obese women . METHODS AND STUDY DESIGN In this r and omised clinical trial , 64 obese women aged 20 - 45 years were selected and divided into two groups : an intervention group ( receiving 400 mg green coffee bean extract for 8 weeks ) and control group ( receiving placebo ) . All participants were on an energy-restricted diet . The body composition , leptin , adiponectin , lipid profile , free fatty acids ( FFAs ) , and fasting blood sugar were compared between the two groups . RESULTS We observed significant reductions in the body weight , body mass and fat mass indices , and waist-to-hip circumference ratio in both groups ; however , the decrease was higher in the intervention group . Moreover , serum total cholesterol , low-density lipoprotein , leptin , and plasma free fatty acids significantly decreased in the intervention group ( p<0.05 ) after adjustment for energy and fibre intake . The serum adiponectin concentration significantly increased in the intervention group ( p<0.05 ) . CONCLUSIONS Green coffee bean extract combined with an energy-restricted diet affects fat accumulation and lipid metabolism and is thus an inexpensive method for weight control in obese people Regular consumption of flavonoids may reduce the risk for CVD . However , the effects of individual flavonoids , for example , quercetin , remain unclear . The present study was undertaken to examine the effects of quercetin supplementation on blood pressure , lipid metabolism , markers of oxidative stress , inflammation , and body composition in an at-risk population of ninety-three overweight or obese subjects aged 25 - 65 years with metabolic syndrome traits . Subjects were r and omised to receive 150 mg quercetin/d in a double-blinded , placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period . Mean fasting plasma quercetin concentrations increased from 71 to 269 nmol/l ( P < 0.001 ) during quercetin treatment . In contrast to placebo , quercetin decreased systolic blood pressure ( SBP ) by 2.6 mmHg ( P < 0.01 ) in the entire study group , by 2.9 mmHg ( P < 0.01 ) in the subgroup of hypertensive subjects and by 3.7 mmHg ( P < 0.001 ) in the subgroup of younger adults aged 25 - 50 years . Quercetin decreased serum HDL-cholesterol concentrations ( P < 0.001 ) , while total cholesterol , TAG and the LDL : HDL-cholesterol and TAG : HDL-cholesterol ratios were unaltered . Quercetin significantly decreased plasma concentrations of atherogenic oxidised LDL , but did not affect TNF-alpha and C-reactive protein when compared with placebo . Quercetin supplementation had no effects on nutritional status . Blood parameters of liver and kidney function , haematology and serum electrolytes did not reveal any adverse effects of quercetin . In conclusion , quercetin reduced SBP and plasma oxidised LDL concentrations in overweight subjects with a high-CVD risk phenotype . Our findings provide further evidence that quercetin may provide protection against CVD Chlorogenic acid has been described as a novel polyphenol with metabolic effects on glucose homeostasis . The aim of this study was to evaluate the effect of chlorogenic acid administration on glycemic control , insulin secretion , and insulin sensitivity in patients with impaired glucose tolerance ( IGT ) . A r and omized , double-blind , placebo-controlled clinical trial was performed in 30 patients with IGT ; 15 patients r and omly assigned to oral chlorogenic acid received 400 mg three times per day for 12 weeks , and the other 15 patients received placebo in the same way . Before and after the intervention , anthropometric and metabolic measurements , including fasting plasma glucose ( FPG ) , glycated hemoglobin A1c , and a lipid profile , were performed . Area under the curve of glucose and insulin as well as the insulinogenic , Stumvoll , and Matsuda indices were calculated . Wilcoxon , Mann-Whitney U , and chi-square tests were performed , and P ≤ .05 was considered statistically significant . There were significant decreases in FPG ( 5.7 ± 0.4 vs. 5.5 ± 0.4 mmol/L , P = .002 ) , insulinogenic index ( 0.71 ± 0.25 vs. 0.63 ± 0.25 , P = .028 ) , body weight , body mass index , waist circumference , triglycerides , total cholesterol , low-density lipoprotein cholesterol , and very low-density lipoprotein levels in the chlorogenic acid group , with an increment in the Matsuda index ( 1.98 ± 0.88 vs. 2.30 ± 1.23 , P = .002 ) . There were no significant differences in the placebo group . In conclusion , chlorogenic acid administration in patients with IGT decreased FPG and insulin secretion , while increasing insulin sensitivity and improving both anthropometric evaluations and the lipid profile BACKGROUND AND AIM Coffee is rich in chlorogenic acids ( CGA ) , whose metabolites may have beneficial effects such as anti-hypertensive effects . However , trial results concerning the effects of coffee on blood pressure ( BP ) are not consistent . A recent study suggested that hydroxyhydroquinone ( HHQ ) , produced by the roasting of green coffee beans , inhibits the effect of CGA . In the present study , the dose-response for CGA in HHQ-free coffee on BP were investigated in mildly hypertensive men and women . METHODS AND RESULTS The trial design was a double-blind , r and omized controlled trial , with five study groups including , control , zero-dose , low-dose , middle-dose and high-dose . The control beverage was identical to ordinary coffee . The others contained reduced HHQ levels , compared to ordinary coffee , and the CGA were adjusted in target concentration . A total of 203 subjects were r and omly allocated . Each subject drank one cup of coffee per day . The study involved a screening and a baseline observation period of 6 weeks and an intervention period of 4 weeks . BP response showed CGA has an anti-hypertensive effect in a dose-dependent manner in HHQ-free coffee , and ordinary coffee showed almost no effect . As a result , a significant correlation between BP change and the three dose-response patterns was observed ( p<0.001 ) . CONCLUSIONS This study demonstrates a dose-dependent decrease in BP for CGA in HHQ-free coffee OBJECTIVES To examine the effect of a high carbohydrate meal on serum caffeine concentration following caffeine intake . DESIGN R and omised , double-blind , crossover . METHODS Fourteen healthy males r and omly completed 4 trials , each separated by 5 days . Participants either remained fasted ( on 2 occasions ) or ingested a high carbohydrate meal ( 2.0gkg(-1 ) carbohydrate , 42.4±0.6kJkg(-1 ) ) prior to consuming either 6 or 9mgkg(-1 ) anhydrous caffeine . Venous blood was sample d for the analysis of serum caffeine at baseline and at 6 time-points over 4h following caffeine intake . RESULTS Peak caffeine concentration occurred 60min following ingestion for both the 6 and 9mgkg(-1 ) fasted ( p<0.001 ) trials compared to 120 and 180min following ingestion for the 6 and 9mgkg(-1 ) fed trials , respectively ( p<0.001 ) . Peak concentration was greater in the 9mgkg(-1 ) fasted trial than the corresponding fed condition ( 70±9μmolL(-1 ) and 56±6μmolL(-1 ) , respectively ) and both were greater than the 6mgkg(-1 ) conditions ( 44±8μmolL(-1 ) and 38±8μmolL(-1 ) for 6mgkg(-1 ) fasted and fed , respectively ) . Area under the caffeine curve was significantly greater ( p<0.001 ) in the 9mgkg(-1 ) fasted trial ( 3262μmolL(-1)h(-1 ) ) , whilst areas were lowest in the 6mgkg(-1 ) fed trial ( 1644μmolL(-1)h(-1 ) ) . CONCLUSIONS A high carbohydrate meal consumed prior to caffeine ingestion significantly reduced serum caffeine concentrations and delayed time to peak concentration . Differences in research findings between caffeine supplementation studies may , at least in part , be related to variations in postpr and ial timing of caffeine intake . The influence of postpr and ial timing should be considered when athletes consume caffeine with the aim of enhancing performance BACKGROUND Epidemiology associates whole-grain ( WG ) consumption with several health benefits . Mounting evidence suggests that WG wheat polyphenols play a role in mechanisms underlying health benefits . OBJECTIVE The objective was to assess circulating concentration , excretion , and the physiologic role of WG wheat polyphenols in subjects with suboptimal dietary and lifestyle behaviors . DESIGN A placebo-controlled , parallel-group r and omized trial with 80 healthy overweight/obese subjects with low intake of fruit and vegetables and sedentary lifestyle was performed . Participants replaced precise portions of refined wheat ( RW ) with a fixed amount of selected WG wheat or RW products for 8 wk . At baseline and every 4 wk , blood , urine , feces , and anthropometric and body composition measures were collected . Profiles of phenolic acids in biological sample s , plasma markers of metabolic disease and inflammation , and fecal microbiota composition were assessed . RESULTS WG consumption for 4 - 8 wk determined a 4-fold increase in serum dihydroferulic acid ( DHFA ) and a 2-fold increase in fecal ferulic acid ( FA ) compared with RW consumption ( no changes ) . Similarly , urinary FA at 8 wk doubled the baseline concentration only in WG subjects . Concomitant reduction in plasma tumor necrosis factor-α ( TNF-α ) after 8 wk and increased interleukin (IL)-10 only after 4 wk with WG compared with RW ( P = 0.04 ) were observed . No significant change in plasma metabolic disease markers over the study period was observed , but a trend toward lower plasma plasminogen activator inhibitor 1 with higher excretion of FA and DHFA in the WG group was found . Fecal FA was associated with baseline low Bifidobacteriales and Bacteroidetes abundances , whereas after WG consumption , it correlated with increased Bacteroidetes and Firmicutes but reduced Clostridium . TNF-α reduction correlated with increased Bacteroides and Lactobacillus . No effect of dietary interventions on anthropometric measurements and body composition was found . CONCLUSIONS WG wheat consumption significantly increased excreted FA and circulating DHFA . Bacterial communities influenced fecal FA and were modified by WG wheat consumption . This trial was registered at clinical trials.gov as NCT01293175 There is mounting evidence that specific dietary polyphenols can enhance vascular health by augmenting nitric oxide . Our aim was to investigate the acute effects of chlorogenic acid , an important dietary phenolic acid present in coffee ( 400 mg , equivalent to 2 cups of coffee ) , on nitric oxide status , endothelial function , and blood pressure . Healthy men and women ( n = 23 ) were recruited to a r and omized , double-blind , placebo-controlled , crossover trial . Chlorogenic acid result ed in significantly higher plasma concentrations of chlorogenic acid ( P < 0.001 ) . Relative to control , the mean post-treatment systolic blood pressure ( -2.41 mmHg , 95 % CI : -0.03 , -4.78 ; P = 0.05 ) and diastolic blood pressure ( -1.53 mmHg , 95 % CI : -0.05 , -3.01 ; P = 0.04 ) were significantly lower with chlorogenic acid . Markers of nitric oxide status ( P > 0.10 ) and the measure of endothelial function ( P = 0.60 ) were not significantly influenced . Chlorogenic acid can lower blood pressure acutely , an effect that , if sustained , would benefit cardiovascular health Coffee is one of the most widely consumed beverages in the world and has a number of potential health benefits . Coffee may influence energy expenditure and energy intake , which in turn may affect body weight . However , the influence of coffee and its constituents - particularly caffeine - on appetite remains largely unexplored . The objective of this study was to examine the impact of coffee consumption ( with and without caffeine ) on appetite sensations , energy intake , gastric emptying , and plasma glucose between breakfast and lunch meals . In a double-blind , r and omised crossover design . Participants ( n = 12 , 9 women ; Mean ± SD age and BMI : 26.3 ± 6.3 y and 22.7 ± 2.2 kg•m⁻² ) completed 4 trials : placebo ( PLA ) , decaffeinated coffee ( DECAF ) , caffeine ( CAF ) , and caffeine with decaffeinated coffee ( COF ) . Participants were given a st and ardised breakfast labelled with ¹³C-octanoic acid and 225 mL of treatment beverage and a capsule containing either caffeine or placebo . Two hours later , another 225 mL of the treatment beverage and capsule was administered . Four and a half hours after breakfast , participants were given access to an ad libitum meal for determination of energy intake . Between meals , participants provided exhaled breath sample s for determination of gastric emptying ; venous blood and appetite sensations . Energy intake was not significantly different between the trials ( Means ± SD , p > 0.05 ; Placebo : 2118 ± 663 kJ ; Decaf : 2128 ± 739 kJ ; Caffeine : 2287 ± 649 kJ ; Coffee : 2016 ± 750 kJ ) ; Other than main effects of time ( p < 0.05 ) , no significant differences were detected for appetite sensations or plasma glucose between treatments ( p > 0.05 ) . Gastric emptying was not significantly different across trials ( p > 0.05 ) . No significant effects of decaffeinated coffee , caffeine or their combination were detected . However , the consumption of caffeine and /or coffee for regulation of energy balance over longer periods of time warrant further investigation The results from a clinical study performed in 12 healthy volunteers with different coffee products containing glucose show that instant coffee enriched with chlorogenic acid induced a reduction in the absorption of glucose of 6.9 % compared with the control . No such effects were seen with normal or decaffeinated instant coffee . In a second , comparative , r and omized , double-blind , 12-week study we investigated the effect on the body mass of 30 overweight people , compared with normal instant coffee . The average losses in mass in the chlorogenic acid enriched and normal instant coffee groups were 5.4 and 1.7 kg , respectively . We conclude that chlorogenic acid enriched instant coffee appears to have a significant effect on the absorption and utilization of glucose from the diet . This effect , if the coffee is used for an extended time , may result in reduced body mass and body fat when compared with the use of normal instant coffee Background Coffee consumption has been associated with a lower risk of type 2 diabetes in prospect i ve cohort studies , but the underlying mechanisms remain unclear . The aim of this study was to evaluate the effects of regular and decaffeinated coffee on biological risk factors for type 2 diabetes . Methods R and omized parallel-arm intervention conducted in 45 healthy overweight volunteers who were nonsmokers and regular coffee consumers . Participants were assigned to consumption of 5 cups ( 177 mL each ) per day of instant caffeinated coffee , decaffeinated coffee , or no coffee ( i.e. , water ) for 8 weeks . Results Average age was 40 years and body mass index was 29.5 kg/m2 . Compared with consuming no coffee , consumption of caffeinated coffee increased adiponectin ( difference in change from baseline 1.4 μg/mL ; 95 % CI : 0.2 , 2.7 ) and interleukin-6 ( difference : 60 % ; 95 % CI : 8 , 138 ) concentrations and consumption of decaffeinated coffee decreased fetuin-A concentrations ( difference : -20 % ; 95 % CI : -35 , -1 ) . For measures of glucose tolerance , insulin sensitivity , and insulin secretion , no significant differences were found between treatment groups . Conclusions Although no changes in glycemia and /or insulin sensitivity were observed after 8 weeks of coffee consumption , improvements in adipocyte and liver function as indicated by changes in adiponectin and fetuin-A concentrations may contribute to beneficial metabolic effects of long-term coffee consumption . Trial Registration clinical trials.gov Recent studies suggest that chlorogenic acids , which are the main components of the polyphenol class in coffee , decrease blood pressure , and that hydroxyhydroquinone ( HHQ ) , which is generated by roasting coffee beans , inhibits the antihypertensive effect of chlorogenic acids in brewed coffee . Here , we examined the vasoreactivity and antihypertensive effects of HHQ-reduced coffee in mild hypertension . The study design was a double blind , r and omized , placebo-controlled intervention study , with a 4-week run-in period , followed by an 8-week test beverage ingestion period . The subjects were Japanese men and women with mild hypertension and vascular failure , who were not taking any antihypertensive drugs . During the test beverage ingestion period , the subjects ingested either active or placebo HHQ-reduced coffee ( chlorogenic acids per 184 ml of coffee : active , 300 mg ; and placebo , 0 mg ) daily . Subjects were r and omly divided into two groups : active group ( n=9 ) and placebo group ( n=12 ) . In the active beverage group , endothelium-dependent , flow-mediated vasodilation impairment was significantly ameliorated and systolic blood pressure was significantly decreased from the baseline , but not in the placebo group . There were no test beverage consumption-related changes in other parameters that may influence blood pressure , such as pulse , cardiac output , body weight or 24-h urine volume . Ingestion of the active beverage significantly decreased urinary isoprostane levels , suggesting a reduced oxidative stress . These findings indicate that HHQ-reduced coffee decreased blood pressure in subjects with mild hypertension . The decreased blood pressure was associated with improved vascular endothelial function Red raspberries contain principally anthocyanins and ellagitannins . After ingestion of raspberries by humans , trace levels of anthocyanins , absorbed in the upper gastrointestinal tract , are excreted in urine in amounts corresponding to < 0.1 % of intake . Urine also contains urolithin-O-glucuronides derived from colonic metabolism of the ellagitannins . Raspberry feedings with ileostomists show that substantial amounts of the anthocyanin and ellagitannin intake are excreted in ileal fluid . In subjects with an intact functioning colon , these compounds would pass to the large intestine . The aim of this study was to identify raspberry-derived phenolic acid catabolites that form in the colon and those that are subsequently excreted in urine . In vitro anaerobic incubation of ellagitannins with fecal suspensions demonstrated conversion to ellagic acid and several urolithins . Fecal suspensions converted 80 % of added ellagic acid to urolithins . In vivo , urolithins are excreted in urine as O-glucuronides , not aglycones , indicating that the colonic microflora convert ellagitannins to urolithins , whereas glucuronidation occurs in the wall of the large intestine and /or postabsorption in the liver . Unlike ellagitannins , raspberry anthocyanins were converted in vitro to phenolic acids by anaerobic fecal suspensions . Urinary excretion of phenolic acids after ingestion of raspberries indicates that after formation in the colon some phenolic acids undergo phase II metabolism , result ing in the formation of products that do not accumulate when anthocyanins are de grade d in fecal suspensions . There is a growing realization that colonic catabolites such as phenolic acids and urolithins may have important roles in the protective effects of a fruit- and vegetable-rich diet Chlorogenic acids ( CGA ) in green coffee bean extract ( GCE ) reduce blood pressure in spontaneously hypertensive rats and humans . The authors examined the blood pressure-lowering effect and safety of CGA in patients with mild hypertension through a placebo-controlled , r and omized clinical trial . Subjects ( n=28 ) were r and omized to receive treatment with CGA ( 140 mg/day ) from GCE or placebo . Blood pressure , pulse rate , body mass index , routine blood test , hematochemistry , urinalysis , and subjective symptoms were recorded throughout the study . In the CGA group , but not the placebo group , blood pressure ( systolic and diastolic ) decreased significantly during the ingestion period . There was no difference in body mass index and pulse rate between groups , nor were there any apparent side effects . Thus , CGA from GCE is effective in decreasing blood pressure and safe for patients with mild hypertension Our previous study revealed the antihypertensive effects of green coffee bean extract ( GCE ) ingestion in spontaneously hypertensive rats . We suggested that this antihypertensive action was due to the fact that GCE contains chlorogenic acid ( CQA ) as a major phenolic compound , and CQA in turn contains ferulic acid as a metabolic component that acts on nitric oxide ( NO ) derived from the vascular endothelium . In this study , the effects of GCE on blood vessels were evaluated in healthy males . The subjects were 20 healthy males with reduced vasodilation responses measured by strain gauge plethysmograms ( SPG ) to ischemic reactive hyperemia . Of the 20 subjects , 10 ( mean age , 37.2 years ) ingested a test drink containing GCE ( CQA : 140 mg/day ) , and the other 10 ( mean age , 34.8 years ) ingested a placebo drink for 4 months . During the ingestion period , SPG , pulse wave velocity ( PWV ) , and serum biochemical parameters were measured , and acceleration plethysmograms ( APG ) were taken . The reactive hyperemia ratio ( RHR ) in the test drink group began to increase after ingestion for 1 month and was significantly higher ( p < 0.05 ) than that in the placebo group after ingestion for 3 months and 4 months . In addition , after ingestion for 4 months , the test drink group showed a significant decrease ( p < 0.01 ) in the plasma total homocysteine level compared with the pre-ingestion level . However , there were no significant differences in PWV or APG between the test drink group and the placebo drink group . The improvement in RHR after ingestion of a drink containing GCE suggested an improvement in vasoreactivity by this component BACKGROUND Coffee , a source of antioxidants , has controversial effects on cardiovascular health . OBJECTIVE We evaluated the bioavailability of chlorogenic acids ( CGAs ) in 2 coffees and the effects of their consumption on the plasma antioxidant capacity ( AC ) , the serum lipid profile , and the vascular function in healthy adults . METHODS Thirty-eight men and 37 women with a mean ± SD age of 38.5 ± 9 y and body mass index of 24.1 ± 2.6 kg/m(2 ) were r and omly assigned to 3 groups : a control group that did not consume coffee or a placebo and 2 groups that consumed 400 mL coffee/d for 8 wk containing a medium ( MCCGA ; 420 mg ) or high ( HCCGA ; 780 mg ) CGA content . Both were low in diterpenes ( 0.83 mg/d ) and caffeine ( 193 mg/d ) . Plasma caffeic and ferulic acid concentrations were measured by GC , and the plasma AC was evaluated with use of the ferric-reducing antioxidant power method . The serum lipid profile , nitric oxide ( NO ) plasma metabolites , vascular endothelial function ( flow-mediated dilation ; FMD ) , and blood pressure ( BP ) were evaluated . RESULTS After coffee consumption ( 1 h and 8 wk ) , caffeic and ferulic acid concentrations increased in the coffee-drinking groups , although the values of the 2 groups were significantly different ( P < 0.001 ) ; caffeic and ferulic acid concentrations were undetectable in the control group . At 1 h after consumption , the plasma AC in the control group was significantly lower than the baseline value ( -2 % ) and significantly increased in the MCCGA ( 6 % ) and HCCGA ( 5 % ) groups ( P < 0.05 ) . After 8 wk , no significant differences in the lipid , FMD , BP , or NO plasma metabolite values were observed between the groups . CONCLUSIONS Both coffees , which contained CGAs and were low in diterpenes and caffeine , provided bioavailable CGAs and had a positive acute effect on the plasma AC in healthy adults and no effect on blood lipids or vascular function . The group that did not drink coffee showed no improvement in serum lipid profile , FMD , BP , or NO plasma metabolites . This trial was registered at registroclinico.sld.cu as RPCEC00000168 A water-soluble green coffee bean extract ( GCE ) has been shown to be effective against hypertension in both spontaneously hypertensive rats and humans . This multicenter , r and omized , double-blind , placebo-controlled , parallel group study evaluated the dose-response relationship of GCE in 117 male volunteers with mild hypertension . Subjects were r and omized into four groups : a placebo and three drug groups that received 46 mg , 93 mg , or 185 mg of GCE once a day . After 28 days , systolic blood pressure ( SBP ) in the placebo , 46 mg , 93 mg , and 185 mg groups was reduced by −1.3±3.0 mmHg , −3.2±4.6 mmHg , −4.7±4.5 mmHg , and −5.6±4.2 mmHg from the baseline , respectively . The decreases in SBP in the 93 mg group ( p<0.05 ) and the 185 mg group ( p<0.01 ) were statistically significant compared with the placebo group . Diastolic blood pressure ( DBP ) in the placebo , 46 mg , 93 mg , and 185 mg groups was reduced by −0.8±3.1 mmHg , −2.9±2.9 mmHg , −3.2±3.2 mmHg , and −3.9±2.8 mmHg from the baseline , respectively , and significant effects were observed in the 93 mg group ( p<0.05 ) and the 185 mg group ( p<0.01 ) compared with the placebo group . Both blood pressures were significantly reduced in a dose-related manner by GCE ( p<0.001 ) . Adverse effects caused by GCE were not observed . The results suggested that daily use of GCE has a blood pressure-lowering effect in patients with mild hypertension OBJECTIVE The aim of this study was to investigate the effects of ingesting caffeine and green coffee bean extract on blood glucose and insulin concentrations during a post-exercise oral glucose tolerance test . METHODS Ten male cyclists ( age : 26 ± 5 y ; height : 179.9 ± 5.4 cm ; weight : 77.6 ± 13.3 kg ; body mass index : 24 ± 4.3 kg/m(2 ) ; VO2 peak : 55.9 ± 8.4 mL·kg·min(-1 ) ) participated in this study . In a r and omized order , each participant completed three 30-min bouts of cycling at 60 % of peak power output . Immediately after exercise , each participant consumed 75 g of dextrose with either 5 mg/kg body weight of caffeine , 10 mg/kg of green coffee bean extract ( 5 mg/kg chlorogenic acid ) , or placebo . Venous blood sample s were collected immediately before and after exercise during completion of the oral glucose tolerance test . RESULTS No significant time × treatment effects for blood glucose and insulin were found . Two-h glucose and insulin area under the curve values , respectively , for the caffeine ( 658 ± 74 mmol/L and 30,005 ± 13,304 pmol/L ) , green coffee bean extract ( 637 ± 100 mmol/L and 31,965 ± 23,586 pmol/L ) , and placebo ( 661 ± 77 mmol/L and 27,020 ± 12,339 pmol/L ) trials were not significantly different ( P > 0.05 ) . CONCLUSION Caffeine and green coffee bean extract did not significantly alter postexercise blood glucose and insulin concentrations when compared with a placebo . More human research is needed to determine the impact of these combined nutritional treatments and exercise on changes in blood glucose and insulin Rye products typically induce low insulin responses and appear to facilitate glucose regulation . The objective of this study was to investigate differences in postpr and ial glucose , insulin , and satiety responses between breads made from five rye varieties . Breads made from whole grain rye ( Amilo , Rekrut , Dankowski Zlote , Nikita , and Haute Loire Pop ) or a white wheat bread ( WWB ) were tested in a r and omized cross-over design in 14 healthy subjects ( 50 g available starch ) . Metabolic responses were also related to the composition of dietary fiber and bioactive compounds in the breads and to the rate of in vitro starch hydrolysis . The Amilo and Rekrut rye breads induced significantly lower insulin indices ( II ) than WWB . Low early postpr and ial glucose and insulin responses ( tAUC 0 - 60 min ) were related to higher amounts of caffeic , ferulic , sinapic , and vanillic acids in the rye breads , indicating that the phenolic acids in rye may influence glycemic regulation . All rye breads induced significantly higher subjective feelings of fullness compared to WWB . A low II was related to a higher feeling of fullness and a lower desire to eat in the late postpr and ial phase ( 180 min ) . The data indicate that some rye varieties may be more insulin-saving than others , possibly due to differences in dietary fiber , rate of starch hydrolysis , and bioactive components such as phenolic acids BACKGROUND Epidemiologic and experimental data have suggested that chlorogenic acid , which is a polyphenol contained in green coffee beans , prevents diet-induced hepatic steatosis and insulin resistance . OBJECTIVE We assessed whether the consumption of chlorogenic acid-rich coffee attenuates the effects of short-term fructose overfeeding , dietary conditions known to increase intrahepatocellular lipids ( IHCLs ) , and blood triglyceride concentrations and to decrease hepatic insulin sensitivity in healthy humans . DESIGN Effects of 3 different coffees were assessed in 10 healthy volunteers in a r and omized , controlled , crossover trial . IHCLs , hepatic glucose production ( HGP ) ( by 6,6-d2 glucose dilution ) , and fasting lipid oxidation were measured after 14 d of consumption of caffeinated coffee high in chlorogenic acid ( C-HCA ) , decaffeinated coffee high in chlorogenic acid , or decaffeinated coffee with regular amounts of chlorogenic acid ( D-RCA ) ; during the last 6 d of the study , the weight-maintenance diet of subjects was supplemented with 4 g fructose · kg(-1 ) · d(-1 ) ( total energy intake ± SD : 143 ± 1 % of weight-maintenance requirements ) . All participants were also studied without coffee supplementation , either with 4 g fructose · kg(-1 ) · d(-1 ) ( high fructose only ) or without high fructose ( control ) . RESULTS Compared with the control diet , the high-fructose diet significantly increased IHCLs by 102 ± 36 % and HGP by 16 ± 3 % and decreased fasting lipid oxidation by 100 ± 29 % ( all P < 0.05 ) . All 3 coffees significantly decreased HGP . Fasting lipid oxidation increased with C-HCA and D-RCA ( P < 0.05 ) . None of the 3 coffees significantly altered IHCLs . CONCLUSIONS Coffee consumption attenuates hepatic insulin resistance but not the increase of IHCLs induced by fructose overfeeding . This effect does not appear to be mediated by differences in the caffeine or chlorogenic acid content . This trial was registered at clinical trials.gov as NCT00827450 The beneficial effects of green tea catechins , such as the proposed improvement in endothelial function , may be influenced by phase II metabolism during and after absorption . The methylation enzyme , catechol-O-methyltransferase ( COMT ) , has a missense mutation rs4680 ( G to A ) , proposed to result in a 40 % reduction in enzyme activity . In the present pilot study , twenty subjects ( ten of each homozygous COMT genotype ) were recruited . Green tea extract capsules ( 836 mg green tea catechins ) were given in a fasted state , and a high-carbohydrate breakfast was given after 60 min . Blood sample s and vascular function measurements were taken at regular intervals . The change in digital volume pulse stiffness index ( SI ) from baseline was shown to be different between genotype groups at 120 and 240 min , with a lower SI in the GG individuals ( P ≤ 0·044 ) . The change in blood pressure from baseline also differed between genotype groups , with a greater increase in systolic ( P = 0·023 ) and diastolic ( P = 0·034 ) blood pressure at 120 min in the GG group . The GG [ corrected ] group was shown to have a greater increase in insulin concentrations at 120 min ( P = 0·019 ) and 180 min ( P = 0·008 ) compared with baseline , despite similar glucose profiles . No genotypic differences were found in vascular reactivity measured using laser Doppler iontophoresis , total nitrite , lipids , plasma total antioxidant capacity or inflammatory markers after ingestion of the green tea extract . In conclusion , SI and insulin response to the glucose load differed between the COMT genotype groups , and this may be suggestive of a green tea extract and genotype interaction OBJECTIVE Coffee consumption has been associated with lower risk of type 2 diabetes . We evaluated the acute effects of decaffeinated coffee and the major coffee components chlorogenic acid and trigonelline on glucose tolerance . RESEARCH DESIGN AND METHODS We conducted a r and omized crossover trial of the effects of 12 g decaffeinated coffee , 1 g chlorogenic acid , 500 mg trigonelline , and placebo ( 1 g mannitol ) on glucose and insulin concentrations during a 2-h oral glucose tolerance test ( OGTT ) in 15 overweight men . RESULTS Chlorogenic acid and trigonelline ingestion significantly reduced glucose ( −0.7 mmol/l , P = 0.007 , and −0.5 mmol/l , P = 0.024 , respectively ) and insulin ( −73 pmol/l , P = 0.038 , and −117 pmol/l , P = 0.007 ) concentrations 15 min following an OGTT compared with placebo . None of the treatments affected insulin or glucose area under the curve values during the OGTT compared with placebo . CONCLUSIONS Chlorogenic acid and trigonelline reduced early glucose and insulin responses during an OGTT Rye bran contains a high amount of phenolic acids with potential health promoting effects . However , due to binding to dietary fibre , the phenolic acids are poorly absorbed in human body . We used bioprocessing with enzymes and yeast to release phenolic acids from the fibre complex and studied the effect of bioprocessing on absorption of phenolic acids in healthy humans . White wheat breads fortified with bioprocessed or native rye bran , and wholegrain rye bread and white wheat bread as controls were served to 15 subjects in a r and omized order in the cross-over design . Urine was collected at the basal state and over 24 hours in four- , eight- , and twelve-hour periods and analyzed for phenolic acids and their metabolites with gas chromatography . A total of six blood sample s were taken over four hours to study the effect of the bread ingestion on postpr and ial glucose and insulin responses . Bioprocessing of rye bran increased the proportion of free ferulic acid ( FA ) and soluble arabinoxylan in the bread . Ingestion of the white wheat bread fortified with bioprocessed rye bran increased ( p < 0.001 ) urinary excretion of FA particularly during the first four hours , indicating increased absorption of FA from the small intestine . The postpr and ial glucose and insulin responses were similar between these breads . Bioprocessing of rye bran did not affect excretion of benzoic , phenylpropionic , and phenylacetic acid metabolites . As a conclusion , bioprocessed rye bran as compared with native rye bran increased absorption of FA from the small intestine , but did not improve postpr and ial glucose and insulin responses BACKGROUND AND AIMS Cocoa flavanols are recognised by their favourable antioxidant and vascular effects . This study investigates the influence on health of the daily consumption of ready-to-eat meals supplemented with cocoa extract within a hypocaloric diet , on middle-aged overweight/obese subjects . METHODS AND RESULTS Fifty healthy male and female middle-aged volunteers [ 57.26 ± 5.24 years and body mass index ( BMI ) 30.59 ± 2.33 kg/m(2 ) ] were recruited to participate in a 4 week r and omised , parallel and double-blind study . After following 3 days on a low-polyphenol diet , 25 volunteers received meals supplemented with 1.4 g of cocoa extract ( 645.3 mg of polyphenols ) and the other 25 participants received control meals , within a 15 % energy restriction diet . On the 4th week of intervention individuals in both dietary groups improved ( p < 0.05 ) anthropometric , body composition , blood pressure and blood biochemical measurements . Oxidised LDL cholesterol ( oxLDL ) , showed a higher reduction ( p = 0.030 ) in the cocoa group . Moreover , myeloperoxidase ( MPO ) levels decreased only in the cocoa supplemented group ( p = 0.007 ) . Intercellular Adhesion Molecule-1 ( sICAM-1 ) decreased significantly in both groups , while Vascular Cell Adhesion Molecule-1 ( sVCAM-1 ) did not present differences after the 4 weeks of intervention . Interestingly , cocoa intake showed a different effect by gender , presenting more beneficial effects in men . CONCLUSIONS The consumption of cocoa extract as part of ready-to-eat meals and within a hypocaloric diet improved oxidative status ( oxLDL ) in middle-aged subjects , being most remarkable in males . REGISTRATION NUMBER Registered at www . clinical trials.gov ( NCT01596309 ) Purpose The purpose of this study was to evaluate acute effects of coffee with a high content of chlorogenic acids and different hydroxyhydroquinone contents on postpr and ial endothelial dysfunction . Methods This was a single-blind , r and omized , placebo-controlled , crossover-within-subject clinical trial . A total of 37 patients with borderline or stage 1 hypertension were r and omized to two study groups . The participants consumed a test meal with a single intake of the test coffee . Subjects in the Study 1 group were r and omized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or coffee with a high content of chlorogenic acids and a high content of hydroxyhydroquinone with crossover . Subjects in the Study 2 group were r and omized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or placebo coffee with crossover . Endothelial function assessed by flow-mediated vasodilation and plasma concentration of 8-isoprostanes were measured at baseline and at 1 and 2 h after coffee intake . Results Compared with baseline values , single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone , but not coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee , significantly improved postpr and ial flow-mediated vasodilation and decreased circulating 8-isoprostane levels . Conclusions These findings suggest that a single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone is effective for improving postpr and ial endothelial dysfunction . Clinical Trial Registration URL for Clinical Trial : https://upload.umin.ac.jp ; Registration Number for Clinical Trial : UMIN000013283 Purpose Coffee is rich in bioactive compounds with health beneficial properties , with green coffee presenting higher phenol content than roasted . We evaluated the effects of regularly consuming realistic amounts of a green/roasted coffee blend on cardiovascular health-related biomarkers . Methods A r and omized , cross-over , controlled study was carried out in 25 normocholesterolemic [ total cholesterol ( TC ) < 200 mg/dL ] and 27 hypercholesterolemic ( TC 200–240 mg/dL ) subjects . During 8 weeks , volunteers consumed 6 g/day of soluble green/roasted ( 35:65 ) coffee or a control beverage ( water or an isotonic drink ) . Blood pressure , heart rate and body weight were monitored at the end of each intervention , and serum lipids [ TC , HDL-C , LDL-C , VLDL-C , triglycerides and phospholipids ] , cytokines and chemokines ( IL-1β , IL-2 , IL-4 , IL-5 , IL-6 , IL-7 , IL-10 , IL-12 , IL-13 , IL-17 , G-CSF , GM-CSF , MCP-1 , MIP-1β , TNF-α , INF-γ ) , adhesion molecules ( ICAM-1 , VCAM-1 ) , and C-reactive protein were measured . Plasma antioxidant capacity ( FRAP , ORAC and ABTS methods ) , and lipid ( malondialdehyde , MDA ) and protein ( carbonyl groups , CG ) oxidation were also determined . Results Attending to the general lineal model of variance for repeated measures , after the green/roasted coffee intervention significant reductions in TC , LDL-C , VLDL-C and triglycerides levels ( p = 0.006 , 0.001 , 0.003 and 0.017 , respectively ) , and a significant group effect were observed ( 0.001 , < 0.001 , 0.019 and 0.027 , respectively ) . Only within the hypercholesterolemic group , attending to the Bonferroni test , the aforementioned lipid parameters were significantly lower after regular green/roasted coffee intake compared to baseline values . Moreover , after the coffee stage , plasma antioxidant capacity improved , according to the increase in ORAC and FRAP values ( p < 0.001 and p < 0.001 , respectively ) and decrease of MDA ( p = 0.015 ) and CG ( p < 0.001 ) levels , without differences between groups . Systolic ( p = 0.001 ) and diastolic ( p < 0.001 ) blood pressure , heart rate ( p = 0.035 ) , and body weight ( p = 0.017 ) were reduced in both normo- and hypercholesterolemic groups . Conclusion Regular consumption of moderate amounts of a soluble green/roasted ( 35:65 ) coffee blend may contribute to improve cardiovascular health in moderately hypercholesterolemic people , as reducing serum lipids , blood pressure and body weight effects , as well as increasing plasma antioxidant capacity , have been observed . Moreover , positive influences on blood pressure , body weight , and plasma antioxidant capacity were obtained in the healthy group . Therefore , incorporation of green coffee beans into the coffee brew can be recommended as part of a dietary strategy to protect from cardiovascular disease Ferulic acid is the most abundant phenolic compound found in vegetables and cereal grains . In vitro and animal studies have shown ferulic acid has anti-hyperlipidemic , anti-oxidative , and anti-inflammatory effects . The objective of this study is to investigate the effects of ferulic acid supplementation on lipid profiles , oxidative stress , and inflammatory status in hyperlipidemia . The study design is a r and omized , double-blind , placebo-controlled trial . Subjects with hyperlipidemia were r and omly divided into two groups . The treatment group ( n = 24 ) was given ferulic acid ( 1000 mg daily ) and the control group ( n = 24 ) was provided with a placebo for six weeks . Lipid profiles , biomarkers of oxidative stress and inflammation were assessed before and after the intervention . Ferulic acid supplementation demonstrated a statistically significant decrease in total cholesterol ( 8.1 % ; p = 0.001 ) , LDL-C ( 9.3 % ; p < 0.001 ) , triglyceride ( 12.1 % ; p = 0.049 ) , and increased HDL-C ( 4.3 % ; p = 0.045 ) compared with the placebo . Ferulic acid also significantly decreased the oxidative stress biomarker , MDA ( 24.5 % ; p < 0.001 ) . Moreover , oxidized LDL-C was significantly decreased in the ferulic acid group ( 7.1 % ; p = 0.002 ) compared with the placebo group . In addition , ferulic acid supplementation demonstrated a statistically significant reduction in the inflammatory markers hs-CRP ( 32.66 % ; p < 0.001 ) and TNF-α ( 13.06 % ; p < 0.001 ) . These data indicate ferulic acid supplementation can improve lipid profiles and oxidative stress , oxidized LDL-C , and inflammation in hyperlipidemic subjects . Therefore , ferulic acid has the potential to reduce cardiovascular disease risk factors Coffee is a rich source of polyphenols , primarily chlorogenic acids ( CGA ) . Certain polyphenols and polyphenol-rich foods and beverages have been shown to improve endothelial function and lower blood pressure ( BP ) . The aim of the present study was to investigate the acute effect of two doses of CGA ( 5-CGA ) on endothelial function and BP . In a cross-over study , 16 healthy men and women received : ( i ) 0 mg purified 5-CGA ( control group ) ; ( ii ) 450 mg purified 5-CGA ; ( iii ) 900 mg purified 5-CGA ; and ( iv ) 200 mg purified (-)-epicatechin ( positive control ) in r and om order one week apart . Peak and continuous mean ( 60 to 240 s post ischaemia ) flow-mediated dilation ( FMD ) was measured at baseline , 1 h and 4 h. BP was measured at baseline and every 30 min to 4 h. Plasma CGA and epicatechin levels were significantly increased at both 1 h and 4 h post their respective treatments . Peak FMD was not significantly altered by either dose of 5-CGA or the epicatechin , relative to control ( p > 0.05 ) . Relative to control , effects on continuous mean FMD response following 450 mg 5-CGA and 900 mg of 5-CGA ( 0.47 ± 0.16 % , p = 0.016 and 0.65 ± 0.16 % , p < 0.001 , respectively ) at 1 h and ( 0.18 ± 0.17 % , p = 0.99 and 0.44 ± 0.16 % , p < 0.05 , respectively ) at 4 h. There was no significant effect of any of the treatments on BP . In conclusion , the present study has found no significant effect of 5-CGA , at 450 and 900 mg , on peak FMD response . However , there were significant improvements in mean post-ischaemic FMD response , particularly at the 1 h time point in this group of healthy individuals Brewed coffee is a widely consumed beverage , and many studies have examined its effects on human health . We investigated the vascular effects of coffee polyphenols ( CPPs ) , hypothesizing that a single ingestion of CPP during glucose loading would improve endothelial function . To test this hypothesis , we conducted a r and omized acute clinical intervention study with crossover design and measured reactive hyperemia index ( RHI ) to assess the acute effects of a 75-g glucose load with CPP in healthy , nondiabetic adult men . Blood glucose and insulin levels were elevated after glucose loading with and without CPP , with no significant differences between treatments . The RHI did not significantly decrease after glucose loading without CPP . With CPP , however , RHI significantly ( P < .05 ) increased over baseline after glucose loading . The difference between treatments was statistically significant ( P < .05 ) . No significant changes were observed in an oxidative stress marker after glucose loading with or without CPP . These findings suggest that a single ingestion of CPP improves peripheral endothelial function after glucose loading in healthy subjects The aim of this study was to evaluate the effects of artichoke leaf extract ( ALE ) supplementation ( 250 mg , 2 b.i.d . ) on the lipid pattern . A r and omized , double-blind , placebo-controlled clinical trial was performed on 92 overweight subjects with primary mild hypercholesterolaemia for 8 weeks . Forty-six subjects were r and omized to supplementation ( age : 54.2 ± 6.6 years , body mass index ( BMI ): 25.8 ± 3.9 kg/m2 , male/female : 20/26 ) and 46 subjects to placebo ( age : 53.8 ± 9.0 years , BMI : 24.8 ± 1.6 kg/m2 , male/female : 21/25 ) . Verum supplementation was associated with a significant increase in mean high-density lipoprotein (HDL)-cholesterol ( p < 0.001 ) and in mean change in HDL-cholesterol ( HDL-C ) ( p = 0.004 ) . A significantly decreased difference was also found for the mean change in total cholesterol ( p = 0.033 ) , low-density lipoprotein (LDL)-cholesterol ( p < 0.001 ) , total cholesterol/HDL ratio ( p < 0.001 ) and LDL/HDL ratio ( p < 0.001 ) , when verum and placebo treatment were compared . These results indicate that ALE could play a relevant role in the management of mild hypercholesterolaemia , favouring in particular the increase in HDL-C , besides decreasing total cholesterol and LDL-cholesterol

There is no clear evidence for supporting or rejecting the routine use of leukoreduction in all patients requiring PRBC transfusion for preventing TRALI , death , infection , non-infectious complications and other adverse events .

BACKGROUND A blood transfusion is an acute intervention , implemented to solve life and health-threatening conditions on a short-term basis . However , blood transfusions have adverse events , some of them potentially related to immune modulation or to a direct transmission of infectious agents ( e.g. cytomegalovirus ) . Leukoreduction is a process in which the white blood cells are intentionally reduced in packed red blood cells ( PRBCs ) in order to reduce the risk of adverse reactions . The potential benefits of leukoreduced PRBCs in all types of transfused patients for decreasing infectious and non-infectious complications remain unclear . OBJECTIVES To determine the clinical effectiveness of leukoreduction of packed red blood cells for preventing adverse reactions following allogeneic blood transfusion .

CONTEXT Allogeneic blood transfusions have immunomodulatory effects and have been associated with activation of human immunodeficiency virus ( HIV ) and cytomegalovirus ( CMV ) in vitro and of HIV in small pilot studies . Retrospective studies suggest that transfusions adversely affect the clinical course of HIV . Data in selected non-HIV-infected patients requiring blood transfusion have suggested clinical benefit with leukocyte-reduced red blood cells ( RBCs ) . OBJECTIVE To compare the effects of leukoreduced and unmodified RBC transfusions on survival , complications of acquired immunodeficiency syndrome , and relevant laboratory markers in HIV-infected patients . DESIGN AND SETTING Double-blind r and omized controlled trial conducted in 11 US academic medical centers from July 1995 through June 1999 , with a median follow-up of 12 months ( 24 months in survivors ) . PATIENTS A total of 531 persons infected with HIV and CMV , aged 14 years or older , who required transfusions for anemia ; 259 received leukoreduced transfusions and 262 received unmodified transfusions ( 10 did not receive the planned transfusion ) . MAIN OUTCOME MEASURES Survival and change in plasma HIV RNA level 7 days after transfusion , compared by type of transfusion . RESULTS At entry , the groups were similar in demographic , clinical , and relevant laboratory characteristics . A total of 3864 RBC units were transfused . Two hundred eighty-nine deaths occurred ( 151 with leukoreduced transfusion ; 138 with unmodified transfusion ) ; median survival was 13.0 and 20.5 months , respectively ( relative hazard [ RH ] , 1.20 ; 95 % confidence interval [ CI ] , 0.95 - 1.51 ; log-rank P = .12 ) . Analyses adjusted for prognostic factors suggested possible worse survival with leukoreduction ( RH , 1.35 ; 95 % CI , 1.06 - 1.72 ) . There was no difference in time to new opportunistic event/death or frequency of transfusion reactions . No changes in plasma HIV RNA level were seen in either group at days 7 , 14 , 21 , or 28 , even in patients not taking antiretroviral drugs . There were no differences in trends between groups in CMV DNA , CD4 cell counts , activated ( CD38 % or human leukocyte antigen-DR ) CD8 cell counts , or plasma cytokine levels . CONCLUSIONS We found no evidence of HIV , CMV , or cytokine activation following blood transfusion in patients with advanced HIV infection . Leukoreduction provided no clinical benefit in these patients . These data demonstrate the importance of conducting controlled studies of effects of leukoreduction in different patient population s , since smaller studies in other patient population s have suggested leukoreduction may be beneficial Background —Leukocytes in allogeneic blood transfusions are believed to be the cause of immunomodulatory events . A few trials on leukocyte removal from transfusions in cardiac surgery have been conducted , and they showed inconclusive results . We found in a previous study a decrease in mortality rates and number of infections in a subgroup of more heavily transfused patients . Methods and Results — Patients ( n= 496 ) undergoing valve surgery ( with or without CABG ) were r and omly assigned in a double-blind fashion to receive st and ard buffy coat – depleted ( PC ) or prestorage , by filtration , leukocyte-depleted erythrocytes ( LD ) . The primary end point was mortality at 90 days , and secondary end points were in-hospital mortality , multiple organ dysfunction syndrome , infections , intensive care unit stay , and hospital stay . The difference in mortality at 90 days was not significant ( PC 12.7 % versus LD 8.4 % ; odds ratio [ OR ] , 1.52 ; 95 % confidence interval [ CI ] , 0.84 to 2.73 ) . The in-hospital mortality rate was almost twice as high in the PC group ( 10.1 % versus 5.5 % in the LD group ; OR , 1.99 ; 95 % CI , 0.99 to 4.00 ) . The incidence of multiple organ dysfunction syndrome in both groups was similar , although more patients with multiple organ dysfunction syndrome died in the PC group . LD was associated with a significantly reduced infection rate ( PC 31.6 % versus LD 21.6 % ; OR , 1.64 ; 95 % CI , 1.08 to 2.49 ) . In both groups , intensive care unit stay and hospital stay were similar , and postoperative complications increased with the number of transfused units . Conclusions —Mortality at 90 days was not significantly different ; however , a beneficial effect of LD in valve surgery was found for the secondary end points of in-hospital mortality and infections OBJECTIVE In elective orthopaedic hip- and knee replacement surgery patients , we studied the effect of implementation of a uniform transfusion policy on RBC usage . STUDY DESIGN AND METHODS A r and omized , controlled study . A new uniform , restrictive transfusion policy was compared with st and ard care , which varied among the three participating hospitals . Only prestorage leucocyte-depleted RBC(s ) were used . Primary end-point was RBC usage , related to length of hospital stay . Secondary end-points were Hb levels , mobilization delay and postoperative complications . RESULTS Six hundred and three patients were evaluated . Adherence to the protocol was over 95 % . Overall mean RBC usage was 0.78 U/patient in the new policy group and 0.86 U/patient in the st and ard care policy group ( mean difference 0.08;95 % CI [ -0.3 ; 0.2 ] ; P = 0.53 ) . In two hospitals , the new transfusion policy result ed in a RBC reduction of 30 % ( 0.58U RBC/patient ) ( P = 0.17 ) and 41 % ( 0.29 U RBC/patient ) ( P = 0.05 ) respectively . In the third hospital , however , RBC usage increased by 39 % ( 0.31 U RBC/patient ) ( P = 0.02 ) with the new policy , due to a more restrictive st and ard care policy in that hospital . Length of hospital stay was not influenced by either policy . CONCLUSIONS Implementation of a uniform transfusion protocol for elective lower joint arthroplasty patients is feasible , but does not always lead to a RBC reduction . Length of hospital stay was not affected Perioperative blood transfusions are reported to be related to cancer recurrence and reduced survival . Different underlying mechanisms have been proposed , and allogeneic leucocytes in transfused blood have been suggested to contribute to this phenomenon BACKGROUND Blood cardioplegia ( BCP ) is widely used for myocardial protection during open heart operation . However , BCP may have a chance to induce neutrophil-mediated myocardial injury during aortic cross-clamping . We clinical ly evaluated the myocardial protective effect of leukocyte-depleted blood cardioplegia ( LDBCP ) for initial and intermittent BCP administration in pediatric patients . METHODS Fifty patients undergoing open heart operation for congenital heart disease between January 1997 and March 1999 were review ed . Twenty-five were administered LDBCP for myocardial protection during ischemic periods ( LDBCP group ) , and the remaining 25 were given BCP without leukocyte depletion ( BCP group ) . RESULTS The difference in plasma concentrations of malondialdehyde between coronary sinus effluent blood and arterial blood just after reperfusion in the LDBCP group ( 1.68 + /- 0.56 micromol/L ) was significantly lower than that in the BCP group ( 2.35 + /- 0.62 micromol/L ; p < 0.01 ) . The LDBCP group showed significantly lower plasma concentrations of human heart fatty acid-binding protein at 50 minutes after reperfusion ( LDBCP group , 103.5 + /- 38.7 IU/L ; BCP group , 144.8 + /- 48.8 IU/L ; p < 0.01 ) and the peak value of creatine kinase-MB during the first 24 postoperative hours ( LDBCP group , 17.0 + /- 8.5 IU/L ; BCP group , 26.0 + /- 11.6 IU/L ; p < 0.01 ) than did the BCP group . The maximum dose of catecholamine was significantly smaller in the LDBCP group ( LDBCP group , 3.20 + /- 2.18 microg x kg(-1 ) x min(-1 ) ; BCP group , 5.60 + /- 2.83 microg x kg(-1 ) x min(-1 ) ; p < 0.01 ) . CONCLUSIONS These results suggest the usefulness of LDBCP for protection from the myocardial injury that can be induced by BCP administration during aortic cross-clamping Introduction Microvascular alterations impair tissue oxygenation during sepsis . A red blood cell ( RBC ) transfusion increases oxygen ( O2 ) delivery but rarely improves tissue O2 uptake in patients with sepsis . Possible causes include RBC alterations due to prolonged storage or residual leukocyte-derived inflammatory mediators . The aim of this study was to compare the effects of two types of transfused RBCs on microcirculation in patients with sepsis . Methods In a prospect i ve r and omized trial , 20 patients with sepsis were divided into two separate groups and received either non-leukodepleted ( n = 10 ) or leukodepleted ( n = 10 ) RBC transfusions . Microvascular density and perfusion were assessed with sidestream dark field ( SDF ) imaging sublingually , before and 1 hour after transfusions . Thenar tissue O2 saturation ( StO2 ) and tissue hemoglobin index ( THI ) were determined with near-infrared spectroscopy , and a vascular occlusion test was performed . The microcirculatory perfused boundary region was assessed in SDF images as an index of glycocalyx damage , and glycocalyx compounds ( syndecan-1 , hyaluronan , and heparan sulfate ) were measured in the serum . Results No differences were observed in microvascular parameters at baseline and after transfusion between the groups , except for the proportion of perfused vessels ( PPV ) and blood flow velocity , which were higher after transfusion in the leukodepleted group . Microvascular flow index in small vessels ( MFI ) and blood flow velocity exhibited different responses to transfusion between the two groups ( P = 0.03 and P = 0.04 , respectively ) , with a positive effect of leukodepleted RBCs . When within-group changes were examined , microcirculatory improvement was observed only in patients who received leukodepleted RBC transfusion as suggested by the increase in De Backer score ( P = 0.02 ) , perfused vessel density ( P = 0.04 ) , PPV ( P = 0.01 ) , and MFI ( P = 0.04 ) . Blood flow velocity decreased in the non-leukodepleted group ( P = 0.03 ) . THI and StO2 upslope increased in both groups . StO2 and StO2 downslope increased in patients who received non-leukodepleted RBC transfusions . Syndecan-1 increased after the transfusion of non-leukodepleted RBCs ( P = 0.03 ) . Conclusions This study does not show a clear superiority of leukodepleted over non-leukodepleted RBC transfusions on microvascular perfusion in patients with sepsis , although it suggests a more favorable effect of leukodepleted RBCs on microcirculatory convective flow . Further studies are needed to confirm these findings .Trial registration Clinical Trials.gov , The frequency of infection in 197 patients undergoing elective colorectal surgery and having either no blood transfusion , transfusion with whole blood , or filtered blood free from leucocytes and platelets was investigated in a prospect i ve r and omized trial . Natural killer cell function was measured before operation and 3 , 7 and 30 days after surgery in 60 consecutive patients . Of the patients 104 required blood transfusion ; 48 received filtered blood and 56 underwent whole blood transfusion . Postoperative infections developed in 13 patients transfused with whole blood ( 23 per cent , 9.5 per cent confidence interval 13–32 per cent ) , in one patient transfused with blood free from leucocytes and platelets ( 2 per cent , 9.5 per cent confidence interval 0.05–11 per cent ) and in two non‐transfused patients ( 2 per cent , 95 per cent conjidence interval 0.3‐8per cent ) ( P < 0.01 ) . Natural killer cell function was significantly ( P < 0.001 ) impaired up to 30 days after surgery in patients transfused with whole blood . These data provide a strong case against the use of whole blood transfusion in patients undergoing elective colorectal surgery We performed a prospect i ve , r and omized trial in CMV seronegative marrow recipients to determine if filtered blood products were as effective as CMV-seronegative blood products for the prevention of transfusion-transmitted CMV infection after marrow transplant . Before transplant , 502 patients were r and omized to receive either filtered or seronegative blood products . Patients were monitored for the development of CMV infection and tissue-documented CMV disease between days 21 and 100 after transplant . Infections occurring after day 21 from transplant were considered related to the transfusion of study blood products and , thus , were considered evaluable infections for the purpose of this trial . In the primary analysis of evaluable infections , there were no significant differences between the probability of CMV infection ( 1.3 % v 2.4 % , P = 1.00 ) or disease ( 0 % v 2.4 % , P = 1.00 ) between the seronegative and filtered arms , respectively , or probability of survival ( P = .6 ) . In a secondary analysis of all infections occurring from day 0 to 100 post-transplant , although the infection rates were similar , the probability of CMV disease in the filtered arm was greater ( 2.4 % v 0 % in the seronegative arm , P = .03 ) . However , the disease rate was still within the pre study clinical ly defined acceptable rate of < or = 5 % . We conclude that filtration is an effective alternative to the use of seronegative blood products for prevention of transfusion-associated CMV infection in marrow transplant patients BACKGROUND Leukocytes in transfused blood are associated with several posttransfusion immunomodulatory effects . Although leukocytes play an important role in reperfusion injury , the contribution of leukocytes in transfused blood products has not been investigated . To estimate the role and the timing of leukocyte filtration of red cells in cardiac surgery , we performed a r and omized study . METHODS AND RESULTS Patients scheduled for cardiac surgery were r and omly allocated to receive either packed cells without buffy coat ( PC , n = 306 ) , fresh-filtered units ( FF , n = 305 ) , or stored-filtered units ( SF , n = 303 ) when transfusion was indicated . We evaluated the periods of hospitalization and stay at the intensive care unit , and the occurrences of postoperative complications up to 60 days after surgery . The average hospital stay was 10.7 days , of which 3.2 days were in the intensive care unit , without significant differences between the groups . In the PC trial arm , 23.0 % of the patients had infections versus 16.9 % and 17.9 % of the patients in the leukocyte-depleted trial arms ( P=.13 ) . Within 60 days , 45 patients had died , 24 patients in the PC trial arm ( 7.8 % ) , versus 11 ( 3.6 % ) and 10 ( 3.3 % ) patients in the FF and SF trial arms , respectively ( P=.015 ) . CONCLUSIONS In cardiac surgery patients , especially when more than three blood transfusions are required , leukocyte depletion by filtration results in a significant reduction of the postoperative mortality that can only partially be explained by the higher incidence of postoperative infections in the PC group Abstract Objective To compare postoperative complications in patients undergoing major surgery who received non-filtered or filtered red blood cell transfusions . Design Prospect i ve , r and omised , double blinded trial . Setting 19 hospitals throughout the Netherl and s ( three university ; 10 clinical ; six general ) . Participants 1051 evaluable patients : 79 patients with ruptured aneurysm , 412 patients undergoing elective surgery for aneurysm , and 560 undergoing gastrointestinal surgery . Interventions The non-filtered products had the buffy coat removed and were plasma reduced . The filtered products had the buffy coat removed , were plasma reduced , and filtered before storage to remove leucocytes . Main outcome measures Mortality and duration of stay in intensive care . Secondary end points were occurrence of multi-organ failure , infections , and length of hospital stay . Results No significant differences were found in mortality ( odds ratio for filtered v non-filtered 0.80 , 95 % confidence interval 0.53 to 1.21 ) and in mean stay in intensive care ( - 0.4 day , - 1.6 to 0.6 day ) . In the filtered group the mean length of hospital stay was 2.4 days shorter ( - 4.8 to 0.0 day ; P = 0.050 ) and the incidence of multi-organ failure was 30 % lower ( odds ratio 0.70 , 0.49 to 1.00 ; P = 0.050 ) . There were no differences in rates of infection ( 0.98 , 0.73 to 1.32 ) . Conclusion The use of filtered transfusions in some types of major surgery may reduce the length of hospital stay and the incidence of postoperative multi-organ failure In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias The objective was design ed to assess the clinical efficiency of preventing febrile nonhemolytic transfusion reactions ( FNHTR ) with transfusion of leukocyte-depleted RBC and platelet concentrates . One hundred patients with cirrhosis of liver , gastric ulcer and cancer were selected to receive RBC concentrates with leukocyte filtration . Another group of 50 patients with liver necrosis , gastric ulcer and cancer were selected to receive non-filtered RBC concentrates . Two hundred and forty patients with acute or chronic leukemia , aplastic anemia , multiple myeloma , thrombocytopenia purpura , diabetes mellitus , cirrhosis of liver , upper gastrointestinal hemorrhage , severe hepatitis , burn and cancer post radioactive or chemical treatment were divided into two group with 120 patients in each one and selected r and omly to receive platelet concentrates . The incidence rates of FNHTR in all patients were investigated . Results showed that there was no FNHTR in 100 transfusions with leukocyte-depleted RBC concentrates . Eight out of 50 patients with non-filtrated RBC concentrates showed FNHTR . The incidence of FNHTR was sixteen ( 16 % ) in non-filtrated transfusion . Twenty-five and 7 patients manifested FNHTR respectively in non-filtrated or filtrated platelets transfusions . The incidence of FNHTR was 20.83 % and 5.83 % respectively in non-filtrated or filtrated platelet transfusion . It is concluded that leukocyte-depleted RBC and platelet concentrates reduces FNH TR in blood transfusion BACKGROUND Cardiopulmonary adverse events after transfusion include transfusion-related acute lung injury ( TRALI ) and transfusion-associated circulatory overload ( TACO ) , which are potentially lethal and incompletely understood . STUDY DESIGN AND METHODS To determine whether the incidence of TRALI and TACO was affected by leukoreduction we conducted a retrospective , before- and -after study of acute transfusion reactions for the 7years before and after introduction of universal leukoreduction in 2000 , involving 778,559 blood components . RESULTS Substantial decreases occurred in the rates of TRALI ( -83 % ; from 2.8 cases per 100,000 components before to 0.48 after universal leukoreduction ; p=0.01 ) , TACO ( -49 % ; 7.4 to 3.8 cases per 100,000 ; p=0.03 ) , and febrile reactions ( -35 % ; 11.4 to 7.4 cases per 10,000 ; p<0.0001 ) . The incidence of allergic reactions remained unchanged ( 7.0 per 100,000 before and after universal leukoreduction ) . These outcomes were primarily attributable to decreased TRALI and /or TACO associated with red blood cell ( RBC ) and platelet ( PLT ) transfusions ( -64 % ) with notably smaller decreases associated with fresh-frozen plasma or cryoprecipitate transfusions ( -29 % ) . The incidence of TRALI and /or TACO after 28,120 washed RBC and 69,325 washed transfusions was zero . CONCLUSION These data suggest novel hypotheses for further testing in animal models , in prospect i ve clinical trials , and via the new US hemovigilance system : 1 ) Is TACO or TRALI mitigated by leukoreduction ? 2 ) Is the mechanism of TACO more complex than excessive blood volume ? and 3 ) Does washing mitigate TRALI and TACO due to PLT and RBC transfusions BACKGROUND Transfusion of red blood cells ( RBCs ) has been associated with immunomodulatory effects . Persistence of donor cells in the recipient may be contributive . STUDY DESIGN AND METHODS A r and omized single-center trial was conducted to compare microchimerism and immune responses in 35 patients undergoing cancer surgery and transfused perioperatively with either unmodified RBCs ( UN-RBCs , n = 18 ) or leukoreduced RBCs ( LR-RBCs , n = 17 ) . Biologic parameters included microchimerism assessment peripheral blood mononuclear cell ( PBMNC ) phenotyping , cytokine production by stimulated PBMNCs , FoxP3 gene expression , and T-cell repertoire ( TCR ) analysis . RESULTS Microchimerism was documented in 8 of 18 patients after UN-RBC transfusion while absent after LR-RBC transfusion ( 0/17 ; p = 0.001 ) . After UN-RBC transfusion , microchimerism was associated with increased interleukin (IL)-10 production ( p = 0.02 ) , reduced TCR alteration ( p = 0.04 ) , and reduced CD56 + cell counts ( p = 0.02 ) when compared to recipients without evidence for microchimerism . FoxP3 gene expression did not differ significantly between both treatment groups nor with the presence or absence of microchimerism in the UN-RBC group . Finally , after an initial early decrease after surgery and transfusion , IL-12 production increased and more significantly so after UN-RBC transfusion versus LR-RBC transfusion ( p = 0.05 ) . CONCLUSION UN-RBC-induced microchimerism is associated with specific immunomodulatory effects in cancer patients who received transfusions during surgery In a r and omized study the effect of whole blood transfusion versus bedside leucocyte‐depleted blood transfusion on lymphocyte proliferation , CD4 + : CD8+ratio , and levels of soluble interleukin 2 receptor ( sIL‐2R ) and interleukin ( IL ) 6 , as well as on the development of postoperative wound infection and intra‐abdominal abscess , was assessed in 60 patients undergoing elective colorectal surgery . Transfusion with whole blood induced a significant decrease in lymphocyte proliferation and CD4+:CD8 + ratio ( P < 0·01 ) as well as a significant increase in sIL‐2R and IL‐6 levels ( P < 0·01 ) . Furthermore , transfusion with whole blood was accompanied by a significant increase in postoperative infectious complications ( P < 0·01 ) . In patients transfused with leucocytedepleted blood only slight and transient changes were observed , which were not significantly different from those observed in non‐transfused patients Objective : The requirement for a blood transfusion after trauma is associated with an increased risk of acute lung injury . Residual leukocytes contaminating red cells are potential mediators of this syndrome . The goal of this trial was to test our hypothesis that prestorage leukoreduction of blood would reduce rates of posttraumatic lung injury . Design : Double blind , r and omized , controlled clinical trial . Setting : University-affiliated level I trauma center in King County , Seattle , WA . Patients : Two hundred sixty-eight injured patients requiring red blood cell transfusion within 24 hrs of injury . Interventions : Prestorage leukoreduced vs. st and ard allogeneic blood transfusions . Measurements and Main Results : We compared the incidence of acute lung injury and acute respiratory distress syndrome at early ( ≤72 hrs ) and late ( > 72 hrs ) time points after injury . In a subset , we compared plasma levels of surfactant protein-D and von Willebr and factor antigen between intervention arms . Rates of acute lung injury ( relative risk [ RR ] 1.06 , 95 % confidence interval [ CI ] .69–1.640 ) and acute respiratory distress syndrome ( RR .96 , 95 % CI 0.48–1.91 ) were not statistically different between intervention arms early after injury . Similarly , no statistically significant effect of leukoreduced transfusion on rates of acute lung injury ( RR .88 , 95 % CI .54–1.44 ) or acute respiratory distress syndrome ( RR .95 , 95 % CI .58–1.57 ) was observed to occur late after injury . There was no significant difference in the number of ventilator-free days or in other ventilator parameters between intervention arms . No statistically significant effect of leukoreduced blood on plasma levels of surfactant protein-D or von Willebr and factor antigen was identified . Conclusions : Prestorage leukoreduction had no effect on the incidence or timing of lung injury or on plasma measures of systemic alveolar and endothelial inflammation in a population of trauma patients requiring transfusion . The relationship between transfusion and lung injury is not obviously explained by mechanistic pathways involving the presence of transfused leukocytes Abstract . Allogeneic blood transfusions are cl aim ed to be an independent risk factor for postoperative infections in open colorectal surgery due to immunomodulation . Leukocyte-depletion of erythrocyte suspensions has been shown in some open r and omized studies to reduce the rate of postoperative infection to levels observed in nontransfused patients . Using a double-blinded , r and omized design , we studied the postoperative infection rate in patients undergoing open colorectal surgery transfused with either leukocyte-depleted erythrocyte suspensions ( LD-SAGM ) or non-leukocyte-depleted erythrocyte suspensions ( SAGM ) . Unselected patients ( n 279 ) were allocated to receive LD-SAGM ( n 139 ) or SAGM ( n 140 ) if transfusion was indicated . Forty-five percent were transfused , yielding 48 patients in the LD-SAGM group and 64 in the SAGM group . Thirteen patients were excluded because they received one type of transfusion in spite of r and omization to the other type . No significant differences in the rates of postoperative infections ( P=0.5250 ) or postoperative complications ( P=0.1779 ) were seen between the two transfused groups . Infection rates were 45 % and 38 % in the transfused groups and 21 % and 23 % in the nontransfused groups . No significant difference between the transfused groups was seen on any single infectious event , mortality rate , or duration of hospitalization . Leukocyte-depletion of erythrocyte suspensions transfused to patients undergoing open colorectal surgery does not reduce postoperative infection rates The results of leucocyte filtration during cardiac surgery are conflicting . This may be due to timing and duration of the filtration procedure , and to flow and pressure conditions in the filter . Therefore , we prospect ively compared three major leucocyte filtration strategies in cardiac surgical patients . Forty patients were r and omly divided into four groups . Group I : leucofiltration of arterial blood throughout cardiopulmonary bypass ( CPB ) ( associated with high-flow and pressure gradients ) , Group II : leucofiltration of a part of the venous return blood in the re-warming phase during CPB ( associated with intermediate flow , but high pressure ) , Group III : leucofiltration of residual heart-lung machine blood during transfusion into the patient after CPB ( associated with low flow and low pressure ) , Group IV : control group without leucofiltration . We measured circulating leucocyte counts , plasma elastase levels and arterial blood oxygenation . Filters were postoperatively examined using scanning electronmicroscopy ( SEM ) . Leucocyte counts increased over time and oxygenation decreased in all groups , without significant differences between the groups . SEM demonstrated extensive protein deposits and damaged leucocytes in the deeper layers of the filters from Group I. This was not observed in the filters from Group III . The postoperative plasma elastase levels increased in Groups II and IV and decreased in Groups I and III . In conclusion , we could not demonstrate a clinical difference among the three leucocyte depletion strategies . However , our laboratory results suggest that leucocyte filtration at low flow and pressure conditions is associated with less leucocyte damage and less release of elastase Cardiopulmonary bypass ( CPB ) leads to a generalized inflammatory reaction , result ing in increased postoperative leucocyte counts and decreased pulmonary function . In adults , removal of leucocytes from the residual heart - lung machine blood after CPB improved postoperative oxygenation . In children , however , the clinical effects of leucocyte filtration of the residual heart - lung machine blood are unknown . Therefore , we measured postoperative leucocyte counts and arterial blood oxygenation in children undergoing congenital cardiac surgery in a r and omized prospect i ve study . Anaesthesia and CPB were st and ardized . After CPB , the residual heart-lung machine blood was collected as usual . In a group of 25 children , this blood was filtered with a leucocyte depletion filter before transfusion . A control group of 25 children received this blood unfiltered . We found that the postoperative leucocyte counts were significantly lower in the filter group than in the control group ( p=0.02 , repeated measurements ANOVA ) . This difference reached a maximum on the second postoperative day ( 12.9 × 109/L filter versus 15.9 × 109/L control , p=0.02 , Student ’s t-test ) . Values for the arterial blood oxygenation on the first postoperative day were not different between the two groups ( 15.5±1 kPa filter versus 14.6±1.3 kPa control , p=0.57 , Student ’s t-test ) . We conclude that leucocyte filtration of the residual heart-lung machine blood reduced systemic leucocyte counts , but did not improve arterial blood oxygenation in children after congenital heart surgery BACKGROUND A beneficial effect of pretransplant transfusions on graft survival was demonstrated in the early 1970s . In the mid-1980s , however , retrospective studies showed that transfusions had lost their graft-protective effect in the cyclosporine era . During the last 10 years , deliberate transfusion pretreatment of transplant patients has been discontinued . METHODS Within a collaborative project of 14 transplant centers , prospect i ve recipients of cadaver kidney grafts were r and omized to receive either three pretransplant transfusions or transplants without transfusions . RESULTS ; The graft survival rate was significantly higher in the 205 transfusion recipients than in the 218 patients who did not receive transfusions ( at 1 year : 90+/-2 % vs. 82+/-3 % , P=0.020 ; at 5 years : 79+/-3 % vs. 70+/-4 % , P=0.025 ) . Cox regression analysis showed that this effect was independent of age , gender , underlying disease , prophylaxis with antilymphocyte antibodies , and preformed lymphocytotoxins . CONCLUSIONS ; Transfusion pretreatment improves the outcome of cadaver kidney transplants even with the use of modern immunosuppressive regimens BACKGROUND Recipient exposure to allogeneic donor WBCs results in transfusion complications for selected population s of recipients . Whether or not WBC reduction should be universally applied is highly controversial . STUDY DESIGN AND METHODS In a general hospital , a r and omized , controlled clinical trial of conversion to universal WBC reduction was conducted . Patients ( 11 % ) with established medical indications for WBC-reduced blood were not eligible . All other patients who required transfusion were assigned at r and om to receive either unmodified blood components or stored WBC-reduced RBCs and platelets . Analysis for each patient was restricted to the first hospitalization . RESULTS All eligible patients ( n = 2780 ) were enrolled . Three specified primary outcome measures were not different between the two groups : 1 ) in-hospital mortality ( 8.5 % control ; 9.0 % WBC-reduced ; OR , 0.94 [ 95 % CI , 0.72 - 1.22 ] ; p = 0.64 ) ; 2 ) hospital length of stay ( LOS ) after transfusion ( median number of days , 6.4 for control and 6.3 for WBC-reduced ; p = 0.21 ) ; and 3 ) total hospital costs ( median , $ 19,500 for control and $ 19,200 for WBC-reduced , p = 0.24 ) . Secondary outcomes ( intensive care LOS , postoperative LOS , antibiotic usage , and readmission rate ) were not different between the two groups . Subgroup analysis based on patient age , sex , amount of blood transfused , or category of surgical procedure showed no effect of WBC reduction . Patients who received WBC-reduced blood had a lower incidence of febrile reactions ( p = 0.06 ) . CONCLUSION A beneficial effect of conversion from selective to universal WBC reduction was not demonstrated BACKGROUND A before and after study was undertaken to investigate the effect of universal leukoreduction ( ULR ) in the UK on postoperative length of hospital stay ( LOS ) and infections . STUDY DESIGN AND METHODS Consecutive patients undergoing elective coronary artery bypass grafting or total hip and /or knee replacement in 11 hospitals received non-WBC-reduced RBCs before implementation of ULR ( T1 , n=997 ) or WBC-reduced RBCs after implementation of ULR ( T2 , n=1098 ) . RESULTS Patients in T1 and T2 were comparable except patients in T2 received on average more units of RBCs but had lower discharge Hct levels . Postoperative LOS ( T1 , 10 + /- 8.9 days ; T2 , 9.6 + /- 6.9 days ) and the proportion of patients with suspected and proven postoperative infections ( T1 , 21.0 % ; T2 , 20.0 % ) were unchanged before and after ULR ( LOS , hazard ratio 1.01 , 95 % CI 0.92 - 1.10 ; infections , OR 0.83 , 95 % CI 0.77 - 1.02 ) . Subgroup analysis showed no significant interaction between storage age or dose of blood on responsiveness of primary outcomes to ULR . Secondary outcomes were unchanged overall . Analysis by surgical procedure gave conflicting results with both increased mortality ( p=0.031 ) and an increased proportion of cardiac patients with proven infections ( p=0.004 ) , whereas the proportion of orthopedic patients with proven infections was reduced ( p=0.002 ) after ULR . CONCLUSION Implementation of ULR had no major impact on postoperative infection or LOS in patients undergoing elective surgical procedures who received transfusion(s ) . Smaller effects , either detrimental or beneficial of ULR , can not be excluded BACKGROUND Allogeneic transfusion is associated with postoperative infections that significantly prolong hospital stays and increase costs . Recent studies suggest that filtering leukocytes from blood prior to transfusion reduces the risk of postoperative infection associated with blood transfusion . We compared the incidence of postoperative infections , hospital stays , and hospital charges of gastrointestinal surgery patients transfused with packed red cells or leukocyte-depleted cells . METHODS Consecutive patients admitted for elective gastrointestinal surgery without previous blood transfusion were r and omized to receive routine packed red cells or packed red cells filtered to remove leukocytes if transfusion was required . Multivariate analysis was used to assess the significance of the relationship between leukocyte-depleted blood and postoperative infectious complications , postoperative stay , and hospital charges . RESULTS Fifty-nine ( 27 % ) of the 221 patients were transfused . The most significant variable related to transfusion was intraoperative blood loss ( P < 0.0001 ) , followed by admission hematocrit ( P < 0.0001 ) and age ( P = 0.0022 ) . Infections were noted in 16 % of the patients : 11 % of untransfused patients , 16 % of leukocyte-depleted blood recipients , and 44 % of patients transfused with packed red cells . Both operative site and nosocomial infections were significantly ( P < 0.001 ) more frequent in patients transfused with packed red cells compared with patients transfused with leukocyte-depleted red cells . Postoperative stays averaged 9 days for untransfused patients , 12 days for leukocyte-depleted recipients , and 18 days for recipients of packed red cells . Hospital charges were $ 19,132 , $ 33,954 , and $ 41,002 , respectively . Both transfusion and infection were significantly ( P < 0.001 ) related to postoperative stay in multivariate analysis . Hospital charges were significantly related to postoperative stay ( P < 0.001 ) , blood loss ( P < 0.001 ) , age ( P < 0.001 ) , infection ( P = 0.007 ) , and r and omization to packed red cells ( P = 0.032 ) . CONCLUSIONS Filtering blood of leukocytes prior to transfusion for elective gastrointestinal surgery is associated with lower risk of postoperative infection , shorter postoperative stays , and lower hospital charges A prospect i ve r and omized study at a single renal transplant center between 1980 and 1982 compared the influence of leukocyte-depleted versus packed red cell pretransplantation blood transfusions on patient sensitization to leukocyte ( HLA ) antigens , likelihood of receiving a graft , and eventual transplantation results . All consenting potential cadaver renal transplant recipients ( n = 107 ) were r and omly assigned to receive transfusions at 6-week intervals with either packed red cells ( Group 1 ) or leukocyte-poor red cells ( Group 2 ) until they were transplanted . Actuarial graft and patient survival were identical for graft recipients in both groups . Although the likelihood of receiving a graft was associated with the level of pretransplant sensitization to leukocyte ( HLA ) antigens ( p less than 0.02 ) as measured by the percent of panel reactive antibody ( PRA ) , it was not associated with the type of blood used . The highest mean peak reactive PRA level for all patients showed a low but significant increase ( 29 + /- 4 versus 43 + /- 5 % ; p less than 0.0005 ) following entry into the transfusion protocol , but the rate of increase was the same for patients in both treatment groups . The likelihood of receiving a transplant was primarily associated with a history of prior graft rejection ( p less than 0.05 ) , and patients with prior graft loss had the greatest increase in sensitization following entry into the transfusion protocol . These findings indicate that using leukocyte-poor red cells for pretransplant transfusions provided no added benefit when compared with packed red cells in terms of patient sensitization , the likelihood of receiving a transplant , or eventual graft survival ABSTRACT Allogeneic blood transfusions in surgical patients have been associated with an increased risk of infectious complications and organ dysfunction . Residual leukocytes contaminating units of packed red blood cells have been incriminated through the induction of anergy and /or a potentiated inflammatory response , leading to the possibility that leukoreduced red blood cell transfusion might mitigate these effects . We set out to evaluate the effect of leukoreduced red cell transfusion on the risk of infections complications in patients requiring transfusion following injury . We conducted a single-center , double-blinded r and omized controlled trial of leukoreduced versus st and ard , nonleukoreduced red blood cell transfusions in injured patients receiving transfusion within 24 hrs of injury . The primary endpoint was infectious complications within 28 days of r and omization . Secondary end points were multiple organ failure , length of stay , febrile episodes , and mortality . Two hundred sixty eight subjects were eligible for analysis . Rates of infectious complications were similar in subjects receiving leukoreduced transfusions ( 30 % ) or st and ard transfusions ( 36 % ) ( [ RR ] , 0.84 [ 0.55 - 1.3 ] ) and there was no statistically significant effect of leukoreduced blood transfusion on mortality [ RR , 1.20 ( 0.74 - 1.9 ) ] , febrile episodes [ RR , 1.01 ( 0.89 - 1.2 ) ] , or organ dysfunction scores ( 5.9 vs. 6.6 ; P = 0.29 ) . Thus , pre-storage leukoreduction of allogeneic red blood cells had a small , but non-significant effect on the rate of infectious complication in this high-risk population requiring transfusion . There was no effect on the rates of febrile episodes , mortality , length of stay , or severity of organ dysfunction BACKGROUND Most previous studies on white cell ( WBC ) reduction by filtration have been small-scale studies conducted under tightly controlled laboratory conditions . Their results would be the ideal , rather than what might be expected during routine operation . STUDY DESIGN AND METHODS To obtain information on routine filtration of blood components , data have been collected from a large-scale , ongoing , multicenter clinical trial design ed to determine the effectiveness of WBC reduction in or ultraviolet B radiation of platelet concentrates before transfusion in preventing platelet alloimmunization and platelet transfusion refractoriness . The WBC content of blood components both before and after filtration was determined by automated cell counters and a manual propidium iodide-staining method , respectively . Platelet and red cell losses during filtration were measured . RESULTS The average platelet losses after filtration were 24 + /- 15 percent and 20 + /- 9 percent for apheresis platelets and pooled platelets , respectively . The frequencies at which filtered platelet concentrates contained high levels of residual WBCs ( > 5 x 10(6 ) ) were 7 percent and 5 percent for apheresis platelets and pooled platelets , respectively . Further analysis of the platelet filtration data showed that greater numbers of total initial WBCs in the pooled platelets were associated with increased percentages of filtration failure ( > 5 x 10(6 ) residual WBCs ) . For packed red cells , the average losses during filtration were 23 + /- 4 percent and 15 + /- 3 percent for CPDA-1 units and Adsol units , respectively . The frequencies at which filtered red cells contained > 5 x 10(6 ) residual WBCs were 2.7 percent for one type of filter and 0.3 percent for another type of filter . CONCLUSION There were significant losses of platelets during filtration , which could add to the costs of WBC reduction and lead to possible increases in donor exposures . Filtration failures still occurred , despite careful observation of the st and ard filtration procedures . The number of total WBCs in pooled platelets before filtration has been identified as an important factor in determining the success of WBC reduction Purpose . To investigate effects of blood transfusion , with/without leucocyte depletion , on duration of hospital stay , need for respiratory support , mortality and long-term survival after curative surgery for colorectal cancer . Methods . The trial was a prospect i ve , r and omised , multicenter study . Six hundred and forty two patients with colorectal cancer were included . Blood transfusion was given when needed during and /or after operation , r and omised to packed red blood cells ( RBC ) or leucocyte-depleted red blood cells ( LDB ) using leucocyte filtration . Assisted ventilation in ICU , hospital stay , malignant and non-malignant specific mortality and overall survival were outcome measures . Results . The RBC group had higher need for assisted ventilation post-operatively ( 8.1 % vs. 3.6 % ) and significantly higher proportion of patients with prolonged ( > 20 days ) hospital stay . After median follow-up time of 99.5 months there was no significant difference in mortality or long-term survival between the groups . The median cumulative survival time of 55 months in LDB vs. 36 months in RBC group did not reach significance level . Non-transfused patients had a significantly lower proportion of prolonged hospital stay , and significantly increased survival , compared to transfused patients . Conclusion . Leucocyte depleted transfusions improved the postoperative course following surgery for colorectal cancer , compared with packed red blood cell transfusions Leukocyte depletion during cardiopulmonary bypass has been demonstrated in animal experiments to improve pulmonary function . Conflicting results have been reported , however , with clinical depletion by arterial line filter of leukocytes at the beginning of cardiopulmonary bypass . In this study , we examined whether leukocyte depletion from the residual heart-lung machine blood at the end of cardiopulmonary bypass would improve lung function and reduce the postoperative inflammatory response . Thirty patients undergoing elective heart operations were r and omly allocated to a leukocyte-depletion group or a control group . In the leukocyte-depletion group ( n = 20 ) , all residual blood ( 1.2 to 2.1 L ) was filtered by leukocyte-removal filters and reinfused after cardiopulmonary bypass , whereas in the control group an identical amount of residual blood after cardiopulmonary bypass was reinfused without filtration ( n = 10 ) . Leukocyte depletion removed more than 97 % of leukocytes from the retransfused blood ( p < 0.01 ) and significantly reduced circulating leukocytes ( p < 0.05 ) and granulocytes ( p < 0.05 ) compared with the control group . Levels of the inflammatory mediator thromboxane B2 determined at the end of operation ( p < 0.05 ) were significantly lower in the depletion group than in the control group , whereas no statistical differences in interleukin-6 levels were found between the two groups . After operation , pulmonary gas exchange function ( arterial oxygen tension at a fraction of inspired oxygen of 0.4 ) was significantly higher in the leukocyte-depletion group 1 hour after arrival to the intensive care unit ( p < 0.05 ) and after extubation ( p < 0.05 ) . There were no statistical differences between the two groups with respect to postoperative circulating platelet levels and blood loss , and no infections were observed during the whole period of hospitalization . These results suggest that leukocyte depletion of the residual heart-lung machine blood improves postoperative lung gas exchange function and is safe for patients who are expected to have a severe inflammatory response after heart operations BACKGROUND RBC transfusion is associated with fever and other reactions in some patients . The Viral Activation Transfusion Study r and omly assigned patients to receive either unmodified or WBC-reduced RBCs and thus offered an opportunity to assess the effect of WBC-reduced RBCs on the incidence of transfusion reactions prospect ively . STUDY DESIGN AND METHODS This prospect i ve , r and omized , double-blind , multicenter study compared prestorage WBC-reduced RBCs to unmodified RBCs in HIV-infected , CMV-seropositive , and transfusion-naive persons who required transfusions for anemia . Primary endpoints were survival and change in the plasma HIV RNA level at 7 days after transfusion . The incidence of transfusion reactions was prospect ively evaluated . RESULTS The two groups had similar baseline characteristics and study endpoints ; 3864 RBC units ( median storage age , 9 days ) were administered to 531 patients during 1745 transfusions . The most frequent signs reported were elevated temperature and hypotension . Subjects who reported fever within the week prior to transfusion were more likely to have an elevation in temperature associated with transfusion . The administration of RBCs that were less than 10 days old was associated with a marginal increase in the incidence of transfusion-associated temperature elevation among recipients of unmodified RBCs , but not among recipients of WBC-reduced RBCs . Caregivers reported fewer instances of both elevated temperature and hypotension than were identified by review of transfusion records . CONCLUSIONS The incidence of elevated temperature and hypotension associated with transfusion in this population was unexpectedly high . Use of WBC-reduced RBCs had no effect on the overall rates of elevated temperature or hypotension associated with transfusion of RBCs . The occurrence of a pre-existing fever was associated with a higher frequency of transfusion-associated elevated temperature In retrospective studies , perioperative blood transfusions were associated with poor prognosis after surgery for cancer and were a major independent risk factor for postoperative bacterial infection . Leucocyte-depleted , in contrast to buffy-coat-depleted , blood has no immunosuppressive effects in transplantation and so might lack detrimental effects on cancer prognosis and postoperative infections . We studied this hypothesis in a controlled trial by r and omly allocating patients to receive either leucocyte-depleted red cells or packed cells without buffy coat when blood was needed . Between 1987 and 1990 , 871 eligible patients with colorectal cancer , including 697 patients operated upon with curative intent , were r and omised in the 16 participating hospitals . Neither the eligible group nor the curative group showed significant differences between the two trial transfusions in survival , disease-free survival , cancer recurrence rates , or overall infection rates after an average follow-up of 36 months . Patients who had a curative resection and who received blood of any sort had a lower 3-year survival than non-transfused patients ( 69 % vs 81 % , p = 0.001 ) and a higher infection rate ( 39 % vs 24 % , p < 0.001 ) . Colorectal cancer recurrence rates , however , were not influenced by blood transfusion ( 30 % vs 26 % , p = 0.22 ) . These combined observations confirm the association between blood transfusion and poor patient survival but indicate that the relation is not due to promotion of cancer Adverse effects of perioperative blood transfusion appear to be storage-time-dependent and may be related to extracellular accumulation of bioactive substances in blood products . In this study the clinical effects of leukofiltered and non-filtered blood products in patients undergoing surgery for burn trauma are investigated . 24 consecutive patients were r and omly selected to receive transfusion with non-filtered blood components ( group A , n = 12 ) or similar products , which were prestorage leukofiltered ( group B , n = 12 ) . The burn injury was scored using the Bull and Fischer index of age and burn surface area . Histamine , interleukin-6 ( IL-6 ) , plasminogen activator inhibitor-1 ( PAI-1 ) , eosinophil cationic protein ( ECP ) and myeloperoxidase ( MPO ) were analysed in plasma or serum collected from all patients 30 min before skin incision , at skin incision and 5 , 10 and 30 min and thereafter every 30 min after skin incision until the grafts were secured by wrapping . Sample s were also taken 8 h after skin incision and in the morning of postoperative days 1 - 5 . The amount of blood products transfused from admission until day 5 postoperatively was recorded . All patients were followed until discharge or death . The Bull and Fischer index was comparable in the two groups . Prestorage leukofiltration reduced the amount of blood products required for transfusion significantly ( p < 0.05 ) compared with non-filtered products . The levels of the various bioactive substances changed during and after the operation . In particular , ECP and MPO levels increased significantly ( p < 0.05 ) in group A patients compared with unchanged ( ECP ) or decreased ( MPO ) levels in group B patients . IL-6 analyses showed , that the trauma had more severe impact on group B patients than on group A patients . Nevertheless , 4 patients died in group A and 2 in group B ; all with a Bull and Fischer index between 1.0 and 2.0 . Prestorage leukocyte filtration may reduce transfusion related accumulation of various bioactive substances and the requirement for blood in burn trauma patients BACKGROUND The beneficial effect of blood transfusions before cadaveric renal transplantation on allograft survival , although previously well documented , has become controversial in light of their adverse effects . Recently , it has been suggested that their clinical benefits are due to HLA-DR sharing between the blood donor and recipient . METHODS In this prospect i ve study , 144 naive patients were r and omly assigned to receive one unit of blood matched for one-HLA-DR antigen ( N = 49 ) , or one unit of mismatched blood ( N = 48 ) , or to remain untransfused ( N = 47 ) . Graft survival and acute rejection rate were analyzed in 106 cadaveric renal allograft recipients receiving the same immunosuppressive protocol . RESULTS Graft survival was similar in the three groups at one and five years : 91.7 and 80 % in untransfused patients , 90.3 and 79.3 % in patients transfused with one DR-antigen-matched unit , and 92.3 and 83.7 % in patients transfused with HLA-mismatched blood . The difference in the incidence of six-month post-transplant acute rejections was not statistically significant in the three groups : 12 out of 36 , 33.3 % in nontransfused patients ; 6 out of 31 , 19.4 % in patients transfused with one DR-matched blood ; and 13 out of 39 , 33.3 % in patients transfused with mismatched blood . CONCLUSION The results of our prospect i ve r and omized trial showed that in a population of naive patients , one transfusion mismatched or matched for one HLA-DR antigen given prior to renal transplantation had no significant effect on the incidence and severity of acute rejection , and did not influence overall long-term graft outcome . Considering the potentially deleterious adverse effects of blood transfusions , the costs , and the considerable logistical efforts required to select and type blood donors , such a procedure can not be recommended in a routine practice for patients awaiting cadaveric kidney transplantation BACKGROUND Activated leukocytes may increase morbidity in cardiac surgery . The objective of this study is to investigate the influence on morbidity of leukocyte-depleting blood filters placed into the arterial line of cardiopulmonary bypass circuits . METHODS Simple , blind , prospect i ve , r and omized and controlled clinical trial carried out in a cardiac surgery ICU at a university center . We included 159 consecutive low-risk patients ( ie , Parsonnet score < 10 ) undergoing cardiac surgery who were initially stratified in three risk levels according to the Parsonnet score at admission into the hospital ( ie , low , < 4 ; middle , 4 to 7 ; and high , 8 to 10 ) . Once stratified , all patients were r and omized to undergo cardiopulmonary bypass either with a conventional blood filter or with a leukocyte filter ( r and omization ratio , 2:1 ) . The outcome variable was morbidity . Patients were considered to have a high morbidity if any of the following clinical situations were present ( ie , pulmonary dysfunction , cardiac dysfunction , perioperative infections , postoperative hyperthermia , and hyperdynamic states ) . RESULTS The leukocyte filter was used in 52 patients and the conventional filter in 107 patients . The morbidity rate was similar in both groups , but patients with leukocyte filter had a lower incidence of perioperative infections , fever , and hyperdynamic states as compared with patients with the conventional filter . CONCLUSIONS Leukocyte filtration in patients undergoing cardiac surgery with extracorporeal perfusion showed no measurable effects on postoperative morbidity . However , although not statistically significant , a decrease was observed in the rates of perioperative infection , fever , and hyperdynamic states BACKGROUND Allogeneic blood transfusion is associated with an increased frequency of postoperative infection . We studied whether such events can be avoided by the intraoperative and postoperative use of leucocyte-depleted blood . METHODS 589 consecutive patients scheduled for elective colorectal surgery were r and omised to receive buffy-coat poor ( n = 299 ) or filtered leucocyte-depleted red-cells ( n = 290 ) when transfusion was indicated . 260 patients actually received blood transfusion . Three patients were excluded from analysis . FINDINGS The 142 patients r and omised to and transfused with buffy-coat-poor blood had a significantly higher frequency of wound infections and intra-abdominal abscesses than the 155 patients who were allocated to this group but who were not transfused . ( 12 vs 1 % , p < 0.0001 ) and ( 5 vs 0 % , p = 0.005 ) , respectively . Those receiving buffy-coat-poor blood also had a significantly higher frequency of wound infections and intra-abdominal abscesses than the 118 r and omised to and receiving leucocyte-depleted blood ( 12 vs 0 % , p < 0.0001 ) and ( 5 vs 0 % , p = 0.017 ) , respectively . Postoperative pneumonia occurred at a significantly higher rate in patients receiving buffy-coat-poor blood : 23 versus 3 % in non-transfused patients ( p < 0.0001 ) , and 23 versus 3 % in patients transfused with leucocyte-depleted blood ( p < 0.001 ) . The mortality rate between the groups was not statistically different . INTERPRETATION Our data suggests that the association between allogeneic blood transfusion and postoperative infection is limited to allogeneic blood products that are not adequately depleted of immunosuppressive leucocytes . This undesirable effect can be reduced by leucocyte depletion with high-efficiency filters In the GRADE approach , r and omized trials are classified as high quality evidence and observational studies as low quality evidence but both can be rated down if a body of evidence is associated with a high risk of publication bias . Even when individual studies included in best- evidence summaries have a low risk of bias , publication bias can result in substantial overestimates of effect . Authors should suspect publication bias when available evidence comes from a number of small studies most of which have been commercially funded . A number of approaches based on examination of the pattern of data are available to help assess publication bias . The most popular of these is the funnel plot ; all , however , have substantial limitations . Publication bias is likely frequent , and caution in the face of early results , particularly with small sample size and number of events , is warranted Background — We present the first prospect i ve r and omized study of primary coronary artery bypass grafting ( CABG ) patients who were analyzed for postoperative infections after undergoing blood and /or blood product transfusion ( BBPT ) with a Pall Purecell leukoreducing filter . Methods and results — One hundred and four patients were enrolled between March 1998 and March 1999 . Seventy-two of the patients received BBPT ( average 5.6 units BBPT/filter patient and 5.6 units/control patient ) . Three patients who had CABG without extracorporeal circulation or mixed transfusions of filtered and unfiltered BBPT were excluded . The remaining 69 transfused patients ( 38 filtered , 31 control ) were analyzed and the incidence of culture proven infections was recorded . Mid-term survival data were obtained from the National Death Index and Kaplan-Meier survival plots were constructed . All patients were stratified and matched according to the EuroSCORE . Thirty-day mortality was 2.6 % and 3.2 % for the filtered and control patients , respectively . There were 5 cases of culture proven infections in 38 filtered patients ( 13.2 % ) and 8 in 31 controls ( 25.8 % ) , P=0.224 . No pulmonary tract infections were recorded in the filter group vs. 4 ( 12.9 % ) in controls , P=0.048 . Reduced length for mechanical ventilation ( 16.3 hours vs. 57.8 , P=0.103 ) , length of stay ( 9.1 vs. 10.8 days , P=0.685 ) , as well as increased 50-month actuarial survival , ( 45.5 vs. 42.3 months , P=0.695 ) in filtered vs. control , respectively , were recorded . Conclusions — The use of leukoreduced BBPT reduced the incidence of pulmonary tract infections in patients undergoing CABG OBJECTIVE Leucocyte filtration of salvaged blood has been suggested to prevent patients from receiving activated leucocytes during auto-transfusion in cardiac surgery . This study examines whether leucocyte filtration of salvaged blood affects the red blood cell ( RBC ) function and whether there is a difference between filtration of the concentrated and diluted blood on RBC function . METHODS Forty patients undergoing cardiac surgery with cardiopulmonary bypass were r and omly divided into a group receiving leucocyte filtration of concentrated blood ( High-Hct , n=20 ) and another group receiving leucocyte filtration of the diluted blood ( Low-Hct , n=20 ) . During operation , all the salvaged blood , as well as the residual blood , from the heart-lung machine was filtered . In the High-Hct group , blood was concentrated with a cell saver prior to filtration , whereas in the Low-Hct group , blood was filtered without concentration . RBC function was represented by RBC aggregation and deformability measured by a laser-assisted optical rotational cell analyser and by the RBC 2,3-diphosphoglycerate ( 2,3-DPG ) and adenosine triphosphate ( ATP ) contents with conventional biochemical tests . RESULTS Leucocyte filtration of diluted blood with a low haematocrit ( 14+/-4 % ) did not affect RBC function . However , when the concentrated blood with a high haematocrit ( 69+/-12 % ) was filtered , there was a reduction of ATP content in RBCs after passing through the filter ( from 1.45+/-0.57 micromol g(-1 ) Hb to 0.92+/-0.75 micromol g(-1 ) Hb , p<0.05 ) . For patients who received the concentrated blood , their in vivo RBC function did not differ from those who received diluted blood . CONCLUSIONS Leucocyte filtration of the diluted salvaged blood during cardiac surgery does not affect RBC function , but it tends to deplete the ATP content of RBCs as the salvaged blood has been concentrated prior to filtration The use of blood products to support patients undergoing the large variety of medical and surgical interventions requiring such support has continued to escalate very significantly over time . Relevantly , significant practice variation in the use of blood products exists among practitioners and institutions , largely because of the lack of robust clinical trial data , in many instances , which are critical for providing practitioners with evidence -based guidelines for appropriate blood product utilization . Recognizing this gap , the National Heart , Lung , and Blood Institute recently established a State-of-the-Science Symposium to help define areas of clinical trial research that would enhance the opportunity for developing appropriate practice guidelines for both Transfusion Medicine and Hemostasis/Thrombosis . Such a Symposium was held in September 2009 to identify important clinical trial research issues in these 2 subject areas of endeavor . The aims of this Symposium were to specifically identify phase 2 and 3 clinical trials that , if conducted over the next 5 to 10 years , could impact the treatment of patients with hemostatic and other disorders as well as to optimize the use of blood products in patients who need such interventions . This article reports on the deliberations that were held relating to the various clinical trial concepts developed by 7 Transfusion Medicine subcommittees . This Symposium generated a rich assortment of clinical trial proposals that will undergo further refinement before final implementation into pilot or full r and omized clinical trials . The various proposals identified many opportunities for clinical trial research and most importantly underscored the ongoing need for well-developed evidence -based clinical trial research in the field of Transfusion Medicine BACKGROUND Despite early promise as a means of reducing the inflammatory response to surgery and subsequent organ damage , the evidence of the clinical value of leukocyte filtration remains equivocal . METHODS Three hundred patients presenting for routine coronary artery bypass surgery were r and omized to a total leukocyte filtration group ( filters in five different locations ) and a control group with a st and ard 40-mum filter in the bypass return line only . Data on efficacy and safety of leukocyte filtration were collected by research and postoperative care staff who were blinded to the mode of filtration . RESULTS Leukofiltration achieved a transient fall in white cells immediately after surgery ( p = 0.07 ) and a sustained fall in platelets , which was still significant on the second postoperative day ( p = 0.0001 ) . However , there were no significant differences in postoperative hospital stay , the primary outcome variable ( p = 0.35 ) , in ICU stay ( p = 0.92 ) , or mortality ( p = 1.0 ) . There were no differences in postoperative cardiac status including cardiac output ( p = 0.16 ) , inotrope ( p = 0.93 ) or balloon pump ( p = 0.48 ) requirement , or 24-hour troponin ( p = 0.60 ) . Similarly there were no differences in pulmonary or renal function ( intubation time ( p = 0.83 ) , respiratory index ( p = 0.19 ) rise in creatinine ( p = 0.13 ) or hemofiltration ( 1.0 ) ) . Leukofitration was not associated with a statistically significant increase in bleeding or requirement for blood or blood products . It was associated with a decrease approaching significance ( p = 0.1 ) in number and severity of postoperative wound infections . Three filters were blocked during use but were changed without incident or compromise to patient safety . CONCLUSIONS Leukocyte filtration is safe but not efficacious in improving short-term outcome BACKGROUND WBC-replete blood transfusion has been suggested as an independent cause of increased postoperative infection . STUDY DESIGN AND METHODS A total of 597 patients undergoing elective coronary artery or heart valve surgery were r and omly assigned to receive plasma-reduced ( PR ) , buffy coat-depleted ( BCD ) , or WBC-filtered ( WCF ) RBCs in the event of requiring blood transfusion . Details of postoperative course were recorded . Further information was collected from the patient 's general practitioner 3 months after discharge . RESULTS No significant difference in inpatient infection rates was observed among patients r and omly assigned to receive PR , BCD , or WCF RBCs . When only those receiving transfusion were analyzed ( n = 509 ) , use of PR RBCs was associated with more events coded as infections ( p < or = 0.05 ) compared with BCD or WCF RBCs . However , when events coded as urinary tract infections were excluded , there was no significant difference among the three groups . Follow-up performed after discharge showed no difference in readmission rates , but a higher reported rate of infection in those r and omly assigned to receive WCF RBCs ( p < 0.02 ) . CONCLUSION No evidence has been found , analyzed by intention to treat , that use of WBC-reduced , BCD , or WCF RBCs reduces postoperative inpatient infection in patients undergoing cardiac bypass surgery A multicentre , controlled trial was carried out to determine whether removal of leucocytes from blood by means of ' Imugard IG500 ' ( Terumo ) filters would prevent transfusion-acquired cytomegalovirus ( CMV ) infection in newborn infants . 72 infants whose mothers were seronegative and who received some seropositive blood were followed for 6 months for evidence of CMV infection . There were no significant differences between the groups who received filtered and unfiltered blood in median gestation , birthweight , or amount of seropositive blood received ( median volume 32.5 ml and 34.5 ml , respectively ) . 9 ( 21 % ) of the 42 infants who received unfiltered blood and none of the 30 who received filtered blood were infected with CMV . All infected infants weighed less than 1500 g at birth ; they represented 31 % of very low birthweight ( VLBW ) infants at risk of CMV infection . None of 24 VLBW infants who received filtered seropositive blood was infected . 1 infected infant died and 5 had clinical features consistent with CMV infection . The results show that transfusion-acquired CMV infection is preventable by filtration of blood through a leucocyte filter . This method has advantages over other methods of removing leucocytes or the use of only seronegative blood for newborn infants AIM We examined the impact of leukocyte filtration during the entire bypass time on postoperative leukocytosis , perioperative hemorrhage and overall clinical outcome in patients undergoing elective cardiac surgery . METHODS Eighty patients who electively underwent cardiac surgery were r and omly allocated to a leukocyte depletion group ( n=40 ) or a control group ( n=40 ) . In patients of the leukocyte depletion group an arterial line filter with leukocyte depleting capacity ( Pall LG6 ) was applied instead of a st and ard arterial line filter . White blood cells and platelet count were estimated preoperatively and at various times postoperatively . Postoperative clinical outcomes were also recorded . RESULTS Repeated measure analysis of variance between groups showed that leukocyte counts were significantly lower in the depletion group postoperatively ( p=0.005 ) whereas no difference was found in the platelet counts ( p=0.37 ) . The catecholamine dose required at the time of weaning from cardiopulmonary bypass and during the first 12 postoperative hours was found to be lower in the leukodepletion group ( p=0.027 and p=0.021 , respectively ) . Furthermore leukodepleted patients showed a transient improvement in the oxygenation index ( p=0.029 ) and a shorter period of mechanical ventilation ( p<0.001 ) . The incidences of postoperative complications were similar between the groups . No difference was observed in regard to postoperative blood loss ( p=0.821 ) and amount of packed red blood cells required for transfusion during the first 24 hours ( p=0.846 ) . The duration of intensive care unit stay and of hospitalization were similar between the groups . CONCLUSION Leukocyte depletion contributes to early postoperative improvement in heart and lung function but does not influence significantly the overall clinical outcome of patients undergoing elective cardiac surgery Background . Ischemia-reperfusion injury secondary to leukocyte activation has been widely recognized as one of the most relevant mechanism leading to postoperative organ dysfunction occurring after a period of ischemia . The aim of the present study was to evaluate in a prospect i ve , r and omized study , the value of leukocyte depleting filter in patients undergoing elective coronary artery bypass surgery . Methods . Twenty patients scheduled for elective on-pump coronary artery bypass surgery were r and omized to undergo cardiopulmonary bypass either with a leukocyte depleting filter incorporated in the extracorporeal circulation arterial line or without a filter . Results . The main finding of this study was the significantly lower postoperative concentrations of cardiac troponin I in the leukocyte filter group ( Tests of between-subjects effects : p = 0.024 ) . There were also slightly better cardiac indices in the leukocyte filter group . A larger amount of blood units was infused intra- and postoperatively in patients undergoing cardiopulmonary bypass with leukocyte filtration ( median , 600 [ IQR , 0–1200 ] vs. 0 [ IQR , 0–600 ] , p = 0.08 ) . Two patients in the leukocyte filter group underwent reoperation for bleeding but none in the control group ( p = 0.48 ) . Intra- and postoperative platelet count was lower in the leukocyte filter group ( Tests of between-subjects effects : p = 0.08 ) . Despite a significant increased concentration of C-reactive protein on the first postoperative day in the control group ( p = 0.029 ) , repeated- measures analysis failed to show any significant increase during the study period ( p = 0.33 ) . Conclusions . The results of this study suggest a myocardial protective effect of leukocyte filter in the setting of elective coronary artery bypass surgery The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating experience . To encourage dissemination of the CONSORT 2010 Statement , this article is freely accessible on bmj.com and will also be published in the Lancet , Obstetrics and Gynecology , PLoS Medicine , Annals of Internal Medicine , Open Medicine , Journal of Clinical Epidemiology , BMC Medicine , and Trials

Results : While AtBM seems to influence attentional bias , its effects on drinking behavior are inconsistent . As for ApBM , the best effects on drinking behavior are obtained in clinical sample s. Effects of ApBM on approach bias are mixed . Interestingly , those clinical RCTs which investigated ApBM effects on bias change as well as on drinking outcome , reported consistent effects in both measures ( i.e. either effects on bias and drinking or no effects ) . Studies on IT are limited to non- clinical sample s and show inconsistent effects on drinking behavior . Conclusions about the overall influence of drinking behavior severity are hampered by the non-uniform use of sample descriptions . Conclusions : In clinical sample s , ApBM has shown more consistent beneficial effects , while evidence on AtBM is more inconsistent , and data on IT still lacks important information . Conclusions about the influence of drinking behavior severity would be facilitated by a uniform use of clearly defined sample descriptions

Background : In patients with alcohol use disorder , novel interventions to increase abstinence have attracted growing attention . Interventions aim ed at modifying cognitive biases linked to alcohol use [ i.e. cognitive bias modification ( CBM ) ] may serve as an add-on to st and ard therapy . This systematic review thoroughly aggregates existing data on the effects of three alcohol-specific computerized interventions , namely attentional bias modification ( AtBM ) , approach bias modification ( ApBM ) , and inhibition training ( IT ) . In doing so , each CBM ’s effects on experimental tasks assessing the relevant biases , drinking behavior , and neurophysiology are summarized . Also , the influence of drinking behavior severity and motivation to change drinking behavior are discussed .

This study aim ed to replicate findings that alcohol consumption and positive implicit beer-related cognitions can be reduced using inhibitory control ( IC ) training , with the addition of an active training control . Frontal EEG asymmetry , an objective psychophysiological index of approach motivation , was used as a dependent measure to examine training outcomes . Participants were r and omly assigned to one of two IC training conditions ( Beer NoGo or Beer Go ) or a Brief Alcohol Intervention ( BAI ) ( i.e. the active training control ) . The IC training tasks consistently paired a stimulus that required a response with images of water ( Beer NoGo ) or images of beer ( Beer Go ) . Alcohol consumption and implicit beer-related cognitions were measured at pre-training , post-training and at one week follow-up . Frontal EEG asymmetry was recorded during a passive image viewing task that presented neutral , healthy , and beer stimuli - at pre-training , post-training and follow-up . Participants in the Beer NoGo and BAI conditions consumed less beer in a taste test immediately after training than Beer Go participants , suggesting that IC training may be as effective as the already established BAI . The taste test findings were in line with the frontal EEG asymmetry data , which indicated that approach motivation for beer stimuli was altered in the expected directions . However , the positive correlation between post-training frontal EEG asymmetry data and taste test consumption was not significant . While there were no significant changes in implicit beer-related cognitions following training , a trending positive relationship between implicit beer-related cognitions at post-training and taste test consumption was reported . Further exploration addressing the limitations of the current study is required in order to clarify the implication s of these findings Rationale Both cue avoidance training ( CAT ) and inhibitory control training ( ICT ) reduce alcohol consumption in the laboratory . However , these interventions have never been directly compared and their mechanisms of action are poorly understood . Objectives We compared the effects of both types of training on alcohol consumption and investigated if they led to theoretically predicted changes in alcohol avoidance ( CAT ) or alcohol inhibition ( ICT ) associations and changes in evaluation of alcohol cues . Methods Heavy drinking young adults ( N = 120 ) were r and omly assigned to one of four groups : ( 1 ) CAT ( repeatedly pushing alcohol cues away with a joystick ) , ( 2 ) sham ( control ) CAT ; ( 3 ) ICT ( repeatedly inhibiting behaviour in response to alcohol cues ) ; or ( 4 ) sham ( control ) ICT . Changes in reaction times and automatic evaluations of alcohol cues were assessed before and after training using assessment versions of tasks used in training and the implicit association test ( IAT ) , respectively . Finally , participants completed a bogus taste test as a measure of ad libitum alcohol consumption . Results Compared to sham conditions , CAT and ICT both led to reduced alcohol consumption although there was no difference between the two . Neither intervention affected performance on the IAT , and changes in reaction time did not suggest the formation of robust alcohol avoidance ( CAT ) or alcohol inhibition ( ICT ) associations after training . Conclusions CAT and ICT yielded equivalent reductions in alcohol consumption in the laboratory . However , these behavioural effects were not accompanied by devaluation of stimuli or the formation of alcohol avoidance or alcohol inhibition associations BACKGROUND Young adult heavy drinking is an important public health concern . Current interventions have efficacy but with only modest effects , and thus , novel interventions are needed . In prior studies , heavy drinkers , including young adults , have demonstrated stronger automatically triggered approach tendencies to alcohol-related stimuli than lighter drinkers . Automatic action tendency retraining has been developed to correct this tendency and consequently reduce alcohol consumption . This study is the first to test multiple iterations of automatic action tendency retraining , followed by laboratory alcohol self-administration . METHODS A total of 72 nontreatment-seeking , heavy drinking young adults ages 21 to 25 were r and omized to automatic action tendency retraining or a control condition ( i.e. , " sham training " ) . Of these , 69 ( 54 % male ) completed 4 iterations of retraining or the control condition over 5 days with an alcohol drinking session on Day 5 . Self-administration was conducted according to a human laboratory paradigm design ed to model individual differences in impaired control ( i.e. , difficulty adhering to limits on alcohol consumption ) . RESULTS Automatic action tendency retraining was not associated with greater reduction in alcohol approach tendency or less alcohol self-administration than the control condition . The laboratory paradigm was probably sufficiently sensitive to detect an effect of an experimental manipulation given the range of self-administration behavior observed , both in terms of number of alcoholic and nonalcoholic drinks and measures of drinking topography . CONCLUSIONS Automatic action tendency retraining was ineffective among heavy drinking young adults without motivation to change their drinking . Details of the retraining procedure may have contributed to the lack of a significant effect . Despite null primary findings , the impaired control laboratory paradigm is a valid laboratory-based measure of young adult alcohol consumption that provides the opportunity to observe drinking topography and self-administration of nonalcoholic beverages ( i.e. , protective behavioral strategies directly related to alcohol use ) There is preliminary evidence that approach avoid training can shift implicit alcohol associations and improve treatment outcomes . We sought to replicate and extend those findings in US undergraduate social drinkers ( Study 1 ) and at-risk drinkers ( Study 2 ) . Three adaptations of the approach avoid task ( AAT ) were tested . The first adaptation – the approach avoid training – was a replication and targeted implicit alcohol approach associations . The remaining two adaptations – the general identity and personalized identity trainings – targeted implicit drinking identity associations , which are robust predictors of hazardous drinking in US undergraduates . Study 1 included 300 undergraduate social drinkers . They were r and omly assigned to real or sham training conditions for one of the three training adaptations , and completed two training sessions , spaced one week apart . Study 2 included 288 undergraduates at risk for alcohol use disorders . The same training procedures were used , but the two training sessions occurred within a single week . Results were not as expected . Across both studies , the approach avoid training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes . The general identity training also yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes with one exception ; individuals who completed real training demonstrated no changes in drinking refusal self-efficacy whereas individuals who completed sham training had reductions in self-efficacy . Finally , across both studies , the personalized identity training yielded no evidence of training effects on implicit alcohol associations or alcohol outcomes . Despite having relatively large sample s and using a well-vali date d training task , study results indicated all three training adaptations were ineffective at this dose in US undergraduates . These findings are important because training studies are costly and labor-intensive . Future research may benefit from focusing on more severe population s , pairing training with other interventions , increasing training dose , and increasing gamification of training tasks CONTEXT Alcohol dependence treatment may include medications , behavioral therapies , or both . It is unknown how combining these treatments may impact their effectiveness , especially in the context of primary care and other nonspecialty setting s. OBJECTIVES To evaluate the efficacy of medication , behavioral therapies , and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers ( median age , 44 years ) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , diagnoses of primary alcohol dependence . INTERVENTIONS Eight groups of patients received medical management with 16 weeks of naltrexone ( 100 mg/d ) or acamprosate ( 3 g/d ) , both , and /or both placebos , with or without a combined behavioral intervention ( CBI ) . A ninth group received CBI only ( no pills ) . Patients were also evaluated for up to 1 year after treatment . MAIN OUTCOME MEASURES Percent days abstinent from alcohol and time to first heavy drinking day . RESULTS All groups showed substantial reduction in drinking . During treatment , patients receiving naltrexone plus medical management ( n = 302 ) , CBI plus medical management and placebos ( n = 305 ) , or both naltrexone and CBI plus medical management ( n = 309 ) had higher percent days abstinent ( 80.6 , 79.2 , and 77.1 , respectively ) than the 75.1 in those receiving placebos and medical management only ( n = 305 ) , a significant naltrexone x behavioral intervention interaction ( P = .009 ) . Naltrexone also reduced risk of a heavy drinking day ( hazard ratio , 0.72 ; 97.5 % CI , 0.53 - 0.98 ; P = .02 ) over time , most evident in those receiving medical management but not CBI . Acamprosate showed no significant effect on drinking vs placebo , either by itself or with any combination of naltrexone , CBI , or both . During treatment , those receiving CBI without pills or medical management ( n = 157 ) had lower percent days abstinent ( 66.6 ) than those receiving placebo plus medical management alone ( n = 153 ) or placebo plus medical management and CBI ( n = 156 ) ( 73.8 and 79.8 , respectively ; P<.001 ) . One year after treatment , these between-group effects were similar but no longer significant . CONCLUSIONS Patients receiving medical management with naltrexone , CBI , or both fared better on drinking outcomes , whereas acamprosate showed no evidence of efficacy , with or without CBI . No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management . Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment . Naltrexone with medical management could be delivered in health care setting s , thus serving alcohol-dependent patients who might otherwise not receive treatment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00006206 BACKGROUND Alcoholism is a progressive neurocognitive developmental disorder . Recent evidence shows that computerized training interventions ( Cognitive Bias Modification , CBM ) can reverse some of these maladaptively changed neurocognitive processes . A first clinical study of a CBM , called alcohol-avoidance training , found that trained alcoholic patients showed less relapse at one-year follow-up than control patients . The present study tested the replication of this result , and questions about mediation and moderation . METHODS 509 alcohol-dependent patients received treatment as usual ( primarily Cognitive Behavior Therapy ) inpatient treatment . Before and after treatment , the implicit approach bias was measured with the Alcohol Approach-Avoidance Task . Half of the patients were r and omly assigned to CBM , the other half received treatment as usual only . Background variables , psychopathology and executive control were tested as possible moderating variables of CBM . One year after treatment , follow-up data about relapse were collected . RESULTS The group receiving CBM developed alcohol-avoidance behavior and reported significantly lower relapse rates at one-year follow-up . Change in alcohol-approach bias mediated this effect . Moderation analyses demonstrated that older patients and patients with a strong approach-bias at pretest profited most from CBM . CONCLUSIONS CBM is a promising treatment add-on in alcohol addiction and may counter some of the maladaptive neurocognitive effects of long-term alcoholism To examine the impact of a computer-delivered , home-based , alcohol-specific attention modification program ( AMP ) , 41 heavy drinking college students were r and omly assigned to AMP or an attention control condition ( ACC ) . Participants selected 10 alcohol-related words most relevant to their own drinking experience as well as 10 neutral words not related to alcohol . These personalized stimuli were used in an attention retaining program based upon the probe detection paradigm twice weekly for 4 weeks . Participants in the AMP condition reported decreased drinking , whereas those in the ACC condition reported no change in their drinking . These preliminary data suggest that a computer-delivered , home-delivered , attention-retraining for alcohol treatment may be an inexpensive and efficacious adjunct to st and ard alcohol treatments 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 Cognitive bias modification ( CBM ) can be used to retrain automatic approach tendencies for alcohol . We investigated whether changing cortical excitability with transcranial direct current stimulation ( tDCS ) could enhance CBM effects in hazardous drinkers . We also studied the underlying mechanisms by including behavioral ( craving , implicit associations , approach tendencies ) and electrophysiological ( event-related potentials ) measurements . METHODS The analytical sample consisted of 78 hazardous drinkers ( Alcohol Use Disorders Identification Test > 8) r and omly assigned to 4 conditions in a 2-by-2 factorial design ( control/active CBM and sham/active tDCS ) . The intervention consisted of 3 sessions of CBM , specifically alcohol approach bias retraining , combined with 15 minutes 1 mA tDCS over the left dorsolateral prefrontal cortex . There was a pre- and post assessment before and after the intervention that included experimental tasks ( Approach Avoidance Task , Implicit Association Task ) and an electroencephalogram with an oddball and cue-reactivity task . RESULTS tDCS decreased cue-induced craving ( but not overall craving ) on post assessment . CBM did not induce an avoidance bias during assessment . During the training , active and control-CBM only differed in bias score during the first session . We found no enhancement effects of tDCS on CBM . Electrophysiological data showed no clear effects of active tDCS or CBM on the P300 . CONCLUSIONS There were no electrophysiological or behavioral effects of repeated CBM and /or tDCS , except for an effect of tDCS on craving . Applied in these specific ways these techniques appear to have limited effects in a hazardous drinking population AIMS Previous research has shown that consistently not responding to alcohol-related stimuli in a go/no-go training procedure reduces drinking behaviour . This study aim ed to examine further the mechanisms underlying this go/no-go training effect . DESIGN , SETTING AND PARTICIPANTS Fifty-seven heavy drinkers were assigned r and omly to two training conditions : in the beer/no-go condition , alcohol-related stimuli were always paired with a stopping response , while in the beer/go condition participants always responded to alcohol-related stimuli . Participants were tested individually in a laboratory at Maastricht University . MEASUREMENTS Weekly alcohol intake , implicit attitudes towards beer , approach-avoidance action tendencies towards beer and response inhibition were measured before and after the training . FINDINGS Results showed a significant reduction in both implicit attitudes ( P = 0.03 ) and alcohol intake ( P = 0.02 ) in the beer/no-go condition , but not in the beer/go condition . There were no significant training effects on action tendencies or response inhibition . CONCLUSIONS Repeatedly stopping pre-potent responses towards alcohol-related stimuli reduces excessive alcohol use via a devaluation of alcohol-related stimuli rather than via increased inhibitory control over alcohol-related responses OBJECTIVE In alcohol-dependent patients , alcohol cues evoke increased activation in mesolimbic brain areas , such as the nucleus accumbens and the amygdala . Moreover , patients show an alcohol approach bias , a tendency to more quickly approach than avoid alcohol cues . Cognitive bias modification training , which aims to retrain approach biases , has been shown to reduce alcohol craving and relapse rates . The authors investigated effects of this training on cue reactivity in alcohol-dependent patients . METHOD In a double-blind r and omized design , 32 abstinent alcohol-dependent patients received either bias modification training or sham training . Both trainings consisted of six sessions of the joystick approach-avoidance task ; the bias modification training entailed pushing away 90 % of alcohol cues and 10 % of soft drink cues , whereas this ratio was 50/50 in the sham training . Alcohol cue reactivity was measured with functional MRI before and after training . RESULTS Before training , alcohol cue-evoked activation was observed in the amygdala bilaterally , as well as in the right nucleus accumbens , although here it fell short of significance . Activation in the amygdala correlated with craving and arousal ratings of alcohol stimuli ; correlations in the nucleus accumbens again fell short of significance . After training , the bias modification group showed greater reductions in cue-evoked activation in the amygdala bilaterally and in behavioral arousal ratings of alcohol pictures , compared with the sham training group . Decreases in right amygdala activity correlated with decreases in craving in the bias modification but not the sham training group . CONCLUSIONS These findings provide evidence that cognitive bias modification affects alcohol cue-induced mesolimbic brain activity . Reductions in neural reactivity may be a key underlying mechanism of the therapeutic effectiveness of this training Conscious strategies such as psychoeducation are commonly used to resolve alcohol ambivalence . However , conscious strategies have had little effect on automatic approach inclination , which is one of the components of alcohol ambivalence . The purpose of this study was to investigate the effect of automatic attentional bias modification that can affect the approach inclination in alcohol ambivalence . The study included 43 problem drinkers with alcohol ambivalence who were recruited from the university and provided informed consent . They were r and omly assigned to either a group that underwent attentional bias modification or a group that underwent psychoeducation . The level of alcohol ambivalence and readiness to change was assessed using self-report question naires , and the pattern of alcohol ambivalence was assessed using eye movements . The results showed that psychoeducation increased problem drinkers ' readiness to change . In addition , attentional bias modification changed their attentional pattern of alcohol ambivalence by decreasing the approach inclination and increasing the avoidance inclination . Based on these results , attentional bias modification was shown to be a useful method for changing the automatic approach inclination as well as the controlled avoidance inclination , and psychoeducation was shown to be a beneficial strategy for increasing problem drinkers ' extrinsic readiness to change BACKGROUND Disinhibition is apparent in users of many substances , including heavy drinkers . Previous research has shown that brief training to improve inhibitory control is associated with reduced alcohol consumption . We investigated whether a new form of inhibitory training would produce greater reductions , relative to a carefully design ed control condition and a proven method of reducing consumption , the Brief Alcohol Intervention ( BAI ) . METHODS One hundred and fourteen regular drinkers were assigned r and omly to one of five training conditions : Control ( no inhibitory training ) ; Beer-NoGo ( inhibit responses linked to task-irrelevant pictures of beer ) ; Restrained-Stop ( requiring more urgent inhibition but without pictures of beer ) ; Combined ( a previously untested form of training requiring urgent inhibition to pictures of beer ) ; or BAI . The outcome measures were alcohol consumption in the week before and after training , and in a bogus taste test administered immediately post-training . RESULTS Participation in the study , regardless of condition , was associated with reductions in weekly consumption . However , only the BAI produced a greater reduction relative to the Control condition . The training tasks were not associated with reductions in taste test consumption . CONCLUSIONS Although concerns about low power limit confidence , the current study suggests that three forms of inhibitory training do not have a substantial effect on drinking beyond the effect of simple assessment , in comparison to a control task which does not promote impulsive responding . Future research needs to establish a training protocol that produces greater reductions in consumption not only relative to the effect of assessment but also relative to a BAI A new training to decrease attentional bias ( attentional bias modification training , ABM ) was tested in a r and omized controlled experimental study with alcohol-dependent patients as an addition to cognitive behavioral therapy . In alcohol dependence , attentional bias has been associated with severity of alcoholism , craving , treatment outcome , and relapse . Forty-three patients with DSM-IV diagnosis of alcohol dependence were r and omly assigned to an ABM intervention or control training . The procedure consisted of five sessions in which patients were trained to disengage attention from alcohol-related stimuli ( ABM condition ) or in which they were trained on an irrelevant reaction-time test ( control condition ) . We measured the effects of ABM on the visual-probe task , with stimuli that were presented in the ABM and with new stimuli . Craving was measured with the Desires for Alcohol Question naire . Follow-up data were gathered for overall treatment success , and relapse up to 3 months after the intervention . ABM was effective in increasing the ability to disengage from alcohol-related cues . This effect generalized to untrained , new stimuli . There were no significant effects on subjective craving . For other outcome measures there were indications of clinical ly relevant effects . Results indicate that ABM among alcohol-dependent patients was effective and that it may affect treatment progression . Large-scale trials are warranted to further investigate this new field According to dual-process models , excessive alcohol use emerges when response inhibition ability is insufficient to inhibit automatic impulses to drink alcohol . This study examined whether strengthening response inhibition for alcohol-related cues decreases alcohol intake . Fifty-two heavy drinking students were r and omly assigned to one of two conditions : In the beer/no-go condition , participants performed a go/no-go task that consistently paired alcohol-related stimuli with a stopping response , to increase response inhibition for alcohol-related stimuli . In the beer/go condition , in contrast , participants were always required to respond to alcohol-related stimuli during the go/no-go task . Before and after the go/no-go manipulation , we measured weekly alcohol intake and implicit attitudes toward alcohol . In addition , we measured alcohol consumption during a taste test immediately after the go/no-go manipulation . Following the manipulation , participants in the beer/no-go condition demonstrated significantly increased negative implicit attitudes toward alcohol , and a significant reduction in weekly alcohol intake , while participants in the beer/go condition showed a non-significant increase in implicit positive attitudes toward alcohol and a significant increase in weekly alcohol intake . This study demonstrates that repeatedly stopping prepotent responses toward alcohol-related stimuli can be an effective strategy to reduce excessive alcohol use BACKGROUND Most contemporary neuroscientific models of alcohol use disorders ( AUD ) incorporate an imbalance between enhanced cue reactivity , which results in a strong urge to consume , and the impaired inhibitory control of that urge . While these phenomena have been frequently investigated separately , studies involving both aspects and thus precisely investigating the postulated imbalance are rare . In this study , inhibition was investigated in an addiction-specific context and individual craving levels were also examined . METHODS This study compared inhibition in alcohol-related and neutral context s in patients with AUD and healthy controls , while also taking into account the individual amount of craving . All subjects performed a Go/NoGo task involving neutral and alcohol-related NoGo trials , while their brain activity was recorded using multichannel electroencephalography . The map strength and topography of the N2 and P3 components of the NoGo event-related potentials were compared between groups and context s using whole-scalp r and omization-based methods . The effects of interest were further investigated with sLORETA source analysis . RESULTS For the N2 component , the context by craving interaction was strong for map strength and map topography . The source analysis indicated that in subjects with high craving , alcohol-related context led to enhanced and prolonged activation in the posterior cingulate and premotor cortical areas . This interaction was specific for craving , but not for diagnostic classification . The amplitude of the P3 component was reduced in subjects with AUD , which replicated previous findings . CONCLUSIONS In subjects with strong craving , the conflict reflected in the NoGo-N2 was enhanced in the alcohol-related context . Such enhanced conflict probably makes the successful inhibition of the urge to drink in high-risk situations even more difficult for this subgroup of patients and should therefore be addressed in individualized treatment planning AIMS The main aim of this study was to test whether automatic action-tendencies to approach alcohol can be modified , and whether this affects drinking behaviour . DESIGN AND PARTICIPANTS Forty-two hazardous drinkers were assigned r and omly to a condition in which they were implicitly trained to avoid or to approach alcohol , using a training variety of the alcohol Approach Avoidance Test ( AAT ) . Participants pushed or pulled a joystick in response to picture-format ( l and scape or portrait ) . The pictures depicted alcoholic or non-alcoholic drinks . Participants in the avoid-alcohol condition pushed most alcoholic and pulled most non-alcoholic drinks . For participants in the approach-alcohol condition these contingencies were reversed . After the implicit training , participants performed a taste test , including beers and soft drinks . Automatic action tendencies at post-test were assessed with the AAT , including both trained and untrained pictures , and with a different test ( Implicit Association Test , IAT ) . We further tested effects on subjective craving . RESULTS Action tendencies for alcohol changed in accordance with training condition , with the largest effects in the clinical ly relevant avoid-alcohol condition . These effects occurred outside subjective awareness and generalized to new pictures in the AAT and to an entirely different test using words , rather than pictures ( IAT ) . In relatively heavy drinking participants who demonstrated changed action tendencies in accordance with their training condition , effects were found on drinking behaviour , with participants in the approach-alcohol condition drinking more alcohol than participants in the avoid-alcohol condition . No effect was found on subjective craving . CONCLUSIONS Retraining automatic processes may help to regain control over addictive impulses , which points to new treatment possibilities AIMS To examine whether alcohol-related attentional bias ( AB ) can be reduced by training heavy drinkers to attend to soft drinks as an alternative to alcohol . Diminishing AB is important because AB has been suggested to be a significant factor in the development , maintenance and relapse of addictive behaviours . AB was trained in a clinical ly relevant design , and we studied the generalization of this training . DESIGN , PARTICIPANTS AND INTERVENTION : We assigned r and omly 106 heavy drinking male college and university students to the attentional re-training ( AR ; modified visual-probe task ) or control condition ( st and ard visual-probe task ) . SETTING Laboratory at Maastricht University . MEASUREMENTS We measured the effects of AR on the visual-probe task with stimuli that were presented in the AR and with new stimuli , and on an alternative measure of AB , the flicker paradigm . We further measured effects on craving and preference for either an alcohol beverage or a soft drink . FINDINGS After AR , participants had learned to avoid alcohol stimuli and had developed an AB for soft drinks . This effect was restricted to stimuli used in the AR . The flicker task , where AB for alcohol was found in both the AR and control groups , was not affected by the AR . No effect was found on craving and the preference task . CONCLUSIONS Although heavy drinkers can learn to attend selectively to an alternative category for alcohol , a single AR is not sufficient to decrease symptoms of problem drinking Following successful outcomes of cognitive bias modification ( CBM ) programs for alcoholism in clinical and community sample s , the present study investigated whether different varieties of CBM ( attention control training and approach-bias re-training ) could be delivered successfully in a fully automated web-based way and whether these interventions would help self-selected problem drinkers to reduce their drinking . Participants were recruited through online advertising , which result ed in 697 interested participants , of whom 615 were screened in . Of the 314 who initiated training , 136 completed a pretest , four sessions of computerized training and a posttest . Participants were r and omly assigned to one of four experimental conditions ( attention control or one of three varieties of approach-bias re-training ) or a sham-training control condition . The general pattern of findings was that participants in all conditions ( including participants in the control-training condition ) reduced their drinking . It is suggested that integrating CBM with online cognitive and motivational interventions could improve results Two studies showed an improvement in clinical outcomes after alcohol approach bias retraining , a form of Cognitive Bias Modification ( CBM ) . We investigated whether transcranial direct current stimulation ( tDCS ) could enhance effects of CBM . TDCS is a neuromodulation technique that can increase neuroplasticity and has previously been found to reduce craving . One hundred alcohol‐dependent in patients ( 91 used for analysis ) were r and omized into three experimental groups in a double‐blind parallel design . The experimental group received four sessions of CBM while receiving 2 mA of anodal tDCS over the dorsolateral prefrontal cortex ( DLPFC ) . There were two control groups : One received sham stimulation during training and one received active stimulation at a different moment . Treatment outcomes were abstinence duration ( primary ) and relapse after 3 and 12 months , craving and approach bias ( secondary ) . Craving and approach bias scores decreased over time ; there were no significant interactions with experimental condition . There was no effect on abstinence duration after three months ( χ2(2 ) = 3.53 , p = 0.77 ) . However , a logistic regression on relapse rates after one year ( st and ard outcome in the clinic , but not‐preregistered ) showed a trend when relevant predictors were included ; relapse was lower in the condition receiving active stimulation during CBM only when comparing to sham stimulation ( B = 1.52 , S.E. = .836 , p = .07 , without predictors : p = .19 ) . No strong evidence for a specific enhancement effect of tDCS on CBM was found . However , in a post‐hoc analysis , tDCS combined with CBM showed a promising trend on treatment outcome . Important limitations are discussed , and replication is necessary to find more reliable effects BACKGROUND Attentional bias modification ( ABM ) techniques for reducing problematic alcohol consumption hold promise as highly accessible and cost-effective treatment approaches . A growing body of literature has examined ABM as a potentially efficacious intervention for reducing drinking and drinking-related cognitions in alcohol-dependent individuals as well as those at-risk of developing problem drinking habits . METHODS This study tested the effectiveness of a single session of visual probe-based ABM training in a cohort of 60 non-treatment-seeking young adult drinkers , with a focus on examining mechanisms underlying training efficacy . Participants were r and omly assigned to a single session of active ABM training or a sham training condition in a laboratory setting . Measures of implicit drinking-related cognitions ( alcohol Stroop and an Implicit Association Task ) and attentional bias ( AB ; alcohol visual probe ) were administered , and subjective alcohol craving was reported in response to in vivo alcohol cues . RESULTS Results showed that active ABM training , relative to sham , result ed in significant differences in measures of implicit alcohol-related cognition , alcohol-related AB , and self-reports of alcohol craving . Mediation analysis showed that reductions in craving were fully mediated by ABM-related reductions in alcohol-Stroop interference scores , suggesting a previously undocumented relationship between the 2 measures . CONCLUSIONS Results document the efficacy of brief ABM to reduce both implicit and explicit processes related to drinking , and highlight the potential intervention- relevance of alcohol-related implicit cognitions in social drinkers OBJECTIVE Recently , the National Institutes of Health ( NIH ) redefined clinical trials to include any study involving behavioral or biomedical interventions . In line with a general framework from experimental medicine , we argue that it is crucial to distinguish between experimental laboratory studies aim ed at revealing psychological mechanisms underlying behavior and r and omized controlled trials ( RCTs ) in clinical sample s aim ed at testing the efficacy of an intervention . METHOD As an illustration , we review ed the current state of the evidence on the efficacy of cognitive bias modification ( CBM ) interventions in alcohol use disorders . RESULTS A recent meta- analysis " cast serious doubts on the clinical utility of CBM interventions for addiction . " That analysis combined experimental laboratory studies and RCTs . We demonstrated that , when studies are differentiated regarding study type ( experimental laboratory study or RCT ) , mode of delivery ( controlled experiment or Internet ) , and population ( healthy volunteers or patients ) , the following effects are found : ( a ) short-lived effects of CBM on drinking behavior in experimental laboratory studies in students , but only when the bias is successfully manipulated ; ( b ) small but robust effects of CBM on treatment outcome when administered as an adjunct to established treatments in clinical setting s in RCTs with alcohol-dependent patients ; and ( c ) nonspecific effects ( reduced drinking irrespective of condition ) in RCTs of CBM administered online to problem drinkers . CONCLUSIONS We discuss how CBM might be improved when it is better integrated into regular treatment , especially cognitive behavioral therapy , and we conclude that disregarding the difference between experimental laboratory studies and RCTs can lead to invalid conclusions Background Modifying attentional processes with attentional bias modification ( ABM ) might be a relevant add‐on to treatment in addiction . This study investigated whether influencing cortical plasticity with transcranial direct current stimulation ( tDCS ) could increase training effects . tDCS could also help alcohol‐dependent patients to overcome craving and reduce relapse , independent of training . These approaches were combined to investigate effects in the treatment of alcoholism . Methods Ninety‐eight patients ( analytical sample = 83 ) were r and omly assigned to 4 groups in a 2‐by‐2 factorial design . Patients received 4 sessions of ABM ( control or real training ) combined with 2 mA tDCS ( active : 20 minutes or sham : 30 seconds ) over the left dorsolateral prefrontal cortex . Alcohol bias and craving were assessed , and treatment outcome was measured as relapse after 1 year . Results Attentional bias scores indicated that during the training only the group with active tDCS and real ABM displayed an overall avoidance bias ( p < 0.05 ) . From pre‐ to post assessment , there were no main or interaction effects of tDCS and ABM on the bias scores , craving , or relapse ( p > 0.2 ) . However , effects on relapse after active tDCS were in the expected direction . Conclusions There was no evidence of a beneficial effect of tDCS or ABM or the combination . Whether the absence of effect was due to issues with the outcome measurements ( e.g. , lack of craving , high dropout , and unreliable measurements ) or aspects of the intervention should be further investigated Background Attentional bias modification ( ABM ) interventions have been developed to address addiction by reducing attentional bias for substance-related cues . This study provides a systematic review of the effectiveness of ABM interventions in decreasing symptoms of addictive behaviour , taking baseline levels of attentional bias and changes in attentional bias into account . Methods We included r and omised and non-r and omised studies that investigated the effectiveness of ABM interventions in heavy-using adults and treatment-seeking individuals with symptoms of substance use disorder to manipulate attentional bias and to reduce substance use-related symptoms . We search ed for relevant English peer- review ed articles without any restriction for the year of publication using PsycINFO , PubMed , and ISI Web in August 2016 . Study quality was assessed regarding reporting , external validity , internal validity , and power of the study . Results Eighteen studies were included : nine studies reported on ABM intervention effects in alcohol use , six studies on nicotine use , and three studies on opiate use . The included studies differed with regard to type of ABM intervention ( modified dot probe task n = 14 ; Alcohol Attention Control Training Programme n = 4 ) , outcome measures , amount and length of provided sessions , and context ( clinic versus laboratory versus home environment ) . The study quality mostly ranged from low average to high average ( one study scored below the quality cut-off ) . Ten studies reported significant changes of symptoms of addictive behaviour , whereas eight studies found no effect of ABM interventions on symptoms . However , when restricted to multi-session ABM intervention studies , eight out of ten studies found effects on symptoms of addiction . Surprisingly , these effects on symptoms of addictive behaviour showed no straightforward relationship with baseline attentional bias and its change from baseline to post-test . Conclusions Despite a number of negative findings and the diversity of studies , multi-session ABM interventions , especially in the case of alcohol and when the Alcohol Attention Control Training Programme was used , appear to have positive effects on symptoms of addictive behaviour . However , more rigorous well-powered future research in clinical sample s is needed before firm conclusions regarding the effectiveness of ABM interventions can be drawn . Systematic review registration Registration number PROSPERO : Objective : We conducted a r and omized controlled trial to compare the effects of three types of Internet-delivered Inhibitory Control Training ( ICT ) with each other and with an active control intervention on alcohol consumption in a community sample of problem drinkers . Method : Two hundred and 46 heavy drinkers , who were motivated to reduce their alcohol consumption ( mean age 41.32 , 130 female ) self-monitored their alcohol consumption for 1 week before being r and omized to receive 1 of 3 variants of ICT ( Associative No-Go , Associative Stop Signal , General Inhibition ) or an active control . Participants then completed up to 14 ICT/control sessions on the Internet over a 4-week period , while regularly recording their alcohol consumption . Results : There were significant reductions in alcohol consumption across all groups over the 4-week training period ( main effect of time , F(2 , 402 ) = 77.12 , p < .01 , & eegr;p2 = .28 , BF10 > 99 ) , however there were no differences between ICT groups , or between ICT groups and the active control group ( Group × Time interaction , F(6 , 402 ) = 1.10 , p = .36 , & eegr;p2 = .02 , BF10 = 0.03 ) . Contrary to hypotheses , there were no changes in general inhibitory control , the disinhibiting effects of alcohol cues , or alcohol affective associations after ICT . Conclusions : In this study , which attempted to translate findings from proof-of-concept laboratory studies into a viable behavior change intervention , we found that multiple sessions of ICT delivered over the Internet did not help heavy drinkers to reduce their alcohol consumption beyond nonspecific effects associated with taking part in a trial Objective : Alcohol-dependent patients show attentional and approach biases for alcohol-related stimuli . Computerized cognitive bias modification ( CBM ) programs aim to retrain these biases and reduce relapse rates as add-ons to treatment . Retraining of alcohol-approach tendencies has already yielded significant reductions of relapse rates in previous studies , and retraining of biased attention toward alcohol is promising approach . The current large-scale r and omized controlled trial compared the clinical effects of these training methods —separately and in combination — to those of sham training methods and a no-training control , as an add-on to regular treatment . Methods : Participants were 1,405 alcohol-dependent patients of an inpatient rehabilitation clinic . In addition to regular treatment , patients were r and omized to receive 6 sessions of approach-bias retraining , 6 sessions of attention-bias retraining , 3 sessions of each of these CBM training varieties , 6 sessions of variants of sham training , or no training . Effects of the training methods were evaluated by measuring treatment success at 1-year follow-up . Results : Primary outcome : The 3 active training conditions yielded higher success rates at 1-year follow-up than sham training or no training ( 8.4 % , on average ) . Secondary results ( available for half of the sample ): Both varieties of CBM had only small effects on the targeted biases ( significant only for the combined training ) . Moreover , neither significant mediation of the clinical effect by the change in trained bias nor significant moderation of the clinical effect was found . Conclusions : Both alcohol-avoidance training and alcohol-attention training increased success rates effectively , as did the combination of both methods . Future studies should test ways to increase training effectiveness further OBJECTIVE Training in an inhibitory control task has produced reductions in alcohol use among heavy drinkers . However , the longevity of effects remains unknown , and much research has used suboptimal control conditions . Here , we assess the effectiveness of " Beer-NoGo " inhibitory training to reduce consumption up to 4 weeks after training compared with a " Beer-Go " control task , an online version of the Brief Alcohol Intervention ( BAI ) , and an Oddball control condition . METHOD Eighty-one regular drinkers were r and omized into one of four training conditions . In the Beer-NoGo condition , participants responded to a letter superimposed on water-related images and refrained from responding to another letter superimposed on beer-related images . The mapping was reversed for the Beer-Go condition , whereas the Oddball control condition was presented with letters only and inhibition was not required . The last condition was an online BAI . Alcohol use was assessed using a bogus taste test and weekly alcohol consumption . RESULTS Taste-test consumption was greater in the Beer-Go condition than in the Beer-NoGo , which did not differ from the Oddball and BAI conditions . All groups reduced alcohol intake during the study ; however , in the first week the Beer-Go group reduced their drinking while the Beer-NoGo group increased . No group differences were apparent at the fourth week . CONCLUSIONS The Beer-NoGo task did not produce effects beyond simple assessment on reducing alcohol use among regular drinkers . Previously reported training effects may be artifacts of the Beer-Go task as a suboptimal control . More robust forms of inhibitory training are necessary if a useful clinical adjunct for managing alcohol abuse is to be developed BACKGROUND Inhibitory control training and working memory training are 2 cognitive interventions that have been considered for alcohol use disorder ( AUD ) . Existing studies have typically relied on small sample s that preclude the evaluation of small effects . Crowdsourcing is a sampling method that can address these limitations by effectively and efficiently recruiting large sample s with varying health histories . This study tested the feasibility and acceptability of delivering cognitive training interventions via crowdsourcing . METHODS Participants with AUD were recruited from the crowdsourcing website Amazon Mechanical Turk ( mTurk ) ( Clinical Trials.gov ; NCT03438539 ) . Following completion of a baseline survey , participants were r and omized to an inhibitory control , working memory , or control training condition . Participants were asked to complete training tasks daily over a 2-week period . Follow-up assessment s evaluating acceptability measures and alcohol and soda consumption were completed immediately following and 2 weeks after training . RESULTS Response rates were satisfactory over the 2-week intervention period ( 65 % of training tasks completed ) , and performance on training tasks was consistent with expected effects . A majority of participants indicated that they were satisfied with the study procedures ( 94.6 % ) , would participate again ( 97.4 % ) , and would consider incorporating the training task in their daily life ( 81.1 % ) . Modest reductions in alcohol consumption were observed ( e.g. , 0.5 drinking day/wk ) , primarily in the inhibitory control group , and these effects were selective to alcohol use and did not extend to soda consumption . CONCLUSIONS These findings demonstrate the feasibility and acceptability of utilizing crowdsourcing methods for interventions development . Such a demonstration helps establish the crowdsourcing setting for future large sample studies testing novel interventions for AUD and other substance use disorders This study tested the effectiveness of a cognitive bias modification ( CBM ) intervention to simultaneously reduce approach biases toward alcohol and increase approach biases toward condoms among high-risk young adults . Participants ( N = 102 ) were r and omly assigned to either a training condition or a sham-training condition . Participants in the training condition were trained to make avoidance movements away from alcohol stimuli and approach movements toward condom stimuli over four training sessions . Approach biases and behavior were assessed at pretest , posttest , and 3-month follow-up . Approach biases changed for both stimulus categories in accordance with training condition . Condom behavior and attitudes also changed as a function of training condition such that participants in the training condition reported fewer instances of condom nonuse and more positive attitudes toward condoms at a 3-month follow-up . Participants in both conditions had significant reductions in alcohol consumption following the intervention and did not differ by training condition BACKGROUND Deriving novel treatments for alcohol use disorders ( AUDs ) is of critical importance , as existing treatments are only modestly effective for reducing drinking . Two promising strategies for treating AUDs include cognitive bias modification ( CBM ) and transcranial direct current stimulation ( tDCS ) . While each strategy has shown positive results in reducing drinking or alcohol-related constructs ( e.g. , craving ) , initial tests of the combination of CBM and tDCS have shown mixed results . The present study investigated the degree to which combining CBM and tDCS ( 2.0 mA anodal current over F10 ) could reduce alcohol approach biases and alcohol consumption . METHODS Seventy-nine at-risk drinkers were r and omized to 1 of 4 conditions in a 2 × 2 factorial design : verum CBM/verum tDCS , verum CBM/sham tDCS , sham CBM/verum tDCS , or sham CBM/sham tDCS . Participants completed a baseline assessment of alcohol approach bias and drinking quantity/frequency ( i.e. , drinks per drinking day [ DDD ] and percent heavy drinking days [ PHDD ] ) , 4 sessions of combined CBM and tDCS , and follow-up assessment s of approach bias and alcohol consumption . RESULTS Results indicated that while participants did demonstrate significant alcohol approach biases at baseline , neither CBM , tDCS , nor the interaction reduced the bias at the follow-up . In addition , there was evidence of a trend toward reducing DDD from baseline to the 1-week/1-month follow-ups , but there was no significant effect of the intervention on either DDD or PHDD . CONCLUSIONS These results partially replicated null results presented in similar CBM/tDCS trials and suggest that this combination , at least with anodal stimulation over dorsolateral or inferior frontal sites , may have limited utility to reduce drinking OBJECTIVE Attention biases may be an important treatment target for both alcohol dependence and social anxiety . This is the first ABM trial to investigate two ( vs. one ) targets of attention bias within a sample with co-occurring symptoms of social anxiety and alcohol dependence . Additionally , we used trial-level bias scores ( TL-BS ) to capture the phenomena of attention bias in a more ecologically valid , dynamic way compared to traditional attention bias scores . METHOD Adult participants ( N = 86 ; 41 % Female ; 52 % African American ; 40 % White ) with elevated social anxiety symptoms and alcohol dependence were r and omly assigned to an 8-session training condition in this 2 ( Social Anxiety ABM vs. Social Anxiety Control ) by 2 ( Alcohol ABM vs. Alcohol Control ) design . Symptoms of social anxiety , alcohol dependence , and attention bias were assessed across time . RESULTS Multilevel models estimated the trajectories for each measure within individuals , and tested whether these trajectories differed according to the r and omized training conditions . Across time , there were significant or trending decreases in all attention TL-BS parameters ( but not traditional attention bias scores ) and most symptom measures . However , there were not significant differences in the trajectories of change between any ABM and control conditions for any symptom measures . CONCLUSIONS These findings add to previous evidence question ing the robustness of ABM and point to the need to extend the effects of ABM to sample s that are racially diverse and /or have co-occurring psychopathology . The results also illustrate the potential importance of calculating trial-level attention bias scores rather than only including traditional bias scores BACKGROUND Relapse is common in alcohol-dependent individuals and can be triggered by alcohol-related cues in the environment . It has been suggested that these individuals develop cognitive biases , in which cues automatically capture attention and elicit an approach action tendency that promotes alcohol seeking . The study aim was to examine whether cognitive bias modification ( CBM ) training targeting approach bias could be delivered during residential alcohol detoxification and improve treatment outcomes . METHODS Using a 2-group parallel-block ( ratio 1:1 ) r and omized controlled trial with allocation concealed to the outcome assessor , 83 alcohol-dependent in patients received either 4 sessions of CBM training where participants were implicitly trained to make avoidance movements in response to pictures of alcoholic beverages and approach movements in response to pictures of nonalcoholic beverages , or 4 sessions of sham training ( controls ) delivered over 4 consecutive days during the 7-day detoxification program . The primary outcome measure was continuous abstinence at 2 weeks postdischarge . Secondary outcomes included time to relapse , frequency and quantity of alcohol consumption , and craving . Outcomes were assessed in a telephonic follow-up interview . RESULTS Seventy-one ( 85 % ) participants were successfully followed up , of whom 61 completed all 4 training sessions . With an intention-to-treat approach , there was a trend for higher abstinence rates in the CBM group relative to controls ( 69 vs. 47 % , p = 0.07 ) ; however , a per- protocol analysis revealed significantly higher abstinence rates among participants completing 4 sessions of CBM relative to controls ( 75 vs. 45 % , p = 0.02 ) . Craving score , time to relapse , mean drinking days , and mean st and ard drinks per drinking day did not differ significantly between the groups . CONCLUSIONS This is the first trial demonstrating the feasibility of CBM delivered during alcohol detoxification and supports earlier research suggesting it may be a useful , low-cost adjunctive treatment to improve treatment outcomes for alcohol-dependent patients

In conclusion , there is evidence that , on average , lifestyle interventions can lead to small increases in children 's daily water consumption .

The aim of this study was to conduct a systematic review and meta- analysis on the effectiveness of interventions to increase children 's water consumption .

BACKGROUND Sugar-sweetened beverages and maternal weight are strong drivers of child obesity , but few studies have targeted these risk factors as an obesity prevention strategy in children . OBJECTIVE The objective of this study was to test the efficacy of a smartphone-delivered intervention to reduce parent-provided sugar-sweetened beverage and juice ( SSB/juice ) consumption among children ages 3 - 5 and maternal weight . METHODS Mothers with overweight or obesity , who had a child ages 3 - 5 that consumed at least 12 fl . oz./day of SSB/juice ( N = 51 dyads ) were r and omized to the Smart Moms group that received one group session , lessons on a mobile website , and text messages , or to a waitlist control group . Mothers self-monitored their children 's beverages in addition to their own beverages , high-calorie foods , and weight . Assessment s at baseline , 3 , and 6 months included dietary recalls to measure SSB/juice intake and objective ly measured maternal weight . RESULTS Using linear mixed models controlling for baseline values , child age and race , there was a greater reduction in child SSB/juice in Smart Moms compared with control at 6 months ( -9.7 oz./day vs. 1.7 oz./day , p < .01 ) . Mothers in Smart Moms lost 2.4 kg at 6 months compared with a 0.9-kg gain in the control group ( p < .01 ) . CONCLUSIONS An intervention delivered using mHealth technologies can target mothers to change child dietary behaviours and improve maternal weight , which suggests a novel approach to family-based obesity prevention OBJECTIVE . The study tested whether a combined environmental and educational intervention solely promoting water consumption was effective in preventing overweight among children in elementary school . METHODS . The participants in this r and omized , controlled cluster trial were second- and third- grade rs from 32 elementary schools in socially deprived areas of 2 German cities . Water fountains were installed and teachers presented 4 prepared classroom lessons in the intervention group schools ( N = 17 ) to promote water consumption . Control group schools ( N = 15 ) did not receive any intervention . The prevalence of overweight ( defined according to the International Obesity Task Force criteria ) , BMI SD scores , and beverage consumption ( in glasses per day ; 1 glass was defined as 200 mL ) self-reported in 24-hour recall question naires , were determined before ( baseline ) and after the intervention . In addition , the water flow of the fountains was measured during the intervention period of 1 school year ( August 2006 to June 2007 ) . RESULTS . Data on 2950 children ( intervention group : N = 1641 ; control group : N = 1309 ; age , mean ± SD : 8.3 ± 0.7 years ) were analyzed . After the intervention , the risk of overweight was reduced by 31 % in the intervention group , compared with the control group , with adjustment for baseline prevalence of overweight and clustering according to school . Changes in BMI SD scores did not differ between the intervention group and the control group . Water consumption after the intervention was 1.1 glasses per day greater in the intervention group . No intervention effect on juice and soft drink consumption was found . Daily water flow of the fountains indicated lasting use during the entire intervention period , but to varying extent . CONCLUSION . Our environmental and educational , school-based intervention proved to be effective in the prevention of overweight among children in elementary school , even in a population from socially deprived areas OBJECTIVE The purpose of the present study was to evaluate the effects of a school-based , 2-year , multi-component intervention on BMI , eating and physical activity behaviour in Fl and ers , Belgium , targeting children aged 3 - 6 years in communities of high and low socio-economic status ( SES ) . DESIGN Cluster-r and omized controlled trial . SETTING Thirty-one pre- primary and primary schools in three different intervention communities and three paired-matched ( on SES profile ) control communities in Fl and ers , Belgium . SUBJECTS BMI Z-scores at baseline and follow-up were calculated for 1102 children . Question naires with sociodemographic data and FFQ were available from 694 of these 1102 children . RESULTS No significant effects were found on BMI Z-scores for the total sample . However , there was a significant decrease in BMI Z-score of 0·11 in the low-SES intervention community compared with the low-SES control community , where the BMI Z-score increased by 0·04 ( F = 6·26 , P = 0·01 ) . No significant intervention effects could be found for eating behaviour , physical activity or screen-time . There were no significant interaction effects of age and gender of the children on the outcome variables . CONCLUSIONS Although no significant effects were found for BMI Z-scores in the total sample , this intervention had a promising effect in the low-SES community of reducing excess weight gain among young children Background The FAN Social Marketing program was developed to improve dietary and physical activity habits of families with children in Ticino , Switzerl and . The aim of this study was to examine if the effects of the program on children ’s food intake differed by intervention group . Methods Effects of the FAN program were tested through a R and omized Controlled Trial . The program lasted 8 weeks , during which participants received tailored communication about nutrition and physical activity . Families were r and omly allocated to one of three groups , where the parent received the intervention by the Web ( G1 ) , Web + e-mail ( G2 ) or Web + SMS ( G3 ) . Children in all groups received tailored print letters by post . Children ’s food consumption was assessed at baseline and immediate post intervention using a 7-day food diary . Generalized linear mixed models with child as a r and om effect and with time , treatment group , and the time by treatment interaction as fixed effects were used to test the impact of the intervention . Results Analyses were conducted with a sample of 608 children . After participating in FAN the marginal means of daily consumption of fruit changed from 0.95 to 1.12 in G1 , from 0.82 to 0.94 in G2 , and from 0.93 to 1.18 in G3 . The margins of the daily consumption of sweets decreased in each group ( 1.67 to 1.56 in G1 , 1.71 to 1.49 in G2 , and 1.72 to 1.62 in G3 ) . The change in vegetable consumption observed from pre to post intervention in G3 ( from 1.13 to 1.21 ) was significantly different from that observed in G1 ( from 1.21 to 1.17 ) . Conclusions A well- design ed Web-based Social Marketing intervention complemented with print letters can help improve children ’s consumption of water , fruit , soft drinks , and sweets . The use of SMS to support greater behavior change , in addition to Web-based communication , result ed only in a small significant positive change for vegetables , while the use of e-mail in addition to Web did not result in any significant difference . Trial registration The trial was retrospectively registered in the IS RCT N registry ( ID IS RCT N48730279 ) OBJECTIVE Consumption of water may help promote health and prevent obesity in children by decreasing consumption of sugar-sweetened beverages . This study used evidence -based strategies to increase water consumption in Mexican-American and Mexican children . MATERIAL S AND METHODS In 2012 , two schools in San Diego , USA and two other in Tlaltizapan , Mexico were recruited to Agua para Niños ( Water for Kids ) , a program design ed to promote water consumption among elementary grade students . Guided by operant psychology , the intervention focused on school and classroom activities to encourage water consumption . One control and one intervention school in each country were included . RESULTS Agua para Niños result ed in increases in observed water consumption and bottle possession among US and Mexican students . Teacher receptivity to the program was very positive in both countries . CONCLUSIONS Agua para Niños yielded sufficiently positive behavioral changes to be used in a future fully r and omized design , and to contribute to school nutrition policy changes The objective of this study was to evaluate an educational module for Latino parents about the health effects of sweet beverages . Latino parents were r and omized to receive the beverage module or a control module . Child beverage consumption was assessed at baseline , 2 weeks , 2 months , and 3 months via a beverage recall survey . At 2-week follow-up , children of intervention participants had a mean reduction in 7-day total sugar-sweetened beverage and 100 % fruit juice consumption of 16 ounces while controls had a mean increase of 4 ounces ( P = .01 ) . At 2-month and 3-month follow-up , there was a reduction in mean total sugar-sweetened beverage and 100 % fruit juice consumption among both intervention and control children . An educational module on beverages for Latino parents reduced child consumption of sweet beverages at 2-week follow-up . However , study participation appears to have also reduced controls ’ beverage consumption suggesting that frequent intensive surveys of beverage intake may be an intervention unto itself UNLABELLED The current pilot study examined the effectiveness of a social network-based intervention using peer influence on self-reported water consumption . A total of 210 children ( 52 % girls ; M age = 10.75 ± SD = 0.80 ) were r and omly assigned to either the intervention ( n = 106 ; 52 % girls ) or control condition ( n = 104 ; 52 % girls ) . In the intervention condition , the most influential children in each classroom were trained to promote water consumption among their peers for eight weeks . The schools in the control condition did not receive any intervention . Water consumption , sugar-sweetened beverage ( SSB ) consumption , and intentions to drink more water in the near future were assessed by self-report measures before and immediately after the intervention . A repeated measure MANCOVA showed a significant multivariate interaction effect between condition and time ( V = 0.07 , F(3 , 204 ) = 5.18 , p = 0.002 , pη(2 ) = 0.07 ) on the dependent variables . Further examination revealed significant univariate interaction effects between condition and time on water ( p = 0.021 ) and SSB consumption ( p = 0.015 ) as well as water drinking intentions ( p = 0.049 ) . Posthoc analyses showed that children in the intervention condition reported a significant increase in their water consumption ( p = 0.018 ) and a decrease in their SSB consumption ( p < 0.001 ) over time , compared to the control condition ( p-values > 0.05 ) . The children who were exposed to the intervention did not report a change in their water drinking intentions over time ( p = 0.576 ) whereas the nonexposed children decreased their intentions ( p = 0.026 ) . These findings show promise for a social network-based intervention using peer influence to positively alter consumption behaviors . TRIAL REGISTRATION This RCT was registered in the Australian New Zeal and Clinical Trials Registry ( ACTRN12614001179628 ) . Study procedures were approved by the Ethics Committee of the Faculty of Social Sciences at Radboud University ( ECSW2014 - 1003 - 203 ) INTRODUCTION Across the U.S. , afterschool programs ( ASPs , 3:00pm-6:00pm ) are trying to achieve nationally endorsed nutrition st and ards ( Healthy Eating St and ards ) calling for fruits/vegetables and water to be served every day , while eliminating sugar-sweetened beverages and foods . The purpose of this study was to evaluate the 2-year changes in the types of foods and beverages served during a community-based intervention design ed to achieve the Healthy Eating St and ards . STUDY DESIGN R and omized delayed treatment trial with an immediate ( 1-year baseline and 2-year intervention ) or delayed ( 2-year baseline and 1-year intervention ) group . SETTING / PARTICIPANTS Twenty ASPs serving 1,700 children ( aged 5 - 12 years ) were recruited , with baseline occurring spring 2013 , and outcome assessment occurring spring 2014 and 2015 . INTERVENTION The multistep intervention , Strategies To Enhance Practice for Healthy Eating , assisted ASP leaders/staff to serve foods/beverages that meet the nutrition st and ards . MAIN OUTCOME MEASURES The foods and beverages served for snack were observed directly . RESULTS Compared with non-intervention years , both the immediate and delayed groups increased the number of days/week that fruits/vegetables ( 0.6 vs 1.7 days/week and 0.6 vs 4.4 days/week , OR=3.80 , 95 % CI=1.45 , 9.95 ) and water ( 2.3 vs 3.7 days/week and 2.7 vs 4.8 days/week , OR=4.65 , 95 % CI=1.69 , 12.79 ) were served . Sugar-sweetened beverages were almost eliminated by post- assessment ( 1.2 vs 0.2 days/week and 3.2 vs 0.0 days/week , OR=0.05 , 95 % CI=0.02 , 0.13 ) . Only the immediate group decreased the number of days/week desserts were served ( 2.9 vs 0.6 days/week , OR=0.10 , 95 % CI=0.03 , 0.33 ) . Implementation barriers for the delayed group included once/month delivery schedules for fruits/vegetables and limited storage space for foods meeting the Healthy Eating St and ards . CONCLUSIONS Improvements in the foods/beverages served in ASPs can be made , yet were hindered by structural barriers related to procurement and storage of perishable foods . Additional efforts are needed to support ASPs as they work toward fully achieving the Healthy Eating St and ards Sugar-sweetened beverage ( SSB ) consumption and the associated childhood obesity are major concerns in the Caribbean , creating a need for interventions promoting water consumption as a healthy alternative . A social network-based intervention ( SNI ) was tested among Aruban children to increase their water consumption and behavioral intention to do so and , consequently , to decrease SSB consumption and the associated behavioral intention . In this study , the moderating effects of descriptive and injunctive norms were tested . A cluster r and omized controlled trial was completed in schools ( mean age = 11 years ± SD = 0.98 ; 54 % girls ) . Children were assigned to the intervention group ( IG ; n = 192 ) or control group ( CG ; n = 185 ) . IG children were exposed to peer influencers promoting water consumption and CG children were not . Regression analyses showed that water consumption increased for IG children with a high injunctive norm score ( p = 0.05 ) ; however , their intention to consume more water remained unchanged ( p = 0.42 ) . Moreover , IG children showed a decrease in SSB consumption ( p = 0.04 ) and an increase in their intention to consume less SSB ( p = 0.00 ) . These findings indicate that SNIs are a promising instrument for health behavioral changes for Aruba and other isl and s in the Caribbean region OBJECTIVE The objective of this paper is to evaluate the behavioural effects , as reported by the parents of the participating boys and girls , of the IDEFICS ( Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS ) intervention . METHODS The effectiveness of the IDEFICS intervention was evaluated through a cluster-controlled trial in eight European countries ( control and intervention communities in each country ) including more than 16,000 children . The 2- to 9.9-year-old children in the intervention group were exposed to a culturally adapted intervention that aim ed to prevent childhood obesity through the community , schools/kindergartens and family . Parents completed question naires to measure water , soft drink and fruit juice intake ; fruit and vegetable intake ; daily TV viewing and other sedentary behaviours ; daily physical activity levels and strengthening of the parent-child relationships at baseline and follow-up ( 2 years later ) . Mixed models with an additional r and om effect for country were used to account for the clustered study design , and results were stratified by sex . RESULTS The pan-European analysis revealed no significant time by condition interaction effects , neither for boys nor girls , i.e. the analysis revealed no intervention effects on the behaviours of the IDEFICS children as reported by their parents ( F = 0.0 to 3.3 , all p > 0.05 ) . Also very few significance s were found in the country-specific analyses . Positive intervention effects were only found for sport club participation in Swedish boys , for screen time in weekends for Spanish boys and for TV viewing in Belgian girls . CONCLUSION Although no expected intervention effects as reported by the parents on diet , physical activity and sedentary behaviours could be shown for the overall IDEFICS cohort , a few favourable intervention effects were found on specific behaviours in some individual countries . More in-depth analyses of the process evaluation data are needed to obtain more insight into the relationship between the level of exposure to the intervention and its effect OBJECTIVE : To examine the long-term relationship between changes in water and beverage intake and weight change . SUBJECTS : Prospect i ve cohort studies of 50 013 women aged 40–64 years in the Nurses ’ Health Study ( NHS , 1986–2006 ) , 52 987 women aged 27–44 years in the NHS II ( 1991–2007 ) and 21 988 men aged 40–64 years in the Health Professionals Follow-up Study ( 1986–2006 ) without obesity and chronic diseases at baseline . MEASURES : We assessed the association of weight change within each 4-year interval , with changes in beverage intakes and other lifestyle behaviors during the same period . Multivariate linear regression with robust variance and accounting for within-person repeated measures were used to evaluate the association . Results across the three cohorts were pooled by an inverse-variance-weighted meta- analysis . RESULTS : Participants gained an average of 1.45 kg ( 5th to 95th percentile : −1.87 to 5.46 ) within each 4-year period . After controlling for age , baseline body mass index and changes in other lifestyle behaviors ( diet , smoking habits , exercise , alcohol , sleep duration , TV watching ) , each 1 cup per day increment of water intake was inversely associated with weight gain within each 4-year period ( −0.13 kg ; 95 % confidence interval ( CI ) : −0.17 to −0.08 ) . The associations for other beverages were : sugar-sweetened beverages ( SSBs ) ( 0.36 kg ; 95 % CI : 0.24–0.48 ) , fruit juice ( 0.22 kg ; 95 % CI : 0.15–0.28 ) , coffee ( −0.14 kg ; 95 % CI : −0.19 to −0.09 ) , tea ( −0.03 kg ; 95 % CI : −0.05 to −0.01 ) , diet beverages ( −0.10 kg ; 95 % CI : −0.14 to −0.06 ) , low-fat milk ( 0.02 kg ; 95 % CI : −0.04 to 0.09 ) and whole milk ( 0.02 kg ; 95 % CI : −0.06 to 0.10 ) . We estimated that replacement of 1 serving per day of SSBs by 1 cup per day of water was associated with 0.49 kg ( 95 % CI : 0.32–0.65 ) less weight gain over each 4-year period , and the replacement estimate of fruit juices by water was 0.35 kg ( 95 % CI : 0.23–0.46 ) . Substitution of SSBs or fruit juices by other beverages ( coffee , tea , diet beverages , low-fat and whole milk ) were all significantly and inversely associated with weight gain . CONCLUSION : Our results suggest that increasing water intake in place of SSBs or fruit juices is associated with lower long-term weight gain Question Can a multifaceted statewide communications campaign motivate behavior change in low-income Colorado families to limit children ’s fruit juice consumption and increase children ’s consumption of tap water to prevent tooth decay ? Purpose Caries is the most common chronic disease of childhood , affecting 40 % of kindergartners and 55 % of third grade rs in Colorado . Frequent consumption of 100 % fruit juice is linked to childhood caries . The purpose of this campaign , “ Cavities Get Around , ” was to motivate families to limit children ’s fruit juice consumption and increase consumption of tap water to protect baby teeth from caries , while also building public will for children ’s oral health . Methods The campaign included targeted media , promotores/organizers , and family education . We focused on fruit juice because audience research showed many families view fruit juice as healthy , and it is also a common beverage among young children up to age of 6 years . We also focused on low-socioeconomic status families because data show higher childhood tooth decay rates in this population . To evaluate progress , we conducted identical pre- and post-surveys , each of 600 r and om low-income parents contacted by l and line , mobile telephone , and Internet , allowing for comparative data . Results Significant progress was achieved compared to 2014 baseline results . Findings from a November 2015 statewide survey of parents included the following : ( 1 ) 22-point increase from 2014 in percentage of children regularly drinking tap water ( from 41 to 63 % ) . ( 2 ) 29-point decrease from 2014 in percentage of respondents who considered fruit juice consumption important to their child ’s health and nutritional needs ( from 72 to 43 % ) . ( 3 ) 19-point reduction in fruit juice consumption among young children ( from 66 % in 2014 to 47 % in 2015 ) . ( 4 ) 6-point reduction in percentage of parents considering baby teeth “ less important ” than adult teeth ( from 21 % in 2014 to 15 % in 2015 ) . The campaign also played a role in new state rules prohibiting childcare centers from serving sugar-sweetened beverages and capping 100 % juice to twice per week . Conclusion The campaign development , strategies , and evaluation results are instructive for others working on health promotion , childhood nutrition , and education interventions Background The HEALTHY study was design ed to respond to the alarming trends in increasing rates of overweight , obesity , and type 2 diabetes mellitus in youth . The objective of this analysis was to examine the effects of the HEALTHY study on student self-reported dietary intakes ( energy , macronutrients and grams consumed of selected food groups ) . Methods HEALTHY was a cluster-r and omized study in 42 public middle schools . Students , n = 3908 , self-reported dietary intake using the Block Kids Question naire . General linear mixed models were used to analyze differences in dietary intake at the end of the study between intervention and control schools . Results The reported average daily fruit consumption was 10 % higher at the end of the study in the intervention schools than in the control schools ( 138 g or approximately 2 servings versus 122 g , respectively , p = 0.0016 ) . The reported water intake was approximately 2 fluid ounces higher in the intervention schools than in the control ( 483 g versus 429 g respectively ; p = 0.008 ) . There were no significant differences between intervention and control for mean intakes of energy , macronutrients , fiber , grains , vegetables , legumes , sweets , sweetened beverages , and higher- or lower-fat milk consumption . Conclusion The HEALTHY study , a five-semester middle school-based intervention program that integrated multiple components in nutrition , physical education , behavior change , and social marketing-based communications , result ed in significant changes to student 's reported fruit and water intake . Subsequent interventions need to go beyond the school environment to change diet behaviors that may affect weight status of children . Clinical Trials Registration Early social and economic deprivation , associated with poor nutrition and physical inactivity , may lead to adverse health trajectories . A cluster-r and omized controlled-trial examining the effect of a school-based comprehensive intervention on nutrition knowledge , eating habits , and behaviors among low socioeconomic status ( LSES ) school-aged children was performed . LSES school-aged children ( 4–7 years ) and their mothers were recruited from 11 schools , located in one town . The intervention was implemented on three levels : children , mothers , and teachers . The intervention ( IArm ) included nutrition classes for children , mothers , and teachers and physical activity ( PA ) classes for children ; the control ( CArm ) received PA only . Interventions were conducted by professional personnel , who were trained during in a two-day session to deliver the specific program in schools . Family data were obtained by parental interviews . Food knowledge observations , packed lunch records , and anthropometric measurements were obtained in school at baseline , six months , and at the end of the school year . Of 258 children enrolled , 220 ( 87.6 % ) completed the six-month program . Only children in the IArm improved their nutrition knowledge and eating-habits and increased food variety and fruit and vegetable consumption , quality score of packed lunches ( p < 0.001 for all ) , habitual water drinking increased ( p = 0.02 ) , and decreased sweet-drink consumption ( p = 0.05 ) . A school-based comprehensive nutrition intervention targeting LSES population improved eating habits , nutritional knowledge , and healthier packed lunches Background Multi-level , longer-term obesity prevention interventions that focus on inequalities are scarce . Fun ‘ n healthy in Morel and ! aim ed to improve child adiposity , school policies and environments , parent engagement , health behaviours and child wellbeing . Methods All children from primary schools in an inner urban , culturally diverse and economically disadvantaged area in Victoria , Australia were eligible for participation . The intervention , fun ‘ n healthy in Morel and ! , used a Health Promoting Schools Framework and provided schools with evidence , school research data and part time support from a Community Development Worker to develop health promoting strategies . Comparison schools continued as normal . Participants were not blinded to intervention status . The primary outcome was change in adiposity . Repeated cross-sectional design with nested longitudinal sub sample . Results Students from twenty-four primary schools ( clusters ) were r and omised ( aged 5–12 years at baseline ) . 1426 students from 12 intervention schools and 1539 students from 10 comparison schools consented to follow up measurements . Despite increased prevalence of healthy weight across all schools , after 3.5 years of intervention there was no statistically significant difference between trial arms in BMI z score post-intervention ( Mean ( sd ) : Intervention 0.68(1.16 ) ; Comparison : 0.72(1.12 ) ; Adjusted mean difference ( AMD ) : -0.05 , CI : -0.19 to 0.08 , p = 0.44 ) . Children from intervention schools consumed more daily fruit serves ( AMD : 0.19 , CI:0.00 to 0.37 , p = 0.10 ) , were more likely to have water ( AOR : 1.71 , CI:1.05 to 2.78 , p = 0.03 ) and vegetables ( AOR : 1.23 , CI : 0.99 to 1.55 , p = 0.07 ) , and less likely to have fruit juice/cordial ( AOR : 0.58 , CI:0.36 to 0.93 , p = 0.02 ) in school lunch compared to children in comparison schools . More intervention schools ( 8/11 ) had healthy eating and physical activity policies compared with comparison schools ( 2/9 ) . Principals and schools highly valued the approach as a catalyst for broader positive school changes . The cost of the intervention per child was $ 65 per year . Conclusion The fun n healthy in Morel and ! intervention did not result in statistically significant differences in BMI z score across trial arms but did result in greater policy implementation , increased parent engagement and re sources , improved child self-rated health , increased fruit , vegetable and water consumption , and reduction in sweet drinks . A longer-term follow up evaluation may be needed to demonstrate whether these changes are sustainable and impact on childhood overweight and obesity . Clinical trial registration ACTRN12607000385448 ( Date su bmi tted 31/05/2007 ; Date registered 23/07/2007 ; Date last up date d 15/12/2009 ) 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 Within the ToyBox- study , a kindergarten-based , family-involved intervention was developed to prevent overweight and obesity in European preschoolers , targeting four key behaviours related to early childhood obesity , including water consumption . The present study aim ed to examine the effect of the ToyBox-intervention ( cluster r and omized controlled trial ) on water intake and beverage consumption in European preschoolers and to investigate if the intervention effects differed by implementation score of kindergartens and parents/caregivers . Method A sample of 4964 preschoolers ( 4.7±0.4 years ; 51.5 % boys ) from six European countries ( Belgium , Bulgaria , Germany , Greece , Pol and , Spain ) was included in the data analyses . A st and ardized protocol was used and parents/caregivers filled in socio-demographic data and a food-frequency question naire . To assess intervention effects , multilevel repeated measures analyses were conducted for the total sample and for the six country-specific sample s. Based on the process evaluation question naire of teachers and parents/caregivers , an implementation score was constructed . To assess differences in water intake and beverage consumption by implementation score in the total sample , multilevel repeated measures analyses were performed . Results Limited intervention effects on water intake from beverages and overall beverage consumption were found . However , important results were found on prepacked fruit juice consumption , with a larger decrease in the intervention group compared to the control group . However , also a decline in plain milk consumption was found . Implementation scores were rather low in both kindergartens and parents/caregivers . Nevertheless , more favorable effects on beverage choices were found in preschoolers whose parents/caregivers and kindergarten teachers had higher implementation scores compared to those with lower implementation scores . Conclusion The ToyBox-intervention can provide the basis for the development of more tailor-made interventions . However , new strategies to improve implementation of interventions should be created BACKGROUND The rapid increase of obesity and diabetes risk beginning in youth , particularly those from disadvantaged communities , calls for prevention efforts . OBJECTIVE To examine the impact of a curriculum intervention , Choice , Control & Change , on the adoption of the energy balance-related behaviors of decreasing sweetened drinks , packaged snacks , fast food , and leisure screen time , and increasing water , fruits and vegetables , and physical activity , and on potential psychosocial mediators of the behaviors . DESIGN Ten middle schools were r and omly assigned within matched pairs to either intervention or comparison/delayed control conditions during the 2006 - 2007 school year . SUBJECTS/ SETTING Students were from low-income New York City neighborhoods ; 562 were in the intervention condition , and 574 in the comparison condition . INTERVENTION Students received the 24 Choice , Control & Change lessons that used science inquiry investigations to enhance motivation for action , and social cognitive and self-determination theories to increase personal agency and autonomous motivation to take action . MAIN OUTCOME MEASURES Self-report instruments to measure energy balance-related behaviors targeted by the curriculum and potential psychosocial mediators of the behaviors . STATISTICAL ANALYSES Analysis of covariance with group ( intervention/control ) as a fixed factor and pretest as covariate . RESULTS Students in intervention schools compared to the delayed intervention controls reported consumption of considerably fewer sweetened drinks and packaged snacks , smaller sizes of fast food , increased intentional walking for exercise , and decreased leisure screen time , but showed no increases in their intakes of water , fruits , and vegetables . They showed substantial increases in positive outcome expectations about the behaviors , self-efficacy , goal intentions , competence , and autonomy . CONCLUSIONS The Choice , Control & Change curriculum was effective in improving many of the specifically targeted behaviors related to reducing obesity risk , indicating that combining inquiry-based science education and behavioral theory is a promising approach OBJECTIVE The Dutch Obesity Intervention in Teenagers ( DOiT ) is a school-based r and omised controlled trial that was effective in decreasing the consumption of sugar-sweetened beverages among adolescents . The present study examined , using mediation analysis , whether this decrease in consumption of sugar-sweetened beverages could be explained by an increase in the consumption of water or diet drinks . DESIGN Participants completed a question naire about their beverage consumption at baseline and at 8 months ( immediately post-intervention ) , 12- and 20-month follow-ups . A series of multi-level linear regression analyses were performed to examine water and diet drink consumption as potential mediators of the intervention effect on the consumption of sugar-sweetened beverages . SETTING Eighteen Dutch secondary schools . SUBJECTS A total of 747 adolescents ( mean age : 12·7 years ) . RESULTS In addition to the DoiT intervention effect of a reduction in the consumption of sugar-sweetened beverages at 8 months ( -284 ml/d ; 95 % CI -420 , -148 ) and 12 months ( -260 ml/d ; 95 % CI -360 , -160 ) , there was also a significant reduction in diet drinks at 8 months ( -52 ml/d ; 95 % CI -89 , -16 ) . There was no significant difference in water consumption at any follow-up . The decrease in sugar-sweetened beverage consumption could not be explained by an increase in water or diet drink consumption at any time point . CONCLUSIONS Interventions aim ed at reducing sugar-sweetened beverage consumption may be effective without changing consumption of other beverages . Reducing sugar-sweetened beverages was , however , a main message of the DOiT intervention . It is possible that a concomitant promotion of water may have result ed in a greater increase in water intake and replacement of sugar-sweetened beverages with water OBJECTIVE To determine the efficacy of a 2-year obesity prevention program in African American girls . DESIGN Memphis GEMS ( Girls ' health Enrichment Multi-site Studies ) was a controlled trial in which girls were r and omly assigned to an obesity prevention program or alternative intervention . SETTING Local community centers and YWCAs ( Young Women 's Christian Associations ) in Memphis , Tennessee . PARTICIPANTS Girls aged 8 to 10 years ( N = 303 ) who were identified by a parent or guardian as African American and who had a body mass index ( BMI ) at or higher than the 25th percentile for age or 1 parent with a BMI of 25 or higher . INTERVENTIONS Group behavioral counseling to promote healthy eating and increased physical activity ( obesity prevention program ) or self-esteem and social efficacy ( alternative intervention ) . MAIN OUTCOME MEASURE The BMI at 2 years . RESULTS The BMI increased in all girls with no treatment effect ( obesity prevention minus alternative intervention ) at 2 years ( mean , 0.09 ; 95 % confidence interval [ CI ] , -0.40 to 0.58 ) . Two-year treatment effects in the expected direction were observed for servings per day of sweetened beverages ( mean , -0.19 ; 95 % CI , -0.39 to 0.09 ) , water ( mean , 0.21 ; 95 % CI , 0.03 to 0.40 ) , and vegetables ( mean , 0.15 ; 95 % CI,-0.02 to 0.30 ) , but there were no effects on physical activity . Post hoc analyses suggested a treatment effect in younger girls ( P for interaction = .08 ) . The mean BMI difference at 2 years was -2.41 ( 95 % CI , -4.83 to 0.02 ) in girls initially aged 8 years and -1.02 ( 95 % CI , -2.31 to 0.27 ) in those initially aged 10 years . CONCLUSIONS The lack of significant BMI change at 2 years indicates that this intervention alone is insufficient for obesity prevention . Effectiveness may require more explicit behavior change goals and a stronger physical activity component as well as supportive changes in environmental context Introduction US legislation requires that schools offer free drinking water where meals are served . However , little information is available about what types of water delivery systems schools should install to meet such requirements . The study objective was to examine the efficacy and cost of 2 water delivery systems ( water dispensers and bottleless water coolers ) in increasing students ’ lunchtime intake of water in low-income middle schools . Methods In 2013 , twelve middle schools in the San Francisco Bay Area participated in a cluster r and omized controlled trial in which they received 6 weeks of promotional activities , received provision of cups , and were assigned to 1 of 2 cafeteria water delivery systems : water dispensers or bottleless water coolers ( or schools served as a control ) . Student surveys ( n = 595 ) and observations examined the interventions ’ effect on students ’ beverage intake and staff surveys and public data assessed intervention cost . Results Analysis occurred from 2013 through 2015 . Mixed-effects logistic regression , accounting for clustering and adjustment for student sociodemographic characteristics , demonstrated a significant increase in the odds of students drinking water in schools with promotion plus water dispensers and cups ( adjusted odds ratio = 3.1 ; 95 % confidence interval , 1.4–6.7 ; P = .004 ) compared with schools with traditional drinking fountains and no cups or promotion . The cost of dispenser and bottleless water cooler programs was similar ( $ 0.04 per student per day ) . Conclusion Instead of relying on traditional drinking fountains , schools should consider installing water sources , such as plastic dispensers with cups , as a low-cost , effective means for increasing students ’ water intake BACKGROUND Providing drinking water to U.S. children during school meals is a recommended health promotion strategy and part of national nutrition policy . Urban school systems have struggled with providing drinking water to children , and little is known about how to ensure that water is served , particularly in afterschool setting s. PURPOSE To assess the effectiveness of an intervention design ed to promote water as the beverage of choice in afterschool programs . DESIGN The Out of School Nutrition and Physical Activity Initiative ( OSNAP ) used a community-based collaboration and low-cost strategies to provide water after school . A group RCT was used to evaluate the intervention . Data were collected in 2010 - 2011 and analyzed in 2011 . SETTING / PARTICIPANTS Twenty afterschool programs in Boston were r and omized to intervention or control ( delayed intervention ) . INTERVENTION Intervention sites participated in learning collaboratives focused on policy and environmental changes to increase healthy eating , drinking , and physical activity opportunities during afterschool time ( material s available at www.osnap.org ) . Collaboration between Boston Public Schools Food and Nutrition Services , afterschool staff , and research ers established water-delivery systems to ensure children were served water during snack time . MAIN OUTCOME MEASURES Average ounces of water served to children per day was recorded by direct observation at each program at baseline and 6-month follow-up over 5 consecutive school days . Secondary measures directly observed included ounces of other beverages served , other snack components , and water-delivery system . RESULTS Participation in the intervention was associated with an increased average volume of water served ( + 3.6 ounces/day ; p=0.01 ) during snack . On average , the intervention led to a daily decrease of 60.9 kcals from beverages served during snack ( p=0.03 ) . CONCLUSIONS This study indicates the OSNAP intervention , including strategies to overcome structural barriers and collaboration with key actors , can increase offerings of water during afterschool snack . OSNAP appears to be an effective strategy to provide water in afterschool setting s that can be helpful in implementing new U.S. Department of Agriculture guidelines regarding water availability during lunch and afterschool snack 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 Introduction Although several studies suggest that drinking water may help prevent obesity , no US studies have examined the effect of school drinking water provision and promotion on student beverage intake . We assessed the acceptability , feasibility , and outcomes of a school-based intervention to improve drinking water consumption among adolescents . Methods The 5-week program , conducted in a Los Angeles middle school in 2008 , consisted of providing cold , filtered drinking water in cafeterias ; distributing reusable water bottles to students and staff ; conducting school promotional activities ; and providing education . Self-reported consumption of water , nondiet soda , sports drinks , and 100 % fruit juice was assessed by conducting surveys among students ( n = 876 ) , preintervention and at 1 week and 2 months postintervention , from the intervention school and the comparison school . Daily water ( in gallons ) distributed in the cafeteria during the intervention was recorded . Results After adjusting for sociodemographic characteristics and baseline intake of water at school , the odds of drinking water at school were higher for students at the intervention school than students at the comparison school . Students from the intervention school had higher adjusted odds of drinking water from fountains and from reusable water bottles at school than students from the comparison school . Intervention effects for other beverages were not significant . Conclusion Provision of filtered , chilled drinking water in school cafeterias coupled with promotion and education is associated with increased consumption of drinking water at school . A r and omized controlled trial is necessary to assess the intervention 's influence on students ' consumption of water and sugar-sweetened beverages , as well as obesity-related outcomes Many children suffer from nutritional deficiencies that may negatively affect their academic performance . This cluster-r and omized controlled trial aim ed to test the effects of micronutrient-fortified milk in Chinese students . Participants received either micronutrient-fortified ( n = 177 ) or unfortified ( n = 183 ) milk for six months . Academic performance , motivation , and learning strategies were estimated by end-of-term tests and the Motivated Strategies for Learning Question naire . Blood sample s were analyzed for micronutrients . In total , 296 students ( 82.2 % ) completed this study . Compared with the control group , students in the intervention group reported higher scores in several academic subjects ( p < 0.05 ) , including language s , mathematics , ethics , and physical performance at the end of follow-up . Students in the intervention group showed greater self-efficacy and use of cognitive strategies in learning , and reported less test anxiety ( p < 0.001 ) . Moreover , vitamin B2 deficiency ( odds ratio ( OR ) = 0.18 , 95 % confidence interval ( CI ) : 0.11~0.30 ) and iron deficiency ( OR = 0.34 , 95 % CI : 0.14~0.81 ) were less likely in the students of the intervention group , whereas vitamin D , vitamin B12 , and selenium deficiencies were not significantly different . “ Cognitive strategy ” had a partial mediating effect on the test scores of English ( 95 % CI : 1.26~3.79 ) and Chinese ( 95 % CI : 0.53~2.21 ) . Our findings suggest that micronutrient-fortified milk may improve students ’ academic performance , motivation , and learning strategies OBJECTIVE To determine whether an educational programme aim ed at discouraging students from drinking sugar-sweetened beverages could prevent excessive weight gain . DESIGN Forty-seven classes in twenty-two schools were r and omised as intervention or control . SUBJECTS Participants were 1140 , 9 - 12-year-old fourth grade rs ( 435 in the intervention group and 608 in the control group ) . Sugar-sweetened beverages and juice intake were measured through one 24 h recall at baseline and another at the end of the trial . The main outcome was the change in BMI ( BMI = weight (kg)/height ( m2 ) ) , measured at the beginning and at the end of the school year . Intention-to-treat analysis was performed taking into account the cluster ( classes ) effect . RESULTS A statistically significant decrease in the daily consumption of carbonated drinks in the intervention compared to control ( mean difference = -56 ml ; 95 % CI -119 , -7 ml ) was followed by a non-significant overall reduction in BMI , P = 0.33 . However , among those students overweight at baseline , the intervention group showed greater BMI reduction ( -0.4 kg/m2 compared with -0.2 kg/m2 in the control group ( P = 0.11 ) ) , and this difference was statistically significant among girls ( P = 0.009 ) . Fruit juice consumption was slightly increased in the intervention group ( P = 0.08 ) , but not among girls . CONCLUSION Decreasing sugar-sweetened beverages intake significantly reduced BMI among overweight children , and mainly among girls . Efforts to reduce energy intake through liquids need to emphasise overall sweetened beverages and addition of sugar on juices Objective To test the effect of a multidimensional lifestyle intervention on aerobic fitness and adiposity in predominantly migrant preschool children . Design Cluster r and omised controlled single blinded trial ( Ballabeina study ) over one school year ; r and omisation was performed after stratification for linguistic region . Setting 40 preschool classes in areas with a high migrant population in the German and French speaking regions of Switzerl and . Participants 652 of the 727 preschool children had informed consent and were present for baseline measures ( mean age 5.1 years ( SD 0.7 ) , 72 % migrants of multicultural origins ) . No children withdrew , but 26 moved away . Intervention The multidimensional culturally tailored lifestyle intervention included a physical activity programme , lessons on nutrition , media use ( use of television and computers ) , and sleep and adaptation of the built environment of the preschool class . It lasted from August 2008 to June 2009 . Main outcome measures Primary outcomes were aerobic fitness ( 20 m shuttle run test ) and body mass index ( BMI ) . Secondary outcomes included motor agility , balance , percentage body fat , waist circumference , physical activity , eating habits , media use , sleep , psychological health , and cognitive abilities . Results Compared with controls , children in the intervention group had an increase in aerobic fitness at the end of the intervention ( adjusted mean difference : 0.32 stages ( 95 % confidence interval 0.07 to 0.57 ; P=0.01 ) but no difference in BMI ( −0.07 kg/m2 , −0.19 to 0.06 ; P=0.31 ) . Relative to controls , children in the intervention group had beneficial effects in motor agility ( −0.54 s , −0.90 to −0.17 ; P=0.004 ) , percentage body fat ( −1.1 % , −2.0 to −0.2 ; P=0.02 ) , and waist circumference ( −1.0 cm , −1.6 to −0.4 ; P=0.001 ) . There were also significant benefits in the intervention group in reported physical activity , media use , and eating habits , but not in the remaining secondary outcomes . Conclusions A multidimensional intervention increased aerobic fitness and reduced body fat but not BMI in predominantly migrant preschool children . Trial registration Clinical Trials NCT00674544 The aim of the Bright Start study was to develop and test the effectiveness of a school environment intervention , supplemented with family involvement , to reduce excessive weight gain by increasing physical activity and healthy eating practice s among kindergarten and first grade American Indian children . Bright Start was a group-r and omized , school-based trial involving 454 children attending 14 schools on the Pine Ridge Reservation in South Dakota . Children were followed from the beginning of their kindergarten year through the end of first grade . Main outcome variables were mean BMI , mean percent body fat , and prevalence of overweight/obese children . The goals of the intervention were to : increase physical activity at school to at least 60 min/day ; modify school meals and snacks ; and involve families in making behavioral and environmental changes at home . At baseline , 32 % of boys and 25 % of girls were overweight/obese . While the intervention was not associated with statistically significant change in mean levels of BMI , BMI -Z , skinfolds or percentage body fat , the intervention was associated with a statistically significant net decrease of 10 % in the prevalence of overweight . Intervention children experienced a 13.4 % incidence of overweight , while the control children experienced a corresponding incidence of 24.8 % ; a difference of −11.4 % ( p=0.033 ) . The intervention significantly reduced parent reported mean child intakes of sugar-sweetened beverages , whole milk and chocolate milk . Changes in duration of school physical activity were not significant . Because obesity is the most daunting health challenge facing American Indian children today , more intervention research is needed to identify effective approaches OBJECTIVE Consumption of sugar-sweetened beverages ( SSB ) is linked to obesity . The authors hypothesized that school-based nutrition education would decrease SSB consumption . DESIGN Self-selected interventional cohort with r and om selection for pre and post measurements . SETTING Arizona Supplemental Nutrition Assistance Program-Education Program-eligible schools . PARTICIPANTS R and omly selected ( 9 % ) fourth- and fifth- grade classroom students . INTERVENTION The University of Arizona Nutrition Network provided general nutrition education training and material s to teachers , to be delivered to their students . The University of Arizona Nutrition Network administered behavioral question naires to students in both fall and spring . MAIN OUTCOME MEASURE(S ) Change in SSB consumption . ANALYSES Descriptive statistics were computed for student demographics and beverage consumption on the day before testing . Paired t tests evaluated change in classroom averages . Linear regression assessed potential correlates of SSB consumption . RESULTS Fall mean SSB consumption was 1.1 ( ± 0.2 ) times ; mean milk and water intake were 1.6 ( ± 0.2 ) and 5.2 ( ± 0.7 ) times , respectively . Beverage consumption increased ( 3.2 % ) in springtime , with increased SSBs ( 14.4 % ) accounting for the majority ( P = .006 ) . Change in SSB consumption was negatively associated with baseline SSB and water consumption but positively associated with baseline milk fat ( P ≤ .05 ) . CONCLUSIONS AND IMPLICATION S The results suggest the need for beverage-specific education to encourage children to consume more healthful beverages in warmer weather OBJECTIVE To assess the short-term impact of a nutritional intervention aim ed at reducing childhood overweight in German pre-school children . DESIGN Using a cluster-r and omized study design with waiting-list controls , we tested a 6-month intervention administered once weekly by a nutrition expert consisting of joint meal preparation and activities for children and parents such as tasting and preparing nutritious , fresh foods . At baseline , 6 and 12 months , a parent-completed question naire assessed fruit and vegetable intakes ( primary outcomes ) and water and sugared drinks consumption ( secondary outcomes ) . Direct measurement assessed BMI , skinfold thickness and waist-to-height-ratio . An intention-to-treat analysis used r and om-effects panel regression models to assess the intervention effect , adjusted for each child 's age , gender , immigrant background and maternal education . SETTING Eighteen pre-schools from three south German regions . SUBJECTS Healthy children aged 3 - 6 years . RESULTS Three hundred and seventy-seven ( 80 % ) eligible pre-school children participated in the study . Of these , 348 provided sufficient data for analysis . The sample mean age was 4·26 ( sd 0·78 ) years ; the majority ( 53·2 % ) were boys . Children 's fruit and vegetable intakes increased significantly ( P < 0·001 and P < 0·05 , respectively ) ; no significant changes in the consumption of water , sugared drinks or anthropometric measurements were noted . CONCLUSIONS Nutritional interventions in pre-schools have the potential to change eating behaviours in young children , which in the long term might reduce risk for developing overweight BACKGROUND Interventions to prevent and control childhood obesity have shown mixed results in terms of short- and long-term changes . OBJECTIVES ' MOVE/me Muevo ' was a 2-year family- and recreation centre-based r and omized controlled trial to promote healthy eating and physical activity among 5- to 8-year-old children . It was hypothesized that children in the intervention group would demonstrate lower post-intervention body mass index ( BMI ) values and improved obesity-related behaviours compared with the control group children . METHODS Thirty recreation centres in San Diego County , California , were r and omized to an intervention or control condition . Five hundred forty-one families were enrolled and children 's BMI , diet , physical activity and other health indicators were tracked from baseline to 2 years post-baseline . Analyses followed an intent-to-treat approach using mixed-effects models . RESULTS No significant intervention effects were observed for the primary outcomes of child 's or parent 's BMI and child 's waist circumference . Moderator analyses , however , showed that girls ( but not boys ) in the intervention condition reduced their BMI . At the 2-year follow-up , intervention condition parents reported that their children were consuming fewer high-fat foods and sugary beverages . CONCLUSIONS Favourable implementation fidelity and high retention rates support the feasibility of this intervention in a large metropolitan area ; however , interventions of greater intensity may be needed to achieve effects on child 's BMI . Also , further research is needed to develop gender-specific intervention strategies so that both genders may benefit from such efforts BACKGROUND As dietary gatekeepers for young children , parents are often the proximal target of family-based dietary interventions . Habit theory offers a novel approach to modifying parental feeding , based on " context -dependent repetition " to promote automatic responding and to reduce decisional conflict . OBJECTIVE This exploratory trial evaluated an intervention promoting habit formation for 3 parental feeding behaviors : serving fruit/vegetables , serving healthy snacks , and serving nonsweetened drinks . The primary outcome was parental habit strength for each behavior . The secondary outcome was children 's food intake . DESIGN Parents of children aged 2 - 6 y ( n = 126 ) were recruited from 6 children 's centers in London and cluster-r and omized to intervention ( n = 3 ) or no-treatment control ( n = 3 ) conditions . Parents in the intervention group ( n = 58 ) received training on habit formation for 3 feeding behaviors ; control participants ( n = 68 ) were asked only to complete the measures . At baseline and after treatment , parents completed vali date d measures of subjective " automaticity " for feeding behaviors and a brief child food-frequency measure . Parents in the intervention group were interviewed about the program . The change between groups , after clustering was controlled for , was analyzed . RESULTS For all parental feeding behaviors , automaticity increased more in the intervention group than in the control group ( P < 0.01 for all ) . Significant intervention effects on children 's intake of vegetables ( P = 0.003 ) , healthy snacks ( P = 0.009 ) , and water ( P = 0.032 ) were observed . Changes in children 's food intake correlated with changes in parental automaticity of feeding behaviors , and program acceptability was high . CONCLUSIONS A habit-based intervention successfully modified parental feeding behaviors , affected children 's diets positively , and was well received by parents . Habit theory provides a promising new tool to support family-based obesity prevention . This trial was registered as IS RCT N09910187 OBJECTIVE To determine if after-school nutrition workshops conducted in public libraries were related to lasting changes in food choice . METHODS " Snack Smart " workshops , based on Social Cognitive Theory , were conducted in 8 branch libraries ( 49 ethnically diverse children , ages 9 to 14 ) to assess changes in consumption of targeted food items by pretest , posttest , and follow-up food frequency question naires . Results were analyzed using the Friedman test for repeated measures and Wilcoxon signed rank test . RESULTS Intake of milk , vegetables , and water significantly increased at 3-week posttest ( P < .05 ) , but only water intake showed a significant change from pretest to follow-up 3 months later . CONCLUSIONS AND IMPLICATION S This low-intensity program did not produce lasting behavior change , as measured by changes in food frequency at 3 months post- intervention . The study supports the need to critically evaluate out-of-school nutrition programs for lasting impact OBJECTIVES This field study tested the feasibility and benefits of a program to promote 6 targeted parental behaviors to prevent obesity in children served by the Special Supplemental Nutrition Program for Women , Infants , and Children ( WIC ) . METHODS Two WIC sites participated in a nonr and omized , controlled 1-year prospect i ve study to assess parents ' self-reported behavior changes . RESULTS Statistical analyses of preintervention and postintervention assessment s of parental behavior demonstrated significant changes in 2 behaviors : frequency of offering the child water and frequency of engaging in active play with the child . In both cases , the intervention proved effective in increasing the desired behavior . CONCLUSIONS The findings demonstrate the feasibility of changing parental behaviors through multidimensional education in a WIC clinic setting Background Dietary habits established in infancy may persist into adulthood and determine long-term health . Objectives The aims of this work were to describe dietary patterns , predictors of adherence to them , and their tracking from ages 1 to 8 y in European children . Methods Three-day food diaries were prospect ively collected at ages 1 , 2 , 3 , 4 , 5 , 6 and 8 y. Foods were allocated to 1 of 29 food groups , which were included in exploratory factor analyses at each children 's age . The tracking of patterns through childhood was assessed by an estimated general equation model . Results At age 1 y ( n = 633 ) , 2 patterns were identified . One was labeled " core foods " ( CORE ) , since it was positively loaded for vegetables , fish , olive oil , and white and red meat , and negatively loaded for ready-to-eat infant products , sugar , and confectioneries . The other was positively loaded for saturated spreads , sugar , fruit juices , and confectioneries , and negatively loaded for olive oil , fish , and cow milk ; this was labeled as the " poor- quality fats and added sugars " ( F&S ) pattern . From ages 2 to 8 y , 3 patterns were repeatedly identified : CORE , F&S , and a " high protein sources " ( PROT ) pattern that was positively loaded for milk , flavored milks , fish , eggs , white and processed meat , chips , and olive oil , and negatively loaded for fresh fruits at almost all time points . Of those children in the highest quartiles of the CORE , F&S , and PROT patterns at 2 y , 45 % , 72 % , and 36 % , respectively , remained in the highest quartile at 8 y [ OR = 2.01 ( 1.08 , 3.8 ) , OR = 3.6 ( 1.5 , 8.4 ) and OR = 0.80 ( 0.4,1.6 ) , respectively ; P = 0.510 ] . Conclusions Dietary patterns are established between 1 and 2 y of age and track into mid-childhood . A dietary pattern characterized by added sugars , unhealthy fats , and poor consumption of fish and olive oil was the most stable throughout childhood . Further analyses will reveal whether those dietary patterns are associated with metabolic disease risk OBJECTIVE The objective of this study is to summarize evidence for strategies design ed to reduce sugar-sweetened beverage ( SSB ) consumption among children aged 0 to 5 years . DATA SOURCES PubMed , Web of Science , EMBASE , CINAHL , ERIC , Cab Abstract s and the Cochrane Central Register of Controlled Trials are the electronic data bases search ed in this systematic review . STUDY SELECTION Each included study evaluated an intervention to reduce SSB consumption in children aged 0 to 5 years , was conducted in a high-income country and was published between 1 January 2000 and 15 December 2017 . DATA SYNTHESIS Twenty-seven studies met the inclusion criteria . The primary intervention setting s were healthcare ( n = 11 ) , preschool/daycare ( n = 4 ) , home ( n = 3 ) , community venues ( n = 3 ) and other setting s ( n = 6 ) . Overarching strategies which successfully reduced SSB consumption included ( i ) in-person individual education , ( ii ) in-person group education , ( iii ) passive education ( e.g. pamphlets ) , ( iv ) use of technology , ( v ) training for childcare/healthcare providers and ( vi ) changes to the physical access of beverages . Studies were of moderate method ological quality ( average score of 20.7/29.0 for r and omized studies ; 3.1/9.0 for non-r and omized studies ) . CONCLUSIONS Evidence suggests that interventions successful at reducing SSB consumption among 0-year to 5-year olds often focused on vulnerable population s , were conducted in preschool/daycare setting s , specifically targeted only SSBs or only oral hygiene , included multiple intervention strategies and had higher intervention intensity/contact time Children 's sugar-sweetened beverages ( SSBs ) consumption presents significant risks for obesity , type 2 diabetes and dental health . But there is a lack of objective data on beverages in children 's overall environments . This study aim ed to determine the nature and extent of children 's beverage availability , purchase and consumption , throughout their day , using wearable cameras for data collection . Data were source d from ' Kids'Cam NZ ' , a study in which r and omly-selected New Zeal and children ( n = 168 ; 11 - 14y , mean 12.6y ) wore cameras for four days ( Thursday-Sunday ) , automatically taking a photo every 7s . Using content analysis , Thursday and Saturday images ( n = 700,201 ) were systematic ally analysed . On average , 18.9 ( 95 % CI 16.8 , 21.4 ) drinks/day were available to the children ( n = 158 ) , of which 7.5 ( 95 % CI 5.8 , 9.7 ; 39.7 % ) were non-core drinks , including 6.4 ( 95 % CI 5.0 , 8.3 ; 33.9 % ) SSBs . At school and home , core drinks ( water and unflavoured milk ) were the most available . In all other locations in which children spent time ( e.g. , recreation venues and food retail outlets ) non-core drinks dominated , at rates 1.5 - 5 times that of core drinks availability . Almost all drinks ( n = 17 ; 10.8 % ) the children purchased were non-core . On average , children ( n = 111 ; 70.3 % ) consumed a drink 2.6 ( 95 % CI 2.1 , 3.1 ) times/day , including one ( 95 % CI 0.7 , 1.3 ) SSB . At school and home core drinks predominated . SSBs were available to most children in all locations in which they spent time , and dominated their drinks purchases and consumption . SSBs appear to be a typical feature of children 's everyday environments , almost certainly making it difficult for children 's beverage intakes to align with guidelines . The findings support calls for governments to urgently enact the SSB-related actions in the WHO Commission 's Ending Childhood Obesity implementation plan and , in turn , improve child health Key Points Question Does a multijurisdictional , multilevel , multicomponent community intervention decrease young child overweight and obesity in the US-Affiliated Pacific region ? Findings Among 27 communities and 8371 children in this r and omized clinical trial , the Children ’s Healthy Living Program decreased overweight and obesity prevalence by 3.95 % among children aged 2 to 8 years in the US-Affiliated Pacific region . Meaning A multilevel , multicomponent approach reduced young child overweight and obesity Background Few interventions have shown efficacy to influence key energy balance behaviors during the preschool years . Objective A r and omized controlled trial ( RCT ) was used to evaluate the efficacy of Food , Fun , and Families ( FFF ) , a 12 week authoritative food parenting intervention for mothers with low-income levels , to reduce preschool-aged children ’s intake of calories from solid fat and added sugar ( SoFAS ) . Methods Mothers were r and omly assigned to receive FFF ( n = 59 ) or to a delayed treatment control ( n = 60 ) . The primary outcome was children ’s daily energy intake from SoFAS at the end of the 12 week intervention , controlling for baseline levels , assessed by 24-h dietary recalls . Secondary outcomes included children ’s daily energy intake , children ’s BMI z-scores , and meal observations of maternal food parenting practice s targeted in FFF ( e.g. providing guided choices ) . Results Participating mothers were predominantly African American ( 91 % ) , with 39 % educated beyond high school and 66 % unemployed . Baseline demographics and child SoFAS intakes did not differ by group . Lost to follow-up was 13 % and did not differ between groups . At post-intervention , FFF children consumed ~ 94 kcal or 23 % less daily energy from SoFAS than children in the control group , adjusting for baseline levels ( 307.8 ( 95%CI = 274.1 , 341.5 ) kcal vs. 401.9 ( 95%CI = 369.8 , 433.9 ) kcal , FFF vs. control ; p < 0.001 ) . FFF mothers also displayed a greater number of authoritative parenting practice s when observed post-intervention with their child at a buffet-style meal ( Wilcoxon z = − 2.54 , p = 0.012 ) . Neither child total daily energy intake nor BMI z-scores differed between groups post-intervention . Conclusions Findings demonstrate the initial efficacy of an authoritative food parenting intervention for families with low-income to reduce SoFAS intake in early childhood . Additional research is needed to evaluate longer-term effects on diet and growth . Trial registration Retrospectively registered at Clinical Trials.gov : # NCT03646201 Background Research has consistently indicated that most children do not consume sufficient fruit and vegetables to provide them with a healthy , balanced diet . This study set out to trial a simple , low-cost behavioural nudge intervention to encourage children to select and consume more fruit and vegetables with their lunchtime meal in a primary school cafeteria . Methods Four primary schools were r and omly allocated to either the control or the intervention condition and baseline data were collected over two days in each school . Following this , changes were made to the choice architecture of the school cafeterias in the intervention schools and maintained over a three-week period . The intervention included improved positioning and serving of fruit , accompanied by attractive labelling of both fruit and vegetables on offer . Next , data were collected over two days in each school , with menus matched in each instance between baseline and follow-up . We employed a vali date d and sensitive photographic method to estimate individual children ’s ( N = 176 ) consumption of vegetables , fruit , vitamin C , fibre , total sugars , and their overall calorie intake . Results Significant increases were recorded in the intervention schools for children ’s consumption of fruit , vitamin C , and fibre . No significant changes were observed in the control condition . The increases in fruit consumption were recorded in a large proportion of individual children , irrespective of their baseline consumption levels . No changes in vegetable consumption were observed in either condition . Conclusions These results are the first to show that modest improvements to the choice architecture of school catering , and inclusion of behavioural nudges , can significantly increase fruit consumption , rather than just selection , in primary -age children . This has implication s for the development of national and international strategies to promote healthy eating in schools . Trial registration AsPredicted : 3943 05/02/2017 . URL : Background Community-based interventions are needed to reduce the burden of childhood obesity . Purpose To evaluate the impact of a multi-level promotora-based ( Community Health Advisor ) intervention to promote healthy eating and physical activity and prevent excess weight gain among Latino children . Methods Thirteen elementary schools were r and omized to one of four intervention conditions : individual/family level ( Family-only ) , school/community level ( Community-only ) , combined ( Family + Community ) , or a measurement-only condition . Participants were 808 Latino parents and their children enrolled in kindergarten through 2nd grade . Measures included parent and child body mass index ( BMI ) and a self-administered parent survey that assessed several parent and child behaviors . Results There were no significant intervention effects on children ’s BMI z-score . The family intervention changed several obesity-related child behaviors ( e.g. , fruit/vegetable consumption ) and these were mediated by changes in parenting variables ( e.g. , parent monitoring ) . Conclusion A promotora-based behavioral intervention was efficacious at changing parental factors and child obesity-related health behaviors

Intra-pregnancy nonsurgical periodontal therapy improved periodontal clinical parameters ( periodontal pocket depth , clinical attachment level , and bleeding on probing ) and reduced biomarker level from gingival crevicular fluid ( GCF ) , and some from blood serum ; however , it did not influence biomarker level from umbilical cord blood . Conclusions These results demonstrated that the intra-pregnancy nonsurgical periodontal therapy decreased periodontal inflammatory biomarker levels from gingival crevicular fluid and some from serum blood , with no influence on inflammatory biomarker level from cord blood , and it did not consistently reduce adverse gestational adverse outcome occurrence .

Background The aim of this systematic review with meta- analysis was to analyze the effects of intra-pregnancy nonsurgical periodontal therapy on periodontal inflammatory biomarkers and adverse pregnancy outcomes .

Periodontal disease ( PD ) in pregnancy is associated with an increased risk of adverse pregnancy outcomes including miscarriage and preterm birth . Evidence exists that periodontal disease treatment may reduce inflammatory mediators in gingival crevicular fluid ( GCF ) and the risk of inflammation-associated pregnancy complications . The aim was to determine if periodontal disease treatment during mid-pregnancy alters local inflammation in GCF and has beneficial effects on clinical dental parameters . Eighty pregnant women with clinical ly diagnosed PD were recruited from a r and omised controlled trial on the treatment of periodontal disease in pregnancy conducted in Perth , Australia . The treatment group underwent intensive PD treatment ( 20 - 28 weeks ' GA ) , while the control group underwent the same treatment postnatally . GCF was collected at 20 and 28 weeks ' gestation and concentrations of cytokines determined by multiplex assay : IL-1β , IL-6 , IL-8 , IL-10 , IL-12p70 , IL-17 , TNF-α and MCP-1 . Periodontal treatment significantly reduced the GCF levels of IL-1β , IL-10 , IL-12p70 and IL-6 at 28 weeks ' GA compared with controls , while levels of MCP-1 , IL-8 and TNF-α exhibited a significant gestational age-dependent increase , but no treatment response . Post-treatment clinical parameters improved with significant reductions in bleeding on probing , clinical attachment loss , and probing depth . No changes in pregnancy-related outcomes were observed , although the severity of periodontal disease was significantly associated with an increased risk of infants born small for gestational age . PD treatment in pregnancy reduces the levels of some inflammatory mediators in the GCF and improves dental parameters , with no overt effects on pregnancy outcome BACKGROUND AND OBJECTIVE A low- grade systemic inflammatory status originating from periodontal infection has been proposed to explain the association between periodontal disease and systemic conditions , including adverse obstetric outcomes . The aim of this study was to evaluate the effect of periodontal therapy during pregnancy on the gingival crevicular fluid and serum levels of six cytokines associated with periodontal disease and preterm birth . MATERIAL AND METHODS A sub sample of 60 women ( 18 - 35 years of age ) up to 20 gestational weeks , previously enrolled in a larger r and omized clinical trial , was recruited for the present study . Participants were r and omly allocated to receive either comprehensive nonsurgical periodontal therapy before 24 gestational weeks ( n = 30 , test group ) or only one appointment for supragingival calculus removal ( n = 30 , control group ) . Clinical data , and sample s of blood and gingival crevicular fluid , were collected at baseline , at 26 - 28 gestational weeks and 30 d after delivery . The levels of interleukin (IL)-1β , IL-6 , IL-8 , IL-10 , IL-12p70 and tumor necrosis factor-α were analyzed by flow cytometry . RESULTS After treatment , a major reduction in periodontal inflammation was observed in the test group , with bleeding on probing decreasing from 49.62 % of sites to 11.66 % of sites ( p < 0.001 ) . Periodontal therapy significantly reduced the levels of IL-1β and IL-8 in gingival crevicular fluid ( p < 0.001 ) . However , no significant effect of therapy was observed on serum cytokine levels . After delivery , the levels of IL-1β in the gingival crevicular fluid of the test group were significantly lower than were those in the control group ( p < 0.001 ) , but there were no significant differences between test and control groups regarding serum cytokine levels . CONCLUSION Although periodontal therapy during pregnancy successfully reduced periodontal inflammation and gingival crevicular fluid cytokine levels , it did not have a significant impact on serum biomarkers BACKGROUND Few studies have examined the potential effects of periodontal treatment during pregnancy on pregnancy outcomes , periodontal status , and inflammatory biomarkers . METHODS A r and omized , delayed-treatment , controlled pilot trial was conducted to evaluate the effects of second-trimester scaling and root planing and the use of a sonic toothbrush on the rate of preterm delivery ( < 37 weeks gestation ) . Secondary outcome measures included changes in periodontal status , levels of eight oral pathogens , levels of gingival crevicular fluid ( GCF ) interleukin-1beta ( IL-1beta ) , prostagl and in E(2 ) ( PGE(2 ) ) , 8-isoprostane ( 8-iso ) , and IL-6 , and serum levels of IL-6 , soluble intercellular adhesion molecule 1 ( sICAM1 ) , 8-isoprostane , soluble glycoprotein 130 ( sGP130 ) , IL-6 soluble receptor ( IL-6sr ) , and C-reactive protein ( CRP ) . Logistic regression models were used to test for effects of treatment on preterm delivery . Secondary outcomes were analyzed by analysis of covariance adjusting for subject baseline values . RESULTS Periodontal intervention result ed in a significantly decreased incidence odds ratio ( OR ) for preterm delivery ( OR = 0.26 ; 95 % confidence interval = 0.08 to 0.85 ) , adjusting for baseline periodontal status which was unbalanced after r and omization . Pregnancy without periodontal treatment was associated with significant increases in probing depths , plaque scores , GCF IL-1beta , and GCF IL-6 levels . Intervention result ed in significant improvements in clinical status ( attachment level , probing depth , plaque , gingivitis , and bleeding on probing scores ) and significant decreases in levels of Prevotella nigrescens and Prevotella intermedia , serum IL-6sr , and GCF IL-1beta . CONCLUSIONS Results from this pilot study ( 67 subjects ) provide further evidence supporting the potential benefits of periodontal treatment on pregnancy outcomes . Treatment was safe , improved periodontal health , and prevented periodontal disease progression . Preliminary data show a 3.8-fold reduction in the rate of preterm delivery , a decrease in periodontal pathogen load , and a decrease in both GCF IL-1beta and serum markers of IL-6 response . However , further studies will be needed to substantiate these early findings BACKGROUND Preterm low birth weight was reported to be related to periodontal infections that might influence the fetus-placenta complex . The aim of this study was to provide periodontal treatment for pregnant women and to evaluate if this treatment can interfere with pregnancy duration and weight of the newborn . METHODS The sample consisted of 450 pregnant women who were under prenatal care at a polyclinic in Três Corações , Brazil . Women with risk factors , such as systemic alterations ( ischemic cardiopathy , hypertension , tuberculosis , diabetes , cancer , anemia , seizure , psychopathology , urinary tract infection , sexually transmitted diseases , asthma , and human immunodeficiency virus ) , and /or users of alcohol , tobacco , and drugs were excluded from the study . Data related to age , socioeconomic level , race , marital status , number of previous pregnancies , and previous preterm delivery also were evaluated . Initially , the sample was divided into two groups : 122 healthy patients ( group 1 ) and 328 patients with periodontal disease ( group 2 ) . In group 2 , 266 patients underwent treatment and 62 patients dropped out . After mothers gave birth , pregnancy duration and the weight of all infants were analyzed and recorded . RESULTS There was no statistical difference between the healthy and treated groups . However , there was a difference in the non-treated group , with a 79 % incidence of preterm low birth weight . Educational level , previous preterm birth , and periodontal disease were related significantly to preterm delivery ( P < 0.001 ) . CONCLUSION Periodontal disease was related significantly to preterm low birth weight BACKGROUND Periodontitis has been associated with increased risk of adverse pregnancy outcomes and elevated C-reactive protein ( CRP ) concentrations in non-pregnant adults . We examined the relationship between periodontitis and CRP among women who provided dental radiographs and had blood collected during early pregnancy , excluding smokers and diabetic patients . METHODS From Project Viva , an ongoing cohort study , we measured plasma CRP in 35 subjects with periodontitis ( i.e. , at least one site with > or =3 mm of alveolar bone loss ) and a r and om sample of 66 periodontally healthy subjects matched on age and race/ethnicity . We performed linear regression analysis with log-transformed CRP levels as the outcome . RESULTS The mean ( + /- SE ) CRP level was 65 % higher ( 95 % confidence interval : -2 % , 180 % ; P = 0.06 ) in women with periodontitis ( 2.46 + /- 0.52 mg/l ) than in controls ( 1.49 + /- 0.22 mg/l ) , adjusting for factors related to CRP levels , including age , race/ethnicity , pre-pregnancy body mass index , alcohol intake , education , income , and gestational age at blood collection . CONCLUSIONS These findings suggest that periodontitis may increase CRP levels in pregnancy . CRP could potentially mediate the association of periodontitis with adverse pregnancy outcomes BACKGROUND The purpose of this study is to present the use of a non-r and omized experimental design with multiple controls , with emphasis on a historical control group , as an alternative method ologic re source for studies on the association between periodontal disease and prematurity/low birth weight . METHODS The sample consisted of 234 pregnant women : 54 in the Test Group ( treatment of periodontal disease ) ; 68 in Control Group I ( without periodontal disease ) ; and 112 in Control Group II ( historical control group , with untreated periodontal disease ) . The diagnosis of periodontal disease was established by means of a complete clinical examination , using measurements of probing depth , gingival recession , clinical attachment loss , and bleeding index . The women in the Test Group were treated for periodontitis and followed-up with periodontal support therapy throughout their pregnancies . After delivery , they were reevaluated regarding their periodontal condition , and information on the newborn 's birth weight was obtained . This was also done for Control Groups I and II . Descriptive analyses on the study variables were performed using the χ(2 ) and Fisher exact tests . Association measurements ( relative risk ) were obtained using a significance level of 5 % . RESULTS The frequency of low birth weight among the Test Group was similar to Control Group I and lower than Control Group II . CONCLUSION The results suggest that successful periodontal therapy in pregnant women suffering from periodontitis is a protective factor promoting the birth of children with normal weight BACKGROUND Recent studies have suggested that periodontal disease is a risk factor for preterm low birth weight ( PLBW ) . A r and omized controlled trial was undertaken to help further evaluate the proposed association between periodontal disease and PLBW . METHODS Four hundred pregnant women with periodontal disease , aged 18 to 35 , were enrolled while receiving prenatal care in Santiago , Chile . Women were r and omly assigned to either an experimental group ( n = 200 ) , which received periodontal treatment before 28 weeks of gestation or to a control group ( n = 200 ) which received periodontal treatment after delivery . Previous and current pregnancies and known risk factors were obtained from patient medical records and interviews . The primary outcome assessed was the delivery at less than 37 weeks of gestation or an infant weighing less than 2,500 g. RESULTS Of the 400 women enrolled , 49 were excluded from the analyses for different reasons . The incidence of PLBW in the treatment group was 1.84 % ( 3/163 ) and in the control group was 10.11 % ( 19/188 ) , ( odds ratio [ OR ] 5.49 , 95 % confidence interval [ CI ] 1.65 to 18.22 , P= 0.001 ) . Multivariate logistic regression analysis showed that periodontal disease was the strongest factor related to PLBW ( OR 4.70 , 95 % CI 1.29 to 17.13 ) . Other factors significantly associated with such deliveries were : previous PLBW ( OR 3.98 , 95 % CI 1.11 to 14.21 ) , less than 6 prenatal visits ( OR 3.70 , 95 % Cl 1.46 to 9.38 ) , and maternal low weight gain ( OR 3.42 , 95 % CI 1.16 to 10.03 ) . CONCLUSIONS Periodontal disease appears to be an independent risk factor for PLBW . Periodontal therapy significantly reduces the rates of PLBW in this population of women with periodontal disease AIM Determine whether periodontitis progression during pregnancy is associated with adverse birth outcomes . METHODS We used clinical data and birth outcomes from the Obstetrics and Periodontal Therapy Study , in which r and omly selected women received periodontal treatment before 21 weeks of gestation ( N=413 ) or after delivery ( 410 ) . Birth outcomes were available for 812 women and follow-up periodontal data for 722 , including 75 whose pregnancies ended < 37 weeks . Periodontitis progression was defined as > or=3 mm loss of clinical attachment . Birth outcomes were compared between non-progressing and progressing groups using the log rank and t tests , separately in all women and in untreated controls . RESULTS The distribution of gestational age at the end of pregnancy ( p>0.1 ) and mean birthweight ( 3295 versus 3184 g , p=0.11 ) did not differ significantly between women with and without disease progression . Gestational age and birthweight were not associated with change from baseline in percentage of tooth sites with bleeding on probing or between those who did versus did not progress according to a published definition of disease progression ( p>0.05 ) . CONCLUSIONS In these women with periodontitis and within this study 's limitations , disease progression was not associated with an increased risk for delivering a pre-term or a low birthweight infant BACKGROUND One hypothesis to explain the association between periodontal disease ( PD ) preterm/low birth weight ( PT/LBW ) is that PT/LBW may be indirectly mediated through translocation of bacteria or bacterial products in the systemic circulation . Transient bacteremias occur in subjects with marginal periodontitis or with gingivitis , and it is possible that bacteria and their products may reach the placental membranes hematogenously and provide the inflammatory effect to induce preterm labor . The effect of gingivitis as a potential risk factor for PT/LBW has still not been studied . A r and omized controlled trial was undertaken to determine the effect of routine plaque control and scaling on the pregnancy outcomes in women with gingivitis . METHODS Eight hundred seventy ( 870 ) pregnant women with gingivitis , aged 18 to 42 , were enrolled while receiving prenatal care in Santiago , Chile . Women were r and omly assigned in a two-to-one fashion to either a treatment group ( N = 580 ) , receiving periodontal treatment before 28 weeks of gestation or to a control group ( N = 290 ) , receiving periodontal treatment after delivery . Periodontal therapy consisted of plaque control , scaling , and daily rinsing with 0.12 % clorhexidine . Maintenance therapy was provided every 2 to 3 weeks until delivery , and consisted of oral hygiene instruction and supragingival plaque removal by instrumentation , as needed . The primary outcomes assessed were delivery at less than 37 weeks of gestation or an infant weighing less than 2,500 g. RESULTS Of the 870 women enrolled , 36 women ( 27 in the treatment group and nine in the control group ) were excluded from the analyses for different reasons . The incidence of PT/LBW in the treatment group was 2.14 % ( 12/560 ) and in the control group , 6.71 % ( 19/283 ) ( odds ratio [ OR ] 3.26 ; 95 % confidence interval [ CI ] 1.56 to 6.83 ; P = 0.0009 ) . Multivariate logistic regression analysis showed that , after adjusting for several known risk factors for PT/LBW , women with gingivitis were at a higher risk of PT/LBW than women who received periodontal treatment ( OR 2.76 ; 95%CI 1.29 to 5.88 ; P = 0.008 ) . CONCLUSIONS Periodontal treatment significantly reduced the PT/LBW rate in this population of women with pregnancy-associated gingivitis . Within the limitations of this study , we conclude that gingivitis appears to be an independent risk factor for PT/LBW for this population BACKGROUND Periodontal disease has been linked to systemic diseases/disorders and a low- grade systemic inflammatory status originated from periodontitis has been proposed as a possible explanation for this association . This study evaluates the relationship , early in pregnancy , between gingival crevicular fluid ( GCF ) and serum levels of a panel of cytokines that have been implicated in PTB and periodontal disease . METHODS One hundred pregnant women aged 18 - 35 years old with a gestational age up to 20 weeks were included ( mean±SD gestational age:16.1±3.5 weeks ) . Four periodontal sites per subject were r and omly selected for GCF collection . Serum and GCF levels of IL-1β , IL-6 , IL-8 , IL-10 , IL-12p70 and TNF-α were analyzed using a cytometric bead array . Regression and correlation analyses were used to assess the relationship between serum and GCF cytokine levels . RESULTS Participants had widespread periodontal inflammation but limited periodontal destruction . Cytokine levels were significantly higher in GCF than serum for all cytokines but IL-10 . GCF levels had small but significant effect on serum levels for IL-10 ( β=0.34±0.09 , p<0.01 ) , IL-12p70 ( β=0.48±0.08 , p<0.01 ) and TNF-α ( β=0.29±0.09 , p<0.01 ) . Periodontal probing depth and bleeding on probing were significantly associated with GCF levels for IL-1β , IL-6 and IL-8 ; however , they had negligible effect on serum cytokine levels . Correlation between GCF and serum levels was non-significant , except for IL-12p70 , which showed a significant but small correlation between the two sources ( r=0.32 , p=0.001 ) . CONCLUSIONS GCF cytokine levels were not strongly associated with serum cytokine levels in pregnant women with widespread periodontal inflammation but limited periodontal destruction

The findings suggest that couple counselling for the prevention of vertical transmission ; gender empowerment , community mobilization , and female condom promotion for female sex workers ; exp and ed female condom distribution for the general population ; and post-exposure HIV prophylaxis for rape survivors are cost-effective HIV interventions . Cash transfers for schoolgirls and school support for orphan girls may also be cost-effective in generalized epidemic setting s. CONCLUSIONS There has been limited research to assess the cost-effectiveness of interventions that seek to address women 's needs and transform harmful gender norms . Our review identified several promising , cost-effective interventions that merit consideration as critical enablers in HIV investment approaches , as well as highlight that broader gender and development interventions can have positive HIV impacts .

INTRODUCTION Harmful gender norms and inequalities , including gender-based violence , are important structural barriers to effective HIV programming . We assess current evidence on what forms of gender-responsive intervention may enhance the effectiveness of basic HIV programmes and be cost-effective .

Women who exchange sex for money or other goods , that is , female sex workers , are at increased risk of experiencing physical and sexual violence from both paying and intimate partners . Exposure to violence can be exacerbated by alcohol use and HIV/STI risk . The purpose of this study is to examine the efficacy of a HIV/STI risk reduction and enhanced HIV/STI risk reduction intervention at decreasing paying and intimate partner violence against Mongolian women who exchange sex and engage in harmful alcohol use . Women are recruited and r and omized to either ( a ) four sessions of a relationship-based HIV/STI risk reduction intervention ( n = 49 ) , ( b ) the same HIV/STI risk reduction intervention plus two additional motivational interviewing sessions ( n = 58 ) , or ( c ) a four session control condition focused on wellness promotion ( n = 59 ) . All the respondents complete assessment s at baseline ( preintervention ) as well as at immediate posttest , 3 and 6 months postintervention . A multilevel logistic model finds that women who participated in the HIV/STI risk reduction group ( OR = 0.14 , p < .00 ) , HIV/STI risk reduction and motivational interview group ( OR = 0.46 , p = .02 ) , and wellness ( OR = 0.20 , p < .00 ) group reduced their exposure to physical and sexual violence in the past 90 days . No significant differences in effects are observed between conditions . This study demonstrates the efficacy of a relationship-based HIV/STI risk reduction intervention , a relationship-based HIV/STI risk reduction intervention combined with motivational interviewing , and a wellness promotion intervention in reducing intimate and paying partner violence against women who exchange sex in Mongolia . The findings have significant implication s for the impact of minimal intervention and the potential role of peer networks and social support in reducing women ’s experiences of violence in re source poor setting Objective We evaluate the effect of clinic-based support by HIV-positive Peer Mentors , in addition to st and ard clinic care , on maternal and infant well-being among Women Living with HIV ( WLH ) from pregnancy through the infant 's first year of life . Methods In a cluster r and omized controlled trial in KwaZulu-Natal , South Africa , eight clinics were r and omized for pregnant WLH to receive either : a St and ard Care condition ( SC ; 4 clinics ; n = 656 WLH ) ; or an Enhanced Intervention ( EI ; 4 clinics ; n = 544 WLH ) . WLH in the EI were invited to attend four antenatal and four postnatal meetings led by HIV-positive Peer Mentors , in addition to SC . WLH were recruited during pregnancy , and at least two post-birth assessment interviews were completed by 57 % of WLH at 1.5 , 6 or 12 months . EI 's effect was ascertained on 19 measures of maternal and infant well-being using r and om effects regressions to control for clinic clustering . A binomial test for correlated outcomes evaluated EI 's overall efficacy . Findings WLH attended an average of 4.1 sessions ( SD = 2.0 ) ; 13 % did not attend any sessions . Significant overall benefits were found in EI compared to SC using the binomial test . Secondarily , over time , WLH in the EI reported significantly fewer depressive symptoms and fewer underweight infants than WLH in the SC condition . EI WLH were significantly more likely to use one feeding method for six months and exclusively breastfeed their infants for at least 6 months . Conclusions WLH benefit by support from HIV-positive Peer Mentors , even though EI participation was partial , with incomplete follow-up rates from 6–12 months . Trial Registration Clinical Trials.gov Objective : To assess effects of a combined microfinance and training intervention on HIV risk behavior among young female participants in rural South Africa . Design : Secondary analysis of quantitative and qualitative data from a cluster r and omized trial , the Intervention with Microfinance for AIDS and Gender Equity study . Methods : Eight villages were pair-matched and r and omly allocated to receive the intervention . At baseline and after 2 years , HIV risk behavior was assessed among female participants aged 14–35 years . Their responses were compared with women of the same age and poverty group from control villages . Intervention effects were calculated using adjusted risk ratios employing village level summaries . Qualitative data collected during the study explored participants ' responses to the intervention including HIV risk behavior . Results : After 2 years of follow-up , when compared with controls , young participants had higher levels of HIV-related communication ( adjusted risk ratio 1.46 , 95 % confidence interval 1.01–2.12 ) , were more likely to have accessed voluntary counseling and testing ( adjusted risk ratio 1.64 , 95 % confidence interval 1.06–2.56 ) , and less likely to have had unprotected sex at last intercourse with a nonspousal partner ( adjusted risk ratio 0.76 , 95 % confidence interval 0.60–0.96 ) . Qualitative data suggest a greater acceptance of intrahousehold communication about HIV and sexuality . Although women noted challenges associated with acceptance of condoms by men , increased confidence and skills associated with participation in the intervention supported their introduction in sexual relationships . Conclusions : In addition to impacts on economic well being , women 's empowerment and intimate partner violence , interventions addressing the economic and social vulnerability of women may contribute to reductions in HIV risk behavior OBJECTIVES We examined the effect of a peer-delivered educational intervention , the Malawi Male Motivator intervention , on couples ' contraceptive uptake . We based the intervention design on the information-motivation-behavioral skills ( IMB ) model . METHODS In 2008 we recruited 400 men from Malawi 's Mangochi province who reported not using any method of contraception . We r and omized them into an intervention arm and a control arm , and administered surveys on contraceptive use at baseline and after the intervention . We also conducted in-depth interviews with a subset of intervention participants . RESULTS After the intervention , contraceptive use increased significantly within both arms ( P < .01 ) , and this increase was significantly greater in the intervention arm than it was in the control arm ( P < .01 ) . Quantitative and qualitative data indicated that increased ease and frequency of communication within couples were the only significant predictors of uptake ( P < .01 ) . CONCLUSIONS Our findings indicate that men facilitated contraceptive use for their partners . Although the IMB model does not fully explain our findings , our results show that the intervention 's content and its training in communication skills are essential mechanisms for successfully enabling men to help couples use a contraceptive Background Violence against female sex workers ( FSWs ) can impede HIV prevention efforts and contravenes their human rights . We developed a multi-layered violence intervention targeting policy makers , secondary stakeholders ( police , lawyers , media ) , and primary stakeholders ( FSWs ) , as part of wider HIV prevention programming involving > 60,000 FSWs in Karnataka state . This study examined if violence against FSWs is associated with reduced condom use and increased STI/HIV risk , and if addressing violence against FSWs within a large-scale HIV prevention program can reduce levels of violence against them . Methods FSWs were r and omly selected to participate in polling booth surveys ( PBS 2006 - 2008 ; short behavioural question naires administered anonymously ) and integrated behavioural-biological assessment s ( IBBAs 2005 - 2009 ; administered face-to-face ) . Results 3,852 FSWs participated in the IBBAs and 7,638 FSWs participated in the PBS . Overall , 11.0 % of FSWs in the IBBAs and 26.4 % of FSWs in the PBS reported being beaten or raped in the past year . FSWs who reported violence in the past year were significantly less likely to report condom use with clients ( zero unprotected sex acts in previous month , 55.4 % vs. 75.5 % , adjusted odds ratio ( AOR ) 0.4 , 95 % confidence interval ( CI ) 0.3 to 0.5 , p < 0.001 ) ; to have accessed the HIV intervention program ( ever contacted by peer educator , 84.9 % vs. 89.6 % , AOR 0.7 , 95 % CI 0.4 to 1.0 , p = 0.04 ) ; or to have ever visited the project sexual health clinic ( 59.0 % vs. 68.1 % , AOR 0.7 , 95 % CI 0.6 to 1.0 , p = 0.02 ) ; and were significantly more likely to be infected with gonorrhea ( 5.0 % vs. 2.6 % , AOR 1.9 , 95 % CI 1.1 to 3.3 , p = 0.02 ) . By the follow-up surveys , significant reductions were seen in the proportions of FSWs reporting violence compared with baseline ( IBBA 13.0 % vs. 9.0 % , AOR 0.7 , 95 % CI 0.5 to 0.9 p = 0.01 ; PBS 27.3 % vs. 18.9 % , crude OR 0.5 , 95 % CI 0.4 to 0.5 , p < 0.001 ) . Conclusions This program demonstrates that a structural approach to addressing violence can be effectively delivered at scale . Addressing violence against FSWs is important for the success of HIV prevention programs , and for protecting their basic human rights The aim of this study is to assess whether the Government of Kenya 's Cash Transfer for Orphans and Vulnerable Children ( Kenya CT-OVC ) can reduce the risk of HIV among young people by postponing sexual debut . The program provides an unconditional transfer of US$ 20 per month directly to the main caregiver in the household . An evaluation of the program was implemented in 2007–2009 in seven districts . Fourteen Locations were r and omly assigned to receive the program and fourteen were assigned to a control arm . A sample of households was enrolled in the evaluation in 2007 . We revisited these households in 2011 and collected information on sexual activity among individuals between 15–25 years of age . We used logistic regression , adjusted for the respondent 's age , sex and relationship to caregiver , the age , sex and schooling of the caregiver and whether or not the household lived in Nairobi at baseline , to compare rates of sexual debut among young people living in program households with those living in control households who had not yet entered the program . Our results , adjusted for these covariates , show that the program reduced the odds of sexual debut by 31 percent . There were no statistically significant effects on secondary outcomes of behavioral risk such as condom use , number of partners and transactional sex . Since the CT-OVC provides cash to the caregiver and not to the child , and there are no explicit conditions associated with receipt , these impacts are indirect , and may have been achieved by keeping young people in school . Our results suggest that large-scale national social cash transfer programs with poverty alleviation objectives may have potential positive spillover benefits in terms of reducing HIV risk among young people in Eastern and Southern Africa This article presents the results of a r and omized trial in South Africa of an adapted evidence -based Woman-Focused intervention on condom use with primary sex partners . The preliminary findings show that regardless of HIV status , condom negotiation was significantly associated with condom use at the 3- and 6-month follow-ups . By intervention group , significant intervention effects were found at 6-month follow-up for HIV-positive and HIV-unknown status women in the Woman-Focused intervention who were more likely than women in the St and ard intervention to report condom use with a primary male partner . Among HIV-positive women , those in the Woman-Focused group and those with greater sexual control were more likely to report condom use at the 6-month follow-up . The findings indicate that gender-based interventions for women may result in increased condom negotiation skills This cost-effectiveness study analyzes the cost per quality -adjusted life year ( QALY ) gained in a r and omized controlled trial that tested school support as a structural intervention to prevent HIV risk factors among Zimbabwe orphan girl adolescents . The intervention significantly reduced early marriage , increased years of schooling completed , and increased health-related quality of life . By reducing early marriage , the literature suggests the intervention reduced HIV infection . The intervention yielded an estimated US$ 1,472 in societal benefits and an estimated gain of 0.36 QALYs per orphan supported . It cost an estimated US$ 6/QALY gained , about 1 % of annual per capita income in Zimbabwe . That is well below the maximum price that the World Health Organization ( WHO ) Commission on Macroeconomics and Health recommends paying for health gains in low and middle income countries . About half the girls in the intervention condition were boarded when they reached high school . For non-boarders , the intervention ’s financial benefits exceeded its costs , yielding an estimated net cost savings of $ 502 per pupil . Without boarding , the intervention would yield net savings even if it were 34 % less effective in replication . Boarding was not cost-effective . It cost an additional $ 1,234 per girl boarded ( over the 3 years of the study , discounted to present value at a 3 % discount rate ) but had no effect on any of the outcome measures relative to girls in the treatment group who did not board . For girls who did not board , the average cost of approximately 3 years of school support was US$ 973 BACKGROUND Measurement of the global burden of disease with disability-adjusted life-years ( DALYs ) requires disability weights that quantify health losses for all non-fatal consequences of disease and injury . There has been extensive debate about a range of conceptual and method ological issues concerning the definition and measurement of these weights . Our primary objective was a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new , st and ardised approach . METHODS We surveyed respondents in two ways : household surveys of adults aged 18 years or older ( face-to-face interviews in Bangladesh , Indonesia , Peru , and Tanzania ; telephone interviews in the USA ) between Oct 28 , 2009 , and June 23 , 2010 ; and an open-access web-based survey between July 26 , 2010 , and May 16 , 2011 . The surveys used paired comparison questions , in which respondents considered two hypothetical individuals with different , r and omly selected health states and indicated which person they regarded as healthier . The web survey added questions about population health equivalence , which compared the overall health benefits of different life-saving or disease-prevention programmes . We analysed paired comparison responses with probit regression analysis on all 220 unique states in the study . We used results from the population health equivalence responses to anchor the results from the paired comparisons on the disability weight scale from 0 ( implying no loss of health ) to 1 ( implying a health loss equivalent to death ) . Additionally , we compared new disability weights with those used in WHO 's most recent up date of the Global Burden of Disease Study for 2004 . FINDINGS 13,902 individuals participated in household surveys and 16,328 in the web survey . Analysis of paired comparison responses indicated a high degree of consistency across surveys : correlations between individual survey results and results from analysis of the pooled data set were 0·9 or higher in all surveys except in Bangladesh ( r=0·75 ) . Most of the 220 disability weights were located on the mild end of the severity scale , with 58 ( 26 % ) having weights below 0·05 . Five ( 11 % ) states had weights below 0·01 , such as mild anaemia , mild hearing or vision loss , and secondary infertility . The health states with the highest disability weights were acute schizophrenia ( 0·76 ) and severe multiple sclerosis ( 0·71 ) . We identified a broad pattern of agreement between the old and new weights ( r=0·70 ) , particularly in the moderate-to-severe range . However , in the mild range below 0·2 , many states had significantly lower weights in our study than previously . INTERPRETATION This study represents the most extensive empirical effort as yet to measure disability weights . By contrast with the popular hypothesis that disability assessment s vary widely across sample s with different cultural environments , we have reported strong evidence of highly consistent results . FUNDING Bill & Melinda Gates Foundation Objective : Increased male participation in antenatal care and uptake of couple voluntary counselling and testing ( VCT ) for HIV could reduce horizontal and vertical HIV transmission in sub-Saharan Africa . Methods : R and omized controlled trial to compare pregnant women 's acceptance of written invitations for VCT and pregnancy information sessions ( PISs ) – the control group – for their male sexual partners ( MSPs ) and uptake of VCT among these pregnancy partners in Khayelitsha , South Africa . Results : All women in the study accepted the invitation letters and agreed to invite their pregnancy partners to attend for VCT or PIS as requested . Thirty-five percent ( 175 of 500 ) pregnant women given VCT invitations for their partners brought their MSPs for antenatal clinic visit compared with 26 % ( 129 of 500 ) given PIS invitations [ relative risk ( RR ) 1.36 , 95 % confidence interval ( CI ) 1.12–1.64 , P = 0.002 ] . Thirty-two percent ( 161 of 500 ) MSPs in the VCT arm underwent HIV testing compared with 11 % ( 57/500 ) in the PIS arm ( RR 2.82 , 95 % CI 2.14–3.72 , P < 0.001 ) . The proportions of women and men reporting unprotected sex during the pregnancy were lower in the MSP VCT arm than in the MSP PIS arm – 25 versus 81 % ( RR 0.30 , 95 % CI 0.22–0.42 , P < 0.001 ) and 26 versus 76 % ( RR 0.34 , 95 % CI 0.25–0.47 , P < 0.001 ) , respectively . No differences were seen in intimate partner violence . Conclusion : Providing pregnant women with a written invitation for their partners increased male participation in antenatal care and uptake of couple VCT in a township in Cape Town , South Africa where community sensitization was conducted and antiretroviral therapy was available BACKGROUND HIV infection and intimate-partner violence share a common risk environment in much of southern Africa . The aim of the Intervention with Microfinance for AIDS and Gender Equity ( IMAGE ) study was to assess a structural intervention that combined a microfinance programme with a gender and HIV training curriculum . METHODS Villages in the rural Limpopo province of South Africa were pair-matched and r and omly allocated to receive the intervention at study onset ( intervention group , n=4 ) or 3 years later ( comparison group , n=4 ) . Loans were provided to poor women who enrolled in the intervention group . A participatory learning and action curriculum was integrated into loan meetings , which took place every 2 weeks . Both arms of the trial were divided into three groups : direct programme participants or matched controls ( cohort one ) , r and omly selected 14 - 35-year-old household co-residents ( cohort two ) , and r and omly selected community members ( cohort three ) . Primary outcomes were experience of intimate-partner violence -- either physical or sexual -- in the past 12 months by a spouse or other sexual intimate ( cohort one ) , unprotected sexual intercourse at last occurrence with a non-spousal partner in the past 12 months ( cohorts two and three ) , and HIV incidence ( cohort three ) . Analyses were done on a per- protocol basis . This trial is registered with Clinical Trials.gov , number NCT00242957 . FINDINGS In cohort one , experience of intimate-partner violence was reduced by 55 % ( adjusted risk ratio [ aRR ] 0.45 , 95 % CI 0.23 - 0.91 ; adjusted risk difference -7.3 % , -16.2 to 1.5 ) . The intervention did not affect the rate of unprotected sexual intercourse with a non-spousal partner in cohort two ( aRR 1.02 , 0.85 - 1.23 ) , and there was no effect on the rate of unprotected sexual intercourse at last occurrence with a non-spousal partner ( 0.89 , 0.66 - 1.19 ) or HIV incidence ( 1.06 , 0.66 - 1.69 ) in cohort three . INTERPRETATION A combined microfinance and training intervention can lead to reductions in levels of intimate-partner violence in programme participants . Social and economic development interventions have the potential to alter risk environments for HIV and intimate-partner violence in southern Africa Background Intimate partner violence ( IPV ) and HIV are important and interconnected public health concerns . While it is recognized that they share common social drivers , there is limited evidence surrounding the potential of community interventions to reduce violence and HIV risk at the community level . The SASA ! study assessed the community-level impact of SASA ! , a community mobilization intervention to prevent violence and reduce HIV-risk behaviors . Methods From 2007 to 2012 a pair-matched cluster r and omized controlled trial ( CRT ) was conducted in eight communities ( four intervention and four control ) in Kampala , Ug and a. Cross-sectional surveys of a r and om sample of community members , 18- to 49-years old , were undertaken at baseline ( n = 1,583 ) and four years post intervention implementation ( n = 2,532 ) . Six violence and HIV-related primary outcomes were defined a priori . An adjusted cluster-level intention-to-treat analysis compared outcomes in intervention and control communities at follow-up . Results The intervention was associated with significantly lower social acceptance of IPV among women ( adjusted risk ratio 0.54 , 95 % confidence interval ( CI ) 0.38 to 0.79 ) and lower acceptance among men ( 0.13 , 95 % CI 0.01 to 1.15 ) ; significantly greater acceptance that a woman can refuse sex among women ( 1.28 , 95 % CI 1.07 to 1.52 ) and men ( 1.31 , 95 % CI 1.00 to 1.70 ) ; 52 % lower past year experience of physical IPV among women ( 0.48 , 95 % CI 0.16 to 1.39 ) ; and lower levels of past year experience of sexual IPV ( 0.76 , 95 % CI 0.33 to 1.72 ) . Women experiencing violence in intervention communities were more likely to receive supportive community responses . Reported past year sexual concurrency by men was significantly lower in intervention compared to control communities ( 0.57 , 95 % CI 0.36 to 0.91 ) . Conclusions This is the first CRT in sub-Saharan Africa to assess the community impact of a mobilization program on the social acceptability of IPV , the past year prevalence of IPV and levels of sexual concurrency . SASA ! achieved important community impacts , and is now being delivered in control communities and replicated in 15 countries . Trial registration Clinical Trials.gov # NCT00790959 , Study protocol available at 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 Summary : To test the efficacy of a sustainable community-level HIV intervention among sex workers , the Sonagachi Project was replicated , including community organizing and advocacy , peer education , condom social marketing , and establishment of a health clinic . Sex workers were r and omly selected in 2 small urban communities in northeastern India ( n = 100 each ) and assessed every 5–6 months over 15 months ( 85 % retention ) . Overall condom use increased significantly in the intervention community ( 39 % ) compared with the control community ( 11 % ) , and the proportion of consistent condom users increased 25 % in the intervention community compared with a 16 % decrease in the control community . This study supports the efficacy of the Sonagachi model intervention in increasing condom use and maintaining low HIV prevalence among sex workers 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 ) Objectives : To quantify the association between intimate partner violence ( IPV ) and incident HIV infection in women in the Rakai Community Cohort Study between 2000 and 2009 . Design and methods : Data were from the Rakai Community Cohort Study annual surveys between 2000 and 2009 . Longitudinal data analysis was used to estimate the adjusted incidence rate ratio ( IRR ) of incident HIV associated with IPV in sexually active women aged 15–49 years , using a multivariable Poisson regression model with r and om effects . The population attributable fraction was calculated . Putative mediators were assessed using Baron and Kenny 's criteria and the Sobel – Goodman test . Results : Women who had ever experienced IPV had an adjusted IRR of incident HIV infection of 1.55 ( 95 % CI 1.25–1.94 , P = 0.000 ) , compared with women who had never experienced IPV . Risk of HIV infection tended to be greater for longer duration of IPV exposure and for women exposed to more severe and more frequent IPV . The adjusted population attributable fraction of incident HIV attributable to IPV was 22.2 % ( 95 % CI 12.5–30.4 ) . There was no evidence that either condom use or number of sex partners in the past year mediated the relationship between IPV and HIV . Conclusion : IPV is associated with incident HIV infection in a population -based cohort in Ug and a , although the adjusted population attributable fraction is modest . The prevention of IPV should be a public health priority , and could contribute to HIV prevention This study evaluated the efficacy of an HIV intervention among female sex workers ( FSWs ) r and omized to an intervention or wait-list control . FSWs ( N = 120 ) completed baseline , 3- and 6-month assessment s. A health educator implemented 2-hour intervention emphasized gender-empowerment , self-efficacy to persuade clients to use condoms , condom application skills , and eroticizing safer sex . Over the 6-month follow-up , FSWs in the intervention reported more consistent condom use with clients ( P = .004 ) and were more likely to apply condoms on clients ( P = .0001 ) . Intervention effects were observed for other psychosocial mediators of safer sex . Brief , gender and culturally congruent interventions can enhance HIV-preventive behaviors among FSWs Female sex workers have been central in India ’s HIV epidemic since it was first diagnosed among them in 1989 . Female sex workers ’ risk of HIV is primarily economically motivated . The Pi pilot study examined the feasibility and association of a microenterprise intervention , the tailoring of canvas bags , on sexual risk behaviors among female sex workers ( N = 100 ) in Chennai . Women were r and omized to an intervention or control arm . Between-group comparisons at baseline and at six-month follow-up were performed . Multivariate linear regression with bootstrapping was conducted to estimate the intervention effect . At baseline , women were a median of 35 years old , 61 % were married and they had an average of two children . Intervention participants reported a significantly lower number of sex partners and significant increases in income at the 6-month follow-up compared to control participants . In a multivariate model , intervention participants had a significantly lower number of paying clients per month at follow-up compared to control participants . By graduation , 75 % of intervention arm participants had made at least one sellable canvas bag and 6 months after the study ’s end , 60 % have continued involvement in bag production . The pilot study demonstrated that microenterprise interventions are successful in both providing FSWs with licit income opportunities and was associated with reductions in HIV risk behaviors This paper describes an HIV prevention intervention design ed in the US that was adapted and implemented in South Africa . Using an experimental design , 93 women who reported recent substance use and sex trading were r and omly assigned to a modified St and ard HIV intervention or to a Woman-Focused HIV prevention intervention . Eighty women completed the one-month follow-up interview . Participants reported high rates of sexual risk and violence at baseline . At follow-up , findings showed decreases in the proportion of women reporting unprotected sex and the daily use of alcohol and cocaine . Daily alcohol and cocaine use decreased more for women receiving the Woman-Focused intervention . Although violence continued to be a problem , at follow-up Woman-Focused participants reported being victimized less often than women receiving the St and ard intervention . This study demonstrates the feasibility of implementing cross-cultural behavioral HIV prevention interventions , and supports the need for future studies of women 's context ual issues and the effectiveness of targeted interventions OBJECTIVES Using a r and omized controlled trial in rural eastern Zimbabwe , we tested whether comprehensive support to keep orphan adolescent girls in school could reduce HIV risk . METHODS All orphan girls in grade 6 in 25 primary schools were invited to participate in the study in fall 2007 ( n = 329 ) . Primary schools were r and omized to condition . All primary schools received a universal daily feeding program ; intervention participants received fees , uniforms , and a school-based helper to monitor attendance and resolve problems . We conducted annual surveys and collected additional information on school dropout , marriage , and pregnancy rates . We analyzed data using generalized estimating equations over 3 time points , controlling for school and age at baseline . RESULTS The intervention reduced school dropout by 82 % and marriage by 63 % after 2 years . Compared with control participants , the intervention group reported greater school bonding , better future expectations , more equitable gender attitudes , and more concerns about the consequences of sex . CONCLUSIONS We found promising evidence that comprehensive school support may reduce HIV risk for orphan girls . Further study , including assessment of dose response , cost benefit , and HIV and herpes simplex virus 2 biomarker measurement , is warranted South Africa is in the midst of one of the world ’s most devastating HIV/AIDS epidemics and there is a well-documented association between violence against women and HIV transmission . Interventions that target men and integrate HIV prevention with gender-based violence prevention may demonstrate synergistic effects . A quasi-experimental field intervention trial was conducted with two communities r and omly assigned to receive either : ( a ) a five session integrated intervention design ed to simultaneously reduce gender-based violence ( GBV ) and HIV risk behaviors ( N = 242 ) or ( b ) a single 3-hour alcohol and HIV risk reduction session ( N = 233 ) . Men were followed for 1- , 3- , and 6-months post intervention with 90 % retention . Results indicated that the GBV/HIV intervention reduced negative attitudes toward women in the short term and reduced violence against women in the longer term . Men in the GBV/HIV intervention also increased their talking with sex partners about condoms and were more likely to have been tested for HIV at the follow-ups . There were few differences between conditions on any HIV transmission risk reduction behavioral outcomes . Further research is needed to examine the potential synergistic effects of alcohol use , gender violence , and HIV prevention interventions Voluntary counseling and testing ( VCT ) for couples ( CVCT ) is an important HIV-prevention effort in sub-Saharan Africa where a substantial proportion of HIV transmission occurs within stable partnerships . This study aim ed to determine the acceptance and effectiveness of CVCT as compared to individual VCT ( IVCT ) . 1,521 women attending three antenatal clinics in Dar es Salaam were r and omized to receive IVCT during that visit or CVCT with their husb and s at a subsequent visit . The proportion of women receiving test results in the CVCT arm was significantly lower than in the IVCT arm ( 39 vs. 71 % ) . HIV prevalence overall was 10 % . In a subgroup analysis of HIV-positive women , those who received CVCT were more likely to use preventive measures against transmission ( 90 vs. 60 % ) and to receive nevirapine for themselves ( 55 vs. 24 % ) and their infants ( 55 vs. 22 % ) as compared to women r and omized to IVCT . Uptake of CVCT is low in the antenatal clinic setting . Community mobilization and couple-friendly clinics are needed to promote CVCT Abstract This study involved evaluation of the short-term impact of the RHANI Wives HIV intervention among wives at risk for HIV from husb and s in Mumbai , India . A two-armed cluster RCT was conducted with 220 women surveyed on marital sex at baseline and 4–5 month follow-up . RHANI Wives was a multisession intervention focused on safer sex , marital communication , gender inequities and violence ; control participants received basic HIV prevention education . Generalized linear mixed models were conducted to assess program impact , with cluster as a r and om effect and with time , treatment group , and the time by treatment interaction as fixed effects . A significant time by treatment effect on proportion of unprotected sex with husb and ( p = 0.01 ) was observed , and the rate of unprotected sex for intervention participants was lower than that of control participants at follow-up ( RR = 0.83 , 95 % CI = 0.75 , 0.93 ) . RHANI Wives is a promising model for women at risk for HIV from husb and This pilot r and omized controlled trial in Kazakhstan aim ed to adapt and test the feasibility of a couple-based HIV/STI risk-reduction intervention ( CHSR ) for couples who are injecting drug users ( IDUs ) . The study examined the preliminary effects of the intervention versus an attentional control wellness promotion ( WP ) condition on HIV risk behavioral outcomes among 40 couples who are IDUs ( n = 80 participants ) . Compared with WP participants , CHSR participants were significantly more likely to increase condom use and decrease unsafe injection acts at the 3-month follow-up . This pilot trial demonstrates the feasibility and preliminary effects of the CHSR in reducing drug-related and sexual HIV risks Objective : To assess the impact and costs of adding female condoms to a male condom promotion and distribution peer education programme for sex workers in Mombasa , Kenya . Design : A 12 month , prospect i ve study of 210 female sex workers . Methods : We interviewed participants about their sexual behaviour every 2 months for a total of seven times and introduced female condoms after the third interview . We also collected cost data and calculated the cost and cost effectiveness of adding the female condom component to the existing programme . Results : Introduction of the female condom in an HIV/AIDS prevention project targeting sex workers led to small , but significant , increases in consistent condom use with all sexual partners . However , there was a high degree of substitution of the female condom for male condoms . The cost per additional consistent condom user at a programme level is estimated to be $ 2160 ( £ 1169 , € 1711 ) ( 95 % CI : 1338 to 11 179 ) . Conclusions : The female condom has some potential for reducing unprotected sex among sex workers . However , given its high cost , and the marginal improvements seen here , governments should limit promotion of the female condom in population s that are already successfully using the male condom . More research is needed to identify effective methods of encouraging sex workers to practise safer sex with their boyfriends Background : The HIV epidemic has a devastating impact among South African women . The current study evaluated the efficacy of SISTA South Africa , a culturally congruent HIV intervention for isiXhosa women in South Africa , which was adapted from SISTA , an HIV intervention for African American women . Methods : A r and omized-controlled trial recruited 342 isiXhosa women aged 18–35 years . Participants were r and omized to the general health comparison or the SISTA South Africa intervention . Xhosa-speaking peer health educators tailored the SISTA South Africa curriculum , while maintaining the core elements of the original SISTA intervention . Participants completed assessment s at baseline and 6 months follow-up . Results : Relative to participants in the comparison , participants in the HIV intervention reduced the frequency of unprotected vaginal intercourse acts ( adjusted mean difference = 1.06 ; P = 0.02 ) , were more likely to report not desiring dry sex ( adjusted odds ratio = 0.229 ; 95 % confidence interval = 0.10 to 0.47 ; P = 0.0001 ) , and were more likely to perceive that their main sexual partner did not desire dry sex ( adjusted odds ratio = 0.24 ; 95 % confidence interval = 0.11 to 0.52 ; P = 0.0001 ) . In addition , women r and omized to the intervention also reported an increase in HIV knowledge , greater relationship control , and had more opposing attitudes toward HIV stigma . The HIV intervention did not reduce sexually transmitted infection incidence . Conclusions : This trial demonstrates that an HIV intervention , which is adapted to enhance its gender and cultural relevance for rural isiXhosa women , can reduce self-reported sexual risk behaviors and enhance mediators of HIV among this vulnerable population

Data from 12 RCTs passed quality assessment criteria and provided evidence of positive changes in non-behavioural outcomes ( e.g. knowledge and self-efficacy ) . Intervention effects on behavioural outcomes , such as condom use , were generally limited and did not demonstrate a negative impact ( e.g. earlier sexual initiation ) . Beneficial effect on at least one , but never all behavioural outcomes assessed was reported by about half the studies , but this was sometimes limited to a participant subgroup .

Several demonstrated no difference or an increased risk of adverse outcome among persons with DM and tight control of HTN as compared to usual control . Several demonstrated lack of benefit of statins among persons with end-stage renal disease . CONCLUSIONS There is limited evidence regarding the effects of multiple comorbidities on treatment outcomes . The majority of studies demonstrated no effect of a single comorbid condition on outcomes .

BACKGROUND There are concerns about the potential for unintentional harms when clinical practice guidelines are applied to patients with multimorbidity . The objective was to summarize the evidence regarding the effect(s ) of comorbidity on the outcomes of medication for an index chronic condition .

BACKGROUND Recent reports suggest that calcium-channel blockers may be harmful in patients with diabetes and hypertension . We previously reported that antihypertensive treatment with the calcium-channel blocker nitrendipine reduced the risk of cardiovascular events . In this post hoc analysis , we compared the outcome of treatment with nitrendipine in diabetic and nondiabetic patients . METHODS After stratification according to center , sex , and presence or absence of previous cardiovascular complications , 4695 patients ( age , > or = 60 years ) with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure below 95 mm Hg were r and omly assigned to receive active treatment or placebo . Active treatment consisted of nitrendipine ( 10 to 40 mg per day ) with the possible addition or substitution of enalapril ( 5 to 20 mg per day ) or hydrochlorothiazide ( 12.5 to 25 mg per day ) or both , titrated to reduce the systolic blood pressure by at least 20 mm Hg and to less than 150 mm Hg . In the control group , matching placebo tablets were administered similarly . RESULTS At r and omization , 492 patients ( 10.5 percent ) had diabetes . After a median follow-up of two years , the systolic and diastolic blood pressures in the placebo and active-treatment groups differed by 8.6 and 3.9 mm Hg , respectively , among the diabetic patients . Among the 4203 patients without diabetes , systolic and diastolic pressures differed by 10.3 and 4.5 mm Hg , respectively , in the two groups . After adjustment for possible confounders , active treatment was found to have reduced overall mortality by 55 percent ( from 45.1 deaths per 1000 patients to 26.4 deaths per 1000 patients ) , mortality from cardiovascular disease by 76 percent , all cardiovascular events combined by 69 percent , fatal and nonfatal strokes by 73 percent , and all cardiac events combined by 63 percent in the group of patients with diabetes . Among the nondiabetic patients , active treatment decreased all cardiovascular events combined by 26 percent and fatal and nonfatal strokes by 38 percent . In the group of patients receiving active treatment , reductions in overall mortality , mortality from cardiovascular disease , and all cardiovascular events were significantly larger among the diabetic patients than among the nondiabetic patients ( P=0.04 , P=0.02 , and P=0.01 , respectively ) . CONCLUSIONS Nitrendipine-based antihypertensive therapy is particularly beneficial in older patients with diabetes and isolated systolic hypertension . Thus , our findings do not support the hypothesis that the use of long-acting calcium-channel blockers may be harmful in diabetic patients Current criteria for the diagnosis of diabetes c A1C $ 6.5 % . The test should be performed in a laboratory using a method that is NGSP certified and st and ardized to the Diabetes Control and Complications Trial ( DCCT ) assay ; or c fasting plasma glucose ( FPG ) $ 126 mg/dL ( 7.0 mmol/L ) . Fasting is defined as no caloric intake for at least 8 h ; or c 2-h plasma glucose $ 200 mg/dL ( 11.1 mmol/L ) during an oral glucose tolerance test ( OGTT ) . The test should be performed as described by the World Health Organization , using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved inwater ; or c in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis , a r and om plasma glucose $ 200 mg/dL ( 11.1 mmol/L ) ; c in the absence of unequivocal hyperglycemia , result should be confirmed by repeat testing Background : Analyses of the risks of stroke were conducted for subjects with and without diabetes , participating in a r and omized , double‐blind , placebo‐controlled trial of a perindopril‐based blood pressure lowering regimen in 6105 people with prior stroke or transient ischaemic attack ( TIA ) , followed for a median of 3.9 years . Findings : Seven hundred and sixty‐one patients had diabetes at baseline . Diabetes increased the risk of recurrent stroke by 35 % ( 95 % CI 10–65 % ) principally through an effect on ischaemic stroke ( 1.53 , 95 % CI 1.23–1.90 ) . Active treatment reduced blood pressure by 9.5/4.6 mmHg in patients with diabetes and by 8.9/3.9 mmHg in patients without diabetes . The proportional risk reductions achieved for stroke in patients with diabetes , 38 % ( 95 % CI 8–58 % ) , and patients without diabetes , 28 % ( 95 % CI 16–39 % ) , were not significantly different ( p homogeneity = 0.5 ) . The absolute reduction in the risk of recurrent stroke in the patients with diabetes was equivalent to one stroke avoided among every 16 ( 95 % CI 9–111 ) patients treated for 5 years . Conclusions : Diabetes is an important risk factor for stroke in patients with established cerebrovascular disease . Treatment with the ACE inhibitor perindopril with discretionary use of the diuretic indapamide produced reductions in the risk of recurrent stroke in patients with diabetes that were at least as great as those achieved in patients without diabetes Aims Thiazolidinediones are insulin sensitizers , and are associated with fluid retention and increased risk of heart failure ( HF ) in people with type 2 diabetes . We assessed fatal and non-fatal HF events and their outcome , and identified HF predictors in the RECORD ( Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes ) trial population . Methods and results In a multicentre , open-label study , we r and omized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA1c of 7.9 % to add-on rosiglitazone ( n = 2220 ) or to a combination of metformin and sulfonylurea ( n = 2227 ) and followed them over 5.5 years on average . Heart failure hospitalizations and deaths were adjudicated by a Clinical Endpoint Committee using pre-specified criteria . Independent predictors of HF events were identified out of a group of 30 pre-specified clinical , demographic , and biological variables . In the rosiglitazone group , the risk of HF death or hospitalization was doubled : HR = 2.10 ( 95 % CI , 1.35–3.27 ) : the excess HF event rate was 2.6 ( 1.1–4.1 ) per 1000 person-years . An excess in HF deaths was observed ( 10 vs. two ) , including four HF deaths as first HF events . By contrast , there was no increase in cardiovascular mortality or hospitalization ( HR = 0.99 , 95 % CI , 0.85–1.16 ) or in cardiovascular deaths ( 60 vs. 71 ) . Independent predictors of HF were rosiglitazone assignment , age , urinary albumin : creatinine ratio , body mass index , and systolic blood pressure at baseline . A history of previous cardiovascular disease was not predictive of HF . Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups . Conclusion These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication . Close follow-up for the risk of HF should be offered to elderly people , people with markedly increased body mass index , people with microalbuminuria/proteinuria , and people with increased systolic blood pressure Summary Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infa rct ion , ischaemic stroke , and the need for coronary revascularisation in people without kidney disease , but its effects in people with moderate-to-severe kidney disease are uncertain . The SHARP trial aim ed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients . Methods This r and omised double-blind trial included 9270 patients with chronic kidney disease ( 3023 on dialysis and 6247 not ) with no known history of myocardial infa rct ion or coronary revascularisation . Patients were r and omly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo . The key prespecified outcome was first major atherosclerotic event ( non-fatal myocardial infa rct ion or coronary death , non-haemorrhagic stroke , or any arterial revascularisation procedure ) . All analyses were by intention to treat . This trial is registered at Clinical Trials.gov , NCT00125593 , and IS RCT N54137607 . Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo . Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L ( SE 0·02 ; with about two-thirds compliance ) during a median follow-up of 4·9 years and produced a 17 % proportional reduction in major atherosclerotic events ( 526 [ 11·3 % ] simvastatin plus ezetimibe vs 619 [ 13·4 % ] placebo ; rate ratio [ RR ] 0·83 , 95 % CI 0·74–0·94 ; log-rank p=0·0021 ) . Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infa rct ion or died from coronary heart disease ( 213 [ 4·6 % ] vs 230 [ 5·0 % ] ; RR 0·92 , 95 % CI 0·76–1·11 ; p=0·37 ) and there were significant reductions in non-haemorrhagic stroke ( 131 [ 2·8 % ] vs 174 [ 3·8 % ] ; RR 0·75 , 95 % CI 0·60–0·94 ; p=0·01 ) and arterial revascularisation procedures ( 284 [ 6·1 % ] vs 352 [ 7·6 % ] ; RR 0·79 , 95 % CI 0·68–0·93 ; p=0·0036 ) . After weighting for subgroup-specific reductions in LDL cholesterol , there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined , and , in particular , they were similar in patients on dialysis and those who were not . The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination ( 9 [ 0·2 % ] vs 5 [ 0·1 % ] ) . There was no evidence of excess risks of hepatitis ( 21 [ 0·5 % ] vs 18 [ 0·4 % ] ) , gallstones ( 106 [ 2·3 % ] vs 106 [ 2·3 % ] ) , or cancer ( 438 [ 9·4 % ] vs 439 [ 9·5 % ] , p=0·89 ) and there was no significant excess of death from any non-vascular cause ( 668 [ 14·4 % ] vs 612 [ 13·2 % ] , p=0·13 ) . Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease . Funding Merck/Schering-Plough Pharmaceuticals ; Australian National Health and Medical Research Council ; British Heart Foundation ; UK Medical Research Council Aim To determine the safety and efficacy of nebivolol in elderly heart failure ( HF ) patients with renal dysfunction . Methods and results SENIORS recruited patients aged 70 years or older with symptomatic HF , irrespective of ejection fraction , and r and omized them to nebivolol or placebo . Patients ( n = 2112 ) were divided by tertile of estimated glomerular filtration rate ( eGFR ) . Mean age of patients was 76.1 years , 35 % of patients had an ejection fraction of > 35 % , and 37 % were women result ing in a unique cohort , far more representative of clinical practice than previous trials . eGFR was strongly associated with outcomes and nebivolol was similarly efficacious across eGFR tertiles . The primary outcome rate ( all-cause mortality or cardiovascular hospital admission ) and adjusted hazard ratio for nebivolol use in those with low eGFR was 40 % and 0.84 ( 95 % CI 0.67–1.07 ) , 31 % and 0.79 ( 0.60–1.04 ) in the middle tertile , and 29 % and 0.86 ( 0.65–1.14 ) in the highest eGFR tertile . There was no interaction noted between renal function and the treatment effect ( P = 0.442 ) . Nebivolol use in patients with moderate renal impairment ( eGFR < 60 ) was not associated with major safety concerns , apart from higher rates of drug-discontinuation due to bradycardia . Conclusion Nebivolol is safe and has a similar effect in elderly HF patients with mild or moderate renal impairment Hypertension is a common risk factor for peripheral arterial disease ( PAD ) . Guidelines suggest treating PAD patients to a blood pressure < 130/80 mm Hg ; therefore , our objective was to explore whether attainment of this target blood pressure is associated with improved outcomes . We performed a post hoc analysis of the INternational VErapamil-SR/Tr and olapril STudy , a r and omized clinical trial , which included hypertensive patients with concomitant PAD and coronary artery disease . There were 2699 PAD patients followed for a mean of 2.7 years ( 60 970 patient-years ) . The primary outcome , all-cause death , nonfatal myocardial infa rct ion , or nonfatal stroke , occurred in 16.3 % of PAD patients versus 9.2 % without PAD ( adjusted hazard ratio : 1.26 [ 95 % CI : 1.13 to 1.40 ] ; P<0.0001 ) . The primary outcome occurred least frequently among PAD patients treated to an average systolic blood pressure of 135 to 145 mm Hg and an average diastolic blood pressure of 60 to 90 mm Hg . PAD patients displayed a J-shape relationship with systolic blood pressure and the primary outcome , although individuals without PAD did not . PAD patients may require a different target blood pressure than those without PAD AIMS To determine whether the risk of adverse cardiovascular ( CV ) outcomes associated with diabetes differs in patients with low and preserved ejection fraction ( EF ) heart failure ( HF ) . METHODS AND RESULTS We analysed outcomes in the C and esartan in Heart failure- Assessment of Reduction in Mortality and morbidity ( CHARM ) programme which r and omized 7599 patients with symptomatic HF and a broad range of EF . The prevalence of diabetes was 28.3 % in patients with preserved EF ( > 40 % ) and 28.5 % in those with low EF ( < or=40 % ) . Diabetes was associated with a greater relative risk of CV death or HF hospitalization in patients with preserved EF [ hazard ratio ( HR ) 2.0 ( 1.70 - 2.36 ) ] than in patients with low EF [ HR 1.60 ( 1.44 - 1.77 ) ; interaction test P = 0.0009 ] . For all-cause mortality , the risk conferred by diabetes was similar in both low and preserved EF groups . The effect of c and esartan in reducing CV morbidity and mortality outcomes was not modified by having diabetes at baseline ( P = 0.09 test for interaction ) . CONCLUSION Diabetes was an independent predictor of CV morbidity and mortality in patients with HF , regardless of EF . The relative risk of CV death or HF hospitalization conferred by diabetes was significantly greater in patients with preserved when compared with those with low EF HF AIM To determine the prevalence of potentially suboptimal medication use and association with adverse outcomes . METHODS A prospect i ve , observational cohort study of 4260 community-dwelling older men from Perth , Western Australia ( mean age of 77 ± 3.6 years ) was conducted . Follow-up was for 4.5 years ( or until death , if sooner ) . Cox proportional hazard models were used to explore associations between suboptimal medication use and prospect i ve clinical outcomes . Logistic regression analyses were used to explore predictors of a fall in the previous 12 months . RESULTS Use of potentially inappropriate medicines ( 48.7 % ) , polypharmacy ( ≥5 medications , 35.8 % ) and potential under-utilization ( 56.7 % ) were highly prevalent , and overall 82.3 % of participants reported some form of potentially suboptimal medication use . A self-reported history of falls in the previous 12 months was independently associated with the number of medicines taken ( odds ratio [OR]= 1.06 , 95 % confidence interval [ CI ] 1.02 , 1.09 ) and use of one or more potentially inappropriate medicines ( OR = 1.23 , 95 % CI 1.04 , 1.45 ) . After adjusting for age , co-morbidity , smoking status , body mass index , hypertension and educational attainment , the number of medicines reported was associated with admission to hospital ( hazard ratio [HR]= 1.04 , 95 % CI 1.03 , 1.06 ) , cardiovascular events ( HR = 1.09 , 95 % CI 1.06 , 1.12 ) and all cause mortality ( HR = 1.04 , 95 % CI 1.00 , 1.07 ) . Use of one or more potentially inappropriate medicines was associated with admission to hospital ( HR = 1.16 , 95 % CI 1.08 , 1.24 ) . Potential under-utilization was associated with cardiovascular events ( HR = 1.20 , 95 % CI 1.03 , 1.40 ) . CONCLUSIONS These data suggest that both medication over-use and under-use occur frequently among older men and may be harmful BACKGROUND Diabetic patients are predisposed to cardiovascular ( CV ) disease and other chronic medical conditions . We compared the safety of duloxetine in patients with ( CV-positive ) and without ( CV-negative ) historical/comorbid cardiovascular conditions at study entry . METHODS Data were pooled from three double-blind studies in which patients ( age > or = 18 years ) with diabetic peripheral neuropathic pain ( DPNP ) were r and omized to 12 weeks of duloxetine ( DLX ) 60 mg qd ( n=344 ) , 60 mg bid ( n=341 ) , or placebo ( PBO , n=339 ) . Safety assessment s included discontinuation rates , spontaneously reported treatment-emergent adverse events ( TEAEs ) , changes in vital signs , and changes in lab analytes . RESULTS Mean age of CV-positive patients ( n=762 ) vs. CV-negative patients ( n=262 ) was 61.1 vs. 56.1 years . The most common historical or comorbid CV conditions were hypertension , coronary artery disease , and myocardial infa rct ion . Discontinuation due to adverse events was higher for DLX than for PBO in both CV-positive and CV-negative patients ( 13.5 % DLX , 6.0 % PBO , and 14.3 % DLX , 3.4 % PBO , respectively ) . Rates of CV-related TEAEs in CV-positive ( 8.4 % DLX ; 9.9 % PBO ) and CV-negative ( 8.6 % DLX ; 5.7 % PBO ) patients were similar ( P>.1 ) . Mean changes in blood pressure for each DLX dose vs. PBO between CV-positive and CV-negative patients were not statistically significant ( P>.1 ) , nor were sustained hypertension rates between CV-positive ( 2.4 % DLX ; 2.8 % PBO ) and CV-negative ( 2.9 % DLX ; 4.7 % PBO ) patients . CONCLUSIONS In this analysis , the safety of duloxetine in patients with DPNP was not found to be significantly different between patients with and without historical or comorbid CV conditions Elevated arterial pressure enhances the risk for cardiovascular ( CV ) events in patients with diabetic nephropathy . The optimal BP and the component of the elevated BP that affect the risk have not been defined . A post hoc analysis was performed to assess the impact of achieved systolic , diastolic , and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial ( IDNT ) and had a baseline serum creatinine above the normal range , up to 266 micromol/L ( 3.0 mg/dL ) , 24-h urine protein > 900 mg/d , and at least 6 mo of follow-up . Patients were r and omized to irbesartan , amlodipine , or placebo , with other antihypertensive agents to a BP goal of < or = 135/85 mmHg . Progressively lower achieved systolic BP ( SBP ) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure ( CHF ) but not myocardial infa rct ions ( MI ) . A SBP below this threshold was associated with increased risk for CV deaths and CHF events . Achieved diastolic BP < 85 mmHg was associated with a trend to increase in all-cause mortality , significant increase in MI , but decreased risk for strokes . Increased pulse pressure predicted increased all-cause mortality , CV mortality , MI , and CHF . It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients . BP < or = 120/85 may be associated with an increase in CV events BACKGROUND Questions about the generalizability of r and omized trial results to clinical practice have arisen because the overall mortality rate is generally lower in trials , potentially because patients who are at lower risk are enrolled . However , little is known about the characteristics of patients included in clinical trials versus those who are not included . METHODS The Thrombolysis In Myocardial Infa rct ion ( TIMI ) 9 Registry prospect ively evaluated patients with ST-elevation myocardial infa rct ion at 20 hospitals during the TIMI 9 trial , which compared hirudin versus heparin with fibrinolysis . We compared the characteristics , treatment , and outcomes of patients enrolled in TIMI 9B ( n = 3002 ) with other fibrinolytic-eligible patients not enrolled in TIMI 9B ( n = 296 ) and with those not eligible for fibrinolysis by American College of Cardiology/American Heart Association criteria , at the same centers ( n = 282 ) , with the latter groups divided by use of reperfusion therapy . RESULTS Across the groups , ranging from those in the TIMI 9 trial to those ineligible for fibrinolysis , we observed a gradient of higher-risk baseline characteristics , lower use of reperfusion therapy , and higher mortality rates ( P < .001 ) . In addition , comparing fibrinolytic-eligible patients in TIMI 9B versus those not enrolled in the trial , the use of aspirin , beta-blockers , and angiotensin-converting enzyme inhibitors was significantly higher in the TIMI 9B trial . Ineligible patients not treated with reperfusion therapy had much lower rates of use of these medications and the highest inhospital mortality rate ( 24 % , adjusted odds ratio 2.8 , P < .0001 ) CONCLUSIONS In this prospect i ve registry , patients not enrolled in a clinical trial had higher risk characteristics and worse outcomes ; however , they also were treated less frequently with guideline -recommended medications , which may have contributed to their higher mortality rates OBJECTIVE The Appropriate Blood Pressure Control in Diabetes ( ABCD ) Trial is a prospect i ve r and omized blinded clinical trial that compares the effects of intensive versus moderate blood pressure control on the incidence and progression of type 2 diabetic complications . The current article discusses the results of 5.3 years of follow-up of 470 patients with hypertension and evaluates the effects of intensive and moderate blood pressure therapy using nisoldipine versus enalapril as the initial antihypertensive medication for nephropathy , retinopathy , and neuropathy . RESEARCH DESIGN AND METHODS The 470 hypertensive subjects , defined as having a baseline diastolic blood pressure of > or = 90 mmHg , were r and omized to intensive blood pressure control ( diastolic blood pressure goal of 75 mmHg ) versus moderate blood pressure control ( diastolic blood pressure goal of 80 - 89 mmHg ) . RESULTS The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group . During the 5-year follow-up period , no difference was observed between intensive versus moderate blood pressure control and those r and omized to nisoldipine versus enalapril with regard to the change in creatinine clearance . After the first year of antihypertensive treatment , creatinine clearance stabilized in both the intensive and moderate blood pressure control groups in those patients with baseline normo- or microalbuminuria . In contrast , patients starting with overt albuminuria demonstrated a steady decline in creatinine clearance of 5 - 6 ml.min-1.1.73 m-2 per year throughout the follow-up period whether they were on intensive or moderate therapy . There was also no difference between the interventions with regard to individuals progressing from normoalbuminuria to microalbuminuria ( 25 % intensive therapy vs. 18 % moderate therapy , P = 0.20 ) or microalbuminuria to overt albuminuria ( 16 % intensive therapy vs. 23 % moderate therapy , P = 0.28 ) . Intensive therapy demonstrated a lower overall incidence of deaths , 5.5 vs. 10.7 % , P = 0.037 . Over a 5-year follow-up period , there was no difference between the intensive and moderate groups with regard to the progression of diabetic retinopathy and neuropathy . In addition , the use of nisoldipine versus enalapril had no differential effect on diabetic retinopathy and neuropathy . CONCLUSIONS Blood pressure control of 138/86 or 132/78 mmHg with either nisoldipine or enalapril as the initial antihypertensive medication appeared to stabilize renal function in hypertensive type 2 diabetic patients without overt albuminuria over a 5-year period . The more intensive blood pressure control decreased all-cause mortality Background —The prevalence , prognostic import , and impact of renal insufficiency on the benefits of ACE inhibitors and & bgr;-blockers in community-dwelling patients with heart failure are uncertain . Methods and Results —We analyzed data from a prospect i ve cohort of 754 patients with heart failure who had ejection fraction , serum creatinine , and weight measured at baseline . Median age was 69 years , and 43 % had an ejection fraction ≥35 % . By the Cockcroft-Gault equation , 118 patients ( 16 % ) had creatinine clearances ≤30 mL/min and 301 ( 40 % ) had creatinine clearances between 30 and 59 mL/min . During follow-up ( median 926 days ) , 385 patients ( 37 % ) died . Even after adjustment for all other prognostic factors , survival was significantly associated with renal function ( P = 0.002 ) in patients with either systolic or diastolic dysfunction ; patients exhibited a 1 % increase in mortality for each 1-mL/min decrease in creatinine clearance . The associations with 1-year mortality reductions were similar for ACE inhibitors ( OR 0.46 [ 95 % CI 0.26 to 0.82 ] versus OR 0.28 [ 95 % CI 0.11 to 0.70 ] ) and & bgr;-blockers ( OR 0.40 [ 95 % CI 0.23 to 0.70 ] versus OR 0.41 [ 95 % CI 0.19 to 0.85 ] ) in patients with creatinine clearances < 60 mL/min versus ≥60 mL/min , although these drugs were used less frequently in patients with renal insufficiency . Conclusions —Renal insufficiency is more prevalent in patients with heart failure than previously reported and is an independent prognostic factor in diastolic and systolic dysfunction . ACE inhibitors and & bgr;-blockers were associated with similar reductions in mortality in patients with and without renal insufficiency Background : β Blocker treatment may worsen glucose metabolism . Objective : To study the development of new onset diabetes in a large cohort of patients with heart failure treated with either metoprolol or carvedilol . Design : Prospect i ve and retrospective analysis of a controlled clinical trial . Setting : Multinational multicentre study . Patients : 3029 patients with chronic heart failure . Interventions : R and omly assigned treatment with carvedilol ( n = 1511 , target dose 50 mg daily ) or metoprolol tartrate ( n = 1518 , target dose 100 mg daily ) . Results : Diabetic events ( diabetic coma , peripheral gangrene , diabetic foot , decreased glucose tolerance or hyperglycaemia ) and new onset diabetes ( clinical diagnosis , repeated high r and om glucose level or glucose lowering drugs ) were assessed in 2298 patients without diabetes at baseline . Diabetic events occurred in 122/1151 ( 10.6 % ) patients in the carvedilol group and 149/1147 ( 13.0 % ) patients in the metoprolol group ( hazard ratio ( HR ) = 0.78 ; 95 % confidence interval ( CI ) 0.61 to 0.99 ; p = 0.039 ) . New onset diabetes was diagnosed in 119/1151 ( 10.3 % ) v 145/1147 ( 12.6 % ) cases in the carvedilol and metoprolol treatment groups ( HR = 0.78 , CI 0.61 to 0.997 ; p = 0.048 ) , respectively . Patients with diabetes at baseline had an increased mortality compared with non-diabetic subjects ( 45.3 % v 33.9 % ; HR = 1.45 , CI 1.28 to 1.65 ) . Both diabetic and non-diabetic subjects at baseline had a similar reduction in mortality with carvedilol compared with metoprolol ( RR = 0.85 ; CI 0.69 to 1.06 and RR = 0.82 ; CI 0.71 to 0.94 , respectively ) . Conclusion : A high prevalence and incidence of diabetes is found in patients with heart failure over a course of 5 years . New onset diabetes is more likely to occur during treatment with metoprolol than during treatment with carvedilol BACKGROUND Adverse events related to drugs occur frequently among in patients , and many of these events are preventable . However , few data are available on adverse drug events among out patients . We conducted a study to determine the rates , types , severity , and preventability of such events among out patients and to identify preventive strategies . METHODS We performed a prospect i ve cohort study , including a survey of patients and a chart review , at four adult primary care practice s in Boston ( two hospital-based and two community-based ) , involving a total of 1202 out patients who received at least one prescription during a four-week period . Prescriptions were computerized at two of the practice s and h and written at the other two . RESULTS Of the 661 patients who responded to the survey ( response rate , 55 percent ) , 162 had adverse drug events ( 25 percent ; 95 percent confidence interval , 20 to 29 percent ) , with a total of 181 events ( 27 per 100 patients ) . Twenty-four of the events ( 13 percent ) were serious , 51 ( 28 percent ) were ameliorable , and 20 ( 11 percent ) were preventable . Of the 51 ameliorable events , 32 ( 63 percent ) were attributed to the physician 's failure to respond to medication-related symptoms and 19 ( 37 percent ) to the patient 's failure to inform the physician of the symptoms . The medication classes most frequently involved in adverse drug events were selective serotonin-reuptake inhibitors ( 10 percent ) , beta-blockers ( 9 percent ) , angiotensin-converting-enzyme inhibitors ( 8 percent ) , and nonsteroidal antiinflammatory agents ( 8 percent ) . On multivariate analysis , only the number of medications taken was significantly associated with adverse events . CONCLUSIONS Adverse events related to drugs are common in primary care , and many are preventable or ameliorable . Monitoring for and acting on symptoms are important . Improving communication between out patients and providers may help prevent adverse events related to drugs OBJECTIVE To investigate the impact of glycemic control on the survival of diabetic subjects with end-stage renal disease ( ESRD ) starting hemodialysis treatment . RESEARCH DESIGN AND METHODS This single-center prospect i ve observational study enrolled 150 diabetic ESRD subjects ( 109 men and 41 women ; age at hemodialysis initiation , 60.5 + /- 10.2 years ) at start of hemodialysis between January 1989 and December 1997 . The subjects were divided into groups according to their glycemic control level at inclusion as follows : good HbA1c < 7.5 % , n = 93 ( group G ) , and poor HbA1c > or = 7.5 % , n = 57 ( group P ) ; and survival was followed until December 1999 , with a mean follow-up period of 2.7 years . RESULTS Group G had better survival than group P ( the control group ) ( P = 0.008 ) . At inclusion , there was no significant difference in age , sex , systolic blood pressure ( SBP ) , BMI , cardio-to-thoracic ratio ( CTR ) on chest X-ray , and serum creatinine ( Cre ) or hemoglobin ( Hb ) levels between the two groups . After adjustment for age and sex , HbA1c was a significant predictor of survival ( hazard ratio 1 . 133 per 1.0 % increment of HbA1c , 95 % CI 1.028 - 1.249 , P = 0.012 ) , as were Cre and CTR . CONCLUSIONS Good glycemic control ( HbA1c < 7.5 % ) predicts better survival of diabetic ESRD patients starting hemodialysis treatment AIMS Revascularization in patients with coronary artery disease changed over the last two decades , favouring the number of patients treated by means of percutaneous coronary interventions ( PCI ) when compared with coronary artery bypass grafting ( CABG ) . Many r and omized controlled trials ( RCTs ) have been performed to compare these two competing revascularization techniques . Because of the strict enrolment criteria of RCTs in which highly selected patients are recruited , the applicability of the results may be limited in clinical practice . The current study evaluates to what extent patients in clinical practice were similar to those who participated in RCTs comparing PCI with CABG . METHODS AND RESULTS Clinical characteristics and 1-year outcome of 4713 patients enrolled in the Euro Heart Survey on Coronary Revascularization were compared with 8647 patients who participated in 14 major RCTs , comparing PCI with CABG . In addition , we analysed which proportion of survey patients would have disqualified for trial participation ( n=3033 , 64 % ) , aim ing at identifying differences between trial-eligible and trial-ineligible survey patients . In general , important differences were observed between trial participants and survey patients . Patients in clinical practice were older , more often had comorbid conditions , single-vessel disease , and left main stem stenosis when compared with trial participants . Almost identical differences were observed between trial-eligible and trial-ineligible survey patients . In clinical practice , PCI was the treatment of choice , even in patients who were trial-ineligible ( 46 % PCI , 26 % CABG , 28 % medical ) . PCI remained the preferred treatment option in patients with multi-vessel disease ( 57 % in trial-eligible and 40 % in trial-ineligible patients , respectively , P<0.001 ) ; yet , the risk profile of patients treated by PCI was better than that for patients treated either by CABG or by medical therapy . In the RCTs , there was no mortality difference between PCI and CABG . In clinical practice , however , we observed 1-year unadjusted survival benefit for PCI vs. CABG ( 2.9 vs. 5.4 % , P<0.001 ) . Survival benefit was only observed in trial-ineligible patients ( 3.3 vs. 6.2 % , P<0.001 ) . CONCLUSION Many patients in clinical practice were not represented in RCTs . Moreover , only 36 % of these patients were considered eligible for participating in a trial comparing PCI with CABG . We demonstrated that RCTs included younger patients with a better cardiovascular risk profile when compared with patients in everyday clinical practice . This study highlights the disparity between patients in clinical practice and patients in whom the studies that provide the evidence for treatment guidelines are performed I F SOME MEDICAL CARE IS GOOD , MORE CARE IS BETter . Right ? Unfortunately , this is often not the case . Across the United States , the rate of use of common medical services varies markedly , but measures of health are not better in areas where more services are provided . In fact , the opposite is true— some measures of health are worse in areas where people receive more health services . How can more health care lead to worse health outcomes ? Almost all tests , imaging procedures , drugs , surgery , and preventive interventions have some risk of adverse effects . In some cases , these harms have been proven to outweigh benefits —for example , treating asymptomatic women with postmenopausal hormone therapy . In other cases , services become widely used with inadequate proof of benefit . For example , arthroscopic debridement of the knee for treatment of osteoarthritis was performed about 650 000 times per year in the United States in the late 1990s , despite the fact that the procedure had not been shown to be beneficial . R and omized trials subsequently demonstrated no benefit of this procedure — but all patients were exposed to the pain and risk associated with surgery AIMS Individuals with diabetes and chronic kidney disease ( CKD ) are at high risk for cardiovascular disease . In these analyses of the ADVANCE trial , we assessed the effects of a fixed combination of perindopril-indapamide on renal and cardiovascular outcomes in patients with type 2 diabetes according to baseline CKD stage . METHODS AND RESULTS Patients with type 2 diabetes were r and omized to perindopril-indapamide ( 4 mg/1.25 mg ) or placebo . Treatment effects on cardiovascular ( cardiovascular death , myocardial infa rct ion , or stroke ) and renal outcomes were compared in subgroups defined by baseline Kidney Disease Outcome Quality Initiative CKD stage . Homogeneity in treatment effect was tested by adding interaction terms to the relevant Cox models . The study included 10 640 participants with known CKD status , of whom 6125 did not have CKD , 2482 were classified as CKD stage 1 or 2 , and 2033 as CKD stage ≥3 . The relative treatment effects on major cardiovascular events were similar across all stages of CKD , with no heterogeneity in the magnitude of the effects for any outcome . In contrast , the absolute treatment effects approximately doubled in those with CKD stage ≥3 when compared to those with no CKD . For every 1000 patients with CKD stage ≥3 treated for 5 years , active treatment prevented 12 cardiovascular events when compared with six events per 1000 patients with no CKD . CONCLUSION The treatment benefits of a routine administration of a fixed combination of perindopril-indapamide to patients with type 2 diabetes on cardiovascular and renal outcomes , and death , are consistent across all stages of CKD at baseline . Absolute risk reductions are larger in patients with CKD highlighting the importance of blood pressure-lowering in this population Diabetes mellitus ( DM ) constitutes a major end-stage renal disease ( ESRD ) health problem . Glycemic control is fundamental to the management of diabetes and its complications , and relies on monitoring of hyperglycemia . We therefore performed a primary data analysis of glycemic control and survival on a large national ESRD data base . Ninety-five percent of patients with DM had type II diabetes ( N = 23,504 ) , and five percent had type I diabetes ( N = 1,371 ) . For the combined population , the mean hemoglobin A1c ( HgbA1c ) was 6.77 % , and the mean r and om blood glucose was 168 mg/dl . Mean HgbA1c values were > 7.0 % in 35 % and > 8.5 % in 14 % . Mean HgbA1c values were below 5 % in 11.3 % of patients . Type I study patients tended to have higher HgbA1c values . Most patients ( 75.8 % ) had three or more r and om blood glucose determinations within 90 days preceding the HgbA1c measurement . The HgbA1c showed only a weak correlation with mean r and om glucose values ( R2 0.3716 ; s.e . = 1.36 ) . The survival rates in the subsequent 12-month period ranged from 80 to 85 % across different HgbA1c strata . Kaplan-Meier survival curves grouped by HgbA1c levels showed no correlation between HgbA1c and survival at 12 months . More studies are needed to refine recommendations for the role of HgbA1c and glycemic control in this patient population BACKGROUND Statins reduce the incidence of cardiovascular events in persons with type 2 diabetes mellitus . However , the benefit of statins in such patients receiving hemodialysis , who are at high risk for cardiovascular disease and death , has not been examined . METHODS We conducted a multicenter , r and omized , double-blind , prospect i ve study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were r and omly assigned to receive 20 mg of atorvastatin per day or matching placebo . The primary end point was a composite of death from cardiac causes , nonfatal myocardial infa rct ion , and stroke . Secondary end points included death from all causes and all cardiac and cerebrovascular events combined . RESULTS After four weeks of treatment , the median level of low-density lipoprotein cholesterol was reduced by 42 percent among patients receiving atorvastatin , and among those receiving placebo it was reduced by 1.3 percent . During a median follow-up period of four years , 469 patients ( 37 percent ) reached the primary end point , of whom 226 were assigned to atorvastatin and 243 to placebo ( relative risk , 0.92 ; 95 percent confidence interval , 0.77 to 1.10 ; P=0.37 ) . Atorvastatin had no significant effect on the individual components of the primary end point , except that the relative risk of fatal stroke among those receiving the drug was 2.03 ( 95 percent confidence interval , 1.05 to 3.93 ; P=0.04 ) . Atorvastatin reduced the rate of all cardiac events combined ( relative risk , 0.82 ; 95 percent confidence interval , 0.68 to 0.99 ; P=0.03 , nominally significant ) but not all cerebrovascular events combined ( relative risk , 1.12 ; 95 percent confidence interval , 0.81 to 1.55 ; P=0.49 ) or total mortality ( relative risk , 0.93 ; 95 percent confidence interval , 0.79 to 1.08 ; P=0.33 ) . CONCLUSIONS Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death , nonfatal myocardial infa rct ion , and stroke in patients with diabetes receiving hemodialysis Abstract Objective : To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes . Design : R and omised controlled trial comparing tight control of blood pressure aim ing at a blood pressure of < 150/85 mm Hg ( with the use of an angiotensin converting enzyme inhibitor captopril or a β blocker atenolol as main treatment ) with less tight control aim ing at a blood pressure of < 180/105 mm Hg . Setting : 20 hospital based clinics in Engl and , Scotl and , and Northern Irel and . Subjects : 1148 hypertensive patients with type 2 diabetes ( mean age 56 , mean blood pressure at entry 160/94 mm Hg ) ; 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years . Main outcome measures : Predefined clinical end points , fatal and non-fatal , related to diabetes , deaths related to diabetes , and all cause mortality . Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography . Results : Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control ( 144/82 mm Hg ) compared with the group assigned to less tight control ( 154/87 mm Hg ) ( P<0.0001 ) . Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24 % in diabetes related end points ( 95 % confidence interval 8 % to 38 % ) ( P=0.0046 ) , 32 % in deaths related to diabetes ( 6 % to 51 % ) ( P=0.019 ) , 44 % in strokes ( 11 % to 65 % ) ( P=0.013 ) , and 37 % in microvascular end points ( 11 % to 56 % ) ( P=0.0092 ) , predominantly owing to a reduced risk of retinal photocoagulation . There was a non-significant reduction in all cause mortality . After nine years of follow up the group assigned to tight blood pressure control also had a 34 % reduction in risk in the proportion of patients with deterioration of retinopathy by two steps ( 99 % confidence interval 11 % to 50 % ) ( P=0.0004 ) and a 47 % reduced risk ( 7 % to 70 % ) ( P=0.004 ) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study ( ETDRS ) chart . After nine years of follow up 29 % of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures . Conclusion : Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinical ly important reduction in the risk of deaths related to diabetes , complications related to diabetes , progression of diabetic retinopathy , and deterioration in visual acuity Aims /hypothesisThere are few data on the target level of glycaemic control among patients with diabetes on haemodialysis . We investigated the impact of glycaemic control on mortality risk among diabetic patients on haemodialysis . Subjects and methods Data were analysed from the Dialysis Outcomes Practice Pattern Study ( DOPPS ) for r and omly selected patients on haemodialysis in Japan . The diagnosis of diabetes at baseline and information on clinical events during follow-up were abstract ed from the medical records . A Cox proportional hazards model was used to evaluate the association between presence or absence of diabetes , glycaemic control ( HbA1c quintiles ) and mortality risk . Results Data from 1,569 patients with and 3,342 patients without diabetes on haemodialysis were analysed . Among patients on haemodialysis , those with diabetes had a higher mortality risk than those without ( multivariable hazard ratio 1.37 , 95 % CI 1.08–1.74 ) . Compared with those in the bottom quintile of HbA1c level , the multivariable-adjusted hazard ratio for mortality was not increased in the bottom second to fourth quintiles of HbA1c ( HbA1c 5.0–5.5 % to 6.2–7.2 % ) , but was significantly increased to 2.36 ( 95 % CI 1.02–5.47 ) in the fifth quintile ( HbA1c ≥ 7.3 % ) . The effect of poor glycaemic control did not statistically correlate with baseline mortality risk ( p = 0.27 ) . Conclusions /interpretationAmong dialysis patients , poorer glycaemic control in those with diabetes was associated with higher mortality risk . This suggests a strong effect of poor glycaemic control above an HbA1c level of about 7.3 % on mortality risk , and that this effect does not appear to be influenced by baseline comorbidity status OBJECTIVES To investigate the relation between chronic kidney disease ( CKD ) and cardiovascular disease ( CVD ) and retrospectively to evaluate the effect of low dose of pravastatin in Japanese hypercholesterolemic patients with CKD enrolled in the large-scale r and omized MEGA Study . METHODS In this post hoc analysis , effect of low dose pravastatin treatment ( 10 - 20 mg daily ) on the primary prevention of the cardiovascular disease and renal function after 5 years was evaluated in 7196 patients with normal kidney function/mild CKD or moderate CKD . Patients were classified based on an estimated glomerular filtration rate ( eGFR ) > or=60 or 30-<60mL/min/1.73m(2 ) as having normal renal function/mild CKD or moderate CKD , respectively . Since Japanese guidelines do not allow statin use in patients with severe kidney disease , such individuals were excluded . RESULTS The incidence of CVD events was 35 - 49 % higher in patients with moderate CKD than in those with normal renal function/mild CKD . Notably , in the moderate CKD group pravastatin significantly reduced CHD by 48 % ( P=0.02 ) , stroke by 73 % ( P<0.01 ) , CVD by 55 % ( P<0.01 ) , and total mortality by 51 % ( P=0.02 ) . Moreover , the change in eGFR during follow-up in patients with moderate CKD was significantly ( P=0.03 ) higher in those assigned to receive diet plus pravastatin ( + 6.3 % ) compared with those on diet alone ( + 5.1 % ) . CONCLUSIONS Risk of CVD is higher in patients with moderate CKD compared with those with normal renal function/mild CKD , and was significantly reduced by treatment with pravastatin . Pravastatin also exerted beneficial effects on renal function in patients with moderate CKD AIMS An analysis was design ed to determine whether chronic heart failure patients at high cardiovascular risk benefited to the same extent from high-dose lisinopril as the whole ATLAS population . METHODS AND RESULTS A retrospective analysis was performed on high-risk heart failure patients in the Assessment of Treatment with Lisinopril And Survival ( ATLAS ) trial ( total number of patients 3164 ) comparing highdose ( 32.5 - 35 mg . day(-1 ) ) vs low-dose ( 2.5 - 5 mg . day(-1 ) ) lisinopril for a median of 46 months . These high-risk patients included those with hypotension , hyponatraemia , compromised renal function , the elderly and patients with diabetes mellitus at baseline . In the whole study population , high-dose lisinopril led to a trend in risk reduction of all-cause mortality ( primary end-point P=0.128 ) and a significant risk reduction in all-cause mortality plus hospitalization ( principal secondary end-point P=0.002 ) . Subgroup analyses were performed for these end-points . There were no consistent interactions between age , baseline sodium , creatinine or potassium values , and treatment effect . Diabetics showed a beneficial response to high-dose therapy that was at least as good as that in non-diabetics . The underlying higher morbidity/mortality rates in diabetics mean that high-dose lisinopril has potential for a larger absolute clinical impact in these patients . CONCLUSION Long-term high-dose lisinopril was as effective and well-tolerated in high-risk patients , including those with diabetes mellitus , as for the ATLAS study population as a whole OBJECTIVES This was a retrospective analysis to determine the effect of diabetes on outcome in patients with advanced heart failure ( HF ) , and to determine the effect of beta-blockade in patients with HF with and without diabetes mellitus . BACKGROUND In chronic HF the impact on clinical outcomes and therapeutic response of the prevalent comorbid condition diabetes mellitus has not been extensively investigated . METHODS We assessed the impact of diabetes on prognosis and effectiveness of beta-blocker therapy with bucindolol in patients with HF enrolled in the Beta-Blocker Evaluation of Survival Trial ( BEST ) . We conducted a retrospective analysis to examine the prognosis of patients with advanced HF with and without diabetes , and the effect of beta-blocker therapy on mortality and HF progression or myocardial infa rct ion ( MI ) . The data base was the 2,708 patients with advanced HF ( 36 % with diabetes and 64 % without diabetes ) who were r and omized to the beta-blocker bucindolol or placebo in BEST and followed for mortality , hospitalization , and MI for an average of two years . RESULTS Patients with diabetes had more severe chronic HF and more coronary risk factors than patients without diabetes . Diabetes was independently associated with increased mortality in patients with ischemic cardiomyopathy ( adjusted hazard ratio 1.33 , 95 % confidence interval 1.12 to 1.58 , p = 0.001 ) , but not in those with a nonischemic etiology ( adjusted hazard ratio 0.98 , 95 % confidence interval 0.74 to 1.30 , p = 0.89 ) . Compared with patients without diabetes , in diabetic patients beta-blocker therapy was at least as effective in reducing death or HF hospitalizations , total hospitalizations , HF hospitalizations , and MI . Ventricular function and physiologic responses to beta-blockade were similar in patients with and without diabetes . CONCLUSIONS Diabetes worsens prognosis in patients with advanced HF , but this worsening appears to be limited to patients with ischemic cardiomyopathy . In advanced HF beta-blockade is effective in reducing major clinical end points in patients with and without diabetes PURPOSE R and omized trials have shown that beta-blockers prevent morbidity and mortality in heart failure . However , whether beta-blockers are effective in older patients or those with conditions that would have led to their exclusion from these trials remains unclear . SUBJECTS AND METHODS The associations between beta-blocker use and outcomes were examined in a population -based cohort of 11,942 older ( age > /=65 years ) patients with incident heart failure between 1994 and 1999 . Cox proportional hazards models were used to adjust for propensity scores , age , sex , comorbid conditions , and other medications . RESULTS The mean ( + /- SD ) age of the patients was 79 + /- 8 years , 5819 ( 49 % ) were men , and 2569 ( 22 % ) had Charlson comorbidity scores of at least 2 . During follow-up ( median , 21 months ) , 3539 patients were hospitalized for heart failure and 6757 died . Overall , 1162 patients received beta-blockers . After adjustment , beta-blocker use was associated with substantial reductions in all-cause mortality ( hazard ratio [ HR ] = 0.72 ; 95 % confidence interval [ CI ] : 0.65 to 0.80 ) , mortality due to heart failure ( HR = 0.65 ; 95 % CI : 0.47 to 0.90 ) , and hospitalizations for heart failure ( HR = 0.82 ; 95 % CI : 0.74 to 0.92 ) . These endpoints were less frequent in patients treated with beta-blockers than in untreated patients in all examined subgroups . All doses of beta-blockers were associated with benefit , but there was a trend towards greater benefit in patients prescribed higher doses . CONCLUSIONS The benefits of beta-blockers seen in r and omized trials extend to older patients and to those with conditions that would have led to their exclusion from the trials . There is a need for a r and omized trial comparing different doses of beta-blockers in heart failure BACKGROUND Despite treatment , there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals . Inadequate reduction of their blood pressure is a likely cause , but the optimum target blood pressure is not known . The impact of acetylsalicylic acid ( aspirin ) has never been investigated in patients with hypertension . We aim ed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension . METHODS 18790 patients , from 26 countries , aged 50 - 80 years ( mean 61.5 years ) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg ( mean 105 mm Hg ) were r and omly assigned a target diastolic blood pressure . 6264 patients were allocated to the target pressure < or = 90 mm Hg , 6264 to < or = 85 mm Hg , and 6262 to < or = 80 mm Hg . Felodipine was given as baseline therapy with the addition of other agents , according to a five-step regimen . In addition , 9399 patients were r and omly assigned 75 mg/day acetylsalicylic acid ( Bamycor , Astra ) and 9391 patients were assigned placebo . FINDINGS Diastolic blood pressure was reduced by 20.3 mm Hg , 22.3 mm Hg , and 24.3 mm Hg , in the < or = 90 mm Hg , < or = 85 mm Hg , and < or = 80 mm Hg target groups , respectively . The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg . Further reduction below these blood pressures was safe . In patients with diabetes mellitus there was a 51 % reduction in major cardiovascular events in target group < or = 80 mm Hg compared with target group < or = 90 mm Hg ( p for trend=0.005 ) . Acetylsalicylic acid reduced major cardiovascular events by 15 % ( p=0.03 ) and all myocardial infa rct ion by 36 % ( p=0.002 ) , with no effect on stroke . There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group , and 129 versus 70 non-fatal major bleeds in the two groups , respectively ( p<0.001 ) . INTERPRETATION Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events . The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg . Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infa rct ion . There was no effect on the incidence of stroke or fatal bleeds , but non-fatal major bleeds were twice as common OBJECTIVE To assess the effect of low-dose , diuretic-based antihypertensive treatment on major cardiovascular disease ( CVD ) event rates in older , non-insulin-treated diabetic patients with isolated systolic hypertension ( ISH ) , compared with nondiabetic patients . DESIGN Double-blind , r and omized , placebo-controlled trial : the Systolic Hypertension in the Elderly Program ( SHEP ) . SETTING Multiple clinical and support centers in the United States . PARTICIPANTS A total of 4736 men and women aged 60 years and older at baseline with ISH ( systolic blood pressure [ BP ] , > or = 160 mm Hg ; diastolic BP , < 90 mm Hg ) at baseline , 583 non-insulin-dependent diabetic patients and 4149 nondiabetic patients ( 4 additional patients not so classifiable were r and omized but not included in these analyses ) . Diabetes mellitus defined as physician diagnosis , taking oral hypoglycemic drugs , fasting glucose level of 7.8 mmol/L or more ( > or = 140 mg/dL ) , or any combination of these characteristics . INTERVENTION The active treatment group received a low dose of chlorthalidone ( 12.5 - 25.0 mg/d ) with a step-up to atenolol ( 25.0 - 50.0 mg/d ) or reserpine ( 0.05 - 0.10 mg/d ) if needed . The placebo group received placebo and any active antihypertensive drugs prescribed by patient 's private physician for persistently high BP . MAIN OUTCOME MEASURES The 5-year rates of major CVD events , nonfatal plus fatal stroke , nonfatal myocardial infa rct ion ( MI ) and fatal coronary heart disease ( CHD ) , major CHD events , and all-cause mortality . RESULTS The SHEP antihypertensive drug regimen lowered BP of both diabetic and nondiabetic patients , with few adverse effects . For both diabetic and nondiabetic patients , all outcome rates were lower for participants r and omized to the active treatment group than for those r and omized to the placebo group . Thus , 5-year major CVD rate was lower by 34 % for active treatment compared with placebo , both for diabetic patients ( 95 % confidence interval [ CI ] , 6%-54 % ) and nondiabetic patients ( 95 % CI , 21%-45 % ) . Absolute risk reduction with active treatment compared with placebo was twice as great for diabetic vs nondiabetic patients ( 101/1000 vs 51/1000 r and omized participants at the 5-year follow-up ) , reflecting the higher risk of diabetic patients . CONCLUSION Low-dose diuretic-based ( chlorthalidone ) treatment is effective in preventing major CVD events , cerebral and cardiac , in both non-insulin-treated diabetic and nondiabetic older patients with ISH BACKGROUND In 1988 , the Systolic Hypertension in China ( Syst-China ) Collaborative Group initiated the placebo-controlled Syst-China trial to investigate whether antihypertensive drug treatment could reduce the incidence of fatal and nonfatal stroke in older Chinese patients with isolated systolic hypertension . OBJECTIVES To explore ( 1 ) whether the benefits of active treatment were evenly distributed across 4 strata , prospect ively defined according to sex and previous cardiovascular complications , and ( 2 ) whether the morbidity and mortality results were influenced by age , level of systolic or diastolic blood pressure ( BP ) , smoking or drinking habits , or diabetes mellitus at enrollment . METHODS Eligible patients had to be 60 years or older with a sitting systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg . After stratification for center , sex , and previous cardiovascular complications , 1253 patients were assigned to active treatment starting with nitrendipine ( 10 - 40 mg/d ) , with the possible addition of captopril ( 12.5 - 50.0 mg/d ) , and /or hydrochlorothiazide ( 12.5 - 50 mg/d ) . In the 1141 control patients , matching placebos were used similarly . RESULTS Male sex , previous cardiovascular complications , older age , higher systolic BP or lower diastolic BP , living in northern China , smoking , and diabetes mellitus significantly and independently increased the risk of 1 or more of the following end points : total or cardiovascular mortality , all fatal and nonfatal cardiovascular end points , all strokes , and all cardiac end points . In the placebo-control group diabetes raised the risk of all end points 2- to 3-fold ( P < or = .05 ) . However , active treatment reduced the excess risk associated with diabetes to a nonsignificant level ( P values ranging from .12-.86 ) except for cardiovascular mortality ( P = .04 ) . Cox regression with adjustments applied for significant covariates suggested that active treatment may reduce total mortality more ( P = .06 ) in women and stroke more ( P = .07 ) in men and that it may provide better protection against cardiac end points in nonsmokers than smokers ( P = .04 ) . Otherwise , the benefits of active treatment were equally manifest , regardless of the enrollment characteristics of the patients , and regardless of whether active treatment consisted of only nitrendipine or of nitrendipine associated with other active drugs . CONCLUSIONS In elderly Chinese patients with isolated systolic hypertension , stepwise antihypertensive drug treatment , starting with the dihydropyridine calcium channel blocker nitrendipine , improved prognosis . The benefit was particularly evident in diabetic patients ; for cardiac end points it tended to be larger in nonsmokers . Otherwise , the benefit of active treatment was not significantly influenced by the characteristics of the patients at enrollment in the trial BACKGROUND In the hierarchy of research design s , the results of r and omized , controlled trials are considered to be evidence of the highest grade , whereas observational studies are viewed as having less validity because they reportedly overestimate treatment effects . We used published meta-analyses to identify r and omized clinical trials and observational studies that examined the same clinical topics . We then compared the results of the original reports according to the type of research design . METHODS A search of the Medline data base for articles published in five major medical journals from 1991 to 1995 identified meta-analyses of r and omized , controlled trials and meta-analyses of either cohort or case-control studies that assessed the same intervention . For each of five topics , summary estimates and 95 percent confidence intervals were calculated on the basis of data from the individual r and omized , controlled trials and the individual observational studies . RESULTS For the five clinical topics and 99 reports evaluated , the average results of the observational studies were remarkably similar to those of the r and omized , controlled trials . For example , analysis of 13 r and omized , controlled trials of the effectiveness of bacille Calmette-Guérin vaccine in preventing active tuberculosis yielded a relative risk of 0.49 ( 95 percent confidence interval , 0.34 to 0.70 ) among vaccinated patients , as compared with an odds ratio of 0.50 ( 95 percent confidence interval , 0.39 to 0.65 ) from 10 case-control studies . In addition , the range of the point estimates for the effect of vaccination was wider for the r and omized , controlled trials ( 0.20 to 1.56 ) than for the observational studies ( 0.17 to 0.84 ) . CONCLUSIONS The results of well- design ed observational studies ( with either a cohort or a case-control design ) do not systematic ally overestimate the magnitude of the effects of treatment as compared with those in r and omized , controlled trials on the same topic BACKGROUND Physicians are still concerned about prescribing beta-blockers in diabetic patients with heart failure . METHODS In the outcome research study ( the Beta-Blockers in Patients With Congestive Heart Failure : Guided Use in Clinical Practice [ BRING-UP ] study ) , the responsible clinicians could decide whether to start beta-blocker treatment and which agent to use . A total of 3091 patients were enrolled by 202 cardiologic centers : 25 % of the recruited patients were already on beta-blockers , 28 % started treatment at the enrollment visit , and 47 % were not started on beta-blockers . RESULTS The 1-year mortality , hospitalization rate , and the combined end point of mortality or hospitalization were higher in diabetic patients ( 15.8 % versus 10.9 % ; relative risk [ RR ] = 1.44 ; 95 % confidence intervals [ CI ] 1.16 - 1.78 , P = .001 ) ( 31.0 % versus 24.0 % ; RR = 1.28 ; 95 % CI 1.11 - 1.49 ; P = .0009 ) ( 40.5 % versus 30.1 % ; RR = 1.35 ; 95 % CI 1.19 - 1.51 ; P = .0001 ) . The event-free analysis of the 4 groups ( diabetic patients not treated with beta-blockers , diabetic patients treated with beta-blockers , nondiabetic patients not treated with beta-blockers , nondiabetic patients treated with beta-blockers ) showed that patients treated with beta-blockers had a higher event-free probability than patients not treated with beta-blockers regardless the presence of diabetes ( P < .0001 ) . CONCLUSIONS On the basis of post hoc analysis , diabetic patients with chronic heart failure benefit from beta-blockers even if at a lower degree . Thus , there are no justifications to avoid beta-blockers in heart failure patients in the presence of diabetes BACKGROUND Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality , although typically their plasma concentrations of LDL cholesterol are similar to those in the general population . Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited , and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk . METHODS 5963 UK adults ( aged 40 - 80 years ) known to have diabetes , and an additional 14573 with occlusive arterial disease ( but no diagnosed diabetes ) , were r and omly allocated to receive 40 mg simvastatin daily or matching placebo . Prespecified analyses in these prior disease subcategories , and other relevant subcategories , were of first major coronary event ( ie , non-fatal myocardial infa rct ion or coronary death ) and of first major vascular event ( ie , major coronary event , stroke or revascularisation ) . Analyses were also conducted of subsequent vascular events during the scheduled treatment period . Comparisons are of all simvastatin-allocated versus all placebo-allocated participants ( ie , intention to treat ) , which yielded an average difference in LDL cholesterol of 1.0 mmol/L ( 39 mg/dL ) during the 5-year treatment period . FINDINGS Both among the participants who presented with diabetes and among those who did not , there were highly significant reductions of about a quarter in the first event rate for major coronary events , for strokes , and for revascularisations . For the first occurrence of any of these major vascular events among participants with diabetes , there was a definite 22 % ( 95 % CI 13 - 30 ) reduction in the event rate ( 601 [ 20.2 % ] simvastatin-allocated vs 748 [ 25.1 % ] placebo-allocated , p<0.0001 ) , which was similar to that among the other high-risk individuals studied . There were also highly significant reductions of 33 % ( 95 % CI 17 - 46 , p=0.0003 ) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry , and of 27 % ( 95 % CI 13 - 40 , p=0.0007 ) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3.0 mmol/L ( 116 mg/dL ) . The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied , including : those with different duration , type , or control of diabetes ; those aged over 65 years at entry or with hypertension ; and those with total cholesterol below 5.0 mmol/L ( 193 mg/dL ) . In addition , among participants who had a first major vascular event following r and omisation , allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period . INTERPRETATION The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations . Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied . After making allowance for non-compliance , actual use of this statin regimen would probably reduce these rates by about a third . For example , among the type of diabetic patient studied without occlusive arterial disease , 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event ( and , among these 45 people , to prevent about 70 first or subsequent events during this treatment period ) . Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events , irrespective of their initial cholesterol concentrations BACKGROUND Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk . However , a benefit of statins in such patients who are undergoing hemodialysis has not been proved . METHODS We conducted an international , multicenter , r and omized , double-blind , prospect i ve trial involving 2776 patients , 50 to 80 years of age , who were undergoing maintenance hemodialysis . We r and omly assigned patients to receive rosuvastatin , 10 mg daily , or placebo . The combined primary end point was death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . Secondary end points included death from all causes and individual cardiac and vascular events . RESULTS After 3 months , the mean reduction in low-density lipoprotein ( LDL ) cholesterol levels was 43 % in patients receiving rosuvastatin , from a mean baseline level of 100 mg per deciliter ( 2.6 mmol per liter ) . During a median follow-up period of 3.8 years , 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point ( 9.2 and 9.5 events per 100 patient-years , respectively ; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group , 0.96 ; 95 % confidence interval [ CI ] , 0.84 to 1.11 ; P=0.59 ) . Rosuvastatin had no effect on individual components of the primary end point . There was also no significant effect on all-cause mortality ( 13.5 vs. 14.0 events per 100 patient-years ; hazard ratio , 0.96 ; 95 % CI , 0.86 to 1.07 ; P=0.51 ) . CONCLUSIONS In patients undergoing hemodialysis , the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . ( Clinical Trials.gov number , NCT00240331 . The future rate of cardiovascular events can be predicted by several well-established risk factors . Even in the absence of classic risk factors , patients with renal disease have an elevated risk for cardiovascular disease ( 1 , 2 ) . This renalcardiovascular association is well established in patients with advanced renal insufficiency ( 2 ) . It has also been reported in patients in the Hypertension Detection and Follow-up Program ( HDFP ) ( 3 ) , in which a serum creatinine concentration greater than 133 mol/L ( 1.5 mg/dL ) was a strong predictor of cardiovascular disease . However , HDFP included only patients with hypertension . In contrast , a recent analysis of data from the Framingham Study did not detect a relationship between mild renal insufficiency ( defined as a serum creatinine concentration of 124 to 265 mol/L [ 1.4 to 3.0 mg/dL ] ) and cardiovascular events ( 4 ) . The Heart Outcomes and Prevention Evaluation ( HOPE ) study investigated the effects of ramipril and vitamin E on major cardiovascular outcomes in 9297 patients at high risk , including those with serum creatinine concentrations up to 200 mol/L ( 2.3 mg/dL ) ( 5 - 7 ) . Our study examined the hypothesis that previous evidence of renal disease ( that is , an elevated serum creatinine concentration 124 mol/L [ 1.4 mg/dL ] ) would independently predict future cardiovascular disease . Since the connection between renal and cardiovascular disease is known to exist in patients with diabetes mellitus and those with hypertension , we analyzed nondiabetic and normotensive patients separately . We also examined whether ramipril continued to be effective in patients with impaired renal function . This was done to determine whether the common clinical practice of withholding angiotensin-converting enzyme ( ACE ) inhibitors in patients with impaired renal excretory function is justified . Methods Patients The design and primary outcomes of the HOPE study have been described elsewhere ( 5 - 7 ) . Briefly , men and women at least 55 years of age from 267 centers were included if they had objective evidence of vascular disease or diabetes combined with another cardiovascular risk factor . The main exclusion criteria were heart failure , intolerance of ACE inhibitors or vitamin E , a serum creatinine concentration greater than 200 mol/L ( 2.3 mg/dL ) , or dipstick-positive proteinuria ( > 1 + ) . Patients were treated with ramipril , vitamin E , or placebo in a double-blind , 2 2 factorial design . Follow-up was 3.5 to 5.5 years ( median , 4.5 years ) , and the primary outcome measure was the incidence of cardiovascular death , myocardial infa rct ion , or stroke . Secondary outcome measures included total mortality , hospitalization for heart failure , and revascularization . At the time of r and omization , urine albumin level and creatinine concentration were measured once in all patients at four central laboratories . The ratio of urine albumin to creatinine was calculated , and a value of at least 2 mg/mmol was defined as microalbuminuria . Serum creatinine concentration was measured in all patients at local laboratories at the time of r and omization . Renal Insufficiency Recent data suggest that in patients older than 55 years of age , a serum creatinine concentration of at least 124 mol/L ( 1.4 mg/dL ) is a good indicator of a glomerular filtration rate less than 80 mL/min ( 8) . Therefore , before beginning this post hoc analysis , we used a serum creatinine concentration of at least 124 mol/L ( 1.4 mg/dL ) to differentiate between patients with and those without renal insufficiency . We also estimated creatinine clearance from serum creatinine concentrations by using the CockcroftGault formula ( 8) , which derives the value from creatinine concentration , age , and body weight ( 140 age [ in years ] body weight [ in kg]/serum creatinine concentration [ in mg/dL ] 72 [ in men ] or 0.85 [ in women ] ) . For calculated creatinine clearance , an a priori value of 65 mL/min was arbitrarily chosen as a definite indicator of renal insufficiency . Statistical Analysis Baseline serum creatinine values were missing in 10 of 9297 patients who were r and omly assigned to receive ramipril , 10 mg/d , or placebo . Only data from the original intention-to-treat analysis ( 5 ) were included in our study . We compared baseline characteristics in patients with and those without renal insufficiency by using chi-square tests for discrete variables and t-tests for continuous variables . Because the ratio of albumin to creatinine was not normally distributed , it was compared by using a Wilcoxon test . In the final analysis , time-to-event in each group was estimated by using Cox regression stratified by center ; this was done because rates of renal insufficiency varied significantly by center ( P=0.006 ) but event rates did not . Association by center was tested by using logistic regression for renal insufficiency and Cox regression for events . Center was treated as a fixed effect in these models ( 9 ) . Multivariate models to predict events were developed by using Cox regression and a backward elimination technique , beginning with univariate significant risk factors , including age ; sex ; waist-to-hip ratio ; body mass index ; and history of hypertension , diabetes , coronary artery disease , peripheral vascular disease , smoking , ramipril use , and renal insufficiency . Age , body mass index , waist-to-hip ratio , and blood pressure were treated as continuous variables . All covariates were tested for possible confounding with renal insufficiency , but no such pattern was found . We used Cox regression models to assess the effect of r and omization to ramipril after controlling for serum creatinine concentration . Statistical tests for interaction were done in the Cox regression analysis to determine whether the effect of ramipril differed in patients with and those without renal insufficiency . We classified patients according to quartiles of serum creatinine concentration and then determined the effect of renal insufficiency on risk for the primary outcome . To do this , we analyzed the rate of the primary outcome across quartiles using Cox regression and testing linearity of the hazard ratios ( HRs ) . Creatinine clearance was also estimated from serum creatinine concentration by using the CockcroftGault formula ( 8) . Because age is used to calculate this value , age was excluded from all multivariate analyses that included creatinine clearance as a variable . All analyses were done by using SAS software for Unix , version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . Role of the Funding Sources The funding sources had no role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results Baseline Characteristics of Patients with Renal Disease As shown in Table 1 , 980 patients had a serum creatinine concentration at least 124 mol/L ( 1.4 mg/dL ) and 8307 patients did not . Baseline variables did not differ between the placebo and ramipril subgroups . Compared with patients who had no evidence of renal insufficiency , those with renal insufficiency were older ; were more likely to be male ; and had a higher baseline prevalence of hypertension , coronary artery disease , peripheral vascular disease , low high-density lipoprotein cholesterol level , and use of antiplatelet and antihypertensive agents . Systolic blood pressure , urine albumin level , and waist-to-hip ratio were also higher in this group . Table 1 . Baseline Characteristics of Patients with and Those without Renal Insufficiency Event Rates in Patients with Renal Insufficiency Renal insufficiency was an important predictor of the primary outcome for all patients , as well as for the ramipril and placebo groups separately . The extent to which renal insufficiency was associated with the primary outcome is shown in Figure 1 and Table 2 . Most impressive is the fact that cardiovascular and all-cause mortality rates were nearly twice as high in patients with renal insufficiency ( HR , 1.90 [ 95 % CI , 1.53 to 2.36 ] and 1.83 [ CI , 1.54 to 2.17 ] , respectively , by Cox regression controlling for ramipril use ; P<0.001 for both comparisons ) , as were hospitalizations for heart failure ( HR , 2.11 [ CI , 1.56 to 2.81 ] ; P<0.001 ) . This effect of renal insufficiency was also observed when calculated creatinine clearance was used instead of serum creatinine concentration ( Table 3 ) . Figure 1 . Primary outcome , myocardial infa rct ion , cardiovascular death , and all death for patients with a serum creatinine concentration less than 1.4 mg/dL ( < 124 mol/L ) or at least 1.4 mg/dL ( 124 mol/L ) . Table 2 . Outcomes in Patients with and Those without Renal Insufficiency Table 3 . Outcomes in Patients with a Creatinine Clearance 65 mL/min or > 65 mL/min Analysis of the group risk for the primary outcome clearly showed that as serum creatinine concentration increases , so does cardiovascular risk . As shown in Figure 2 , the incidence of the primary outcome increased with each quartile of serum creatinine concentration ( P<0.001 for linear trend of HR across quartiles ) . Figure 2 . Primary outcome according to quartiles of serum creatinine concentration . P P We performed a multivariate analysis to determine whether the observed relationship between the incidence of the primary outcome and renal insufficiency could be explained by the association of impaired renal function with the variables identified in Table 1 . In this analysis , an elevated serum creatinine concentration and microalbuminuria were highly significant , independent renal risk factors for the aggregate primary outcome of cardiovascular death , myocardial infa rct ion , or stroke ( HR , 1.40 [ CI , 1.16 to 1.69 ] and 1.59 [ CI , 1.37 to 1.84 ] , respectively ; P<0.001 for both comparisons ) . Other factors that independently and significantly predicted the primary outcome measure were coronary artery disease ( HR , 1.51 [ CI , 1.22 to 1.85 ] ) , peripheral vascular disease ( HR , 1.49 [ CI , 1.29 to 1.70 ] ) , diabetes mellitus ( HR , 1.42 [ CI , 1.23 to 1.65 ] ) , male sex ( HR , 1.20 [ CI , 1.01 to 1.43 ] ) , 1-year increase in age ( BACKGROUND There is no evidence from r and omized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus . We investigated whether therapy targeting normal systolic pressure ( i.e. , < 120 mm Hg ) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events . METHODS A total of 4733 participants with type 2 diabetes were r and omly assigned to intensive therapy , targeting a systolic pressure of less than 120 mm Hg , or st and ard therapy , targeting a systolic pressure of less than 140 mm Hg . The primary composite outcome was nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS After 1 year , the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the st and ard-therapy group . The annual rate of the primary outcome was 1.87 % in the intensive-therapy group and 2.09 % in the st and ard-therapy group ( hazard ratio with intensive therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.73 to 1.06 ; P=0.20 ) . The annual rates of death from any cause were 1.28 % and 1.19 % in the two groups , respectively ( hazard ratio , 1.07 ; 95 % CI , 0.85 to 1.35 ; P=0.55 ) . The annual rates of stroke , a prespecified secondary outcome , were 0.32 % and 0.53 % in the two groups , respectively ( hazard ratio , 0.59 ; 95 % CI , 0.39 to 0.89 ; P=0.01 ) . Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group ( 3.3 % ) and 30 of the 2371 participants in the st and ard-therapy group ( 1.3 % ) ( P<0.001 ) . CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events . ( Clinical Trials.gov number , NCT00000620 . BACKGROUND The objective of the current study was to examine the efficacy and tolerability of the beta-blocker metoprolol succinate controlled release/extended release ( CR/XL ) in patients with diabetes in the Metoprolol CR/XL R and omized Intervention Trial in Chronic Heart Failure ( MERIT-HF ) . METHODS The Cox proportional hazards model was used to calculate hazard ratios ( HR ) for convenience expressed as relative risks ( risk reduction = 1-HR ) , and 95 % confidence intervals ( CI ) . RESULTS The risk of hospitalization for heart failure was 76 % higher in diabetics compared to non-diabetics ( 95 % CI 38 % to 123 % ) . Metoprolol CR/XL was well tolerated and reduced the risk of hospitalization for heart failure by 37 % in the diabetic group ( 95 % CI 53 % to 15 % ) , and by 35 % in the non-diabetic group ( 95 % CI 48 % to 19 % ) . Pooling of mortality data from the Cardiac Insufficiency Bisoprolol Study II ( CIBIS II ) , MERIT-HF , and the Carvedilol Prospect i ve R and omized Cumulative Survival Study ( COPERNICUS ) showed similar survival benefits in patients with diabetes ( 25 % ; 95 % CI 40 % to 4 % ) and without diabetes ( 36 % ; 95 % CI 44 % to 27 % ) ; test of diabetes by treatment interaction was non-significant . Adverse events were reported more often on placebo than on metoprolol CR/XL . CONCLUSIONS Patients with heart failure and diabetes have a much higher risk of hospitalization than patients without diabetes . Regardless of diabetic status , a highly significant reduction in hospitalizations for heart failure was observed with metoprolol CR/XL therapy , which was very well tolerated also by patients with diabetes . Furthermore , the pooled data showed a statistically significant survival benefit in patients with diabetes AIMS The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation ( AF ) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF , among individuals with type 2 diabetes . METHODS AND RESULTS About 11 140 patients with type 2 diabetes ( 7.6 % of whom had AF at baseline ) were r and omized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . We compared total mortality and cardiovascular disease outcomes and effects of r and omized treatment for 4.3 years on such outcomes between patients with and without AF at baseline . After multiple adjustments , AF was associated with a 61 % ( 95 % confidence interval 31 - 96 , P < 0.0001 ) greater risk of all-cause mortality and comparable higher risks of cardiovascular death , stroke , and heart failure ( all P < 0.001 ) . Routine treatment with a fixed combination of perindopril and indapamide produced similar relative , but greater absolute , risk reductions for all-cause and cardiovascular mortalities in patients with AF , compared with those without AF . The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline . CONCLUSION Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes . This arrhythmia identifies individuals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment . Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors Context The effectiveness of glycemic control in reducing cardiovascular events among patients with type 2 diabetes is uncertain . Recent analyses of trial data suggest that the benefit of tight control may differ according to a person 's age and comorbid conditions . Contribution This observational study of 2613 patients with type 2 diabetes in 205 practice s in Italy found that tight control was associated with lower risk for cardiovascular events over 5 years in patients with low to moderate , but not high , comorbidity . Caution Observational data can not prove a causal association between glycemic control and outcomes . Implication The relationship of glycemic control and cardiovascular outcomes differs by patients ' level of comorbidity . The Editors Major professional organizations recommend that attaining a hemoglobin A1c ( HbA1c ) value less than 7.0 % may be less appropriate for patients with limited life expectancy , advanced complications , and extensive comorbidity ( 13 ) . Evidence suggests that the benefit of intensive glucose-lowering therapy is not uniform across all patients with type 2 diabetes . Three large r and omized , controlled trials that used HbA1c targets of 6.5 % or lower ( 46 ) each found no association between intensive therapy and an overall reduction in risk for macrovascular complications . However , when data from these and other trials were considered in 2 recent meta-analyses ( 7 , 8) , the investigators observed statistically significant relationships between tight glycemic control and reduced cardiovascular events . Post hoc analyses of data from these clinical trials suggest that benefit from aggressive glycemic control may be confined to younger diabetic patients ( 4 ) and patients without previous heart disease ( 4 , 5 ) . Data from the 10-year posttrial follow-up ( 9 ) to the UKPDS ( United Kingdom Prospect i ve Diabetes Study ) ( 10 ) also showed a reduction in cardiovascular events from intensive glucose-lowering therapy initiated in a young and healthy sample of patients with recently diagnosed type 2 diabetes . Recent decision analyses based on UKPDS risk models suggest that , independent of age , high levels of comorbidity may diminish the benefits of achieving tight control ( 11 ) , owing to the complex interplay of multiple conditions , their treatments , and their burden on patient re sources ( 12 ) . Among the comorbid conditions prevalent among diabetic patients , cardiovascular diseases are the most important contributors to mortality and subsequent cardiovascular events . However , additional conditions , such as chronic lung disease , may also bring functional impairment , treatment burden , and risk for adverse events and may diminish a patient 's likelihood to benefit from tight control ( 13 , 14 ) . In a 5-year observational study of a community-based sample of older patients with type 2 diabetes , we tested whether attaining glycemic control targets of HbA1c levels of 6.5 % or less or 7.0 % or less at baseline provided differential benefits for patients with higher versus lower levels of comorbidity . We further compared the unique contribution of comorbid conditions with that of other risk factors ( such as age or duration of diabetes ) to the differential benefit from glycemic control on future cardiovascular events . Methods Our study , described in detail elsewhere ( 1517 ) , was a 5-year longitudinal observational study ( 1999 to 2004 ) that examined the association of the quality of diabetes care with the incidence of cardiovascular events and mortality . Patients were followed for a median of 4.96 years ( interquartile range , 3.35 to 5.00 years ) . Patients We identified medical practice s in all regions of Italy and selected them according to their willingness to participate in the project . Participating practice s included 101 of approximately 605 eligible diabetes outpatient clinics and 103 of approximately 1000 eligible community-based general practitioners enrolled in a nationwide network of practitioners interested in facilitating research . We considered all patients with type 2 diabetes mellitus ( fasting venous plasma glucose concentration 7.8 mmol/L [ 140 mg/dL ] on 2 separate occasions or treated with antidiabetic drugs ) to be eligible for the project , regardless of age , diabetes duration , or treatment . At the diabetes outpatient clinics , patients were r and omly sample d from clinic rosters and stratified by patient age ( < 65 or 65 years ) . We asked each diabetes outpatient clinic to recruit at least 30 patients . Community-based general practitioners consecutively enrolled only patients for whom they were primarily responsible for diabetes care , up to a maximum of 10 patients . Clinical Measures The main outcome of the study was incident cardiovascular events , defined as any of the following outcomes : angina , myocardial infa rct ion , stroke , transient ischemic attack , coronary revascularization procedures , lower limb complications ( claudication , ulcer , gangrene , amputation , or aorticfemoral revascularization procedures ) , or cardiovascular mortality . Participating physicians certified the occurrence of any cardiovascular event over the 5-year study period , on the basis of study -wide criteria . In addition , participating physicians reported the death of any study patient from any cause ; this information was used to compute total mortality rates . Participating physicians abstract ed demographic and clinical data , including age , body mass index , duration of diabetes , HbA1c level , lipid levels , and blood pressure ( collected and entered into models as continuous variables ) , as well as sex , smoking status and the presence of diabetes complications ( collected and entered into models as categorical variables ) from clinical records and reported these data to the coordinating center at Mario Negri Sud . Because normal ranges for HbA1c varied in the different centers , the percentage change with respect to the upper normal value ( actual value vs. upper limit of normal ) was estimated and multiplied by 6.0 ( 16 ) . Total cholesterol was used as a measure of lipid control because low-density lipoprotein levels were not routinely measured in many of the study patients . We used the last blood pressure value in the clinical record before the data collection point . Data were collected at baseline and at 6-month intervals for 5 years . Measure of Comorbidity We requested that all recruited patients complete the Total Illness Burden Index ( TIBI ) question naire ( 1820 ) . The TIBI , which was specifically developed for office practice population s , uses patient reports to assess the presence and severity of 8 dimensions of comorbid conditions , problems , and diseases ( atherosclerotic heart disease , lung disease , congestive heart failure , arthritis , genitourinary disease , vision loss , gastrointestinal conditions , and foot disease ) by using items similar to those in the traditional review of systems . We scored these responses to assess the severity of the 8 dimensions and then aggregated the scores by using an algorithm that weighted each dimension according to its predicted effect on functional outcomes . We also performed analyses that used a version of the TIBI score that excluded previous cardiovascular events to examine the effects of the noncardiac components of the TIBI on future events . We refer to this version as the noncardiovascular TIBI score . The TIBI can be completed and scored in office practice s for use by physicians at the time of treatment and has been vali date d as a predictor of 3.5-year mortality ( 20 ) and health-related quality of life ( 18 , 19 ) . Statistical Analysis We conducted univariate analyses to describe patient characteristics and reported means and SDs for continuous variables and frequencies and percentages for categorical variables . We calculated the probabilities of incident cardiovascular events by using the KaplanMeier method and carried out comparisons by using the log-rank test . We divided patients into 2 prespecified subgroups at a threshold TIBI score of 12 , which has been demonstrated to discriminate between persons at greater and lesser risk for death ( 20 ) . We defined patients with TIBI scores less than 12 as the low-to-moderate comorbidity subgroup and patients with scores of 12 or greater as the high comorbidity subgroup . To account for the hierarchical nature of the data ( patients clustered within center ) , and to control for possible confounding or clustering by center of variables , we used multivariate Cox proportional hazards regression models , stratified by center , to investigate whether a dichotomized TIBI score was an independent predictor of clinical outcomes . In all analyses , we expressed outcome risk in terms of hazard ratios ( HRs ) with 95 % CIs in models adjusted for age ( as a continuous variable ) and sex ( as a categorical variable ) . To demonstrate that the threshold TIBI score of 12 differentiated patients ' risk both for cardiovascular events and for total mortality in the current sample , we computed hazard ratios for relative risk for each outcome between participants with TIBI scores of 12 or greater and patients with scores less than 12 . To demonstrate that any association observed between comorbidity and outcome risk was not an artifact of the selected TIBI score cut-point , we computed hazard ratios for both cardiovascular event risk and mortality risk by using the TIBI score as a continuous , independent variable . We replicated the analysis by using the noncardiovascular TIBI score to examine its association with future cardiovascular events and mortality . To determine whether the benefit of attaining recommended targets for glycemic control was greater for patients with low-to-moderate or high levels of comorbidity , we tested whether baseline HbA1c levels of 6.5 % or less or 7.0 % or less were associated with lower incidence of cardiovascular events in each comorbidity subgroup . To examine whether any observed association between attaining glycemic control targets and reduced cardiovascular event risk was sensitive

The results of this analysis indicated that taurolidine-citrate , compared to heparin , was more effective in preventing catheter-related infection ; therefore , it could be considered as a superior strategy . Nevertheless , compared to heparin-gentamicin combination , taurolidine-citrate is an inferior strategy because of its higher cost and lower infection prevention . CONCLUSION Compared to heparin , taurolidine-citrate is a superior option , but it is an inferior strategy compared to heparin-gentamicin combination .

BACKGROUND Prevention of catheter-related infection is of prime importance , . However , because of the risks caused by the leakage of circulating antibiotics and development of resistance to antibiotics , they are replaced by lock solutions . The aim of this study was to evaluate the efficacy and cost- effectiveness of taurolidine-citrate as a hemodialysis catheter lock solution compared to other common alternatives in Iran .

Background Taurolidin/Citrate ( TauroLock ™ ) , a lock solution with broad spectrum antimicrobial activity , may prevent bloodstream infection ( BSI ) due to coagulase-negative staphylococci ( CoNS or ' MRSE ' in case of methicillin-resistant isolates ) in pediatric cancer patients with a long term central venous access device ( CVAD , Port- or/Broviac-/Hickman-catheter type ) . Methods In a single center prospect i ve 48-months cohort study we compared all patients receiving anticancer chemotherapy from April 2003 to March 2005 ( group 1 , heparin lock with 200 IU/ml sterile normal saline 0.9 % ; Canusal ® Wockhardt UK Ltd , Wrexham , Wales ) and all patients from April 2005 to March 2007 ( group 2 ; taurolidine 1.35%/Sodium Citrate 4 % ; TauroLock ™ , Tauropharm , Waldbüttelbrunn , Germany ) . Results In group 1 ( heparin ) , 90 patients had 98 CVAD in use during the surveillance period . 14 of 30 ( 47 % ) BSI were ' primary Gram positive BSI due to CoNS ( n = 4 ) or MRSE ( n = 10 ) ' [ incidence density ( ID ) ; 2.30 per 1000 inpatient CVAD-utilization days].In group 2 ( TauroLock ™ ) , 89 patients had 95 CVAD in use during the surveillance period . 3 of 25 ( 12 % ) BSI were caused by CoNS . ( ID , 0.45 ) . The difference in the ID between the two groups was statistically significant ( P = 0.004 ) . Conclusion The use of Taurolidin/Citrate ( TauroLock ™ ) significantly reduced the number and incidence density of primary catheter-associated BSI due to CoNS and MRSE in pediatric cancer patients BACKGROUND Bacteremia is a major cause of morbidity in patients using intravascular catheters . Interdialytic locking with antibiotics decreases the incidence of bacteremia , but risks antibiotic resistance . Taurolidine is a nontoxic broad-spectrum antimicrobial agent that has not been associated with resistance . Preliminary evidence suggests that taurolidine-citrate locks decrease bacteremia , but cause flow problems in established catheters . STUDY DESIGN Double-blind r and omized controlled trial . INTERVENTION Interdialytic locking with taurolidine and citrate ( 1.35 % taurolidine and 4 % citrate ) compared with heparin ( 5,000 U/mL ) started at catheter insertion . SETTING & PARTICIPANTS 110 adult hemodialysis patients with tunneled cuffed intravascular catheters inserted at 3 centers in Northwest Engl and . OUTCOMES & MEASUREMENTS Primary end points were time to first bacteremia episode from any cause and time to first use of thrombolytic therapy . RESULTS There were 11 bacteremic episodes in the taurolidine-citrate group and 23 in the heparin group ( 1.4 and 2.4 episodes/1,000 patient-days , respectively ; P = 0.1 ) . There was no significant benefit of taurolidine-citrate versus heparin for time to first bacteremia ( hazard ratio , 0.66 ; 95 % CI , 0.2 - 1.6 : P = 0.4 ) . Taurolidine-citrate was associated with fewer infections caused by Gram-negative organisms than heparin ( 0.2 vs 1.1 infections/1,000 patient-days ; P = 0.02 ) ; however , there was no difference for Gram-positive organisms ( 1.1 vs 1.2 infections/1,000 patient-days ; P = 0.8 ) . There was a greater need for thrombolytic therapy in the taurolidine-citrate versus heparin group ( hazard ratio , 2.5 ; 95 % CI , 1.3 - 5.2 ; P = 0.008 ) . LIMITATIONS Small sample size . The study included bacteremia from all causes and was not specific for catheter-related bacteremia . CONCLUSIONS Taurolidine-citrate use did not decrease all-cause bacteremia and was associated with a greater need for thrombolytic treatment . There was a decrease in infections caused by Gram-negative organisms and a trend to a lower frequency of bacteremia , which warrants further study Background : Use of uncuffed catheters ( UCs ) in hemodialysis patients is common practice . An antibiotic lock has been recommended to prevent catheter-related bacteremia ( CRB ) , although insufficient data are available about the appropriate antimicrobial agent and dose with prolonged use of UCs . Methods : This open-label r and omized study was conducted to compare gentamicin/heparin ( group A ) and taurolidine/citrate ( group B ) , as catheter-lock solutions , in 119 chronic hemodialysis patients in whom a total of 150 UCs were placed . A well-matched historical control group ( heparin ) included 67 UCs in 58 patients ( group C ) . Results : CRB episodes developed in 6 and 8 patients in groups A and B , respectively , significantly fewer than in group C ( 20 patients ) . Cumulative CRB-free catheter survival at 90 days was 82 % for A and 78 % for B , which is significantly higher than the 26 % for C. Similar Gram-positive infection rates were found in all groups . The Gram-negative infection rate was significantly lower in B compared to C. No significant differences in thrombosis rates were observed between the groups . Conclusions : Gentamicin/heparin and taurolidine/citrate , used for locking UC , were similarly effective at preventing CRB and catheter thrombosis for up to 3 months , until a functional permanent vascular access became available . Both antimicrobial lock solutions were superior to heparin in CRB prevention with similar thrombosis rates BACKGROUND The use of haemodialysis catheters is complicated by catheter-related sepsis . Intraluminal colonization of the catheter with bacteria is important in the pathogenesis of catheter-related sepsis . The use of a catheter lock solution containing the antimicrobial taurolidine might prevent bacterial colonization , thereby reducing the incidence of catheter-related sepsis . METHODS In a r and omized prospect i ve trial , patients receiving a dialysis catheter were included and catheters were locked with either heparin or a citrate-taurolidine-containing solution . Blood cultures drawn from the catheter lumen were routinely taken every 2 weeks and at time of removal of the catheter to detect bacterial colonization . Catheter-related sepsis and exit-site infections were registered for both groups . RESULTS A total of 76 catheters were inserted in 58 patients . The incidence of catheter colonization progressed slowly over time with no differences between dialysis catheters filled with heparin or citrate-taurolidine-containing solution . The number of exit-site infections was also similar between both groups . In the heparin group , four cases of catheter-related sepsis occurred as opposed to no sepsis episodes in the patients with catheters locked with the citrate-taurolidine-containing solution ( P<0.5 ) . No side effects with the use of citrate-taurolidine catheter lock solution were noted . CONCLUSIONS This study shows that catheter filling with a solution containing the antimicrobial taurolidine may significantly reduce the incidence of catheter-related sepsis . Taurolidine appears to be effective and safe and does not carry the risk for side effects that have been reported for other antimicrobial lock solutions containing gentamicin or high concentrations of citrate BACKGROUND Intravenous catheters for haemodialysis increase the risk of sepsis . This study investigates the use of a taurolidine/citrate catheter-locking agent for patients receiving hospital-based haemodialysis , auditing the number and cost of infections before and after its introduction . METHODS The incidence and cost of treatment of catheter sepsis occurring in all patients receiving haemodialysis via a line were investigated over 6-month periods before and after introducing the taurolidine/citrate line-locking agent . RESULTS A reduction of 4.62 infections per 1000 catheter days , or 88.5 % , was shown after the introduction of the new line-locking agent . The total costs of line infections in the first 6 months were 52,500 euros , ( 41,000 pounds ) ; after the introduction of the taurolidine/citrate locks , these reduced to 33,300 euros , ( 26 , 000 pounds ) , a reduction of 19,200 euros ( 15,000 pounds ) . CONCLUSIONS The use of a taurolidine/citrate haemodialysis catheter-locking agent in our haemodialysis population has significantly reduced the line sepsis rate , with a positive impact on morbidity , mortality and cost BACKGROUND A catheter lock solution containing 1.35 % taurolidine and 4 % citrate could potentially disrupt bacterial surface adherence and consecutive biofilm production due to the anti-adherence properties of taurolidine and the anticlotting and chelator activities of both compounds . AIM To compare the impact on microbial catheter colonization and infectious complications of heparin and taurolidine citrate as central venous catheter ( CVC ) lock solutions in paediatric patients with haematological malignancies . METHODS Seventy-one patients aged 1.4 - 18 years were r and omized to two treatment groups using either heparin ( N = 36 ) or taurolidine citrate ( N = 35 ) . Infectious complications and clinical side-effects were prospect ively monitored and microbial colonization of catheters was assessed at the time of removal . FINDINGS There were two bloodstream infections in the taurolidine citrate group versus nine in the heparin group ( 0.3 vs 1.3 infections per 1000 catheter-days ; P = 0.03 ) . Fever of unknown origin and catheter occlusions were observed with a similar frequency in both groups . Microbial colonization was found in 25.4 % catheters . The time of no-lock use , but not the type of lock solution or time of observation , was a significant predictor of catheter colonization ( P = 0.004 ) . Colonization was not observed in CVCs used immediately with taurolidine citrate lock . Seven patients in the taurolidine citrate group ( 20 % ) experienced side-effects ( nausea , vomiting , abnormal taste sensations ) . CONCLUSION The use of taurolidine citrate lock solution was associated with a significant reduction in bloodstream infection in immunocompromised paediatric patients . Taurolidine citrate may prevent colonization of CVCs if used from the time of insertion , but not after a period of no-lock catheter use

The results of this systematic review and meta- analysis favor a protective effect of neuromuscular training programs on the risk of ACL rupture in female athletes . This protective effect is more pronounced in soccer players .

BACKGROUND A number of reports have been published on the effectiveness and design of intervention programs for the prevention of rupture of the anterior cruciate ligament ( ACL ) in female athletes . The purpose of this study was to systematic ally review the literature to determine the effectiveness of neuromuscular training programs in preventing ACL injury in female athletes .

Objective To evaluate the effectiveness of neuromuscular training in reducing the rate of acute knee injury in adolescent female football players . Design Stratified cluster r and omised controlled trial with clubs as the unit of r and omisation . Setting 230 Swedish football clubs ( 121 in the intervention group , 109 in the control group ) were followed for one season ( 2009 , seven months ) . Participants 4564 players aged 12 - 17 years ( 2479 in the intervention group , 2085 in the control group ) completed the study . Intervention 15 minute neuromuscular warm-up programme ( targeting core stability , balance , and proper knee alignment ) to be carried out twice a week throughout the season . Main outcome measures The primary outcome was rate of anterior cruciate ligament injury ; secondary outcomes were rates of severe knee injury ( > 4 weeks ’ absence ) and any acute knee injury . Results Seven players ( 0.28 % ) in the intervention group , and 14 ( 0.67 % ) in the control group had an anterior cruciate ligament injury . By Cox regression analysis according to intention to treat , a 64 % reduction in the rate of anterior cruciate ligament injury was seen in the intervention group ( rate ratio 0.36 , 95 % confidence interval 0.15 to 0.85 ) . The absolute rate difference was −0.07 ( 95 % confidence interval −0.13 to 0.001 ) per 1000 playing hours in favour of the intervention group . No significant rate reductions were seen for secondary outcomes . Conclusions A neuromuscular warm-up programme significantly reduced the rate of anterior cruciate ligament injury in adolescent female football players . However , the absolute rate difference did not reach statistical significance , possibly owing to the small number of events . Trial registration Clinical trials NCT00894595 Background : Few authors have investigated the effectiveness of preventive intervention in European team h and ball . Purpose : The aim of the present study was to evaluate the effects of a prevention program on the incidence of injuries in female European team h and ball players . Study design : Prospect i ve controlled study . Methods : Ten female h and ball teams ( 134 players ) took part in the prevention program ( 1 . Information about injury mechanism , 2 . Balance-board exercises , 3 . Jump training ) while 10 other teams ( 142 players ) were instructed to train as usual . Over one season all injuries were documented weekly . Results : Ankle sprain was the most frequent diagnosis in both groups with 11 ankle sprains in the control group and 7 ankle sprains in the intervention group ( Odds ratio : 0.55 , 95 % confidence interval : 0.22–1.43 ) . The knee was the second frequent injury site . In the control group 5 of all knee injuries were anterior cruciate ligament ( ACL ) ruptures ( incidence : 0.21 per 1000 h ) in comparison with one in the intervention group ( incidence : 0.04 per 1000 h ) . Odds ratio was 0.17 with 95 % confidence interval of 0.02–1.5 . Conclusions : This study confirms that proprioceptive and neuromuscular training is appropriate for the prevention of knee and ankle injuries among female European team h and ball players Proprioceptive training has been shown to reduce the incidence of ankle sprains in different sports . It can also improve rehabilitation after anterior cruciate ligament ( ACL ) injuries whether treated operatively or nonoperatively . Since ACL injuries lead to long absence from sports and are one of the main causes of permanent sports disability , it is essential to try to prevent them . In a prospect i ve controlled study of 600 soccer players in 40 semiprofessional or amateur teams , we studied the possible preventive effect of a gradually increasing proprioceptive training on four different types of wobble-boards during three soccer seasons . Three hundred players were instructed to train 20 min per day with 5 different phases of increasing difficulty . The first phase consisted of balance training without any balance board ; phase 2 of training on a rectangular balance board ; phase 3 of training on a round board ; phase 4 of training on a combined round and rectangular board ; phase 5 of training on a so-called BABS board . A control group of 300 players from other , comparable teams trained “ normally ” and received no special balance training . Both groups were observed for three whole soccer seasons , and possible ACL lesions were diagnosed by clinical examination , KT-1000 measurements , magnetic resonance imaging or computed tomography , and arthroscopy . We found an incidence of 1.15 ACL injuries per team per year in the control group and 0.15 injuries per team per year in the proprioceptively trained group ( P<0.001 ) . Proprioceptive training can thus significantly reduce the incidence of ACL injuries in soccer players A set of exercises -- the " 11"--have been selected to prevent football injuries . The purpose of this cluster-r and omized controlled trial was to investigate the effect of the " 11 " on injury risk in female youth football . Teams were r and omized to an intervention ( n=59 teams , 1091 players ) or a control group ( n=54 teams , 1001 players ) . The intervention group was taught the " 11 , " exercises for core stability , lower extremity strength , neuromuscular control and agility , to be used as a 15-min warm-up program for football training over an 8-month season . A total of 396 players ( 20 % ) sustained 483 injuries . No difference was observed in the overall injury rate between the intervention ( 3.6 injuries/1000 h , confidence interval ( CI ) 3.2 - 4.1 ) and control group ( 3.7 , CI 3.2 - 4.1 ; RR=1.0 , CI 0.8 - 1.2 ; P=0.94 ) nor in the incidence for any type of injury . During the first 4 months of the season , the training program was used during 60 % of the football training sessions , but only 14 out of 58 intervention teams completed more than 20 prevention training sessions . In conclusion , we observed no effect of the injury prevention program on the injury rate , most likely because the compliance with the program was low OBJECTIVE To determine the numbers needed to treat ( NNT ) and relative risk reduction ( RRR ) associated with neuromuscular training programs aim ed at preventing noncontact anterior cruciate ligament ( ACL ) injuries in female athletes . DATA SOURCES We search ed PubMed , MEDLINE , SPORT Discus , CINAHL , and Web of Science from 1966 through 2005 using the terms knee , injury , anterior cruciate ligament , ACL , prevention , plyometric , and neuromuscular training . STUDY SELECTION Selected articles were from peer- review ed journals written in English that described original research studies comparing neuromuscular training programs with control programs to determine the number of noncontact ACL injuries per event exposure or hours of playing time . Five studies met the inclusion criteria and were independently rated by 3 review ers using the Physiotherapy Evidence Data base ( PEDro ) scale . Consensus PEDro scores ranged from 4 to 7 out of 10 . DATA EXTRACTION We used numbers of subjects , ACL injuries , and injury exposure rates to calculate NNT and RRR for each study . The NNT calculations from all studies were based on the number of players across 1 competitive season and were described as NNT benefit or NNT harm . DATA SYNTHESIS All 5 studies demonstrated a prophylactic effect due to the neuromuscular training programs . The pooled NNT estimates showed that 89 individuals ( 95 % confidence interval : 66 to 136 ) would need to participate in the prophylactic training program to prevent 1 ACL injury over the course of 1 competitive season . Pooled RRR was 70 % ( 95 % confidence interval : 54 % to 80 % ) among individuals who participated in the intervention program . One high- quality r and omized control trial and 4 medium- quality prospect i ve cohort studies showed mostly consistent findings . Thus , a Strength of Recommendation Taxonomy level of evidence of 1 with a grade B recommendation supports the use of neuromuscular training programs in the prevention of noncontact ACL injuries in female athletes BACKGROUND Studies have suggested that exercise programs can reduce the incidence of noncontact injuries of the anterior cruciate ligament in female athletes . We conducted a two-year prospect i ve study to assess the effects of a knee ligament injury prevention exercise program on the incidence of noncontact anterior cruciate ligament injuries in high-school female athletes . METHODS A prospect i ve cohort design was used to study high-school female athletes ( playing soccer , basketball , and volleyball ) from fifteen schools ( 112 teams ) for two consecutive seasons . The schools were divided into treatment and control groups . The treatment group participated in a plyometric-based exercise program twice a week throughout the season . Practice and game exposures and compliance with the exercise program were recorded on a weekly basis . Suspected noncontact anterior cruciate ligament injuries were confirmed on the basis of the history as well as at the time of surgery and /or with magnetic resonance imaging . RESULTS A total of 1439 athletes ( 862 in the control group and 577 in the treatment group ) were monitored . There were six confirmed noncontact anterior cruciate ligament injuries : three in the treatment group , and three in the control group . The incidence of noncontact anterior cruciate ligament injuries per 1000 exposures was 0.167 in the treatment group and 0.078 in the control group , yielding an odds ratio of 2.05 , which was not significant ( p > 0.05 ) . CONCLUSIONS Our results suggest that a twenty-minute plyometric-based exercise program that focuses on the mechanics of l and ing from a jump and deceleration when running performed twice a week throughout the season will not reduce the rate of noncontact anterior cruciate ligament injuries in high-school female athletes To assess the effect of a neuromuscular training program on the incidence of anterior cruciate ligament ( ACL ) injuries in female team h and ball athletes , a prospect i ve intervention study of female team h and ball athletes from divisions I , II , and III in Norway was conducted . The control season ( 1998 - 1999 ) included 60 teams ( 942 athletes ) , the first intervention season ( 1999 - 2000 ) included 58 teams ( 855 athletes ) , and the second intervention season ( 2000 - 2001 ) included 52 teams ( 850 athletes ) . For the intervention teams , a five-phase program ( duration , 15 minutes ) with three different balance exercises focusing on neuromuscular control and planting and l and ing skills was developed and introduced to the athletes in the autumn of 1999 and revised before the start of the season in 2000 . Each intervention team was instructed in the program and supplied with an instructional video , poster , six balance mats , and six wobble boards . Additionally , a physical therapist was assigned to each team for follow-up during the second intervention season . The number of ACL injuries during the three seasons and compliance with the program were assessed . Twenty-nine ACL injuries occurred during the control season , 23 during the first intervention season ( odds ratio [ OR ] , 0.87 [ 0.50 - 1.52 ] ; P = 0.62 ) , and 17 during the second intervention season ( OR , 0.64 [ 0.35 - 1.18 ] ; P = 0.15 ) . In the elite division , 13 injuries occurred during the control season , 6 during the first intervention season ( OR , 0.51 [ 0.19 - 1.35 ] ; P = 0.17 ) , and 5 during the second intervention season ( OR , 0.37 [ 0.13 - 1.05 ] ; P = 0.06 ) . For the entire cohort , no difference in injury rates was noted during the second intervention season between compliers and noncompliers ( OR , 0.52 [ 0.15 - 1.82 ] , P = 0.31 ) . In the elite division , the risk of injury was reduced among athletes who completed the ACL injury prevention program ( OR , 0.06 [ 0.01 - 0.54 ] , P = 0.01 ) compared with those who did not . The results demonstrate that it is possible to prevent ACL injuries with specific neuromuscular training Objective To investigate whether a neuromuscular training programme is effective in preventing non-contact leg injuries in female floorball players . Design Cluster r and omised controlled study . Setting 28 top level female floorball teams in Finl and . Participants 457 players ( mean age 24 years)—256 ( 14 teams ) in the intervention group and 201 ( 14 teams ) in the control group — followedup for one league season ( six months ) . Intervention A neuromuscular training programme to enhance players ’ motor skills and body control , as well as to activate and prepare their neuromuscular system for sports specific manoeuvres . Main outcome measure Acute non-contact injuries of the legs . Results During the season , 72 acute non-contact leg injuries occurred , 20 in the intervention group and 52 in the control group . The injury incidence per 1000 hours playing and practise in the intervention group was 0.65 ( 95 % confidence interval 0.37 to 1.13 ) and in the control group was 2.08 ( 1.58 to 2.72 ) . The risk of non-contact leg injury was 66 % lower ( adjusted incidence rate ratio 0.34 , 95 % confidence interval 0.20 to 0.57 ) in the intervention group . Conclusion A neuromuscular training programme was effective in preventing acute non-contact injuries of the legs in female floorball players . Neuromuscular training can be recommended in the weekly training of these athletes . Trial registration Current Controlled Trials IS RCT N26550281

Elcatonin therapies and non-elcatonin medications had comparable fracture rates and bone mineral density change . Conclusions Based on current evidence , C-E may be considered for treating postmenopausal osteoporosis because it benefits on pain relief and complications . Moreover , it shows comparable fracture rate and bone mineral density change as compared with anti-osteoporosis and calcium supplements .

Summary The present systematic review aim ed to evaluate bone mineral density ( BMD ) change and complication rates of elcatonin on treating postmenopausal osteoporosis . The result confirmed efficacy of elcatonin and safety in combination therapies of elcatonin ( C-E ) . Introduction Postmenopausal osteoporosis is an important issue in global aging trends . One treatment of osteoporosis is elcatonin , a kind of calcitonin . However , it has been challenged for long time because of safety . Many trials investigated on this topic , but they were design ed differently . Those design s can be categorized in monotherapy of elcatonin ( M-E ) and C-E. Unfortunately , no synthesized evidence dealt this topic .

Summary A r and omized controlled trial was performed to compare the short-term effects of alendronate ( ALN ) and ECT on pain and quality of life ( QOL ) in postmenopausal women with osteoporosis . Back pain and QOL [ Short-Form Health Survey ( SF-8 ) ] significantly improved at 1 , 3 , and 6 months in both groups , with greater improvements in the ALN group than in the ECT group . These results suggested that ALN reduced back pain and improved QOL more markedly than ECT in postmenopausal osteoporotic women with back pain . Introduction Intramuscular ECT is known to reduce pain via the central nervous system . A multicenter r and omized controlled trial was performed to compare the short-term effects of ALN and ECT on pain and QOL in postmenopausal women with osteoporosis . Methods One hundred and 94 postmenopausal osteoporotic women with back pain ( mean age 79.8 years , range 60–96 years ) were r and omly divided into two groups : the ALN group ( 35 mg weekly ) and the ECT group ( intramuscular 20 units a week ) . The duration of the study was 6 months . The trial was completed in 97 ( 100 % ) women of the ALN group and 96 ( 99.0 % ) women of the ECT group . Urinary levels of cross-linked N-terminal telopeptide of type I collagen ( NTX ) , serum alkaline phosphatase ( ALP ) , face scale score ( FSS , back pain ) , and SF-8 ( QOL ) were monitored . Results Urinary NTX levels significantly decreased at 3 months in the ALN group , but not in the ECT group . Serum ALP levels significantly decreased at 6 months in the both groups , with a greater reduction in the ALN group . The FSS and SF-8 significantly improved at 1 , 3 , and 6 months in both groups , with greater improvements in the ALN group than in the ECT group . Conclusions ALN suppressed bone turnover , reduced back pain , and improved QOL more markedly than ECT in postmenopausal osteoporotic women with back pain OBJECTIVE To evaluate the efficacy and safety of rhPTH ( 1 - 34 ) vs. elcatonin . METHODS Sixty patients with primary OP were r and omly divided into two groups according to the ratio of 3:1 . rhPTH ( 1 - 34 ) group ( PTH group ) was treated with subcutaneous injection of rhPTH ( 1 - 34 ) 20 μ g daily for 18 months , and the elcatonin group ( CT group ) was treated with intramuscular injection of elcatonin 20 U weekly for 12 months . Bone mineral density ( BMD ) of the lumbar spine 2 - 4 ( L2 - 4 ) and femoral neck , serum calcium and phosphorus , urinary calcium , serum bone specific alkaline phosphatase ( BSAP ) , and urinary c-terminal telopeptides of type I collagen/creatinine ( uCTX-I/Cr ) were tested at baseline , and 6 , 12 , and 18 months after treatment . RESULTS In PTH group , BMD of L2 - 4 at 6 , 12 , and 18 months , BDM of femoral neck at 18 month , BSAP at 6 and 12 months and uCTX- I/Cr at 6 , 12 and 18 months were all significantly raised . In CT group , BMD of L2 - 4 at 12 month and that of femoral neck at 12 and 18 months were significantly elevated , while BSAP was significantly decreased at 12 and 18 months , and no significant difference on CTX- I/Cr was observed . When BMD growth and growth rate between two groups were compared , PTH group had better improvement in L2 - 4 BMD and growth rate than CT group at 6 , 12 , and 18 months . BMD growth and growth rate of femoral neck at 12 month and its growth at 18 month in CT group were higher than in PTH group , but there was no significant difference between two groups regarding the growth rates at 18 month . Besides , there were no significant differences regarding the rates of adverse reactions between two groups . CONCLUSIONS rhPTH ( 1 - 34 ) , is safe and effective in the treatment of primary OP . It is superior to elcatonin in improving vertebral BMD at onset time , growth rate and growth range , but inferior to elcatonin at BMD of femoral neck The aim of this study was to compare the efficacy of elcatonin injections and oral nonsteroidal anti-inflammatory drugs ( NSAIDs ) for patients with osteoporosis who have acute lumbar pain after experiencing new vertebral compression fractures . Two hundred twenty-eight Japanese female patients ( mean age 77.3 years ) with acute lumbar pain from osteoporotic vertebral fractures were r and omly divided into two groups . Patients in one group were given an NSAID ( NSAIDs group ) and patients in the other group were given weekly intramuscular injections of 20 units of elcatonin ( elcatonin group ) . All patients underwent follow-up examinations up to 6 weeks from the start of the trial . Outcome measures were the level of functional impairment according to the Japan Question naire for Osteoporotic Pain ( JQ22 ) , the Rol and –Morris Disability Question naire ( RDQ ) , and a visual analog scale ( VAS ) of pain intensity . Statistical analyses focused on ( 1 ) the time course of pain and functional level using linear mixed effects models to analyze the longitudinal data and ( 2 ) the effectiveness of elcatonin injection with mean difference values and 95 % confidence intervals . Significant differences were seen over time between the initial values and the postintervention values ( 4 and 6 weeks ) in JQ22 , RDQ , and VAS scores ( effect size d > 0.4 ) in each group . The mean differences between the elcatonin group and the NSAIDs group in each measure at 4 and 6 weeks were −4.8 and −8.3 for the JQ22 , −1.3 and −2.6 for the RDQ , and −11.3 and −11.5 for the VAS , shifted to elcatonin . Once weekly elcatonin injection was more effective than NSAIDs for treating acute lumbar pain and improving mobility in Japanese women with osteoporotic vertebral fractures OBJECTIVE To evaluate three different therapeutic regimens for the prevention of osteoporosis in natural and surgical postmenopausal women who had been found to have rapid bone loss in analytical studies . METHODS A total of 104 naturally or surgically postmenopausal women were studied , and subsequently followed-up during 1 year for avoidance of the influence of seasonal variation on bone mass , a factor overlooked in several studies . They were r and omized into four groups of 26 patients each : the untreated control group ( mean age 50 + /- 5 years ) ; the hormonal replacement treatment ( HRT ) group ( mean age 48 + /- 6 years ) , which was treated for 24 days each month with transdermal 17 beta-estradiol , 50 mg/day , together with medroxiprogesterone , 10 mg during 12 days ; the calcium group ( mean age 50 + /- 4 years ) , which was treated with elemental calcium , 1 g/day ; and the calcitonin group ( mean age 50 + /- 5 years ) , which was treated for 10 days each month with eel calcitonin , 40 IU/day and with elemental calcium , 500 mg/day . Full-body bone densitometry , for measuring total body bone mineral content ( TB BMC ) , was carried out in all the women at baseline and 1 year . TB BMC was corrected for body weight by dividing its value by body weight ( TB BMC /W ) . RESULTS After 1 year TB BMC /W was lower in every group : -2.14 % ( P < 0.001 ) in the control group ; -0.14 % ( P = NS ) in the HRT group ( P < 0.05 vs. controls ) ; -0.18 % ( P = NS ) in the calcium group ( P < 0.05 vs. controls ) ; and -0.06 % ( P = NS ) in the calcitonin group ( P < 0.01 vs. controls ; P < 0.05 vs. calcium and HRT ) . CONCLUSIONS These findings show that all three treatments are effective in the prevention of postmenopausal loss of bone mass BACKGROUND Recombinant human parathyroid hormone ( 1 - 34 ) ( rhPTH ( 1 - 34 ) ) is the first agent in a unique class of anabolic therapies acting on the skeleton . The efficacy and safety of long-term administration of rhPTH ( 1 - 34 ) in Chinese postmenopausal women had not been evaluated . This study compared the clinical efficacy and safety of rhPTH ( 1 - 34 ) with elcatonin for treating postmenopausal women with osteoporosis in 11 urban areas of China . METHODS A total of 453 postmenopausal women with osteoporosis were enrolled in an 18-month , multi-center , r and omized , controlled study . They were r and omized to receive either rhPTH ( 1 - 34 ) 20 µg ( 200 U ) daily for 18 months , or elcatonin 20 U weekly for 12 months . Lumbar spine ( L1 - 4 ) and femoral neck bone mineral density ( BMD ) , fracture rate , back pain as well as biochemical markers of bone turnover were measured . Adverse events were recorded . RESULTS rhPTH ( 1 - 34 ) increased lumbar BMD significantly more than did elcatonin after 6 , 12 , and 18 months of treatment ( 4.3 % vs. 1.9 % , 6.8 % vs. 2.7 % , 9.5 % vs. 2.9 % , P < 0.01 ) . There was only a small but significant increase of femoral neck BMD after 18 months ( 2.6 % , P < 0.01 ) in rhPTH groups . There were larger increases in bone turnover markers in the rhPTH ( 1 - 34 ) group than those in the elcatonin group after 6 , 12 , and 18 months ( serum bone-specific alkaline phosphatase ( BSAP ) 93.7 % vs. -3.6 % ; 117.8 % vs. -4.1 % ; 49.2 % vs. -5.8 % , P < 0.01 ; urinary C-telopeptide/creatinine ( CTX/Cr ) 250.0 % vs. -29.5 % ; 330.0 % vs. -41.4 % , 273.0 % vs. -10.6 % , P < 0.01 ) . rhPTH ( 1 - 34 ) showed similar effect of pain relief as elcatonin . The incidence of clinical fractures was 5.36 % ( 6/112 ) in elcatonin group and 3.2 % ( 11/341 ) in rhPTH ( 1 - 34 ) group ( P = 0.303 ) . Both treatments were well tolerated . Hypercaluria ( 9.4 % ) and hypercalcemia ( 7.0 % ) in rhPTH ( 1 - 34 ) group were transient and caused no clinical symptoms . Pruritus ( 8.2 % vs. 2.7 % , P = 0.044 ) and redness of injection site ( 4.4 % vs. 0 , P = 0.024 ) were more frequent in rhPTH ( 1 - 34 ) . Nausea/vomiting ( 16.1 % vs. 6.2 % , P = 0.001 ) and hot flushes ( 7.1 % vs. 0.6 % , P < 0.001 ) were more common in elcatonin group . CONCLUSIONS rhPTH ( 1 - 34 ) was associated with greater increases in lumbar spine BMD and bone formation markers . It could increase femoral BMD after 18 months of treatment . rhPTH could improve back pain effectively . The results of the present study indicate that rhPTH ( 1 - 34 ) is an effective , safe agent in treating Chinese postmenopausal women with osteoporosis UNLABELLED In this longitudinal , prospect i ve , and population -based study ( n = 1044 ) , seven BTMs were assessed before and after trauma in 113 elderly women ( 85 with fractures ) . Markers were not altered in the immediate postfracture period but were clearly elevated during fracture repair . Recent fracture should thus be taken into account when markers are used in clinical practice . INTRODUCTION Fracture may influence the levels of bone turnover markers ( BTM ) and have implication s for their use in clinical practice . In this longitudinal , prospect i ve , and population -based study , we assessed prefracture levels of BTMs and compared them with postfracture levels of the same individuals immediately after fracture and during fracture repair . This is the first study in which the effect of fracture on bone markers has been evaluated with prefracture sample s available . MATERIAL S AND METHODS Serum and urine were collected at the emergency unit from 85 women ( 77.9 + /- 1.8 yr ) who sustained a fracture after low-energy trauma and 28 controls ( 77.8 + /- 2.0 yr ) with similar trauma but no fracture . All were participants of the Malmö OPRA study ( n = 1044 ) , and pretrauma sample s were collected 1.05 + /- 0.85 yr before . Bone turnover was assessed by seven different BTMs reflecting different stages of bone metabolism { C-terminal cross-linked telopeptides of type I collagen [ S-CTX ] , S-TRACP5b , N-terminal propeptides of type I collagen [ S-PINP ] , serum osteocalcin ( S-OC[1 - 49 ] and S-TotalOC ) , urinary deoxypyridinoline [ U-DPD ] , and urinary osteocalcin [U-OC]}. RESULTS BTMs sample d within a few hours after fracture were not altered from preinjury levels . Both bone formation and bone resorption markers were , however , significantly increased 4 mo after fracture . The elevation was most pronounced after hip fracture . Bone turnover remained elevated up to 12 mo after fracture . CONCLUSIONS We believe this study extends our knowledge on the skeletal postfracture metabolic processes . In addition , it may provide a basis for future means to monitor pharmacological intervention promoting fracture healing Since the proportion of the ageing population in Japan is increasing , a comprehensive and evidence based strategy is urgently required for the prevention of musculoskeletal diseases , including osteoarthritis ( OA ) and osteoporosis ( OP ) , both of which affect the activities of daily living ( ADL ) and quality of life ( QOL ) and increase morbidity and mortality . However , few prospect i ve , longitudinal studies for the purpose of developing such a strategy have been conducted , and little information is available regarding the prevalence and incidence of musculoskeletal disorders , including OA and OP , as well as pain and disability in the Japanese population . It is difficult to design rational clinical and public health approaches for the diagnosis , evaluation and prevention of OA and OP without such epidemiological data . The Research on Osteoarthritis/osteoporosis Against Disability ( ROAD ) study was established in 2005 by N.Y. , T.A. , H.O. , S.M. , H.K. and K.N. ( principal investigators ) . The principal investigators are affiliated with the 22nd Century Medical and Research Center , University of Tokyo Health-related quality of life ( HRQOL ; “ QOL ” hereafter ) was evaluated in Japanese osteoporotic patients using three question naires ; the SF-36 ( MOS 36-Item Short-Form Health Survey ; generic , profile-type ) , the EQ-5D ( Euro Qol-5 Dimensions ; generic , preference-based ) , and the JOQOL ( Japanese Osteoporosis Quality of Life 1999 ; disease-targeted ) . The eight subscales and two summary scores of the SF-36 were impaired in these patients even after correction for age and sex . The scores on the EQ-5D and JOQOL correlated well with the subscales of the SF-36 that represent the physical aspects of physical function and bodily pain , which suggests that physical aspects are important determinants of overall QOL status in osteoporotic patients . Although the QOL scores did not correlate with bone mineral density , they were markedly influenced by the presence of vertebral fractures . In particular , the presence of two or more vertebral fractures greatly decreased the QOL scores . We then evaluated the QOL scores before and after treatment . The patients were either given calcium supplementation alone or calcium plus once-weekly elcatonin ( Elcitonin , Asahi Kasei Pharma , Tokyo , Japan ) injection . Elcatonin treatment markedly improved diverse aspects of the QOL , whereas calcium alone did not . The current data suggest that osteoporosis , especially in the presence of vertebral fracture , is associated with compromised QOL , and therapeutic intervention for osteoporosis should be evaluated in terms of QOL , as well as in terms of increases in bone mineral density and fracture prevention Elderly patients with osteoporotic vertebral fractures often experience severe pain that reduces their quality of life ( QOL ) . Calcitonin , a bone resorption inhibitor , has been reported to alleviate pain in such patients ; however , few clinical studies have demonstrated this effect . The objective of this study was to compare changes in pain scores , activities of daily living ( ADL ) , QOL , bone resorption , bone mineral density ( BMD ) , and fracture healing among patients with new vertebral fractures who received different treatment modalities . We conducted an open-label , multicenter , r and omized , parallel control group study comprising 107 female patients ≥55 years old with acute back pain from vertebral fracture . All subjects received either intramuscular injections of elcatonin , a derivative of calcitonin , or an oral nonsteroidal antiinflammatory drug ( NSAID ) combined with an active vitamin D3 ( VD3 ) analogue for 6 months . The pain was assessed using a visual analogue scale , and ADL and QOL were assessed using question naires . BMD was measured using dual-energy X-ray absorptiometry . A two-tailed significance level of 5 % was used . The elcatonin IM group had significantly higher QOL score at 2 weeks and later , and significantly lower VAS and ADL scores than those in the NSAID + VD3 group at 1 month and later . The elcatonin IM group had significantly reduced TRACP-5b levels compared with those in the NSAID + VD3 group at 3 months and later and significantly higher percent changes in BMD than the NSAID + VD3 group . These results suggest that elcatonin significantly alleviated pain , inhibited bone resorption , and improved ADL , QOL , and BMD compared with NSAID + VD3 Abstract : Thirty postmenopausal women with reduced bone mineral density were divided r and omly into two groups based on the chronological sequence of their first visit to the Osteoporosis Clinic of Katsuragi Hospital . Group I was given 600 mg ipriflavone orally daily and group II was weekly injected intramuscularly with 20 units elcatonin , Asu1–7 eel calcitonin ( carbocalcitonin ) . Lumbar spine BMD was measured by dual-energy X-ray absorptiometry , and trabecular bone mineral density at the distal radius , cortical bone density , and relative cortical volume at the radial diaphysis by peripheral computed tomography before the beginning of the study and at the 4th , 8th , and 12th month . Markers of bone metabolism — serum total alkaline phosphatase , bone-specific alkaline phosphatase , tartrate-resistant acid phosphatase , osteocalcin , intact osteocalcin , PICP and ICTP , and urinary pyridinoline , deoxypyridinoline , and calcium/creatinine (Ca/Cr)—were also measured at the same interval . Plasma parathyroid hormone ( PTH ) and calcitonin ( CT ) were measured at the same time . Radial trabecular bone density showed a significantly higher rate of increase in group I ( ipriflavone group ) than in group II ( elcatonin group ) at the 4th month , whereas lumbar spine BMD showed more pronounced increase in the elcatonin group than in the ipriflavone group throughout the study period . Bone metabolism markers tended to decline in both groups . Total and intact osteocalcin showed a significant fall from the baseline throughout the study period only in the ipriflavone group . Urine pyridinoline and deoxypyridinoline showed a significant fall from the baseline at the 12th month only in the ipriflavone group . On comparing bone gainers with increase of lumbar spine BMD by 2 % or more with bone losers with a decrease by 2 % or more , only urine Ca/Cr was significantly different , lower in the former than in the latter , despite the general tendency for bone resorption markers to decrease in bone gainers and to increase in bone losers A comparative study of 90 post-menopausal osteoporotic women , has been carried out . The patients were divided in 3 homogeneous groups . According to 3 different schemes : Group A = 30 patients received carbocalcitonin i.m . 40 UMRC/day/1 month and 40 UMRC/alternating days/2 months followed by 1 month of wash-out for 11 months ; Group B = 30 patients received carbolcitonin nasal-spray 80 UMRC/day/1 month and 80 UMRC/alternating day/2 months followed by 1 month of wash-out for 11 months ; Group C = 30 patients received ipriflavone x os ( 600 mg/day/3 months followed by 1 month of wash-out for 3 times ) . BMC significantly was increased in all Groups after 7 and 11 months . In conclusion , carbocalcitonin and ipriflavone seem to show a similar improving densitometric effect in post-menopausal osteoporosis Summary The secreted protein acidic and rich in cysteine ( SPARC ) , also known as osteonectin , plays an important role in osteoblast formation , maturation , and survival . Here , we report the effects of recombinant human parathyroid hormone ( 1 - 34 ) [ rhPTH ( 1 - 34 ) ] , a bone formation-stimulating agent , and elcatonin on plasma SPARC levels in patients with osteoporosis . The rhPTH ( 1 - 34 ) treatment significantly increased plasma SPARC levels , and the change of plasma SPARC correlated positively with changes of lumbar bone mineral density ( BMD ) at L2–L4 . These results unveil that SPARC may be a novel marker related to the regulation of bone formation . Introduction rhPTH ( 1 - 34 ) is known to influence osteoclast maturation and activity through modulation of osteoblast-derived cytokines . SPARC is the most abundant noncollagenous extracellular matrix protein in the bone . So far , however , no study has reported the effects of rhPTH ( 1 - 34 ) administration on plasma SPARC levels in patients with osteoporosis . The purpose of this study was to compare the response of SPARC and BMD to rhPTH ( 1 - 34 ) and elcatonin in postmenopausal women with osteoporosis . Methods Women were r and omized to either once-daily subcutaneous injection of rhPTH ( 1 - 34 ) ( 20 μg , N = 89 ) or once-weekly intramuscular injection of elcatonin ( 200 U , N = 35 ) for 12 months . Plasma biochemical markers of bone turnover and BMD were measured at baseline , 6 and 12 months after treatment . Results At baseline , plasma SPARC levels correlated positively with lumbar spine BMD in all patients ( r = 0.45 , p = 0.001 ) . Compared with baseline , at 12 months , rhPTH ( 1 - 34 ) significantly increased lumbar spine BMD and plasma SPARC levels ( p = 0.008 and p = 0.001 , respectively ) , whereas elcatonin was ineffective . More importantly , the changes of plasma SPARC correlated positively with changes of lumbar BMD at L2–L4 ( r = 0.47 , p = 0.001 ) in the rhPTH (1 - 34)-treated group , but not in the elcatonin group . Conclusion The increase in plasma SPARC levels during the rhPTH ( 1 - 34 ) treatment may have contributed to the anabolic effect on bone formation , and SPARC may be a novel marker related to the regulation of bone formation A total of 104 postmenopausal women were r and omly assigned to different therapeutic regimens : ( a ) calcitonin , ( b ) estrogen/progestogen ( HRT ) plus calcitonin , ( c ) estrogen/progestogen ( HRT ) , ( d ) and the control group . The bone mass of the lumbar vertebrae of all patients was assessed with a dual beam photon absorptiometer ( Norl and GD 153 ) . The 73 patients who completed the 1-yr study showed that postmenopausal bone loss could be prevented by either estrogen/progestogen ( HRT ) or calcitonin . In addition , the combination of hormonal replacement therapy and calcitonin not only prevented post-menopausal bone loss but result ed in a significant 10 % gain in bone mass ( P < 0.001 ) OBJECTIVE To compare the clinical efficacy and safety between recombinant human parathyroid hormone ( rhPTH ) ( 1 - 34 ) and elcatonin in the treatment of postmenopausal women with osteoporosis in China . METHODS This 6 month , multicenter , r and omized and controlled study enrolled 205 postmenopausal women with osteoporosis . They were r and omized to receive either rhPTH ( 1 - 34 ) 20 µg ( 200 U ) daily or elcatonin 20 U weekly . Lumbar spine ( L1 - 4 ) and femoral neck bone mineral density ( BMD ) and biochemical markers of bone turnover were measured . In the meantime adverse events were recorded . RESULTS The results showed that both rhPTH ( 1 - 34 ) and elcatonin increased L1 - 4 BMD significantly at the endpoint of the study , but femoral neck BMD did not change significantly . From baseline to endpoint , BMD of L1 - 4 and femoral neck in the rhPTH ( 1 - 34 ) group increased by 5.51 % ( P<0.01 ) and 0.65 % ( P>0.05 ) , but BMD of L1 - 4 and femoral neck in elcatonin group increased by 1.55 % ( P<0.05 ) and 0.11 % ( P>0.05 ) . Moreover , the rhPTH ( 1 - 34 ) group had better improvement in L1 - 4 BMD than the elcatonin group at 3 , 6 months , but there was no difference of BMD in these two groups with regard to femoral neck . There were greater mean increases of the bone markers in the rhPTH ( 1 - 34 ) group than those in the elcatonin group at 3 , 6 months [ serum bone-specific alkaline phosphatase ( BSAP ) 36.79 % vs 0.31 % ; 92.42 % vs -0.17 % ; the ratio of urine N-telopeptide of type I collagen and creatinine ( NTX/Cr ) 48.91 % vs -5.32 % ; 68.82 % vs -10.86 % ] . Both kinds of treatment were well tolerated and there were no differences between the two groups in the rates of adverse events and serious adverse events . CONCLUSION It is concluded that rhPTH ( 1 - 34 ) has more positive effects on bone formation than elcatonin as shown by the greater increments of L1 - 4 BMD and bone formation markers and the less occurrence of adverse events as well as no significant change in hepatic , renal or hemopoietic function BACKGROUND Recombinant human parathyroid hormone ( 1 - 34 ) ( rhPTH ( 1 - 34 ) ) given by injection is a new seventh class drug of biological products , which is prepared by adopting gene recombination technique . rhPTH ( 1 - 34 ) is mainly used to treat osteoporosis , especially for postmenopausal women . This study compared the clinical efficacy and safety of rhPTH ( 1 - 34 ) with elcatonin for treating postmenopausal women with osteoporosis in 11 urban areas of China . METHODS Two hundred and five women with osteoporosis were enrolled in a 6-month , multicenter , r and omized , controlled study . They were r and omized to receive either rhPTH ( 1 - 34 ) 20 microg ( 200 U ) daily or elcatonin 20 U weekly . Lumbar spine ( L1 - 4 ) and femoral neck bone mineral density ( BMD ) , as well as biochemical markers of bone turnover were measured . Adverse events were recorded . RESULTS rhPTH ( 1 - 34 ) increased lumbar BMD significantly more than did elcatonin at 3 months and 6 months ( 2.38 % vs 0.59 % , P < 0.05 ; 5.51 % vs 1.55 % , P < 0.01 ) , but there were no significant increases of BMD in these two groups at femoral neck . There were larger mean increases in bone markers in the rhPTH ( 1 - 34 ) group than in the elcatonin group at 3 months and 6 months ( serum bone-specific alkaline phosphatase ( BSAP ) 36.79 % vs 0.31 % ; 92.42 % vs -0.17 % ; urinary N-telopeptide/creatinine ( NTX/Cr ) 48.91 % vs -5.32 % ; 68.82 % vs -10.86 % ) . Both treatments were well tolerated and there were no significant differences detected between the two groups in the proportion of any adverse events and any serious adverse events ( 67.0 % vs 59.0 % ; 0 vs 0 ) . CONCLUSIONS rhPTH ( 1 - 34 ) has more positive effects on bone formation , as shown by the larger increments of lumbar BMD and bone formation markers , than elcatonin , with only mild adverse events and no significant change in the liver , kidney or hematological indices Abstract Objective : Very few reports have described changes in bone mineral density ( BMD ) with long-term , once weekly administration of elcatonin , and its effects in reducing incident fractures remain unverified . Therefore , the efficacy and safety of once weekly elcatonin were examined over a 3 year period . Methods : This was a multicenter , double-blinded , r and omized , placebo-controlled study . Postmenopausal women with primary osteoporosis received either 20 units of elcatonin ( EL group , n = 433 ) or placebo ( P group , n = 436 ) once a week for 144 weeks ( 3 years ) intramuscularly . The primary endpoint was the incidence of new vertebral fractures at 24 , 48 , 72 , 96 , 120 , and 144 weeks after the start . Secondary endpoints were the incidence of non-vertebral fractures , changes in lumbar , hip total and femoral neck BMD , and the incidence of adverse drug reactions ( ADRs ) . Results : No significant reduction in the incidence of new vertebral fractures was found in the EL group . The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration . Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD , no significant differences were observed between groups . The incidence of ADRs was significantly greater in the EL group , although these have all been previously reported and no new safety concerns were identified . Conclusions : Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems , but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated BACKGROUND Evidence related to the effectiveness of combination drug therapy for the treatment of osteoporosis is currently considered insufficient . Therefore , this study was performed to clarify the effects of monotherapy , and combination therapy , with a bisphosphonate ( minodronic acid hydrate ) , a bone resorption inhibitor , and calcitonin ( elcatonin ) , which is effective for the alleviation of pain due to vertebral fractures in osteoporotic patients . METHODS Study participants comprised of 51 female subjects with post-menopausal osteoporosis , whose main complaint was acute lower back pain caused by vertebral fractures . Subjects were r and omly allocated into three groups and then administered with either intramuscular injections of elcatonin at a dose of 20 units weekly , minodronic acid hydrate at a dose of 1 mg daily , or a combination of these two drugs . As primary endpoints , time-dependent changes in levels of pain were assessed using a visual analog scale from baseline to 6 months of duration . In addition , we examined the effects of monotherapies , and a combination therapy on bone resorption , with changes in bone mineral density at 4 sites and advanced hip assessment parameters from baseline to 6 months . A two-tailed significance level of 5 % was used for hypothesis testing . RESULTS Elcatonin monotherapy showed some alleviation of pain immediately after any vertebral fractures , which was more than in the minodronic acid hydrate monotherapy group . In addition , the minodronic acid hydrate monotherapy group experienced more effective inhibited bone resorption than the elcatonin monotherapy group . In the combination therapy , the efficacy for alleviating pain and inhibiting bone resorption was equivalent to the effect observed in the elcatonin and minodronic acid hydrate monotherapy groups respectively , with further improved values of bone mineral density observed in the femoral neck and lumbar vertebrae , and in parameters of advanced hip assessment compared with both monotherapy groups . CONCLUSIONS Combination therapy with elcatonin and minodronic acid hydrate appears to be an effective treatment for osteoporosis patients with lower back pain , caused by fresh vertebral fractures Calcitonin has been reported to reduce acute and chronic back pain in osteoporotic patients . The additive effect of calcitonin with a bisphosphonate on chronic back pain remains unclear . The purpose of this study was to evaluate the effect of combining elcatonin ( eel calcitonin ) with risedronate for patients with chronic back pain . Forty-five postmenopausal women diagnosed as having osteoporosis with chronic back pain persisting for more than 3 months , after excluding women with fresh vertebral fractures within the last 6 months , were r and omly allocated to a risedronate group ( risedronate alone , n = 22 ) and a combined group ( risedronate and elcatonin , n = 23 ) . The study period was 6 months . Pain was evaluated with a visual analogue scale ( VAS ) and the Rol and -Morris question naire ( RDQ ) . Back extensor strength , bone mineral density , and quality of life on the SF-36 and the Japanese osteoporosis quality of life score were also evaluated . Significant improvements were found in the combined group for VAS at final follow-up compared with baseline and 3 months , mental health status on the SF-36 , and JOQOL domains for back pain and general health . The JOQOL domain for back pain improved significantly , but no change was found in the VAS or other domains in the risedronate group . Bone mineral density increased significantly in the two groups , but no significant difference was found between the groups . Back extensor strength did not change in both groups . In conclusion , the use of elcatonin in addition to risedronate for more than 3 months reduced chronic back pain . The additional therapy of risedronate with elcatonin may be a useful and practical choice for the treatment of osteoporosis with chronic back pain persisting more than 3 months

Conclusion : With best possible evidence , it can be inferred that nonsurgical periodontal therapy is safe during pregnancy .

Background and Objectives : The poor maternal oral health in the pregnancy has an impact on the fetus through the oral-systemic link . Various studies have proven the relationship between poor maternal oral health and the occurrence of adverse pregnancy outcomes . Hence , periodontal therapy becomes indispensable during pregnancy . Previous systematic review s and meta- analysis conducted to assess the influence of periodontal therapy on the occurrence of adverse pregnancy outcomes have shown inconsistent results . Hence , we conducted the present review to assess the influence of periodontal therapy on the occurrence of adverse pregnancy outcomes including the studies published till date .

Objectives The aim of this study was to evaluate the effects of non-surgical treatment of periodontal disease during the second trimester of gestation on adverse pregnancy outcomes . Material and Methods Pregnant patients during the 1st and 2nd trimesters at antenatal care in a Public Health Center were divided into 2 groups : NIG – " no intervention " ( n=17 ) or IG- " intervention " ( n=16 ) . IG patients were su bmi tted to a non-surgical periodontal treatment performed by a single periodontist consisting of scaling and root planning ( SRP ) , professional prophylaxis ( PROPH ) and oral hygiene instruction ( OHI ) . NIG received PROPH and OHI during pregnancy and were referred for treatment after delivery . Periodontal evaluation was performed by a single trained examiner , blinded to periodontal treatment , according to probing depth ( PD ) , clinical attachment level ( CAL ) , plaque index ( PI ) and sulcular bleeding index ( SBI ) at baseline and 35 gestational weeks-28 days post-partum . Primary adverse pregnancy outcomes were preterm birth ( < 37 weeks ) , low birth weight ( < 2.5 kg ) , late abortion ( 14 - 24 weeks ) or abortion ( < 14 weeks ) . The results obtained were statistically evaluated according to OR , unpaired t test and paired t test at 5 % significance level . Results No significant differences were observed between groups at baseline examination . Periodontal treatment result ed in stabilization of CAL and PI ( p>0.05 ) at IG and worsening of all periodontal parameters at NIG ( p<0.0001 ) , except for PI . Significant differences in periodontal conditions of IG and NIG were observed at 2nd examination ( p<0.001 ) . The rate of adverse pregnancy outcomes was 47.05 % in NIG and 6.25 % in IG . Periodontal treatment during pregnancy was associated to a decreased risk of developing adverse pregnancy outcomes [ OR=13.50 ; CI : 1.47 - 123.45 ; p=0.02 ] . Conclusions Periodontal treatment during the second trimester of gestation contributes to decrease adverse pregnancy outcomes BACKGROUND One hypothesis to explain the association between periodontal disease ( PD ) preterm/low birth weight ( PT/LBW ) is that PT/LBW may be indirectly mediated through translocation of bacteria or bacterial products in the systemic circulation . Transient bacteremias occur in subjects with marginal periodontitis or with gingivitis , and it is possible that bacteria and their products may reach the placental membranes hematogenously and provide the inflammatory effect to induce preterm labor . The effect of gingivitis as a potential risk factor for PT/LBW has still not been studied . A r and omized controlled trial was undertaken to determine the effect of routine plaque control and scaling on the pregnancy outcomes in women with gingivitis . METHODS Eight hundred seventy ( 870 ) pregnant women with gingivitis , aged 18 to 42 , were enrolled while receiving prenatal care in Santiago , Chile . Women were r and omly assigned in a two-to-one fashion to either a treatment group ( N = 580 ) , receiving periodontal treatment before 28 weeks of gestation or to a control group ( N = 290 ) , receiving periodontal treatment after delivery . Periodontal therapy consisted of plaque control , scaling , and daily rinsing with 0.12 % clorhexidine . Maintenance therapy was provided every 2 to 3 weeks until delivery , and consisted of oral hygiene instruction and supragingival plaque removal by instrumentation , as needed . The primary outcomes assessed were delivery at less than 37 weeks of gestation or an infant weighing less than 2,500 g. RESULTS Of the 870 women enrolled , 36 women ( 27 in the treatment group and nine in the control group ) were excluded from the analyses for different reasons . The incidence of PT/LBW in the treatment group was 2.14 % ( 12/560 ) and in the control group , 6.71 % ( 19/283 ) ( odds ratio [ OR ] 3.26 ; 95 % confidence interval [ CI ] 1.56 to 6.83 ; P = 0.0009 ) . Multivariate logistic regression analysis showed that , after adjusting for several known risk factors for PT/LBW , women with gingivitis were at a higher risk of PT/LBW than women who received periodontal treatment ( OR 2.76 ; 95%CI 1.29 to 5.88 ; P = 0.008 ) . CONCLUSIONS Periodontal treatment significantly reduced the PT/LBW rate in this population of women with pregnancy-associated gingivitis . Within the limitions of this study , we conclude that gingivitis appears to be an independent risk factor for PT/LBW for this population Periodontal disease ( PD ) in pregnancy is associated with an increased risk of adverse pregnancy outcomes including miscarriage and preterm birth . Evidence exists that periodontal disease treatment may reduce inflammatory mediators in gingival crevicular fluid ( GCF ) and the risk of inflammation-associated pregnancy complications . The aim was to determine if periodontal disease treatment during mid-pregnancy alters local inflammation in GCF and has beneficial effects on clinical dental parameters . Eighty pregnant women with clinical ly diagnosed PD were recruited from a r and omised controlled trial on the treatment of periodontal disease in pregnancy conducted in Perth , Australia . The treatment group underwent intensive PD treatment ( 20 - 28 weeks ' GA ) , while the control group underwent the same treatment postnatally . GCF was collected at 20 and 28 weeks ' gestation and concentrations of cytokines determined by multiplex assay : IL-1β , IL-6 , IL-8 , IL-10 , IL-12p70 , IL-17 , TNF-α and MCP-1 . Periodontal treatment significantly reduced the GCF levels of IL-1β , IL-10 , IL-12p70 and IL-6 at 28 weeks ' GA compared with controls , while levels of MCP-1 , IL-8 and TNF-α exhibited a significant gestational age-dependent increase , but no treatment response . Post-treatment clinical parameters improved with significant reductions in bleeding on probing , clinical attachment loss , and probing depth . No changes in pregnancy-related outcomes were observed , although the severity of periodontal disease was significantly associated with an increased risk of infants born small for gestational age . PD treatment in pregnancy reduces the levels of some inflammatory mediators in the GCF and improves dental parameters , with no overt effects on pregnancy outcome Periodontitis has been associated with adverse pregnancy outcomes . Results from intervention studies are few and controversial . The present study assessed the effects of non-surgical periodontal treatment in the occurrence of adverse pregnancy outcomes . Two hundred forty-six eligible women were r and omly divided into two groups : periodontitis intervention ( n = 122 ; undergoing non-surgical treatment during gestation ) and periodontitis control ( n = 124 ; not treated during gestation ) . Univariate analysis was performed and estimates of relative risk were reported . Data from 225 women were analyzed . No differences for preterm birth ( p = 0.721 ) , low birth weight ( p = 0.198 ) , and preterm low birth weight ( p = 0.732 ) rates were observed . Relative risk estimates for preterm birth , low birth weight , and preterm low birth weight in the periodontitis intervention group were 0.915 ( 95 % CI 0.561–1.493 ) , 0.735 ( 95 % CI 0.459–1.179 ) , and 0.927 ( 0.601–1.431 ) , respectively . Non-surgical periodontal treatment during the second semester of gestation did not reduce the risk for preterm birth , low birth weight , and preterm low birth weight Considering the high prevalence of preterm birth ( PTB ) and low birth weight ( LBW ) and their complications as well as the role played by periodontal disease in their incidence and the lack of any report of periodontal therapy on these problems in Iran , the goal of the present research was to determine the effects of periodontal treatment on PLBW incidence among women with moderate or advanced periodontitis who were referred to Javaheri hospital ( 2004 - 2005 ) . This clinical trial research was conducted on 30 pregnant women age ranging from 18 - 35 years old , with moderate or advanced periodontitis . Fifteen subjects r and omly underwent the first phase of periodontal treatment including scaling , root planning and the use of 0.2 % chlorhexidine mouth rinse for one week . None of these steps were taken for the controls . After necessary follow ups , the effect of periodontal treatment on birth term and birth weight were analyzed statistically . This research was conducted on 30 subjects , 15 controls and 15 cases in study group . In the control group , the observed rate of PLBW was 26.7 % whereas among periodontally treated group , phase I , PLBW infant was not observed ( P < 0.05 ) . Infants birth weight were ( 3059.3 - 389.7 ) gms in study group and ( 3371 - 394.2 ) gms in the control group and respectively ( P < 0.05 ) . Periodontal therapy , phase I , results in a reduction in PLBW incidence rate . Therefore , the application of such a simple method among periodontally diseased pregnant women is recommended BACKGROUND The purpose of the present study is to investigate the potential link between maternal periodontitis and pregnancy outcomes , including preterm birth ( < 37 weeks ) and low birth weight ( < 2,500 g ) . METHODS Ninety nine pregnant females with mild/moderate periodontitis were r and omly allocated to a control ( n = 50 ) or test ( n = 49 ) group . Test group participants received intrapregnancy non-surgical periodontal treatment , whereas this was deferred until after delivery for controls . Demographic and baseline clinical data were obtained for all participants at initial assessment pretreatment . Clinical data were rerecorded for test participants at review 8 weeks after treatment . Birth outcomes were completed at delivery by midwives who also collected cord blood sample s when possible ; the latter were analyzed to determine the presence/levels of cytokines interleukin (IL)-1β , IL-6 , and IL-8 . All data were analyzed on an intention-to-treat basis using appropriate statistical tests . RESULTS R and om allocation of participants result ed in well-balanced control and test groups . All test group participants and all but one control participant gave birth to a live infant . No significant differences were detected between control and test groups with regard to birth outcome measures of birth weight and gestational age or in relation to cytokine prevalence/levels . CONCLUSION Intrapregnancy non-surgical periodontal treatment , completed at 20 to 24 weeks , did not reduce the risk of preterm , low-birth-weight delivery in this population BACKGROUND Few studies have examined the potential effects of periodontal treatment during pregnancy on pregnancy outcomes , periodontal status , and inflammatory biomarkers . METHODS A r and omized , delayed-treatment , controlled pilot trial was conducted to evaluate the effects of second-trimester scaling and root planing and the use of a sonic toothbrush on the rate of preterm delivery ( < 37 weeks gestation ) . Secondary outcome measures included changes in periodontal status , levels of eight oral pathogens , levels of gingival crevicular fluid ( GCF ) interleukin-1beta ( IL-1beta ) , prostagl and in E(2 ) ( PGE(2 ) ) , 8-isoprostane ( 8-iso ) , and IL-6 , and serum levels of IL-6 , soluble intercellular adhesion molecule 1 ( sICAM1 ) , 8-isoprostane , soluble glycoprotein 130 ( sGP130 ) , IL-6 soluble receptor ( IL-6sr ) , and C-reactive protein ( CRP ) . Logistic regression models were used to test for effects of treatment on preterm delivery . Secondary outcomes were analyzed by analysis of covariance adjusting for subject baseline values . RESULTS Periodontal intervention result ed in a significantly decreased incidence odds ratio ( OR ) for preterm delivery ( OR = 0.26 ; 95 % confidence interval = 0.08 to 0.85 ) , adjusting for baseline periodontal status which was unbalanced after r and omization . Pregnancy without periodontal treatment was associated with significant increases in probing depths , plaque scores , GCF IL-1beta , and GCF IL-6 levels . Intervention result ed in significant improvements in clinical status ( attachment level , probing depth , plaque , gingivitis , and bleeding on probing scores ) and significant decreases in levels of Prevotella nigrescens and Prevotella intermedia , serum IL-6sr , and GCF IL-1beta . CONCLUSIONS Results from this pilot study ( 67 subjects ) provide further evidence supporting the potential benefits of periodontal treatment on pregnancy outcomes . Treatment was safe , improved periodontal health , and prevented periodontal disease progression . Preliminary data show a 3.8-fold reduction in the rate of preterm delivery , a decrease in periodontal pathogen load , and a decrease in both GCF IL-1beta and serum markers of IL-6 response . However , further studies will be needed to substantiate these early findings BACKGROUND A recent clinical trial ( Obstetrics and Periodontal Therapy [ OPT ] Study ) demonstrated that periodontal therapy during pregnancy improved periodontal outcomes but failed to impact preterm birth . The present study evaluated seven target bacteria , Aggregatibacter actinomycetemcomitans ( previously Actinobacillus actinomycetemcomitans ) , Porphyromonas gingivalis , Treponema denticola , Tannerella forsythia ( previously T. forsythensis ) , Prevotella intermedia , Campylobacter rectus , and Fusobacterium nucleatum , in subgingival dental plaque of pregnant women in the OPT Study and their association with birth outcomes . METHODS Pregnant women were r and omly assigned to receive periodontal treatment before 21 weeks ' gestation or after delivery . Subgingival plaque was sample d at baseline ( 13 to 16 weeks ; 6 days of gestation ) and at 29 to 32 weeks . We analyzed subgingival plaque sample s from women who experienced fetal loss , delivered a live preterm infant ( preterm women ) , or delivered a full-term infant ( full-term women ) . Sample s were analyzed using quantitative polymerase chain reaction . Associations between preterm birth and bacterial counts and percentages were tested using multiple linear regression . RESULTS No significant differences were observed at baseline between preterm and full-term women for any measured bacterial species or group of species , after accounting for multiple comparisons . Changes in bacterial counts and proportions during pregnancy also were not associated with birth outcomes . In full-term and preterm women , periodontal therapy significantly reduced ( P < 0.01 ) counts of all target species except for A. actinomycetemcomitans . CONCLUSIONS In pregnant women with periodontitis , non-surgical periodontal therapy significantly reduced levels of periodontal pathogens . Baseline levels of selected periodontal pathogens or changes in these bacteria result ing from therapy were not associated with preterm birth BACKGROUND Preterm low birth weight was reported to be related to periodontal infections that might influence the fetus-placenta complex . The aim of this study was to provide periodontal treatment for pregnant women and to evaluate if this treatment can interfere with pregnancy duration and weight of the newborn . METHODS The sample consisted of 450 pregnant women who were under prenatal care at a polyclinic in Três Corações , Brazil . Women with risk factors , such as systemic alterations ( ischemic cardiopathy , hypertension , tuberculosis , diabetes , cancer , anemia , seizure , psychopathology , urinary tract infection , sexually transmitted diseases , asthma , and human immunodeficiency virus ) , and /or users of alcohol , tobacco , and drugs were excluded from the study . Data related to age , socioeconomic level , race , marital status , number of previous pregnancies , and previous preterm delivery also were evaluated . Initially , the sample was divided into two groups : 122 healthy patients ( group 1 ) and 328 patients with periodontal disease ( group 2 ) . In group 2 , 266 patients underwent treatment and 62 patients dropped out . After mothers gave birth , pregnancy duration and the weight of all infants were analyzed and recorded . RESULTS There was no statistical difference between the healthy and treated groups . However , there was a difference in the non-treated group , with a 79 % incidence of preterm low birth weight . Educational level , previous preterm birth , and periodontal disease were related significantly to preterm delivery ( P < 0.001 ) . CONCLUSION Periodontal disease was related significantly to preterm low birth weight Objective This r and omized controlled clinical trial was carried out to assess the effect of comprehensive nonsurgical periodontal treatment and strict plaque control performed during pregnancy on the reduction of preterm and /or low birth weight rates ( PTLBW ) . Material and methods Three hundred and three women were r and omly allocated to receive periodontal treatment either during pregnancy ( n = 147 , test group ) or after delivery ( n = 156 , control group ) . During pregnancy , the control group received only one session of supragingival scaling and oral hygiene instruction . In contrast , the test group received comprehensive periodontal treatment including multiple sessions of scaling and root planing , oral hygiene instructions , and frequent maintenance visits . Results At baseline , periodontal inflammation was observed in approximately 50 % of sites and attachment loss affected < 15 % of sites . Compared to controls , women in the test group had significant reductions in the percentage of sites with plaque ( 48.5 % vs. 10.3 % , p < 0.001 ) , gingival bleeding ( 23.3 % vs. 2.5 % , p < 0.001 ) , calculus ( 21.3 % vs. 4.1 % , p < 0.001 ) , bleeding on probing ( 38.1 % vs. 2.6 % , p < 0.001 ) and probing depth ≥3 mm ( 19.97 % vs. −2.45 % , p < 0.001 ) . No significant differences were observed between the groups in the occurrence of PT ( 11.7 % vs. 9.1 % , p = 0.57 ) , LBW ( 5.6 % vs. 4.1 % , p = 0.59 ) , and PTLBW ( 4.15 % vs. 2.60 % , p = 0.53 ) . Conclusions Comprehensive periodontal treatment and strict plaque control significantly improved periodontal health ; however , no reduction of PTLBW rates was observed . Thus , remaining periodontal inflammation posttreatment can not explain the lack of effect of periodontal treatment on PTLBW . Clinical relevance This study demonstrated that periodontal diseases may be successfully treated during pregnancy . Our results do not support a potential beneficial effect of periodontal treatment on PTLBW OBJECTIVE : To investigate whether treating periodontal disease prevents preterm birth and other major complications of pregnancy . METHODS : This single-center trial was conducted across six obstetric sites in metropolitan Perth , Western Australia . Pregnant women identified by history to be at risk ( n=3,737 ) were examined for periodontal disease . Approximately 1,000 women with periodontal disease were allocated at r and om to receive periodontal treatment commencing around 20 weeks of gestation ( n=542 ) or 6 weeks after the pregnancy was completed ( controls ; n=540 ) . The treatment included mechanical removal of oral biofilms together with oral hygiene instruction and motivation at a minimum of three weekly visits , with further visits if required . RESULTS : There were no differences between the control and treatment groups in preterm birth ( 9.3 % compared with 9.7 % , odds ratio [ OR ] 1.05 , 95 % confidence interval [ CI 0.7–1.58 ] , P=.81 ) , birth weight ( 3,450 compared with 3,410 g , P=.12 ) , preeclampsia ( 4.1 % compared with 3.4 % , OR 0.82 , 95 % CI 0.44–1.56 , P=.55 ) , or other obstetric endpoints . There were four unexplained stillbirths in the control group and no pregnancy losses in the treated group ( P=.12 ) . Measures of fetal and neonatal well-being were similar in the two groups , including abnormalities in fetal heart rate recordings ( P=.26 ) , umbilical artery flow studies ( P=.96 ) , and umbilical artery blood gas values ( P=.37 ) . The periodontal treatment was highly successful in improving health of the gums ( P<.01 ) . CONCLUSION : The evidence provided by the present study does not support the hypothesis that treatment of periodontal disease during pregnancy in this population prevents preterm birth , fetal growth restriction , or preeclampsia . Periodontal treatment was not hazardous to the women or their pregnancies . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00133926 . LEVEL OF EVIDENCE : BACKGROUND There is convincing evidence to suggest that infections affecting the mother during pregnancy may produce alterations in the normal cytokine- and hormone-regulated gestation , which could result in preterm labor , premature rupture of membranes , and preterm birth ( PTB ) . Studies in the late 1990s associated periodontitis with preterm low birth weight ( PLBW ) deliveries , and this may have similar pathogenic mechanisms as other maternal infections . This study determined the effect of non-surgical periodontal therapy on pregnancy outcome . METHODS A total of 200 pregnant women with periodontitis were r and omly assigned to treatment and control groups . Detailed data about previous and current pregnancies were obtained . All women received a full-mouth periodontal examination , including oral hygiene index-simplified , bleeding index , and clinical attachment level . The women in the treatment group received non-surgical periodontal therapy during the gestational period , and those in the control group received periodontal treatment after delivery . Periodontal therapy included plaque control instructions and scaling and root planing performed under local anesthesia . The outcome measures assessed were gestational age and birth weight of the infant . PTB was recorded when delivery occurred at < 37 weeks of gestation , and low birth weight ( LBW ) was recorded when the infant weighed<2,500 g. RESULTS There were 53 PTBs in the treatment group and 68 PTBs in the control group . Twenty-six LBW infants were recorded in the treatment group , and 48 LBW infants were noted in the control group . The mean gestational ages were 33.8+/-2.8 weeks and 32.7+/-2.8 weeks in the treatment and control groups , respectively . The difference was statistically significant at P<0.006 . The mean birth weight was 2,565.3+/-331.2 g in the treatment group and 2,459.6+/-380.7 g in the control group , with the difference being statistically significant at P<0.044 . A multiple regression model showed a significant effect of periodontal treatment on birth outcomes . CONCLUSIONS Non-surgical periodontal therapy can reduce the risk for preterm births in mothers who are affected by periodontitis . Additional multicentered , r and omized , controlled clinical trials are required to confirm this link between periodontitis and PLBW BACKGROUND The purpose s of this study were to determine : 1 ) if periodontal treatment in pregnant women before 21 weeks of gestation alters levels of inflammatory mediators in serum ; and 2 ) if changes in these mediators are associated with birth outcomes . METHODS A total of 823 pregnant women with periodontitis were r and omly assigned to receive scaling and root planing before 21 weeks of gestation or after delivery . Serum obtained between 13 and 16 weeks , 6 days ( study baseline ) and 29 to 32 weeks of gestation was analyzed for C-reactive protein ; prostagl and in E(2 ) ; matrix metalloproteinase-9 ; fibrinogen ; endotoxin ; interleukin (IL)-1 beta , -6 , and -8 , and tumor necrosis factor-alpha . Cox regression , multiple linear regression , and the t , chi(2 ) , and Fisher exact tests were used to examine associations among the biomarkers , periodontal treatment , and gestational age at delivery and birth weight . RESULTS A total of 796 women had baseline serum data , and 620 women had baseline and follow-up serum and birth data . Periodontal treatment did not significantly alter the level of any biomarker ( P > 0.05 ) . Neither baseline levels nor the change from baseline in any biomarker were significantly associated with preterm birth or infant birth weight ( P > 0.05 ) . In treatment subjects , the change in endotoxin was negatively associated with the change in probing depth ( P < 0.05 ) . CONCLUSIONS Non-surgical mechanical periodontal treatment in pregnant women , delivered before 21 weeks of gestation , did not reduce systemic ( serum ) markers of inflammation . In pregnant women with periodontitis , levels of these markers at 13 to 17 weeks and 29 to 32 weeks of gestation were not associated with infant birth weight or a risk for preterm birth BACKGROUND Recent studies have suggested that periodontal disease is a risk factor for preterm low birth weight ( PLBW ) . A r and omized controlled trial was undertaken to help further evaluate the proposed association between periodontal disease and PLBW . METHODS Four hundred pregnant women with periodontal disease , aged 18 to 35 , were enrolled while receiving prenatal care in Santiago , Chile . Women were r and omly assigned to either an experimental group ( n = 200 ) , which received periodontal treatment before 28 weeks of gestation or to a control group ( n = 200 ) which received periodontal treatment after delivery . Previous and current pregnancies and known risk factors were obtained from patient medical records and interviews . The primary outcome assessed was the delivery at less than 37 weeks of gestation or an infant weighing less than 2,500 g. RESULTS Of the 400 women enrolled , 49 were excluded from the analyses for different reasons . The incidence of PLBW in the treatment group was 1.84 % ( 3/163 ) and in the control group was 10.11 % ( 19/188 ) , ( odds ratio [ OR ] 5.49 , 95 % confidence interval [ CI ] 1.65 to 18.22 , P= 0.001 ) . Multivariate logistic regression analysis showed that periodontal disease was the strongest factor related to PLBW ( OR 4.70 , 95 % CI 1.29 to 17.13 ) . Other factors significantly associated with such deliveries were : previous PLBW ( OR 3.98 , 95 % CI 1.11 to 14.21 ) , less than 6 prenatal visits ( OR 3.70 , 95 % Cl 1.46 to 9.38 ) , and maternal low weight gain ( OR 3.42 , 95 % CI 1.16 to 10.03 ) . CONCLUSIONS Periodontal disease appears to be an independent risk factor for PLBW . Periodontal therapy significantly reduces the rates of PLBW in this population of women with periodontal disease BACKGROUND Previous case-control and prospect i ve studies have shown an association between the presence of periodontitis and the risk of preterm birth ( PTB ) . The goal of this pilot trial was to determine the feasibility of conducting a trial to determine whether treatment of periodontitis reduces the risk of spontaneous preterm birth ( SPTB ) . METHODS Three hundred sixty-six ( 366 ) women with periodontitis between 21 and 25 weeks ' gestation were recruited and r and omized to one of three treatment groups with stratification on the following two factors : 1 ) previous SPTB at < 35 weeks and 2 ) body mass index < 19.8 or bacterial vaginosis as assessed by Gram stain . The treatment groups consisted of : 1 ) dental prophylaxis plus placebo capsule ; 2 ) scaling and root planing ( SRP ) plus placebo capsule ; and 3 ) SRP plus metronidazole capsule ( 250 mg t.i.d . for one week ) . An additional group of 723 pregnant women meeting the same criteria for periodontitis and enrolled in a prospect i ve study served as an untreated reference group . RESULTS The rate of PTB at < 35 weeks was 4.9 % in the prophylaxis group , compared to 3.3 % in the SRP plus metronidazole group and 0.8 % in the SRP plus placebo group ( P = 0.75 and 0.12 , respectively ) . The rate of PTB at < 35 weeks was 6.3 % in the reference group . CONCLUSIONS This trial indicates that performing SRP in pregnant women with periodontitis may reduce PTB in this population . Adjunctive metronidazole therapy did not improve pregnancy outcome . Larger trials will be needed to achieve statistical significance , especially at less than 35 weeks gestational age t d p reterm birth is one of the most complicated and challenging research issues in perinatal medicine . Despite decades f scientific inquiry , the preterm birth rate has remained contant or increased annually in the United States . Nearly 12 % of ll deliveries occur at 37 weeks of gestation . Spontaneous reterm birth is a complex and heterogeneous public health roblem with multiple risk factors . Some of these risk factors re social ( such as maternal race/ethnicity and poverty ) , and ome are individual ( such as underweight , tobacco use , and aternal infection ) . Many of these risk factors occur in comination , which complicates preventive strategies . Periodontal disease is an infectious stimulus that has been ssociated with preterm birth . Periodontal disease is a Gramegative anaerobic infection of the mouth that occurs in 40 % f pregnant women . Infection and subsequent inflammation f the gingival and local support attachments of the teeth can esult in tissue , bone , and , ultimately , tooth loss . This destrucive process involves both direct tissue damage from plaque acterial products and indirect damage through bacterial stimlation of local and systemic inflammatory and immune reponses . In a recent meta analysis of the association between aternal periodontal disease and preterm birth , Vergnes and ixou examined 17 studies and reported a pooled estimate dds ratio for preterm birth of 2.83 ( 95 % confidence interval CI ] , 1.95– 4.10 ; P .0001 ) . Polyzos et al conducted a met analysis of r and omized clinical trials to determine whether eriodontal treatment during pregnancy reduced preterm irth . After examination of 7 trials that included 2663 patients 1491 patients were assigned r and omly to periodontal treatent and 1172 patients were assigned to no treatment ) , they ound that periodontal treatment during pregnancy result ed in ignificantly lower preterm birth ( odds ratio , 0.55 ; 95 % CI , .35– 0.86 ; P .008 ) . Although these data support a relationship between materal periodontal disease and preterm birth , several studies

Conclusions Based upon the current systematic review , LLLT ( PBM ) may be considered an effective treatment approach for women with BCRL .

Background Breast cancer related lymphedema ( BCRL ) is a prevalent complication secondary to cancer treatments which significantly impacts the physical and psychological health of breast cancer survivors . Previous research shows increasing use of low level laser therapy ( LLLT ) , now commonly referred to as photobiomodulation ( PBM ) therapy , for BCRL . This systematic review evaluated the effectiveness of LLLT ( PBM ) in the management of BCRL .

Various studies have shown biostimulation effects of laser irradiation by producing metabolic changes within the cells . Little is known about the biological effect of laser irradiation on the oral tissues . Among the many physiological effects , it is important to recognize that low-level laser therapy ( LLLT ) may affect release of growth factors from fibroblasts . Therefore , the aim of the present study was to determine whether the laser irradiation can enhance the release of basic fibroblast growth factor ( bFGF ) , insulin-like growth factor-1 ( IGF-1 ) , and receptor of IGF-1 ( IGFBP3 ) from human gingival fibroblasts ( HGF ) . The number of all sample s in the study were 30 , and the sample s were r and omly divided into three equal groups ; In the first group ( single dose group ) , HGF were irradiated with laser energy of 685 nm , for 140 s , 2 J/cm2 for one time , and in the second group , energy at the same dose was applied for two consecutive days ( double dose group ) . The third group served as nonirradiated control group . Proliferation , viability , and bFGF , IGF-1 , IGFBP3 analysis of control and irradiated cultures were compared with each other . Both of the irradiated groups revealed higher proliferation and viability in comparison to the control group . Comparison of the single-dose group with the control group revealed statistically significant increases in bFGF ( p < 0.01 ) and IGF-1 ( p < 0.01 ) , but IGFBP3 increased insignificantly ( p > 0.05 ) . When the double dose group was compared with the control group , significant increases were determined in all of the parameters ( p < 0.01 ) . In the comparison of the differences between the two irradiated groups ( one dose and two doses ) , none of the parameters displayed any statistically significant difference ( p > 0.05 ) . In both of the laser groups , LLLT increased the cell proliferation and cell viability . The results of this study showed that LLLT increased the proliferation of HGF cells and release of bFGF , IGF-1 , and IGFBP3 from these cells . LLLT may play an important role in periodontal wound healing and regeneration by enhancing the production of the growth factors Evidence -based practice involves the use of evidence from systematic review s and r and omised controlled trials , but the extent of this evidence in physiotherapy has not previously been surveyed . The aim of this survey is to describe the quantity and quality of r and omised controlled trials and the quantity of systematic review s relevant to physiotherapy . The Physiotherapy Evidence Data base ( PEDro ) was search ed . The quality of trials was assessed with the PEDro scale . The search identified a total of 2,376 r and omised controlled trials and 332 systematic review s. The first trial was published in 1955 and the first review was published in 1982 . Since that time , the number of trials and review s has grown exponentially . The mean PEDro quality score has increased from 2.8 in trials published between 1955 and 1959 to 5.0 for trials published between 1995 and 1999 . There is a substantial body of evidence about the effects of physiotherapy . However , there remains scope for improvements in the quality of the conduct and reporting of clinical trials Objective : To compare the long-term efficacy of pneumatic compression and low-level laser therapies in the management of postmastectomy lymphoedema . Design : R and omized controlled trial . Setting : Department of Physical Medicine and Rehabilitation of Cukurova University , Turkey . Subjects : Forty-seven patients with postmastectomy lymphoedema were enrolled in the study . Interventions : Patients were r and omly allocated to pneumatic compression ( group I , n=24 ) and low-level laser ( group II , n=23 ) groups . Group I received 2 hours of compression therapy and group II received 20 minutes of laser therapy for four weeks . All patients were advised to perform daily limb exercises . Main measures : Demographic features , difference between sum of the circumferences of affected and unaffected limbs ( ▵ C ) , pain with visual analogue scale and grip strength were recorded . Results : Mean age of the patients was 48.3 ( 10.4 ) years . ▵ C decreased significantly at one , three and six months within both groups , and the decrease was still significant at month 12 only in group II ( P = 0.004 ) . Improvement of group II was greater than that of group I post treatment ( P = 0.04 ) and at month 12 after 12 months ( P = 0.02 ) . Pain was significantly reduced in group I only at posttreatment evaluation , whereas in group II it was significant post treatment and at follow-up visits . No significant difference was detected in pain scores between the two groups . Grip strength was improved in both groups , but the differences between groups were not significant . Conclusions : Patients in both groups improved after the interventions . Group II had better long-term results than group I. Low-level laser might be a useful modality in the treatment of postmastectomy lymphoedema The current study describes the results of a double blind , placebo‐controlled , r and omized , single crossover trial of the treatment of patients with postmastectomy lymphedema ( PML ) with low‐level laser therapy ( LLLT ) Abstract Background and Objective : As Light Emitting Diode ( LED ) devices are commercially introduced as an alternative for Low Level Laser ( LLL ) Therapy , the ability of LED in influencing wound healing processes at cellular level was examined . Study Design / Material s and Methods : Cultured fibroblasts were treated in a controlled , r and omized manner , during three consecutive days , either with an infrared LLL or with a LED light source emitting several wavelengths ( 950 nm , 660 nm and 570 nm ) and respective power outputs . Treatment duration varied in relation to varying surface energy densities ( radiant exposures ) . Results : Statistical analysis revealed a higher rate of proliferation ( p ≤ 0.001 ) in all irradiated cultures in comparison with the controls . Green light yielded a significantly higher number of cells , than red ( p ≤ 0.001 ) and infrared LED light ( p ≤ 0.001 ) and than the cultures irradiated with the LLL ( p ≤ 0.001 ) ; the red probe provided a higher increase ( p ≤ 0.001 ) than the infrared LED probe and than the LLL source . Conclusion : LED and LLL irradiation result ed in an increased fibroblast proliferation in vitro . This study therefore postulates possible stimulatory effects on wound healing in vivo at the applied dosimetric parameters The aim of this paper was to study the effects of low-level laser therapy ( LLLT ) in the treatment of postmastectomy lymphedema . Eleven women with unilateral postmastectomy lymphedema were enrolled in a double-blind controlled trial . Patients were r and omly assigned to laser and sham groups and received laser or placebo irradiation ( Ga – As laser device with a wavelength of 890 nm and fluence of 1.5 J/cm2 ) over the arm and axillary areas . Changes in patients ’ limb circumference , pain score , range of motion , heaviness of the affected limb , and desire to continue the treatment were measured before the treatment and at follow-up sessions ( weeks 3 , 9 , 12 , 18 , and 22 ) and were compared to pretreatment values . Results showed that of the 11 enrolled patients , eight completed the treatment sessions . Reduction in limb circumference was detected in both groups , although it was more pronounced in the laser group up to the end of 22nd week . Desire to continue treatment at each session and baseline score in the laser group was greater than in the sham group in all sessions . Pain reduction in the laser group was more than in the sham group except for the weeks 3 and 9 . No substantial differences were seen in other two parameters between the two treatment groups . In conclusion , despite our encouraging results , further studies of the effects of LLLT in management of postmastectomy lymphedema should be undertaken to determine the optimal physiological and physical parameters to obtain the most effective clinical response 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 PURPOSE / OBJECTIVES To examine the impact of advanced practice nurse (APN)-administered low-level laser therapy ( LLLT ) as both a st and -alone and complementary treatment for arm volume , symptoms , and quality of life ( QOL ) in women with breast cancer-related lymphedema . DESIGN A three-group , pilot , r and omized clinical trial . SETTING A private rehabilitation practice in the southeastern United States . SAMPLE 46 breast cancer survivors with treatment-related lymphedema . METHODS Patients were screened for eligibility and then r and omized to either manual lymphatic drainage ( MLD ) for 40 minutes , LLLT for 20 minutes , or 20 minutes of MLD followed by 20 minutes of LLLT . Compression b and aging was applied after each treatment . Data were collected pretreatment , daily , weekly , and at the end of treatment . MAIN RESEARCH VARIABLES Independent variables consisted of three types of APN-administered lymphedema treatment . Outcome variables included limb volume , extracellular fluid , psychological and physical symptoms , and QOL . FINDINGS No statistically significant between-group differences were found in volume reduction ; however , all groups had clinical ly and statistically significant reduction in volume . No group differences were noted in psychological and physical symptoms or QOL ; however , treatment-related improvements were noted in symptom burden within all groups . Skin improvement was noted in each group that received LLLT . CONCLUSIONS LLLT with b and aging may offer a time-saving therapeutic option to conventional MLD . Alternatively , compression b and aging alone could account for the demonstrated volume reduction . IMPLICATION S FOR NURSING APNs can effectively treat lymphedema . APNs in private healthcare practice s can serve as valuable research collaborators . KNOWLEDGE TRANSLATION Lasers may provide effective , less burdensome treatment for lymphedema . APNs with lymphedema certification can effectively treat this patient population with the use of LLLT . In addition , bioelectrical impedance and tape measurements can be used to assess lymphedema Muscle regeneration is a complex phenomenon , involving replacement of damaged fibers by new muscle fibers . During this process , there is a tendency to form scar tissue or fibrosis by deposition of collagen that could be detrimental to muscle function . New therapies that could regulate fibrosis and favor muscle regeneration would be important for physical therapy . Low-level laser therapy ( LLLT ) has been studied for clinical treatment of skeletal muscle injuries and disorders , even though the molecular and cellular mechanisms have not yet been clarified . The aim of this study was to evaluate the effects of LLLT on molecular markers involved in muscle fibrosis and regeneration after cryolesion of the tibialis anterior ( TA ) muscle in rats . Sixty Wistar rats were r and omly divided into three groups : control , injured TA muscle without LLLT , injured TA muscle treated with LLLT . The injured region was irradiated daily for four consecutive days , starting immediately after the lesion using an AlGaAs laser ( 808 nm , 30 mW , 180 J/cm2 ; 3.8 W/cm2 , 1.4 J ) . The animals were sacrificed on the fourth day after injury . LLLT significantly reduced the lesion percentage area in the injured muscle ( p < 0.05 ) , increased mRNA levels of the transcription factors MyoD and myogenin ( p < 0.01 ) and the pro-angiogenic vascular endothelial growth factor ( p < 0.01 ) . Moreover , LLLT decreased the expression of the profibrotic transforming growth factor TGF-β mRNA ( p < 0.01 ) and reduced type I collagen deposition ( p < 0.01 ) . These results suggest that LLLT could be an effective therapeutic approach for promoting skeletal muscle regeneration while preventing tissue fibrosis after muscle injury Secondary prevention involves monitoring and screening to prevent negative sequelae from chronic diseases such as cancer . Breast cancer treatment sequelae , such as lymphedema , may occur early or late and often negatively affect function . Secondary prevention through prospect i ve physical therapy surveillance aids in early identification and treatment of breast cancer – related lymphedema ( BCRL ) . Early intervention may reduce the need for intensive rehabilitation and may be cost saving . This perspective article compares a prospect i ve surveillance model with a traditional model of impairment-based care and examines direct treatment costs associated with each program . Intervention and supply costs were estimated based on the Medicare 2009 physician fee schedule for 2 groups : ( 1 ) a prospect i ve surveillance model group ( PSM group ) and ( 2 ) a traditional model group ( TM group ) . The PSM group comprised all women with breast cancer who were receiving interval prospect i ve surveillance , assuming that one third would develop early-stage BCRL . The prospect i ve surveillance model includes the cost of screening all women plus the cost of intervention for early-stage BCRL . The TM group comprised women referred for BCRL treatment using a traditional model of referral based on late-stage lymphedema . The traditional model cost includes the direct cost of treating patients with advanced-stage lymphedema . The cost to manage early-stage BCRL per patient per year using a prospect i ve surveillance model is $ 636.19 . The cost to manage late-stage BCRL per patient per year using a traditional model is $ 3,124.92 . The prospect i ve surveillance model is emerging as the st and ard of care in breast cancer treatment and is a potential cost-saving mechanism for BCRL treatment . Further analysis of indirect costs and utility is necessary to assess cost-effectiveness . A shift in the paradigm of physical therapy toward a prospect i ve surveillance model is warranted OBJECTIVE We aim ed to investigate the effects of low-level laser therapy ( LLLT ) in managing postmastectomy lymphedema . BACKGROUND DATA Postmastectomy lymphedema ( PML ) is a common complication of breast cancer treatment that causes various symptoms , functional impairment , or even psychosocial morbidity . A prospect i ve , single-blinded , controlled clinical trial was conducted to examine the effectiveness of LLLT on managing PML . METHODS Twenty-one women suffering from unilateral PML were r and omly allocated to receive either 12 sessions of LLLT in 4 wk ( the laser group ) or no laser irradiation ( the control group ) . Volumetry and tonometry were used to monitor arm volume and tissue resistance ; the Disabilities of Arm , Shoulder , and H and ( DASH ) question naire was used for measuring subjective symptoms . Outcome measures were assessed before and after the treatment period and at the 4 wk follow-up . RESULTS Reduction in arm volume and increase in tissue softening was found in the laser group only . At the follow-up session , significant between-group differences ( all p < 0.05 ) were found in arm volume and tissue resistance at the anterior torso and forearm region . The laser group had a 16 % reduction in the arm volume at the end of the treatment period , that dropped to 28 % in the follow-up . Moreover , the laser group demonstrated a cumulative increase from 15 % to 33 % in the tonometry readings over the forearm and anterior torso . The DASH score of the laser group showed progressive improvement over time . CONCLUSION LLLT was effective in the management of PML , and the effects were maintained to the 4 wk follow-up Background The optimal time frame to improve the quality and cosmetic appearance of scars by laser therapy has not been clearly eluci date d by prior controlled clinical trials . Objective To determine the efficacy of the 585-nm pulsed dye laser ( PDL ) in the treatment of surgical scars starting on the day of suture removal . Methods Eleven patients ( skin types I – IV ) with 12 postoperative linear scars that were greater than 2 cm were treated three times on monthly intervals with the 585-nm PDL ( 450 μs , 10-mm spot size , 3.5 J/cm2 with 10 % overlap ) on one scar half , whereas the other half received no treatment . Scars were later evaluated by a blinded examiner using the Vancouver Scar Scale ( VSS ) for pigmentation , vascularity , pliability , and height . Scars were then blindly examined for cosmetic appearance using a visual analog scale . Results One month after the last treatment , final scar analysis by the blinded examiner revealed a significant difference between treated and untreated sites , with the treated halves scoring better in all scar parameters in the VSS and in cosmetic appearance . The treated halves demonstrated an overall average improvement in the VSS between the first treatment score and the final score of 54 % versus 10 % in the controls ( P = 0.0002 ) . The cosmetic appearance score ( 0 = worst ; 10 = best ) at final assessment was significantly better for the treated scars , scoring 7.3 versus the averaged control score of 5.2 ( P = 0.016 ) . Conclusion The 585-nm PDL is effective and safe in improving the quality and cosmetic appearance of surgical scars in skin types I – IV starting on the day of suture removal

RESULTS Apixaban ( Eliquis ® , Bristol-Myers Squibb , USA ; Pfizer , USA ) [ 5 mg bd ( twice daily ) ] was ranked as among the best interventions for stroke prevention in AF , and had the highest expected net benefit . Edoxaban ( Lixiana ® , Daiichi Sankyo , Japan ) [ 60 mg od ( once daily ) ] was ranked second for major bleeding and all-cause mortality . Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE . For acute treatment and secondary prevention of VTE , we found little evidence that NOACs offer an efficacy advantage over warfarin , but the risk of bleeding complications was lower for some NOACs than for warfarin . For a willingness-to-pay threshold of > £ 5000 , apixaban ( 5 mg bd ) had the highest expected net benefit for acute treatment of VTE . Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE : our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication . CONCLUSIONS NOACs have advantages over warfarin in patients with AF , but we found no strong evidence that they should replace warfarin or LMWH in primary prevention , treatment or secondary prevention of VTE .

BACKGROUND Warfarin is effective for stroke prevention in atrial fibrillation ( AF ) , but anticoagulation is underused in clinical care . The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin ( LMWH ) : warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism ( VTE ) . Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects . Warfarin is cheap but therapeutic monitoring increases treatment costs . Novel oral anticoagulants ( NOACs ) have more rapid onset and offset of action than warfarin , and more predictable dosing requirements . OBJECTIVE To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention , treatment and secondary prevention of VTE .

R and omized clinical trials have identified a population of acute medically ill patients who remain at risk for venous thromboembolism ( VTE ) beyond the st and ard duration of therapy and hospital discharge . The aim of the APEX study is to determine whether extended administration of oral betrixaban ( 35 - 42 days ) is superior to a st and ard short course of prophylaxis with subcutaneous enoxaparin ( 10 ± 4 days followed by placebo ) in patients with known risk factors for post-discharge VTE . Patients initially are r and omized to receive either betrixaban or enoxaparin ( and matching placebo ) in a double dummy design . Following a st and ard duration period of enoxaparin treatment ( with placebo tablets ) or betrixaban ( with placebo injections ) , patients receive only betrixaban ( or alternative matching placebo ) . Patients are considered for enrollment if they are older than 40 years , have a specified medical illness , and restricted mobility . They must also meet the APEX criteria for increased VTE risk ( aged ≥75 years , baseline D-Dimer ≥2 × upper the limit of " normal " , or 2 additional ancillary risk factors for VTE ) . The primary efficacy end point is the composite of asymptomatic proximal deep venous thrombosis , symptomatic deep venous thrombosis , non-fatal ( pulmonary embolus ) pulmonary embolism , or VTE-related death through day 35 . The primary safety outcome is the occurrence of major bleeding . We hypothesize that extended duration betrixaban VTE prophylaxis will be safe and more effective than st and ard short duration enoxaparin in preventing VTE in acute medically ill patients with known risk factors for post hospital discharge VTE Background Venous thromboembolism comprising pulmonary embolism and deep vein thrombosis is a common condition with an incidence of approximately 1 per 1,000 per annum causing both mortality and serious morbidity . The principal aim of treatment of a venous thromboembolism with heparin and warfarin is to prevent extension or recurrence of clot . However , the recurrence rate following a deep vein thrombosis remains approximately 10 % per annum following treatment cessation irrespective of the duration of anticoagulation therapy . Patients with raised D-dimer levels after discontinuing oral anticoagulation treatment have also been shown to be at high risk of recurrence . Post thrombotic syndrome is a complication of a deep vein thrombosis which can lead to chronic venous insufficiency and ulceration . It has a cumulative incidence after 2 years of around 25 % and it has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure . Methods / design Patients with a first idiopathic venous thromboembolism will be recruited through anticoagulation clinics and r and omly allocated to either continuing or discontinuing warfarin treatment for a further 2 years and followed up on a six monthly basis . At each visit D-dimer levels will be measured using a Roche Cobas h 232 POC device . In addition a venous sample will be taken for laboratory D-dimer analysis at the end of the study . Patients will be examined for signs and symptoms of PTS using the Villalta scale and complete VEINES and EQ5D quality of life question naires . Discussion The primary aim of the study is to investigate whether extending oral anticoagulation treatment ( prior to discontinuing treatment ) beyond 3–6 months for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism prevents recurrence . The study will also determine the role of extending anticoagulation for patients with elevated D-dimer levels prior to discontinuing treatment and identify the potential of D-dimer point of care testing for identification of high risk patients within a primary care setting .Trial registration IS RCT Background — Dabigatran and warfarin have been compared for the treatment of acute venous thromboembolism ( VTE ) in a previous trial . We undertook this study to extend those findings . Methods and Results — In a r and omized , double-blind , double-dummy trial of 2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days , we compared dabigatran 150 mg twice daily with warfarin . The primary outcome , recurrent symptomatic , objective ly confirmed VTE and related deaths during 6 months of treatment occurred in 30 of the 1279 dabigatran patients ( 2.3 % ) compared with 28 of the 1289 warfarin patients ( 2.2 % ; hazard ratio , 1.08 ; 95 % confidence interval [ CI ] , 0.64–1.80 ; absolute risk difference , 0.2 % ; 95 % CI , −1.0 to 1.3 ; P<0.001 for the prespecified noninferiority margin for both criteria ) . The safety end point , major bleeding , occurred in 15 patients receiving dabigatran ( 1.2 % ) and in 22 receiving warfarin ( 1.7 % ; hazard ratio , 0.69 ; 95 % CI , 0.36–1.32 ) . Any bleeding occurred in 200 dabigatran ( 15.6 % ) and 285 warfarin ( 22.1 % ; hazard ratio , 0.67 ; 95 % CI , 0.56–0.81 ) patients . Deaths , adverse events , and acute coronary syndromes were similar in both groups . Pooled analysis of this study RE-COVER II and the RE-COVER trial gave hazard ratios for recurrent VTE of 1.09 ( 95 % CI , 0.76–1.57 ) , for major bleeding of 0.73 ( 95 % CI , 0.48–1.11 ) , and for any bleeding of 0.70 ( 95 % CI , 0.61–0.79 ) . Conclusion — Dabigatran has similar effects on VTE recurrence and a lower risk of bleeding compared with warfarin for the treatment of acute VTE . Clinical Trial Registration — URL : www . clinical trials.gov . Unique identifiers : NCT00680186 and NCT00291330 Background — Recent studies have investigated alternatives to warfarin for stroke prophylaxis in patients with atrial fibrillation ( AF ) , but whether these alternatives are cost-effective is unknown . Methods and Results — On the basis of the results from R and omized Evaluation of Long Term Anticoagulation Therapy ( RE-LY ) and other trials , we developed a decision- analysis model to compare the cost and quality -adjusted survival of various antithrombotic therapies . We ran our Markov model in a hypothetical cohort of 70-year-old patients with AF using a cost-effectiveness threshold of $ 50 000/ quality -adjusted life-year . We estimated the cost of dabigatran as US $ 9 a day . For a patient with an average risk of major hemorrhage ( ≈3%/y ) , the most cost-effective therapy depended on stroke risk . For patients with the lowest stroke rate ( CHADS2 stroke score of 0 ) , only aspirin was cost-effective . For patients with a moderate stroke rate ( CHADS2 score of 1 or 2 ) , warfarin was cost-effective unless the risk of hemorrhage was high or quality of international normalized ratio control was poor ( time in the therapeutic range < 57.1 % ) . For patients with a high stroke risk ( CHADS2 stroke score ≥3 ) , dabigatran 150 mg ( twice daily ) was cost-effective unless international normalized ratio control was excellent ( time in the therapeutic range > 72.6 % ) . Neither dabigatran 110 mg nor dual therapy ( aspirin and clopidogrel ) was cost-effective . Conclusions — Dabigatran 150 mg ( twice daily ) was cost-effective in AF population s at high risk of hemorrhage or high risk of stroke unless international normalized ratio control with warfarin was excellent . Warfarin was cost-effective in moderate-risk AF population s unless international normalized ratio control was poor BACKGROUND Apixaban , an oral potent reversible direct inhibitor of activated factor X , has shown promise in the prevention of venous thromboembolism following major orthopedic surgery . We conducted a dose-ranging study in patients with deep vein thrombosis . METHODS Consecutive patients with symptomatic deep vein thrombosis were included and r and omized to receive 84 - 91 days of apixaban 5 mg twice-daily , 10 mg twice-daily , or 20 mg once-daily , or low molecular weight heparin ( LMWH ) followed by a vitamin K antagonist ( VKA ) . The primary efficacy outcome was the composite of symptomatic recurrent venous thromboembolism and asymptomatic deterioration of bilateral compression ultrasound or perfusion lung scan . The principal safety outcome was the composite of major and clinical ly relevant , non-major bleeding . RESULTS The mean age of the 520 included patients was 59 years , and 62 % were male . The primary outcome occurred in 17 of the 358 apixaban-treated patients [ 4.7 % , 95 % confidence interval ( CI ) 2.8 - 7.5 % ] and in five of the 118 LMWH/VKA-treated patients ( 4.2 % , 95 % CI 1.4 - 9.6 % ) who were evaluable . The incidence in all three apixaban groups was low and comparable without evidence of a dose response . The principal safety outcome occurred in 28 ( 7.3 % ) of the 385 apixaban-treated patients and in 10 ( 7.9 % ) of the 126 LMWH/VKA-treated patients . No dose response for apixaban was observed . CONCLUSION These observations warrant further evaluation of apixaban in phase III studies . The attractive fixed-dose regimen of this compound may meet the dem and to simplify anticoagulant treatment in patients with established venous thromboembolism Objectives To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom . Design Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY ( R and omized Evaluation of Long-Term Anticoagulation Therapy ) study to a lifetime horizon . Setting UK National Health Service . Population Cohorts of 50 000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS2 ( Congestive heart failure , Hypertension , Age≥75 years , Diabetes mellitus , previous Stroke/transient ischaemic attack ) score of 2.1 . Main outcome measures Quality adjusted life years ( QALYs ) gained and incremental cost per QALY of dabigatran compared with warfarin . Results Compared with warfarin , low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 ( 95 % central range −0.083 to 0.267 ) and 0.146 ( −0.029 to 0.322 ) QALYs . Positive incremental net benefits result ed for high dose dabigatran in 94 % of simulations versus warfarin and in 76 % of those versus low dose dabigatran . In the economic analysis , high dose dabigatran dominated the low dose , had an incremental cost effectiveness ratio of £ 23 082 ( € 26 700 ; $ 35 800 ) per QALY gained versus warfarin , and was more cost effective in patients with a baseline CHADS2 score of 3 or above . However , at centres that achieved good control of international normalised ratio , such as those in the UK , dabigatran 150 mg was not cost effective , at £ 42 386 per QALY gained . Conclusions This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin . However , no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified . High dose dabigatran will be cost effective only for patients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled BACKGROUND Apixaban , an oral factor Xa inhibitor administered in fixed doses , may simplify the treatment of venous thromboembolism . METHODS In this r and omized , double-blind study , we compared apixaban ( at a dose of 10 mg twice daily for 7 days , followed by 5 mg twice daily for 6 months ) with conventional therapy ( subcutaneous enoxaparin , followed by warfarin ) in 5395 patients with acute venous thromboembolism . The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism . The principal safety outcomes were major bleeding alone and major bleeding plus clinical ly relevant nonmajor bleeding . RESULTS The primary efficacy outcome occurred in 59 of 2609 patients ( 2.3 % ) in the apixaban group , as compared with 71 of 2635 ( 2.7 % ) in the conventional-therapy group ( relative risk , 0.84 ; 95 % confidence interval [ CI ] , 0.60 to 1.18 ; difference in risk [ apixaban minus conventional therapy ] , -0.4 percentage points ; 95 % CI , -1.3 to 0.4 ) . Apixaban was noninferior to conventional therapy ( P<0.001 ) for predefined upper limits of the 95 % confidence intervals for both relative risk ( < 1.80 ) and difference in risk ( < 3.5 percentage points ) . Major bleeding occurred in 0.6 % of patients who received apixaban and in 1.8 % of those who received conventional therapy ( relative risk , 0.31 ; 95 % CI , 0.17 to 0.55 ; P<0.001 for superiority ) . The composite outcome of major bleeding and clinical ly relevant nonmajor bleeding occurred in 4.3 % of the patients in the apixaban group , as compared with 9.7 % of those in the conventional-therapy group ( relative risk , 0.44 ; 95 % CI , 0.36 to 0.55 ; P<0.001 ) . Rates of other adverse events were similar in the two groups . CONCLUSIONS A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding ( Funded by Pfizer and Bristol-Myers Squibb ; Clinical Trials.gov number , NCT00643201 ) BACKGROUND In ROCKET AF ( Rivaroxaban Once-Daily , Oral , Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ) , a large r and omized , clinical trial , rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation . OBJECTIVE To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)-naive and VKA-experienced patients . DESIGN Prespecified subgroup analysis . ( Clinical Trials.gov : NCT00403767 ) . SETTING Global . PATIENTS 14,264 persons with atrial fibrillation . MEASUREMENTS Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKA-naive and VKA-experienced patients . RESULTS Overall , 7897 ( 55.4 % ) patients were VKA-experienced and 6367 ( 44.6 % ) were VKA-naive . The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent : Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients ( hazard ratio [ HR ] , 0.81 [ 95 % CI , 0.64 to 1.03 ] ) and 1.98 versus 2.09 for VKA-experienced patients ( HR , 0.94 [ CI , 0.75 to 1.18 ] ; interaction P = 0.36 ) . During the first 7 days , rivaroxaban was associated with more bleeding than warfarin ( HR in VKA-naive patients , 5.83 [ CI , 3.25 to 10.44 ] , and in VKA-experienced patients , 6.66 [ CI , 3.83 to 11.58 ] ; interaction P = 0.53 ) . After 30 days , rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients ( HR , 0.84 [ CI , 0.74 to 0.95 ] ) and similar bleeding in VKA-experienced patients ( HR , 1.06 [ CI , 0.96 to 1.17 ] ; interaction P = 0.003 ) . LIMITATION The trial was not design ed to detect differences in these subgroups . CONCLUSION The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial . There were more bleeding events within 7 days of study drug initiation with rivaroxaban , but after 30 days , rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients . This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy . PRIMARY FUNDING SOURCE Johnson & Johnson and Bayer HealthCare Background and Purpose — Intracranial hemorrhage is the most devastating complication of anticoagulation . Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined . Methods — Analysis of 18 113 participants with atrial fibrillation in the R and omized Evaluation of Long-term anticoagulant therapY ( RE-LY ) trial assigned to adjusted-dose warfarin ( target international normalized ratio , 2–3 ) or dabigatran ( 150 mg or 110 mg , both twice daily ) . Results — During a mean of 2.0 years of follow-up , 154 intracranial hemorrhages occurred in 153 participants : 46 % intracerebral ( 49 % mortality ) , 45 % subdural ( 24 % mortality ) , and 8 % subarachnoid ( 31 % mortality ) . The rates of intracranial hemorrhage were 0.76 % , 0.31 % , and 0.23 % per year among those assigned to warfarin , dabigatran 150 mg , and dabigatran 110 mg , respectively ( P<0.001 for either dabigatran dose versus warfarin ) . Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg ( n=13 and n=11 , respectively ) versus warfarin ( n=32 ; P<0.01 for both ) . Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran ( 11 patients with each dose ) compared with warfarin ( 24 patients ; P<0.05 for both dabigatran doses versus warfarin ) . Independent predictors of intracranial hemorrhage were assignment to warfarin ( relative risk , 2.9 ; P<0.001 ) , aspirin use ( relative risk , 1.6 ; P=0.01 ) , age ( relative risk , 1.1 per year ; P<0.001 ) , and previous stroke/transient ischemic attack ( relative risk , 1.8 ; P=0.001 ) . Conclusions — The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran . Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin . Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage Background and Purpose — Intracranial hemorrhage rates are higher in Asians than non-Asians , especially in patients receiving warfarin . This r and omized evaluation of long-term anticoagulation therapy subgroup analysis assessed dabigatran etexilate ( DE ) and warfarin effects on stroke and bleeding rates in patients from Asian and non-Asian countries . Methods — There were 2782 patients ( 15 % ) from 10 Asian countries and 15 331 patients from 34 non-Asian countries . A Cox regression model , with terms for treatment , region , and their interaction was used . Results — Rates of stroke or systemic embolism in Asians were 3.06 % per year on warfarin , 2.50 % per year on DE 110 mg BID ( DE 110 ) , and 1.39 % per year on DE 150 mg BID ( DE 150 ) ; in non-Asians , the rates were 1.48 % , 1.37 % , and 1.06 % per year with no significant treatment-by-region interactions . Hemorrhagic stroke on warfarin occurred more often in Asians than non-Asians ( hazard ratio [ HR ] , 2.4 ; 95 % confidence interval [ CI ] , 1.3–4.7 ; P=0.007 ) , with significant reductions for DE compared with warfarin in both Asian ( DE 110 versus warfarin HR , 0.15 ; 95 % CI , 0.03–0.66 and DE 150 versus warfarin HR , 0.22 ; 95 % CI , 0.06–0.77 ) and non-Asian ( DE 110 versus warfarin HR , 0.37 ; 95 % CI , 0.19–0.72 and DE 150 versus warfarin HR , 0.28 ; 95 % CI , 0.13–0.58 ) patients . Major bleeding rates in Asians were significantly lower on DE ( both doses ) than warfarin ( warfarin 3.82 % per year , DE 110 2.22 % per year , and DE 150 2.17 % per year ) . Conclusions — Hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians , despite similar blood pressure , younger age , and lower international normalized ratio values . Hemorrhagic strokes were significantly reduced by DE in both Asians and non-Asians . DE benefits were consistent across Asian and non-Asian subgroups . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00262600 OBJECTIVES The goal of this study was to analyze the impact of dabigatran plasma concentrations , patient demographics , and aspirin ( ASA ) use on frequencies of ischemic strokes/systemic emboli and major bleeds in atrial fibrillation patients . BACKGROUND The efficacy and safety of dabigatran etexilate were demonstrated in the RE-LY ( R and omized Evaluation of Long-Term Anticoagulation Therapy ) trial , but a therapeutic concentration range has not been defined . METHODS In a pre-specified analysis of RE-LY , plasma concentrations of dabigatran were determined in patients treated with dabigatran etexilate 110 mg twice daily ( bid ) or 150 mg bid and correlated with the clinical outcomes of ischemic stroke/systemic embolism and major bleeding using univariate and multivariate logistic regression and Cox regression models . Patient demographics and ASA use were assessed descriptively and as covariates . RESULTS Plasma concentrations were obtained from 9,183 patients , with 112 ischemic strokes/systemic emboli ( 1.3 % ) and 323 major bleeds ( 3.8 % ) recorded . Dabigatran levels were dependent on renal function , age , weight , and female sex , but not ethnicity , geographic region , ASA use , or clopidogrel use . A multiple logistic regression model ( c-statistic 0.657 , 95 % confidence interval [ CI ] : 0.61 to 0.71 ) showed that the risk of ischemic events was inversely related to trough dabigatran concentrations ( p = 0.045 ) , with age and previous stroke ( both p < 0.0001 ) as significant covariates . Multiple logistic regression ( c-statistic 0.715 , 95 % CI : 0.69 to 0.74 ) showed major bleeding risk increased with dabigatran exposure ( p < 0.0001 ) , age ( p < 0.0001 ) , ASA use ( p < 0.0003 ) , and diabetes ( p = 0.018 ) as significant covariates . CONCLUSIONS Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations . Age was the most important covariate . Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics . ( R and omized Evaluation of Long Term Anticoagulant Therapy [ RE-LY ] With Dabigatran Etexilate ; NCT00262600 ) Abstract Objective : To investigate the effectiveness of aspirin and coumarin in preventing thromboembolism in patients with non-rheumatic atrial fibrillation in general practice . Design : R and omised controlled trial . Participants : 729 patients aged ≥60 years with atrial fibrillation , recruited in general practice , who had no established indication for coumarin . Mean age was 75 years and mean follow up 2.7 years . Setting : Primary care in the Netherl and s. Interventions : Patients eligible for st and ard intensity coumarin ( international normalised ratio 2.5 - 3.5 ) were r and omly assigned to st and ard anticoagulation , very low intensity coumarin ( international normalised ratio 1.1 - 1.6 ) , or aspirin ( 150 mg/day ) ( stratum 1 ) . Patients ineligible for st and ard anticoagulation were r and omly assigned to low anticoagulation or aspirin ( stratum 2 ) . Main outcome measures : Stroke , systemic embolism , major haemorrhage , and vascular death . Results : 108 primary events occurred ( annual event rate 5.5 % ) , including 13 major haemorrhages ( 0.7 % a year ) . The hazard ratio was 0.91 ( 0.61 to 1.36 ) for low anticoagulation versus aspirin and 0.78 ( 0.34 to 1.81 ) for st and ard anticoagulation versus aspirin . Non-vascular death was less common in the low anticoagulation group than in the aspirin group ( 0.41 , 0.20 to 0.82 ) . There was no significant difference between the treatment groups in bleeding incidence . High systolic and low diastolic blood pressure and age were independent prognostic factors . Conclusion : In a general practice population ( without established indications for coumarin ) neither low nor st and ard intensity anticoagulation is better than aspirin in preventing primary outcome events . Aspirin may therefore be the first choice in patients with atrial fibrillation in general practice . Key messages Studies have shown that patients with non-rheumatic atrial fibrillation may benefit from anticoagulation This study in a general practice population found no benefit of st and ard or low dose anticoagulation on risk of stroke , systemic embolism , major haemorrhage , or vascular death when compared with aspirin Hypertension and age were prognostic factors for event occurrence Aspirin is the treatment of choice for preventing thromboembolism in primary care patients at low The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation ( AF ) . In this 12-week , parallel-group , multicentre , multinational study , 1,146 patients with AF and risk of stroke were r and omised to edoxaban 30 mg qd , 30 mg bid , 60 mg qd , or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0 - 3.0 . The study was double-blind to edoxaban dose , but open-label to warfarin . Primary outcomes were occurrence of major and /or clinical ly relevant non-major bleeding and elevated hepatic enzymes and /or bilirubin . Mean age was 65 + /- 8.7 years and 64.4 % were warfarin-naïve . Whereas major plus clinical ly relevant non-major bleeding occurred in 3.2 % of patients r and omised to warfarin , the incidence of bleeding was significantly higher with the edoxaban 60 mg bid ( 10.6 % ; p=0.002 ) and 30 mg bid regimens ( 7.8 % ; p=0.029 ) , but not with the edoxaban 60 mg qd ( 3.8 % ) or 30 mg qd regimens ( 3.0 % ) . For the same total daily dose of 60 mg , both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group . There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups . The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin . In contrast , the edoxaban bid regimens were associated with more bleeding than warfarin . These results suggest that in this three-month study , edoxaban 30 or 60 mg qd are safe and well-tolerated Objective To develop and vali date version two of the QRISK cardiovascular disease risk algorithm ( QRISK2 ) to provide accurate estimates of cardiovascular risk in patients from different ethnic groups in Engl and and Wales and to compare its performance with the modified version of Framingham score recommended by the National Institute for Health and Clinical Excellence ( NICE ) . Design Prospect i ve open cohort study with routinely collected data from general practice , 1 January 1993 to 31 March 2008 . Setting 531 practice s in Engl and and Wales contributing to the national Q RESEARCH data base . Participants 2.3 million patients aged 35 - 74 ( over 16 million person years ) with 140 000 cardiovascular events . Overall population ( derivation and validation cohorts ) comprised 2.22 million people who were white or whose ethnic group was not recorded , 22 013 south Asian , 11 595 black African , 10 402 black Caribbean , and 19 792 from Chinese or other Asian or other ethnic groups . Main outcome measures First ( incident ) diagnosis of cardiovascular disease ( coronary heart disease , stroke , and transient ischaemic attack ) recorded in general practice records or linked Office for National Statistics death certificates . Risk factors included self assigned ethnicity , age , sex , smoking status , systolic blood pressure , ratio of total serum cholesterol : high density lipoprotein cholesterol , body mass index , family history of coronary heart disease in first degree relative under 60 years , Townsend deprivation score , treated hypertension , type 2 diabetes , renal disease , atrial fibrillation , and rheumatoid arthritis . Results The validation statistics indicated that QRISK2 had improved discrimination and calibration compared with the modified Framingham score . The QRISK2 algorithm explained 43 % of the variation in women and 38 % in men compared with 39 % and 35 % , respectively , by the modified Framingham score . Of the 112 156 patients classified as high risk ( that is , ≥20 % risk over 10 years ) by the modified Framingham score , 46 094 ( 41.1 % ) would be reclassified at low risk with QRISK2 . The 10 year observed risk among these reclassified patients was 16.6 % ( 95 % confidence interval 16.1 % to 17.0%)—that is , below the 20 % treatment threshold . Of the 78 024 patients classified at high risk on QRISK2 , 11 962 ( 15.3 % ) would be reclassified at low risk by the modified Framingham score . The 10 year observed risk among these patients was 23.3 % ( 22.2 % to 24.4%)—that is , above the 20 % threshold . In the validation cohort , the annual incidence rate of cardiovascular events among those with a QRISK2 score of ≥20 % was 30.6 per 1000 person years ( 29.8 to 31.5 ) for women and 32.5 per 1000 person years ( 31.9 to 33.1 ) for men . The corresponding figures for the modified Framingham equation were 25.7 per 1000 person years ( 25.0 to 26.3 ) for women and 26.4 ( 26.0 to 26.8 ) for men ) . At the 20 % threshold , the population identified by QRISK2 was at higher risk of a CV event than the population identified by the Framingham score . Conclusions Incorporating ethnicity , deprivation , and other clinical conditions into the QRISK2 algorithm for risk of cardiovascular disease improves the accuracy of identification of those at high risk in a nationally representative population . At the 20 % threshold , QRISK2 is likely to be a more efficient and equitable tool for treatment decisions for the primary prevention of cardiovascular disease . As the validation was performed in a similar population to the population from which the algorithm was derived , it potentially has a “ home advantage . ” Further validation in other population s is therefore advised Edoxaban is an oral , reversible , direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation ( AF ) . A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS2 score ≥1 . In a multicentre , active-controlled , double-blind edoxaban and open-label warfarin , parallel-group study , a total of 235 patients from four Asian countries were r and omly assigned to edoxaban 30 mg qd , 60 mg qd or warfarin dose adjusted to international normalised ratio of 2 - 3 for three months . The primary endpoint was the incidence of central ly adjudicated all bleeding events ( major , clinical ly relevant non-major and minor ) . Secondary endpoints included thromboembolic events , biomarkers of thrombus formation and all adverse events ( AEs ) . The incidence of all bleeding events ( 95 % CI ) was 20.3 % ( 12.9 , 30.4 ) for edoxaban 30 mg , 23.8 % ( 15.8 , 34.1 ) for edoxaban 60 mg , and 29.3 % ( 20.2 , 40.4 ) for warfarin . A subgroup analysis suggested low body weight ( ≤60 kg ) may affect the incidence of bleeding events with edoxaban . The incidence of study drug-related AEs was 22 % for edoxaban 30 mg , 29 % for edoxaban 60 mg and 33 % for warfarin . No thromboembolic events occurred in any treatment group . In conclusion , this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients with edoxaban 30 mg and 60 mg compared with warfarin . Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group Background and Purpose — The cost-effectiveness of dabigatran for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack has not been directly assessed . Methods — A Markov decision model was constructed using data from the R and omized Evaluation of Long-Term Therapy ( RE-LY ) trial , other trials of warfarin therapy for atrial fibrillation , and the published cost of dabigatran . We compared the cost and quality -adjusted life expectancy associated with 150 mg dabigatran twice daily versus warfarin therapy targeted to an international normalized ratio of 2 to 3 . The target population was a cohort of patients aged ≥70 years with nonvalvular atrial fibrillation , prior stroke or transient ischemic attack , and no contraindication to anticoagulation . Results — In the base case , dabigatran was associated with 4.27 quality -adjusted life-years compared with 3.91 quality -adjusted life-years with warfarin . Dabigatran provided 0.36 additional quality -adjusted life-years at a cost of $ 9000 , yielding an incremental cost-effectiveness ratio of $ 25 000 . In sensitivity analyses , the cost-effectiveness of dabigatran was inversely related to the quality of international normalized ratio control achieved with warfarin therapy . In Monte Carlo analysis , dabigatran was cost-effective in 57 % of simulations using a threshold of $ 50 000 per quality -adjusted life-year and 78 % of simulations using a threshold of $ 100 000 per quality -adjusted life-year . Conclusions — Dabigatran appears to be cost-effective relative to warfarin for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack . Our analysis is limited by its reliance on data from a sub study of a single r and omized trial , and our results may not apply in setting s with uncommonly good international normalized ratio control using warfarin BACKGROUND Heparins and warfarin are currently used as venous thromboembolism ( VTE ) prophylaxis in surgery . Inhibition of factor ( F ) Xa provides a specific mechanism of anticoagulation and the potential for an improved benefit-risk profile . OBJECTIVES To evaluate the safety and efficacy of apixaban , a potent , direct , oral inhibitor of FXa , in patients following total knee replacement ( TKR ) , and to investigate dose-response relationships . PATIENTS / METHODS A total of 1238 patients were r and omized to one of six double-blind apixaban doses [ 5 , 10 or 20 mg day(-1 ) administered as a single ( q.d . ) or a twice-daily divided dose ( b.i.d . ) ] , enoxaparin ( 30 mg b.i.d . ) or open-label warfarin ( titrated to an International Normalized Ratio of 1.8 - 3.0 ) . Treatment lasted 10 - 14 days , commencing 12 - 24 h after surgery with apixaban or enoxaparin , and on the evening of surgery with warfarin . The primary efficacy outcome was a composite of VTE ( m and atory venography ) and all-cause mortality during treatment . The primary safety outcome was major bleeding . RESULTS A total of 1217 patients were eligible for safety and 856 patients for efficacy analysis . All apixaban groups had lower primary efficacy event rates than either comparator . The primary outcome rate decreased with increasing apixaban dose ( P = 0.09 with q.d./b.i.d . regimens combined , P = 0.19 for q.d . and P = 0.13 for b.i.d . dosing).A significant dose-related increase in the incidence of total adjudicated bleeding events was noted in the q.d . ( P = 0.01 ) and b.i.d . ( P = 0.02 ) apixaban groups ; there was no difference between q.d . and b.i.d . regimens . CONCLUSIONS Apixaban in doses of 2.5 mg b.i.d . or 5 mg q.d . has a promising benefit-risk profile compared with the current st and ards of care following TKR Venous thromboembolism ( VTE ) has a significant impact on healthcare costs but is largely preventable with anticoagulant prophylaxis using low-molecular-weight heparins ( LMWHs ) , such as enoxaparin or dalteparin . Rivaroxaban and dabigatran etexilate are two new oral anticoagulants ( NOACs ) both compared with enoxaparin in separate trials . A decision analytic model with a healthcare and national payer perspective over a five-year time horizon was used to evaluate the cost-effectiveness of the NOACs for VTE prophylaxis after total hip replacement ( THR ) or total knee replacement ( TKR ) in France , Italy and Spain . Efficacy and safety data were obtained from r and omised controlled trials of rivaroxaban vs enoxaparin and an indirect statistical comparison for rivaroxaban vs dabigatran . Rivaroxaban demonstrated dominance across all comparisons , indications and countries . In THR , total per-patient costs were reduced by up to € 160 in the enoxaparin comparison and € 115 in the dabigatran comparison , respectively . In addition , quality -adjusted life-years ( QALYs ) were increased by up to 0.0011 and 0.0012 in each comparison , respectively . Similarly , total costs were reduced in TKR by up to € 137 and € 28 in the enoxaparin and dabigatran comparisons , respectively . The total number of QALYs was increased by up to 0.0014 in the enoxaparin comparison and 0.0005 in the dabigatran comparison . The results were driven by costs since the incremental benefits were minimal . Rivaroxaban use could result in substantial healthcare cost savings and improved quality of life . The results are applicable across three European countries with differing healthcare systems so , potentially , could be generalised to a much wider population BACKGROUND AND OBJECTIVE In contrast to the extensive documentation on the short-term outcome of patients with acute deep vein thrombosis ( DVT ) of the lower extremities , little is known about the long-term clinical course of this disease . To determine the clinical course of patients with a first episode of symptomatic DVTn over an 8-year follow-up period . The primary aims were to assess the long-term incidence of recurrent venous thromboembolism and that of the post-thrombotic syndrome . In addition , we determined mortality and evaluated potential risk factors for all these outcomes . METHODS This was design ed as a prospect i ve cohort follow-up study . Consecutive symptomatic out patients with a first episode of venography proven DVT were treated with an initial course of full-dose ( low molecular weight ) heparin , followed by at least three months of oral anticoagulants . After discharge , they were instructed to wear compression elastic stockings for at least two years . Follow-up assessment s were scheduled at three and six months , and then every six months up to eight years . Diagnosis of recurrent venous thromboembolism was made according to st and ard criteria . The presence of post-thrombotic syndrome was evaluated using a st and ardized scale . RESULTS A total of 528 consecutive patients with a first episode of venography confirmed DVT were included in the study . The cumulative incidence of recurrent venous thromboembolism after two , five and eight years was 17.2 , 24.3 and 29.7 % , respectively . Malignancy and impaired coagulation inhibition increased the risk of recurrent venous thromboembolism ( RR = 1.48 and 2.0 , respectively ) . In contrast , surgery and recent trauma or fracture were associated with a diminished risk of recurrent venous thromboembolism ( RR = 0.65 and 0.39 , respectively ) . The cumulative incidence of post-thrombotic syndrome after two , five and eight years was 24.5 , 29.6 and 29.8 % , respectively . The development of ipsilateral recurrent DVT was strongly associated with the risk for post-thrombotic syndrome ( risk ratio , 2.4 ) . Survival after eight years was 69 % . The presence of malignancy increased the risk of death remarkably ( risk ratio , 7.1 ) . INTERPRETATION AND CONCLUSIONS Symptomatic DVT carries a high risk for recurrent venous thromboembolism that persists for many years , especially in patients without transient risk factors for DVT . The post-thrombotic syndrome occurs in almost one-third of patients and is strongly related to recurrent ipsilateral DVT . Our findings challenge the widely adopted short course of anticoagulation in patients with symptomatic DVT BACKGROUND The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism . METHODS In a r and omized , double-blind , noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days ( interquartile range , 8 to 11 ) , we compared oral dabigatran , administered at a dose of 150 mg twice daily , with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0 . The primary outcome was the 6-month incidence of recurrent symptomatic , objective ly confirmed venous thromboembolism and related deaths . Safety end points included bleeding events , acute coronary syndromes , other adverse events , and results of liver-function tests . RESULTS A total of 30 of the 1274 patients r and omly assigned to receive dabigatran ( 2.4 % ) , as compared with 27 of the 1265 patients r and omly assigned to warfarin ( 2.1 % ) , had recurrent venous thromboembolism ; the difference in risk was 0.4 percentage points ( 95 % confidence interval [ CI ] , -0.8 to 1.5 ; P<0.001 for the prespecified noninferiority margin ) . The hazard ratio with dabigatran was 1.10 ( 95 % CI , 0.65 to 1.84 ) . Major bleeding episodes occurred in 20 patients assigned to dabigatran ( 1.6 % ) and in 24 patients assigned to warfarin ( 1.9 % ) ( hazard ratio with dabigatran , 0.82 ; 95 % CI , 0.45 to 1.48 ) , and episodes of any bleeding were observed in 205 patients assigned to dabigatran ( 16.1 % ) and 277 patients assigned to warfarin ( 21.9 % ; hazard ratio with dabigatran , 0.71 ; 95 % CI , 0.59 to 0.85 ) . The numbers of deaths , acute coronary syndromes , and abnormal liver-function tests were similar in the two groups . Adverse events leading to discontinuation of the study drug occurred in 9.0 % of patients assigned to dabigatran and in 6.8 % of patients assigned to warfarin ( P=0.05 ) . CONCLUSIONS For the treatment of acute venous thromboembolism , a fixed dose of dabigatran is as effective as warfarin , has a safety profile that is similar to that of warfarin , and does not require laboratory monitoring . ( Clinical Trials.gov number , NCT00291330 . Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed 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 Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects . The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known . METHODS We conducted a r and omized , double-blind , double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation ( median follow-up , 2.8 years ) . The primary efficacy end point was stroke or systemic embolism . Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period . The principal safety end point was major bleeding . RESULTS The annualized rate of the primary end point during treatment was 1.50 % with warfarin ( median time in the therapeutic range , 68.4 % ) , as compared with 1.18 % with high-dose edoxaban ( hazard ratio , 0.79 ; 97.5 % confidence interval [ CI ] , 0.63 to 0.99 ; P<0.001 for noninferiority ) and 1.61 % with low-dose edoxaban ( hazard ratio , 1.07 ; 97.5 % CI , 0.87 to 1.31 ; P=0.005 for noninferiority ) . In the intention-to-treat analysis , there was a trend favoring high-dose edoxaban versus warfarin ( hazard ratio , 0.87 ; 97.5 % CI , 0.73 to 1.04 ; P=0.08 ) and an unfavorable trend with low-dose edoxaban versus warfarin ( hazard ratio , 1.13 ; 97.5 % CI , 0.96 to 1.34 ; P=0.10 ) . The annualized rate of major bleeding was 3.43 % with warfarin versus 2.75 % with high-dose edoxaban ( hazard ratio , 0.80 ; 95 % CI , 0.71 to 0.91 ; P<0.001 ) and 1.61 % with low-dose edoxaban ( hazard ratio , 0.47 ; 95 % CI , 0.41 to 0.55 ; P<0.001 ) . The corresponding annualized rates of death from cardiovascular causes were 3.17 % versus 2.74 % ( hazard ratio , 0.86 ; 95 % CI , 0.77 to 0.97 ; P=0.01 ) , and 2.71 % ( hazard ratio , 0.85 ; 95 % CI , 0.76 to 0.96 ; P=0.008 ) , and the corresponding rates of the key secondary end point ( a composite of stroke , systemic embolism , or death from cardiovascular causes ) were 4.43 % versus 3.85 % ( hazard ratio , 0.87 ; 95 % CI , 0.78 to 0.96 ; P=0.005 ) , and 4.23 % ( hazard ratio , 0.95 ; 95 % CI , 0.86 to 1.05 ; P=0.32 ) . CONCLUSIONS Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes . ( Funded by Daiichi Sankyo Pharma Development ; ENGAGE AF-TIMI 48 Clinical Trials.gov number , NCT00781391 . ) Background Atrial fibrillation in the absence of rheumatic valvular disease is associated with a fivefold to sevenfold increased risk of ischemic stroke . Methods and Main Results . The Stroke Prevention in Atrial Fibrillation Study , a multicenter , r and omized trial , compared 325 mg/day aspirin ( double-blind ) or warfarin with placebo for prevention of ischemic stroke and systemic embolism ( primary events ) , and included 1,330 in patients and out patients with constant or intermittent atrial fibrillation . During a mean follow-up of 1.3 years , the rate of primary events in patients assigned to placebo was 6.3 % per year and was reduced by 42 % in those assigned to aspirin ( 3.6 % per year , p = 0.02 ; 95 % confidence interval , 9–63 % ) . In the subgroup of warfarin-eligible patients ( most less than 76 years old ) , warfarin dose-adjusted to prolong prothrombin time to 1.3-fold to 1.8-fold that of control reduced the risk of primary events by 67 % ( warfarin versus placebo , 2.3 % versus 7.4 % per year , p = 0.01 ; 95 % confidence interval , 27–85 % ) . Primary events or death were reduced 58 % ( p = 0.01 ) by warfarin and 32 % ( p = 0.02 ) by aspirin . The risk of significant bleeding was 1.5 % , 1.4 % , and 1.6%o per year in patients assigned to warfarin , aspirin , and placebo , respectively . Conclusions Aspirin and warfarin are both effective in reducing ischemic stroke and systemic embolism in patients with atrial fibrillation . Because warfarin-eligible patients composed a subset of all aspirin-eligible patients , the magnitude of reduction in events by warfarin versus aspirin can not be compared . Too few events occurred in warfarin-eligible patients to directly assess the relative benefit of aspirin compared with warfarin , and the trial is continuing to address this issue . Patients with nonrheumatic atrial fibrillation who can safely take either aspirin or warfarin should receive prophylactic antithrombotic therapy to reduce the risk of stroke OBJECTIVE To investigate whether warfarin is more effective and superior to aspirin for the prevention of thromboembolism in nonvalvular atrial fibrillation in Chinese . METHODS In a multicenter r and omized trial , the patients diagnosed as nonvalvular atrial fibrillation were r and omized to receive aspirin 150 mg - 160 mg once daily or adjusted-dose warfarin ( international normalized ratio , 2.0 - 3.0 ) . We compared the effect of the two therapy on the primary end point of ischemic stroke or death from any cause and on the combined end-point ( stroke , death , peripheral arteries embolism , TIA , acute myocardial infa rct ion , serious bleeding ) during a median follow-up period of 19 months . RESULTS Of the 704 patients , 420 ( 59.7 % ) were male . The average patient age was ( 63.3 + /- 9.9 ) years . The median follow-up period is 19 months . The mean dose of warfarin was ( 3.2 + /- 0.7 ) mg . Compared with aspirin , the primary end point of death or ischemic stroke was reduced by warfarin ( 2.7 % vs 6.0 % , P = 0.03 , OR 0.44 , 95 % CI 0.198 - 0.960 ) and the relative risk decreased by 56 % . The thromboembolism event in the aspirin group was significantly higher than that in warfarin group ( 10.6 % vs 5.4 % , P = 0.01 , OR 0.48 , 95 % CI 0.269 - 0.858 ) . There was no significant differences of the mortality rate between the two groups ( 1.2 % vs 2.2 % , P > 0.05 ) . The secondary end point was nonsignificantly reduced in warfarin group than that in aspirin group , while the combined end point is statistically decreased by adjusted-dose warfarin ( 8.4 % vs 13.0 % , P = 0.047 ) . Warfarin treatment was associated with increased bleeding rate compared to aspirin ( 6.9 % vs 2.4 % , P < 0.05 ) , although the major bleeding rate is rather low ( 1.5 % ) . All the major bleeding events occurred with INR above 3.0 . CONCLUSIONS R and omized control study demonstrated that anticoagulation with adjusted-dosed warfarin ( INR 2.0 - 3.0 ) can significantly reduced the risk of thromboembolism event with slightly increased hemorrhage , compared to aspirin in Chinese population . Under intensive monitoring , warfarin is effective and safe for the moderate to high risk atrial fibrillation patients Background — Rivaroxaban ( BAY 59 - 7939)—an oral , direct Factor Xa inhibitor — could be an alternative to heparins and warfarin for the prevention and treatment of thromboembolic disorders . Methods and Results — This r and omized , double-blind , double-dummy , active-comparator – controlled , multinational , dose-ranging study assessed the efficacy and safety of once-daily rivaroxaban relative to enoxaparin for prevention of venous thromboembolism in patients undergoing elective total hip replacement . Patients ( n=873 ) were r and omized to once-daily oral rivaroxaban doses of 5 , 10 , 20 , 30 , or 40 mg ( initiated 6 to 8 hours after surgery ) or a once-daily subcutaneous enoxaparin dose of 40 mg ( given the evening before and ≥6 hours after surgery ) . Study drugs were continued for an additional 5 to 9 days ; m and atory bilateral venography was performed the following day . The primary end point ( composite of any deep vein thrombosis , objective ly confirmed pulmonary embolism , and all-cause mortality ) was observed in 14.9 % , 10.6 % , 8.5 % , 13.5 % , 6.4 % , and 25.2 % of patients receiving 5 , 10 , 20 , 30 , and 40 mg rivaroxaban , and 40 mg enoxaparin , respectively ( n=618 , per- protocol population ) . No significant dose – response relationship was found for efficacy ( P=0.0852 ) . Major postoperative bleeding was observed in 2.3 % , 0.7 % , 4.3 % , 4.9 % , 5.1 % , and 1.9 % of patients receiving 5 , 10 , 20 , 30 , and 40 mg rivaroxaban , and 40 mg enoxaparin , respectively ( n=845 , safety population ) , representing a significant dose – response relationship ( P=0.0391 ) . Conclusions — Rivaroxaban showed efficacy and safety similar to enoxaparin for thromboprophylaxis after total hip replacement , with the convenience of once-daily oral dosing and without the need for coagulation monitoring . When both efficacy and safety are considered , these results suggest that 10 mg rivaroxaban once daily should be investigated in phase III studies Background — An effective and safe oral anticoagulant that needs no monitoring for dose adjustment is urgently needed for the treatment of diseases that require long-term anticoagulation . Rivaroxaban ( BAY 59 - 7939 ) is an oral direct factor Xa inhibitor currently under clinical development . Methods and Results — This r and omized , parallel-group phase II trial in patients with proximal deep-vein thrombosis explored the efficacy and safety of rivaroxaban 10 , 20 , or 30 mg BID or 40 mg once daily compared with enoxaparin 1 mg/kg BID followed by vitamin K antagonist . Each treatment was administered for 12 weeks . The primary efficacy end point was an improvement in thrombotic burden at day 21 ( assessed by quantitative compression ultrasonography ; ≥4-point improvement in thrombus score ) without recurrent symptomatic venous thromboembolism or venous thromboembolism – related death . The primary safety end point was major bleeding during 12 weeks of treatment . Outcomes were adjudicated central ly without knowledge of treatment allocation . The primary efficacy end point was achieved in 53 ( 53.0 % ) of 100 , 58 ( 59.2 % ) of 98 , 62 ( 56.9 % ) of 109 , and 49 ( 43.8 % ) of 112 patients receiving rivaroxaban 10 , 20 , or 30 mg BID or 40 mg once daily , respectively , compared with 50 ( 45.9 % ) of 109 patients treated with enoxaparin/vitamin K antagonist . There was no significant trend in the dose – response relationship between rivaroxaban BID and the primary efficacy end point ( P=0.67 ) . Major bleeding was observed in 1.7 % , 1.7 % , 3.3 % , and 1.7 % of patients receiving rivaroxaban 10 , 20 , or 30 mg BID or 40 mg once daily , respectively . There were no major bleeding events with enoxaparin/vitamin K antagonist . Conclusions — Results of this proof-of-concept and dose-finding study support phase III evaluation of the orally active direct factor Xa inhibitor rivaroxaban , because efficacy and safety were apparent in the treatment of proximal deep-vein thrombosis across a 3-fold range of fixed daily dosing BACKGROUND In the AVERROES study , apixaban , a novel factor Xa inhibitor , reduced the risk of stroke or systemic embolism in patients with atrial fibrillation who were at high risk of stroke but unsuitable for vitamin K antagonist therapy . We aim ed to investigate whether the subgroup of patients with previous stroke or transient ischaemic attack ( TIA ) would show a greater benefit from apixaban compared with aspirin than would patients without previous cerebrovascular events . METHODS In AVERROES , 5599 patients ( mean age 70 years ) with atrial fibrillation who were at increased risk of stroke and unsuitable for vitamin K antagonist therapy were r and omly assigned to receive apixaban ( 5 mg twice daily ) or aspirin ( 81 - 324 mg per day ) . The mean follow-up was 1·1 years . The primary efficacy outcome was stroke or systemic embolism ; the primary safety outcome was major bleeding . Patients and investigators were masked to study treatment . In this prespecified subgroup analysis , we used Kaplan-Meier estimates of 1-year event risk and Cox proportional hazards regression models to compare the effects of apixaban in patients with and without previous stroke or TIA . AVERROES is registered at Clinical Trials.gov , number NCT00496769 . FINDINGS In patients with previous stroke or TIA , ten events of stroke or systemic embolism occurred in the apixaban group ( n=390 , cumulative hazard 2·39 % per year ) compared with 33 in the aspirin group ( n=374 , 9·16 % per year ; hazard ratio [ HR ] 0·29 , 95 % CI 0·15 - 0·60 ) . In those without previous stroke or TIA , 41 events occurred in the apixaban group ( n=2417 , 1·68 % per year ) compared with 80 in the aspirin group ( n=2415 , 3·06 % per year ; HR 0·51 , 95 % CI 0·35 - 0·74 ) . The p value for interaction of the effects of aspirin and apixaban with previous cerebrovascular events was 0·17 . Major bleeding was more frequent in patients with history of stroke or TIA than in patients without ( HR 2·88 , 95 % CI 1·77 - 4·55 ) but risk of this event did not differ between treatment groups . INTERPRETATION In patients with atrial fibrillation , apixaban is similarly effective whether or not patients have had a previous stroke or TIA . Given that those with previous stroke or TIA have a higher risk of stroke , the absolute benefits might be greater in these patients . FUNDING Bristol-Myers Squibb and Pfizer Background and objective Non-valvular atrial fibrillation ( NVAF ) increases the risk of systemic thromboembolic events ; therefore , anticoagulant treatment with vitamin K antagonists is widely prescribed . Recently , new oral anticoagulants ( NOAs ) directly inhibiting thrombin ( dabigatran ) or factor Xa ( rivaroxaban and apixaban ) demonstrated their non-inferiority with respect to warfarin in reducing the thromboembolic risk . The aim of this study was to estimate the cost effectiveness of NOAs in an Italian setting . Methods A Markov decision model including ten health states and death was developed , and a 3-month Markov cycle and lifetime horizon were adopted . Transition probabilities and quality of life were estimated from three r and omized trials and from additional reports in the literature . Analysis was performed in the context of the Italian National Health System . First- and second-order sensitivity analyses were made to test the robustness of the results . The mean European cost of dabigatran ( € 2.58/day ) was assigned to each NOA . Results The incremental cost-utility ratio was below € 25,000/ quality -adjusted life-year ( QALY ) gained for each NOA and each CHADS2 level , but differences among drugs were found . This result was sensitive to the time in ( warfarin ) therapeutic range and time horizon . Conclusions Our analysis suggests that NOAs are a cost-effective treatment for the prevention of stroke in patients with NVAF in the Italian healthcare setting Abstract Objective To ascertain the current burden of adverse drug reactions ( ADRs ) through a prospect i ve analysis of all admissions to hospital . Design Prospect i ve observational study . Setting Two large general hospitals in Merseyside , Engl and . Participants 18 820 patients aged > 16 years admitted over six months and assessed for cause of admission . Main outcome measures Prevalence of admissions due to an ADR , length of stay , avoidability , and outcome . Results There were 1225 admissions related to an ADR , giving a prevalence of 6.5 % , with the ADR directly leading to the admission in 80 % of cases . The median bed stay was eight days , accounting for 4 % of the hospital bed capacity . The projected annual cost of such admissions to the NHS is £ 466 m ( € 706 m , $ 847 m ) . The overall fatality was 0.15 % . Most reactions were either definitely or possibly avoidable . Drugs most commonly implicated in causing these admissions included low dose aspirin , diuretics , warfarin , and non-steroidal anti-inflammatory drugs other than aspirin , the most common reaction being gastrointestinal bleeding . Conclusion The burden of ADRs on the NHS is high , accounting for considerable morbidity , mortality , and extra costs . Although many of the implicated drugs have proved benefit , measures need to be put into place to reduce the burden of ADRs and thereby further improve the benefit : harm ratio of the drugs BACKGROUND cost of anticoagulation with dabigatran is largely based on estimation of complication rates derived from clinical trials . OBJECTIVE to investigate cost of anticoagulation with dabigatran in comparison with warfarin in clinical practice . METHODS a prospect i ve observational study of patients with non-vavular atrial fibrillation ( NVAF ) referred to anticoagulation clinic . Patients were interviewed ( 4 - 6 weekly by telephone ) about bleeding events . Costs of anticoagulation were calculated as : ( i ) drug cost , ( ii ) international normalised ratio ( INR ) monitoring cost and ( iii ) bleeding cost . For cost calculation of dabigatran , INR monitoring cost was omitted . RESULTS a total of 402 patients were included and followed up for a mean ( SD ) of 19 ( 8.1 ) months . Annual cost of anticoagulation was £ 207.3 and £ 1,573.5 per patient for warfarin and dabigatran , respectively . Drug price constituted 13.6 % of the total cost for warfarin and 94 % for dabigatran . Total cost of anticoagulation to prevent one stroke per year was £ 6,219 , £ 28,086.5 and £ 25,181 for warfarin , dabigatran 110 and 150 mg , respectively . CONCLUSION cost of anticoagulation is mainly driven by drug price for dabigatran and quality of INR control for warfarin . Until the price of dabigatran is review ed , warfarin remains suitable for the majority of patients with NVAF Atrial fibrillation ( AF ) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists ( VKAs ) . Vitamin K antagonist use is limited , in part , by the high incidence of complications when patients ' international normalized ratios ( INRs ) deviate from the target range . The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor , apixaban , is noninferior to warfarin at reducing the combined endpoint of stroke ( ischemic or hemorrhagic ) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke . We have r and omized 18,206 patients from over 1,000 centers in 40 countries . Patients were r and omly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind , double-dummy design . International normalized ratios are monitored and warfarin ( or placebo ) is adjusted aim ing for a target INR range of 2 to 3 using a blinded , encrypted point-of-care device . Minimum treatment is 12 months , and maximum expected exposure is 4 years . Time to accrual of at least 448 primary efficacy events will determine treatment duration . The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke ( ischemic or hemorrhagic ) and systemic embolism , and for all-cause death . These will be tested after the primary objective using a closed test procedure . The noninferiority boundary is 1.38 ; apixaban will be declared noninferior if the 95 % CI excludes the possibility that the primary outcome rate with apixaban is > 1.38 times higher than with warfarin . ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism ; whether apixaban has particular benefits in the warfarin-naïve population ; whether it reduces the combined rate of stroke , systemic embolism , and death ; and whether it impacts bleeding BACKGROUND After hip replacement surgery , prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism . Our aim was to assess the oral , direct thrombin inhibitor dabigatran etexilate for such prophylaxis . METHODS In this double-blind study , we r and omised 3494 patients undergoing total hip replacement to treatment for 28 - 35 days with dabigatran etexilate 220 mg ( n=1157 ) or 150 mg ( 1174 ) once daily , starting with a half-dose 1 - 4 h after surgery , or subcutaneous enoxaparin 40 mg once daily ( 1162 ) , starting the evening before surgery . The primary efficacy outcome was the composite of total venous thromboembolism ( venographic or symptomatic ) and death from all causes during treatment . On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo , the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7 % . Efficacy analyses were done by modified intention to treat . This trial is registered with Clinical Trials.gov , number NCT00168818 . FINDINGS Median treatment duration was 33 days . 880 patients in the dabigatran etexilate 220 mg group , 874 in the dabigatran etexilate 150 mg group , and 897 in the enoxaparin group were available for the primary efficacy outcome analysis ; the main reasons for exclusion in all three groups were the lack of adequate venographic data . The primary efficacy outcome occurred in 60 ( 6.7 % ) of 897 individuals in the enoxaparin group versus 53 ( 6.0 % ) of 880 patients in the dabigatran etexilate 220 mg group ( absolute difference -0.7 % , 95 % CI -2.9 to 1.6 % ) and 75 ( 8.6 % ) of 874 people in the 150 mg group ( 1.9 % , -0.6 to 4.4 % ) . Both doses were thus non-inferior to enoxaparin . There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin ( p=0.44 for 220 mg , p=0.60 for 150 mg ) . The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups . INTERPRETATION Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery , with a similar safety profile BACKGROUND In ROCKET AF , rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation ( AF ) . We aim ed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack ( TIA ) . METHODS In ROCKET AF , patients with AF who were at increased risk of stroke were r and omly assigned ( 1:1 ) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin ( international normalised ratio 2·0 - 3·0 ) . Patients and investigators were masked to treatment allocation . Between Dec 18 , 2006 , and June 17 , 2009 , 14 264 patients from 1178 centres in 45 countries were r and omly assigned . The primary endpoint was the composite of stroke or non-CNS systemic embolism . In this sub study we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA . Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population . ROCKET AF is registered with Clinical Trials.gov , number NCT00403767 . FINDINGS 7468 ( 52 % ) patients had a previous stroke ( n=4907 ) or TIA ( n=2561 ) and 6796 ( 48 % ) had no previous stroke or TIA . The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA ( 2·79 % rivaroxaban vs 2·96 % warfarin ; hazard ratio [ HR ] 0·94 , 95 % CI 0·77 - 1·16 ) and those without ( 1·44%vs 1·88 % ; 0·77 , 0·58 - 1·01 ; interaction p=0·23 ) . The number of major and non-major clinical ly relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA ( 13·31 % rivaroxaban vs 13·87 % warfarin ; HR 0·96 , 95 % CI 0·87 - 1·07 ) and those without ( 16·69%vs 15·19 % ; 1·10 , 0·99 - 1·21 ; interaction p=0·08 ) . INTERPRETATION There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA . These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF . FUNDING Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare Introduction Two novel agents , dabigatran and rivaroxaban , recently gained market authorisation for prevention of venous thromboembolism ( VTE ) after hip and knee arthroplasty . However , safety data of the new oral anticoagulants with a long-term use of 42 days are not available for total knee arthroplasty ( TKA ) . Furthermore , there are no clinical trials comparing dabigatran and /or rivaroxaban with nadroparin , which is used in most Dutch departments of orthopaedic surgery . Our aim is to compare the 42-day use of dabigatran and rivaroxaban versus nadroparin after TKA in a clinical explorative pilot study by assessing the incidence of major bleeding and clinical ly relevant non-major bleeding using a st and ardised model of bleeding definitions . Methods and analysis A r and omised open-label pilot study was conducted . Patients ≥18 years and weighing more than 40 kg who were scheduled for a primary elective TKA were included . Patients were r and omly assigned to three groups . Patients took either a daily oral dose of dabigatran etexilate 220 mg ( n=50 ) , 10 mg of oral rivaroxaban ( n=50 ) or subcutaneous nadroparin 0.3 ml ( n=50 ) for 42 days . The primary safety outcome measure was the incidence of bleeding events . Major bleeding events and clinical ly relevant non-major bleeding events were defined according to accepted guidelines . The secondary measures of this study were the occurrence of VTE , time until the bleeding event , compliance , duration of hospital stay , rehospitalisation , outpatient clinic visits and interventions following complications . Additionally , coagulation monitoring , knee flexion range of motion and Knee injury and Osteoarthritis Outcome Score were evaluated . Dissemination The results of this trial provided insight into the validity of design for an adequately powered multicentre study investigating the safety of the new oral anticoagulants compared with nadroparin , an anticoagulant applied for prevention of VTE after knee arthroplasty in the Dutch situation . Trial registration number Clinical Trials.gov : NCT01431456 Aims Patients with atrial fibrillation ( AF ) are at increased risk of stroke . Betrixaban is a novel oral factor Xa inhibitor administered once daily , mostly excreted unchanged in the bile and with low ( 17 % ) renal excretion . Methods and results Patients with AF and more than one risk factor for stroke were r and omized to one of three blinded doses of betrixaban ( 40 , 60 , or 80 mg once daily ) or unblinded warfarin , adjusted to an international normalized ratio of 2.0–3.0 . The primary outcome was major or clinical ly relevant non-major bleeding . The mean follow-up was 147 days . Among 508 patients r and omized , the mean CHADS2 score was 2.2 ; 87 % of patients had previously received vitamin K antagonist therapy . The time in therapeutic range on warfarin was 63.4 % . There were one , five , five , and seven patients with a primary outcome on betrixaban 40 , 60 , 80 mg daily , or warfarin , respectively . The rate of the primary outcome was lowest on betrixaban 40 mg ( hazard ratio compared with warfarin = 0.14 , exact stratified log-rank P-value 0.04 , unadjusted for multiple testing ) . Rates of the primary outcome with betrixaban 60 or 80 mg were more similar to those of wafarin . Two ischaemic strokes occurred , one each on betrixaban 60 and 80 mg daily . There were two vascular deaths , one each on betrixaban 40 mg and warfarin . Betrixaban was associated with higher rates of diarrhoea than warfarin . Conclusion Betrixaban was well tolerated and had similar or lower rates of bleeding compared with well-controlled warfarin in patients with AF at risk for stroke AIMS We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation ( AF ) . METHODS AND RESULTS In ARISTOTLE , 18 201 patients were r and omized to apixaban 5 mg twice daily or warfarin . Concomitant aspirin use was left to the discretion of the treating physician . In this predefined analysis , simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use . Outcome measures included stroke or systemic embolism , ischaemic stroke , myocardial infa rct ion , mortality , major bleeding , haemorrhagic stroke , major or clinical ly relevant non-major bleeding , and any bleeding . On Day 1 , 4434 ( 24 % ) patients were taking aspirin . Irrespective of concomitant aspirin use , apixaban reduced stroke or systemic embolism [ with aspirin : apixaban 1.12 % vs. warfarin 1.91 % , hazard ratio ( HR ) 0.58 , 95 % confidence interval ( CI ) 0.39 - 0.85 vs. without aspirin : apixaban 1.11 % vs. warfarin 1.32 % , HR 0.84 , 95 % CI 0.66 - 1.07 ; P interaction = 0.10 ] and caused less major bleeding than warfarin ( with aspirin : apixaban 3.10 % vs. warfarin 3.92 % , HR 0.77 , 95 % CI 0.60 - 0.99 vs. without aspirin : apixaban 1.82 % vs. warfarin 2.78 % , HR without aspirin 0.65 , 95 % CI 0.55 - 0.78 ; P interaction = 0.29 ) . Similar results were seen in the subgroups of patients with and without arterial vascular disease . CONCLUSION Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin , irrespective of concomitant aspirin use IMPORTANCE Myocardial infa rct ion ( MI ) is an established risk factor for atrial fibrillation ( AF ) . However , the extent to which AF is a risk factor for MI has not been investigated . OBJECTIVE To examine the risk of incident MI associated with AF . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve cohort of 23,928 participants residing in the continental United States and without coronary heart disease at baseline were enrolled from the Reasons for Geographic and Racial Differences in Stroke ( REGARDS ) cohort between 2003 and 2007 , with follow-up through December 2009 . MAIN OUTCOMES AND MEASURES Expert-adjudicated total MI events ( fatal and nonfatal ) . RESULTS Over 6.9 years of follow-up ( median 4.5 years ) , 648 incident MI events occurred . In a sociodemographic-adjusted model , AF was associated with about 2-fold increased risk of MI ( hazard ratio [ HR ] , 1.96 [ 95 % CI , 1.52 - 2.52 ] ) . This association remained significant ( HR , 1.70 [ 95 % CI , 1.26 - 2.30 ] ) after further adjustment for total cholesterol , high-density lipoprotein cholesterol , smoking status , systolic blood pressure , blood pressure-lowering drugs , body mass index , diabetes , warfarin use , aspirin use , statin use , history of stroke and vascular disease , estimated glomerular filtration rate , albumin to creatinine ratio , and C-reactive protein level . In subgroup analysis , the risk of MI associated with AF was significantly higher in women ( HR , 2.16 [ 95 % CI , 1.41 - 3.31 ] ) than in men ( HR , 1.39 [ 95 % CI , 0.91 - 2.10 ] ) and in blacks ( HR , 2.53 [ 95 % CI , 1.67 - 3.86 ] ) than in whites ( HR , 1.26 [ 95 % CI , 0.83 - 1.93 ] ) ; for interactions , P = .03 and P = .02 , respectively . On the other h and , there were no significant differences in the risk of MI associated with AF in older ( ≥75 years ) vs younger ( < 75 years ) participants ( HR , 2.00 [ 95 % CI , 1.16 - 3.35 ] and HR , 1.60 [ 95 % CI , 1.11 - 2.30 ] , respectively ) ; for interaction , P = .44 . CONCLUSIONS AND RELEVANCE AF is independently associated with an increased risk of incident MI , especially in women and blacks . These findings add to the growing concerns of the seriousness of AF as a public health burden : in addition to being a well-known risk factor for stroke , AF is also associated with increased risk of MI Prophylaxis against venous thromboembolism after elective total hip replacement is routinely recommended . Our preference has been to use mechanical prophylaxis without anticoagulant drugs . A r and omised controlled trial was performed to evaluate whether the incidence of post-operative venous thromboembolism was reduced by using pharmacological anticoagulation with either fondaparinux or enoxaparin in addition to our prophylactic mechanical regimen . A total of 255 Japanese patients who underwent primary unilateral cementless total hip replacement were r and omly assigned to one of three postoperative regimens , namely injection of placebo ( saline ) , fondaparinux or enoxaparin . There were 85 patients in each group . All also received the same mechanical prophylaxis during and after the operation , regardless of their assigned group . The primary measurement of efficacy was the presence of a venous thromboembolic event by day 11 , defined as deep-vein thrombosis detected by ultrasonography , documented symptomatic deep-vein thrombosis or documented symptomatic pulmonary embolism . The duration of follow-up was 12 weeks . The rate of venous thromboembolism was 7.2 % with the placebo , 7.1 % with fondaparinux and 6.0 % with enoxaparin ( p = 0.95 for the comparison of all three groups ) . Our study confirmed the effectiveness and safety of mechanical thromboprophylaxis without the use of anticoagulant drugs after total hip replacement in Japanese patients BACKGROUND The global ROCKET AF study evaluated once-daily rivaroxaban vs. warfarin for stroke and systemic embolism prevention in patients with atrial fibrillation ( AF ) . A separate trial , J-ROCKET AF , compared the safety of a Japan-specific rivaroxaban dose with warfarin administered according to Japanese guidelines in Japanese patients with AF . METHODS AND RESULTS J-ROCKET AF was a prospect i ve , r and omized , double-blind , phase III trial . Patients ( n=1,280 ) with non-valvular AF at increased risk for stroke were r and omized to receive 15 mg once-daily rivaroxaban or warfarin dose-adjusted according to Japanese guidelines . The primary objective was to determine non-inferiority of rivaroxaban against warfarin for the principal safety outcome of major and non-major clinical ly relevant bleeding , in the on-treatment safety population . The primary efficacy endpoint was the composite of stroke and systemic embolism . Non-inferiority of rivaroxaban to warfarin was confirmed ; the rate of the principal safety outcome was 18.04 % per year in rivaroxaban-treated patients and 16.42 % per year in warfarin-treated patients ( hazard ratio [ HR ] 1.11 ; 95 % confidence interval 0.87 - 1.42 ; P<0.001 [ non-inferiority ] ) . Intracranial hemorrhage rates were 0.8 % with rivaroxaban and 1.6 % with warfarin . There was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban vs. warfarin ( HR , 0.49 ; P=0.050 ) . CONCLUSIONS J-ROCKET AF demonstrated the safety of a Japan-specific rivaroxaban dose and supports bridging the global ROCKET AF results into Japanese clinical practice BACKGROUND Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation , many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients . METHODS The Second Copenhagen Atrial Fibrillation , Aspirin , and Anticoagulation Study was a r and omized , controlled trial examining the following therapies : warfarin sodium , 1.25 mg/d ; warfarin sodium , 1.25 mg/d , plus aspirin , 300 mg/d ; and aspirin , 300 mg/d . These were compared with adjusted-dose warfarin therapy ( international normalized ratio of prothrombin time [ INR ] , 2.0 - 3.0 ) . Stroke or a systemic thromboembolic event was the primary outcome event . Transient ischemic attack , acute myocardial infa rct ion , and death were secondary events . Data were h and led as survival data , and risk factors were identified using the Cox proportional hazards model . The trial was scheduled for 6 years from May 1 , 1993 , but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study , our trial was prematurely terminated on October 2 , 1996 . RESULTS We included 677 patients ( median age , 74 years ) . The cumulative primary event rate after 1 year was 5.8 % in patients receiving minidose warfarin ; 7.2 % , warfarin plus aspirin ; 3.6 % , aspirin ; and 2.8 % , adjusted-dose warfarin ( P = .67 ) . After 3 years , no difference among the groups was seen . Major bleeding events were rare . CONCLUSIONS Although the difference was insignificant , adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment . The results do not justify a change in the current recommendation of adjusted-dose warfarin ( INR , 2.0 - 3.0 ) for stroke prevention in atrial fibrillation BACKGROUND Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis ( idiopathic thrombosis ) are often treated with anticoagulant therapy for three months . Such patients may benefit from longer treatment , however , because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped . METHODS In this double-blind study , we r and omly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin , with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0 , or to receive placebo for a further 24 months . Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding . RESULTS A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months . Of 83 patients assigned to continue to receive placebo , 17 had a recurrent episode of venous thromboembolism ( 27.4 percent per patient-year ) , as compared with 1 of 79 patients assigned to receive warfarin ( 1.3 percent per patient-year , P<0.001 ) . Warfarin result ed in a 95 percent reduction in the risk of recurrent venous thromboembolism ( 95 percent confidence interval , 63 to 99 percent ) . Three patients assigned to the warfarin group had nonfatal major bleeding ( two had gastrointestinal bleeding and one genitourinary bleeding ) , as compared with none of those assigned to the placebo group ( 3.8 vs. 0 percent per patient-year , P=0.09 ) . CONCLUSIONS Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months The incidence of deep-vein thrombosis and the need for thromboprophylaxis following isolated trauma below the knee is uncertain . We have investigated this with a prospect i ve r and omised double-blind controlled trial using low molecular weight heparin with saline injection as placebo in patients aged between 18 and 75 years who had sustained an isolated fracture below the knee which required operative fixation . All patients had surgery within 48 hours of injury and were r and omised to receive either the placebo or low molecular weight heparin for 14 days , after which they underwent bilateral lower limb venography , interpreted by three independent radiologists . Further follow-up was undertaken at two , six , eight and 12 weeks . A total of 238 patients fulfilled all the inclusion criteria , with 127 in the low molecular weight heparin group and 111 in the placebo group , all of whom underwent bilateral venography . There was no statistically significant difference in the incidence of deep-vein thrombosis between those patients treated with low molecular weight heparin or the placebo ( p = 0.22 ) . The number of deep-vein thromboses in the two groups was 11 ( 8.7 % ) and 14 ( 12.6 % ) , respectively . Age and the type of fracture were significantly associated with the rate of deep-vein thrombosis ( p = 0.001 and p = 0.009 , respectively ) but gender , comorbidities and the body mass index were not . The overall incidence of deep-vein thrombosis in this series was 11 % . There was no clinical or statistical significant reduction in the incidence of deep-vein thrombosis with the use of thromboprophylaxis . However , we accept that owing to a cessation of funding , recruitment to this trial had to be ended prior to establishing the necessary sample size . Our results can not , therefore , categorically exclude the possibility that low molecular weight heparin treatment could be beneficial . We recommend a further multicentre trial be undertaken to resolve this matter Betrixaban is an oral direct inhibitor of factor Xa ( FXa ) being developed for the prevention of venous thromboembolism ( VTE ) . Its antithrombotic effects had not been previously tested in patients . This exploratory clinical trial in the US and Canada r and omized 215 patients undergoing elective total knee replacement ( TKR ) in a 2:2:1 ratio to receive post-operative betrixaban 15 mg or 40 mg p.o . bid or enoxaparin 30 mg s.c . q12h , respectively , for 10 - 14 days . The betrixaban dosage was blinded , but enoxaparin was not . Primary efficacy outcome was the incidence of VTE , consisting of deep-vein thrombosis ( DVT ) on m and atory unilateral ( operated leg ) venography , symptomatic proximal DVT , or pulmonary embolism ( PE ) through Day 10 - 14 . Safety outcomes included major and clinical ly significant non-major bleeds through 48 h after treatment . All efficacy and bleeding outcomes were adjudicated by a blinded independent central adjudication committee . Of 214 treated patients , 175 ( 82 % ) were evaluable for primary efficacy . VTE incidence was 14/70 ( 20 % ; 95 % CI : 11 , 31 ) for betrixaban 15 mg , 10/65 ( 15 % ; 95 % CI : 8 , 27 ) for betrixaban 40 mg , and 4/40 ( 10 % ; 95 % CI : 3 , 24 ) for enoxaparin . No bleeds were reported for betrixaban 15 mg , 2 ( 2.4 % ) clinical ly significant non-major bleeds with betrixaban 40 mg , and one ( 2.3 % ) major and two ( 4.6 % ) clinical ly significant non-major bleeds with enoxaparin . A dose- and concentration-dependent effect of betrixaban on inhibition of thrombin generation and anti-Xa levels was observed . Betrixaban demonstrated antithrombotic activity and appeared well tolerated in knee replacement patients at the doses studied Students of Markov decision models are often taught to add a half-cycle 's worth of incremental utility to the cumulative total for each health state . The reason for this ` ` half-cycle correction ' ' is often illustrated by a graph of the proportion of the hypothetical Markov cohort remaining in a given state . The ideal graph is shown as a smooth , declining , curve that represents the transition of patients r and omly throughout each cycle . On the same graph , the effect of the accounting of state membership at the end of each cycle in discrete , computer-based approximations of the ideal Markov process is shown . Students are able to clearly see that the cumulative incremental utility in the discrete case underestimates the desired quantity . Likewise , they find the concept of shifting the ideal curve to the right by one-half cycle to reduce the latter discrepancy to be intuitive . However , students often find the approximate equivalence of shifting the ideal state membership curve and adding a half-cycle 's worth of incremental utility to the total for the state at the beginning of a discrete Markov process to be a difficult cognitive leap . This article describes 2 pedagogical devices , algebraic and intuitive/visual approaches , that may assist the instructor of Markov theory to convey the latter concept . Elements of adult learning theory are discussed , which may help the instructor to choose which approach to employ . Implementation of the half-cycle correction in commonly used decision-analytic software is also discussed BACKGROUND Chronic thromboembolic pulmonary hypertension ( CTPH ) is associated with considerable morbidity and mortality . Its incidence after pulmonary embolism and associated risk factors are not well documented . METHODS We conducted a prospect i ve , long-term , follow-up study to assess the incidence of symptomatic CTPH in consecutive patients with an acute episode of pulmonary embolism but without prior venous thromboembolism . Patients with unexplained persistent dyspnea during follow-up underwent transthoracic echocardiography and , if supportive findings were present , ventilation-perfusion lung scanning and pulmonary angiography . CTPH was considered to be present if systolic and mean pulmonary-artery pressures exceeded 40 mm Hg and 25 mm Hg , respectively ; pulmonary-capillary wedge pressure was normal ; and there was angiographic evidence of disease . RESULTS The cumulative incidence of symptomatic CTPH was 1.0 percent ( 95 percent confidence interval , 0.0 to 2.4 ) at six months , 3.1 percent ( 95 percent confidence interval , 0.7 to 5.5 ) at one year , and 3.8 percent ( 95 percent confidence interval , 1.1 to 6.5 ) at two years . No cases occurred after two years among the patients with more than two years of follow-up data . The following increased the risk of CTPH : a previous pulmonary embolism ( odds ratio , 19.0 ) , younger age ( odds ratio , 1.79 per decade ) , a larger perfusion defect ( odds ratio , 2.22 per decile decrement in perfusion ) , and idiopathic pulmonary embolism at presentation ( odds ratio , 5.70 ) . CONCLUSIONS CTPH is a relatively common , serious complication of pulmonary embolism . Diagnostic and therapeutic strategies for the early identification and prevention of CTPH are needed BACKGROUND Apixaban ( 5 mg BID ) , dabigatran ( available as 150 mg and 110 mg BID in Europe ) , and rivaroxaban ( 20 mg once daily ) are 3 novel oral anticoagulants ( NOACs ) currently approved for stroke prevention in patients with atrial fibrillation ( AF ) . OBJECTIVE The objective of this study was to evaluate the cost-effectiveness of apixaban against other NOACs from the perspective of the United Kingdom National Health Services . METHODS A Markov model was developed to evaluate the pharmacoeconomic impact of apixaban versus other NOACs over a lifetime . Pair-wise indirect treatment comparisons were conducted against other NOACs by using ARISTOTLE ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ) , RE-LY ( R and omized Evaluation of Long-Term Anticoagulation Therapy ) , and ROCKET-AF ( Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation ) trial results for the following end points : ischemic stroke , hemorrhagic stroke , intracranial hemorrhage , other major bleeds , clinical ly relevant nonmajor bleeds , myocardial infa rct ion , and treatment discontinuations . Outcomes were life-years , quality -adjusted life years gained , direct health care costs , and incremental cost-effectiveness ratios . RESULTS Apixaban was projected to increase life expectancy versus other NOACs , including dabigatran ( both doses ) and rivaroxaban . A small increase in therapeutic management costs was observed with apixaban due to projected gains in life expectancy and lower discontinuation rates anticipated on apixaban versus other NOACs through lifetime . The estimated incremental cost-effectiveness ratio was £ 9611 , £ 4497 , and £ 5305 per quality -adjusted life-year gained with apixaban compared with dabigatran 150 mg BID , dabigatran 110 mg BID , and rivaroxaban 20 mg once daily , respectively . Sensitivity analyses indicated that results were robust over a wide range of inputs . CONCLUSIONS Although our analysis was limited by the absence of head-to-head trials , based on the indirect comparison data available , our model projects that apixaban may be a cost-effective alternative to dabigatran 150 mg BID , dabigatran 110 mg BID , and rivaroxaban 20 mg once daily for stroke prevention in AF patients from the perspective of the United Kingdom National Health Services BACKGROUND The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment . Rivaroxaban , an oral factor Xa inhibitor , may provide more consistent and predictable anticoagulation than warfarin . METHODS In a double-blind trial , we r and omly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban ( at a daily dose of 20 mg ) or dose-adjusted warfarin . The per- protocol , as-treated primary analysis was design ed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism . RESULTS In the primary analysis , the primary end point occurred in 188 patients in the rivaroxaban group ( 1.7 % per year ) and in 241 in the warfarin group ( 2.2 % per year ) ( hazard ratio in the rivaroxaban group , 0.79 ; 95 % confidence interval [ CI ] , 0.66 to 0.96 ; P<0.001 for noninferiority ) . In the intention-to-treat analysis , the primary end point occurred in 269 patients in the rivaroxaban group ( 2.1 % per year ) and in 306 patients in the warfarin group ( 2.4 % per year ) ( hazard ratio , 0.88 ; 95 % CI , 0.74 to 1.03 ; P<0.001 for noninferiority ; P=0.12 for superiority ) . Major and nonmajor clinical ly relevant bleeding occurred in 1475 patients in the rivaroxaban group ( 14.9 % per year ) and in 1449 in the warfarin group ( 14.5 % per year ) ( hazard ratio , 1.03 ; 95 % CI , 0.96 to 1.11 ; P=0.44 ) , with significant reductions in intracranial hemorrhage ( 0.5 % vs. 0.7 % , P=0.02 ) and fatal bleeding ( 0.2 % vs. 0.5 % , P=0.003 ) in the rivaroxaban group . CONCLUSIONS In patients with atrial fibrillation , rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism . There was no significant between-group difference in the risk of major bleeding , although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group . ( Funded by Johnson & Johnson and Bayer ; ROCKET AF Clinical Trials.gov number , NCT00403767 . ) BACKGROUND In the ARISTOTLE trial , the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation ( AF ) . Patients with AF and previous stroke or transient ischaemic attack ( TIA ) have a high risk of stroke . We therefore aim ed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA . METHODS Between Dec 19 , 2006 , and April 2 , 2010 , patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries . 18,201 patients with AF or atrial flutter were r and omly assigned to receive apixaban 5 mg twice daily or warfarin ( target international normalised ratio 2·0 - 3·0 ) . The median duration of follow-up was 1·8 years ( IQR 1·4 - 2·3 ) . The primary efficacy outcome was stroke or systemic embolism , analysed by intention to treat . The primary safety outcome was major bleeding in the on-treatment population . All participants , investigators , and sponsors were masked to treatment assignments . In this subgroup analysis , we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA . The ARISTOTLE trial is registered with Clinical Trials.gov , number NTC00412984 . FINDINGS Of the trial population , 3436 ( 19 % ) had a previous stroke or TIA . In the subgroup of patients with previous stroke or TIA , the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group ( hazard ratio [ HR ] 0·76 , 95 % CI 0·56 to 1·03 ) ; in the subgroup of patients without previous stroke or TIA , the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin ( HR 0·82 , 95 % CI 0·65 to 1·03 ; p for interaction=0·71 ) . The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up ( 95 % CI -0·08 to 1·63 ) in patients with and 0·22 ( -0·03 to 0·47 ) in those without previous stroke or TIA . The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years ( 95 % CI 0·09 - 2·04 ) in patients with and 0·93 ( 0·54 - 1·32 ) in those without previous stroke or TIA . INTERPRETATION The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA . Owing to the higher risk of these outcomes in patients with previous stroke or TIA , the absolute benefits of apixaban might be greater in this population . FUNDING Bristol-Myers Squibb and Pfizer BACKGROUND The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain . We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin . METHODS In this double-blind , double-dummy , placebo-controlled trial , we r and omly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least 3 days to receive apixaban , administered orally at a dose of 2.5 mg twice daily for 30 days , or enoxaparin , administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days . The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism , pulmonary embolism , symptomatic deep-vein thrombosis , or asymptomatic proximal-leg deep-vein thrombosis , as detected with the use of systematic bilateral compression ultrasonography on day 30 . The primary safety outcome was bleeding . All efficacy and safety outcomes were independently adjudicated . RESULTS A total of 6528 subjects underwent r and omization , 4495 of whom could be evaluated for the primary efficacy outcome --2211 in the apixaban group and 2284 in the enoxaparin group . Among the patients who could be evaluated , 2.71 % in the apixaban group ( 60 patients ) and 3.06 % in the enoxaparin group ( 70 patients ) met the criteria for the primary efficacy outcome ( relative risk with apixaban , 0.87 ; 95 % confidence interval [ CI ] , 0.62 to 1.23 ; P=0.44 ) . By day 30 , major bleeding had occurred in 0.47 % of the patients in the apixaban group ( 15 of 3184 patients ) and in 0.19 % of the patients in the enoxaparin group ( 6 of 3217 patients ) ( relative risk , 2.58 ; 95 % CI , 1.02 to 7.24 ; P=0.04 ) . CONCLUSIONS In medically ill patients , an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin . Apixaban was associated with significantly more major bleeding events than was enoxaparin . ( Funded by Bristol-Myers Squibb and Pfizer ; Clinical Trials.gov number , NCT00457002 . ) INTRODUCTION This phase 3 trial compared the safety and efficacy of edoxaban , an oral direct factor Xa inhibitor , with enoxaparin sodium ( enoxaparin ) for thromboprophylaxis after total knee arthroplasty ( TKA ) in patients in Japan and Taiwan . MATERIAL S AND METHODS In this r and omized , double-blind , double-dummy study , patients received oral edoxaban 30 mg once daily beginning 6 to 24 hours postsurgery or enoxaparin 2000 IU ( equivalent to 20 mg ) subcutaneously twice daily beginning 24 to 36 hours postsurgery for 11 to 14 days . The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis . Safety endpoints included the incidence of major bleeding , clinical ly relevant non-major ( CRNM ) bleeding , major bleeding or CRNM bleeding , all bleeding events , adverse events , and adverse drug reactions . RESULTS Of 716 patients enrolled , 360 and 356 were r and omized to receive edoxaban or enoxaparin , respectively . The primary efficacy outcome occurred in 22/299 ( 7.4 % ) and 41/295 ( 13.9 % ) patients in the edoxaban and enoxaparin groups , respectively ( relative risk reduction=46.8 % ) , indicating non-inferiority ( P < 0.001 ) and superiority ( P=0.010 ) of edoxaban versus enoxaparin . In the edoxaban and enoxaparin groups , major bleeding occurred in 4/354 ( 1.1 % ) versus 1/349 ( 0.3 % ) patients ( P=0.373 ) ; major or CRNM bleeding occurred in 22/354 ( 6.2 % ) versus 13/349 ( 3.7 % ) patients ( P=0.129 ) , respectively . CONCLUSIONS Edoxaban 30 mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000 IU twice daily following TKA and demonstrated a similar incidence of bleeding events BACKGROUND Oral anticoagulants , such as dabigatran etexilate , an oral , direct thrombin inhibitor , that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism ( VTE ) after total knee replacement surgery . METHODS In this r and omized , double-blind study , 2076 patients undergoing total knee replacement received dabigatran etexilate , 150 mg or 220 mg once-daily , starting with a half-dose 1 - 4 hours after surgery , or subcutaneous enoxaparin 40 mg once-daily , starting the evening before surgery , for 6 - 10 days . Patients were followed-up for 3 months . The primary efficacy outcome was a composite of total VTE ( venographic or symptomatic ) and mortality during treatment , and the primary safety outcome was the incidence of bleeding events . RESULTS The primary efficacy outcome occurred in 37.7 % ( 193 of 512 ) of the enoxaparin group versus 36.4 % ( 183 of 503 ) of the dabigatran etexilate 220 mg group ( absolute difference , -1.3 % ; 95 % CI , -7.3 to 4.6 ) and 40.5 % ( 213 of 526 ) of the 150 mg group ( 2.8 % ; 95 % CI , -3.1 to 8.7 ) . Both doses were noninferior to enoxaparin based on the pre-specified noninferiority criterion . The incidence of major bleeding did not differ significantly between the three groups ( 1.3 % versus 1.5 % and 1.3 % respectively ) . No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up . CONCLUSIONS Dabigatran etexilate ( 220 mg or 150 mg ) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery Background : Patients treated with total knee arthroplasty are at high risk for the development of venous thromboembolism postoperatively . This study compared the efficacy and safety of two common thromboprophylactic agents , enoxaparin ( a low‐molecular-weight heparin ) and warfarin . Methods : Three hundred and forty‐nine patients were included in a prospect i ve , r and omized , multicenter , open-label , parallel-group clinical trial . Treatment with enoxaparin ( 30 mg , administered subcutaneously twice daily ) or warfarin ( adjusted to an international normalized ratio of 2 to 3 ) was initiated during the immediate postoperative period , within eight hours after the surgery , and was continued for four to fourteen days . Venous thromboembolism was defined as deep‐vein thrombosis documented by contrast venography , symptomatic deep‐vein thrombosis documented by lower-extremity ultrasonography , or symptomatic pulmonary embolism confirmed by a positive lung scan or pulmonary angiography . Results : In the all‐treated- patients group , eighty ( 45 % ) of the 176 warfarin‐treated patients had venous thromboembolism : fifty‐nine ( 34 % ) had distal deep‐vein thrombosis ; twenty ( 11 % ) , proximal deep‐vein thrombosis ; and one ( 0.6 % ) , pulmonary embolism . Venous thromboembolism developed in significantly fewer ( p = 0.0001 ) enoxaparin‐treated patients ( forty-four of 173 ; 25 % ) : forty‐one ( 24 % ) had distal deep‐vein thrombosis , three ( 2 % ) had proximal deep‐vein thrombosis , and none had pulmonary embolism . The enoxaparin‐treated patients also had a significantly lower prevalence of proximal deep‐vein thrombosis ( p = 0.002 ) . The estimated odds for the development of venous thromboembolism were 2.52 times greater ( 95 % confidence interval , 2.00 to 3.19 ) with warfarin than they were with enoxaparin . Major hemorrhage occurred in four warfarin‐treated patients and nine enoxaparin‐treated patients ; with the numbers available , this difference was not significant ( p = 0.17 ) . Clinical ly important operative‐site hemorrhage occurred in six ( 3 % ) of the warfarin-treated patients and twelve ( 7 % ) of the enoxaparin-treated patients ( p = 0.15 ) . Conclusions : A fixed 30-mg subcutaneous dose of enoxaparin , administered twice daily , with the first dose administered within eight hours after the completion of surgery , was significantly more effective than adjusted‐dose warfarin in reducing the occurrence of asymptomatic venous thromboembolism , including proximal deep‐vein thrombosis , in patients undergoing total knee arthroplasty . With the numbers available , there was no significant difference between groups with regard to the occurrence of major hemorrhagic complications ; however , the rate of overall hemorrhagic complications was higher in the enoxaparin group Edoxaban is a new oral direct factor Xa inhibitor . The purpose of this study was to evaluate the efficacy and safety of different doses of edoxaban for the prevention of venous thromboembolism ( VTE ) in patients undergoing elective total hip replacement . A total of 903 patients were r and omised to oral edoxaban 15 , 30 , 60 or 90 mg once daily or subcutaneous dalteparin once daily ( initial dose 2,500 IU , subsequent doses 5,000 IU ) . Both drugs were begun 6 - 8 hours postoperatively and continued for 7 - 10 days , when bilateral venography was performed . The primary efficacy endpoint was the incidence of total VTE , which included proximal and /or distal deep-vein thrombosis ( DVT ) by venography or symptomatic , objective ly confirmed DVT or pulmonary embolism during the treatment period . The primary safety outcome was the incidence of the composite of major and clinical ly relevant non-major bleeding . All venograms and bleeding events were review ed by a central independent adjudication committee blinded as to treatment allocation . Of the 903 patients r and omised , 776 were evaluable for the primary efficacy analysis . The incidences of VTE were 28.2 % , 21.2 % , 15.2 % , and 10.6 % in patients receiving edoxaban 15 , 30 , 60 and 90 mg , respectively , compared with 43.8 % in the dalteparin group ( p<0.005 ) . There was a statistically significant ( p<0.001 ) dose-response for efficacy across the edoxaban dose groups for total VTE and for major VTE . The incidence of clinical ly relevant bleeding was low and similar across the groups . Oral edoxaban once daily is effective for preventing VTE after total hip replacement INTRODUCTION Edoxaban is an oral , direct , once-daily factor Xa inhibitor . This study evaluated the safety and efficacy of edoxaban compared to subcutaneous enoxaparin in Japanese patients undergoing hip fracture surgery . MATERIAL S AND METHODS In this multicenter , r and omized , open-label , active-comparator , phase 3 trial , 92 patients were r and omized 2:1 to receive edoxaban 30 mg once daily ( n=62 ) or enoxaparin sodium ( enoxaparin ) 2000IU ( equivalent to 20 mg ) twice daily ( n=30 ) for 11 to 14days . The primary endpoints were the incidence of major or clinical ly relevant non-major ( CRNM ) bleeding and incidence of any bleeding events ( major , CRNM , or minor bleeding ) . Secondary efficacy endpoints included the incidence of thromboembolic events , venous thromboembolism-related deaths , and all-cause deaths . Additional adverse events were recorded throughout the study . RESULTS In the edoxaban and enoxaparin treatment groups , the incidence of major or CRNM bleeding was 3.4 % and 6.9 % , respectively , while any bleeding event occurred in 25.4 % and 17.2 % of patients , respectively . The incidence of thromboembolic events was 6.5 % in the edoxaban group and 3.7 % in the enoxaparin group . All events were asymptomatic deep vein thrombosis . The incidence of adverse events was 72.9 % and 82.8 % in the edoxaban and enoxaparin groups , respectively . CONCLUSIONS Compared to subcutaneous enoxaparin 2000IU twice daily , oral edoxaban 30 mg once daily demonstrated similar safety and efficacy in the prevention of thromboembolic events in Japanese patients undergoing hip fracture surgery . CLINICAL TRIALS REGISTRATION NUMBER NCT01181141 BACKGROUND Guidelines recommend warfarin as the st and ard of care for patients with atrial fibrillation ( AF ) at moderate or high risk for stroke . This phase II study assessed the effects of 2 doses of the factor Xa inhibitor apixaban vs. warfarin in Japanese patients with non-valvular AF . The composite primary endpoint was major and clinical ly relevant non-major ( CRNM ) bleeding . METHODS AND RESULTS Two hundred and twenty-two patients with AF and 1 or more additional risk factors for stroke were r and omized ( 1:1:1 ) to double-blind apixaban 2.5 or 5 mg b.i.d . or open-label warfarin ( target international normalized ratio 2.0 - 3.0 ; 2.0 - 2.6 if age ≥ 70 years ) for 12 weeks . The primary endpoint occurred in 1 patient ( 1.4 % ) in each apixaban group and 4 ( 5.3 % ) warfarin patients . There were no strokes , systemic emboli , myocardial infa rct ions , or deaths in either apixaban group . The warfarin group had 2 ischemic strokes and 1 subarachnoid hemorrhage , but there were no deaths . Major and CRNM bleeds each occurred with higher frequency in the warfarin group vs. either apixaban group . Most adverse events were mild or moderate . No patients had hepatic aminotransferase elevations greater than 3 times the upper limit of normal . CONCLUSIONS In Japanese patients with AF , apixaban 2.5 and 5 mg b.i.d . were well tolerated over 12 weeks . A global phase III trial , which includes Japanese patients , is ongoing ( Clinical Trials.gov Identifier NCT00787150 ) Abstract Background : In order to evaluate the cost effectiveness of preventive strategies for myocardial infa rct ion ( MI ) , direct cost estimates are required . However , Australian-specific cost estimates for MI are not available . Objective : The CosMIC ( Cost of Myocardial Infa rct ion to the Community ) in Australia study was design ed to determine the re source use and estimate the direct costs associated with MI in the Australian Health Care System . This information could subsequently be used in cost-effectiveness evaluations . Methods : A prospect i ve , multicentre survey was undertaken to investigate the costs associated with the initial hospitalization and the 12-month sequelae for patients with a first-ever MI . During the recruitment period 312 patients with MI from ten hospitals met the eligibility criteria . Of the 141 who consented to participate and were enrolled , three were withdrawn and 138 were included in the final analysis . Detailed data were collected for 12 months after the index hospitalization from several overlapping sources . All costs were considered from the point of view of total direct cost of care , i.e. regardless of who generated or paid for the service . Results : The mean length of hospital stay for the initial acute episode was 7.4 days and the mean cost was $ A10 934 ( 95 % confidence interval [ CI ] 9588 , 12 280 ) based on 2005 Australian dollars . There were 127 cardiac-related readmissions for 55 ( 40 % ) patients and the mean length of stay was 2.6 days . The mean total direct cost of an MI per patient was $ A20 502 ( 95 % CI 18 428 , 22 576 ) . The majority of the costs were for hospitalizations ( initial and readmissions ) , which accounted for 77 % of the total 12-month costs , whilst hospitalization costs for the initial acute event accounted for 53 % of all costs . During the 12-month follow-up period , out-of-hospital medical service costs ( Medicare Benefits Schedule services ) contributed to 7 % of the total costs incurred , medications 6 % , ambulance costs 3 % and all other outpatient services and carer costs 7 % . Conclusion : The CosMIC study addresses the significant uncertainty associated with MI cost-of-illness data in Australia by providing an estimation of direct costs associated with MI in an Australian population . These direct costs can be used to determine the cost effectiveness of prevention strategies BACKGROUND Edoxaban is a once-daily ( QD ) oral , direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation ( NVAF ) . The aim of this study was to evaluate the safety of edoxaban in Japanese patients with NVAF . METHODS AND RESULTS A total of 536 NVAF patients ( CHADS2 ≥1 ) were r and omized to receive double-blinded edoxaban 30 , 45 , or 60 mg QD or open-label warfarin ( international normalized ratio [ INR ] 2.0 - 3.0 for age < 70 years ; 1.6 - 2.6 for age ≥70 years ) for 12 weeks . The primary endpoint was the incidence of all bleeding events ( major , clinical ly relevant non-major , and minor bleeds ) . Patients underwent CT and /or MRI to assess asymptomatic intracranial hemorrhage ( ICH ) . Secondary endpoints included thromboembolic events and pharmacodynamic indices . The mean incidence of all bleeding events for edoxaban 30 , 45 , and 60 mg , and warfarin was 18.5 % , 22.4 % , 27.7 % , and 20.0 % , respectively . There were no statistically significant differences among the edoxaban groups and no significant differences from the warfarin group . There were no asymptomatic ICH events in any group . One episode of cerebral infa rct ion was observed in the edoxaban 45-mg group . Subgroup analysis suggested low body weight ( ≤60 kg ) was associated with higher bleeding risk . CONCLUSIONS Edoxaban 30 , 45 , and 60 mg QD in patients with NVAF was associated with a numerical increase in all bleeding across the dose range , but this was not statistically significant , nor was any dose compared with warfarin BACKGROUND Venous thromboembolic disease in the form of deep venous thrombosis and pulmonary embolism is a major risk after a total hip arthroplasty . Enoxaparin , a low-molecular-weight heparin , has been shown to reduce the prevalence of deep venous thrombosis after total hip arthroplasty . Warfarin , an orally administered anticoagulant , has been used historically to reduce the risk of deep venous thrombosis after total hip arthroplasty . METHODS We compared enoxaparin and adjusted-dose warfarin with respect to their safety and their efficacy in the prevention of clinical ly important venous thromboembolic disease , defined as distal or proximal deep venous thrombosis or pulmonary embolism , or both , during hospitalization after total hip arthroplasty . We also evaluated the prevalence of complications and mortality from venous thromboembolic disease within three months after discharge . RESULTS Three thous and and eleven patients at 156 centers were r and omly assigned to prophylactic treatment with injection of enoxaparin or oral administration of adjusted-dose warfarin during hospitalization . During the study , fifty-five ( 3.6 percent ) of the 1516 patients who were managed with enoxaparin and fifty-six ( 3.7 percent ) of the 1495 patients who were managed with warfarin had venous thromboembolic disease . Twenty-one patients ( 0.7 percent ) , which included four ( 0.3 percent ) of those managed with enoxaparin and seventeen ( 1.1 percent ) of those managed with warfarin ( p = 0.0083 ) , had venous thromboembolic disease during hospitalization . After discharge from the hospital , venous thromboembolic disease developed in ninety patients ( 3.0 percent ) : fifty-one ( 3.4 percent ) of those managed with enoxaparin and thirty-nine ( 2.6 percent ) of those managed with warfarin . One patient who had been managed with enoxaparin died because of a pulmonary embolism , which was confirmed at autopsy . Three additional patients ( one who had been managed with enoxaparin and two who had been managed with warfarin ) died , and the deaths were attributed to venous thromboembolic disease ; however , no autopsies were performed . Twenty-six patients ( 0.9 percent ) ( eighteen managed with enoxaparin and eight managed with warfarin ) had clinical ly important bleeding . CONCLUSIONS Inpatient programs providing treatment with either enoxaparin ( thirty milligrams every twelve hours ) or adjusted-dose warfarin for a mean of 7.3 days afforded protection against venous thromboembolic disease , with overall rates of morbidity and mortality of 3.7 and 0.6 percent , respectively , and a very low rate of major bleeding complications ( 0.9 percent ) for three months after total hip arthroplasty . During hospitalization , the patients managed with enoxaparin had a lower rate of venous thromboembolic disease than those managed with adjusted-dose warfarin ( p = 0.0083 ) . This benefit was lost after the medication was discontinued , with no difference in the prevalences of venous thromboembolic disease between the two groups at three months after discharge from the hospital The Canadian Atrial Fibrillation Anticoagulation Study was a r and omized double-blind placebo-controlled trial to assess the potential of warfarin to reduce systemic thromboembolism and its inherent risk of hemorrhage . As a result of the publication of two other " positive " studies of similar design and objective , this study was stopped early before completion of its planned recruitment of 630 patients . There were 187 patients r and omized to warfarin and 191 to placebo . Permanent discontinuation of study medication occurred in 26 % of warfarin-treated and 23 % of placebo-treated patients . The target range of the international normalized ratio was 2 to 3 . For the warfarin-treated patients , the international normalized ratio was in the target range 43.7 % of the study days , above it 16.6 % of the study days and below it 39.6 % of the study days . Fatal or major bleeding occurred at annual rates of 2.5 % in warfarin-treated and 0.5 % in placebo-treated patients . Minor bleeding occurred in 16 % of patients receiving warfarin and 9 % receiving placebo . The primary outcome event cluster was nonlacunar stroke , non central nervous systemic embolism and fatal or intracranial hemorrhage . Events were included in the primary analysis of efficacy if they occurred within 28 days of permanent discontinuation of the study medication . The annual rates of the primary outcome event cluster were 3.5 % in warfarin-treated and 5.2 % in placebo-treated patients , with a relative risk reduction of 37 % ( 95 % confidence limits , -63.5 % , 75.5 % , p = 0.17 ) . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND Edoxaban ( the free base of DU-176b ) is an oral , direct factor (F)Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events . OBJECTIVES The aim of the present study was to evaluate the efficacy and safety of edoxaban for the prevention of venous thromboembolism ( VTE ) in patients undergoing total knee arthroplasty ( TKA ) . PATIENTS / METHODS This was a r and omized , double-blind , placebo-controlled , multicenter study conducted in Japan . A total of 523 Japanese patients were assigned to receive edoxaban 5 , 15 , 30 or 60 mg once daily or placebo for 11 - 14 days . A placebo control was used as neither low-molecular-weight heparin ( LMWH ) nor fondaparinux had been approved for thromboprophylaxis at the time of the study in Japan . The primary efficacy outcome was the incidence of VTE ( lower-extremity deep vein thrombosis , symptomatic pulmonary embolism or symptomatic deep vein thrombosis ) . The primary safety outcome was the incidence of major and clinical ly relevant non-major bleeding . RESULTS Edoxaban produced a significant dose-related reduction in VTE : the incidence of VTE was 29.5 % , 26.1 % , 12.5 % and 9.1 % in the edoxaban 5- , 15- , 30- and 60-mg treatment groups vs. 48.3 % in the placebo group . The incidence of major and clinical ly relevant non-major bleeding was similar across all groups without any significant differences among edoxaban doses or between edoxaban and placebo . CONCLUSIONS Edoxaban demonstrated significant dose-dependent reductions in VTE in patients undergoing TKA with a bleeding incidence similar to placebo . [ This trial is registered with JAPIC , JapicCTI-060283 ( ja ) . ] This trial compared the efficacy and safety of oral dabigatran , a direct thrombin inhibitor , versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty . A total of 2,055 patients were r and omised to 28 - 35 days treatment with oral dabigatran , 220 mg once-daily , starting with a half-dose 1 - 4 hours after surgery , or subcutaneous enoxaparin 40 mg once-daily , starting the evening before surgery . The primary efficacy outcome was a composite of total venous thromboembolism [ VTE ] ( venographic or symptomatic ) and death from all-causes . The main secondary composite outcome was major VTE ( proximal deep-vein thrombosis or non-fatal pulmonary embolism ) plus VTE-related death . The main safety outcome was major bleeding . In total , 2,013 were treated , of whom 1,577 operated patients were included in the primary efficacy analysis . The primary efficacy outcome occurred in 7.7 % of the dabigatran group versus 8.8 % of the enoxaparin group , risk difference ( RD ) -1.1 % ( 95%CI -3.8 to 1.6 % ) ; p<0.0001 for the pre-specified non-inferiority margin . Major VTE plus VTE-related death occurred in 2.2 % of the dabigatran group versus 4.2 % of the enoxaparin group , RD -1.9 % ( -3.6 % to -0.2 % ) ; p=0.03 . Major bleeding occurred in 1.4 % of the dabigatran group and 0.9 % of the enoxaparin group ( p=0.40 ) . The incidence of adverse events , including liver enzyme elevations and cardiac events , during treatment was similar between the groups . Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty , and superior to enoxaparin for reducing the risk of major VTE . The risk of bleeding and safety profiles were similar BACKGROUND In patients with idiopathic deep venous thrombosis , continuing anticoagulant therapy beyond three months is associated with a reduced incidence of recurrent thrombosis during the period of therapy . Whether this benefit persists after anticoagulant therapy is discontinued is controversial . METHODS Patients with a first episode of idiopathic proximal deep venous thrombosis who had completed three months of oral anticoagulant therapy ( with warfarin , in 97 percent of the cases and acenocoumarol in 3 percent ) were r and omly assigned to the discontinuation of oral anticoagulants or to their continuation for nine additional months . The primary study outcome was recurrence of symptomatic , objective ly confirmed venous thromboembolism during at least two years of follow-up . RESULTS The primary intention-to-treat analysis showed that of 134 patients assigned to continued oral anticoagulant therapy , 21 had a recurrence of venous thromboembolism ( 15.7 percent ; average follow-up , 37.8 months ) , as compared with 21 of 133 patients assigned to the discontinuation of oral anticoagulant therapy ( 15.8 percent ; average follow-up , 37.2 months ) , result ing in a relative risk of 0.99 ( 95 percent confidence interval , 0.57 to 1.73 ) . During the initial nine months after r and omization ( after all patients received three months of therapy ) , 1 patient had a recurrence while receiving oral anticoagulant therapy ( 0.7 percent ) , as compared with 11 of the patients assigned to the discontinuation of oral anticoagulant therapy ( 8.3 percent ; P=0.003 ) . The incidence of recurrence after the discontinuation of treatment was 5.1 percent per patient-year in patients in whom oral anticoagulant therapy was discontinued after 3 months ( 95 percent confidence interval , 3.2 to 7.5 percent ; average interval since discontinuation , 37.2 months ) and 5.0 percent per patient-year in patients who received an additional 9 months of oral anticoagulant therapy ( 95 percent confidence interval , 3.1 to 7.8 percent ; average interval since discontinuation , 29.4 months ) . None of the recurrences were fatal . Four patients had non-fatal major bleeding during the extended period of anticoagulant therapy ( 3.0 percent ) . CONCLUSIONS In patients with idiopathic deep venous thrombosis , the clinical benefit associated with extending the duration of anticoagulant therapy to one year is not maintained after the therapy is discontinued BACKGROUND Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation , but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown . We assessed whether warfarin reduced risk of major stroke , arterial embolism , or other intracranial haemorrhage compared with aspirin in elderly patients . METHODS 973 patients aged 75 years or over ( mean age 81.5 years , SD 4.2 ) with atrial fibrillation were recruited from primary care and r and omly assigned to warfarin ( target international normalised ratio 2 - 3 ) or aspirin ( 75 mg per day ) . Follow-up was for a mean of 2.7 years ( SD 1.2 ) . The primary endpoint was fatal or disabling stroke ( ischaemic or haemorrhagic ) , intracranial haemorrhage , or clinical ly significant arterial embolism . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N89345269 . FINDINGS There were 24 primary events ( 21 strokes , two other intracranial haemorrhages , and one systemic embolus ) in people assigned to warfarin and 48 primary events ( 44 strokes , one other intracranial haemorrhage , and three systemic emboli ) in people assigned to aspirin ( yearly risk 1.8%vs 3.8 % , relative risk 0.48 , 95 % CI 0.28 - 0.80 , p=0.003 ; absolute yearly risk reduction 2 % , 95 % CI 0.7 - 3.2 ) . Yearly risk of extracranial haemorrhage was 1.4 % ( warfarin ) versus 1.6 % ( aspirin ) ( relative risk 0.87 , 0.43 - 1.73 ; absolute risk reduction 0.2 % , -0.7 to 1.2 ) . INTERPRETATION These data support the use of anticoagulation therapy for people aged over 75 who have atrial fibrillation , unless there are contraindications or the patient decides that the benefits are not worth the inconvenience INTRODUCTION Rivaroxaban ( BAY 59 - 7939 ) is a novel , oral , direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders . The aim of this study was to demonstrate proof-of-principle for rivaroxaban . MATERIAL S AND METHODS This was an open-label , dose-escalation study to assess the efficacy and safety of rivaroxaban , relative to enoxaparin , for the prevention of venous thromboembolism ( VTE ) after total hip replacement surgery . Patients were r and omized in a 3:1 ratio to rivaroxaban ( 2.5 , 5 , 10 , 20 and 30 mg twice daily [ bid ] or 30 mg once daily [ od ] starting 6 - 8 h after surgery ) or enoxaparin ( 40 mg od starting the evening before surgery ) . Therapy continued until m and atory bilateral venography was performed 5 - 9 days after surgery . RESULTS A total of 625 patients received therapy , of whom 466 patients were eligible for the per- protocol efficacy analysis . The primary efficacy endpoint - deep vein thrombosis ( DVT ) , pulmonary embolism ( PE ) or all-cause mortality - occurred in 22.2 % , 23.8 % , 20.0 % , 10.2 % , 17.4 % , 15.1 % and 16.8 % of patients receiving rivaroxaban 2.5 , 5 , 10 , 20 , 30 mg bid , 30 mg od and enoxaparin , respectively . The dose-response relationship with rivaroxaban for the primary efficacy endpoint was not statistically significant ( p=0.0504 ) , although major VTE ( proximal DVT , PE and VTE-related death ) decreased dose dependently with rivaroxaban ( p=0.0108 ) . Major , post-operative bleeding increased dose dependently with rivaroxaban ( p=0.0008 ) , occurring in 0 - 10.8 % of patients , compared with 0 % in patients receiving enoxaparin . CONCLUSIONS This study demonstrated proof-of-principle for rivaroxaban for the prevention of VTE after total hip replacement surgery OBJECTIVE To examine the cost-effectiveness of prescribing warfarin sodium in patients who have nonvalvular atrial fibrillation ( NVAF ) with or without additional stroke risk factors ( a prior stroke or transient ischemic attack , diabetes , hypertension , or heart disease ) . DESIGN Decision and cost-effectiveness analyses . The probabilities for stroke , hemorrhage , and death were obtained from published r and omized controlled trials . The quality -of-life estimates were obtained by interviewing 74 patients with atrial fibrillation . Costs were estimated from literature review , phone survey , and Medicare reimbursement . PATIENTS In the base case , the patients were 65 years of age and good c and i date s for warfarin therapy . INTERVENTIONS Treatment with warfarin , aspirin , or no therapy in the decision analytic model . MAIN OUTCOME MEASURES Quality -adjusted survival and marginal cost-effectiveness of warfarin as compared with aspirin or no therapy . RESULTS For patients with NVAF and additional risk factors for stroke , warfarin therapy led to a greater quality -adjusted survival and to cost savings . For patients with NVAF and one additional risk factor , warfarin therapy cost $ 8000 per quality -adjusted life-year saved . For 65-year-old patients with NVAF alone , warfarin cost about $ 370,000 per quality -adjusted life-year saved , as compared with aspirin therapy . However , for 75-year-old patients with NVAF alone , prescribing warfarin cost $ 110,000 per quality -adjusted life-year saved . For patients who were not prescribed warfarin , aspirin was preferred to no therapy on the basis of both quality -adjusted survival and cost in all patients , regardless of the number of risk factors present . CONCLUSIONS Treatment with warfarin is cost-effective in patients with NVAF and one or more additional risk factors for stroke . In 65-year-old patients with NVAF but no other risk factors for stroke , prescribing warfarin instead of aspirin would affect quality -adjusted survival minimally but increase costs significantly BACKGROUND BAY 59 - 7939 , a novel , oral , direct factor Xa inhibitor , is in clinical development for the prevention of venous thromboembolism ( VTE ) , a frequent complication following orthopaedic surgery . METHODS In a multicenter , parallel-group , double-blind , double-dummy study , 621 patients undergoing elective total knee replacement were r and omly assigned to oral BAY 59 - 7939 ( 2.5 , 5 , 10 , 20 , and 30 mg b.i.d . , initiated 6 - 8 h postsurgery ) , or subcutaneous enoxaparin ( 30 mg b.i.d . , initiated 12 - 24 h postsurgery ) . Treatment was continued until m and atory bilateral venography 5 - 9 days after surgery . The primary efficacy endpoint was a composite of any deep vein thrombosis ( proximal and /or distal ) , confirmed non-fatal pulmonary embolism and all-cause mortality during treatment . The primary safety endpoint was major , postoperative bleeding during treatment . RESULTS Of the 613 patients treated , 366 ( 59.7 % ) were evaluable for the primary efficacy analysis . The primary efficacy endpoint occurred in 31.7 % , 40.4 % , 23.3 % , 35.1 % , and 25.4 % of patients receiving 2.5 , 5 , 10 , 20 and 30 mg b.i.d . doses of BAY 59 - 7939 , respectively ( test for trend , P = 0.29 ) , compared with 44.3 % in the enoxaparin group . The frequency of major , postoperative bleeding increased with increasing doses of BAY 59 - 7939 ( test for trend , P = 0.0007 ) , with no significant difference between any dose group compared with enoxaparin . Bleeding endpoints were lower for the 2.5 - 10 mg b.i.d . doses compared with higher doses of BAY 59 - 7939 . CONCLUSIONS Oral administration of 2.5 - 10 mg b.i.d . of BAY 59 - 7939 , early in the postoperative period , showed potential efficacy and an acceptable safety profile , similar to enoxaparin , for the prevention of VTE in patients undergoing elective total knee replacement BACKGROUND Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism ( VTE ) following orthopedic surgery . METHODS In a multicenter , parallel-group , double-blind study , 1973 patients undergoing total hip or knee replacement were r and omized to 6 - 10 days of oral dabigatran etexilate ( 50 , 150 mg twice daily , 300 mg once daily , 225 mg twice daily ) , starting 1 - 4 h after surgery , or subcutaneous enoxaparin ( 40 mg once daily ) starting 12 h prior to surgery . The primary efficacy outcome was the incidence of VTE ( detected by bilateral venography or symptomatic events ) during treatment . RESULTS Of the 1949 treated patients , 1464 ( 75 % ) patients were evaluable for the efficacy analysis . VTE occurred in 28.5 % , 17.4 % , 16.6 % , 13.1 % and 24 % of patients assigned to dabigatran etexilate 50 , 150 mg twice daily , 300 mg once daily , 225 mg twice daily and enoxaparin , respectively . A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate ( P < 0.0001 ) . Compared with enoxaparin , VTE was significantly lower in patients receiving 150 mg twice daily [ odds ratio ( OR ) 0.65 , P = 0.04 ] , 300 mg once daily ( OR 0.61 , P = 0.02 ) and 225 mg twice daily ( OR 0.47 , P = 0.0007 ) . Compared with enoxaparin , major bleeding was significantly lower with 50 mg twice daily ( 0.3 % vs. 2.0 % , P = 0.047 ) but elevated with higher doses , nearly reaching statistical significance with the 300 mg once-daily dose ( 4.7 % , P = 0.051 ) . CONCLUSIONS Oral administration of dabigatran etexilate , commenced early in the postoperative period , was effective and safe across a range of doses . Further optimization of the efficacy/safety balance will be addressed in future studies BACKGROUND Joint replacement surgery is an appropriate model for dose-ranging studies investigating new anticoagulants . OBJECTIVES To assess the efficacy and safety of a novel , oral , direct factor Xa ( FXa ) inhibitor -- BAY 59 - 7939 - -relative to enoxaparin in patients undergoing elective total hip replacement . METHODS In this double-blind , double-dummy , dose-ranging study , patients were r and omized to oral BAY 59 - 7939 ( 2.5 , 5 , 10 , 20 , or 30 mg b.i.d . ) , starting 6 - 8 h after surgery , or s.c . enoxaparin 40 mg once daily , starting on the evening before surgery . Treatment was continued until m and atory bilateral venography was performed 5 - 9 days after surgery . RESULTS Of 706 patients treated , 548 were eligible for the primary efficacy analysis . The primary efficacy endpoint was the incidence of any deep vein thrombosis , non-fatal pulmonary embolism , and all-cause mortality ; rates were 15 % , 14 % , 12 % , 18 % , and 7 % for BAY 59 - 7939 2.5 , 5 , 10 , 20 , and 30 mg b.i.d . , respectively , compared with 17 % for enoxaparin . The primary efficacy analysis did not demonstrate any significant trend in dose-response relationship for BAY 59 - 7939 . The primary safety endpoint was major , postoperative bleeding ; there was a significant increase in the frequency of events with increasing doses of BAY 59 - 7939 ( P = 0.045 ) , but no significant differences between individual BAY 59 - 7939 doses and enoxaparin . CONCLUSIONS When efficacy and safety were considered together , the oral , direct FXa inhibitor BAY 59 - 7939 , at 2.5 - 10 mg b.i.d . , compared favorably with enoxaparin for the prevention of venous thromboembolism in patients undergoing elective total hip replacement From November , 1985 , to June , 1988 , 1007 out patients with chronic non-rheumatic atrial fibrillation ( AF ) entered a r and omised trial ; 335 received anticoagulation with warfarin openly , and in a double-blind study 336 received aspirin 75 mg once daily and 336 placebo . Each patient was followed up for 2 years or until termination of the trial . The primary endpoint was a thromboembolic complication ( stroke , transient cerebral ischaemic attack , or embolic complications to the viscera and extremities ) . The secondary endpoint was death . The incidence of thromboembolic complications and vascular mortality were significantly lower in the warfarin group than in the aspirin and placebo groups , which did not differ significantly . 5 patients on warfarin had thromboembolic complications compared with 20 patients on aspirin and 21 on placebo . 21 patients on warfarin were withdrawn because of non-fatal bleeding complications compared with 2 on aspirin and none on placebo . Thus , anticoagulation therapy with warfarin can be recommended to prevent thromboembolic complications in patients with chronic non-rheumatic AF BACKGROUND Prophylaxis for venous thromboembolism is recommended for at least 10 days after total knee arthroplasty ; oral regimens could enable shorter hospital stays . We aim ed to test the efficacy and safety of oral rivaroxaban for the prevention of venous thromboembolism after total knee arthroplasty . METHODS In a r and omised , double-blind , phase III study , 3148 patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily , beginning 6 - 8 h after surgery , or subcutaneous enoxaparin 30 mg every 12 h , starting 12 - 24 h after surgery . Patients had m and atory bilateral venography between days 11 and 15 . The primary efficacy outcome was the composite of any deep-vein thrombosis , non-fatal pulmonary embolism , or death from any cause up to day 17 after surgery . Efficacy was assessed as non-inferiority of rivaroxaban compared with enoxaparin in the per- protocol population ( absolute non-inferiority limit -4 % ) ; if non-inferiority was shown , we assessed whether rivaroxaban had superior efficacy in the modified intention-to-treat population . The primary safety outcome was major bleeding . This trial is registered with Clinical Trials.gov , number NCT00362232 . FINDINGS The primary efficacy outcome occurred in 67 ( 6.9 % ) of 965 patients given rivaroxaban and in 97 ( 10.1 % ) of 959 given enoxaparin ( absolute risk reduction 3.19 % , 95 % CI 0.71 - 5.67 ; p=0.0118 ) . Ten ( 0.7 % ) of 1526 patients given rivaroxaban and four ( 0.3 % ) of 1508 given enoxaparin had major bleeding ( p=0.1096 ) . INTERPRETATION Oral rivaroxaban 10 mg once daily for 10 - 14 days was significantly superior to subcutaneous enoxaparin 30 mg given every 12 h for the prevention of venous thromboembolism after total knee arthroplasty . FUNDING Bayer Schering Pharma AG , Johnson & Johnson Pharmaceutical Research & Development Dabigatran , an oral once-daily unmonitored thrombin inhibitor , has been tested elsewhere using enoxaparin 40 mg once daily . We used the North American enoxaparin 30 mg BID regimen as the comparator . This was a double-blind , central ly r and omized trial . Unilateral total knee arthroplasty patients were r and omized to receive oral dabigatran etexilate 220 or 150 mg once daily , or enoxaparin 30 mg SC BID after surgery , blinded . Dosing stopped at contrast venography , 12 to 15 days after surgery . Among 1896 patients , dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin ( venous thromboembolism rates of 31 % [ P = .02 vs enoxaparin ] , 34 % [ P < .001 vs enoxaparin ] , and 25 % , respectively ) . Bleeding rates were similar , and no drug-related hepatic illness was recognized . Dabigatran , effective compared to once-daily enoxaparin , showed inferior efficacy to the twice-daily North American enoxaparin regimen , probably because of the latter 's more intense and prolonged dosing OBJECTIVE To compare the effectiveness and safety of fixed-dose enoxaparin and adjusted dose warfarin in preventing venous thromboembolism after knee arthroplasty . DESIGN A r and omized , double-blind controlled trial . SETTING 8 university hospitals . PATIENTS 670 consecutive patients who had knee arthroplasty . INTERVENTION Patients were r and omly assigned to receive enoxaparin ( 30 mg subcutaneously every 12 hours ) or adjusted-dose warfarin ( international normalized ratio , 2.0 to 3.0 ) . Both regimens were started after surgery . MEASUREMENTS The primary end point was the incidence of deep venous thrombosis in patients with adequate bilateral venograms ; the secondary end point was hemorrhage . RESULTS Among the 417 patients with adequate venograms , 109 of 211 warfarin recipients ( 51.7 % ) had deep venous thrombosis compared with 76 of 206 enoxaparin recipients ( 36.9 % ) ( P = 0.003 ) . The absolute risk difference was 14.8 % in favor of enoxaparin ( 95 % Cl , 5.3 % to 24.1 % ) Twenty-two warfarin recipients ( 10.4 % ) and 24 enoxaparin recipients ( 11.7 % ) had proximal venous thrombosis ( P>0.2 ) . The absolute risk difference was 1.2 % in favor of warfarin ( Cl , -7.2 % to 4.8 % ) . The incidence of major bleeding was 1.8 % ( 6 of 334 patients ) in the warfarin group and 2.1 % ( 7 of 336 patients ) in the enoxaparin group ( P>0.2 ) . The absolute risk difference was 0.3 % in favor of warfarin ( Cl , -2.4 % to 1.8 % ) . CONCLUSIONS A postoperative , fixed-dose enoxaparin regimen is more effective than adjusted-dose warfarin in preventing deep venous thrombosis after knee arthroplasty . No differences were seen in the incidence of proximal venous thrombosis or clinical ly overt hemorrhage BACKGROUND Based on the current underst and ing that venous thrombosis starts perioperatively , administration of just-in-time low-molecular-weight heparin immediately before or in close proximity after hip arthroplasty may be more effective than usual clinical practice . METHODS We performed a r and omized , double-blind trial comparing subcutaneous dalteparin sodium given once daily immediately before or early after surgery with the use of postoperative warfarin sodium in 1472 patients undergoing elective hip arthroplasties . The primary end point was deep vein thrombosis detected using contrast venography performed after surgery ( mean , 5 . 7 days ) in each group . RESULTS The frequencies of deep vein thrombosis for patients with interpretable venograms receiving preoperative and postoperative dalteparin for all deep vein thrombosis were 36 ( 10.7 % ) of 337 ( P<.001 ) and 44 ( 13.1 % ) of 336 ( P<.001 ) , respectively , vs 81 ( 24.0 % ) of 338 for warfarin ; for proximal deep vein thrombosis , 3 ( 0.8 % ) of 354 ( P = .04 ) and 3 ( 0.8 % ) of 358 ( P = .03 ) , respectively , vs 11 ( 3.0 % ) of 363 . Relative risk reductions for the dalteparin groups ranged from 45 % to 72 % . Symptomatic thrombi were less frequent in the preoperative dalteparin group ( 5/337 patients [ 1.5 % ] ) vs the warfarin group ( 15/338 patients [ 4.4 % ] ) ( P = .02 ) . Serious bleeding was similar among groups . Increased major bleeding at the surgical site was observed for patients receiving preoperative dalteparin vs warfarin ( P = .01 ) . CONCLUSIONS A modified dalteparin regimen in close proximity to surgery result ed in substantive risk reductions for all and proximal deep vein thrombosis , compared with warfarin therapy . Such findings have not been observed with low-molecular-weight heparin therapy commenced 12 hours preoperatively or 12 to 24 hours postoperatively vs oral anticoagulants . Increased major but not serious bleeding occurred in patients receiving preoperative dalteparin . Dalteparin therapy initiated postoperatively provided superior efficacy vs warfarin without significantly increased overt bleeding AIMS We aim ed to investigate the prevalence and incidence of atrial fibrillation ( AF ) in a large European population -based study . METHODS AND RESULTS The study is part of the Rotterdam study , a population -based prospect i ve cohort study among subjects aged 55 years and above . The prevalence at baseline was assessed in 6808 participants . Incidence of AF was investigated during a mean follow-up period of 6.9 years in 6432 persons . We identified 376 prevalent and 437 incident cases . Overall prevalence was 5.5 % , rising from 0.7 % in the age group 55 - 59 years to 17.8 % in those aged 85 years and above . The overall incidence rate was 9.9/1000 person-years . The incidence rate in the age group 55 - 59 years was 1.1/1000 person-years , rose to 20.7/1000 person-years in the age group 80 - 84 years and stabilized in those aged 85 years and above . Prevalence and incidence were higher in men than in women . The lifetime risk to develop AF at the age of 55 years was 23.8 % in men and 22.2 % in women . CONCLUSION In this prospect i ve study in a European population , the prevalence and incidence of AF increased with age and were higher in men than in women . The high lifetime risk to develop AF was similar to North American epidemiological data BACKGROUND We investigated the efficacy of rivaroxaban , an orally active direct factor Xa inhibitor , in preventing venous thrombosis after total knee arthroplasty . METHODS In this r and omized , double-blind trial , 2531 patients who were to undergo total knee arthroplasty received either oral rivaroxaban , 10 mg once daily , beginning 6 to 8 hours after surgery , or subcutaneous enoxaparin , 40 mg once daily , beginning 12 hours before surgery . The primary efficacy outcome was the composite of any deep-vein thrombosis , nonfatal pulmonary embolism , or death from any cause within 13 to 17 days after surgery . Secondary efficacy outcomes included major venous thromboembolism ( i.e. , proximal deep-vein thrombosis , nonfatal pulmonary embolism , or death related to venous thromboembolism ) and symptomatic venous thromboembolism . The primary safety outcome was major bleeding . RESULTS The primary efficacy outcome occurred in 79 of 824 patients ( 9.6 % ) who received rivaroxaban and in 166 of 878 ( 18.9 % ) who received enoxaparin ( absolute risk reduction , 9.2 % ; 95 % confidence interval [ CI ] , 5.9 to 12.4 ; P<0.001 ) . Major venous thromboembolism occurred in 9 of 908 patients ( 1.0 % ) given rivaroxaban and 24 of 925 ( 2.6 % ) given enoxaparin ( absolute risk reduction , 1.6 % ; 95 % CI , 0.4 to 2.8 ; P=0.01 ) . Symptomatic events occurred less frequently with rivaroxaban than with enoxaparin ( P=0.005 ) . Major bleeding occurred in 0.6 % of patients in the rivaroxaban group and 0.5 % of patients in the enoxaparin group . The incidence of drug-related adverse events , mainly gastrointestinal , was 12.0 % in the rivaroxaban group and 13.0 % in the enoxaparin group . CONCLUSIONS Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty , with similar rates of bleeding . ( Clinical Trials.gov number , NCT00361894 . BACKGROUND Non-valvular atrial fibrillation is associated with an increased risk of ischemic stroke ; however , the appropriate intensity of anticoagulation therapy for Chinese patients has not been determined . The purpose of this study was to compare the safety and the efficacy of st and ard-intensity warfarin therapy , low-intensity warfarin therapy , and aspirin therapy for the prevention of ischemic events in Chinese patients with non-valvular atrial fibrillation ( NVAF ) . METHODS A total of 786 patients from 75 Chinese hospitals were enrolled in this study and r and omized into three therapy groups : st and ard-intensity warfarin ( international normalized ratio ( INR ) 2.1 to 2.5 ) group , low-intensity warfarin ( INR 1.6 to 2.0 ) group and aspirin ( 200 mg per day ) group . All patients were evaluated by physicians at 1 , 3 , 6 , 9 , 12 , 15 , 18 , 21 and 24 months after r and omization to obtain a patient question naire , physical examination and related laboratory tests . RESULTS The annual event rates of ischemic stroke , transient ischemic attack ( TIA ) or systemic thromboembolism were 2.6 % , 3.1 % and 6.9 % in the st and ard-intensity warfarin , low-intensity warfarin and aspirin groups , respectively ( P = 0.027 ) . Thromboembolic event rates in both warfarin groups were significantly lower than that in the aspirin group ( P = 0.018 , P = 0.044 ) , and there was no significant difference between the two warfarin groups . Severe hemorrhagic events occurred in 15 patients , 7 ( 2.6 % ) in the st and ard-intensity warfarin group , 7 ( 2.4 % ) in the low-intensity warfarin group and 1 ( 0.4 % ) in the aspirin group . The severe hemorrhagic event rates in the warfarin groups were higher than that in the aspirin group , but the difference did not reach statistical significance ( P = 0.101 ) . The mild hemorrhagic and total hemorrhagic event rates in the warfarin groups ( whether in the st and ard-intensity warfarin group or low-intensity warfarin group ) were much higher than that in the aspirin group with the annual event rates of total hemorrhages of 10.2 % , 7.6 % and 2.2 % , respectively , in the 3 groups ( P = 0.001 ) . Furthermore , there was no significant difference in all cause mortality among the three study groups . CONCLUSION In Chinese patients with NVAF , the warfarin therapy ( INR 1.6 - 2.5 ) for the prevention of thromboembolic events was superior to aspirin BACKGROUND Warfarin reduces the risk for ischemic stroke in patients with atrial fibrillation ( AF ) but increases the risk for hemorrhage . Dabigatran is a fixed-dose , oral direct thrombin inhibitor with similar or reduced rates of ischemic stroke and intracranial hemorrhage in patients with AF compared with those of warfarin . OBJECTIVE To estimate the quality -adjusted survival , costs , and cost-effectiveness of dabigatran compared with adjusted-dose warfarin for preventing ischemic stroke in patients 65 years or older with nonvalvular AF . DESIGN Markov decision model . DATA SOURCES The RE-LY ( R and omized Evaluation of Long-Term Anticoagulation Therapy ) trial and other published studies of anticoagulation . The cost of dabigatran was estimated on the basis of pricing in the United Kingdom . TARGET POPULATION Patients aged 65 years or older with nonvalvular AF and risk factors for stroke ( CHADS₂ score ≥1 or equivalent ) and no contraindications to anticoagulation . TIME HORIZON Lifetime . PERSPECTIVE Societal . INTERVENTION Warfarin anticoagulation ( target international normalized ratio , 2.0 to 3.0 ) ; dabigatran , 110 mg twice daily ( low dose ) ; and dabigatran , 150 mg twice daily ( high dose ) . OUTCOME MEASURES Quality -adjusted life-years ( QALYs ) , costs ( in 2008 U.S. dollars ) , and incremental cost-effectiveness ratios . RESULTS OF BASE-CASE ANALYSIS The quality -adjusted life expectancy was 10.28 QALYs with warfarin , 10.70 QALYs with low-dose dabigatran , and 10.84 QALYs with high-dose dabigatran . Total costs were $ 143 193 for warfarin , $ 164 576 for low-dose dabigatran , and $ 168 398 for high-dose dabigatran . The incremental cost-effectiveness ratios compared with warfarin were $ 51 229 per QALY for low-dose dabigatran and $ 45 372 per QALY for high-dose dabigatran . RESULTS OF SENSITIVITY ANALYSIS The model was sensitive to the cost of dabigatran but was relatively insensitive to other model inputs . The incremental cost-effectiveness ratio increased to $ 50 000 per QALY at a cost of $ 13.70 per day for high-dose dabigatran but remained less than $ 85 000 per QALY over the full range of model inputs evaluated . The cost-effectiveness of high-dose dabigatran improved with increasing risk for stroke and intracranial hemorrhage . LIMITATION Event rates were largely derived from a single r and omized clinical trial and extrapolated to a 35-year time frame from clinical trials with approximately 2-year follow-up . CONCLUSION In patients aged 65 years or older with nonvalvular AF at increased risk for stroke ( CHADS₂ score ≥1 or equivalent ) , dabigatran may be a cost-effective alternative to warfarin depending on pricing in the United States . PRIMARY FUNDING SOURCE American Heart Association and Veterans Affairs Health Services Research & Development Service This is the first evaluation of dabigatran , an oral direct thrombin inhibitor , in patients with atrial fibrillation ( AF ) . Patients ( n = 502 ) were r and omized to receive blinded doses of 50- , 150- , or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks . Dabigatran plasma concentrations , activated partial thromboplastin time , D-dimer , urinary 11-dehydrothromboxane B(2 ) ( DTB2 ) , and liver function were measured at baseline and at 1 , 2 , 4 , 8 , and 12 weeks . Clinical end points were assessed according to the treatment received at the time of the event . Overall , 92 % of patients completed the study . Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin ( 4 of 64 ) , and the incidence was significant versus 300-mg dabigatran alone ( 0 of 105 , p < 0.02 ) . Total bleeding events were more frequent in the 300-mg ( 39 of 169 , 23 % ) and 150-mg ( 30 of 169 , 18 % ) dabigatran groups compared with the 50-mg groups ( 7 of 107 , 7 % ; p = 0.0002 and p = 0.01 , respectively ) . Thromboembolic events were limited to the 50-mg dabigatran dose groups ( 2 of 107 , 2 % ) . The mean trough d-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin ( international normalized ratio of 2 to 3 ) . Aminotransferase levels > 3 times the upper limit of normal were observed in 0.9 % of the dabigatran recipients and in none of the warfarin recipients . Two dabigatran recipients had aminotransferase levels > 5 times the upper limit of normal as a result of gallstones , which resolved . Trough activated partial thromboplastin time values were 1.2 , 1.5 , and 1.8 times the baseline level for the 50- , 150- , and 300-mg dabigatran groups , respectively . DTB2 concentrations after 12 weeks of 50- , 150- , and 300-mg dabigatran treatment were increased by 31 % , 17 % , and 23 % , respectively , versus baseline ( p = 0.02 , p = 0.03 , and p = 0.0004 ) . In conclusion , major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups . The 2 highest doses of dabigatran suppress D-dimer concentrations . Serious liver toxicity was not seen . The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution BACKGROUND Apixaban , an oral factor Xa inhibitor that can be administered in a simple , fixed-dose regimen , may be an option for the extended treatment of venous thromboembolism . METHODS In this r and omized , double-blind study , we compared two doses of apixaban ( 2.5 mg and 5 mg , twice daily ) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy . The study drugs were administered for 12 months . RESULTS A total of 2486 patients underwent r and omization , of whom 2482 were included in the intention-to-treat analyses . Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients ( 8.8 % ) who were receiving placebo , as compared with 14 of the 840 patients ( 1.7 % ) who were receiving 2.5 mg of apixaban ( a difference of 7.2 percentage points ; 95 % confidence interval [ CI ] , 5.0 to 9.3 ) and 14 of the 813 patients ( 1.7 % ) who were receiving 5 mg of apixaban ( a difference of 7.0 percentage points ; 95 % CI , 4.9 to 9.1 ) ( P<0.001 for both comparisons ) . The rates of major bleeding were 0.5 % in the placebo group , 0.2 % in the 2.5-mg apixaban group , and 0.1 % in the 5-mg apixaban group . The rates of clinical ly relevant nonmajor bleeding were 2.3 % in the placebo group , 3.0 % in the 2.5-mg apixaban group , and 4.2 % in the 5-mg apixaban group . The rate of death from any cause was 1.7 % in the placebo group , as compared with 0.8 % in the 2.5-mg apixaban group and 0.5 % in the 5-mg apixaban group . CONCLUSIONS Extended anticoagulation with apixaban at either a treatment dose ( 5 mg ) or a thromboprophylactic dose ( 2.5 mg ) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding . ( Funded by Bristol-Myers Squibb and Pfizer ; AMPLIFY-EXT Clinical Trials.gov number , NCT00633893 . ) BACKGROUND AND PURPOSE Previous cost-effectiveness analyses analyzed warfarin for stroke prevention in r and omized trial setting s. Given the complexities of warfarin treatment , cost-effectiveness should be examined within a real-world setting . METHODS Our model followed patients with atrial fibrillation at moderate to high risk of stroke through primary and recurrent ischemic stroke , hemorrhages -- intracranial and extracranial , and the result ing disability . Four scenarios were examined : ( 1 ) all patients start on warfarin with perfect control , that is , international normalized ratio ( INR ) values always within range ; ( 2 ) all patients start on warfarin with trial-like control , where INR can fall outside the recommended range ; ( 3 ) all patients start on warfarin with real-world INR control ; and ( 4 ) real-world prescription ( and control ) of warfarin , aspirin , or neither for warfarin-eligible patients . Reported warfarin discontinuation rates were used . Main outcomes were total number of events , quality adjusted life years , and costs in a US setting . RESULTS The total number of primary and recurrent ischemic strokes in a 1,000-patient cohort ( age 70 years , lifetime analysis ) was 626 , 832 , 984 , and 1,171 in scenarios 1 to 4 , respectively . The corresponding mean quality adjusted life years per patient were 7.21 , 6.92 , 6.75 , and 6.67 for scenarios 1 to 4 , respectively . Costs per patient were $ 68,039 , $ 77,764 , $ 84,518 , and $ 87,248 in scenarios 1 to 4 , respectively . If " perfect " adherence to warfarin was assumed , except for discontinuations for clinical reasons , strokes would decrease to 503 , 737 , 909 , and 1,120 in scenarios 1 to 4 , respectively . CONCLUSIONS Clinical and cost outcomes are strongly dependent on the quality of anticoagulation and rates of warfarin discontinuation . Clinicians should work to improve both . Policy makers should use real-world INR control and warfarin discontinuation rates when assessing cost-effectiveness BACKGROUND Rivaroxaban , an oral factor Xa inhibitor , may provide a simple , fixed-dose regimen for treating acute deep-vein thrombosis ( DVT ) and for continued treatment , without the need for laboratory monitoring . METHODS We conducted an open-label , r and omized , event-driven , noninferiority study that compared oral rivaroxaban alone ( 15 mg twice daily for 3 weeks , followed by 20 mg once daily ) with subcutaneous enoxaparin followed by a vitamin K antagonist ( either warfarin or acenocoumarol ) for 3 , 6 , or 12 months in patients with acute , symptomatic DVT . In parallel , we carried out a double-blind , r and omized , event-driven superiority study that compared rivaroxaban alone ( 20 mg once daily ) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism . The primary efficacy outcome for both studies was recurrent venous thromboembolism . The principal safety outcome was major bleeding or clinical ly relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study . RESULTS The study of rivaroxaban for acute DVT included 3449 patients : 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist . Rivaroxaban had noninferior efficacy with respect to the primary outcome ( 36 events [ 2.1 % ] , vs. 51 events with enoxaparin-vitamin K antagonist [ 3.0 % ] ; hazard ratio , 0.68 ; 95 % confidence interval [ CI ] , 0.44 to 1.04 ; P<0.001 ) . The principal safety outcome occurred in 8.1 % of the patients in each group . In the continued-treatment study , which included 602 patients in the rivaroxaban group and 594 in the placebo group , rivaroxaban had superior efficacy ( 8 events [ 1.3 % ] , vs. 42 with placebo [ 7.1 % ] ; hazard ratio , 0.18 ; 95 % CI , 0.09 to 0.39 ; P<0.001 ) . Four patients in the rivaroxaban group had nonfatal major bleeding ( 0.7 % ) , versus none in the placebo group ( P=0.11 ) . CONCLUSIONS Rivaroxaban offers a simple , single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation . ( Funded by Bayer Schering Pharma and Ortho-McNeil ; Clinical Trials.gov numbers , NCT00440193 and NCT00439725 . ) BACKGROUND Low-molecular-weight heparins such as enoxaparin are preferred for prevention of venous thromboembolism after major joint replacement . Apixaban , an orally active factor Xa inhibitor , might be as effective , have lower bleeding risk , and be easier to use than is enoxaparin . We assessed efficacy and safety of these drugs after elective total knee replacement . METHODS In ADVANCE-2 , a multicentre , r and omised , double-blind phase 3 study , patients undergoing elective unilateral or bilateral total knee replacement were r and omly allocated through an interactive central telephone system to receive oral apixaban 2.5 mg twice daily ( n=1528 ) or subcutaneous enoxaparin 40 mg once daily ( 1529 ) . The r and omisation schedule was generated by the Bristol-Myers Squibb r and omisation centre and stratified by study site and by unilateral or bilateral surgery with a block size of four . Investigators , patients , statisticians , adjudicators , and steering committee were masked to allocation . Apixaban was started 12 - 24 h after wound closure and enoxaparin 12 h before surgery ; both drugs were continued for 10 - 14 days , when bilateral ascending venography was scheduled . Primary outcome was the composite of asymptomatic and symptomatic deep vein thrombosis , non-fatal pulmonary embolism , and all-cause death during treatment . The statistical plan required non-inferiority of apixaban before testing for superiority ; analysis was by intention to treat for non-inferiority testing . The study is registered at Clinical Trials.gov , number NCT00452530 . FINDINGS 1973 of 3057 patients allocated to treatment ( 1528 apixaban , 1529 enoxaparin ) were eligible for primary efficacy analysis . The primary outcome was reported in 147 ( 15 % ) of 976 apixaban patients and 243 ( 24 % ) of 997 enoxaparin patients ( relative risk 0.62 [ 95 % CI 0.51 - 0.74 ] ; p<0.0001 ; absolute risk reduction 9.3 % [ 5.8 - 12.7 ] ) . Major or clinical ly relevant non-major bleeding occurred in 53 ( 4 % ) of 1501 patients receiving apixaban and 72 ( 5 % ) of 1508 treated with enoxaparin ( p=0.09 ) . INTERPRETATION Apixaban 2.5 mg twice daily , starting on the morning after total knee replacement , offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin , without increased bleeding . FUNDING Bristol-Myers Squibb ; Pfizer OBJECTIVE To compare the therapeutic warfarin and aspirin efficacies for treatments of atrial fibrillation ( AF ) complicated with stable coronary heart disease particularly in older Chinese patients . METHODS In our prospect i ve study 101 patients with AF and stable coronary heart disease older than 80 years were r and omized into two groups . One group ( n = 51 ) basically received 1.25 mg/day warfarin per os , followed by addition of 0.5 - 1.0 mg/day from day 3 - 5 if the international normalized ratio ( INR ) was initially < 1.5 and in order to achieve a maintained INR between 1.6 and 2.5 ( warfarin group ) . The second group ( n = 50 ) received 100 mg aspirin per day ( control group ) . All patients were medicated and monitored for a period of 2 years . The primary endpoint was the occurrence of ischemic stroke or systemic embolism , and the composite secondary endpoint was non-fatal myocardial infa rct ion and all causes of death . For safety evaluation , the hemorrhage rates were recorded . RESULTS The warfarin medication was superior regarding the overall occurrence of ischemic stroke or systemic embolism as well as non-fatal myocardial infa rct ion and all causes of death outcomes compared to aspirin administration during the 2 years of medication ( 17.6 % vs. 36.0 % , p = 0.03 ) , while there was no significant difference of mild ( 5 vs. 4 ) , severe ( 2 vs. 1 ) , and fatal ( 1 vs. 1 ) hemorrhage incidences between the warfarin and aspirin groups ( p > 0.05 ) . CONCLUSION Warfarin was found to be more efficacious than aspirin for an anticoagulation therapy of older Chinese patients with AF and stable coronary heart disease AIMS The impact of some risk factors for stroke and bleeding , and the value of stroke and bleeding risk scores , in atrial fibrillation ( AF ) , has been debated , as clinical trial cohorts have not adequately tested these . Our objective was to investigate risk factors for stroke and bleeding in AF , and application of the new CHA(2)DS(2)-VASc and HAS-BLED schemes for stroke and bleeding risk assessment s , respectively . METHODS AND RESULTS We used the Swedish Atrial Fibrillation cohort study , a nationwide cohort study of 182 678 subjects with a diagnosis of AF at any Swedish hospital between 1 July 2005 and 31 December 2008 , who were prospect ively followed for an average of 1.5 years ( 260 000 years at risk ) . With the use of the National Swedish Drug Registry , all patients who used an oral anticoagulant anytime during follow-up were identified . Most of the analyses were made on a subset of 90 490 patients who never used anticoagulants . Risk factors for stroke , the composite thromboembolism endpoint ( stroke , TIA , or systemic embolism ) , and bleeding , and the performance of published stroke and bleeding risk stratification schemes were investigated . On multivariable analysis , significant associations were found between the following ' new ' risk factors and thromboembolic events ; peripheral artery disease [ hazard ratio ( HR ) 1.22 ( 95 % CI 1.12 - 1.32 ) ] , ' vascular disease ' [ HR 1.14 ( 1.06 - 1.23 ) ] , prior myocardial infa rct ion [ HR 1.09 ( 1.03 - 1.15 ) ] , and female gender [ HR 1.17 ( 1.11 - 1.22 ) ] . Previous embolic events , intracranial haemorrhage ( ICH ) , hypertension , diabetes , and renal failure were other independent predictors of the composite thromboembolism endpoint , while thyroid disease ( or hyperthyroidism ) was not an independent stroke risk factor . C-statistics for the composite thromboembolic endpoint with the CHADS(2 ) and CHA(2)DS(2)-VASc schemes were 0.66 ( 0.65 - 0.66 ) and 0.67 ( 0.67 - 0.68 ) , respectively . On multivariable analysis , age , prior ischaemic stroke or thromboembolism , prior major bleeding events , and hypertension were significant predictors of ICH and major bleeding . Heart failure , diabetes , renal failure , liver disease , anaemia or platelet/coagulation defect , alcohol abuse , and cancer were other significant predictors for major bleeding , but not ICH . The ability for predicting ICH and major bleeding with both bleeding risk schemes ( HEMORR(2)HAGES , HAS-BLED ) were similar , with c-statistics of ~0.6 . CONCLUSION Several independent risk factors ( prior ICH , myocardial infa rct ion , vascular disease , and renal failure ) predict ischaemic stroke and /or the composite thromboembolism endpoint in AF , but thyroid disease ( or hyperthyroidism ) was not an independent risk factor for stroke . There is a better performance for CHA(2)DS(2)-VASc over CHADS(2 ) schemes for the composite thromboembolism endpoint . While both tested bleeding risk schemes have similar predictive value , the HAS-BLED score has the advantage of simplicity AIMS It is uncertain whether the benefit from apixaban varies by type and duration of atrial fibrillation ( AF ) . METHODS AND RESULTS A total of 18 201 patients with AF [ 2786 ( 15.3 % ) with paroxysmal and 15 412 ( 84.7 % ) with persistent or permanent ] were r and omized to apixaban or warfarin . In this pre-specified secondary analysis , we compared outcomes and treatment effect of apixaban vs. warfarin by AF type and duration . The primary efficacy endpoint was a composite of ischaemic or haemorrhagic stroke or systemic embolism . The secondary efficacy endpoint was all-cause mortality . There was a consistent reduction in stroke or systemic embolism ( P for interaction = 0.71 ) , all-cause mortality ( P for interaction = 0.75 ) , and major bleeding ( P for interaction = 0.50 ) with apixaban compared with warfarin for both AF types . Apixaban was superior to warfarin in all studied endpoints , regardless of AF duration at study entry ( P for all interactions > 0.13 ) . The rate of stroke or systemic embolism was significantly higher in patients with persistent or permanent AF than patients with paroxysmal AF ( 1.52 vs. 0.98 % ; P = 0.003 , adjusted P = 0.015 ) . There was also a trend towards higher mortality in patients with persistent or permanent AF ( 3.90 vs. 2.81 % ; P = 0.0002 , adjusted P = 0.066 ) . CONCLUSION The risks of stroke , mortality , and major bleeding were lower with apixaban than warfarin regardless of AF type and duration . Although the risk of stroke or systemic embolism was lower in paroxysmal than persistent or permanent AF , apixaban is an attractive alternative to warfarin in patients with AF and at least one other risk factor for stroke , regardless of the type or duration of AF BACKGROUND Nonrheumatic atrial fibrillation is common among the elderly and is associated with an increased risk of stroke . We investigated whether anticoagulation with warfarin would reduce this risk . METHODS We conducted a r and omized , double-blind , placebo-controlled study to evaluate low-intensity anticoagulation with warfarin ( prothrombin-time ratio , 1.2 to 1.5 ) in 571 men with chronic nonrheumatic atrial fibrillation ; 525 patients had not previously had a cerebral infa rct ion , whereas 46 patients had previously had such an event . The primary end point was cerebral infa rct ion ; secondary end points were cerebral hemorrhage and death . RESULTS Among the patients with no history of stroke , cerebral infa rct ion occurred in 19 of the 265 patients in the placebo group during an average follow-up of 1.7 years ( 4.3 percent per year ) and in 4 of the 260 patients in the warfarin group during an average follow-up of 1.8 years ( 0.9 percent per year ) . The reduction in risk with warfarin therapy was 0.79 ( 95 percent confidence interval , 0.52 to 0.90 ; P = 0.001 ) . The annual event rate among the 228 patients over 70 years of age was 4.8 percent in the placebo group and 0.9 percent in the warfarin group ( risk reduction , 0.79 ; P = 0.02 ) . The only cerebral hemorrhage occurred in a 73-year-old patient in the warfarin group . Other major hemorrhages , all gastrointestinal , occurred in 10 patients : 4 in the placebo group , for a rate of 0.9 percent per year , and 6 in the warfarin group , for a rate of 1.3 percent per year . There were 37 deaths that were not preceded by a cerebral end point--22 in the placebo group and 15 in the warfarin group ( risk reduction , 0.31 ; P = 0.19 ) . Cerebral infa rct ion was more common among patients with a history of cerebral infa rct ion ( 9.3 percent per year in the placebo group and 6.1 percent per year in the warfarin group ) than among those without such a history . CONCLUSIONS Low-intensity anticoagulation with warfarin prevented cerebral infa rct ion in patients with nonrheumatic atrial fibrillation without producing an excess risk of major hemorrhage . This benefit extended to patients over 70 years of age BACKGROUND This phase 3 trial compared the efficacy and safety of rivaroxaban , an oral direct inhibitor of factor Xa , with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty . METHODS In this r and omized , double-blind study , we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily , beginning after surgery , or 40 mg of enoxaparin subcutaneously once daily , beginning the evening before surgery , plus a placebo tablet or injection . The primary efficacy outcome was the composite of deep-vein thrombosis ( either symptomatic or detected by bilateral venography if the patient was asymptomatic ) , nonfatal pulmonary embolism , or death from any cause at 36 days ( range , 30 to 42 ) . The main secondary efficacy outcome was major venous thromboembolism ( proximal deep-vein thrombosis , nonfatal pulmonary embolism , or death from venous thromboembolism ) . The primary safety outcome was major bleeding . RESULTS A total of 3153 patients were included in the superiority analysis ( after 1388 exclusions ) , and 4433 were included in the safety analysis ( after 108 exclusions ) . The primary efficacy outcome occurred in 18 of 1595 patients ( 1.1 % ) in the rivaroxaban group and in 58 of 1558 patients ( 3.7 % ) in the enoxaparin group ( absolute risk reduction , 2.6 % ; 95 % confidence interval [ CI ] , 1.5 to 3.7 ; P<0.001 ) . Major venous thromboembolism occurred in 4 of 1686 patients ( 0.2 % ) in the rivaroxaban group and in 33 of 1678 patients ( 2.0 % ) in the enoxaparin group ( absolute risk reduction , 1.7 % ; 95 % CI , 1.0 to 2.5 ; P<0.001 ) . Major bleeding occurred in 6 of 2209 patients ( 0.3 % ) in the rivaroxaban group and in 2 of 2224 patients ( 0.1 % ) in the enoxaparin group ( P=0.18 ) . CONCLUSIONS A once-daily , 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily , 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty . The two drugs had similar safety profiles . ( Clinical Trials.gov number , NCT00329628 . BACKGROUND The optimal strategy for thromboprophylaxis after major joint replacement has not been established . Low-molecular-weight heparins such as enoxaparin predominantly target factor Xa but to some extent also inhibit thrombin . Apixaban , a specific factor Xa inhibitor , may provide effective thromboprophylaxis with a low risk of bleeding and improved ease of use . METHODS In a double-blind , double-dummy study , we r and omly assigned patients undergoing total knee replacement to receive 2.5 mg of apixaban orally twice daily or 30 mg of enoxaparin subcutaneously every 12 hours . Both medications were started 12 to 24 hours after surgery and continued for 10 to 14 days . Bilateral venography was then performed . The primary efficacy outcome was a composite of asymptomatic and symptomatic deep-vein thrombosis , nonfatal pulmonary embolism , and death from any cause during treatment . Patients were followed for 60 days after anticoagulation therapy was stopped . RESULTS A total of 3195 patients underwent r and omization , with 1599 assigned to the apixaban group and 1596 to the enoxaparin group ; 908 subjects were not eligible for the efficacy analysis . The overall rate of primary events was much lower than anticipated . The rate of the primary efficacy outcome was 9.0 % with apixaban as compared with 8.8 % with enoxaparin ( relative risk , 1.02 ; 95 % confidence interval , 0.78 to 1.32 ) . The composite incidence of major bleeding and clinical ly relevant nonmajor bleeding was 2.9 % with apixaban and 4.3 % with enoxaparin ( P=0.03 ) . CONCLUSIONS As compared with enoxaparin for efficacy of thromboprophylaxis after knee replacement , apixaban did not meet the prespecified statistical criteria for noninferiority , but its use was associated with lower rates of clinical ly relevant bleeding and it had a similar adverse-event profile . ( Clinical Trials.gov number , NCT00371683 . BACKGROUND There are various regimens for thromboprophylaxis after hip replacement . Low-molecular-weight heparins such as enoxaparin predominantly inhibit factor Xa but also inhibit thrombin to some degree . Orally active , specific factor Xa inhibitors such as apixaban may provide effective thromboprophylaxis with a lower risk of bleeding and improved ease of use . METHODS In this double-blind , double-dummy study , we r and omly assigned 5407 patients undergoing total hip replacement to receive apixaban at a dose of 2.5 mg orally twice daily or enoxaparin at a dose of 40 mg subcutaneously every 24 hours . Apixaban therapy was initiated 12 to 24 hours after closure of the surgical wound ; enoxaparin therapy was initiated 12 hours before surgery . Prophylaxis was continued for 35 days after surgery , followed by bilateral venographic studies . The primary efficacy outcome was the composite of asymptomatic or symptomatic deep-vein thrombosis , nonfatal pulmonary embolism , or death from any cause during the treatment period . Patients were followed for an additional 60 days after the last intended dose of study medication . RESULTS A total of 1949 patients in the apixaban group ( 72.0 % ) and 1917 patients in the enoxaparin group ( 71.0 % ) could be evaluated for the primary efficacy analysis . The primary efficacy outcome occurred in 27 patients in the apixaban group ( 1.4 % ) and in 74 patients in the enoxaparin group ( 3.9 % ) ( relative risk with apixaban , 0.36 ; 95 % confidence interval [ CI ] , 0.22 to 0.54 ; P<0.001 for both noninferiority and superiority ; absolute risk reduction , 2.5 percentage points ; 95 % CI , 1.5 to 3.5 ) . The composite outcome of major and clinical ly relevant nonmajor bleeding occurred in 129 of 2673 patients assigned to apixaban ( 4.8 % ) and 134 of 2659 assigned to enoxaparin ( 5.0 % ) ( absolute difference in risk , -0.2 percentage points ; 95 % CI , -1.4 to 1.0 ) . CONCLUSIONS Among patients undergoing hip replacement , thromboprophylaxis with apixaban , as compared with enoxaparin , was associated with lower rates of venous thromboembolism , without increased bleeding . ( Funded by Bristol-Myers Squibb and Pfizer ; Clinical Trials.gov number , NCT00423319 . ) BACKGROUND The clinical ly appropriate duration of thromboprophylaxis in hospitalized patients with acute medical illnesses is unknown . In this multicenter , r and omized , double-blind trial , we evaluated the efficacy and safety of oral rivaroxaban administered for an extended period , as compared with subcutaneous enoxaparin administered for a st and ard period , followed by placebo . METHODS We r and omly assigned patients 40 years of age or older who were hospitalized for an acute medical illness to receive subcutaneous enoxaparin , 40 mg once daily , for 10±4 days and oral placebo for 35±4 days or to receive subcutaneous placebo for 10±4 days and oral rivaroxaban , 10 mg once daily , for 35±4 days . The primary efficacy outcomes were the composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 10 ( noninferiority test ) and up to day 35 ( superiority test ) . The principal safety outcome was the composite of major or clinical ly relevant nonmajor bleeding . RESULTS A total of 8101 patients underwent r and omization . A primary efficacy outcome event occurred in 78 of 2938 patients ( 2.7 % ) receiving rivaroxaban and 82 of 2993 patients ( 2.7 % ) receiving enoxaparin at day 10 ( relative risk with rivaroxaban , 0.97 ; 95 % confidence interval [ CI ] , 0.71 to 1.31 ; P=0.003 for noninferiority ) and in 131 of 2967 patients ( 4.4 % ) who received rivaroxaban and 175 of 3057 patients ( 5.7 % ) who received enoxaparin followed by placebo at day 35 ( relative risk , 0.77 ; 95 % CI , 0.62 to 0.96 ; P=0.02 ) . A principal safety outcome event occurred in 111 of 3997 patients ( 2.8 % ) in the rivaroxaban group and 49 of 4001 patients ( 1.2 % ) in the enoxaparin group at day 10 ( P<0.001 ) and in 164 patients ( 4.1 % ) and 67 patients ( 1.7 % ) in the respective groups at day 35 ( P<0.001 ) . CONCLUSIONS In acutely ill medical patients , rivaroxaban was noninferior to enoxaparin for st and ard- duration thromboprophylaxis . Extended- duration rivaroxaban reduced the risk of venous thromboembolism . Rivaroxaban was associated with an increased risk of bleeding . ( Funded by Bayer HealthCare Pharmaceuticals and Janssen Research and Development ; MAGELLAN Clinical Trials.gov number , NCT00571649 . ) BACKGROUND Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients , an associated reduction in the rate of death from any cause has not been shown . METHODS We conducted a double-blind , placebo-controlled , r and omized trial to assess the effect of subcutaneous enoxaparin ( 40 mg daily ) as compared with placebo -- both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression -- on the rate of death from any cause among hospitalized , acutely ill medical patients at participating sites in China , India , Korea , Malaysia , Mexico , the Philippines , and Tunisia . Inclusion criteria were an age of at least 40 years and hospitalization for acute decompensated heart failure , severe systemic infection with at least one risk factor for venous thromboembolism , or active cancer . The primary efficacy outcome was the rate of death from any cause at 30 days after r and omization . The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period . RESULTS A total of 8307 patients were r and omly assigned to receive enoxaparin plus elastic stockings with graduated compression ( 4171 patients ) or placebo plus elastic stockings with graduated compression ( 4136 patients ) and were included in the intention-to-treat population . The rate of death from any cause at day 30 was 4.9 % in the enoxaparin group as compared with 4.8 % in the placebo group ( risk ratio , 1.0 ; 95 % confidence interval [ CI ] , 0.8 to 1.2 ; P=0.83 ) . The rate of major bleeding was 0.4 % in the enoxaparin group and 0.3 % in the placebo group ( risk ratio , 1.4 ; 95 % CI , 0.7 to 3.1 ; P=0.35 ) . CONCLUSIONS The use of enoxaparin plus elastic stockings with graduated compression , as compared with elastic stockings with graduated compression alone , was not associated with a reduction in the rate of death from any cause among hospitalized , acutely ill medical patients . ( Funded by Sanofi ; LIFENOX Clinical Trials.gov number , NCT00622648 . ) BACKGROUND Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear . METHODS In a r and omized , double-blind , noninferiority study , we r and omly assigned patients with acute venous thromboembolism , who had initially received heparin , to receive edoxaban at a dose of 60 mg once daily , or 30 mg once daily ( e.g. , in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg ) , or to receive warfarin . Patients received the study drug for 3 to 12 months . The primary efficacy outcome was recurrent symptomatic venous thromboembolism . The principal safety outcome was major or clinical ly relevant nonmajor bleeding . RESULTS A total of 4921 patients presented with deep-vein thrombosis , and 3319 with a pulmonary embolism . Among patients receiving warfarin , the time in the therapeutic range was 63.5 % . Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome , which occurred in 130 patients in the edoxaban group ( 3.2 % ) and 146 patients in the warfarin group ( 3.5 % ) ( hazard ratio , 0.89 ; 95 % confidence interval [ CI ] , 0.70 to 1.13 ; P<0.001 for noninferiority ) . The safety outcome occurred in 349 patients ( 8.5 % ) in the edoxaban group and 423 patients ( 10.3 % ) in the warfarin group ( hazard ratio , 0.81 ; 95 % CI , 0.71 to 0.94 ; P=0.004 for superiority ) . The rates of other adverse events were similar in the two groups . A total of 938 patients with pulmonary embolism had right ventricular dysfunction , as assessed by measurement of N-terminal pro-brain natriuretic peptide levels ; the rate of recurrent venous thromboembolism in this subgroup was 3.3 % in the edoxaban group and 6.2 % in the warfarin group ( hazard ratio , 0.52 ; 95 % CI , 0.28 to 0.98 ) . CONCLUSIONS Edoxaban administered once daily after initial treatment with heparin was noninferior to high- quality st and ard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism , including those with severe pulmonary embolism . ( Funded by Daiichi-Sankyo ; Hokusai-VTE Clinical Trials.gov number , NCT00986154 . ) BACKGROUND A substantial portion of patients with atrial fibrillation ( AF ) also have coronary artery disease ( CAD ) and are at risk for coronary events . Warfarin is known to reduce these events , but increase the risk of bleeding . We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD . METHODS AND RESULTS In ARISTOTLE , 18,201 patients with AF were r and omized to apixaban or warfarin . History of CAD was defined as documented CAD , prior myocardial infa rct ion , and /or history of coronary revascularization . We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by r and omized treatment using Cox models . A total of 6639 ( 36.5 % ) patients had prior CAD . These patients were more often male , more likely to have prior stroke , diabetes , and hypertension , and more often received aspirin at baseline ( 42.2 % vs. 24.5 % ) . The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause ( hazard ratio [ HR ] 0.95 , 95 % confidence interval [ CI ] 0.71 - 1.27 , P for interaction=0.12 ; HR 0.96 , 95 % CI 0.81 - 1.13 , P for interaction=0.28 ) . Rates of myocardial infa rct ion were numerically lower with apixaban than warfarin among patients with and without prior CAD . The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD . CONCLUSIONS In patients with AF , apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin , regardless of the presence of prior CAD . Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death , our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients BACKGROUND Vitamin K antagonists have been the st and ard oral antithrombotic used for more than a half century for prevention and treatment of thromboembolism . Their limitations include multiple food and drug interactions and need for frequent monitoring and dose adjustments . Edoxaban is a selective and direct factor Xa inhibitor that may provide effective , safe , and more convenient anticoagulation . STUDY DESIGN ENGAGE AF-TIMI 48 is a phase 3 , r and omized , double-blind , double-dummy , multinational , noninferiority design megatrial comparing 2 exposure strategies of edoxaban to warfarin . Approximately 20,500 subjects will be r and omized to edoxaban high exposure ( 60 mg daily , adjusted for drug clearance ) , edoxaban low exposure ( 30 mg daily , adjusted for drug clearance ) , or warfarin titrated to an international normalized ratio of 2.0 to 3.0 . The edoxaban strategies provide for dynamic dose reductions in subjects with anticipated increased drug exposure . Blinded treatment is maintained through the use of sham international normalized ratios in patients receiving edoxaban . Eligibility criteria include electrical documentation of atrial fibrillation ≤12 months and a CHADS(2 ) score ≥2 . R and omization is stratified by CHADS(2 ) score and anticipated drug exposure . The primary objective is to determine whether edoxaban is noninferior to warfarin for the prevention of stroke and systemic embolism . The primary safety end point is modified International Society on Thrombosis and Haemostasis major bleeding . Recruitment began in November 2008 . The expected median follow-up is 24 months . CONCLUSIONS ENGAGE AF-TIMI 48 is a phase 3 comparison of the novel oral factor Xa inhibitor edoxaban to warfarin for the prevention of thromboembolism in patients with atrial fibrillation BACKGROUND The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge . Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin . METHODS 2509 patients scheduled to undergo elective total hip arthroplasty were r and omly assigned , stratified according to centre , with a computer-generated r and omisation code , to receive oral rivaroxaban 10 mg once daily for 31 - 39 days ( with placebo injection for 10 - 14 days ; n=1252 ) , or enoxaparin 40 mg once daily subcutaneously for 10 - 14 days ( with placebo tablet for 31 - 39 days ; n=1257 ) . The primary efficacy outcome was the composite of deep-vein thrombosis ( symptomatic or asymptomatic detected by m and atory , bilateral venography ) , non-fatal pulmonary embolism , and all-cause mortality up to day 30 - 42 . Analyses were done in the modified intention-to-treat population , which consisted of all patients who had received at least one dose of study medication , had undergone planned surgery , and had adequate assessment of thromboembolism . This study is registered at Clinical Trials.gov , number NCT00332020 . FINDINGS The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group . The primary outcome occurred in 17 ( 2.0 % ) patients in the rivaroxaban group , compared with 81 ( 9.3 % ) in the enoxaparin group ( absolute risk reduction 7.3 % , 95 % CI 5.2 - 9.4 ; p<0.0001 ) . The incidence of any on-treatment bleeding was much the same in both groups ( 81 [ 6.6 % ] events in 1228 patients in the rivaroxaban safety population vs 68 [ 5.5 % ] of 1229 patients in the enoxaparin safety population ; p=0.25 ) . INTERPRETATION Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism , including symptomatic events , in patients undergoing total hip arthroplasty We performed a r and omized dose-ranging study , double-blind for rivaroxaban doses and open-label for the comparator ( low-molecular-weight heparin followed by vitamin K antagonists ) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombosis . A total of 543 patients with acute deep-venous thrombosis received rivaroxaban 20 , 30 , or 40 mg once daily or comparator . Treatment lasted for 84 days . The primary efficacy outcome was the 3-month incidence of the composite of symptomatic venous thromboembolic complications and asymptomatic deterioration in thrombotic burden as assessed by comparison of ultrasound and perfusion lung scanning at day 84 with baseline . The main safety outcome was the composite of major bleeding and clinical ly relevant nonmajor bleeding . A total of 449 ( 83 % ) of the 543 patients could be included in the per- protocol population . The primary efficacy outcome occurred in 6.1 % , 5.4 % , and 6.6 % of the rivaroxaban 20- , 30- , and 40-mg treatment groups , respectively , and in 9.9 % of those receiving st and ard therapy . The main safety outcome occurred in 5.9 % , 6.0 % , and 2.2 % of the rivaroxaban 20- , 30- , and 40-mg treatment groups , respectively , and in 8.8 % of those receiving st and ard therapy . These results with simple fixed-dose oral regimens justify phase 3 evaluations ( www . Clinical Trials.gov no . NCT00395772 )

Level I evidence exists against the use of diuretics for radiocontrast-induced acute tubular necrosis , and loop diuretics given after vascular surgery . There is level II evidence that diuretics do not improve outcome in patients with established acute renal failure . Level II evidence also exists against the use of dopamine in the prevention of acute tubular necrosis in multiple subsets of patients . Conclusions Routine use of diuretics or dopamine for the prevention of acute renal failure can not be justified on the basis of available evidence

Objective To evaluate the impact of diuretics and dopamine for both the prevention and treatment of renal dysfunction in the acute care setting .

W hat n ~ les of evidence should apply when evpert committees meet to generate recommendations for the clinical management of patients ? Should only the thoroughly vali date d results of r and omized clinical trials be admissible to avoid or minimize the application of useless or harmful therapy ? Or , to maximize the potential benefits to patients ( inclr ~ ding those possible from unproved remedies ) , should a synthesis of the experiences of experienced clinicians form the basis for such recommendations ? Ample precedent exists for the latter approach even when attempts are made to replace it . ' However , for the following reasons , the nonexperimental evidence that forms the recalled experiences of seasoned clinicians will tend to overestimate efficacy : A r and omized study was conducted on 66 patients with acute established oliguric renal failure . Intravenous doses of furosemide ranging from 1.5 to 6.0 mg/kg were given every 4 h to 33 of the patients ; the remaining 33 patients served as controls . A persisting diuretic response was observed in 5 treated patients and in 2 controls . Hemodialyses were required in most of them . Furosemide did not significantly modify in cured patients the mean oliguric period , the number of dialyses and the mean period of renal insufficiency Thirty-six patients with preoperative renal dysfunction were studied to evaluate the effects of dopamine ( D ) and dopamine-nitroprusside ( DN ) on renal function during cardiopulmonary bypass ( CPB ) . No differences from the control group ( C ) were found in creatinine clearance , fractional sodium excretion , osmolarity and free-water clearance . Sodium output/intake ratio during CPB was higher in group D than in groups C and DN ( P less than 0.05 ) ; water output/intake ratio was higher in group D than in group C ( P less than 0.05 ) . Urine lysozime levels and alpha-glycosidase/creatinine ratios increased similarly in the three groups , suggesting ischemic tubular cell damage . No patients showed acute postoperative renal failure or a worsening of their renal dysfunction . The data suggest an increased water and sodium excretion during CPB with a dopamine infusion , possibly result ing from a renal vasodilator effect that was abolished by simultaneous nitroprusside administration Fifty-eight patients in established acute renal failure following trauma or surgery were allocated in a prospect i ve and r and om fashion to two different diuretic regimes . In the control group , 1 g frusemide was given as a single injection over four hours . In the test group , frusemide was then continued either intravenously or orally in a dose of 3 g/24 hr until a urine output of 200 ml/hr was sustained or until the plasma creatinine fell below 300 mumoles/l . Oliguria was reversed or prevented in 24 of 28 patients given sustained frusemide , but in only 2 patients given a single injection . However , the number of dialyses and duration of renal failure and mortality were not different in the two groups . The serious complication of deafness occurred in two patients and in one of them this was permanent Previous studies suggest a role for renal vasoconstriction in the pathogenesis of radiocontrast-induced nephropathy ( RCIN ) . A renal vasodilator such as dopamine may be protective . However , the effect of dopamine on renal blood flow ( RBF ) in patients with chronic renal failure ( CRF ) is controversial . Patients with CRF of diabetic ( DM ) or nondiabetic ( NDM ) origin were hydrated with 0.45 % NaCl intravenously at 100 mL/h for 12 h and then r and omized to either 0.45 % NaCl IV at 100 mL/h ( Group 1 ) or dopamine IV at 2 micrograms/kg/min in 0.45 % NaCl at 100 mL/h for 2 h during and after cardiac catheterization . Mean arterial pressure ( MAP ) , cardiac output ( CO ) , and RBF were measured at baseline ( t = 0 ) , after 5 min of vehicle ( Group 1 ) or dopamine ( Group 2 ) but before ionic radiocontrast ( t = 5 min ) , after ventriculogram ( t = 15 min ) , and after coronary angiography ( t = 65 min ) . Serum creatinine ( SCr ) was measured at baseline and 24 and 48 h after cardiac catheterization . RCIN was defined as a 25 % increase of SCr above baseline 48 h after cardiac catheterization . Baseline characteristics demonstrated the groups to be equivalent in age , SCr , creatinine clearance , CO , MAP , RBF , and radiocontrast dose administered . The incidence of RCIN was not different between Group 1 and Group 2 ( Group 1 , 6 of 15 patients ; Group 2 , 5 of 15 patients ) . Dopamine infusion was associated with a significant increase in RBF at 5 min ( Group 1 , 110 + /- 13 % ; Group 2 , 193 + /- 40 % at t = 5 , p < .05 ) . RBF remained elevated throughout the catheterization in Group 2 . ( ABSTRACT TRUNCATED AT 250 WORDS PURPOSE To evaluate the protective effect of low-dose dopamine given as continuous infusion in patients who undergo chemotherapy with the nephrotoxin cisplatin . PATIENTS AND METHODS Forty-two patients who received high-dose cisplatin-containing chemotherapy entered a prospect i ve , r and omized , double-blind , placebo-controlled trial . Twenty-one patients received dopamine , and 21 received placebo . Patients were to receive either infusional dopamine 2 micrograms/kg/min over 48 hours or placebo . Cisplatin 125 mg/m2 was administered 12 hours after initiating dopamine ( group D ) or placebo ( group P ) . This schedule was repeated twice , 1 week apart . Measurements of serum creatinine , urinary electrolytes and creatinine , urinary excretion of epidermal growth factor ( EGF ) , ototoxicity , parameters of hematopoietic recovery , and duration of hospitalization were analyzed . RESULTS We observed an increase in serum creatinine level to a peak of 1.9 mg/dL ( range , 0.8 to 7.8 ) in the dopamine group , in comparison to 1.4 mg/dL ( range , 0.9 to 3.3 ) in the placebo group ( P = .04 ) . Urinary magnesium excretion increased and EGF excretion decreased in both groups . Urinary sodium , chloride , and potassium excretion were increased in both groups , but more so in the placebo group . Dopamine had no measurable effect on hearing loss , duration of hospitalization , or hematopoietic recovery . CONCLUSION The use of prophylactic dopamine increased peak serum creatinine levels relative to placebo and failed to prevent cisplatin-induced renal toxicity or ototoxicity . Determination of whether dopamine could reverse chemotherapy-induced renal damage would require a r and omized prospect i ve trial BACKGROUND Injections of radiocontrast agents are a frequent cause of acute decreases in renal function , occurring most often in patients with chronic renal insufficiency and diabetes mellitus . METHODS We prospect ively studied 78 patients with chronic renal insufficiency ( mean [ + /- SD ] serum creatinine concentration , 2.1 + /- 0.6 mg per deciliter [ 186 + /- 53 mumol per liter ] ) who underwent cardiac angiography . The patients were r and omly assigned to receive 0.45 percent saline alone for 12 hours before and 12 hours after angiography , saline plus mannitol , or saline plus furosemide . The mannitol and furosemide were given just before angiography . Serum creatinine was measured before and for 48 hours after angiography , and urine was collected for 24 hours after angiography . An acute radiocontrast-induced decrease in renal function was defined as an increase in the base-line serum creatinine concentration of at least 0.5 mg per deciliter ( 44 mumol per liter ) within 48 hours after the injection of radiocontrast agents . RESULTS Twenty of the 78 patients ( 26 percent ) had an increase in the serum creatinine concentration of at least 0.5 mg per deciliter after angiography . Among the 28 patients in the saline group , 3 ( 11 percent ) had such an increase in serum creatinine , as compared with 7 of 25 in the mannitol group ( 28 percent ) and 10 of 25 in the furosemide group ( 40 percent ) ( P = 0.05 ) . The mean increase in serum creatinine 48 hours after angiography was significantly greater in the furosemide group ( P = 0.01 ) than in the saline group . CONCLUSIONS In patients with chronic renal insufficiency who are undergoing cardiac angiography , hydration with 0.45 percent saline provides better protection against acute decreases in renal function induced by radiocontrast agents than does hydration with 0.45 percent saline plus mannitol or furosemide OBJECTIVE To determine the effect on renal function of postoperative continuous , intravenous furosemide after major thoraco-abdominal or vascular surgery . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Intensive care unit of a referral hospital in Eastern Switzerl and . METHODS Furosemide ( 1 mg/h ) or placebo was administered to 121 consecutive patients admitted to the intensive care unit after major abdominal , chest or vascular surgery and continued throughout the intensive care treatment period . Enrollment was performed during a 6 months period . No patient was excluded . Renal function was determined serially by measuring creatinine clearances and plasma creatinine concentrations . RESULTS Postoperatively , creatinine clearance decreased significantly to 83 % ( furosemide ) and to 81 % ( placebo group ) of the initial value ( p = 0.004 ) . This decrease was not affected significantly by furosemide . Retrospective subgroup analysis using stepwise regression also did not show any differences between the groups . Hypokalemia was detected in 36 ( furosemide ) versus 19 % of the blood sample ( placebo , p = 0.006 ) . CONCLUSIONS Low-dose intravenous furosemide appears to offer no advantage over placebo in an unselected group of patients with moderate postoperative renal impairment . As no patients with acute renal failure necessitating dialysis were observed during the study period , the effect of furosemide in more severe postoperative renal impairment and the effects of higher doses of loop diuretics remain to be investigated We have compared low dose dopamine with dobutamine in conserving renal function in 142 children younger than 10 yr undergoing cardiopulmonary bypass ( CPB ) . Patients were allocated r and omly to receive a continuous infusion of either dopamine 2.5 micrograms kg-1 min-1 ( group 1 ) or dobutamine 2.5 micrograms kg-1 min-1 ( group 2 ) from the time of induction of anaesthesia . Administration of inotropes and diuretics was controlled strictly to agreed regimens . There was no clinical or statistically significant difference between the two groups in postoperative urine output , serum concentration of creatinine , fractional sodium excretion or need for diuretic therapy . This was true also of the subgroup of patients who received no other inotropic support . However , the subgroup of patients in group 1 who underwent periods of CPB in excess of 2 h ( n = 17 ) had persistently greater postoperative serum concentrations of creatinine . Low dose dopamine did not appear to be superior to dobutamine for protection of renal function in these patients Objective : Low‐dose dopamine has been used in critically ill patients to minimize renal dysfunction without sufficient data to support its use . The aim of this study was to determine whether low‐dose dopamine improves renal function , and whether dobutamine , a nondopaminergic inotrope , improves renal function . Design : Prospect i ve , r and omized , double‐blind trial . Patients : Twenty‐three patients at risk for renal dysfunction were entered into the study . Five patients were later withdrawn . Study data for the remaining 18 patients were : mean age 55 yrs ; mean Acute Physiology and Chronic Health Evaluation ( APACHE ) II score of 18 ; mean weight 71 kg ) . The following conditions were present : mechanical ventilation ( n = 17 [ inverse‐ratio ventilation , n = 6 ] ) ; inotrope administration ( n = 11 ) ; sepsis ( n = 13 ) ; and adult respiratory distress syndrome or multiple organ failure syndrome ( n = 9 ) . Interventions : The study patients were administered dopamine ( 200 & mgr;g/min ) , dobutamine ( 175 & mgr;g/min ) , and placebo ( 5 % dextrose ) over 5 hrs each in a r and omized order . Ventilator setting s , fluid management , and preexisting inotropic support were not altered during the study . Measurements and Main Results : Systemic hemodynamic values and indices of renal function ( 4‐hr urine volume , fractional excretion of sodium , and creatinine clearance ) were measured during the last 4 hrs of each infusion . Dopamine produced a diuresis ( 145 ± 148 mL/ hr ) compared with placebo ( 90 ± 44 mL/hr ; p < .01 ) without a change in creatinine clearance . Conversely , dobutamine caused a significant increase in creatinine clearance ( 97 ± 54 mL/ min ) compared with placebo ( 79 ± 38 mL/min ; p < .01 ) , without an increase in urine output . Conclusions : In stable critically ill patients , dopamine acted primarily as a diuretic and did not improve creatinine clearance . Dobutamine improved creatinine clearance without a significant change in urine output . ( Crit Care Med 1994 ; 22:1919–1925 1 . The nephrotoxic effects of cyclosporin A may diminish the ability of the transplanted kidney to increase the glomerular filtration rate and effective renal plasma flow during infusion of dopamine or amino acids . 2 . The present study included 16 renal transplant recipients transplanted for more than 6 months . Eight of the patients were on immunosuppressive treatment including cyclosporin A [ cyclosporin A group ; cyclosporin A dose , 2.7 + /- 0.4 mg/kg ; S-creatinine , 105 + /- 12 mumol/l ( means + /- SEM ) ] , whereas eight patients had never received cyclosporin A ( non-cyclosporin A group ; S-creatinine , 89 + /- 6 mumol/l ) . The renal response to infusion of dopamine and of amino acids was investigated on two separate days . All clearance measurements were carried out at nadir cyclosporin A blood levels . 3 . Effective renal plasma flow increased significantly in the non-cyclosporin A group and cyclosporin A group by 31.0 + /- 4.1 % and 35.9 + /- 6.6 % , respectively , during infusion of dopamine , and by 18.7 + /- 6.7 % and 13.9 + /- 5.3 % , respectively , during infusion of amino acids . Glomerular filtration rate increased significantly in the non-cyclosporin A group and cyclosporin A group by 15.7 + /- 3.3 % and 18.3 + /- 4.7 % , respectively , during infusion of dopamine , and by 18.9 + /- 4.5 % and 15.0 + /- 3.7 % , respectively , during infusion of amino acids . 4 . Furthermore , the amino acid- and dopamine-induced increases in proximal tubular outflow ( renal clearance of lithium ) and calculated changes in renal proximal and distal tubular h and ling of sodium ( and water ) were comparable between the two groups of patients . Dopamine caused significant natriuresis in both groups . 5 . In conclusion , low-dose cyclosporin A seems not to attenuate the renal haemodynamic and tubular response to infusions of amino acids and of dopamine in renal transplant recipients with a good graft function An intravenous infusion of dopamine at 2.5 microgram/kg/min was administered for 40 minutes to anesthetized cardiac surgical patients , and their renal function was measured . Five patients had the usual preoperative regimen of reduced fluid intake for the night and morning before surgery ( nonhydrated ) , and five patients received normal saline , 2 mL/kg/hr intravenously , for 6 hours before anesthesia ( hydrated ) . Renal function ( measured by urine output , sodium excretion , free water clearance , and fractional excretion of sodium ) was similar immediately before starting the dopamine infusion . All four variables were significantly higher in the hydrated group after 10 minutes ; this difference becoming maximal after 40 minutes . Twenty minutes after stopping the dopamine infusion , renal function was similar in the two groups . This study indicates that preoperatively fluid-restricted patients demonstrate powerful salt and water conservation with reduced natriuretic and diuretic responses to a low-dose dopamine infusion when compared with hydrated patients . Patients with adequate fluid loading and intravascular volume will demonstrate a marked natriuresis and diuresis in response to low-dose dopamine infusion The efficacy of renal-dose dopamine to improve renal function or reduce renal impairment was studied in 52 patients undergoing elective coronary artery bypass surgery . The patients were prospect ively r and omised in a double-blind fashion to receive dopamine at 200 μg/min ( group D ) or placebo ( group P ) from induction for 24 hours . Although dopamine improved haemodynamics , there was no effect on urine output at 4 hours ( D = 917 , P=1231 ml : P = 0.066 ) ; urine output at 24 hours ( D=3659 , P=3304 ml : P = 0.36 ) ; creatinine clearance at 0–4 hours ( D = 104 , P=127 ml/min : P = 0.27 ) ; creatinine clearance on admission to ICU-4 hours ( D=94.8 , P=83.4 ml/min : P = 0.48 ) ; creatinine clearance at 20–24 hours ( D = 91.2 , P=107 ml/min : P = 0.48 ) ; free-water clearance at 0–4 hours ( D=29.6 , P= -59.8 ml/hr : P = 0.069 ) ; free-water clearance at 20–24 hours ( D=43.2 , P= -48.9 ml/hr : P = 0.55 ) . The incidence of transient renal impairment was similar in both groups ( D=36 % , P=50 % : P = 0.65 ) . Our study failed to demonstrate that routine prophylactic renal-dose dopamine is associated with improvement in renal function , or with prevention of transient renal impairment in patients undergoing coronary artery bypass surgery The increasingly frequent use of contrast-enhanced imaging for diagnosis or intervention in patients with peripheral vascular disease has generated concern about the incidence and avoidance of contrast-induced nephrotoxicity ( CIN ) . In this prospect i ve study , we sought to identify those patients at greater risk of developing CIN and to evaluate the efficacy of vasodilator therapy with dopamine in limiting this complication . Baseline serum creatinine ( Cr ) concentrations were obtained on admission and daily for up to 72 hr after angiography in 222 patients undergoing 232 angiographic procedures . The preangiographic treatment was varied at 2-month intervals for 1 year . All patients received an intravenous infusion of 5 % dextrose and 0.45 % normal saline at a rate of 75 to 125 ml/hr . During the first interval patients received 12.5 g of 25 % mannitol immediately prior to their contrast load , in addition to intravenous fluids . During the next 2-month period the patients were given renal dose dopamine intravenously ( 3 micrograms/kg/min ) commencing the evening before angiography and continued to the next morning . During the latter half of the study the treatment regimens were modified so that the use of mannitol was restricted to patients with diabetes mellitus and dopamine to patients with serum creatinine concentrations of > or = 2 mg/dl . Postangiographic elevation in Cr occurred in 2 , 10.4 , and 62 % of studies in patients with baseline creatinine levels of < or = 1.2 mg/dl , 1.3 to 1.9 mg/dl , and > or = 2.0 mg/dl , respectively . None of the patients receiving dopamine experienced an elevation in creatinine . There was no statistical correlation between age , diabetes , or medication with calcium channel blockers and CIN . ( ABSTRACT TRUNCATED AT 250 WORDS A r and omized trial was undertaken to reassess the effectiveness of mannitol in preventing postoperative renal impairment in patients with obstructive jaundice . The study included 31 patients with obstructive jaundice ( bilirubin , 3 mg/dl or higher ) r and omly allocated in two groups to receive ( n = 17 ) or not receive ( n = 14 ) preoperative mannitol . Sixty-five percent of patients had a creatinine clearance below 70 ml/min before surgery . Serum bilirubin and bacteribilia had no relation with preoperative renal function . No relation was found between serum bilirubin value and the percentage fall in postoperative creatinine clearance . Compared with the preoperative values , the postoperative creatinine clearance was significantly impaired in the mannitol group ( p = 0.03 ) and remained almost unaltered in the no-mannitol group . Three patients ( 9.7 % ) died of acute renal failure ; two were in the mannitol group and one was in the no-mannitol group . Serum fibrin degradation products were not sensitive markers for impending renal failure . There was no significant difference in postoperative serum sodium concentration or in the urinary sodium excretion . Administration of mannitol did not improve the postoperative renal function of jaundiced patients , nor did it prove beneficial in preventing renal failure . Our results suggest that severe disturbances of body-fluid compartments may be the basic mechanism underlying kidney dysfunction in obstructive jaundice and that further water depletion induced by mannitol may indeed prove detrimental The purpose of the study was to determine the efficacy of furosemide in addition to intravenous fluids in the prevention of radiocontrast nephropathy . 18 patients , referred to a radiocontrast study , considered at risk because of preexisting renal insufficiency , were enrolled in a prospect i ve , r and omized , controlled trial , performed at the secondary care center of a 1,100-bed private university hospital . In addition to fluids , the treatment group received furosemide ( mean dose 110 mg ) intravenously 30 min prior to the injection of contrast material . The control group received fluids ( mean 3 liters ) . Radiological studies were mostly angiographies performed with both ionic and non-ionic contrast material , at an average dose of 245 ml . Renal function significantly deteriorated in the group pretreated with furosemide ( p < 0.005 by ANOVA ) , with a rise in serum creatinine from 145 + /- 13 to 182 + /- 16 mumol/l at 24 h , while no change occurred in the control group ( from 141 + /- 6 to 142 + /- 7 mumol/l ) . Renal failure was associated with weight loss in the furosemide-treated group . Furosemide may be deleterious in the prevention of radiocontrast nephropathy Dopamine is administered frequently in the operating theatre and intensive care unit patients undergoing mechanical ventilation with the aim of specifically enhancing renal blood flow . In an uncontrolled , open study , we administered sequentially different doses of dopamine ( 0 , 2 , 4 , 8 and 0 microgram kg-1 min-1 ) during a 1-h period each . Systemic haemodynamic and renal haemodynamic variables were measured simultaneously using a pulmonary artery catheter and radiopharmaceuticals , respectively . We studied seven haemodynamically stable patients ( mean age 66 yr ) , with a serum creatinine concentration < 160 mumol litre-1 , after elective infrarenal abdominal aortic reconstruction . All patients received extradural analgesia with bupivacaine and sufentanil , and none had a previous history of heart failure . Dopamine induced a dose-dependent increase in cardiac index which returned to baseline after cessation of the dopamine infusion . Glomerular filtration rate ( GFR ) increased with all doses of dopamine , whereas renal blood flow ( RBF ) increased significantly only with the 2- and 4-microgram kg-1 min-1 doses . However , the ratio RBF/cardiac output remained unchanged with the 2- and 4-microgram kg-1 min-1 doses , but decreased with 8 micrograms kg-1 min-1 from 14 (1.5)% to 10 (1.3)% . We conclude that dopamine increased RBF and GFR as a result of an increase in cardiac output OBJECTIVE To determine whether dopamine prevents deterioration of central haemodynamics and renal function in aortoiliac surgery . DESIGN Prospect i ve , r and omised and placebo-controlled . SETTING University hospital . MATERIAL S Thirty patients for elective vascular surgery with implantation of an aortobifemoral or an aortobiiliac graft due to aortoiliac arteriosclerosis had infusion of dopamine 3 micrograms/kg/min or placebo during the operation and 24 h postoperatively . Thoracic epidural analgesia and general anaesthesia were used . CHIEF OUTCOME MEASURES Central haemodynamic measurements were registered . The effective renal plasma flow ( ERPF ) , the glomerular filtration rate ( GFR ) , angiotensin II , aldosterone , arginine vasopressin ( AVP ) , atrial natriuretic peptide ( ANP ) , endothelin and excretion of water and electrolytes were measured preoperatively , 1 h postoperatively and 24 h postoperatively . MAIN RESULTS During the operation the dopamine group had higher cardiac index and heart rate together with lower pulmonary artery wedge blood pressure . ERPF and GFR did not differ between the groups . In the dopamine group ERPF was increased in all patients at the first postoperative clearance . The fractional excretion of sodium , the per- and postoperative diuresis and AVP were increased in the dopamine group as compared to the placebo group . Postoperatively , ANP in the placebo group was raised as compared to the preoperative level . CONCLUSIONS Peroperatively , dopamine counteracted depression of left ventricular function . The increased ERPF at the first postoperative clearance in the dopamine group indicates either improved peroperative haemodynamics or a synergistic effect between dopamine and epidural sympathetic blockade . Dopamine also improved diuresis and natriuresis Sixteen patients diagnosed with an aneurysm of abdominal aorta or Leriche disease underwent elective aortic surgery involving crossclamping of infrarenal aorta ( ICC ) . These patients were r and omized into two equal groups and 8 patients were infused with nifedipine starting from the isolation of aorta until the end of surgery ( group A ) while another 8 patients were infused with low-dose dopamine ( group B ) over the same surgical course . Plasma endothelin ( ET ) was measured before the induction of anesthesia , at the beginning and at the end of the clamp period and at the end of the operation . Intraoperatively , creatinine clearance and urinary excretion of PGE2 , 6-keto PGF1 alpha and TxB2 were also determined before , during and after aortic crossclamping . Preoperative GFR as well as preinduction cardiac index ( CI ) and pulmonary capillary wedge pressure ( PCWP ) of the two groups did not differ . During cross-clamping plasma ET rose significantly in both groups . However , after clamp removal , plasma ET decreased in group A while it remained elevated in group B. Urinary excretion of TxB2 , PGE2 and 6-keto PGF1 alpha increased during clamp in both groups , but the ratio of PGE2 + 6-keto PGF1 alpha/TxB2 during and after clamp was significantly higher in group A than in B. Postclamp creatinine clearance decreased in group B , and increased in group A ; postoperative value of GFR was unchanged in group A and decreased significantly in group B. In conclusion , infusion of nifedipine , in contrast to dopamine , prevented the decrease of GFR in patients undergoing aortic surgery . This effect could be mediated by a nifedipine modulation of ET vascular synthesis and /or a preferential renal synthesis of vasodilating prostanoids We studied three groups of patients without previous renal impairment , undergoing elective coronary artery bypass surgery . Group H ( n = 7 ) underwent open heart surgery using moderate hypothermia ( 28 degrees C ) ; Groups N and M ( n = 8 , each ) were managed at normothermia . The extracorporeal circuit was primed with Hartmann 's solution 2.5 L with the addition of mannitol 0.5 g/kg in Group M. Serum concentrations of sodium and creatinine , and the urinary concentrations of microalbumin and N-acetyl-beta-D-glucosaminidase ( NAG ) were measured in each patient at six different time intervals : T0 , 6 h prior to surgery ; T1 , between sternotomy and 45 min into cardiopulmonary bypass ( CPB ) ; T2 , in the interval from 45 min into , to prior to weaning off CPB ; T3 , from coming off CPB to skin closure ; T4 , in the first 6 h in the intensive care unit ; and T5 , at 6 days postoperatively . Creatinine clearance ( CCR ) and fractional sodium excretion ( FENA ) were calculated at each time point . Urine output during CPB at Interval T2 was significantly higher in Group H compared to Group N ( P = 0.03 ) but not Group M. We found no significant differences in CCR , FENA , microalbuminuria , and urinary NAG among the three groups at any time . However , there were overall significant changes in measured variables over time compared to baseline . We conclude that CPB is associated with a significant alteration in renal function as shown by increased FENA , microalbuminuria , and urinary NAG . The use of hypothermic or normothermic CPB and the use of prophylactic mannitol did not produce any significant modification of these changes OBJECTIVE To assess the effect of low-dose dopamine on urine output and natriuresis in critically ill oliguric patients and the relationship of this response to the renin-angiotensin aldosterone system . DESIGN A prospect i ve , controlled study . SETTING A multidisciplinary intensive care unit of a teaching hospital . SUBJECTS Critically ill , volume-resuscitated , oliguric patients . INTERVENTION Dopamine was infused at a rate of 2 micrograms/kg/min . The change in urine output and sodium excretion was measured over a 6-hour period . Plasma Renin Activity ( PRA ) and serum aldosterone were measured before commencing low-dose dopamine . OUTCOME MEASURE Patients whose mean urine output increased by greater than 20 ml/hour were considered to have responded to low-dose dopamine . RESULTS Nine patients were studied . Five of the nine patients responded to low-dose dopamine . The mean increase in urine volume was 58.4 ml/hr in the responders compared with 5.0 ml/hr in the nonresponders . The mean PRA ( normal , 0.8 to 2.5 ng/ml/hr ) was 5.7 ng/ml/hr in the responders compared with 26.8 ng/ml/hr in the nonresponders ( p = 0.042 ) . A significant inverse correlation existed between the PRA and the increase in urinary output ( r = -0.75 ; p = 0.019 ) . CONCLUSION The response to renal dopamine in critically ill patients appears to be dependent on the interaction between the vasodilating-natriuretic effect of dopamine and the vasoconstricting antinatriuretic effect of the renin-angiotensin aldosterone system Patients undergoing orthotopic liver transplantation frequently receive dopamine infusions to preserve renal function . To test the benefit of such infusions on renal function , 48 nonanuric patients presenting for OLT were entered into a r and omized double-blind protocol . After exclusion of 1 patient for intraoperative nephrectomy , 22 patients received dopamine at a rate of 3 micrograms.kg-1.min-1 during surgery and the first postoperative 48 h , and a control group of 25 patients received saline . Venovenous bypass was used in 45 of 47 patients . During the hepatic vascular anastomoses , the donor liver was flushed with cold saline . In 7 patients , the flush contained mannitol ( 50 g ) as part of a surgical protocol to investigate its role as a potential free radical scavenger . Initially , it appeared that there was an increase in urine output during the neohepatic phase in those patients receiving dopamine versus controls ( 4.20 + /- 3.3 vs 2.10 + /- 1.3 ml.kg-1.h-1 , respectively ) . Upon further statistical analysis , this increase was associated with inclusion of mannitol in the liver flush of 5 patients in the dopamine group . After excluding all patients receiving flush containing mannitol , there was no significant difference in urine output during the neohepatic phase between the dopamine group and controls ( 2.94 + /- 0.45 and 2.10 + /- 0.28 ml.kg-1.h-1 , respectively ) . The glomerular filtration rates at 1 month after surgery were similar and decreased approximately 40 % in each group . Although a beneficial effect of dopamine in all situations can not be ruled out the authors conclude that routine perioperative use of dopamine is of little value in nonanuric patients presenting for orthotopic liver transplantation OBJECTIVE To test the hypothesis that a continuous , low-dose infusion of a loop diuretic is more efficacious and better tolerated than conventional intermittent bolus therapy in patients with severe chronic renal insufficiency ( CRI ) . DESIGN R and omized , crossover clinical trial with subjects serving as their own controls . SETTING The General Clinical Research Center of Indiana University Hospital , Indianapolis , Indiana . PATIENTS Eight adult volunteers with severe stable CRI ( mean creatinine clearance , 0.28 mL/s ; range , 0.15 to 0.47 mL/s ) were recruited from the outpatient nephrology clinics of Indiana University Medical Center . INTERVENTIONS On admission , diuretic drugs were withdrawn and patients were equilibrated on an 80 mmol/d sodium , 60 mmol/d potassium metabolic diet . Patients were r and omized to receive a 12-mg intravenous dose of bumetanide given either as two 6-mg bolus doses separated by 6 hours or as the same total dose administered as a 12-hour continuous infusion . When sodium balance was re-established , each patient was crossed over to the alternative study limb . All patients completed both phases of the study . MEASUREMENTS AND RESULTS Comparable amounts of bumetanide appeared in the urine during the study period ( infusion , 912 + /- 428 micrograms ; bolus , 944 + /- 421 micrograms ; difference , 32 micrograms ; 95 % CI , -16 micrograms to 80 micrograms , P = 0.16 ) . The continuous infusion result ed in significantly greater net sodium excretion ( infusion , 236 + /- 77 mmol ; bolus , 188 + /- 50 mmol ; difference , 48 mmol ; CI , 16 mmol to 80 mmol , P = 0.01 ) . No patient had episodes of drug-induced myalgias during the continuous infusion compared with 3 of 8 patients with bolus therapy . CONCLUSIONS In patients with severe CRI , a continuous intravenous infusion of bumetanide is more effective and less toxic than conventional intermittent bolus therapy . Continuous administration will probably be useful in patients with severe CRI who have not achieved an adequate natriuresis or who show evidence of drug toxicity with st and ard diuretic dosing regimens . A similar benefit may occur in selected diuretic-resistant patients with cardiac or hepatic disease , and studies in these patients seem warranted & NA ; We studied the effect of a low‐dose dopamine infusion on graft function in 60 patients undergoing transplantation with cadaveric kidneys in a prospect i ve controlled trial . Recipients were allocated to either a control or a dopamine group , the latter receiving a 3 & mgr;g·kg‐1·min‐1 infusion of dopamine starting intraoperatively . Evaluation of dopamine 's effect was undertaken in two stages , namely , ( i ) initial graft function 1 wk after transplantation and ( ii ) graft survival at 3 mo . Initial graft function was determined by the ability of the transplanted kidney to reduce serum creatinine , and the development of acute tubular necrosis as confirmed by renal biopsy . Of the dopamine group 33.3 % developed acute tubular necrosis compared to 23.3 % of the control group . The second‐stage evaluation was based on plasma creatinine levels and the requirement for dialysis within 3 mo of transplantation . 92.8 % of the dopamine group and 76.9 % of the control group had good graft function . No statistically significant difference between the two groups was found . The perioperative infusion of dopamine at 3 & mgr;g·kg‐1 · min‐1 was not shown to have any beneficial effect on the transplanted kidney in patients who do not have serious vascular disease , or who do not receive kidneys subjected to prolonged hypotension or prolonged preservation or anastamotic times . ( Anesth Analg 1993;76:362‐5 A prospect i ve study was undertaken to assess postoperative renal dysfunction in patients with obstructive jaundice and to determine the effectiveness of dopamine in reducing its incidence . A total of 23 patients undergoing surgical relief of obstructive jaundice ( serum bilirubin level above 100 μmol l−1 ) were r and omized into two groups . Those in the control group ( n = 10 ) received 3 litres 5 per cent dextrose intravenously during the 24 h before surgery plus a bolus of intravenous frusemide 1 mg kg−1 at induction of anaesthesia . The second group ( n = 13 ) received a similar fluid and frusemide regimen plus an infusion of dopamine 3 μg kg−1 min−1 starting at induction of anaesthesia and continuing for 48 h after surgery . Postoperative oliguria occurred in two of the ten patients in the control group and in three of the 13 given dopamine ( P = 0.74 ) . No patient developed acute renal failure . There was no significant difference in mean levels of serum bilirubin , urea and creatinine , creatinine clearance and 24‐h urinary output , on the day before and on days 1–5 after operation , between the two groups . It is concluded that , with careful preoperative resuscitation and control of fluid and electrolyte balance , the incidence of postoperative renal dysfunction in patients with obstructive jaundice is not as high as in some previous studies and is unaltered by administration of perioperative low‐dose dopamine Objective : To quantify the magnitude and time course of the effect of low‐dose dopamine ( 2.5 & mgr;g/kg/min ) infusions on urine output in oliguric patients . Design : A prospect i ve , clinical study . Setting : A surgical intensive care unit ( ICU ) at a university hospital . Patients : A total of 19 surgical ICU patients with oliguria ( < 0.5 mL/kg/hr ) after resuscitation to pulmonary artery occlusion pressures > 10 mm Hg , mean arterial pressures > 65 mm Hg , and cardiac index > 2 L/min/m2 . Patients with acute renal failure and those patients receiving diuretics were excluded . Measurements and Main Results : Urine output was monitored hourly before and after dopamine was instituted for the treatment of oliguria . Spot urine electrolyte determinations and urine specific gravity measurements were obtained . Patients with urine output improvement ( > 50 % increase ) had dopamine stopped after 4 hrs . If urine output decreased to < 0.5 mL/kg/hr , dopamine was resumed . There were no dopamine‐induced changes in heart rate , pulmonary artery occlusion pressure , mean arterial pressure , or cardiac index . Mean urine output increased from 0.29 to 1.04 mL/kg/hr ( p < .001 ) while patients were receiving dopamine . Timeto‐peak response to dopamine was 7 hrs . Urine output increased to > 0.5 mL/kg/hr in 95 % of patients , doubled in 89 % of patients , and exceeded 1.0 mL/kg/hr in 84 % of patients . After dopamine was stopped , urine output decreased to < 0.5 mL/ kg/hr in 79 % of patients and responded to resumption of dopamine in 100 % of patients . There were no significant changes in urine sodium concentration or specific gravity . Conclusions : Low‐dose dopamine infusion alone produces a drug‐dependent increase in urine output in oliguric , euvolemic ICU patients . Maximal effect is temporally variable . ( Crit Care Med 1994 ; 22:61‐66

RESULTS A deregulated oxidative pathway is clearly evident with elevated superoxide dismutase , decreased catalase and increased lipid peroxidation . However , similar results have been obtained in other inflammatory skin diseases such as psoriasis , atopic dermatitis , lichen planus and urticaria . Some isolated successes have been reported with oral ginkgo biloba , polypodium leucotomos and vitamin C and E preparations , while other clinical trials have failed to show reproducible results . The use of topical antioxidants delivers in general no beneficial results . The oxidative pathway is affected in vitiligo , but its unique initiating or contributory role in the pathogenesis is less evident .

BACKGROUND The pathogenesis of vitiligo remains a topic of extensive debate . This is partly due to the moderate efficacy of current treatments . The role of the oxidative stress pathway in vitiligo is a popular although controversial research topic . OBJECTIVE To clarify the role of the oxidative stress pathway in vitiligo compared to other inflammatory skin disorders and to assess the therapeutic role of antioxidants .

Background Vitiligo is a common hypopigmentation disorder with significant psychological impact if occurring before adulthood . A pilot clinical trial to determine the feasibility of an RCT was conducted and is reported here . Methods 12 participants 12 to 35 years old were recruited to a prospect i ve open-label pilot trial and treated with 60 mg of st and ardized G. biloba two times per day for 12 weeks . The criteria for feasibility included successful recruitment , 75 % or greater retention , effectiveness and lack of serious adverse reactions . Effectiveness was assessed using the Vitiligo Area Scoring Index ( VASI ) and the Vitiligo European Task Force ( VETF ) , which are vali date d outcome measures evaluating the area and intensity of depigmentation of vitiligo lesions . Other outcomes included photographs and adverse reactions . Safety was assessed by serum coagulation factors ( platelets , PTT , INR ) at baseline and week 12 . Results After 2 months of recruitment , the eligible upper age limit was raised from 18 to 35 years of age in order to facilitate recruitment of the required sample size . Eleven participants completed the trial with 85 % or greater adherence to the protocol . The total VASI score improved by 0.5 ( P = 0.021 ) from 5.0 to 4.5 , range of scale 0 ( no depigmentation ) to 100 ( completely depigmented ) . The progression of vitiligo stopped in all participants ; the total VASI indicated an average repigmentation of vitiligo lesions of 15 % . VETF total vitiligo lesion area decreased 0.4 % ( P = 0.102 ) from 5.9 to 5.6 from baseline to week 12 . VETF staging score improved by 0.7 ( P = 0.101 ) from 6.6 to 5.8 , and the VETF spreading score improved by 3.9 ( P < 0.001 ) ) from 2.7 to -1.2 . There were no statistically significant changes in platelet count , PTT , or INR . Conclusions The criteria for feasibility were met after increasing the maximum age limit of the successful recruitment criterion ; participant retention , safety and effectiveness criteria were also met . Ingestion of 60 mg of Ginkgo biloba BID was associated with a significant improvement in total VASI vitiligo measures and VETF spread , and a trend towards improvement on VETF measures of vitiligo lesion area and staging . Larger , r and omized double-blind clinical studies are warranted and appear feasible . Trial Registration Clinical trials.gov registration number Objective : Pseudocatalase/superoxide dismutase ( PSD ) is a topical gel considered having therapeutic effects in vitiligo . This study was design ed to evaluate the efficacy of this combination in vitiligo . Methods : This was a pilot r and omized , double-blind , placebo-controlled trial on 46 symmetrical vitiligo lesions of limbs in 23 patients referring to dermatology clinics , Isfahan , Iran in 2010 . Patients were received this formula or placebo gels for the right and left lesions . Lesion area and degree of pigmentation were assessed at baseline , 2 , 4 , and 6 months . Findings : There were no significant changes in lesion area and perifollicular pigmentation in each group ( P > 0.05 ) . Conclusion : The results indicated no significant therapeutic effect for PSD in vitiligo Summary For effective treatment of vitiligo , it is as important to arrest the progression of the disease as it is to induce repigmentation . Recently , oxidative stress has been shown to play an important role in the pathogenesis of vitiligo . Ginkgo biloba extract has been shown to have antioxidant and immunomodulatory properties . In a double‐blind placebo‐controlled trial , we evaluated the efficacy of G. biloba extract in controlling the activity of the disease process in patients with limited and slow‐spreading vitiligo and in inducing repigmentation of vitiliginous areas . Fifty‐two patients were assigned to two treatment groups ( A and B ) in a double‐blind fashion , but only 47 patients could be evaluated , because one patient in group A and four patients in group B withdrew for reasons unrelated to the study . Patients in group A were given G. biloba extract 40 mg three times daily whereas patients in group B received placebo in similar doses . A statistically significant cessation of active progression of depigmentation was noted in patients treated with G. biloba ( P = 0.006 ) . Marked to complete repigmentation was seen in 10 patients in group A , whereas only two patients in group B showed similar repigmentation . The G. biloba extract was well tolerated . G. biloba extract seems to be a simple , safe and fairly effective therapy for arresting the progression of the disease Narrow-b and UVB has been reported to be efficacious in patients with vitiligo . The epidermis of patients with vitiligo showed reduction in the levels of catalase , in association with high levels of hydrogen peroxidase ( H2O2 ) that is toxic for melanocytes . Based on these findings , we studied the efficacy and safety of a topical gel containing catalase and superoxide dismutase ( Vitix ) in combination with narrow-b and UVB . The study included 22 patients of which 19 completed the 6-month study period . Patients applied the gel containing catalase and superoxide dismutase twice a day and received narrow-b and UVB 3 times per week . Two different dermatologists evaluated the grade of repigmentation by photograph comparison . At the end of therapy , more than 50 % of overall repigmentation was noticed in 11 of 19 ( 57.9 % ) patients . More than 75 % repigmentation was recorded in three ( 15.79 % ) , 26%-50 % repigmentation in six ( 31.58 % ) patients and 1%-25 % repigmentation in one ( 5.26 % ) patient , whereas one ( 5.26 % ) of 19 patients showed no repigmentation at all . The best response was achieved on the face and neck , with more than 50 % repigmentation observed in 11 of 14 ( 78.6 % ) patients . Development of new lesions was not observed . Adverse events were mild and transient . The study showed that the combination therapy of narrow-b and UVB and gel containing catalase and dismutase is a therapeutic option that could be considered in the management of vitiligo . Further evaluation of this combination in multicenter , double-blind , placebo-controlled studies should be undertaken Background : Generalized vitiligo is a disease with unpredictable bursts of activity , goal of treatment during the active phase being to stabilize the lesions . This emphasizes the need for a prospect i ve marker for monitoring disease activity to help decide the duration of therapy . Aims and Objectives : In the present study , we examined whether reactive oxygen species ( ROS ) generated in erythrocytes can be translated into a marker of activity in vitiligo . Material s and Methods : Level of intracellular ROS was measured flow cytometrically in erythrocytes from venous blood of 21 patients with generalized vitiligo and 21 healthy volunteers using the probe dichlorodihydrofluorescein diacetate . Results : The levels of ROS differed significantly between patients and healthy controls , as well as between active versus stable disease groups . In the active disease group , ROS levels were significantly lower in those being treated with systemic steroids than those that were not . ROS levels poorly correlated with disease duration or body surface area involved . Conclusion : A long-term study based on these findings can be conducted to further vali date the potential role of ROS in monitoring disease activity vitiligo Narrow b and UVB is succeeding psoralen and UVA irradiation as the main treatment of vitiligo vulgaris in several European countries . Vitamin B12 and folic acid deficiency in some vitiligo patients has prompted research ers to investigate the efficacy of these vitamins in the treatment of vitiligo . In the present controlled study we investigated the value of narrow b and UVB phototherapy in the treatment of vitiligo and the possible additive effect of vitamin B12 and folic acid . Twenty-seven patients with long-term stable vitiligo were included and r and omized in a " UVB only " ( UVB ) or " UVB combined with vitamin B12 and folic acid " ( UVB+ ) group . Patients were irradiated thrice weekly for one year , whilst repigmentation was carefully monitored . In 92 % ( 25/27 ) of the patients up to 100 % repigmentation was seen . Repigmentation was notable in lesions on the face , neck and throat , lower arm , chest , back and lower legs , whilst repigmentation on the h and s , wrists , feet and ankles proved to be minimal . Maximum repigmentation rates did not differ significantly between the UVB group and the UVB+ group . Our study reconfirms that narrow b and UVB phototherapy is an effective treatment for vitiligo and shows that co-treatment with vitamin B12 and folic acid does not improve the outcome of treatment of vitiligo with narrow b and UVB phototherapy Phyllanthus emblica , vitamin E , and caroteinods are compounds showing antioxidative , anti-inflammatory , and repigmenting effects , whose role in vitiligo treatment has not been evaluated so far . Sixty-five subjects ( group A ) were treated with one tablet of an oral supplement containing P. emblica ( 100 mg ) , vitamin E ( 10 mg ) , and carotenoids ( 4.7 mg ) three times/day for 6 months and compared with a control group ( group B , 65 patients ) , which instead was not treated with antioxidants . Both groups were simultaneously treated with a comparable topical therapy and /or phototherapy . After a 6 months follow-up , a significantly higher number of patients in group A had a mild repigmentation on the head/neck regions ( p = 0.019 ) and on the trunk ( trend , p = 0.051 ) . The number of patients who presented no repigmentation in head/neck , trunk , upper , and lower limbs was significantly higher in group B ( respectively , p = 0.009 , p = 0.001 , p = 0.001 , p = 0.025 ) . Moreover , group B patients showed higher signs of inflammation ( p = 0.002 ) , a more rapid growth of the lesions ( p = 0.039 ) , a higher percentage of worsening disease ( p = 0.003 ) , and more erythema ( p = 0.059 ) , whereas group A patients showed a higher percentage of steady disease ( p = 0.065 ) . Our results suggest that the supplement with antioxidants in patients with vitiligo might represent a valuable instrument to increase the effectiveness of other vitiligo treatments . [ Correction added after online publication 06-Oct-2014 : the dosages of vitamin E and carotenoids have been up date d. ] Background : Vitiligo is an acquired idiopathic cutaneous disease characterized by pearly white patches of variable shapes and sizes . Various medical and surgical therapeutic options have been proposed to achieve repigmentation ; phototherapy is one of the most efficient options . Topical therapies have been a mainstay of vitiligo treatment , with or without phototherapy . Aim of the work : To compare the efficacy of combined topical antioxidant hydrogel and excimer light versus excimer light alone in treating vitiligo . Patients and Methods : Thirty patients were included in this comparative , prospect i ve , r and omized study . For each patient , at least 2–4 vitiliginous macules were r and omly selected and treated while an untreated vitiliginous macule served as control . Lesions were divided into two groups : Group A received combination therapy of daily topical antioxidant plus excimer light , while Group B received only excimer light . Lesions were treated twice a week for a maximum of 24 sessions . Initial fluencies were adjusted individually according to the minimal erythema dose in vitiliginous skin . Efficacy based on repigmentation percentages were blindly evaluated by two independent physicians . Results : Group A lesions showed significant efficacy than group B ( p < 0.001 ) , specially on treating UV-sensitive lesions with no side effects . Conclusion : Topical antioxidant and excimer light represents a valuable , effective therapy for localized vitiligo BACKGROUND Among all the topical immunomodulators , vitiligo 's mainstay therapy includes topical corticosteroids . Many other non-immune theories have also been suggested for vitiligo 's pathogenesis , but the role of oxidative stress has gained more importance in recent years . OBJECTIVE To compare the effect of topical 0.05 % betamethasone vs. catalase/dismutase superoxide ( C/DSO ) . STUDY DESIGN R and omized , matched-paired , double-blind trial . SETTING Dermatology Section , University of Antioquia , Medellín , Colombia . SUBJECTS Patients ( aged > 18 years or between 12 and 18 years ) with parent 's informed consent , with stable or active bilateral vitiligo . INTERVENTION Topical 0.05 % betamethasone or C/DSO . METHODS Two lesions similar to each other in size were chosen . All assessment s were made by two blinded investigators , and photographs were subjected to morphometry analysis . MAIN OUTCOME Skin repigmentation by digital morphometry . RESULTS Twenty-five patients were enrolled in the study ( 21 women and 4 men ) . Mean age of participants was 40 years ( range : 12 - 74 years ) . One patient on C/DSO experienced a mild local erythematous papular rash that self-resolved . At 4 months of therapy , there was no statistical difference on the percentage of repigmentation between betamethasone and C/DSO ( 5.63 % + /- 27.9 vs. 3.22 % + /- 25.8 , respectively , P = 0.758 ) . After 10 months of therapy , the percentage of skin repigmentation increased to 18.5 + /- 93.14 % with betamethasone and to 12.4 + /- 59 % with C/DSO , but again , we found no statistical differences ( P = 0.79 ) . DISCUSSION AND CONCLUSIONS Few studies have described objective methods to evaluate repigmentation among vitiligo patients . Digital morphometry provides an objective assessment of repigmentation in vitiligo . Objective vitiligo repigmentation with topical C/DSO at 10 months is similar to topical 0.05 % betamethasone . Although a mild adverse effect was related to the use of C/DSO , such finding was not severe enough to discontinue treatment BACKGROUND The first choice treatment for vitiligo vulgaris is narrow-b and UVB ( NB-UVB ) , but no satisfactory treatment exists . OBJECTIVES To investigate if Polypodium leucotomos , an antioxidative and immunomodulatory plant extract , improves NB-UVB-induced repigmentation . METHODS Fifty patients with vitiligo vulgaris r and omly received 250 mg oral P. leucotomos or placebo three times daily , combined with NB-UVB twice weekly for 25 - 26 weeks . RESULTS Repigmentation was higher in the P. leucotomos group vs. placebo in the head and neck area ( 44 % vs. 27 % , P = 0.06 ) . Small repigmentation increases ( P = n.s . ) were observed for the trunk ( 6 % increased repigmentation ) , extremities ( 4 % ) , and h and s and feet ( 5 % ) in the P. leucotomos group vs. placebo . Patients attending more than 80 % of required NB-UVB sessions showed increased repigmentation in the head and neck area in the P. leucotomos group vs. placebo ( 50 % vs. 19 % , P < 0.002 ) ; no significant differences were seen in the other body areas . Patients with skin types 2 and 3 showed more repigmentation in the head and neck area in the P. leucotomos group vs. placebo ( 47 % vs. 21 % , P = 0.01 ) , and no significant differences were seen in the other body areas . No conclusions could be drawn on skin types 4 and 5 due to low patient numbers . CONCLUSION There is a clear trend towards an increase in repigmentation of vitiligo vulgaris affecting the head and neck area when NB-UVB phototherapy is combined with oral P. leucotomos . This effect may be more pronounced in light skin types BACKGROUND Low catalase levels and cellular vacuolation in the epidermis of patients with vitiligo support major oxidative stress in this compartment . There is now in vivo evidence for increased epidermal hydrogen peroxide ( H(2)O(2 ) ) accumulation in this patient group by utilizing noninvasive Fourier Transform Raman spectroscopy ( FT Raman ) . Epidermal H(2)O(2 ) can be removed with a topical application of narrow b and UVB activated pseudocatalase cream ( PC-KUS ) . ( Mn/EDTA-bicarbonate complex , patent No. EPO 58471 1 A ) , yielding initiation of repigmentation . Dead Sea climatotherapy is another successful treatment modality for vitiligo , but the mode of action has escaped definition so far . METHODS Epidermal hydrogen peroxide ( H(2)O(2 ) ) was assessed in vivo before and after 21 days treatment at the Dead Sea using noninvasive Fourier-Transform Raman spectroscopy . The effectiveness of repigmentation was followed in 59 patients with vitiligo by comparing Dead Sea climatotherapy alone with the combination of Dead Sea climatotherapy/pseudocatalase cream ( PC-KUS ) as well as Dead Sea climatotherapy/placebo cream . Clinical repigmentation was documented by st and ardized black/white photography using non-UV coated bulbs as flashlight and by color photography . RESULTS This study on 59 patients who had vitiligo for an average time of 17 years ( range 3 - 53 years ) confirmed in vivo H(2)O(2 ) accumulation in mM concentrations in the epidermis of untreated patients . Furthermore , we demonstrated a pseudocatalase activity after 15 min of Dead Sea bathing , but the decrease of epidermal H(2)O(2 ) levels was significantly less compared to narrowb and UVB activated pseudocatalase cream ( PC-KUS ) . Initiation of repigmentation was already observed between day 10 and day 16 after a combination of Dead Sea climatotherapy/pseudocatalase cream compared to conventional pseudocatalase monotherapy ( 8 - 14 weeks ) and Dead Sea climatotherapy alone ( 5 - 6 weeks ) . CONCLUSION The results of this study show a significantly faster initiation of repigmentation in vitiligo after a combination of short-term climatotherapy ( 21 days ) at the Dead Sea in combination with a pseudocatalase cream ( PC-KUS ) compared to either conventional climatotherapy at the Dead Sea alone or with placebo cream in combination with climatotherapy . This combined therapy is significantly faster in repigmentation than narrowb and UVB activated pseudocatalase cream ( PC-KUS ) treatment alone . The results of this study support the necessity of epidermal H2O2 removal as well as the influence of solar UV-light in the successful treatment of vitiligo The aim of this 2-year study was to test the hypothesis that folic acid , vitamin B12 and sun exposure could be helpful in treating vitiligo . One hundred patients with vitiligo were treated with oral folic acid and vitamin B12 after being informed that sun exposure might enhance repigmentation . They were requested to keep a record of sun exposure in summer and UVB irradiation in winter . The minimal treatment time suggested was 3 - 6 months but should be longer if improvement was achieved . Clear repigmentation occurred in 52 patients , including 37 who exposed their skin to summer sun and 6 who used UVB lamps in winter . Repigmentation was most evident on sun-exposed areas , where 38 % of the patients had previously noted repigmentation during summer months . Total repigmentation was seen in 6 patients . The spread of vitiligo stopped in 64 % of the patients after treatment . Folic acid and vitamin B12 supplementation combined with sun exposure can induce repigmentation better than either the vitamins or sun exposure alone . Treatment should continue as long as the white areas continue to repigment . Further studies are needed to determine ideal minimal dosages of vitamins and UV exposure , as well as treatment time BACKGROUND Recent findings suggest the involvement of oxidative stress in the pathogenesis of chronic idiopathic urticaria ( CIU ) . It has been demonstrated that desloratadine has an antioxidant activity in vitro . We evaluated the effects of desloratadine on markers of oxidative stress in patients with CIU . METHODS Blood sample s were obtained from 10 patients with CIU before and after 4 weeks of treatment with desloratadine . Blood sample s from 10 healthy volunteers were used as controls . In platelets from both patients and controls , radical oxygen species ( ROS ) production was measured using spectrofluorimetric detection of dichloro-fluorescein oxidation , and superoxide dismutase ( SOD ) activity was determined by means of the xanthine-xanthine oxidase system . RESULTS Radical oxygen species concentrations and SOD activity were significantly elevated in patients with CIU at baseline as compared with control subjects . Treatment with desloratadine caused a relevant reduction of ROS levels and SOD activity ( P<0.005 ) . CONCLUSIONS These preliminary results suggest that desloratadine exerts antioxidant effects also in vivo Narrowb and ultraviolet B phototherapy ( NB-UVB ) is the most widely and effective therapeutic option in vitiligo . Antioxidant supplementation has also been reported to be useful . The purpose of this study was to determine the efficacy of oral antioxidants with NB-UVB in the treatment of vitiligo . Twenty-four patients with stable vitiligo were recruited and divided r and omly into 2 groups . They were treated with NB-UVB plus oral vitamin E in group A and with NB-UVB only in group B. Improvement was recorded according to the extent of repigmentation in the existing lesions . Both plasma malondialdehyde ( MDA ; product of lipid peroxidation ) and reduced glutathione ( GSH ) were measured before and after treatment . Twenty patients completed the study . Marked to excellent repigmentation was noted in 72.7 % and 55.6 % of the patients in group A and group B , respectively . Of the patients , 70 % in group A and 85 % in group B experienced mild erythema . After treatment , there was a significant reduction in plasma MDA in group A than in group B , but the increase in plasma GSH was not significant . In conclusion , oral vitamin E may represent a valuable adjuvant therapy , preventing lipid peroxidation in the cellular membrane of melanocytes and increasing the effectiveness of NB-UVB Vitiligo is an acquired depigmentation disorder affecting 0.1 % to > 8.8 % in Indian population . Psoralen and ultraviolet A radiation ( PUVA ) is a gold st and ard treatment for vitiligo , however , response is still empirical . In order to investigate whether drug response variation is influenced by the repair ability of PUVA treated vitiligo subjects , single cell gel electrophoresis ( SCGE ) for genotoxicity and serum malonaldehyde ( MDA ) for cytotoxicity were performed on 107 subjects ( 77 cases and 30 healthy controls ) in South Indian population . In vitro repair ability was assessed by considering the residual damage . A significant difference was observed between the patients and controls with regard to their mean values of DNA damage and MDA levels ( p<0.05 ) . On categorization to fast and slow responders based on the time of response , patients exhibited a significant deviation in residual DNA damage , suggestive of variation with respect to DNA repair efficiency ( p<0.05 ) . This is the first study to our knowledge with respect to PUVA drug response variation in vitiligo in relation to DNA repair . Large systematic studies on DNA repair may help in a better underst and ing of the mechanisms involved in the PUVA drug response variation The aim of this research was to determine levels in blood of vitamin E , beta carotene , lipid peroxidation as malondialdehyde ( MDA ) , reduced glutathione ( GSH ) and glutathione peroxidase ( GSH-Px ) activity in patients with psoriasis . Studies were carried out on 34 patients with moderate and severe psoriases and healthy age-matched controls . Red blood cell ( RBC ) and plasma sample s from healthy and patient subjects were taken . Levels of GSH and the activity of GSH-Px in both plasma and RBC sample s were significantly ( P<0.001 ) lower in patients with psoriasis than in controls , whereas beta carotene levels in plasma and MDA levels in RBC sample s were significantly ( P<0.01 , P<0.001 ) higher in patients with psoriasis than in controls . However , vitamin E and MDA levels in plasma did not differ statistically . Although being far from conclusive , these results provide some evidence for a potential role of increased lipid peroxidation and decreased antioxidants in psoriasis

RESULTS Exposure to a high training load ( duration , frequency , or running distance ) increases the risk of injury , and thus modification of the training schedule can reduce the incidence of injury . Wearing a knee brace with a patellar support ring may be effective in the prevention of anterior knee pain caused by running . This review provides evidence for the effectiveness of the modification of training schedules in reducing lower limb soft tissue running injuries .

OBJECTIVES To assess the available evidence for preventive strategies for lower limb soft tissue injuries caused by running .

Eighty-seven male inmates from a state prison and 70 inmates from a county jail volunteered as subjects . The subjects , age 20 to 35 yrs , were assigned r and omly into a control or exercise group . Their Vo2max and treadmill performance values were determined before and after a 20 week jogging program . Training intensity was between 85 and 90 percent of maximum heart rate and involved workouts 3 days/week for 15 , 30 , or 45-min duration at the state prison and for 30-min 1 , 3 , or 5 days/week at the country jail . Cardiorespiratory fitness improved in direct proportion to frequency and duration of training . Injury , occurred in 22 % , 24 % and 54 % of the 15 , 30 , and 45-min duration groups and in 0 % , 12 % , and 39 % of the 1 , 3 , and 5-day/week groups , respectively . Attrition result ing from injury occurred in 0 % , 0 % , and 17 % and in 0 % , 4 % , and 6 % of the same respective groups . Attrition due to lack of interest was similar for all training groups ( 25 % ) , but was significantly lower in the control groups ( 10 % ) . Although the results showed a greater increase in cardiorespiratory fitness for the 45-min duration and 5-day/week groups , these programs are not recommened for beginning joggers because of the significantly greater percent of injuries In a r and omized prospect i ve study among 390 recruits , the hypothesis that improved shoe shock attenuation could lessen the incidence of overuse injuries was tested . During the 14 weeks of training , 90 % of the recruits sustained overuse injuries . Recruits training in a modified basketball shoe had a statistically significant lower incidence of metatarsal stress fractures and foot overuse injuries , compared with st and ard infantry boots , but their overall incidence of overuse injuries was not reduced . The effect of improved shoe shock attenuation was limited to those overuse injuries result ing from vertical impact loads Three hundred fifty male recruits were r and omly allocated to either the st and ard recruit training program ( N = 180 ) or substituted a weighted-march activity for all formal run periods ( N = 170 ) in the physical training program . All injuries were seen at a single medical facility , and the cause , location , and severity of injury were recorded in the medical documents . Lower-limb injuries constituted 79.8 % of all Run injuries and 61.1 % of all Walk injuries . Foot ( 18.9 % ) , knee ( 16.7 % ) , ankle ( 13.3 % ) , and shoulder ( 8.9 % ) were the most common sites of injury in the Walk group . In the Run group , the most common sites were knee ( 32.1 % ) , ankle ( 18.3 % ) , foot ( 11.9 % ) , and shin ( 7.3 % ) . There were two stress fractures ( tibial ) in the Run group and none in the Walk group , giving the Run group an incidence of 1.1 % . There were 10 medical discharges in the Walk group and 16 in the Run group . Ten ( 62.5 % ) of the Run and 2 ( 20 % ) of the Walk discharges were due to lower-limb causes . Of these , only 1 ( 10 % ) of the Walk and 4 ( 25 % ) of the Run injuries were not considered to be pre-existing conditions . Marching ( 30.0 % ) , physical training ( 25.5 % ) , and the obstacle course ( 11.1 % ) were the most frequent causes of injury in the Walk group . In the Run group , the leading causes were running ( 36.6 % ) , physical training ( 19.2 % ) , and the obstacle course ( 14.6 % ) . Running was the major cause of knee injury in the Run group ( 17/35 ) , whereas physical training was the major cause of knee injury in the Walk group ( 5/15 ) . Running was also the major cause of other lower-limb injuries in the Run group ( 19/58 ) , whereas marching was the major cause in the Walk group ( 19/50 ) . Lower-limb injuries were more frequent in the Run group , with running cited as the major cause of these injuries Soccer referees participating in large soccer tournaments may develop overuse injuries . In this study the effect of shock absorbing heel inserts in the incidence of soreness was investigated . Forty-eight referees were r and omly selected to wear shock absorbing heel inserts ( SAH ) in the 5 day-tournament , while 43 referees were the control group . A daily question naire inquiring about complaints from the locomotive system was completed for each referee and in case of any soreness they were examined by doctors to document and classify the anatomical site . Calf , thigh , back , achilles tendon and knee were the most common localizations of overuse symptoms . The incidence of soreness in achilles tendon , calf and back were significantly reduced by the use of ( SAH ) inserts Three hundred fifty male recruits were r and omly allocated to either the st and ard recruit training program ( N = 180 ) or substituted a weighted march activity for all running periods in the physical training program ( N = 170 ) . There were no other differences in the formal training program . The incidence of injury was 37.6 and 46.6 % in the walk and run groups , respectively . The rate of injury was 52.9/100 recruits in the walk group and 61.7/100 in the run group . The exposure incidence was 12.8/1,000 hours of physical training in the walk group and 14.9/1,000 hours in the run group . There was no statistically significantly difference in the total number of injured recruits in the two groups ( 64 vs. 85 , chi(2 ) = 2.90 , p = 0.09 , relative risk [ RR ] = 1.24 ) . There were , however , significantly more lower-limb ( 43 vs. 75 , chi(2 ) = 9.77 , p = 0.0018 , RR = 1.65 ) and knee injuries ( 15 vs. 35 , chi(2 ) = 6.54 , p = 0.011 , RR = 2.14 ) in the Run group . Lower-limb injuries constituted 79.8 % of all Run injuries and 61.1 % of all Walk injuries . Injuries in the Run group produced more morbidity , with nearly double the number of days of restriction , hospitalization , and not fit for duty . St and ardized morbidity rates showed an average of 5.4 days of restriction per injury in the Run group and 3.96 days of restriction per injury in the Walk group . Reduction of running distance in the physical training program result ed in significant reductions in both the incidence of lower-limb injury and the overall severity of injury The purpose of this intervention study was to prove that increasing flexibility of the hamstring musculotendinous unit would decrease the number of lower extremity overuse injuries that occur in military infantry basic trainees . Two different companies going through basic training at the same time were used . Hamstring flexibility was checked at the beginning and at the end of the 13-week infantry basic training course . The control company ( N 148 ) proceeded through normal basic training . The intervention company ( N 150 ) followed the same program but added three hamstring stretching sessions to their already scheduled fitness program . All subsequent lower extremity overuse injuries were recorded through the troop medical clinic . Hamstring flexibility increased significantly in the intervention group compared with the control group . The number of injuries was also significantly lower in the intervention group . Forty-three injuries occurred in the control group for an incidence rate of 29.1 % , compared with 25 injuries in the intervention group for an incidence rate of 16.7 % . Thus , in this study , the number of lower extremity overuse injuries was significantly lower in infantry basic trainees with increased hamstring flexibility Our prospect i ve study evaluates the use of a knee brace with a silicon patellar support ring as a method of preventing anterior knee pain from developing in young persons undergoing strenuous physical exercise . We studied 60 young athletes , who qualified for a strenu ous physical training course and who had not suffered from anterior knee pain previously . Twenty-seven sub jects were in the brace group and 33 were in the nonbrace control group . The incidence of anterior knee pain syndrome increased with the intensity of exertion as the study progressed ; i.e. , subjects ran 6 km in the 1 st week , gradually increasing each week up to 42 km/week at the 8th week . Yet , there was a significant reduction in the incidence of the syndrome at the end of the study in male athletes who had applied the braces before exercise sessions and in the brace group as a whole , compared with the control group . Prophylactic use of the brace , as described , did not reduce the ability of the athletes who wore braces to improve their physical fitness parameters in response to exercise . These data indicate that the use of a brace may be an effective way to prevent the development of anterior knee pain syndromes in persons participating in strenuous and intensive physical exercise Sedentary individuals , particularly new military recruits , who start a physical training program have a substantial risk of developing an overuse injury of the lower limb . In this study we investigated the effect of neoprene insoles on the incidence of overuse injuries during 9 weeks of basic military training . The experimental group consisted of 237 r and omly selected new recruits , while 1151 recruits were the control group . Insoles were given to the experimental group and compliance was monitored . A panel of doctors documented and classi fied all injuries occurring during the 9 week period . A total of 54 ( 22.8 % ) and 237 ( 31.9 % ) injuries were reported in the experimental and control groups , re spectively . In both groups , the majority of injuries were overuse ( experimental group , 90.7 % ; control group , 86.4 % ) . The mean weekly incidence of total overuse injuries and tibial stress syndrome was significantly lower ( P < 0.05 ) in the experimental group . The mean incidence of stress fractures was lower in the experimental group but not significantly so ( 0.05 < P < 0.1 ) . This study shows that the incidence of total overuse injuries and tibial stress syndrome during 9 weeks of basic military training can be reduced by wearing insoles The purpose of this study was to evaluate the effect of a health education intervention on running injuries . The intervention consisted of information on , and the sub sequent performance of , st and ardized warm-up , cool- down , and stretching exercises . Four hundred twenty- one male recreational runners were matched for age , weekly running distance , and general knowledge of preventing sports injuries . They were r and omly split into an intervention and a control group : 167 control and 159 intervention subjects participated throughout the study . During the 16-week study , both groups kept a daily diary on their running distance and time , and reported all injuries . In addition , the intervention group was asked to note compliance with the st and ardized program . At the end of the study period , knowledge and attitude were again measured . There were 23 injuries in the control group and 26 in the intervention group . Injury incidence for control and intervention sub jects was 4.9 and 5.5 running injuries per 1000 hours , respectively . The intervention was not effective in re ducing the number of running injuries ; it proved signifi cantly effective ( P < 0.05 ) in improving specific knowl edge of warm-up and cool-down techniques in the intervention group . This positive change can perhaps be regarded as a first step on the way to a change of behavior , which may eventually lead to a reduction of running injuries PURPOSE This study investigated the effect of muscle stretching during warm-up on the risk of exercise-related injury . METHODS 1538 male army recruits were r and omly allocated to stretch or control groups . During the ensuing 12 wk of training , both groups performed active warm-up exercises before physical training sessions . In addition , the stretch group performed one 20-s static stretch under supervision for each of six major leg muscle groups during every warm-up . The control group did not stretch . RESULTS 333 lower-limb injuries were recorded during the training period , including 214 soft-tissue injuries . There were 158 injuries in the stretch group and 175 in the control group . There was no significant effect of preexercise stretching on all-injuries risk ( hazard ratio [ HR ] = 0.95 , 95 % CI 0.77 - 1.18 ) , soft-tissue injury risk ( HR = 0.83 , 95 % CI 0.63 - 1.09 ) , or bone injury risk ( HR = 1.22 , 95 % CI 0.86 - 1.76 ) . Fitness ( 20-m progressive shuttle run test score ) , age , and enlistment date all significantly predicted injury risk ( P < 0.01 for each ) , but height , weight , and body mass index did not . CONCLUSION A typical muscle stretching protocol performed during preexercise warm-ups does not produce clinical ly meaningful reductions in risk of exercise-related injury in army recruits . Fitness may be an important , modifiable risk factor

Subgroup analyses indicated that a lesser improvement in MWD was observed in the subgroup with more diabetes patients , and that the subgroup with better baseline walking ability exhibited greater improvement in walking performance . In addition , similar improvements in walking performance were observed for exercise programs of different duration s and modalities . Regardless of exercise length and modality , regularly intensive walking exercise improves walking ability in PAD patients more than usual care . The presence of diabetes may attenuate the improvements in walking performance in patients with PAD following exercise

BACKGROUND Supervised treadmill exercise is the recommended therapy for peripheral arterial disease ( PAD ) patients with intermittent claudication ( IC ) . However , most PAD patients do not exhibit typical symptoms of IC . The aim of the present study was to explore the efficacy and safety of intensive walking exercise in PAD patients with and without IC .

OBJECTIVE : To assess the acute metabolic and cardiovascular responses to walking exercise at an intensity corresponding to the heart rate of claudication pain onset and to investigate the effects of a 12-week walking training program at this intensity on walking capacity . METHODS : Twenty-nine patients with intermittent claudication were r and omly allocated to the walking training ( n = 17 ) or control ( CO , n = 12 ) group . The walking training group performed an acute exercise session comprising 15 × 2-min bouts of walking at the heart rate of claudication pain onset , with 2-min interpolated rest intervals . The claudication symptoms and cardiovascular and metabolic responses were evaluated . Walking training was then performed at the same intensity twice each week for 12 weeks , while the control group engaged in twice weekly stretching classes . The claudication onset distance and total walking distance were evaluated before and after the interventions . Brazilian Registry Clinical Trials : RBR-7M3D8W . RESULTS : During the acute exercise session , the heart rate was maintained within tight limits . The exercise intensity was above the anaerobic threshold and > 80 % of the heart rate peak and VO2peak . After the exercise training period , the walking exercise group ( n = 13 ) showed increased claudication onset distance ( 309±153 vs. 413±201 m ) and total walking distance ( 784±182 vs. 1,100±236 m ) compared to the control group ( n = 12 ) ( p<0.05 ) . CONCLUSION : Walking exercise prescribed at the heart rate of claudication pain onset enables patients with intermittent claudication to exercise with tolerable levels of pain and improves walking performance BACKGROUND This prospect i ve , r and omized controlled clinical trial determined whether an optimal exercise program length exists to efficaciously change claudication onset time ( COT ) and peak walking time ( PWT ) in patients with peripheral artery disease and claudication . METHODS The study r and omized 142 patients to supervised exercise ( n = 106 ) or a usual care control group ( n = 36 ) , with 80 completing the exercise program and 27 completing the control intervention . The exercise program consisted of intermittent walking to nearly maximal claudication pain 3 days per week . COT and PWT were the primary outcomes obtained from a treadmill exercise test at baseline and bimonthly during the study . RESULTS After exercise , changes in COT ( P < .001 ) and PWT ( P < .001 ) were consistently greater than changes after the control intervention . In the exercise program , COT and PWT increased from baseline to month 2 ( P < .05 ) and from months 2 to 4 ( P < .05 ) but did not significantly change from months 4 to 6 ( P > .05 ) . When changes were expressed per mile walked during the first 2 months , middle 2 months , and final 2 months of exercise , COT and PWT only increased during the first 2 months ( P < .05 ) . CONCLUSIONS Exercise-mediated gains in COT and PWT occur rapidly within the first 2 months of exercise rehabilitation and are maintained with further training . The clinical significance is that a relatively short 2-month exercise program may be preferred to a longer program to treat claudication because adherence is higher , costs associated with personnel and use of facilities are lower per patient , and more patients can be trained for a given amount of personnel time and re source utilization BACKGROUND In patients with intermittent claudication , a supervised walking exercise program increases peak exercise performance and community-based functional status . Patients with peripheral arterial disease also have muscle weakness in the affected extremity that may contribute to the walking impairment . However , the potential benefits of training modalities other than walking exercise , such as strength training , have not been critically evaluated in this patient population . The present study tested the hypothesis that a strength training program would be as effective as treadmill walking exercise and that combinations of strengthening and walking exercise would be more effective than either alone in improving exercise performance . METHODS AND RESULTS Twenty-nine patients with disabling claudication were r and omized to 12 weeks of supervised walking exercise on a treadmill ( 3 h/wk at a work intensity sufficient to produce claudication ) , strength training ( 3 h/wk of resistive training of five muscle groups of each leg ) , or a nonexercising control group . Grade d treadmill testing was performed to maximally tolerated claudication pain to define changes in peak exercise performance . After 12 weeks , patients in the treadmill training program had a 74 + /- 58 % increase in peak walking time as well as improvements in peak oxygen consumption ( VO2 ) and the onset of claudication pain . Patients in the strength-trained group had a 36 + /- 48 % increase in peak walking time but no change in peak VO2 or claudication onset time . Control subjects had no changes in any of these measures over the 12-week period . After the first 12 weeks , patients in the initial walking exercise group continued for 12 more weeks of supervised treadmill training . This result ed in an additional 49 + /- 53 % increase in peak walking time ( total of 128 + /- 99 % increase over the 24 weeks ) . After the initial 12 weeks , patients in the strength-trained group began 12 weeks of supervised treadmill training , and patients in the control group participated in a 12-week combined program of strengthening and treadmill walking exercise . The combined strength and treadmill training program and treadmill training after 12 weeks of strength training result ed in increases in peak exercise performance similar to those observed with 12 weeks of treadmill training alone . CONCLUSIONS A supervised treadmill walking exercise program is an effective means to improve exercise performance in patients with intermittent claudication , with continued improvement over 24 weeks of training . In contrast , 12 weeks of strength training was less effective than 12 weeks of supervised treadmill walking exercise . Finally , strength training , whether sequential or concomitant , did not augment the response to a walking exercise program PURPOSE A pilot study was conducted to test the feasibility of supervised treadmill exercise training to improve functioning in study participants with peripheral arterial disease who did not have classical symptoms of intermittent claudication . METHODS For this study , 32 men and women with peripheral arterial disease but no symptoms of claudication were r and omized to exercise training or usual care . The intervention was a 12-week supervised treadmill walking program . Outcomes included 6-minute walk distance , maximum treadmill walking distance , and 4-meter walking velocity . Participant-reported community walking ability was measured with the Walking Impairment Question naire ( WIQ ) . Inflammatory blood factor levels also were measured . RESULTS Altogether , 25 participants who completed follow-up testing were included in intention-to-treat analyses . Of 24 participants ( 58 % ) r and omized to exercise , 14 completed the entire exercise training program . The participants r and omized to the intervention showed greater improvement in their WIQ walking speed score than the control subjects ( P = .05 ) . The participants r and omized to the intervention showed improvements in their 6-minute walk distance ( 1134 + /- 347 vs 1266 + /- 295 feet ; P = .03 ) , maximal treadmill walking distance ( 389 + /- 248 vs 585 + /- 293 feet ; P < .001 ) , WIQ distance score ( 52.3 + /- 29.1 vs 63.1 + /- 25.1 ; P = .002 ) , and WIQ speed score ( 48.7 + /- 26.8 vs 59.7 + /- 22.7 ; P = .008 ) . The participants r and omized to the control condition showed improvements in maximal treadmill walking distance ( 362 + /- 180 vs 513 + /- 237 feet ; P = .014 ) . There were no significant changes in the inflammatory blood factors after exercise . CONCLUSIONS This pilot study demonstrated that a supervised treadmill walking program may be feasible and may improve functioning for individuals with peripheral arterial disease who do not have classical symptoms of intermittent claudication . Further study is needed with a larger sample to identify optimal exercise methods that improve lower extremity functioning in men and women with peripheral arterial disease who do not have intermittent claudication Patients with atherosclerotic peripheral arterial disease ( PAD ) of the lower extremities have impaired walking ability due to exercise-induced muscle ischemia and the result ant pain of intermittent claudication . To evaluate the benefit of exercise training as a treatment for patients with PAD , as well as possible mechanisms associated with improvement , we r and omly assigned 19 men with disabling claudication to treated and control groups . Treatment consisted of supervised treadmill walking ( 1 hr/day , 3 days/wk , for 12 weeks ) with progressive increases in speed and grade as tolerated . Grade d treadmill testing was performed to maximal toleration of claudication pain on entry and after 12 weeks of training to define changes in peak exercise performance . After 12 weeks , treated subjects had increased their peak walking time 123 % , peak oxygen consumption 30 % , and pain-free walking time 165 % ( all p less than 0.05 ) . Control subjects had no change in peak oxygen consumption , but after 12 weeks , peak walking time increased 20 % ( p less than 0.05 ) . In treated subjects , maximal calf blood flow ( measured by a plethysmograph ) increased 38 + /- 45 % ( p less than 0.05 ) , but the change in flow was not correlated to the increase in peak walking time . Elevated plasma concentrations of acylcarnitines have been associated with the functional impairment of PAD and may reflect the metabolic state of ischemic skeletal muscle . In treated subjects , a 26 % decrease in resting plasma short-chain acylcarnitine concentration was correlated with improvement in peak walking time ( r = -0.78 , p less than 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Background — This prospect i ve , r and omized , controlled clinical trial compared changes in exercise performance and daily ambulatory activity in peripheral artery disease patients with intermittent claudication after a home-based exercise program , a supervised exercise program , and usual-care control . Methods and Results — Of the 119 patients r and omized , 29 completed home-based exercise , 33 completed supervised exercise , and 30 completed usual-care control . Both exercise programs consisted of intermittent walking to nearly maximal claudication pain for 12 weeks . Patients wore a step activity monitor during each exercise session . Primary outcome measures included claudication onset time and peak walking time obtained from a treadmill exercise test ; secondary outcome measures included daily ambulatory cadences measured during a 7-day monitoring period . Adherence to home-based and supervised exercise was similar ( P=0.712 ) and exceeded 80 % . Both exercise programs increased claudication onset time ( P<0.001 ) and peak walking time ( P<0.01 ) , whereas only home-based exercise increased daily average cadence ( P<0.01 ) . No changes were seen in the control group ( P>0.05 ) . The changes in claudication onset time and peak walking time were similar between the 2 exercise groups ( P>0.05 ) , whereas the change in daily average cadence was greater with home-based exercise ( P<0.05 ) . Conclusions — A home-based exercise program , quantified with a step activity monitor , has high adherence and is efficacious in improving claudication measures similar to a st and ard supervised exercise program . Furthermore , home-based exercise appears more efficacious in increasing daily ambulatory activity in the community setting than supervised exercise . Clinical Trial Registration — URL : http://www . Clinical Trials . Gov . Unique identifier : NCT00618670 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 The molecular mechanisms by which physical training improves peripheral and coronary artery disease are poorly understood . Bone marrow-derived endothelial progenitor cells ( EPCs ) are thought to exert beneficial effects on atherosclerosis , angiogenesis , and vascular repair . METHODS AND RESULTS To study the effect of physical activity on the bone marrow , EPCs were quantified by fluorescence-activated cell sorter analysis in mice r and omized to running wheels ( 5.1+/-0.8 km/d , n=12 to 16 per group ) or no running wheel . Numbers of EPCs circulating in the peripheral blood of trained mice were enhanced to 267+/-19 % , 289+/-22 % , and 280+/-25 % of control levels after 7 , 14 , and 28 days , respectively , accompanied by a similar increase of EPCs in the bone marrow and EPCs exp and ed from spleen-derived mononuclear cells . eNOS-/- mice and wild-type mice treated with N(G)-nitro-l-arginine methyl ester showed lower EPC numbers at baseline and a significantly attenuated increase of EPC in response to physical activity . Exercise NO dependently increased serum levels of vascular endothelial growth factor and reduced the rate of apoptosis in spleen-derived EPCs . Running inhibited neointima formation after carotid artery injury by 22+/-2 % . Neoangiogenesis , as assessed in a subcutaneous disc model , was increased by 41+/-16 % compared with controls . In patients with stable coronary artery disease ( n=19 ) , moderate exercise training for 28 days led to a significant increase in circulating EPCs and reduced EPC apoptosis . CONCLUSIONS Physical activity increases the production and circulating numbers of EPCs via a partially NO-dependent , antiapoptotic effect that could potentially underlie exercise-related beneficial effects on cardiovascular diseases PURPOSE To determine if improvements in physical function and peripheral circulation after 6 months of exercise rehabilitation could be sustained over a subsequent 12-month maintenance exercise program in older patients with intermittent claudication . METHODS Seventeen patients r and omized to exercise rehabilitation and 14 patients r and omized to usual care control completed this 18-month study . Patients exercised three times per week during the first 6 months of a progressive exercise program , followed by two times per week during the final 12 months of a maintenance program . Patients were studied at baseline , 6 months , and 18 months during the study . RESULTS Eighteen months of exercise rehabilitation increased the initial claudication distance by 373 meters ( 189 % ) ( P < .001 ) , the absolute claudication distance by 358 meters ( 80 % ) ( P < .001 ) , walking economy by 11 % ( P < .001 ) , 6-minute walk distance by 10 % ( P < .001 ) , daily physical activity by 31 % , and maximal calf blood flow by 18 % ( P < .001 ) . These changes were similar to those found after 6 months of exercise rehabilitation ( P = NS ) , and were significantly greater than the changes in the control group throughout the study ( P < .05 ) . CONCLUSION Improvements in claudication distances , walking economy , 6-minute walk distance , physical activity level , and peripheral circulation after 6 months of exercise rehabilitation are sustained for an additional 12 months in older patients with intermittent claudication using a less frequent exercise maintenance program AIMS To determine if type 2 diabetes mellitus ( T2D ) differentiates endothelial function and plasma nitrite response ( a marker of nitric oxide bioavailability ) during exercise in peripheral arterial disease ( PAD ) subjects prior to and following 3 months supervised exercise training ( SET ) . METHODS In subjects with T2D+PAD ( n = 13 ) and PAD-only ( n = 14 ) , endothelial function was measured using brachial artery flow-mediated dilation . On a separate day , venous blood draws were performed at rest and 10 min following a symptom-limited grade d treadmill test ( SL-GXT ) . Plasma sample s were snap-frozen for analysis of nitrite by reductive chemiluminescence . All testing was repeated following 3 months of SET . RESULTS Prior to training both groups demonstrated endothelial dysfunction , which was correlated with a net decrease in plasma nitrite following a SL-GXT ( p ≤ 0.05 ) . Following SET , the PAD-only group demonstrated an improvement in endothelial function ( p ≤ 0.05 ) and COT ( p ≤ 0.05 ) , which was related to a net increase in plasma nitrite following the SL-GXT ( both p ≤ 0.05 ) . The T2D+PAD group had none of these increases . CONCLUSIONS T2D in the presence of PAD attenuated improvements in endothelial function , net plasma nitrite , and COT following SET . This suggests that T2D maybe associated with an inability to endogenously increase vascular NO bioavailability to SET PURPOSE The purpose of this r and omized trial was to compare the efficacy of a low-intensity exercise rehabilitation program vs a high-intensity program in changing physical function , peripheral circulation , and health-related quality of life in peripheral arterial disease ( PAD ) patients limited by intermittent claudication . METHODS Thirty-one patients r and omized to low-intensity exercise rehabilitation and 33 patients r and omized to high-intensity exercise rehabilitation completed the study . The 6-month exercise rehabilitation programs consisted of intermittent treadmill walking to near maximal claudication pain 3 days per week at either 40 % ( low-intensity group ) or 80 % ( high-intensity group ) of maximal exercise capacity . Total work performed in the two training regimens was similar by having the patients in the low-intensity group exercise for a longer duration than patients in the high-intensity group . Measurements of physical function , peripheral circulation , and health-related quality of life were obtained on each patient before and after the rehabilitation programs . RESULTS After the exercise rehabilitation programs , patients in the two groups had similar improvements in these measures . Initial claudication distance increased by 109 % in the low-intensity group ( P < .01 ) and by 109 % in the high-intensity group ( P < .01 ) , and absolute claudication distance increased by 61 % ( P < 0.01 ) and 63 % ( P < .01 ) in the low-intensity and high-intensity groups , respectively . Furthermore , both exercise programs elicited improvements ( P < .05 ) in peak oxygen uptake , ischemic window , and health-related quality of life . CONCLUSION The efficacy of low-intensity exercise rehabilitation is similar to high-intensity rehabilitation in improving markers of functional independence in PAD patients limited by intermittent claudication , provided that a few additional minutes of walking is accomplished to elicit a similar volume of exercise OBJECTIVE The purpose of the study was to examine the effects of a 12-month exercise program on lower limb mobility ( temporal-spatial gait parameters and gait kinematics ) , walking performance , peak physiological responses , and physical activity levels in individuals with symptoms of intermittent claudication due to peripheral arterial disease ( PAD-IC ) . METHODS Participants ( n = 21 ) with an appropriate history of PAD-IC , ankle-brachial pressure index ( ABI ) < 0.9 in at least one leg and a positive Edinburgh claudication question naire response were prospect ively recruited . Participants were r and omly allocated to either a control PAD-IC group ( CPAD-IC ) ( n = 11 ) that received st and ard medical therapy and a treatment PAD-IC group ( TPAD-IC ) ( n = 10 ) , which also took part in a 12-month supervised exercise program . A further group of participants ( n = 11 ) free of PAD ( ABI > 0.9 ) and who were non-regular exercisers were recruited from the community to act as age and mass matched controls ( CON ) . Lower limb mobility was determined via two-dimensional video motion analysis . A grade d treadmill test was used to assess walking performance and peak physiological responses to exercise . Physical activity levels were measured via a 7-day pedometer recording . Differences between groups were analyzed via repeated measures analysis of variance ( ANOVA ) . RESULTS The 12-month supervised exercise program had no significant effect on lower limb mobility , peak physiological responses , or physical activity levels in TPAD-IC compared with CPAD-IC participants . However , the TPAD-IC participants demonstrated significantly greater walking performance ( 171 % improvement in pain free walking time and 120 % improvement in maximal walking time compared with baseline ) . CONCLUSION The results of this study confirm that a 12-month supervised exercise program will result in improved walking performance , but does not have an impact on lower limb mobility , peak physiological responses , or physical activity levels of PAD-IC patients BACKGROUND In this r and omized trial we compared two treadmill trainings , based on exercises performed to moderate claudication pain vs pain-free training , with respect to their effects on walking ability and endothelial function . METHODS A total of sixty patients with stable intermittent claudication were r and omized to the pain-free treadmill training ( repetitive intervals to onset of claudication pain ) or moderate treadmill training ( repetitive intervals to moderate claudication pain ) . In both groups exercises were performed 3 times a week for 3 months . Changes in flow mediated dilatation ( FMD ) and treadmill walking performance as well as plasma levels of C-reactive protein ( hs-CRP ) and fibrinogen were assessed before and after the program . RESULTS Fifty-two patients completed the training program . Post-training maximal walking time was prolonged by 100 % ( p<0.001 ) vs 98 % ( p<0.001 ) , and pain-free walking time by 120 % ( p<0.001 ) vs 93 % ( p<0.001 ) in the moderate training group as compared to the pain-free training group , respectively . FMD increased by 56 % ( p<0.001 ) in the moderate training group and by 36 % ( p<0.01 ) in the pain-free training group . No significant changes in the levels of hs-CRP and fibrinogen were seen after treadmill program in either group . CONCLUSIONS Both pain-free treadmill training and the moderate treadmill training have similar efficacy on walking ability in patients with claudication . The improvement of post-training FMD indicates systemic effect of both treadmill programs on endothelial function . Both programs appear to be safe therapeutic modes , since none of them escalates the inflammation . Pain-free treadmill training seems useful and effective therapeutic option for patients with claudication Mika P , Spodaryk K , Cencora A , Unnithan VB , Mika A : Experimental model of pain-free treadmill training in patients with claudication . Am J Phys Med Rehabil 2005;84:756–762 . Objective : Treadmill training in claudication is often based on walking exercise to a pain threshold or longer to the maximum muscle pain of the lower limbs . This kind of exercise may cause an inflammatory response . The purpose of this study was to determine whether pain-free treadmill training using walking exercise to 85 % of the distance to onset of claudication pain can significantly improve pain-free walking distance in patients with intermittent claudication and to evaluate whether this kind of program may induce an inflammatory response leading to the progression of atherosclerosis . Design : A total of 98 patients aged 50–70 yrs with stable intermittent claudication were r and omized into a supervised treadmill training program or a comparison group . Patients in the treatment group participated in 12 wks of supervised treadmill training . We examined the effects of 12 wks of pain-free treadmill training on pain-free walking distance , total leukocyte count , neutrophil count , and microalbuminuria in patients with claudication . Results : A total of 80 participants completed the program . Exercise rehabilitation increased the time to onset of claudication pain by 119.2 % , from 87.4 ± 38 m to 191.6 ± 94.8 m ( P < 0.001 ) . There was no increase in total leukocyte count , neutrophil count , or microalbuminuria after 12 wks of treadmill exercise ( P > 0.05 ) Conclusion : A pain-free training program can be used in the treatment of claudication as a low-risk program , increasing walking ability without potential harmful effects of ischemia – reperfusion injury BACKGROUND In this prospect i ve study we evaluated the effects of treadmill training on patients ' walking ability , as well as endothelial function , high-sensitivity C-reactive protein ( hs-CRP ) , and fibrinogen concentration . METHODS A total of 67 patients with stable intermittent claudication were included in a 12-week supervised training program . An observational follow-up period then lasted a mean of 37 weeks . Forty patients completed follow-up . Changes in blood pressure , flow-mediated dilatation ( FMD ) , and treadmill walking performance expressed as maximal walking time ( MWT ) were assessed before and after the training program and during the follow-up period . Moreover , ankle/brachial index ( ABI ) , plasma levels of hs-CRP , fibrinogen , as well as a lipid profile were assessed before and after the training program . RESULTS Maximal walking time improved significantly after treadmill training by 90 % ( p<0.001 ) and after follow-up by 64 % ( p<0.001 ) in comparison to baseline . FMD values increased by 43 % ( p<0.001 ) after the training program , and by 29 % ( p=0.058 ) after follow-up , compared to baseline . We noticed a significant decrease in hs-CRP concentration ( p=0.025 ) and an increase in ABI values ( p=0.039 ) in response to the treadmill training program . No effect on lipid profile was observed . CONCLUSIONS The 12-week treadmill training program prolonged the asymptomatic walking distance . The improvement in FMD indicates a systemic effect of the treadmill program on endothelial function . The supervised treadmill training provides an effective and safe treatment option in patients with PAD . The effects of unsupervised exercise during follow-up period after treadmill programs remain tentative and underestimated Introduction : Peripheral atherosclerotic disease ( PAD ) is a condition characterized by low functional capacity which is associated with impaired free living , ambulation and low exercise tolerance . The purpose of this r and omized controlled study was to evaluate whether changes in maximal walking time are associated with adaptations in cardiovascular function following supervised exercise CONTEXT Neither supervised treadmill exercise nor strength training for patients with peripheral arterial disease ( PAD ) without intermittent claudication have been established as beneficial . OBJECTIVE To determine whether supervised treadmill exercise or lower extremity resistance training improve functional performance of patients with PAD with or without claudication . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled clinical trial performed at an urban academic medical center between April 1 , 2004 , and August 8 , 2008 , involving 156 patients with PAD who were r and omly assigned to supervised treadmill exercise , to lower extremity resistance training , or to a control group . MAIN OUTCOME MEASURES Six-minute walk performance and the short physical performance battery . Secondary outcomes were brachial artery flow-mediated dilation , treadmill walking performance , the Walking Impairment Question naire , and the 36-Item Short Form Health Survey physical functioning ( SF-36 PF ) score . RESULTS For the 6-minute walk , those in the supervised treadmill exercise group increased their distance walked by 35.9 m ( 95 % confidence interval [ CI ] , 15.3 - 56.5 m ; P < .001 ) compared with the control group , whereas those in the resistance training group increased their distance walked by 12.4 m ( 95 % CI , -8.42 to 33.3 m ; P = .24 ) compared with the control group . Neither exercise group improved its short physical performance battery scores . For brachial artery flow-mediated dilation , those in the treadmill group had a mean improvement of 1.53 % ( 95 % CI , 0.35%-2.70 % ; P = .02 ) compared with the control group . The treadmill group had greater increases in maximal treadmill walking time ( 3.44 minutes ; 95 % CI , 2.05 - 4.84 minutes ; P < .001 ) ; walking impairment distance score ( 10.7 ; 95 % CI , 1.56 - 19.9 ; P = .02 ) ; and SF-36 PF score ( 7.5 ; 95 % CI , 0.00 - 15.0 ; P = .02 ) than the control group . The resistance training group had greater increases in maximal treadmill walking time ( 1.90 minutes ; 95 % CI , 0.49 - 3.31 minutes ; P = .009 ) ; walking impairment scores for distance ( 6.92 ; 95 % CI , 1.07 - 12.8 ; P = .02 ) and stair climbing ( 10.4 ; 95 % CI , 0.00 - 20.8 ; P = .03 ) ; and SF-36 PF score ( 7.5 ; 95 % CI , 0.0 - 15.0 ; P = .04 ) than the control group . CONCLUSIONS Supervised treadmill training improved 6-minute walk performance , treadmill walking performance , brachial artery flow-mediated dilation , and quality of life but did not improve the short physical performance battery scores of PAD participants with and without intermittent claudication . Lower extremity resistance training improved functional performance measured by treadmill walking , quality of life , and stair climbing ability . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00106327 No study has shown the effects of acute resistance exercise on vasodilatory capacity of patients with peripheral artery disease . The aim of this study was to analyse the effects of a single session of resistance exercise on blood flow , reactive hyperemia , plasma nitrite , and plasma malondialdehyde in patients with peripheral artery disease . Fourteen peripheral artery disease patients underwent , in a r and om order , 2 experimental sessions : control ( rest for 30 min ) and resistance exercise ( 8 exercises , 2 sets of 10 repetitions at an intensity of 5 - 7 in the OMNI Resistance Exercise Scale ) . Blood flow , reactive hyperemia , plasma nitrite , and malondialdehyde were measured before and 40 min after the interventions in both sessions . Data were compared between sessions by analysis of covariance , using pre-intervention values as covariates . The increases in blood flow , reactive hyperemia , and log plasma nitrite were greater ( p ≤ 0.05 ) after resistance exercise than the control session ( 3.2 ± 0.1 vs. 2.7 ± 0.1 mL · 100 mL(-1 ) tissue · min(-1 ) , 8.0 ± 0.1 vs. 5.7 ± 0.1 AU , and 1.36 ± 0.01 vs. 1.26 ± 0.01 μmol ∙ L(-1 ) , respectively ) . On the other h and , malondialdehyde was similar between sessions ( p > 0.05 ) . In peripheral arterial disease patients , a single session of resistance exercise increases blood flow and reactive hyperemia , which seems to be mediated , in part , by increases in nitric oxide release Objective : To assess the effect of pain-free treadmill training on changes of plasma fibrinogen , haematocrit , lipid profile , and walking ability in patients with claudication . Design : R and omized control trial . Methods : Sixty-eight patients with peripheral obstructive arterial disease and intermittent claudication ( Fontaine stage II ) were r and omly assigned into the treadmill training ( repetitive intervals to onset of claudication pain , three times a week ) or a control group ( no change in physical activity ) over 3 months . Both groups performed treadmill test to assess pain-free walking time ( PFWT ) and maximal walking time ( MWT ) and had blood analyses [ for haematocrit , fibrinogen , triglycerides , and cholesterol : total , high-density lipoprotein ( HDL ) and low-density lipoprotein ( LDL ) ] done at baseline and after 6 and 12 weeks of the study . Results : Total and LDL cholesterol levels in the training group decreased ( p < 0.05 ) by 14.8 % and 20,5 % , respectively . Significant ( p < 0.05 ) HDL cholesterol increased ( 14.6 % ) and triglycerides decreased ( 19 % ) in the training group but changes of all these lipids were insignificant in the control group over the 3 months . Haematocrit and fibrinogen changes were insignificant in both groups . PFWT was prolonged by 109 % and MWT increased by 54 % in the training group ( p < 0.01 ) , but not in the control group . Conclusion : The improvement in walking time over 3 months of pain-free treadmill training parallels with progressive normalization of lipid profiles in patients with claudication Objectives To assess the effect of pain-free treadmill training on red blood cell deformability and walking distance in patients with claudication . Design R and omized-controlled trial of exercise training . Setting Patients were recruited from the primary care , vascular outpatient clinic . Patients A total of 60 patients with peripheral arterial occlusive disease ( stage II according to Leriche-Fontaine ) were r and omized into the treadmill program or a control group . Fifty-five patients completed the study ( 27 in the exercising group and 28 in the control group ) . Interventions Patients in the exercising group were walking on the treadmill 3 times a week for 3 months . Each session consisted of 1 hour repetitive walking [ performed to 85 % of the pain-free walking time ( PFWT ) ] was supervised by a qualified physiotherapist . Main Outcome Measurements Changes in erythrocyte deformability and treadmill walking performance ( PFWT , maximal walking time ) were assessed in both groups before the study and after 3 months . Results After 3 months of treadmill training , red blood cell deformability in the exercising group significantly increased ( P<0.01 ) . No significant changes were seen in the erythrocyte deformability in the control group . PFWT was prolonged by 102 % from 191±34 to 386±60 seconds ( P<0.01 ) , and maximal walking time increased by 49 % from 438±62 to 656±79 seconds ( P<0.01 ) in the exercising group , whereas these changes were insignificant in the control group . Conclusions A significant improvement of walking ability over 3 months of pain-free treadmill training is associated with a significant increase in red cell deformability in patients with claudication Abstract The efficacy of treadmill walking training to improve pain-free ( PFWD ) and maximal ( MWD ) walking distance in patients with claudication is well documented . The effects of aerobic arm-ergometry to improve PFWD and MWD compared to treadmill walking or usual care are not known . Forty-one participants ( 29 male , 12 female , mean age 67.7 years , 92.7 % smoking history , 36.6 % with diabetes ) with lifestyle-limiting claudication were r and omized to 12 weeks of 3 hours/week of supervised exercise training using either arm-ergometry , treadmill walking , or a combination , versus control . PFWD and MWD were assessed before and after training , and after 12 weeks of follow-up . The 12-week MWD increased significantly in the arm-ergometry ( + 53 % ) , treadmill ( + 69 % ) , and combination ( + 68 % ) groups ( p < 0.002 versus control ) . The 24-week MWD was maintained in the arm-ergometry ( p = 0.009 ) and treadmill ( p = 0.019 ) groups , whereas the combination group declined ( p = 0.751 ) versus control . The 12-week PFWD increased significantly in the arm-ergometry group ( + 82 % ; p = 0.025 versus control ) . Change in PFWD in treadmill ( + 54 % ; p = 0.196 versus control ) and combination ( + 60 % ; p = 0.107 versus control ) groups did not reach statistical significance . PFWD improvement was maintained in the arm-ergometry group after a 12-week follow-up ( + 123 % ; p = 0.011 versus control ) . In conclusion , these pilot data demonstrate for the first time that dynamic arm exercise training can improve walking capability in people with peripheral arterial disease (PAD)-induced claudication compared to participants receiving usual care and that improvement was not different from that seen with treadmill walking exercise training . Dynamic arm exercise may be a therapeutic exercise option for patients with PAD Summary Background The classic symptom of peripheral arterial disease is the intermittent claudication ( IC ) . Generally , endurance training is recommended to improve patients ’ walking performance . A potential benefit of the combination with strength training and the optimal duration of such an exercise program remain unclear . Methods and results We evaluated the effects of a supervised exercise program combining endurance and strength training lasting 6 or 12 months in patients with IC . A total of 94 patients joined this study ; 42 completed the 6-month training program ( group A ) , whereas 52 patients completed the 12-month protocol ( group B ) . Both groups exhibited a significant increase in all parameters evaluated , but greater benefit was found in the 12-month training group . The absolute claudication distance increased similarly by 27.5 and 29.5 % , respectively , in both groups ( not significant ) ; however , group B exhibited a greater increase in walking speed ( 12.1 vs. 5.3 % , p < 0.001 ) . All strength parameters increased significantly in both the groups showing an increase for “ pushing ” by 90.0 % ( group A ) and 90.2 % ( group B ) , for “ pulling ” by 64.2 % ( group A ) and 75.3 % ( group B ) , and for “ tiptoe st and ing ” by 70.5 % ( group A ) and 113.7 % ( group B ; p < 0.05 ) . Conclusion The results of this study indicate that a combined exercise program significantly increases walking speed , absolute claudication distance , and muscle strength parameters . A greater benefit seems to result from a 12-month training program . ZusammenfassungHintergrundDas klassische Symptom der peripheren arteriellen Verschlusskrankheit ist die Claudicatio intermittens ( CI ) . I m Allgemeinen wird ein Ausdauertraining empfohlen , um die Gehleistung der Patienten zu verbessern . Ein möglicher Nutzen einer Kombination mit Krafttraining und die optimale Dauer solcher Trainingsprogramme sind aber unklar . Method en und ErgebnisseWir evaluierten den Effekt eines sechs beziehungsweise 12 Monate dauernden überwachten Trainingsprogrammes , in dem Kraft- und Ausdauertraining kombiniert waren , auf Patienten mit CI . 94 Patienten nahmen an dieser Studie teil , 42 absolvierten das 6-Monate-Trainingsprogramm ( Gruppe A ) , 52 das 12-Monate-Trainingsprogramm ( Gruppe B ) . In beiden Gruppen zeigte sich ein signifikanter Anstieg in den evaluierten Parametern , wobei ein größerer Nutzen in der 12-Monats-Gruppe gefunden wurde . Die absolute Claudicatio-Strecke stieg gleichermaßen um 27,5 % beziehungsweisen 29,5 % in beiden Gruppen ( n.s . ) , wobei Gruppe B einen größeren Anstieg in der Gehgeschwindigkeit aufwies ( 12,1 % vs. 5,3 % , p < 0,001 ) . Alle Kraftparameter stiegen signifikant in beiden Gruppen an und zeigten einen Anstieg beim „ Drücken “ um 90,0 % ( Gruppe A ) beziehungsweise 90,2 % ( Gruppe B ) , für „ Ziehen “ 64,2 % beziehungsweise 75,3 % und bei den „ Zehenspitzenständen “ um 70,5 % beziehungsweise 113,7 % ( A vs. B , p < 0,05).SchlussfolgerungDie Ergebnisse dieser Studie zeigen , dass die Kombination von Kraft- und Ausdauertraining signifikant die Gehgeschwindigkeit , die absolute Claudicatio-Strecke und die Kraft-Parameter erhöhen . Das 12-Monate-Trainingsprogramm scheint dabei einen größeren Nutzen zu erzielen OBJECTIVE To determine the effects of 12-week exercise programme on ambulatory function , free-living daily physical activity and health-related quality of life in disabled older patients with intermittent claudication . DESIGN Prospect i ve , r and omized controlled trial . SETTING University Medical Center and Veterans Affairs Medical Center , Taipei , Taiwan . SUBJECTS Thirty-two of 64 patients with Fontaine stage II peripheral arterial occlusive disease ( PAOD ) were r and omized to exercise training and 32 to usual care control . Five patients from the exercise group and six patients from the control group dropped out , leaving 27 and 26 patients , respectively , completing the study in each group . INTERVENTIONS Twelve weeks of treadmill exercise training . MAIN OUTCOME MEASURES Treadmill walking time to onset of claudication pain and to maximal claudication pain , 6-min walk distance , self-reported ambulatory ability and perceived health-related quality of life ( QOL ) . RESULTS Compliance of exercise programme was 83 % of the possible sessions . Exercise training increased treadmill walking time to onset of claudication pain by 88 % ( P < 0.001 ) , time to maximal pain by 70 % ( P < 0.001 ) , and 6-min walk distance by 21 % ( P < 0.001 ) . SUBJECTS Perception of health-related QOL improved from 12 % to 178 % in the exercise group . These improvements were significantly better than the changes in the control group ( P < 0.05 ) . CONCLUSIONS Significant improvements in claudication following 12-week exercise training in elderly PAOD patients were observed . Increase in treadmill walking time to maximal claudication pain in these patients translated into the improvement of perceived physical health , which enabled the patients to become more functionally independent OBJECTIVE The initial treatment for intermittent claudication is supervised exercise therapy ( SET ) . Owing to limited capacity and patient transports costs of clinic-based SET , a concept of SET provided by local physiotherapists was developed . We hypothesized that provision of daily feedback with an accelerometer in addition to SET would further increase walking distance . METHODS This multicenter r and omized trial was set in vascular surgery outpatient clinics and included 304 patients with intermittent claudication . Patients were r and omized to exercise therapy in the form of " go home and walk " advice ( WA ) , SET , or SET with feedback . Local physiotherapists provided SET . The primary outcome measure was the change in absolute claudication distance . Secondary outcomes were the change in functional claudication distance and results on the Walking Impairment Question naire ( WIQ ) and Short-Form 36 ( SF-36 ) Health Survey after 12 months . RESULTS In 11 centers , 102 , 109 , and 93 patients were included , respectively , in the WA , SET , and SET with feedback groups , and data for 83 , 93 , and 76 , respectively , could be analyzed . The median ( interquartile range ) change in walking distance between 12 months and baseline in meters was 110 ( 0 - 300 ) in the WA group , 310 ( 145 - 995 ) in the SET group , and 360 ( 173 - 697 ) in the SET with feedback group ( P < .001 WA vs SET ) . WIQ scores and relevant domains of the SF-36 improved statistically significantly in the SET groups . CONCLUSIONS SET is more effective than WA in improving walking distance , WIQ scores , and quality of life for patients with intermittent claudication . Additional feedback with an accelerometer did not result in further improvement . SET programs should be made available for all patients with intermittent claudication BACKGROUND It is not clear whether subgroups of patients with peripheral artery disease ( PAD ) and claudication respond more favorably to exercise rehabilitation than others . We determined whether sex and diabetes were factors associated with the response to exercise rehabilitation in patients with claudication . METHODS Eighty patients were r and omized to home-based and supervised exercise programs , and 60 finished with complete exercise intervention data . Exercise consisted of intermittent walking to near maximal claudication pain for 3 months . Primary outcome measures included claudication onset time ( COT ) and peak walking time . Patients were partitioned into diabetic and nondiabetic groups and then further partitioned by sex to form four groups . RESULTS Overall , exercise adherence was high ( 84 % ) , and there was no significant difference ( P > .05 ) in the amount of exercise completed among the four groups . All groups had significant improvements ( P < .05 ) in COT and peak walking time after exercise rehabilitation , except for diabetic women ( P > .05 ) . Only 37 % of women with diabetes had an increase in COT compared with 100 % of men with diabetes ( P < .01 ) , and their risk ratio for nonresponse was 9.2 ( P < .0001 ) . CONCLUSIONS Women with PAD and claudication , particularly those with diabetes , represent a vulnerable subgroup of patients who respond poorly to a program of exercise rehabilitation . Diabetic women with PAD and claudication may need a greater dose of exercise or another intervention separate from or in combination with exercise to elicit improvements in claudication measures that are similar to nondiabetic women and to diabetic and nondiabetic men OBJECTIVE We used outdoor walking distance measured during 40 minutes as " real-life " outdoor walking capacity in 49 patients with intermittent claudication ( IC ) . The outdoor walking distance was measured by a global positioning system application for a smartphone . The relationships of self-reported maximum walking distance ( SR-MWD ) , the MWD on a grade d treadmill test , and the 6-minute maximum walk distance ( 6MWD ) vs outdoors walking capacity were investigated . Also studied were the associations of SR-MWD , MWD , and 6MWD with health-related quality of life assessed with the disease-specific instrument the Vascular Quality of Life Question naire ( VascuQoL ) . METHODS In this prospect i ve observational cohort study , 49 IC patients underwent an outdoor walking capacity test for 40 minutes , and MWD and 6MWD were measured . SR-MWD was recorded , and all subjects completed the VascuQoL question naire . Associations between the different walk estimates and outdoor walking capacity and health-related quality of life were investigated by correlation analysis ( Spearman ρ ) . RESULTS Outdoor walking distance during 40 minutes was a median 2495 m ( range , 1110 - 3300 m ) . SR-MWD correlated moderately and MWD correlated strongly to outdoor walking capacity ( r = 0.56 and r = 0.65 ; P < .001 , respectively ) . The 6MWD test showed the largest correlation to the outdoor walking capacity ( r = 0.78 ; P < .001 ) . The 6MWD was the only test that showed correlations with the VascuQoL sum score ( r = 0.53 ; P < .01 ) and all of the domain scores , whereas SR-MWD and MWD showed weak correlations to the VascuQoL. CONCLUSIONS The distance walked during the 6-minute walk test is closely correlated to outdoor walking capacity and health-related quality of life in IC patients . Our data support the use of 6MWD for routine clinical evaluation of walking capacity in IC patients

It appears that ADDs were effective in reducing medication storage errors and the time that nurses spent taking inventory of narcotics and controlled substances . There was no definitive evidence that using ADDs increased the time that nurses or pharmacists spent with patients , reduced medication errors result ing in patient harm , or reduced costs in Canadian hospitals . However , pharmacy technicians spent more time stocking the machines . ADDs have limited potential to decrease medication errors and increase efficiencies , but their impact is highly institution-specific , and use of this technology requires proper integration into an institution 's medication distribution process .

BACKGROUND Technologies have been developed over the past 20 years to automate the stages of drug distribution in hospitals , including ordering , dispensing , delivery , and administration of medications , in attempts to decrease medication error rates . De central ized automated dispensing devices ( ADDs ) represent one such technology that is being adopted by hospitals across Canada , but the touted benefits , in terms of improved patient safety and cost savings , are increasingly being question ed . OBJECTIVE To summarize and evaluate the existing literature reporting the clinical and economic impacts of using de central ized ADDs in hospitals .

STUDY OBJECTIVE Our objectives are to describe the outcomes of patients presenting to the emergency department ( ED ) because of an adverse drug event and to compare them with outcomes of patients presenting for other reasons . METHODS This prospect i ve observational study was conducted at Vancouver General Hospital , a 955-bed tertiary care hospital . We prospect ively enrolled adults presenting to the ED between March and June 2006 , using a systematic sampling algorithm . Pharmacists and physicians independently evaluated patients for adverse drug events . An independent committee review ed and adjudicated cases in which assessment s were discordant or uncertain . Data from the index visit were linked to vital statistics , administrative health services utilization , and cost of care data . RESULTS Of 1,000 patients , 122 ( 12.2 % ; 95 % confidence interval [ CI ] 10.3 % to 14.4 % ) presented to the ED because of an adverse drug event . Of these , 48 presented because of an adverse drug reaction ( one type of adverse drug event defined as an unintended response that occurred despite use of an appropriate drug dosage ) . We found no difference in mortality among patients presenting with and without adverse drug reactions ( 14.6 % versus 5.9 % ; hazard ratio 1.57 ; 95 % CI 0.70 to 3.52 ) . After adjustment , patients with adverse drug events had a higher risk of spending additional days in the hospital per month ( 6.3 % versus 3.4 % ; odds ratio 1.52 ; 95 % CI 1.43 to 1.62 ) and higher rate of outpatient health care encounters ( 1.73 versus 1.22 ; rate ratio 1.20 ; 95 % CI 1.03 to 1.40 ) . The adjusted median monthly cost of care was 1.90 times higher ( Can $ 325 versus $ 96 ; 95 % CI 1.18 to 3.08 ) . CONCLUSION ED patients presenting with an adverse drug event incurred greater health services utilization and costs during a 6-month follow-up period compared with patients presenting for other reasons PURPOSE Results of the 2011 ASHP national survey of pharmacy practice in hospital setting s that pertain to dispensing and administration are presented . METHODS A stratified r and om sample of pharmacy directors at 1401 general and children 's medical-surgical hospitals in the United States were surveyed by mail . RESULTS In this national probability sample survey , the response rate was 40.1 % . De central ization of the medication-use system continues , with 40 % of hospitals using a de central ized system and 58 % of hospitals planning to use a de central ized model in the future . Automated dispensing cabinets were used by 89 % of hospitals , robots were used by 11 % , carousels were used in 18 % , and machine-readable coding was used in 34 % of hospitals to verify doses before dispensing . Overall , 65 % of hospitals had a United States Pharmacopeia chapter 797 compliant cleanroom for compounding sterile preparations . Medication administration records ( MARs ) have become increasingly computerized , with 67 % of hospitals using electronic MARs . Bar-code-assisted medication administration was used in 50 % of hospitals , and 68 % of hospitals had smart infusion pumps . Health information is becoming more electronic , with 67 % of hospitals having partially or completely implemented an electronic health record and 34 % of hospitals having computerized prescriber order entry . The use of these technologies has substantially increased over the past year . The average number of full-time equivalent staff per 100 occupied beds averaged 17.5 for pharmacists and 15.0 for technicians . Directors of pharmacy reported declining vacancy rates for pharmacists . CONCLUSION Pharmacists continue to improve medication use at the dispensing and administration steps of the medication-use system . The adoption of new technology is changing the philosophy of medication distribution , and health information is rapidly becoming electronic Objectives : We aim ed to assess the impact of an automated dispensing system on the incidence of medication errors related to picking , preparation , and administration of drugs in a medical intensive care unit . We also evaluated the clinical significance of such errors and user satisfaction . Design : Preintervention and postintervention study involving a control and an intervention medical intensive care unit . Setting : Two medical intensive care units in the same department of a 2,000-bed university hospital . Patients : Adult medical intensive care patients . Interventions : After a 2-month observation period , we implemented an automated dispensing system in one of the units ( study unit ) chosen r and omly , with the other unit being the control . Measurements and Main Results : The overall error rate was expressed as a percentage of total opportunities for error . The severity of errors was classified according to National Coordinating Council for Medication Error Reporting and Prevention categories by an expert committee . User satisfaction was assessed through self-administered question naires completed by nurses . A total of 1,476 medications for 115 patients were observed . After automated dispensing system implementation , we observed a reduced percentage of total opportunities for error in the study compared to the control unit ( 13.5 % and 18.6 % , respectively ; p < .05 ) ; however , no significant difference was observed before automated dispensing system implementation ( 20.4 % and 19.3 % , respectively ; not significant ) . Before- and -after comparisons in the study unit also showed a significantly reduced percentage of total opportunities for error ( 20.4 % and 13.5 % ; p < .01 ) . An analysis of detailed opportunities for error showed a significant impact of the automated dispensing system in reducing preparation errors ( p < .05 ) . Most errors caused no harm ( National Coordinating Council for Medication Error Reporting and Prevention category C ) . The automated dispensing system did not reduce errors causing harm . Finally , the mean for working conditions improved from 1.0 ± 0.8 to 2.5 ± 0.8 on the four-point Likert scale . Conclusions : The implementation of an automated dispensing system reduced overall medication errors related to picking , preparation , and administration of drugs in the intensive care unit . Furthermore , most nurses favored the new drug dispensation organization Automated medication distribution systems have helped solve issues of efficiency and effectiveness . Cost-benefit analysis conducted by nursing and pharmacy departments can help to objectify the decision to adopt this technology PURPOSE The results of the 2014 ASHP national survey of pharmacy practice in hospital setting s that pertain to dispensing and administration are described . METHODS A stratified r and om sample of pharmacy directors at 1435 general and children 's medical-surgical hospitals in the United States were surveyed by mail . RESULTS In this national probability sample survey , the response rate was 29.7 % . Ninety-seven percent of hospitals used automated dispensing cabinets in their medication distribution systems , 65.7 % of which used individually secured lidded pockets as the predominant configuration . Overall , 44.8 % of hospitals used some form of machine-readable coding to verify doses before dispensing in the pharmacy . Overall , 65 % of hospital pharmacy departments reported having a cleanroom compliant with United States Pharmacopeia chapter 797 . Pharmacists review ed and approved all medication orders before the first dose was administered , either onsite or by remote order view , except in procedure areas and emergency situations , in 81.2 % of hospitals . Adoption rates of electronic health information have rapidly increased , with the widespread use of electronic health records , computer prescriber order entry , barcodes , and smart pumps . Overall , 31.4 % of hospitals had pharmacists practicing in ambulatory or primary care clinics . Transitions-of-care services offered by the pharmacy department have generally increased since 2012 . Discharge prescription services increased from 11.8 % of hospitals in 2012 to 21.5 % in 2014 . Approximately 15 % of hospitals out source d pharmacy management operations to a contract pharmacy services provider , an increase from 8 % in 2011 . CONCLUSION Health-system pharmacists continue to have a positive impact on improving healthcare through programs that improve the efficiency , safety , and clinical outcomes of medication use in health systems

A large effect was found on muscle cross-sectional area following strength training , with small to moderate effects on muscle volume and thickness . CONCLUSION AND IMPLICATION S There is preliminary evidence that strength training leads to hypertrophy in children and adolescents with CP . A paucity of studies exist measuring morphological and architectural parameters following strength training in these individuals .

AIM The aim of this study was to systematic ally review the current literature to determine the impact of strength training on skeletal muscle morphology and architecture in individuals aged 4 - 20 years with spastic type cerebral palsy .

The objective of the study was to evaluate the effectiveness of functional progressive resistance exercise ( PRE ) training on walking ability in children with cerebral palsy ( CP ) . Fifty-one ambulant children with spastic CP ( mean age 10 years 5 months , 29 boys ) were r and omized to an intervention ( n=26 ) or control group ( n=25 , receiving usual care ) . The intervention consisted of 12 weeks functional PRE circuit training , for 3 times a week . Main outcome measures were walking ability and participation . Secondary outcomes were muscle strength and anaerobic muscle power . Possible adverse outcomes were spasticity and passive range of motion ( ROM ) . Muscle strength increased significantly in the training group compared to the control group , but walking ability , participation and anaerobic muscle power did not change . Spasticity and ROM remained unchanged , except for a significant decrease in rectus femoris length in the intervention group . It is concluded that twelve weeks of functional PRE-training does not improve walking ability , despite improved muscle strength AIM The aim of this study was to investigate whether individualized resistance training improves the physical mobility of young people with cerebral palsy ( CP ) . METHOD Forty-eight participants with spastic diplegic CP ( 26 males , 22 females ; mean age 18y 1mo , SD 1y 11mo ) classified as level II or III on the Gross Motor Function Classification System were allocated r and omly to progressive resistance training or usual-care control . Resistance training was completed twice weekly for 12 weeks at a community gymnasium under the supervision of a physiotherapist . Exercises were based on instrumented gait analysis and targeted muscles contributing to walking difficulties . Outcomes at 12 weeks and 24 weeks included objective measures of mobility ( 6-min walk test , instrumented gait analysis , and Gross Motor Function Measure dimensions D and E ) , participant-rated measures of mobility ( Functional Mobility Scale and Functional Assessment Question naire ) , and muscle performance . RESULTS The strength of targeted muscles increased by 27 % ( 95 % CI 8 - 46 % ) compared with control group . There were no between-group differences in any objective measure of mobility at 12 weeks ( 6-min walk test : mean difference 0.1 m ; 95 % CI -21 to 21 m ) or at 24 weeks . Participant-rated mobility improved ( Functional Mobility Scale at 5 m : mean 0.6 units ; 95 % CI 0.1 - 1.1 units ; Functional Assessment Question naire : 0.8 units ; 95 % CI 0.1 - 1.6 units ) compared with control group at 12 weeks . INTERPRETATION Individualized progressive resistance training increased strength in adolescents and young adults with spastic diplegic CP . Despite participant-rated benefits , the increased strength did not result in objective improvements in mobility AIM The aim of the present study was to assess and compare the improvements of muscle strength and power induced by a 16-week resistive programme in a population of 16 older men aged 65 - 81 years . METHODS Training was performed three times per week at an intensity of 80 % of one repetition maximum ( 1RM ) and consisted of both calf raise and leg press exercises . Before- , during- and after-training , maximum isometric and isokinetic torques , maximum power , 1RM , muscle cross-sectional area ( CSA ) and electromyographic activity ( EMG ) of the plantar flexors ( PF ) and knee extensors ( KE ) were examined . RESULTS For the KE and PF , respectively , training result ed in a 29.9 + /- 4.4 % ( mean + /- SE ) and 21.6 + /- 5.4 % increase in 1RM ( P < 0.001 - 0.01 ) , a 19.4 + /- 4.3 and 12.4 + /- 4.7 % ( P < 0.001 - 0.05 ) increase in maximum isometric torque , and a 24.1 + /- 6.3 and 33.1 + /- 10.9 % ( P < 0.05 ) increase in maximum muscle power , calculated from torque-angular velocity curves . The large increase in torque and power was partly accounted by a significant increase in the CSA of the PF ( 5.0 + /- 0.7 % ) and KE ( 7.4 + /- 0.7 % ) , while no significant changes in integrated EMG activity of vastus lateralis and soleus muscles , and in extrapolated maximum shortening velocity were found . After training , a significant increase in torque/CSA ( 10.3 + /- 4 % , P < 0.05 ) was found for the KE but not for the PF . CONCLUSION Hence , hypertrophy can not alone justify the increase in torque , and other factors , such as an increase in individual fibre-specific tension ( in the case of KE ) , a decrease in antagonist muscles ' coactivation , an improved co-ordination and an increased neural drive of the other heads of quadriceps may have contributed to the increments in strength . The significant increase in muscle power seems particularly noteworthy with respect to daily activities involving the displacement of the body over time , namely , the generation of muscle power Abstract The aims of this study were to assess changes in muscle architecture , isometric and dynamic strength of the leg extensor muscles , result ing from dynamic resistance training , and the relationships between strength and muscle architecture variables . The participants ( n = 30 ) were r and omly assigned to one of two groups . The training group ( n = 16 ; age 21.8 ± 2.3 years , body mass 74.8 ± 9.2 kg , height 1.75 ± 0.08 m ) performed dynamic resistance training for 13 weeks . The control group ( n = 14 ; age 19.9 ± 1.5 years , body mass 74.0 ± 8.5 kg , height 1.76 ± 0.05 m ) did not perform any resistance training . Maximal dynamic and isometric strength were tested in both groups , before and after the training period . The members of the training group used the free-weight squat lift ( 90 ° ) as their training exercise . The concentric phase of the squat was performed explosively . Skeletal muscle architecture of the vastus lateralis was visualized using ultrasonography . At the end of the study , significant increases in vastus lateralis muscle thickness ( + 6.9 % , P < 0.001 ) , fascicle length ( + 10.3 % , P < 0.05 ) , one-repetition maximum ( + 8.2 % , P < 0.05 ) , rate of force development ( + 23.8 % , P < 0.05 ) and average force produced in the first 500 ms ( + 11.7 % , P < 0.05 ) were seen only in the training group . Adaptations to the muscle architecture in the training group limited the loss of fibre force , and improved the capacity for developing higher velocities of contraction . The architectural changes in the training group were similar to those seen in studies where high-speed training was performed . In conclusion , dynamic resistance training with light loads leads to increases in muscle thickness and fascicle length , which might be related to a more efficient transmission of fibre force to the tendon BACKGROUND Fascicle length and fascicle excursion measurements in children with cerebral palsy have yielded inconsistent results . The purpose of this study was to measure in vivo passive fascicle lengths and fascicle excursions in the Medial Gastrocnemius muscle of children with cerebral palsy and typically developing controls . METHODS We measured 11 children with spastic cerebral palsy and 14 controls between the ages of 9 and 16years . Ultrasound imaging was used to measure fascicle lengths while a dynamometer moved the ankle joint through the range of motion . A common range of motion for all subjects was used for analysis of fascicle excursion . FINDINGS Fascicle lengths in children with cerebral palsy were 43 % smaller than those for control subjects throughout the range of motion . The relative fascicle excursion was 92 % greater on average for the cerebral palsy compared to the control group children . The muscle excursion for the control group children was greater than for the cerebral palsy group children . INTERPRETATION Since the fascicles in children with spastic cerebral palsy are shorter , but they go through the same excursion as fascicles in typically developing children , sarcomeres within the medial gastrocnemius muscle must be working over a larger range of sarcomere lengths . Combined with findings of overstretched sarcomeres in spastic muscles reported in the literature , our results suggest that the increased passive forces and the weakness found in spastic muscles may be caused by a decrease in contractile filament overlap as sarcomeres are pulled to extreme lengths in children with cerebral palsy Background . Everyday activities for youth with cerebral palsy ( CP ) require muscle power , but the velocity component of muscle contraction is neglected with traditional strength training ( ST ) . Objective . To determine whether velocity training ( VT ) , which includes resistance training at increasingly higher velocities , would induce specific muscle adaptations not observed with ST . Methods . Sixteen ambulatory youth with CP were r and omized to VT or ST . Participants trained the knee extensors 3 times per week for 24 sessions on a Biodex dynamometer . At each session , 6 sets of 5 concentric repetitions were performed either at 30 deg/s ( ST group ) or progressively higher velocities from 30 deg/s to 120 deg/s ( VT group ) . Outcomes included muscle architecture , power , strength , walking speed , and functional walking performance . Results . A significant increase in rectus femoris fascicle length was observed after VT with a decrease after ST . Rectus femoris cross-sectional area increased in both groups . Both showed significant increases in isokinetic strength at all tested speeds ; however , peak velocity and power improved after VT only . Self-selected and fast walking speed and functional walking performance improved after VT only . Conclusions . Muscle architecture in CP is capable of adapting differentially to the training stimulus . VT was equally effective as traditional ST in improving isokinetic strength of the knee extensors but more effective in improving velocity of movement , muscle power , and walking performance . Differences may be partially attributed to specificity of training effects on muscle architecture , such as the increase in fascicle length after VT . Strengthening interventions involving higher velocity movements should be incorporated into clinical practice Background . To date , no reports have investigated neuromuscular electrical stimulation ( NMES ) to increase muscle force production of children with cerebral palsy ( CP ) using high-force contractions and low repetitions . Objective . The aims of this study were to determine if isometric NMES or volitional training in children with CP could increase muscle strength and walking speed and to examine the mechanisms that may contribute to increased force production . Methods . Eleven children with spastic diplegia were assigned to an NMES training group or to a volitional training group . Participants in the NMES group had electrodes implanted percutaneously to activate the quadriceps femoris and triceps surae muscles . The volitional group trained with maximal effort contractions . Both groups performed a 12-week isometric strength-training program . Maximum voluntary isometric contraction ( MVIC ) force , voluntary muscle activation , quadriceps and triceps surae cross-sectional area ( CSA ) , and walking speed were measured pre- and post-strength training . Results . The NMEStrained group had greater increases in normalized force production for both the quadriceps femoris and triceps surae . Similarly , only the NMES group showed an increase in walking speed after training . Changes in voluntary muscle activation explained approximately 67 % and 37 % of the changes seen in the MVIC of the NMES and volitional groups , respectively . Quadriceps femoris maximum CSA increased significantly for the NMES group only . Conclusions . This study was the first to quantitatively show strength gains with the use of NMES in children with CP . These results support the need for future experimental studies that will examine the clinical effectiveness of NMES strength training 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 Abstract The purpose of this study was to investigate the time course of skeletal muscle adaptations result ing from high-intensity , upper and lower body dynamic resistance training ( WT ) . A group of 17 men and 20 women were recruited for WT , and 6 men and 7 women served as a control group . The WT group performed six dynamic resistance exercises to fatigue using 8–12 repetition maximum ( RM ) . The subjects trained 3 days a week for 12 weeks . One-RM knee extension ( KE ) and chest press ( CP ) exercises were measured at baseline and at weeks 2 , 4 , 6 , 8 , and 12 for the WT group . Muscle thickness ( MTH ) was measured by ultrasound at eight anatomical sites . One-RM CP and KE strength had increased significantly at week 4 for the female WT group . For the men in the WT group , 1 RM had increased significantly at week 2 for KE and at week 6 for CP . The mean relative increases in KE and CP strength were 19 % and 19 % for the men and 19 % and 27 % for the women , respectively , after 12 weeks of WT . Resistance training elicited a significant increase in MTH of the chest and triceps muscles at week 6 in both sexes . There were non-significant trends for increases in quadriceps MTH for the WT groups . The relative increases in upper and lower body MTH were 12%–21 % and 7%–9 % in the men and 10%–31 % and 7%–8 % in the women respectively , after 12 weeks of WT . These results would suggest that increases in MTH in the upper body are greater and occur earlier compared to the lower extremity , during the first 12 weeks of a total body WT programme . The time-course and proportions of the increase in strength and MTH were similar for both the men and the women Purpose : Investigate the combination effects of strength training and Botulinum Toxin Type-A ( BoNT-A ) on muscle strength and morphology in children with Cerebral Palsy ( CP ) . Methods : Fifteen children receiving BoNT-A , classified as Spastic Diplegic CP , GMFCS I-II , and aged 5–12 years were recruited for this study . R and omly allocated to 10 weeks of strength training either before or after BoNT-A , children were assessed over 6 months . Eight of the 15 children also completed a control period . The Modified Ashworth Scale measured spasticity . The Goal Attainment Scale ( GAS ) assessed achievement of functional goals . Magnetic Resonance Imaging assessed muscle volume ( MV ) . Instrumented dynamometry assessed strength . Results : Spasticity was significantly reduced following BoNT-A injection ( p = 0.033 ) . Children made significant isokinetic strength gains ( mean p = 0.022 , ES = 0.57 ) in the intervention period compared to the control period ( mean p = 0.15 , ES = 0.56 ) . Irrespective of timing , significant strength improvements were seen immediately ( 10 weeks ) and over 6 months for all children . This was also the case for improvements in the GAS ( immediately : mean p = 0.007 , ES = 4.17 , 6 months : mean p = 0.029 , ES = 0.99 ) , and improvements in MV in all assessed muscles . Conclusion : The simultaneous use of BoNT-A and strength training was successful in spasticity reduction , improving strength and achieving functional goals , over and above treatment with BoNT-A alone . Muscles targeted for BoNT-A injection should be included in strength training . Implication s for Rehabilitation Cerebral Palsy Botulinum toxin type-A ( BoNT-A ) and strength training are available interventions that , on their own have found success in managing spasticity and muscle weakness ( both significant motor impairments ) , respectively in children with Cerebral Palsy ( CP ) . This study has demonstrated that the concurrent treatment of BoNT-A and strength training can achieve positive outcomes in terms of strength , spasticity and for the achievement of set functional goals . The results of this study show that the improved muscle strength can be associated with hypertrophy , which could indicate the potential role of strength training in altering the rate of muscle growth , in an aim to improve the failure of muscle growth associated with CP . Home based strength training , based on a child ’s individual goals is shown to be successful in improving strength and goal attainment for children with CP Children with spastic cerebral palsy ( CP ) have small , weak muscles . However , change in muscle size due to resistance training in this group is unknown . We investigated the effect of plantarflexor strengthening on muscle volume , gait , and function in 13 ambulant children with spastic CP ( seven males , six females ; mean age 10 y 11 mo , SD 3 y 0 mo , range 6 y 11 mo-16 y 11 mo ; eight with diplegia , five with hemiplegia ; Gross Motor Function Classification System level I , six ; level II , five ; level III , two ) . Assessment s were performed before training , 5 and 10 weeks into training , and at a 3-month follow-up . Medial and lateral gastrocnemius volumes were computed from three-dimensional ultrasound images . The number of unilateral heel raises able to be achieved on each side was assessed . Function was measured using three-dimensional gait analysis , the ' timed up and go ' test , the Gillette Functional Assessment Question naire , and the Functional Mobility Scale . Training involved heel raises or Thera-B and resistance , 4 times a week for 10 weeks . Medial and lateral gastrocnemius volumes increased by 17 and 14 % at week 5 ( p=0.03 , p=0.028 ) . This increase was maintained at week 10 and follow-up ( medial gastrocnemius p=0.001 , p<0.001 ; lateral gastrocnemius p=0.006 , p=0.007 ) . Heel raises ( mean number ) increased by week 5 ( p=0.002 ) . This was maintained at week 10 and follow-up ( p<0.001 ; p<0.001 ) . No significant change in measured function was observed . Muscle volume increased in response to training in children with spastic CP . The role of progressive strength training in maintaining long-term function is discussed This study investigated changes in elderly muscle joint angle-torque relation induced by resistance training . Older adults were assigned to either training ( n = 9 , age 74.3 + /- 3.5 years ; mean + /-s.d . ) or to control groups ( n = 9 , age 67.1 + /- 2 years ) . Leg-extension and leg-press exercises were performed three times per week for 14 weeks . Maximal isometric knee extension torque was measured across the knee joint angle range of movement . Vastus lateralis muscle architecture was examined in vivo using ultrasonography . The vastus lateralis muscle fascicle force was estimated from the measured joint torque , enabling construction of the fascicle length-force relation . Electromyographic ( EMG ) activity was measured from representative agonist and antagonist muscles . Training altered the angle-torque relation : ( a ) displacing it by 9 - 31 % towards higher torque values ( P < 0.05 ) ; and ( b ) shifting the optimal angle from 70 deg ( corresponding torque : 121.4 + /- 61 N m ) before to 60 deg ( 134.2 + /- 57.2 N m ; P < 0.05 ) after training . Training also altered the fascicle length-force relation : ( a ) displacing it by 11 - 35 % towards higher force values ; and ( b ) shifting the optimal fascicle length from 83.7 + /- 8 mm ( corresponding force : 847.9 + /- 365.3 N ) before to 93.2 + /- 12.5 mm ( 939.3 + /- 347.8 N ; P < 0.01 ) after training . The upward displacement of the angle-torque relation was mainly due to a training-induced increase in agonist activation , whilst the shift in the optimal angle was associated with changes in muscle-tendon properties

Main findings of the review were : ( 1 ) school-based interventions generally lead to short term improvements in physical activity levels ; ( 2 ) improvements in physical activity levels by school-based interventions were limited to school related physical activity with no conclusive transfer to leisure time physical activity ; ( 3 ) including parents appeared to enhance school-based interventions ; ( 4 ) the support of peers and the influence of direct environmental changes increased the physical activity level of secondary school children ; ( 5 ) the assumption that a multi-component approach should produce synergistic results can not be confirmed ; ( 6 ) when interventions aim ed to affect more than one health behaviour the intervention appeared to be less effective in favour of physical activity . Conclusion Overall , the current European literature supports the short-term effectiveness of school-based physical activity promotion programmes .

Background Although physical activity is considered to yield substantial health benefits , the level of physical activity among European teenagers is not sufficient . Adolescence is characterized by a decline in physical activity level . Many studies investigated the effectiveness of interventions promoting physical activity among young people , but none dealt with the available evidence specific for Europe . This review was conducted to summarize the effectiveness of interventions to promote physical activity among European teenagers .

OBJECTIVES This study examined the role of behavioral and material factors in explaining educational differences in all-cause mortality , taking into account the overlap between both types of factors . METHODS Prospect i ve data were used on 15,451 participants in a Dutch longitudinal study . Relative hazards of all-cause mortality by educational level were calculated before and after adjustment for behavioral factors ( alcohol intake , smoking , body mass index , physical activity , dietary habits ) and material factors ( financial problems , neighborhood conditions , housing conditions , crowding , employment status , a proxy of income ) . RESULTS Mortality was higher in lower educational groups . Four behavioral factors ( alcohol , smoking , body mass index , physical activity ) and 3 material factors ( financial problems , employment status , income proxy ) explained part of the educational differences in mortality . With the overlap between both types of factors accounted for , material factors were more important than behavioral factors in explaining mortality differences by educational level . CONCLUSIONS The association between educational level and mortality can be largely explained by material factors . Thus , improving the material situation of people might substantially reduce educational differences in mortality A r and omised control trial evaluated the effectiveness of a theory-based persuasive leaflet design ed to encourage students to undertake at least one additional physical exercise session a week . Participants were 503 secondary school students attending a school in South-East Engl and . The leaflet was written to target potentially modifiable cognitive antecedents of exercise specified by the Theory of Planned Behaviour . It was separately augmented with two cognitive change techniques , result ing in three intervention conditions , leaflet alone ; leaflet plus motivational quiz , and leaflet plus implementation intention prompt , as well as a no-leaflet control condition . Cognitions and behaviour were measured immediately before and 3 weeks after intervention . The results showed that all three-leaflet interventions significantly increased reported exercise , intention to exercise and related cognitions , compared to the control condition , but did not differ in their impact . Mediation analysis showed that intervention effects on exercise were partially mediated by intentions and perceived behavioural control OBJECTIVE : To evaluate the 6-month impact of a physical activity ( PA ) multilevel intervention on activity patterns and psychological predictors of PA among adolescents . The intervention was directed at changing knowledge and attitudes and at providing social support and environmental conditions that encourage PA of adolescents inside and outside school . SUBJECTS AND DESIGN : R and omised , controlled ongoing field trial ( ICAPS ) in middle-school 's first-level adolescents from eight schools selected in the department of the Bas-Rhin ( Eastern France ) with a cohort of 954 adolescents ( 92 % of the eligible students ) initially aged 11.7±0.6 y. The 6-month changes in participation in leisure organised PA ( LOPA ) , high sedentary ( SED ) behaviour ( > 3h/day ) , self-efficacy ( SELF ) and intention ( INTENT ) towards PA were analysed after controlling for baseline measures and different covariables ( age , overweight , socioprofessional occupation ) , taking into account the cluster r and omisation design . RESULTS : The proportion of intervention adolescents not engaged in organised PA was reduced by 50 % whereas it was unchanged among control students . After adjustment for baseline covariables , LOPA participation significantly increased among the intervention adolescents ( odds ratio ( 95 % confidence interval ) (OR)=3.38 ( 1.42–8.05 ) in girls ; 1.73 ( 1.12–2.66 ) in boys ) , while high SED was reduced ( OR=0.54 ( 0.38–0.77 ) in girls ; 0.52 ( 0.35–0.76 ) in boys ) . The intervention improved SELF in girls , whatever their baseline LOPA ( P<10−4 ) and INTENT in girls with no baseline LOPA ( P=0.04 ) . SELF tended to improve in boys with no baseline LOPA , without reaching statistical significance . When included in the regression , follow-up LOPA was associated with improvement of SELF in girls ( P=0.02 ) and of INTENT in girls with no baseline PA ( P<0.02 ) . The intervention effect was then attenuated . CONCLUSION : After 6 months of intervention , ICAPS was associated with a significant improvement of activity patterns and psychological predictors , indicating a promising approach for modifying the long-term PA level of adolescents BACKGROUND The aim of this study was to investigate stability of physical activity from childhood and adolescence to adulthood in multiple age cohorts , and analyze how well adult physical activity can be predicted by various physical activity variables measured in childhood and adolescence . METHODS The data were drawn from the Cardiovascular Risk in Young Finns Study . The study was started in 1980 , when cohorts of r and omly sample d boys and girls aged 3 , 6 , 9 , 12 , 15 , and 18 years ( total of 2309 subjects ) were examined for the first time . The measurements were repeated in 1983 , 1986 , 1989 , 1992 , and 2001 . In 2001 , the subjects ( n = 1563 , 68 % ) were aged 24 , 27 , 30 , 33 , 36 , and 39 years , respectively . Physical activity was measured by means of a short self-report question naire that was administered individually in connection with a medical examination . On the basis of a question naire , a physical activity index ( PAI ) was calculated . There were no significant differences in the 1980 PAI between participants and dropouts in 2001 . RESULTS Spearmans rank order correlation coefficients for the 21-year tracking period varied from 0.33 to 0.44 in males , and from 0.14 to 0.26 in females . At shorter time intervals the correlation was higher . On average , the tracking correlation was lower in females than in males . Persistent physical activity , defined as a score in the most active third of the PAI in two or three consecutive measurements , increased the odds that an individual would be active in adulthood . Odds ratios for 3-year continuous activity versus continuous inactivity varied from 4.30 to 7.10 in males and 2.90 to 5.60 in females . The corresponding odds ratios for 6-year persistence were 8.70 to 10.80 and 5.90 to 9.40 . CONCLUSIONS It was concluded that a high level of physical activity at ages 9 to 18 , especially when continuous , significantly predicted a high level of adult physical activity . Although the correlations were low or moderate , we consider it important that school-age physical activity appears to influence adult physical activity , and through it , the public health of the general population OBJECTIVES ICAPS ( Intervention Centred on Adolescents ' Physical activity and Sedentary behaviour ) is aim ed at preventing excessive weight gain and cardiovascular risk in adolescents by promoting physical activity ( PA ) with an emphasis on recreational and daily-life PA , with a lifelong perspective . DESIGN R and omized study design ed to last for four years . Study cohort constituted of 954 first-level students ( 91 % of eligible pupils ) , aged 11.7 + /- 0.6 y ( mean + /- SD ) from four pairs of schools r and omly selected in eastern France , after sociogeographical stratification . In each pair , intervention status was r and omised at school-level . The program , not limited to school setting s , involves multiple partners with three objectives : 1 ) changing attitudes through debates and access to attractive activities during breaks and after-school hours , 2 ) encouraging social support , 3 ) providing environmental conditions that enable PA . Adapted times and places , open participation , emphasis on fun , meeting with others and absence of competitive aspects are used to reduce usual barriers to PA . Accessibility and safety are permanent concerns . RESULTS Prevalence of overweight was 23.7 % . High participation rates were attained ( 50 % participated in at least one weekly activity ) . At six-month , the proportion of intervention adolescents not performing supervised PA out of academic PA was reduced by half ( 36 % to 17 % vs 42 % to 42 % in controls P < 10 - 4 ) ; the proportion of those spending > 3 h/day in sedentary occupations decreased ( 34 % to 28 % vs 27 % to 36 % ; P < 10 - 4 ) . CONCLUSION These data demonstrate the feasibility of implementing a multilevel PA intervention program in adolescents . Six-month results document increased PA and decreased sedentary behaviour Abstract Objectives : To evaluate the effectiveness of inviting teenagers to general practice consultations to discuss health behaviour concerns and appropriate follow up care . Design : R and omised controlled trial , with participants r and omised to a consultation ( intervention ) or usual care ( control ) . Question naires completed at baseline , 3 months , and 12 months . Setting : Eight general practice s in Hertfordshire , Engl and . Participants : 1516 teenagers aged 14 - 15 years . Intervention : Consultations with practice nurses to discuss health concerns and develop plans for healthier lifestyles . Main outcome measures : Mental and physical health , “ stage of change ” for health related behaviour , and use of health services . Results : At baseline 970 teenagers completed question naires ; 23 % smoked , 35 % had been drunk in the previous three months , 64 % considered they ate unhealthily , 39 % took little exercise , and 36 % had possible depression . 41 % ( 304 ) of teenagers invited attended for a consultation ; over one third ( 112 ) were offered follow up care . More intervention group teenagers reported positive movement in stage of change for diet and exercise and in at least one of four behaviours ( diet , exercise , smoking , drinking alcohol ) at 3 months ( 41 % v 31 % , P<0.01 ) , but this did not persist at 12 months . There was marginally more positive change in actual behaviour by intervention teenagers at 3 months ( 16 % v 12 % , P=0.06 ) . Recognition of possible depression result ed in improved mental health outcomes at 3 and 12 months . 97 % of attenders said they would recommend the intervention to a friend . Conclusions : Change in behaviour was slight but encouraging , and the intervention was well received and relatively cheap Interventions to promote physical activity are important in preventing children from becoming overweight . Many projects have been developed but only a few showed ( moderate ) effects . JUMP-in is a systematic ally developed primary -school-based intervention that focuses on the use of theory , environmental changes , parental influences and cooperation with multi-level parties in intervention development . The effects of JUMP-in were evaluated with a quasi-experimental pre-test/post-test research design . In total , 510 children from Grade s 4 , 5 and 6 of four intervention schools and two control schools in Amsterdam were followed for an intervention period of one school year . Changes in physical activity as well as in the social cognitive determinants were assessed using self-reports . In addition , a process evaluation has been executed . The results show that JUMP-in was effective in influencing physical activity , especially among children from Grade 6 . Children in the control group decreased their level of physical activity considerably , while activity levels in intervention children from Grade 6 remained stable . The intervention effects could not be explained by changes in the measured social cognitive determinants . In contrast , process information illuminated differences in intervention effects between the participating schools . The results from the JUMP-in study show the importance of intervention design s that focus on a theory-based mix of relevant environmental and social cognitive factors Physical activity levels in young adults are low . Research supports the use of the Transtheoretical Model of behaviour change ( TM ) in design ing physical activity interventions . This study used a pre-post r and omized control design to investigate the effectiveness of a self-instructional intervention for helping sedentary young adults to initiate physical activity . Post-intervention , significantly more of the experimental group ( 80 % ) , in comparison to the control group ( 68 % ) , improved their exercise stage of change ( SOC ) from baseline ( P < 0.05 ) . Discriminant analyses revealed that discrimination between stage improvement/non-improvement was possible using the processes of change data . Stage improvers scored significantly higher on all of the behavioral and four out of five of the cognitive processes of change . For stage improvers , the processes of self-re-evaluation and self-liberation were most frequently used , whilst social liberation was used significantly more by the experimental than the control group . This inexpensive , self-instructional intervention , based on the TM and the ' active living message ' , is an effective method of assisting sedentary young adults to progress through the exercise SOC Low levels of physical activity coupled with high levels of television viewing have been linked with obesity in children . The objective of this study was to assess the efficacy of ' Switch Off-Get Active ' , a 16-week controlled health education intervention , in increasing physical activity and reducing screen time and BMI in primary school children . A secondary objective was to compare children with high and low screen time . Participants were 312 children aged 10.2+/-0.7 years , attending nine schools in areas of social disadvantage . The 10-lesson , teacher-led intervention , conducted in spring 2003 , emphasised self-monitoring , budgeting of time and selective viewing . Differences , adjusted for baseline values by ANCOVA , existed between intervention and control children at follow-up for self-reported physical activity ( intervention + 0.84 30 min blocks/day , 95%CI 0.11 - 1.57 , p<0.05 ) and self-efficacy for physical activity ( p<0.05 ) but not self-reported screen time ( intervention--0.41 blocks/day , 95%CI--0.93 - 0.12 , p=0.13 ) or BMI ( p=0.63 ) . Cross-sectional comparisons at baseline indicated lower physical activity , self-efficacy for physical activity and aerobic fitness and a higher BMI in children with high screen time . In conclusion , health education interventions can increase physical activity in primary school children but follow-ups of longer duration may be needed to demonstrate intervention effects on BMI Background Aim ing at an active lifestyle , healthy food habits and non-smoking among Swedish children , the Swedish Heart Lung Foundation initiated the health educational programme ‘ An adventure with Pelle Pump ' . A study kit , including theoretical and practical material on heart-lung function and healthy behaviour , was offered to all fourth grade rs in Sweden . The impact of the programme was examined by study ing health behaviours and health knowledge among programme participants using non- participants as a control population . Methods A question naire on health behaviour and health knowledge was answered by a r and om sample of 1369 children from different social classes and living conditions . Children subjected to the programme formed the programme group ( n = 523 ) and those without exposure served as a control group ( n = 846 ) . Results Children in the programme group had a significantly higher level of knowledge ( P < 0.001 ) on questions relating to health behaviour and bodily functions . The actual health behaviour was , however , not affected by the programme . Conclusion Children exposed to a health education programme had , compared with a control population , 2 years after completing the programme , an increased level of knowledge ; however , no difference was found in health behaviour PURPOSE To evaluate the effects of a middle school physical activity intervention , new in combining an environmental and computer tailored component ; and to evaluate the effects of parental involvement . METHODS A clustered r and omized controlled design was used . A r and om sample of 15 schools with 7th and 8th grade rs was r and omly assigned to one of three conditions : ( a ) intervention with parental support , ( b ) intervention alone , and ( c ) control group . The intervention was new in combining environmental strategies with computer-tailored feedback to increase levels of moderate to vigorous physical activity . The intervention was implemented by the school staff . Physical activity was measured through a question naire in the total sample and with accelerometers in a sub sample of adolescents . RESULTS The intervention with parental support led to an increase in self-reported school-related physical activity of , on average , 6.4 minutes per day ( p < or = .05 , d = .40 ) . Physical activity of light intensity measured with accelerometers decreased with , on average , 36 minutes per day as a result of the intervention with parental support ( p < or = .05 , d = .54 ) . Physical activity of moderate to vigorous intensity measured with accelerometers significantly increased with on average 4 minutes per day in the intervention group with parental support , while it decreased with almost 7 minutes per day in the control group ( p < or = .05 , d = .46 ) . CONCLUSIONS The physical activity intervention , implemented by the school staff , result ed in enhanced physical activity behaviors in both middle school boys and girls . The combination of environmental approaches with computer-tailored interventions seemed promising OBJECTIVE To evaluate acceptability , feasibility and effectiveness of computer-tailored physical activity education among adolescents . METHODS Two classes of 7th grade rs from 10 r and omly selected schools were assigned to the intervention ( computer-tailored intervention , n=139 ) or control ( no-intervention , n=142 ) condition . Question naires were completed 1 week before and 3 months after the intervention . The computer-tailored intervention was completed during classes . RESULTS Students had few problems with the diagnostic questions and with the use of a computer . About half of the students evaluated the advice as interesting and easy to underst and and about 40 % as personally relevant , easy to use and credible . Half of students evaluated the advice as too long and only 33 % reported to have used the advice . The computer-tailored intervention was effective for increasing school related physical activity levels with on average 25 min per week ( F=3.4 , P < or = .05 ) , but not for increasing total physical activity or leisure time physical activity . CONCLUSIONS A 1-h computer-tailored intervention offered during class-time has the potential to increase school related physical activity . PRACTICE IMPLICATION S Although favourable effects of large scale implementation may be expected , some adaptations that might increase effectiveness should be investigated in the future PURPOSE To investigate the effect of a six-month teacher-led osteogenic physical activity program , vs. a self-led activity program , on ultrasound measurements of bone in inactive teenage girls . METHODS Ninety sedentary girls [ mean ( SD ) age 16.3 ( .6 ) years ] were identified from 300 assessed for physical activity across five schools in southeast Irel and . Schools were matched and r and omly assigned to a teacher-led physical activity ( TLPA ) program , a self-led physical activity ( SLPA ) program , or a control group . Broadb and ultrasound attenuation ( BUA ) , speed of sound ( SOS ) , and os calcis stiffness index ( OCSI ) were measured using a portable ultrasound machine . Anthropometry , aerobic fitness , calcium intake , and physical activity were assessed , and focus groups held one month after program completion . Descriptive statistics , paired t-tests , and analysis of variance were used to analyze the data . RESULTS Both intervention groups demonstrated significant improvements ( p < .05 ) in BUA , SOS , OCSI and aerobic fitness , i.e. , TLPA : + 14.9 % , + 21.9 % , + 15.9 % , and + 8.5 % , respectively , and SLPA : + 10.6 % , + 30.3 % , + 15.6 % , and + 5.1 % , respectively , with no change in controls . Differences between intervention groups and controls were significant for BUA and OCSI ( p < .05 ) . TLPA and SLPA groups engaged in an average of 4.5 and 3.4 hours/week of physical activity , respectively , over the intervention period . The SLPA group continued to exercise after the intervention had ceased , whereas the TLPA group did not . CONCLUSIONS Previously inactive teenage girls can adhere to an osteogenic activity program whether supervised or directing their own activity . Longer-term , sustainable initiatives with this age group are needed and might focus on developing personal skills for physical activity BACKGROUND This study examines whether the adolescents ' current levels of physical activity are increased by their physicians ' advice provided in the office , in accordance with the American Medical Association recommendation . METHODS The first adolescent ( 12 - 21 years old ) of whichever age and gender , passing through six family physicians ' offices during a 6-month period was assigned to the intervention group , and the second adolescent of the same age and gender was assigned to the control group . Each patient was classified as active , partially active , and inactive , according to how they answered the questions about their physical activity levels , and patients in the intervention group were then provided with reinforcement , increase , or initiation counseling , respectively . Identical procedures were repeated at the 6- and 12-month office visits . Changes in prevalence of activity , as well as , duration , frequency , and intensity of exercise and /or sports were verified at each visit . RESULTS Of the 87.5 % of the original sample that completed the survey , 6- and 12-month data were available for 70.1 % . Among the 392 adolescents that finished the study , those provided with counseling had 41.5 % more active adolescents , as well as 26.8 % , 38.0 % and 26.2 % higher duration , frequency and intensity , respectively , than the control group . CONCLUSIONS The proportion of active adolescents , as well as , the duration , frequency and intensity of leisure time exercise and /or sports are increased by physician advice BACKGROUND During recess , children can be active on a daily basis , making it an important school environmental factor for the promotion of health-related physical activity . The aim of the present study was to investigate the effects of providing game equipment on children 's physical activity levels during morning recess and lunch break in elementary schools . METHODS Seven elementary schools were r and omly assigned to the intervention group ( four schools ) , including 122 children ( 75 boys , 47 girls , mean age : 10.8 + /- 0.6 years ) , and to the control group ( three schools ) , including 113 children ( 46 boys , 67 girls , mean age : 10.9 + /- 0.7 years ) . Children 's activity levels were measured before and three months after providing game equipment , using MTI accelerometers . RESULTS During lunch break , children 's moderate and vigorous physical activity significantly increased in the intervention group ( moderate : from 38 to 50 % , vigorous : from 10 to 11 % ) , while it decreased in the control group ( moderate : from 44 to 39 % , vigorous : from 11 to 5 % ) . At morning recess , providing game equipment was effective in increasing children 's moderate physical activity ( from 41 to 45 % ) , while it decreased in the control group ( from 41 to 34 % ) . CONCLUSION Providing game equipment during recess periods was found to be effective in increasing children 's physical activity levels . This finding suggests that promoting physical activity through game equipment provision during recess periods can contribute to reach the daily activity levels recommended for good health The aim of the present study was to evaluate the effects of a middle school physical activity and healthy eating intervention , including an environmental and computer-tailored component , and to investigate the effects of parental involvement . A r and om sample of 15 schools with seventh and eight grade rs was r and omly assigned to one of three conditions : ( i ) intervention with parental involvement , ( ii ) intervention alone and ( iii ) control group . In 10 schools , an intervention , combining environmental changes with computer-tailored feedback , was implemented over 2 school years . In five intervention schools , increased parental support was added . Physical activity was measured with question naires in the total sample and with accelerometers in a sub- sample of children . Fat intake , fruit , water and soft drink consumption were measured using food-frequency question naires . Results showed significant positive intervention effects on physical activity in both genders and on fat intake in girls . Parental involvement did not increase intervention effects . It can be concluded that physical activity and eating behaviours of middle school children can be improved by school-based strategies combining environmental and personal interventions . The use of personalized computer-tailored interventions seems to be a promising tool for targeting adolescents but needs to be further explored

The cognitive domains of attention , executive function , and memory ( visual and verbal ) showed the most consistent improvements . CCT and V RCT were moderately effective in long-term improvement of cognition for those at high risk of cognitive decline . Total intervention time did not mediate efficacy .

The aim of this study was to assess the efficacy of cognitive training , specifically computerized cognitive training ( CCT ) and virtual reality cognitive training ( V RCT ) , programs for individuals living with mild cognitive impairment ( MCI ) or dementia and therefore at high risk of cognitive decline .

OBJECTIVES To investigate the efficacy of a novel brain plasticity-based computerized cognitive training program in older adults and to evaluate the effect on untrained measures of memory and attention and participant-reported outcomes . DESIGN Multisite r and omized controlled double-blind trial with two treatment groups . SETTING Communities in northern and southern California and Minnesota . PARTICIPANTS Community-dwelling adults aged 65 and older ( N=487 ) without a diagnosis of clinical ly significant cognitive impairment . INTERVENTION Participants were r and omized to receive a broadly-available brain plasticity-based computerized cognitive training program ( intervention ) or a novelty- and intensity-matched general cognitive stimulation program modeling treatment as usual ( active control ) . Duration of training was 1 hour per day , 5 days per week , for 8 weeks , for a total of 40 hours . MEASUREMENTS The primary outcome was a composite score calculated from six subtests of the Repeatable Battery for the Assessment of Neuropsychological Status that use the auditory modality ( RBANS Auditory Memory/Attention ) . Secondary measures were derived from performance on the experimental program , st and ardized neuropsychological assessment s of memory and attention , and participant-reported outcomes . RESULTS RBANS Auditory Memory/Attention improvement was significantly greater ( P=.02 ) in the experimental group ( 3.9 points , 95 % confidence interval (CI)=2.7 - 5.1 ) than in the control group ( 1.8 points , 95 % CI=0.6 - 3.0 ) . Multiple secondary measures of memory and attention showed significantly greater improvements in the experimental group ( word list total score , word list delayed recall , digits backwards , letter-number sequencing ; P<.05 ) , as did the participant-reported outcome measure ( P=.001 ) . No advantage for the experimental group was seen in narrative memory . CONCLUSION The experimental program improved generalized measures of memory and attention more than an active control program OBJECTIVE This study evaluates the efficacy at 12 months of a computer-based cognitive training ( CBCT ) program , adjunctive to traditional cognitive training ( TCT ) , on the basis of pen- and -paper exercises . METHODS Sixty patients with multi-domain mild cognitive impairment and mild Alzheimer 's disease who were already receiving cognitive training , recruited from a day hospital , were assigned into two groups following a simple r and omization procedure ( computerized r and om numbers ) : ( i ) a group that received CBCT during 3 months and TCT ( CBCT + TCT ) , n = 37 , and ( ii ) a group that received only TCT , n = 23 . Patients were assessed at baseline and after 3 and 12 months of treatment by a neuropsychologist blinded to group assignment , with a neuropsychological battery ( primary outcomes ) and measures of decision making , memory complaints , and emotional disturbances . RESULTS With the use of repeated- measures analyses of covariance , the CBCT + TCT group showed less anxiety symptoms ( F = 5.13 , p = 0.03 , d = 1.12 ) and less disadvantageous choices ( F = 4.70 , p = 0.04 , d = 0.89 ) in decision making than the TCT group at 12 months . No significant improvement or worsening was observed in the other measures examined . However , positive effect sizes favoring the CBCT + TCT group were observed in all variables . CONCLUSIONS The addition of a CBCT program was effective in anxiety and decision making but had no significant effects on outcomes in basic cognitive functions in patients who were already receiving cognitive training , possibly due to a ceiling effect . Future studies should compare the efficacy of CBCT with TCT in naïve patients Does the structure of an adult human brain alter in response to environmental dem and s ? Here we use whole-brain magnetic-resonance imaging to visualize learning-induced plasticity in the brains of volunteers who have learned to juggle . We find that these individuals show a transient and selective structural change in brain areas that are associated with the processing and storage of complex visual motion . This discovery of a stimulus-dependent alteration in the brain 's macroscopic structure contradicts the traditionally held view that cortical plasticity is associated with functional rather than anatomical changes BACKGROUND Dementia cases may reach 100 million by 2050 . Interventions are sought to curb or prevent cognitive decline . Exercise yields cognitive benefits , but few older adults exercise . Virtual reality-enhanced exercise or " exergames " may elicit greater participation . PURPOSE To test the following hypotheses : ( 1 ) stationary cycling with virtual reality tours ( " cybercycle " ) will enhance executive function and clinical status more than traditional exercise ; ( 2 ) exercise effort will explain improvement ; and ( 3 ) brain-derived neurotrophic growth factor ( BDNF ) will increase . DESIGN Multi-site cluster r and omized clinical trial ( RCT ) of the impact of 3 months of cybercycling versus traditional exercise , on cognitive function in older adults . Data were collected in 2008 - 2010 ; analyses were conducted in 2010 - 2011 . SETTING / PARTICIPANTS 102 older adults from eight retirement communities enrolled ; 79 were r and omized and 63 completed . INTERVENTIONS A recumbent stationary ergometer was utilized ; virtual reality tours and competitors were enabled on the cybercycle . MAIN OUTCOME MEASURES Executive function ( Color Trails Difference , Stroop C , Digits Backward ) ; clinical status ( mild cognitive impairment ; MCI ) ; exercise effort/fitness ; and plasma BDNF . RESULTS Intent-to-treat analyses , controlling for age , education , and cluster r and omization , revealed a significant group X time interaction for composite executive function ( p=0.002 ) . Cybercycling yielded a medium effect over traditional exercise ( d=0.50 ) . Cybercyclists had a 23 % relative risk reduction in clinical progression to MCI . Exercise effort and fitness were comparable , suggesting another underlying mechanism . A significant group X time interaction for BDNF ( p=0.05 ) indicated enhanced neuroplasticity among cybercyclists . CONCLUSIONS Cybercycling older adults achieved better cognitive function than traditional exercisers , for the same effort , suggesting that simultaneous cognitive and physical exercise has greater potential for preventing cognitive decline . TRIAL REGISTRATION This study is registered at Clinical trials.gov NCT01167400 Objective : To determine the usefulness of an interactive multimedia internet-based system ( IMIS ) for the cognitive stimulation of Alzheimer ’s disease . Methods : This is a 24-week , single-blind , r and omised pilot study conducted on 46 mildly impaired patients suspected of having Alzheimer ’s disease receiving stable treatment with cholinesterase inhibitors ( ChEIs ) . The patients were divided into three groups : ( 1 ) those who received 3 weekly , 20-min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program ( IPP ) ; ( 2 ) those who received only IPP sessions ; and ( 3 ) those who received only ChEI treatment . The primary outcome measure was the Alzheimer ’s Disease Assessment Scale-Cognitive ( ADAS-Cog ) . Secondary outcome measures were : Mini-Mental State Examination ( MMSE ) , Syndrom Kurztest , Boston Naming Test , Verbal Fluency , and the Rivermead Behavioral Memory Test story recall subtest . Results : After 12 weeks , the patients treated with both IMIS and IPP had improved outcome scores on the ADAS-Cog and MMSE , which was maintained through 24 weeks of follow-up . The patients treated with IPP alone had better outcome than those treated with ChEIs alone , but the effects were attenuated after 24 weeks . All patients had improved scores in all of the IMIS individual tasks , attaining higher levels of difficulty in all cases . Conclusion : Although both the IPP and IMIS improved cognition in patients with Alzheimer ’s disease , the IMIS program provided an improvement above and beyond that seen with IPP alone , which lasted for 24 weeks We performed a pilot r and omized , controlled trial of intensive , computer-based cognitive training in 47 subjects with mild cognitive impairment . The intervention group performed exercises specifically design ed to improve auditory processing speed and accuracy for 100 min/d , 5 d/wk for 6 weeks ; the control group performed more passive computer activities ( reading , listening , visuospatial game ) for similar amounts of time . Subjects had a mean age of 74 years and 60 % were men ; 77 % successfully completed training . On our primary outcome , Repeatable Battery for Assessment of Neuropsychological Status total scores improved 0.36 st and ard deviations ( SD ) in the intervention group ( P=0.097 ) compared with 0.03 SD in the control group ( P=0.88 ) for a nonsignificant difference between the groups of 0.33 SD ( P=0.26 ) . On 12 secondary outcome measures , most differences between the groups were not statistically significant . However , we observed a pattern in which effect sizes for verbal learning and memory measures tended to favor the intervention group whereas effect sizes for language and visuospatial function measures tended to favor the control group , which raises the possibility that these training programs may have domain-specific effects . We conclude that intensive , computer-based mental activity is feasible in subjects with mild cognitive impairment and that larger trials are warranted Despite the growing interest in cognitive training programs as a potential non-pharmacological approach to slowing cognitive decline in mild cognitive impairment ( MCI ) , there has been little research on the differential effectiveness of training among subtypes of MCI ( i.e. , amnestic , single non-amnestic , and multi-domain ) . The current study examined the longitudinal effects of cognitive speed of processing training ( SOPT ) among older adults with psychometricallydefined MCI from the Advanced Cognitive Training for Independent and Vital Elderly ( ACTIVE ) trial . Mixed model ANOVAs examined the effectiveness of SOPT in participants with MCI relative to controls and also compared training effectiveness in MCI subgroups to appropriate controls . A mixed effects model compared SOPT training effects longitudinally across five years relative to controls . A second mixed effects model compared the durability of training gains between the MCI subtypes across 5 years . All subtypes of MCI showed immediate improvement post-training relative to controls , with the single non-amnestic subtype showing the most benefit . Additionally , all subtypes showed similar trajectories across five years . There were no significant changes in performance across time , indicating initial training gains were maintained . These results provide support for the effectiveness and potential durability of SOPT among persons with MCI regardless of subtype . Future research should investigate if SOPT transfers to improvements in the everyday functioning of those with MCI A r and omized pilot experiment examined the neural substrates of response to cognitive training in participants with mild cognitive impairment ( MCI ) . Participants performed exercises previously demonstrated to improve verbal memory and an active control group performed other computer activities . An auditory-verbal fMRI task was conducted before and after the two-month training program . Verbal memory scores improved significantly and left hippocampal activation increased significantly in the experimental group ( gains in 5 of 6 participants ) relative to the control group ( reductions in all 6 participants ) . Results suggest that the hippocampus in MCI may retain sufficient neuroplasticity to benefit from cognitive training 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 The extent to which mental and physical exercise may slow cognitive decline in adults with early signs of cognitive impairment is unknown . This article provides the rationale and methodology of the first trial to investigate the isolated and combined effects of cognitive training ( CT ) and progressive resistance training ( PRT ) on general cognitive function and functional independence in older adults with early cognitive impairment : Study of Mental and Regular Training ( SMART ) . Our secondary aim is to quantify the differential adaptations to these interventions in terms of brain morphology and function , cardiovascular and metabolic function , exercise capacity , psychological state and body composition , to identify the potential mechanisms of benefit and broader health status effects . Methods SMART is a double-blind r and omized , double sham-controlled trial . One hundred and thirty-two community-dwelling volunteers will be recruited . Primary inclusion criteria are : at risk for cognitive decline as defined by neuropsychology assessment , low physical activity levels , stable disease , and age over 55 years . The two active interventions are computerized CT and whole body , high intensity PRT . The two sham interventions are educational videos and seated calisthenics . Participants are r and omized into 1 of 4 supervised training groups ( 2 d/wk × 6 mo ) in a fully factorial design . Primary outcomes measured at baseline , 6 , and 18 months are the Alzheimer 's Disease Assessment Scale ( ADAS-Cog ) , neuropsychological test scores , and Bayer Informant Instrumental Activities of Daily Living ( B-IADLs ) . Secondary outcomes are psychological well-being , quality of life , cardiovascular and musculoskeletal function , body composition , insulin resistance , systemic inflammation and anabolic/neurotrophic hormones , and brain morphology and function via Magnetic Resonance Imaging ( MRI ) and Spectroscopy ( fMRS ) . Discussion SMART will provide a novel evaluation of the immediate and long term benefits of CT , PRT , and combined CT and PRT on global cognitive function and brain morphology , as well as potential underlying mechanisms of adaptation in older adults at risk of further cognitive decline . Trial Registration Australia and New Zeal and Clinical Trials Register ( ANZCTR ) : CONTEXT Cognitive function in older adults is related to independent living and need for care . However , few studies have addressed whether improving cognitive functions might have short- or long-term effects on activities related to living independently . OBJECTIVE To evaluate whether 3 cognitive training interventions improve mental abilities and daily functioning in older , independent-living adults . DESIGN R and omized , controlled , single-blind trial with recruitment conducted from March 1998 to October 1999 and 2-year follow-up through December 2001 . SETTING AND PARTICIPANTS Volunteer sample of 2832 persons aged 65 to 94 years recruited from senior housing , community centers , and hospital/clinics in 6 metropolitan areas in the United States . INTERVENTIONS Participants were r and omly assigned to 1 of 4 groups : 10-session group training for memory ( verbal episodic memory ; n = 711 ) , or reasoning ( ability to solve problems that follow a serial pattern ; n = 705 ) , or speed of processing ( visual search and identification ; n = 712 ) ; or a no-contact control group ( n = 704 ) . For the 3 treatment groups , 4-session booster training was offered to a 60 % r and om sample 11 months later . MAIN OUTCOME MEASURES Cognitive function and cognitively dem and ing everyday functioning . RESULTS Thirty participants were incorrectly r and omized and were excluded from the analysis . Each intervention improved the targeted cognitive ability compared with baseline , durable to 2 years ( P<.001 for all ) . Eighty-seven percent of speed- , 74 % of reasoning- , and 26 % of memory-trained participants demonstrated reliable cognitive improvement immediately after the intervention period . Booster training enhanced training gains in speed ( P<.001 ) and reasoning ( P<.001 ) interventions ( speed booster , 92 % ; no booster , 68 % ; reasoning booster , 72 % ; no booster , 49 % ) , which were maintained at 2-year follow-up ( P<.001 for both ) . No training effects on everyday functioning were detected at 2 years . CONCLUSIONS Results support the effectiveness and durability of the cognitive training interventions in improving targeted cognitive abilities . Training effects were of a magnitude equivalent to the amount of decline expected in elderly persons without dementia over 7- to 14-year intervals . Because of minimal functional decline across all groups , longer follow-up is likely required to observe training effects on everyday function OBJECTIVES The Advanced Cognitive Training for Independent and Vital Elderly ( ACTIVE ) study used three cognitive interventions ( memory , reasoning , or speed of processing ) in order to improve cognitive abilities . In this article , we evaluate ACTIVE 's ability to avoid extensive decline in health-related quality of life ( HRQoL ) . METHODS ACTIVE enrolled 2,802 adults aged 65 or older and r and omized them into one of three cognitive interventions or a no-contact control group . Research ers obtained data on 2,147 participants at the 24-month follow-up . We measured HRQoL by using the eight Short Form-36 scales , and we defined clinical ly relevant decline on each as a drop of 0.5 st and ard deviations from baseline . We defined extensive HRQoL decline as clinical ly relevant drops on four or more Short Form-36 scales , and we assessed this by using multiple logistic regression methods that adjusted for sociodemographic , cognitive , and health status covariates , and incorporated propensity score derived weights in order to adjust for potential attrition bias . RESULTS We found that 25.0 % of ACTIVE participants had extensive HRQoL decline . Participants in the speed-of-processing intervention arm were less likely to have extensive HRQoL decline ( adjusted odds ratio = 0.643 ; p = .004 ) compared with controls , and participants in the memory and reasoning arms were equivalent to controls ( adjusted odds ratios = 1.149 and 1.014 , respectively ; ps = .322 and .919 , respectively ) . DISCUSSION Although all three intervention arms improved cognitive ability , only the speed-of-processing arm protected against extensive clinical ly relevant decline in Normal aging is associated with progressive functional losses in perception , cognition , and memory . Although the root causes of age-related cognitive decline are incompletely understood , psychophysical and neuropsychological evidence suggests that a significant contribution stems from poorer signal-to-noise conditions and down-regulated neuromodulatory system function in older brains . Because the brain retains a lifelong capacity for plasticity and adaptive reorganization , dimensions of negative reorganization should be at least partially reversible through the use of an appropriately design ed training program . We report here results from such a training program targeting age-related cognitive decline . Data from a r and omized , controlled trial using st and ardized measures of neuropsychological function as outcomes are presented . Significant improvements in assessment s directly related to the training tasks and significant generalization of improvements to nonrelated st and ardized neuropsychological measures of memory ( effect size of 0.25 ) were documented in the group using the training program . Memory enhancement appeared to be sustained after a 3-month no-contact follow-up period . Matched active control and no-contact control groups showed no significant change in memory function after training or at the 3-month follow-up . This study demonstrates that intensive , plasticity-engaging training can result in an enhancement of cognitive function in normal mature adults Dementia is a highly invalidating condition and , given the progressive aging of the population , one of the major issues that health systems will have to face in future years . Recently there has been an increase in the potential of diagnostic tools and pharmacological treatments for dementia ; moreover , considerable interest has been expressed regarding non pharmacological interventions . However , the current evidence in support of non pharmacological treatments in patients affected by dementia still does not allow to draw definitive conclusions on what is the most effective treatment to apply , largely because of method ological difficulties and limitations of the studies so far carried out due to the complex nature of the disease . To address this need , we carried out a single blind r and omized controlled study on the efficacy of computer cognitive rehabilitation in patients with mild cognitive decline . We here present preliminary data on 11 patients with diagnosis of Alzheimer 's Disease ( AD ) and mild cognitive decline r and omly assigned to treatment ( a ) or control ( b ) condition ( i.e. specific vs. aspecific treatment ) . The specific treatment ( a ) consisted in a cycle of 12 individual sessions of computer exercises , while the control condition ( b ) consisted in sessions of semi-structured interviews with patients , conducted with the same frequency and time period as ( a ) . Cognitive , behavioural and functional assessment was performed by an expert evaluator , blinded to the patients ' group allocation . Preliminary results show a significant performance decline only in the control group at the 9-month follow-up compared to both baseline and the 3-month follow-up . Our results suggest that computer based cognitive training in patients with AD and mild cognitive decline is effective at least in delaying the continuous progression of cognitive impairment in AD The Advanced Cognitive Training for Independent and Vital Elderly ( ACTIVE ) trial is a r and omized , controlled , single-masked trial design ed to determine whether cognitive training interventions ( memory , reasoning , and speed of information processing ) , which have previously been found to be successful at improving mental abilities under laboratory or small-scale field conditions , can affect cognitively based measures of daily functioning . Enrollment began during 1998 ; 2-year follow-up will be completed by January 2002 . Primary outcomes focus on measures of cognitively dem and ing everyday functioning , including financial management , food preparation , medication use , and driving . Secondary outcomes include health-related quality of life , mobility , and health-service utilization . Trial participants ( n = 2832 ) are aged 65 and over , and at entry into the trial , did not have significant cognitive , physical , or functional decline . Because of its size and the carefully developed rigor , ACTIVE may serve as a guide for future behavioral medicine trials of this nature The study aims to assess the efficacy of the Big Brain Academy ( BBA ) , a computerized cognitive training program ( CT ) based on video games , compared to the Integrated Psychostimulation Program ( IPP ) , a classical CT tool for patients with Alzheimer 's disease ( AD ) . A total of 45 patients with AD at the mild stage were r and omly assigned to three experimental conditions . Two treatment groups were established , in which patients received either a stimulation program with BBA ( EABB ) or a traditional stimulation program ( EAPI ) , based on paper- and -pencil tasks , for twelve weeks . A third group , the control group ( EANT ) , did not receive any treatment during this period . The differential effectiveness of the programs was evaluated through pre-post design , considering neuropsychological , behavioral , and functional st and ard measures as outcome variables . The EABB group showed significantly slower rates of cognitive decline compared to the EAPI and EANT groups . Furthermore , the EABB group reported significantly greater decrease in depressive symptoms in comparison with the EAPI and EANT groups . The BBA program was more effective than IPP to reduce cognitive decline and depressive symptoms in patients with AD This study evaluated the efficacy of a cognitive intervention for attentional control in older adults with mild cognitive impairment ( MCI ) with an executive deficit . It also sought to verify if the benefits of training generalised to primary and secondary outcome measures . Participants ( n = 24 ) were r and omly assigned to a training programme or active control condition . The experimental group completed a computer-based training programme involving Variable Priority ( VP ) coordination of both components of a dual task , to which was added a self-regulatory strategy design ed to augment meta-cognition . The active control group performed Fixed Priority ( FP ) training : rote practice of the same dual task involving a visual detection task combined with an alpha-arithmetic task . Six one-hour training sessions were held three times a week for two weeks . Participants were tested pre- and post-training to detect improvement and transfer effects . Both groups improved on the visual detection and alpha-arithmetic tasks completed in focused attention , but only participants receiving VP training significantly improved their dual-task cost in accuracy for the visual detection task . As for transfer effects , both FP and VP training produced improvements on select outcome measures : focused attention , speed of processing , and switching abilities . No reliable advantage for generalisability of VP over FP training was found . Overall , these findings indicate that cognitive intervention may improve attentional control in persons with MCI and an executive deficit Accurate clinical staging of dementia in older subjects has not previously been achieved despite the use of such methods as psychometric testing , behavioural rating , and various combinations of simpler psychometric and behavioural evaluations . The Clinical Dementia Rating ( CRD ) , a global rating device , was developed for a prospect i ve study of mild senile dementia -- Alzheimer type ( SDAT ) . Reliability , validity , and correlational data are discussed . The CRD was found to distinguish unambiguously among older subjects with a wide range of cognitive function , from healthy to severely impaired Background . Memory decline is a prevalent aspect of aging but may also be the first sign of cognitive pathology . Virtual reality ( VR ) using immersion and interaction may provide new approaches to the treatment of memory deficits in elderly individuals . Objective . The authors implemented a VR training intervention to try to lessen cognitive decline and improve memory functions . Methods . The authors r and omly assigned 36 elderly residents of a rest care facility ( median age 80 years ) who were impaired on the Verbal Story Recall Test either to the experimental group ( EG ) or the control group ( CG ) . The EG underwent 6 months of VR memory training ( VRMT ) that involved auditory stimulation and VR experiences in path finding . The initial training phase lasted 3 months ( 3 auditory and 3 VR sessions every 2 weeks ) , and there was a booster training phase during the following 3 months ( 1 auditory and 1 VR session per week ) . The CG underwent equivalent face-to-face training sessions using music therapy . Both groups participated in social and creative and assisted-mobility activities . Neuropsychological and functional evaluations were performed at baseline , after the initial training phase , and after the booster training phase . Results .The EG showed significant improvements in memory tests , especially in long-term recall with an effect size of 0.7 and in several other aspects of cognition . In contrast , the CG showed progressive decline . Conclusions . The authors suggest that VRMT may improve memory function in elderly adults by enhancing focused attention OBJECTIVES To examine the effects of cognitive stimulation ( mahjong ) and physical exercise ( tai chi [ TC ] ) on cognitive performance in persons with dementia . DESIGN Cluster-r and omized open-label controlled design . SETTING Nursing homes . PARTICIPANTS One hundred ten residents , most of whom were cholinesterase-inhibitor naive . Inclusion criteria were Mini-Mental State Examination ( MMSE ) = 10 - 24 and suffering from at least very mild dementia ( Clinical Dementia Rating ≥ 0.5 ) . Exclusion criteria were being bedbound , audio/visual impairment , regular activity participation before study , or contraindications for physical or group activities . INTERVENTIONS Homes were r and omized into three conditions ( mahjong , TC , and simple h and icrafts [ control ] ) . Activities were conducted three times weekly for 12 weeks . MEASUREMENTS Primary outcome was MMSE . Secondary outcomes were immediate/delayed recall , categorical fluency , and digit span . Various biological risk factors , including apolipoprotein E ε4 allele , were included as covariates . Measures were collected at 0 ( baseline ) , 3 ( posttreatment ) , 6 , and 9 months . RESULTS Intent-to-treat analyses were performed using mixed-effects regression . Mahjong 's effect varied by time for MMSE , delayed recall , and forward digit span . TC had similar effects but not for delayed recall . The typical pattern was that control participants deteriorated while mahjong and TC participants maintained their abilities over time , leading to enlarged treatment effects as time progressed . By 9 months , mahjong and TC differed from control by 4.5 points ( 95 % confidence interval : 2.0 - 6.9 ; d = 0.48 ) and 3.7 points ( 95 % confidence interval : 1.4 - 6.0 ; d = 0.40 ) , respectively , on MMSE . No treatment effects were observed for immediate recall and backward digit span . CONCLUSIONS Mahjong and TC can preserve functioning or delay decline in certain cognitive domains , even in those with significant cognitive impairment

The main findings of the review were that acute aerobic exercise improves positive well-being and have the potential to reduce psychological distress and could help reduce the risks of future CVD . However , due to the limited number of studies , it is still unclear which form of exercise yields superior psychological benefits .

Introduction : Psychological distress and depression are risk factors for cardiovascular disease ( CVD ) . As such , a reduction in psychological distress and increase in positive well-being may be important to reduce the risk for future development of CVD . Exercise training may be a good strategy to prevent and assist in the management of psychological disorders . The psychological effects of the initial exercise sessions may be important to increase exercise adherence . The aims of this systematic review were ( a ) to examine whether acute aerobic , resistance , or a combination of the 2 exercises improves psychological well-being and reduces psychological distress in individuals with healthy weight and those who are overweight/obese but free from psychological disorders , and ( b ) if so , to examine which form of exercise might yield superior results .

BACKGROUND Although exercise has been shown to relieve depression , little is known about its mechanism or dose-response characteristics . We hypothesized that high intensity progressive resistance training ( PRT ) would be more effective than either low intensity PRT or st and ard care by a general practitioner ( GP ) in depressed elderly persons , and that high intensity PRT would provide superior benefits in quality of life , sleep quality , and self-efficacy . METHODS Sixty community-dwelling adults > 60 years with major or minor depression were r and omized to supervised high intensity PRT ( 80 % maximum load ) or low intensity PRT ( 20 % maximum load ) 3 days per week for 8 weeks , or GP care . RESULTS A 50 % reduction in the Hamilton Rating Scale of Depression score was achieved in 61 % of the high intensity , 29 % of the low intensity , and 21 % of the GP care group ( p = .03 ) . Strength gain was directly associated with reduction in depressive symptoms ( r = 0.40 , p = .004 ) , as was baseline social support network type ( F = 3.52 , p = .015 ) , whereas personality type , self-efficacy , and locus of control were unrelated to the antidepressant effect . Vitality quality -of-life scale improved more in the high intensity group than in the others ( p = .04 ) . Sleep quality improved significantly in all participants ( p < .0001 ) , with the greatest relative change in high intensity PRT ( p = .05 ) . CONCLUSIONS High intensity PRT is more effective than is low intensity PRT or GP care for the treatment of older depressed patients BACKGROUND Previous observational and interventional studies have suggested that regular physical exercise may be associated with reduced symptoms of depression . However , the extent to which exercise training may reduce depressive symptoms in older patients with major depressive disorder ( MDD ) has not been systematic ally evaluated . OBJECTIVE To assess the effectiveness of an aerobic exercise program compared with st and ard medication ( ie , antidepressants ) for treatment of MDD in older patients , we conducted a 16-week r and omized controlled trial . METHODS One hundred fifty-six men and women with MDD ( age , > or = 50 years ) were assigned r and omly to a program of aerobic exercise , antidepressants ( sertraline hydrochloride ) , or combined exercise and medication . Subjects underwent comprehensive evaluations of depression , including the presence and severity of MDD using Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria and Hamilton Rating Scale for Depression ( HAM-D ) and Beck Depression Inventory ( BDI ) scores before and after treatment . Secondary outcome measures included aerobic capacity , life satisfaction , self-esteem , anxiety , and dysfunctional cognitions . RESULTS After 16 weeks of treatment , the groups did not differ statistically on HAM-D or BDI scores ( P = .67 ) ; adjustment for baseline levels of depression yielded an essentially identical result . Growth curve models revealed that all groups exhibited statistically and clinical ly significant reductions on HAM-D and BDI scores . However , patients receiving medication alone exhibited the fastest initial response ; among patients receiving combination therapy , those with less severe depressive symptoms initially showed a more rapid response than those with initially more severe depressive symptoms . CONCLUSIONS An exercise training program may be considered an alternative to antidepressants for treatment of depression in older persons . Although antidepressants may facilitate a more rapid initial therapeutic response than exercise , after 16 weeks of treatment exercise was equally effective in reducing depression among patients with MDD Purpose . Worsening of schizophrenia symptoms is related to stress and anxiety . People with schizophrenia often experience difficulties in coping with stress and possess a limited repertoire of coping strategies . A r and omised comparative trial was undertaken in patients with schizophrenia to evaluate changes in state anxiety , psychological stress and subjective well-being after single sessions of yoga and aerobic exercise compared with a control condition . Method . Forty participants performed a single 30-min yoga session , 20-min of aerobic exercise on a bicycle ergometre at self-selected intensity and a 20-min no exercise control condition in r and om order . Results . After single sessions of yoga and aerobic exercise individuals with schizophrenia or schizoaffective disorder showed significantly decreased state anxiety ( p < 0.0001 ) , decreased psychological stress ( p < 0.0001 ) and increased subjective well-being ( p < 0.0001 ) compared to a no exercise control condition . Effect sizes ranged from 0.82 for psychological stress after aerobic exercise to 1.01 for state anxiety after yoga . The magnitude of the changes did not differ significantly between yoga and aerobic exercise . Conclusion . People with schizophrenia and physiotherapists can choose either yoga or aerobic exercise in reducing acute stress and anxiety taking into account the personal preference of each individual The purpose of the present study was to examine the effects of exercise intensity on feeling states following two acute bouts of exercise ( i.e. , 50 % and 80 % of age-predicted maximal heart rate reserve : HRR ) in highly fit and unfit females . It was hypothesized that highly fit females would have increased positive well-being and /or reduced psychological distress post-exercise ( high intensity ) compared to unfit females while both groups would experience similar feeling states following moderate intensity exercise . Twelve highly fit and 12 unfit females completed 3 conditions : attention control and fitness test , and two acute bouts of exercise ( 30 minutes on a bicycle ergometer ) at 50 % and 80 % age-predicted HRR . Pre- and post-exercise feeling states were measured via the Subjective Experiences Exercise Scale ( McAuley & Courneya , 1994 ) . Analyses indicated a time x condition x fitness interaction F(2,21)=6.07 , p<.01 ( eta2 = .37 ) for psychological distress . Follow-up univariate analyses revealed no change in the 50 % or control conditions , however , psychological distress significantly increased for the unfit participants F(1,11)=4.68,p<.05 ( eta2 = .29 ) while there was no change for the highly fit participants F(1,11)=2.14,p>.05 ( eta2 = .16 ) in the 80 % intensity condition . No fitness differences emerged with respect to positive well-being or fatigue . Therefore , the present study 's results substantiate the need to consider fitness level in dose-response studies , particularly ones which examine negative feeling states PURPOSE This study was design ed to determine if a single bout of moderate-intensity aerobic exercise would improve mood and well-being in 40 ( 15 male , 25 female ) individuals who were receiving treatment for major depressive disorder ( MDD ) . METHODS All participants were r and omly assigned to exercise at 60 - 70 % of age-predicted maximal heart rate for 30 min or to a 30-min period of quiet rest . Participants completed both the Profile of Mood States ( POMS ) and Subjective Exercise Experiences Scale ( SEES ) as indicators of mood 5 min before , and 5 , 30 , and 60 min following their experimental condition . RESULTS Both groups reported similar reductions in measures of psychological distress , depression , confusion , fatigue , tension , and anger . Only the exercise group , however , reported a significant increase in positive well-being and vigor scores . CONCLUSION Although 30 min of either moderate-intensity treadmill exercise or quiet rest is sufficient to improve the mood and well-being of patients with MDD , exercise appears to have a greater effect on the positively valenced states measured This study investigated the hypothesis that the effects of acute aerobic exercise on feeling states may be influenced by the objective dose of activity , subjective responses during exercise , and preexisting levels of feeling states . College-age women ( N = 80 ) completed baseline measures and were then r and omly assigned to 1 of 4 conditions : attention control for 10 min , or exercise for 10 min , 25 min , or 40 min . Levels of exertion and affect were assessed during exercise , and posttesting occurred 20 min following activity . Exercise enhanced revitalization in comparison with the control condition ; however , this effect occurred only for participants scoring low to moderate on the pretest . In addition , in-task feeling states predicted postexercise revitalization even after we controlled for the treatment , the pretest , and the Pretest x Treatment interaction Objective The purpose of this study was to assess the status of 156 adult volunteers with major depressive disorder ( MDD ) 6 months after completion of a study in which they were r and omly assigned to a 4-month course of aerobic e-ercise , sertraline therapy , or a combination of e-ercise and sertraline . Methods The presence and severity of depression were assessed by clinical interview using the Diagnostic Interview Schedule and the Hamilton Rating Scale for Depression ( HRSD ) and by self-report using the Beck Depression Inventory . Assessment s were performed at baseline , after 4 months of treatment , and 6 months after treatment was concluded ( ie , after 10 months ) . Results After 4 months patients in all three groups e-hibited significant improvement ; the proportion of remitted participants ( ie , those who no longer met diagnostic criteria for MDD and had an HRSD score < 8) was comparable across the three treatment conditions . After 10 months , however , remitted subjects in the e-ercise group had significantly lower relapse rates ( p = .01 ) than subjects in the medication group . Exercising on one ’s own during the follow-up period was associated with a reduced probability of depression diagnosis at the end of that period ( odds ratio = 0.49 , p = .0009 ) . Conclusions Among individuals with MDD , e-ercise therapy is feasible and is associated with significant therapeutic benefit , especially if e-ercise is continued over time This study investigated : ( a ) whether moderate intensity aerobic exercise exerted a significant affective influence during , and postexercise , ( b ) the nature of the affective response to exercise in relation to positive and negative affects , and affects associated with physiological distress , and ( c ) whether exercise induced affect was significantly influenced by exercise behaviour . Habitual exercisers ( n = 15 ) and sedentary participants ( n = 13 ) undertook three r and omly allocated interventions ; ( a ) exercise ( EX ; i.e. , 20 min of cycling at 60 % estimated VO2max ) , ( b ) normal workstation duties for 60 min ( WRK ) , and ( c ) a 60 min sedentary lunch break ( SED ) . Affect was measured pre , post , and 90 min postintervention , as well as every 5 min during exercise , using the Subjective Exercise Experiences Scale ( SEES ; McAuley & Courneya , 1994 ) . Exercise behaviour had no significant affect on affective responses to exercise in this study ( p > .05 ) . Significant ( p < .05 ) postintervention increases in positive affect were found for EX compared to WRK and SED indicating that exercise did produce a positive affective influence . Despite enduring postexercise ( i.e. , 90 min ) improvements in both positive and negative affects , and affects related to fatigue , the affective response during exercise was characterised by significant ( p < .05 ) decreases in levels of positive affect and increased levels of affects related to fatigue BACKGROUND Depression in elderly people may be contributed to by the multiple losses of aging . Exercise has the potential to positively impact many of these losses simultaneously . We tested the hypothesis that progressive resistance training ( PRT ) would reduce depression while improving physiologic capacity , quality of life , morale , function and self-efficacy without adverse events in an older , significantly depressed population . METHODS We conducted a 10-week r and omized controlled trial of volunteers aged 60 and above with major or minor depression or dysthymia . Subjects were r and omized for 10 weeks to either a supervised PRT program three times a week or an attention-control group . RESULTS A total of 32 subjects aged 60 - 84 , mean age 71.3 + /- 1.2 yr , were r and omized and completed the study . No significant adverse events occurred . Median compliance was 95 % . PRT significantly reduced all depression measures ( Beck Depression Inventory in exercisers 21.3 + /- 1.8 to 9.8 + /- 2.4 versus controls 18.4 + /- 1.7 to 13.8 + /- 2 , p = .002 ; Hamilton Rating Scale of Depression in exercisers 12.3 + /- 0.9 to 5.3 + /- 1.3 versus controls 11.4 + /- 1.0 to 8.9 + /- 1.3 , p = .008 ) . Quality of life subscales of bodily pain ( p = .001 ) , vitality ( p = .002 ) , social functioning ( p = .008 ) , and role emotional ( p = .02 ) were all significantly improved by exercise compared to controls . Strength increased a mean of 33 % + /- 4 % in exercisers and decreased 2 % + /- 2 % in controls ( p < .0001 ) . In a multiple stepwise regression model , intensity of training was a significant independent predictor of decrease in depression scores ( r2 = .617 , p = .0002 ) . CONCLUSIONS PRT is an effective antidepressant in depressed elders , while also improving strength , morale , and quality of life This laboratory experiment used r and om digit dialing procedures to recruit a community sample of physically inactive participants into a study that was design ed to examine the impact of different intensities of acute aerobic exercise on feeling states . Sedentary men ( n 5 36 ) and women ( n 5 36 ) were r and omly assigned to experience a single bout of aerobic exercise at one of three intensities ( 30 % , 50 % , 70 % of HRR ) . Each participant attended two counterbalanced laboratory sessions , one involving an attention-control manipulation and the other involving aerobic exercise . Before and after each session , they completed a feeling state question naire . Data suggested that there were neither widespread mood-enhancing effects of acute exercise nor evidence for a strong dose-response relationship Recent physical activity recommendations call for activities that are of moderate intensity and can be performed intermittently during the day , such as walking . These proclamations were based partly on the assumption that moderate activities are generally more enjoyable than physically dem and ing ones , and they are , therefore , also more likely to be continued over the long haul . However , little is actually known about the affective outcomes of short bouts of walking and extant findings are equivocal . Four experimental studies examined the affective responses associated with short ( 10- to 15-min ) bouts of walking using a dimensional conceptual model of affect , namely , the circumplex . Results consistently showed that walking was associated with shifts toward increased activation and more positive affective valence . Recovery from walking for 10–15 min was associated with a return toward calmness and relaxation . This pattern was robust across different self-report measures of the circumplex affective dimensions , across ecological setting s ( field and laboratory ) , across time , and across sample In recent years , there has been a growing recognition of the role ofexercise in maintaining and promoting mental health , psychological well being , and health-related quality of life . A main focus for research ers has been to study the effects of acute bouts of exercise on transient psychological states ( Gauvin & Spence , 1998 ) . This is particularly important , as feeling states that occur during and following acute exercise are likely predictors of whether individuals are willing to adopt and maintain physically active lifestyles ( Rejeski , 1992 ) . There is evidence to suggest that acute exercise is associated with reduced anxiety ( Petruzzello , L and ers , Hatfield , Kubitz , & Salazar , 1991 ) , decreased mild depression ( North , McCullagh , & Tran , 1990 ) , and increased positive affect ( Gauvin , Rejeski , & Norris , 1996 ; McAuley & Courneya , 1994 ; Treasure & Newbery , 1998;Watt & Spinks , 1997 ) . Similarly , people who successfully complete a bout of acute exercise report increases in self-efficacy ( Turner , Rejeski , & Brawley , 1997 ) . Furthermore , changes in affect are likely related to changes in self-efficacy(McAuley , Talbot , & Martinez , 1999 ; Treasure & Newbery , 1998 ) . However , as Gauvin and Brawley ( 1993 ) and Morgan ( 1994 , 1997 ) pointed out , clear conclusions can not be drawn from these studies , as pretest sensitization was never taken into consideration . That is , exposure to a pretest might increase participants ' sensitivity to the experimental treatment , which prevents generalization of the results from the pretested sample to an unpretested population ( Rosenthal & Rosnow , 1991 ) An experiment was conducted to examine the acute emotional and psychophysiological effects of a single bout of aerobic exercise . Forty active and 40 inactive college students were r and omly assigned to an aerobic exercise or a waiting-period control condition . Self-report measures of mood and cardiovascular response measures to challenging cognitive tasks were collected before and after the 20-min exercise/control period to examine any exercise-induced changes . The results indicated that mood was significantly altered by the exercise activity , with reductions in tension and anxiety specifically evident . Exercise was not found to have any effects on cardiovascular reactivity . A test of aerobic fitness confirmed fitness differences between active and inactive participants , but no mood or reactivity effects related to activity status were obtained . These results suggest that both active and inactive individuals experience acute reductions in anxiety following single bouts of exercise , even in the absence of changes in cardiovascular reactivity . Implication s for the continued investigation of the acute effects of exercise are discussed Self-efficacy was experimentally manipulated in an exercise context , and its effect on affective responses was examined . College women ( N = 46 ) were r and omly assigned to a high- or low-efficacy condition , and efficacy expectations were manipulated by means of bogus feedback and graphs depicting contrived normative data . The manipulation successfully influenced affective responses , with participants in the high-efficacy group reporting more positive and less negative affect than did the low-efficacy group . Efficacy was significantly related to feeling-state responses during and after activity but only in the high-efficacy condition . The results suggest that self-efficacy can be manipulated and that these changes are related to the affective experience associated with exercise . Such findings may have important implication s for the roles played by self-efficacy and affect in exercise adherence Objective : Acute aerobic exercise is associated with a reduction in state anxiety and an improvement in subjective well-being . The objective of the present study was to contrast the effects of aerobic exercise at self-selected intensity versus prescribed intensity on state anxiety and subjective well-being ( negative affect , positive well-being and fatigue ) in patients with depressive and /or anxiety disorders . In addition , the potential impact of heart rate feedback was assessed . Methods : Nineteen men and 29 women performed three test conditions on a bicycle ergometer during 20 minutes : two tests at self-selected intensity ; one with and another without heart rate feedback , and a third test at the prescribed intensity of 50 % of the maximal heart rate reserve according to Karvonen . Tests were executed in r and om order . State anxiety and subjective well-being were evaluated using the state anxiety inventory and the subjective exercise experiences scale . Results : After 20 minutes cycling , patients showed significantly decreased state anxiety and negative affect in the three conditions . The magnitude of the reduction did not differ significantly between the three conditions . Only cycling at self-selected intensity enhanced positive well-being . Cycling at 50 % of the maximal heart rate reserve decreased fatigue , whereas cycling at self-selected intensity increased fatigue . Conclusions : The response in state anxiety and negative affect was unaffected by the type of aerobic exercise . Self-selected intensity influenced exercise-induced changes in positive well-being and fatigue in a positive and negative way , respectively Resting electroencephalograph ( EEG ) asymmetry is a biological marker of the propensity to respond affectively to , and a measure of change in affect associated with , acute aerobic exercise . This study examined the EEG-affect-exercise relationship . Twenty participants performed each of three r and omly assigned 30-min conditions : ( a ) a nonexercise control , ( b ) a cycling exercise at 55 % VO2max , and ( c ) a cycling exercise at 70 % VO2max . EEG and affect were assessed pre- and 0 , 5 , 10 , 20 , and 30 min postcondition . No significant results were seen in the control or 55 % conditions . In the 70 % exercise condition , greater relative left frontal activation preexercise predicted increased positive affect and reduced state anxiety postexercise . Participants ( n = 7 ) with extreme relative left frontal activation postexercise reported concomitant decreases in anxiety , whereas participants ( n = 7 ) with extreme relative right frontal activation postexercise reported increases in anxiety . These findings ( a ) replicate prior work , ( b ) suggest a dose-response intensity effect , and ( c ) support the idea that exercise is an emotion-eliciting event . Affective responses seem to be mediated in part by differential resting levels of activation in the anterior brain regions . Ongoing anterior brain activation reflected concurrent postexercise affect A prospect i ve cohort of 74,332 men and women was used to investigate the association of body mass index and height with suicide , anxiety , and depression . Participants in the Nord-Trøndelag Health Study ( Norway , 1984 - 1986 ) ( HUNT 1 ) were aged 20 years or more and followed up until December 31 , 2002 . Anxiety and depression were measured with the Hospital Anxiety and Depression Rating Scale ( HADS ) in 1995 - 1997 . There were 183 suicides . Suicide risk decreased with increasing body mass index at baseline ( 1984 - 1986 ) in men and women . In models controlling for a range of psychological , social , and lifestyle factors , the hazard ratio per st and ard deviation increase in body mass index was 0.82 ( 95 % confidence interval : 0.68 , 0.98 ) . In contrast , in the subset of participants ( n = 44,396 ) with HADS measures , body mass index at baseline ( 1984 - 1986 ) was positively associated with depression . In fully adjusted models , the odds ratio for depression per st and ard deviation increase in body mass index ( HADS-D : > or = 8) was 1.11 ( 95 % confidence interval : 1.07 , 1.15 ) . In fully adjusted models , there was no association of height with the incidence of suicide or depression . Raised body mass index is associated with an increased risk of depression but reduced risk of suicide in men and women . The mechanisms underlying these different associations require clarification OBJECTIVE : To investigate the associations of anxiety and depression symptoms with weight change and incident obesity in men and women . DESIGN : We conducted a prospect i ve cohort study using the Norwegian Nord-Trøndelag Health Study (HUNT).SUBJECTS : The study cohort included 25 180 men and women , 19–55 years of age from the second survey of the HUNT ( 1995–1997 ) . MEASUREMENTS : Anxiety and depression symptoms were measured using the Hospital Anxiety and Depression Scale . Weight change was determined for the study period of an average 11 years . Incident obesity was new-onset obesity classified as having a body mass index of ⩾30.0 kg m2 at follow-up . The associations of anxiety or depression with weight change in kilograms ( kg ) was estimated using linear regression models . Risk ratios ( RRs ) for incident obesity associated with anxiety or depression were estimated using log-binomial regression . RESULTS : In men , any anxiety or depression was associated with an average 0.81 kg ( 95 % confidence interval ( CI ) 0.27–1.34 ) larger weight change after 11 years compared with those without such symptoms ( mean weight change : 5.04 versus 4.24 kg ) . Women with any anxiety or depression had an average 0.98 kg ( 95 % confidence interval ( CI ) 0.49–1.47 ) larger weight change compared with those without such symptoms ( mean weight change : 5.02 versus 4.04 kg ) . Participants with any anxiety or depression had a significantly elevated cumulative incidence of obesity ( men : RR 1.37 , 95 % CI 1.13–1.65 ; women : RR 1.18 , 95 % CI 1.00–1.40 ) . CONCLUSION : We found that symptoms of anxiety and depression were associated with larger weight change and an increased cumulative incidence of obesity in both men and women

On a patient , rather than per implant basis , the meta-analyses showed no statistically significant differences for prosthesis and implant failures , though trends , especially in fully edentulous patients , favoured 2-stage ( submerged ) implants . The 1-stage approach might be preferable in partially edentulous patients since it avoids one surgical intervention and shortens treatment times , while a 2-stage submerged approach could be indicated when an implant has not obtained an optimal primary stability or when barriers are used for guided tissue regeneration , or when it is expected that removable temporary prostheses could transmit excessive forces on the penetrating abutments especially in fully edentulous patients

BACKGROUND Implants may be placed penetrating the oral mucosa ( 1-stage procedure ) or can be completely buried under the oral mucosa ( 2-stage procedure ) during the healing phase of the bone at the implant surface . With a 2-stage procedure the risk of having unwanted loading onto the implants is minimized , but a second minor surgical intervention is needed to connect the healing abutments and more time is needed prior to start the prosthetic phase because of the wound-healing period required in relation to the second surgical intervention . OBJECTIVES To evaluate whether a 1-stage implant placement procedure is as effective as a 2-stage procedure .

PURPOSE The aim of this study was to evaluate the feasibility of using a 2-stage implant system in a single-stage procedure and to study the impact of the microgap between the implant and the abutment . MATERIAL S AND METHODS Sixty edentulous patients ( Cawood class V or VI ) participated in this study . After r and omization , 20 patients received 2 IMZ implants placed in a single-stage procedure , 20 patients received 2 IMZ implants placed in the traditional 2-stage procedure , and 20 patients were treated with 2 ITI implants ( single-stage procedure ) . The implants were placed in the canine area of the m and ible . After 3 months , m and ibular overdentures were fabricated , supported by a bar- and -clip attachment . A st and ardized clinical and radiographic evaluation was performed immediately after prosthesis placement and after 12 and 24 months . RESULTS One IMZ implant of the 1-stage group and 1 IMZ implant of the 2-stage group were lost after 6 and 12 months , respectively . Apart from several significant but clinical ly irrelevant differences , the 3 groups did not appear to differ markedly with regard to clinical parameters during the evaluation period . The mean bone loss within the first 2 years of functioning ( 1.1 mm IMZ 1-stage , 0.8 mm IMZ 2-stage , 1.2 mm ITI ) was comparable for the 3 groups . DISCUSSION AND CONCLUSIONS The results of this study suggest that dental implants design ed for a submerged implantation procedure can also be used in a single-stage procedure and may be as predictable as when the same implants used in a 2-stage procedure or as 1-stage implants . Placement of the microgap at the crestal level in 2-stage implants did not appear to have an adverse effect on the amount of peri-implant bone loss at 2 years in this study population AIM The aim of this study was to compare the clinical outcome of submerged vs. non-submerged tapered implants placed into fresh extraction sockets . MATERIAL S AND METHODS A prospect i ve , controlled , multicenter , r and omized , clinical trial has been performed in two centers in Rome and Torino ( Italy ) . Thirty healthy patients were recruited according to the following inclusion criteria : need for an immediate post extraction implant , ages between 18 and 70 , horizontal defect depth < 2 mm , smokers < 10 cigarettes/day and absence of any circumstance or condition that could represent contraindications to implant surgery . The patients were r and omly allocated to submerged or non-submerged treatment groups immediately after flap elevation and tooth extraction . Submerged implants were exposed 8 weeks after the first surgery ; all implants were loaded with provisional restorations 12 weeks after the first surgery and with definitive restoration 12 weeks thereafter . Clinical and radiographic parameters were evaluated at baseline , at implant loading and at the 1-year follow-up visit . RESULTS The results showed statistically significant differences between the two groups in the mean value of keratinized tissue ( KT ) height after surgery that was significantly reduced for submerged implants when compared with transmucosal implants ( mean reduction of KT at year follow-up : T group 0.2 mm , S group 1.3 mm ; P=0.007 ) . CONCLUSION Similar outcomes were found for submerged and non-submerged implants placed in fresh extraction sockets with a horizontal peri-implant defect smaller than 2 mm , except for a reduction of KT in the submerged group . Either with a submerged or a non-submerged procedure , 1 mm of mean soft tissue recession is seen after 1 year when compared with the pre- extraction situation The osseointegration of endosseous dental implants is well documented . Implants have proven to be a viable treatment option for the replacement of missing teeth . The surgical phase of implant dentistry for most implant systems involves two stages — the placement of the implant and its subsequent uncovering . The IMZ ( Interpore International ) implant system is classically a two-stage system . No significant differences were demonstrated in osseointegration and soft tissue healing for IMZ implants placed in one-stage and two-stage procedures in this pilot study 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 BACKGROUND The use of a submerged implant system in a nonsubmerged surgical procedure has been reported to have promising results . At the time this study was initiated , no prospect i ve , comparative studies with r and omization between submerged and nonsubmerged surgical techniques had been published . PURPOSE To evaluate the submerged and nonsubmerged surgical techniques when treating m and ibular edentulism using a submerged implant system , with regard to implant survival and complications . MATERIAL S AND METHODS A total of 77 patients were included and treated at nine clinics in Sweden and Norway . In total , 404 Brånemark System implants ( st and ard and MkII implants ) were inserted in the edentulous m and ible ; 198 implants according to the nonsubmerged protocol and 206 implants according to the traditional submerged procedure . The follow-up period was up to 36 months after prosthesis insertion . RESULTS In the nonsubmerged group , 17 implants out of 198 implants ( 8.6 % ) were lost and in the submerged group , 5 out of 206 implants ( 2.4 % ) were lost . All implant failures occurred before the delivery of the final prosthesis . No major complications were reported during the implant surgery . However , at the clinical check-up postoperatively and at the abutment connection surgery , 6 patients in the nonsubmerged group complained of pain at the implant sites , whereas there were no complaints of pain in the submerged group . CONCLUSIONS The results of this study suggest that a turned Brånemark implant design ed for a submerged implant placement procedure can be used in a nonsubmerged procedure and may be as predictable as the conventional submerged approach The aim of this prospect i ve study was to compare the clinical integration and survival of Brånemark fixtures when using the conventional 2-stage surgical procedure to 1-stage surgical approach in completely and partially edentulous m and ibles . A total of 85 patients were consecutively treated for partial ( n = 35 ) or complete ( n = 50 ) m and ibular edentulousness . Fixtures removed because of mobility , pain or infection were counted as failures . The first 10 patients of each group were selected for radiographical analysis of crestal bone changes 1 year after prosthesis insertion . In 33 patients with edentulous m and ibles , 170 fixtures were placed in a 1-stage approach . In this group , 4 fixtures ( 2.4 % ) were lost prior to prosthetic restoration . Seventeen edentulous patients received a total of 70 fixtures in a 2-stage procedure . Out of these , 5 fixtures ( 7.1 % ) were lost at abutment connection . In 17 partially edentulous patients , 41 fixtures were inserted in a 1-stage approach . Two fixtures ( 5 % ) were lost in this group . Finally , 18 partially edentulous patients received a total of 49 fixtures in a 2-stage procedure . Out of these , 6 fixtures ( 12 % ) were lost at abutment connection . In total 313 of the 330 installed m and ibular implants were loaded between 6 and 12 months ( 94.8 % success ) . No further losses occurred in the implants functioning at least 1 year ( 267 implants ) or at least 2 years ( 59 implants ) . Statistical analysis ( Chi square test ) revealed no difference in fixture survival between the treatment modalities . Radiographical analysis after 1 year of functional loading showed the typical bone resorption changes up to the most coronal implant thread in both modalities . Although this study pertains to relatively early loading of 2 years , the results seem to indicate that in the m and ible a 1-stage surgical approach with Brånemark fixtures may be as predictable as the conventional 2-stage procedure OBJECTIVE To evaluate bone-level alterations that occurred at implants of the Astra Tech(R ) System that were placed in the load carrying , posterior parts of the dentition using either a submerged ( two-stage ) or a non-submerged ( one-stage ) installation protocol . MATERIAL AND METHODS Eighty-four patients that required 115 fixed partial dentures ( FPDs or cases ) entered the prospect i ve study . All subjects were assigned one patient and > or = one case numbers . For the r and omization of cases , a custom-made program based on balanced r and om permuted blocks was utilized . The cases were assigned to two treatment groups , namely one-stage installation procedure , non-submerged technique ( group A ) and two-stage installation procedure , submerged technique ( group B ) . Several subjects contributed with cases to both groups A and B. Periodontal , endodontal and open caries lesions were treated prior to implant installation . All patients received careful oral hygiene instruction and training in self-performed plaque control measures . The surgical technique used for fixture installation followed the outline described in the manual for the Astra Tech System . The FPDs were placed 3 months ( m and ible ) and 6 months ( maxilla ) following implant installation . Immediately following FPD placement , a baseline examination was performed that included assessment of plaque , soft-tissue inflammation and bone level . Clinicians who were otherwise not involved in the study performed the radiographic measurements . Clinical and radiographical examinations were repeated once a year after the baseline examination . DATA ANALYSIS The primary outcome variable was the change in the bone level at the implants from the time of placement of the bridge ( FPD ) to the 1- and 2-year reexaminations . Fisher 's permutation test was used to test if differences existed between groups A and B , and between patients ( men/women , smokers/non-smokers , age ) , sites ( maxilla/m and ible ) and implants ( length , diameter ) . Pitman 's test was used to study correlations between bone shape and quality data and different radiographic bone-level data . RESULTS It was demonstrated that tissue healing following implant installation appeared to be independent of the surgical protocol , i.e. whether the marginal portions of the implants during surgery were fully or only partly submerged under the ridge mucosa . Thus , ( i ) in both treatment groups the number of implants that failed to osseointegrate ( early failures ) was small ( < 2 % ) ; ( ii ) at the end of the recommended periods of bone healing prior to loading , - in both groups , maxilla=6 months and m and ible=3 months - the level of the marginal bone was close to the coronal rim of the fixture ; group A : 1.54+/-0.92 mm , group B : 1.31+/-0.77 mm . The current study also demonstrated that irrespective of surgical protocol ( two-stage , one-stage ) , implants supporting the FPDs exhibited only small amount of radiographic bone loss during the first year of function ( group A : 0.02+/-038 mm , group B : 0.17+/-0.64 mm ) . Moreover , during the second year of function , the amount of additional bone loss that occurred in the two treatment groups was close to zero . CONCLUSION Periimplant bone-level change during function seemed to be unrelated to whether initial soft- and hard-tissue healing following implant installation had occurred under submerged or non-submerged conditions OBJECTIVE The aim of this study was to evaluate the feasibility of using a two-part implant system in a one-stage procedure and to monitor the microflora in the peri-implant area in relation to clinical and radiographic outcome . MATERIAL AND METHODS After r and omisation , 40 edentulous patients ( Cawood & Howell class V-VI ) received two IMZ implants in the anterior m and ible inserted by either a one-stage ( n = 20 ) or a two-stage ( n = 20 ) surgical procedure for overdenture treatment . A st and ardised clinical and radiographic evaluation was performed after denture insertion as well as 6 and 12 months thereafter . Twelve months after loading , peri-implant sample s were collected and analysed for the presence of putative periodontal pathogens using culture technique . RESULTS No striking differences were found between the two groups with regard to the clinical parameters during the evaluation period . The mean bone loss in the first year of functioning was 0.6 mm in both groups . With regard to the gingiva score , plaque score , bleeding score or bone loss between T0 and T12 , no associations were found with the presence of the cultured microorganisms . An association was present between pockets > or= 4 mm and the presence of Peptostreptococcus micros in the two-stage group . CONCLUSIONS The short-term results indicate that two-part implants inserted in a one-stage procedure may be as predictable as inserted in the common two-stage procedure . The peri-implant sulcus can and does harbour potential periodontal pathogens without significant signs of tissue breakdown BACKGROUND The aim of this study was to evaluate the feasibility of using a two-piece implant system in a non-submerged procedure and to study the impact of the microgap between the implant and abutment . METHODS Sixty edentulous patients ( Cawood Class V-VI ) participated in this study . After r and omization , 20 patients received two two-piece implants placed in a non-submerged procedure , 20 patients received two two-piece implants placed in the traditional submerged procedure , and 20 patients were treated with two one-piece dental implants placed in the traditional non-submerged procedure . The implants were placed in the m and ible for overdenture treatment . A st and ardized clinical evaluation was performed and radiographs were taken immediately after denture insertion and yearly up to 5 years . Peri-implant sample s were collected 12 , 36 , and 60 months after loading with sterile paper points and analyzed for the presence of putative periodontal pathogens using culture techniques . RESULTS One two-piece implant of the non-submerged group and one two-piece implant of the submerged group were lost after 6 and 12 months , respectively . After 5 years of functioning , no significant clinical , radiological , or microbiological differences were found between the three groups . No association was found between the level of the microgap and the amount of bone loss . CONCLUSIONS The results of this study indicate that dental implants design ed for a submerged implantation procedure can also be used in a non-submerged procedure and may be as predictable as when used in a submerged procedure or as one-piece implants . The microgap at the crestal level in two-piece implants does not appear to have an adverse effect on the amount of peri-implant bone loss

Results : We summarize the literature which highlights that a range of effective VR approaches are available . A range of benefits were associated with VR interventions , including improvement in motor functions , greater community participation , and improved psychological and cognitive function . Conclusions : The results from this review provide support for the use of VR as part of a neurorehabilitation program in maximizing recovery

Background : Virtual reality ( VR ) experiences ( through games and virtual environments ) are increasingly being used in physical , cognitive , and psychological interventions . However , the impact of VR as an approach to rehabilitation is not fully understood , and its advantages over traditional rehabilitation techniques are yet to be established . Healthy population s have been used in the development and testing of VR approaches meant to be used in the future by people with neurological disorders .

Stroke patients usually suffer from asymmetric posture due to hemi-paresis that can result in reduced postural controllability leading to a balance deficit . This deficit increases the risk of falls , which often makes them dependent on caregivers for community ambulation , thus deteriorating their quality of life . Conventional balance training involves rehabilitation exercises performed under physiotherapist ’s supervision , where the scarcity of trained professionals as well as the cost of clinic-based rehabilitation programs can deter stroke survivors from undergoing regular balance training . Thus , research ers have been exploring technology-assisted solutions , e.g. , home-based virtual reality ( VR ) setup . In this paper , we developed a VR-based balance training ( VBaT ) platform , where VR-augmented user-interface using Nintendo Wii balance boardwas tested in a laboratory setting for its feasibility . The VBaT offered tasks of varying difficulties to the participants that adapted to individual performance capability during balance training . We performed a preliminaryusability study with 7 stroke survivors ( post-stroke period > 6 months ) . Preliminary results indicate the potential of theVBaT system to cause improvement in overall average task performance over the course of training while using the VBaT. Thus the VBaT system is proposed to be a step toward an effective balance training platform for people with balance disorder Abstract Objective : To contrast changes in clinical and kinematic measures of upper extremity movement in response to virtually simulated and traditionally presented rehabilitation interventions in persons with upper extremity hemiparesis due to chronic stroke . Design : Non-r and omized controlled trial . Setting : Ambulatory research facility . Participants : Subjects were a volunteer sample of twenty one community-dwelling adults ( mean age : 51 ± 12 years ) with residual hemiparesis due to stroke more than 6 months before enrollment ( mean : 74 ± 48 months ) , recruited at support groups . Partial range , against gravity shoulder movement and at least 10 ° of active finger extension were required for inclusion . All subjects completed the study without adverse events . Interventions : A 2 weeks , 24-hour program of robotic/virtually simulated , arm and finger rehabilitation activities was compared to the same dose of traditionally presented arm and finger activities . Results : Subjects in both groups demonstrated statistically significant improvements in the ability to interact with real-world objects as measured by the Wolf Motor Function Test ( P = 0.01 ) . The robotic/virtually simulated activity ( VR ) group but not the traditional , repetitive task practice ( RTP ) group demonstrated significant improvements in peak reaching velocity ( P = 0.03 ) and finger extension excursion ( P = 0.03 ) . Both groups also demonstrated similar improvements in kinematic measures of reaching and grasping performance such as increased shoulder and elbow excursion along with decreased trunk excursion . Conclusions : Kinematic measurements identified differing adaptations to training that clinical measurements did not . These adaptations were targeted in the design of four of the six simulations performed by the simulated activity group . Finer grained measures may be necessary to accurately depict the relative benefits of dose matched motor interventions Abstract Purpose state : The aim of this preliminary study was to test a data glove , CyberTouch ™ , combined with a virtual reality ( VR ) environment , for using in therapeutic training of reaching movements after spinal cord injury ( SCI ) . Method : Nine patients with thoracic SCI were selected to perform a pilot study by comparing two treatments : patients in the intervention group ( IG ) conducted a VR training based on the use of a data glove , CyberTouch ™ for 2 weeks , while patients in the control group ( CG ) only underwent the traditional rehabilitation . Furthermore , two functional parameters were implemented in order to assess patient ’s performance of the sessions : normalized trajectory lengths and repeatability . Results : Although no statistical significance was found , the data glove group seemed to obtain clinical changes in the muscle balance ( MB ) and functional parameters , and in the dexterity , coordination and fine grip tests . Moreover , every patient showed variations in at least one of the functional parameters , either along Y-axis trajectory or Z-axis trajectory . Conclusions : This study might be a step forward for the investigation of new uses of motion capture systems in neurorehabilitation , making it possible to train activities of daily living ( ADLs ) in motivational environments while measuring objective ly the patient ’s functional evolution . Implication s for Rehabilitation Key findings : A motion capture application based on a data glove is presented , for being used as a virtual reality tool for rehabilitation . This application has provided objective data about patient ’s functional performance . What the study has added : ( 1 ) This study allows to open new areas of research based on the use of different motion capture systems as rehabilitation tools , making it possible to train Activities of Daily Living in motivational environments . ( 2 ) Furthermore , this study could be a contribution for the development of clinical protocol s to identify which types of patients will benefit most from the VR treatments , which interfaces are more suitable to be used in neurorehabilitation , and what types of virtual exercises will work best Background Many studies have demonstrated the usefulness of repetitive task practice by using robotic-assisted gait training ( RAGT ) devices , including Lokomat , for the treatment of lower limb paresis . Virtual reality ( VR ) has proved to be a valuable tool to improve neurorehabilitation training . The aim of our pilot r and omized clinical trial was to underst and the neurophysiological basis of motor function recovery induced by the association between RAGT ( by using Lokomat device ) and VR ( an animated avatar in a 2D VR ) by study ing electroencephalographic ( EEG ) oscillations . Methods Twenty-four patients suffering from a first unilateral ischemic stroke in the chronic phase were r and omized into two groups . One group performed 40 sessions of Lokomat with VR ( RAGT + VR ) , whereas the other group underwent Lokomat without VR ( RAGT-VR ) . The outcomes ( clinical , kinematic , and EEG ) were measured before and after the robotic intervention . Results As compared to the RAGT-VR group , all the patients of the RAGT + VR group improved in the Rivermead Mobility Index and Tinetti Performance Oriented Mobility Assessment . Moreover , they showed stronger event-related spectral perturbations in the high-γ and β b and s and larger fronto- central cortical activations in the affected hemisphere . Conclusions The robotic-based rehabilitation combined with VR in patients with chronic hemiparesis induced an improvement in gait and balance . EEG data suggest that the use of VR may entrain several brain areas ( probably encompassing the mirror neuron system ) involved in motor planning and learning , thus leading to an enhanced motor performance . Trial registration Retrospectively registered in Clinical Trials on 21 - 11 - 2016 , n . NCT02971371 Abstract Purpose : To describe the novel BrightArm Duo bimanual upper extremity ( UE ) rehabilitation system ; to determine its technology acceptance and clinical benefit for older hemiplegic participants . Methods : The system table tilted to adjust arm gravity loading . Participants wore arm supports that sensed grasp strength and wrist position on the table . Wrist weights further increased shoulder exertion . Games were design ed to improve UE strength , motor function , cognition and emotive state and adapted automatically to each participant . The system underwent feasibility trials spanning 8 weeks in two skilled nursing facilities ( SNFs ) . Participants were evaluated pre-therapy and post-therapy using st and ardized clinical measures . Computerized measures of supported arm reach , table tilt and number of arm repetitions were stored on a remote server . Outcomes : Seven participants had significant improvements in their active range of shoulder movement , supported arm reach , shoulder strength , grasp strength and their ability to focus . The group demonstrated higher arm function measured with FMA ( p = 0.01 ) and CAHAI ( p = 0.05 ) , and had an improvement in depression ( Becks Depression Inventory , II ) . BrightArm Duo technology was well accepted by participants with a rating of 4.4 out of 5 points . Conclusions : Given these findings , it will be beneficial to evaluate the BrightArm Duo application in SNF maintenance programs . Implication s for Rehabilitation Integrative rehabilitation that addresses both physical and cognitive domains is promising for post-stroke maintenance in skilled nursing facilities . Simultaneous bilateral arm exercise may improve arm function in older hemiplegic patients several years after stroke . Virtual reality games that adapt to the patient can increase attention and working memory while decreasing depression in elderly Background Down syndrome ( DS ) has unique physical , motor and cognitive characteristics . Despite cognitive and motor difficulties , there is a possibility of intervention based on the knowledge of motor learning . However , it is important to study the motor learning process in individuals with DS during a virtual reality task to justify the use of virtual reality to organize intervention programs . The aim of this study was to analyze the motor learning process in individuals with DS during a virtual reality task . Methods A total of 40 individuals participated in this study , 20 of whom had DS ( 24 males and 8 females , mean age of 19 years , ranging between 14 and 30 yrs . ) and 20 typically developing individuals ( TD ) who were matched by age and gender to the individuals with DS . To examine this issue , we used software that uses 3D images and reproduced a coincidence-timing task . Results The results showed that all individuals improved performance in the virtual task , but the individuals with DS that started the task with worse performance showed higher difference from the beginning . Besides that , they were able to retain and transfer the performance with increase of speed of the task . Conclusion Individuals with DS are able to learn movements from virtual tasks , even though the movement time was higher compared to the TD individuals . The results showed that individuals with DS who started with low performance improved coincidence- timing task with virtual objects , but were less accurate than typically developing individuals . Trial registration Clinical Trials.gov Identifier : NCT02719600 Background Dexterous manipulation of the h and , one of the features of human motor control , is often compromised after stroke , to the detriment of basic functions . Despite the importance of independent movement of the digits to activities of daily living , relatively few studies have assessed the impact of specifically targeting individuated movements of the digits on h and rehabilitation . The purpose of this study was to investigate the impact of such finger individuation training , by means of a novel mechatronic-virtual reality system , on fine motor control after stroke . Methods An actuated virtual keypad ( AVK ) system was developed in which the impaired h and controls a virtual h and playing a set of keys . Creation of individuated digit movements is assisted by a pneumatically actuated glove , the PneuGlove . A study examining efficacy of the AVK system was subsequently performed . Participants had chronic , moderate h and impairment result ing from a single stroke incurred at least 6 months prior . Each subject underwent 18 hour-long sessions of extensive therapy ( 3x per week for 6 weeks ) targeted at finger individuation . Subjects were r and omly divided into two groups : the first group ( Keypad : N = 7 ) utilized the AVK system while the other group ( OT : N = 7 ) received a similarly intensive dose of occupational therapy ; both groups worked directly with a licensed occupational therapist . Outcome measures such as the Jebsen-Taylor H and Function Test ( JTHFT ) , Action research Arm Test ( ARAT ) , Fugl-Meyer Upper Extremity Motor Assessment /H and subcomponent ( FMUE/FMH ) , grip and pinch strengths were collected at baseline , post-treatment and one-month post-treatment . Results While both groups exhibited some signs of change after the training sessions , only the Keypad group displayed statistically significant improvement both for measures of impairment ( FMH : p = 0.048 ) and measures of task performance ( JTHFT : p = 0.021 ) . Additionally , the finger individuation index – a measure of finger independence – improved only for the Keypad group after training ( p = 0.05 ) in the subset ( Keypad : N = 4 ; OT : N = 5 ) of these participants for which it was measured . Conclusions Actively assisted individuation therapy comprised of non task-specific modalities , such as can be achieved with virtual platforms like the AVK described here , may prove to be valuable clinical tools for increasing the effectiveness and efficiency of therapy following stroke Immersive virtual reality ( IVR ) offers new possibilities to perform treatments in an ecological and interactive environment with multimodal online feedbacks . Sixteen school-aged children ( mean age 11 ± 2.4 years ) with Bilateral CP — diplegia , attending mainstream schools were recruited for a pilot study in a pre – post treatment experimental design . The intervention was focused on walking competences and endurance and performed by the Gait Real-time Analysis Interactive Lab ( GRAIL ) , an innovative treadmill platform based on IVR . The participants underwent eighteen therapy sessions in 4 weeks . Functional evaluations , instrumental measures including GAIT analysis and parental question naire were utilized to assess the treatment effects . Walking pattern ( stride length left and right side , respectively p = 0.001 and 0.003 ; walking speed p = 0.001 ) , endurance ( 6MWT , p = 0.026 ) , gross motor abilities ( GMFM-88 , p = 0.041 ) and most kinematic and kinetic parameters significantly improved after the intervention . The changes were mainly predicted by age and cognitive abilities . The effect could have been due to the possibility of IVR to foster integration of motor/perceptual competences beyond the training of the walking ability , giving a chance of improvement also to older and already treated children The video game-based therapy emerged as a potential valid tool in improving balance in several neurological conditions with controversial results , whereas little information is available regarding the use of this therapy in subacute stroke patients . The aim of this study was to investigate the efficacy of balance training using video game-based intervention on functional balance and disability in individuals with hemiparesis due to stroke in subacute phase . Fifty adult stroke patients participated to the study : 25 subjects were r and omly assigned to balance training with Wii Fit , and the other 25 subjects were assigned to usual balance therapy . Both groups were also treated with conventional physical therapy ( 40 min 2 times/day ) . The main outcome was functional balance ( Berg Balance Scale-BBS ) , and secondary outcomes were disability ( Barthel Index-BI ) , walking ability ( Functional Ambulation Category ) , and walking speed ( 10-meters walking test ) . Wii Fit training was more effective than usual balance therapy in improving balance ( BBS : 53 versus 48 , P = 0.004 ) and independency in activity of daily living ( BI : 98 versus 93 , P = 0.021 ) . A balance training performed with a Wii Fit as an add on to the conventional therapy was found to be more effective than conventional therapy alone in improving balance and reducing disability in patients with subacute stroke Background Virtual reality ( VR ) has recently been explored as a tool for neurorehabilitation to enable individuals with Parkinson ’s disease ( PD ) to practice challenging skills in a safe environment . Current technological advances have enabled the use of affordable , fully immersive head-mounted displays ( HMDs ) for potential therapeutic applications . However , while previous studies have used HMDs in individuals with PD , these were only used for short bouts of walking . Clinical applications of VR for gait training would likely involve an extended exposure to the virtual environment , which has the potential to cause individuals with PD to experience simulator-related adverse effects due to their age or pathology . Thus , our objective was to evaluate the safety of using an HMD for longer bouts of walking in fully immersive VR for older adults and individuals with PD . Methods Thirty-three participants ( 11 healthy young , 11 healthy older adults , and 11 individuals with PD ) were recruited for this study . Participants walked for 20 min while viewing a virtual city scene through an HMD ( Oculus Rift DK2 ) . Safety was evaluated using the mini-BESTest , measures of center of pressure ( CoP ) excursion , and question naires addressing symptoms of simulator sickness ( SSQ ) and measures of stress and arousal . Results Most participants successfully completed all trials without any discomfort . There were no significant changes for any of our groups in symptoms of simulator sickness or measures of static and dynamic balance after exposure to the virtual environment . Surprisingly , measures of stress decreased in all groups while the PD group also increased the level of arousal after exposure . Conclusions Older adults and individuals with PD were able to successfully use immersive VR during walking without adverse effects . This provides systematic evidence supporting the safety of immersive VR for gait training in these population Previous functional near-infrared spectroscopy ( fNIRS ) studies indicated that the prefrontal cortex ( PFC ) is involved in the maintenance of the postural balance after external perturbations . So far , no studies have been conducted to investigate the PFC hemodynamic response to virtual reality ( VR ) tasks that could be adopted in the field of functional neurorehabilitation . The aim of this fNIRS study was to assess PFC oxygenation response during an incremental and a control swing balance task ( ISBT and CSBT , respectively ) in a semi-immersive VR environment driven by a depth-sensing camera . It was hypothesized that : i ) the PFC would be bilaterally activated in response to the increase of the ISBT difficulty , as this cortical region is involved in the allocation of attentional re sources to maintain postural control ; and ii ) the PFC activation would be greater in the right than in the left hemisphere considering its dominance for visual control of body balance . To verify these hypotheses , 16 healthy male subjects were requested to st and barefoot while watching a 3 dimensional virtual representation of themselves projected onto a screen . They were asked to maintain their equilibrium on a virtual blue swing board susceptible to external destabilizing perturbations ( i.e. , r and omizing the forward-backward direction of the impressed pulse force ) during a 3-min ISBT ( performed at four levels of difficulty ) or during a 3-min CSBT ( performed constantly at the lowest level of difficulty of the ISBT ) . The center of mass ( COM ) , at each frame , was calculated and projected on the floor . When the subjects were unable to maintain the COM over the board , this became red ( error ) . After each error , the time required to bring back the COM on the board was calculated ( returning time ) . An eight-channel continuous wave fNIRS system was employed for measuring oxygenation changes ( oxygenated-hemoglobin , O2Hb ; deoxygenated-hemoglobin , HHb ) related to the PFC activation ( Brodmann Areas 10 , 11 and 46 ) . The results have indicated that the errors increased between the first and the second level of difficulty of the ISBT , then decreased and remained constant ; the returning time progressively increased during the first three levels of difficulty and then remained constant . During the CSBT , the errors and the returning time did not change . In the ISBT , the increase of the first three levels of difficulty was accompanied by a progressive increase in PFC O2Hb and a less consistent decrease in HHb . A tendency to plateau was observable for PFC O2Hb and HHb changes in the fourth level of difficulty of the ISBT , which could be partly explained by a learning effect . A right hemispheric lateralization was not found . A lower amplitude of increase in O2Hb and decrease in HHb was found in the PFC in response to the CSBT with respect to the ISBT . This study has demonstrated that the oxygenation increased over the PFC while performing an ISBT in a semi-immersive VR environment . These data reinforce the involvement of the PFC in attention-dem and ing balance tasks . Considering the adaptability of this virtual balance task to specific neurological disorders , the absence of motion sensing devices , and the motivating/safe semi-immersive VR environment , the ISBT adopted in this study could be considered valuable for diagnostic testing and for assessing the effectiveness of functional neurorehabilitation Abstract Background : The Nintendo ® Wii is a simple and affordable virtual therapy alternative . It may be used at home , and it is a motivating recreational activity that provides continuous feedback . However , studies comparing the use of the Nintendo ® Wii to conventional physical therapy are needed . Objective : To compare the effect of a rehabilitation treatment using the Nintendo ® Wii ( NW ) with conventional physical therapy ( CPT ) to improve the sensorimotor function and quality of life for post-stroke hemiparetic patients . Methods : The present study applied a r and omized , blind , and controlled clinical trial . In total , 30 patients with post-stroke hemiparesis were evaluated . A total of 15 patients were r and omly assigned to each group . The SF-36 quality of life and Fugl – Meyer scales were used to evaluate the patients . Results : After treatment , the only variable that differed between the groups was the physical functioning domain of the SF-36 in the group that received conventional physical therapy . A significant difference was observed between both groups before and after treatment in terms of the following Fugl – Meyer scale items : passive movement and pain , motor function of the upper limbs ( ULs ) , and balance . The CPT group also showed a significant difference with regard to their UL and lower limb ( LL ) coordination . The SF-36 scale analysis revealed a significant difference within both groups with regard to the following domains : physical functioning , role limitation due to physical aspects , vitality , and role limitation due to emotional aspects . The NW group also exhibited a significant difference in the mental health domain . The results indicate that both approaches improved the patients ' performance in a similar manner . Conclusion : Virtual rehabilitation using the Nintendo Wii ® and CPT both effectively treat post-stroke hemiparetic patients by improving passive movement and pain scores , motor function of the upper limb , balance , physical functioning , vitality , and the physical and emotional aspects of role functioning Background . Obstacle crossing is a balance-challenging task and can cause falls in people with Parkinson ’s disease ( PD ) . However , programs for people with PD that effectively target obstacle crossing and dynamic balance have not been established . Objective . To examine the effects of virtual reality – based exercise on obstacle crossing performance and dynamic balance in participants with PD . Methods . Thirty-six participants with a diagnosis of PD ( Hoehn and Yahr score ranging 1 to 3 ) were r and omly assigned to one of three groups . In the exercise groups , participants received virtual reality – based Wii Fit exercise ( VRWii group ) or traditional exercise ( TE group ) for 45 minutes , followed by 15 minutes of treadmill training in each session for a total of 12 sessions over 6 weeks . Participants in the control group received no structured exercise program . Primary outcomes included obstacle crossing performance ( crossing velocity , stride length , and vertical toe obstacle clearance ) and dynamic balance ( maximal excursion , movement velocity , and directional control measured by the limits-of-stability test ) . Secondary outcomes included sensory organization test ( SOT ) , Parkinson ’s Disease Question naire ( PDQ39 ) , fall efficacy scale ( FES-I ) , and timed up and go test ( TUG ) . All outcomes were assessed at baseline , after training , and at 1-month follow-up . Results . The VRWii group showed greater improvement in obstacle crossing velocity , crossing stride length , dynamic balance , SOT , TUG , FES-I , and PDQ39 than the control group . VRWii training also result ed in greater improvement in movement velocity of limits-of-stability test than TE training . Conclusions . VRWii training significantly improved obstacle crossing performance and dynamic balance , supporting implementation of VRWii training in participants with PD BACKGROUND Previous studies reported controversial results about the efficacy of video-game based therapy ( VGT ) in improving neurorehabilitation outcomes in children with cerebral palsy ( CP ) . AIM Primary aim was to investigate the effectiveness of VGT with respect to conventional therapy ( CT ) in improving upper limb motor outcomes in a group of children with CP . Secondary aim was to quantify if VGT leads children to perform a higher number of movements . DESIGN A cross-over r and omized controlled trial ( RCT ) for investigating the primary aim and a cross-sectional study for investigating the secondary aim of this study . SETTING S Out patients . POPULATION INCLUSION CRITERIA clinical diagnosis of CP , age between 4 and 14 years , level of GMFC between I and IV . EXCLUSION CRITERIA QI<35 , severe comorbidities , incapacity to st and even with an external support . METHODS Twenty-two children with CP ( 6.89±1.91-year old ) were enrolled in a cross-over RCT with 16 sessions of VGT ( using Xbox with Kinect device ) and then 16 of CT or vice versa . Upper limb functioning was assessed using the Quality of Upper Extremities Skills Test ( QUEST ) and h and abilities using Abilh and -kids score . According to the secondary aim of this study a secondary cross-sectional study has been performed . Eight children with CP ( 6.50±1.60-year old ) were enrolled into a trial in which five wireless triaxial accelerometers were positioned on their forearms , legs and trunk for quantifying the physical activity during VGT vs. CT . RESULTS QUEST scores significantly improved only after VGT ( P=0.003 ) , and not after CT ( P=0.056 ) . The reverse occurred for Abilh and -kids scores ( P=0.165 vs. P=0.013 , respectively ) . Quantity of performed movements was three times higher in VGT than in CT ( + 198 % , P=0.027 ) . CONCLUSION VGT result ed effective in improving the motor functions of upper limb extremities in children with CP , conceivably for the increased quantity of limb movements , but failed in improving the manual abilities for performing activities of daily living which benefited more from CT . CLINICAL REHABILITATION IMPACT VGT performed using the X-Box with Kinect device could enhance the number of upper limb movements in children with CP during rehabilitation and in turn improving upper limb motor skills , but CT remained superior for improving performances in manual activities of daily living

Conclusion TOT may have more valid effects than TVT in operative time and hospital stay . Besides , TOT method showed fewer complications and blood loss than TVT , but there was no significant difference between them . The scores of VAS , incontinence impact question naire short form-7 ( IIQ-7 ) , and urogenital distress inventory short form-6 ( UDI-6 ) were higher in TOT than TVT , but still no significant difference was observed .

Background To evaluate the evidence available on the effects and safety of tension-free vaginal tape ( TVT ) versus transobturator tape ( TOT ) for female stress urinary incontinence therapy based on r and omized controlled trials ( RCTs ) .

Introduction and hypothesisThe purpose of the study was to evaluate and compare the clinical values of tension-free vaginal tape ( TVT ) , tension-free vaginal tape-transobturator ( TVT-O ) , or tension-free vaginal tape-Secur ( TVT-Secur ) as treatment for female stress urinary incontinence . Methods The pre-operative and 1-year post-operative follow-up protocol s for patients who were treated with serial mid-urethral tension-free tape procedures in two hospitals from October 2008 to December 2009 were prospect ively studied . These patients were r and omly allocated to TVT , TVT-O , or TVT-Secur . Results A total of 102 women participated . At the 1-year follow-up , complications were not statistically different across the three groups except for pain in the thigh , which was more common in the TVT-O group . The overall efficacy and cure rate were similar between the TVT and TVT-O groups , but were significantly lower in the TVT-Secur group . Conclusions A comparison of the three procedures shows that TVT-O is easy to operate and is as safe as TVT-Secur , and it has similar long-term efficacy to TVT , though , as one of the third-generation mid-urethral tension-free tapes , TVT-Secur is still being evaluated . Basing on the outcome of our study , it had rare complications but unsatisfactory efficacy , and we suggest that TVT-Secur is not fit for severe cases . However , observation and comparison of these groups in a larger sample size on a longer term are needed Objective To compare the outcomes of tension- free vaginal tape ( TVT ) and transobturator tape ( TOT ) in the treatment of female stress urinary incontinence with or without concomitant pelvic organ prolapse ( POP ) . Methods One hundred and forty patients with SUI were r and omly allocated to TVT ( n = 70 ) or TOT ( n = 70 ) . The objective outcomes were assessed with a stress test , 1-h pad test . Subjective outcomes were assessed with UDI-6/(IIQ-7 ) question naires . Results The surgical outcomes revealed no significant difference between TVT and TOT surgical route . Both the subjective and objective cure rates were 91.4 % in the TOT group , while 90 and 92.8 % in the TVT group , respectively . The results showed the association to pelvic floor surgical techniques did not diminish a year later . TOT procedure has a shorter operative time for patients without concomitant surgery . Conclusion The efficacy and safety of TVT procedure were similar to that of TOT procedure for female stress urinary incontinence with or without concomitant POP The aim of this r and omized clinical trial was to compare the cure rate and the rate of complications of the tension-free vaginal tape ( TVT ) with those of the tension free vaginal tape obturator ( TVT-O ) procedure after one year of follow-up . The study was powered to show a ten per cent difference in cure rate and /or rate of complications . Of the initially treated 267 women 134 in the TVT group and 131 in the TVT-O group were evaluated . A cough stress test and a 24 h pad test were used as objective outcome measures . Subjective outcome was assessed by different condition-specific quality of life question naires and general health by the EQ-5D question naire . Objective cure rate was 95.5 % in the TVT patients and 93.1 % in TVT-O patients . Subjective cure rates showed significant improvement at one the year follow up in both groups . No significant differences in cure rates between groups were seen . The complication rate was equal in both groups Purpose To evaluate in a comprehensive way TVT in comparison with TOT , the results of a single-center RCT are presented . Many studies addressed efficacy and safety of TVT and TOT . Methods Women included were adults having predominant SUI with positive stress test . They were r and omized to get either TVT ( Gynecare ® ) or TOT ( Aris ® ) . All women were seen 1 week , 3 , 6 , 12 , 18 , and 24 months . Results Seventy-one women completed 2-year follow-up . Median age was 47 ( range 33–60 years ) . Mean ± SD BMI in TVT group was 34 ± 5 while in TOT group was 32 ± 5 kg/m2 . POP of any degree was seen in 50 % ( 35 women ) . At 1 year , pad test – negative women were 31 and 29 for TVT and TOT , respectively . At 2 years , figures became 28 in TVT group and 27 in TOT . At 1 year , UDI 6 and IIQ 7 decreased by 78.5 and 81 % for TVT and by 69 % and 75 % for TOT group . At 2 year , comparable percentages were 73 and 79 % for TVT and 69 and 82 % for TOT . Fifteen unique patients had adverse events , 10 of them had TOT . Conclusions Both tapes have similar efficacy , regarding cure of incontinence . TVT is more effective , albeit insignificantly , than TOT at 2 years . However , serious adverse events were more frequent with TVT , yet TOT has more unique adverse events BACKGROUND Contemporary surgical treatment of female stress urinary incontinence ( SUI ) includes retropubic and transobturator ( TO ) midurethral slings ( MUS ) . Case series of single-incision slings ( SIS ) have shown similar outcomes with lower morbidity . OBJECTIVE Our aim was to assess the cure rates , complications , and quality -of-life impact of one st and ard TO MUS and two SIS . DESIGN , SETTING , AND PARTICIPANTS Ninety consecutive patients with clinical ly and urodynamically proven SUI were enrolled in an exploratory r and omised phase 2 trial . Patients with previous SUI surgery , major pelvic organ prolapse , mixed incontinence , or detrusor overactivity were excluded . INTERVENTIONS Patients were treated r and omly with TVT-O , TVT-Secur , or Mini-Arc . MEASUREMENTS Postoperative visits were scheduled at 6 and 12 mo . The King 's Health Question naire ( KHQ ) was repeated at 6 mo . Cure was defined as the absence of urine leakage , no pad use , and a negative cough test at 12 mo . Pain and other complications were also investigated . RESULTS AND LIMITATIONS Cure rate was 83 % after TVT-O , 67 % after TVT-Secur , and 87 % after Mini-Arc . Improvement was found in 10 % , 13 % , and 7 % of the patients , respectively . Failures were 7 % after TVT-O and Mini-Arc and 20 % after TVT-Secur . TVT-O and Mini-Arc improved at least 15 points in > 80 % of the patients in six KHQ domains , whereas TVT-Secur could only achieve improvement in three of the nine domains . The pain score was lower in the Mini-Arc group . Complications were more numerous after TVT-O. This study has the limitations inherent in a phase 2 trial with a follow-up limited to 12 mo . CONCLUSIONS Mini-Arc offers cure and improvement rates similar to TVT-O , whereas TVT-Secur may yield an inferior outcome . These findings recommend the urgent launch of large r and omised phase 3 studies comparing conventional MUS with SIS , with Mini-Arc the advised option Introduction and hypothesisA study was conducted to compare the efficacy and complications of TVT and TVT-O. Methods This study is a prospect i ve r and omized trial involving 300 women with primary SUI ; 149 received TVT , and 151 patients were treated with TVT-O. At the 1 year follow-up , 141 TVT patients and 147 TVT-O patients ( dropout , 5.3 % and 2.6 % ) were evaluated using urodynamic studies , vali date d question naires , and a 1-h pad test . Results The mean operating time was shorter in the TVT-O group ( p < 0.001 ) . Urinary retention was not significantly different ( p > 0.05 ) . Inner thigh discomfort was reported by 5.4 % of TVT-O patients . In the TVT and the TVT-O groups , respectively , 90.1 % and 88.4 % women were objective ly cured . The satisfaction with the surgical outcome reflects the significant decrease in the question naire mean symptom scores in both groups . Postoperative de novo urgency was significantly more common in the TVT-O patients ( p = 0.015 ) . Conclusion The groups showed comparable objective and subjective cure rates OBJECTIVES This prospect i ve , multicentre , r and omised study compared the safety and success rate of tension-free vaginal tape ( TVT ) and transobturator tape ( TOT ) in treatment of female stress urinary incontinence . METHODS Of 148 women , 73 were r and omised to TVT and 75 to TOT . Preoperative workups included case history , clinical examination , Urogenital Distress Inventory and Impact Incontinence Quality of life question naires , 1-h pad test , pelvic ultrasound , and urodynamics . Intra- and postoperative complications were the primary end point ; subjective and objective changes in SUI , and postoperative voiding dysfunctions were secondary end points . Patients were classified into two main categories : dry ( no leakage during clinical and /or stress test and /or reported by patients ) versus wet . Patients who referred being wet were separated into " improved " or " failure " on subjective analysis . Other outcome variables were quality of life question naires and VAS scale . Clinical checkups were conducted at 3 , 6 , 12 mo , and then annually . RESULTS Both techniques are safe and no significant differences emerged in intra- and postoperative complications . At a mean follow-up of 31 mo , the overall objective cure ( dry ) was 71.4 % for TVT and 77.3 % for TOT ( p = ns ) . When one considered " dry " plus " wet but improved , " these values increased to 90 % and 90.6 % , respectively ( p = ns ) . Median satisfaction rate was 9 ( range : 1 - 10 ) for both procedures . Postoperative storage symptoms are a controversial issue ; they persisted in 44 % of patients in TVT group versus 24 % in TOT group ( p<0.053 ) . CONCLUSIONS TOT appears as safe and effective as TVT in surgery for female SUI , with minimal complications at mean follow-up of 31 mo The aim of the study was to compare the efficacy and complications of the Transobturator tape ( Monarc ) vs the tension-free vaginal tape obturator ( TVT-O ) in women with urodynamic stress incontinence . A prospect i ve , r and omized study was conducted . One-hundred and twenty patients were included in the study , and 114 of them were available at 12 months follow-up . Sixty-one patients were subjected to the TVT-O procedure and 53 to the Monarc procedure . Subjective and objective cure and improvement rate and complications incidence were assessed . The objective cure rate was 87 % for the TVT-O procedure and 90 % for the Monarc group . The subjective cure rate was 80 % for the TVT-O group and 77 % for the Monarc group . The improvement was 13 and 11.5 % for the TVT-O and Monarc groups , respectively . There was one accidental injury to the urethra with the Monarc technique . The Monarc technique presents success rates and complications comparable to the TVT-O method at 1 year follow-up Introduction and hypothesisThe purpose of this study is to compare the retropubic tension-free vaginal tape ( TVT ) procedure with the inside-out transobturator approach ( TVT-O ) . Methods Multicenter r and omized controlled trial . One hundred forty-nine patients were r and omly allocated to either TVT ( n = 75 ) or TVT-O ( n = 74 ) . Interview , medical examination , pain scores , success rates , and quality of life assessment were recorded pre-operatively , and 2 , 6 , 12 , and 24 months post-operatively . Results One hundred forty-nine patients underwent surgery , and 132 completed a 24-month follow-up . Bladder injury rate was 5 % ( 4/75 ) in the TVT group and 2 % ( 2/74 ) in the TVT-O group ( p = 0.68 ) . There was no significant difference between the two groups , concerning overall cure rate and the patients ' satisfaction rate at 24 months follow-up . The range of mean pain scores was significantly higher after the TVT-O procedure post-operatively but not at 24 months follow-up . Conclusion TVT and TVT-O procedures both have an outcome associated with an increase in quality of life with no significant differences in satisfaction rates at 2 years follow-up BACKGROUND Midurethral slings have become the most preferred surgical treatment for female urinary incontinence . OBJECTIVE To compare the efficacy and safety of two midurethral sling procedures with a different technique of sling insertion 5 yr after intervention . DESIGN , SETTING , AND PARTICIPANTS Multicenter r and omized clinical trial conducted in seven public hospitals in Finl and including primary cases of stress urinary incontinence . INTERVENTION Surgical treatment with the retropubic tension-free vaginal tape ( TVT ) procedure or the transobturator tension-free vaginal tape ( TVT-O ) procedure . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Objective treatment success criteria were a negative stress test , a negative 24-h pad test , and no retreatment for stress incontinence . Patient satisfaction was assessed by condition-specific quality -of-life question naires . RESULTS AND LIMITATIONS A total of 95 % of the included women could be assessed according to the protocol 5 yr after surgery . The objective cure rate was 84.7 % in the TVT group and 86.2 % in the TVT-O group , with no statistical difference between the groups . Subjective treatment satisfaction was 94.2 % in the TVT group and 91.7 % in the TVT-O group , with no difference between groups . Complication rates were low , with no difference between groups . CONCLUSIONS Both objective and subjective cure rates were > 80 % in both groups even when women lost to follow-up were included as failures . The complication rates were low , with no difference between the groups . No late-onset adverse effects of the tape material were seen . PATIENT SUMMARY Female urinary stress incontinence can be treated surgically with minimally invasive midurethral sling procedures . Two main approaches of sling placement have been developed : the retropubic and the transobturatory . We compared both approaches and followed the patients for 5 yr . We found no difference in cure rate between the procedures , and patient satisfaction was high . TRIAL REGISTRATION Clinical Trials.gov identifier NCT00379314 PURPOSE Few studies have characterized longer-term outcomes after retropubic and transobturator mid urethral slings . MATERIAL S AND METHODS Women completing 2-year participation in a r and omized equivalence trial who had not undergone surgical re-treatment for stress urinary incontinence were invited to participate in a 5-year observational cohort . The primary outcome , treatment success , was defined as no re-treatment or self-reported stress incontinence symptoms . Secondary outcomes included urinary symptoms and quality of life , satisfaction , sexual function and adverse events . RESULTS Of 597 women 404 ( 68 % ) from the original trial enrolled in the study . Five years after surgical treatment success was 7.9 % greater in women assigned to the retropubic sling compared to the transobturator sling ( 51.3 % vs 43.4 % , 95 % CI -1.4 , 17.2 ) , not meeting prespecified criteria for equivalence . Satisfaction decreased during 5 years but remained high and similar between arms ( retropubic sling 79 % vs transobturator sling 85 % , p=0.15 ) . Urinary symptoms and quality of life worsened with time ( p < 0.001 ) , and women with a retropubic sling reported greater urinary urgency ( p=0.001 ) , more negative impact on quality of life ( p=0.02 ) and worse sexual function ( p=0.001 ) . There was no difference in the proportion of women experiencing at least 1 adverse event ( p=0.17 ) . Seven new mesh erosions were noted ( retropubic sling 3 , transobturator sling 4 ) . CONCLUSIONS Treatment success decreased during 5 years for retropubic and transobturator slings , and did not meet the prespecified criteria for equivalence with retropubic demonstrating a slight benefit . However , satisfaction remained high in both arms . Women undergoing a transobturator sling procedure reported more sustained improvement in urinary symptoms and sexual function . New mesh erosions occurred in both arms over time , although at a similarly low rate OBJECTIVES To compare tension-free vaginal tape ( TVT ) and trans-obturator suburethral tape from inside to outside ( TVT-O ) for surgical treatment of stress urinary incontinence ( SUI ) for complications ( primary end point ) and success rate ( secondary end point ) . METHODS Seventy-two consecutive patients , with a mean age of 53.2 yr ( range : 38 - 69 yr ) and affected by SUI , were included in this r and omised controlled trial . After preoperative assessment , patients were r and omly allocated to the TVT or TVT-O procedure . Operative time , perioperative complications , and hospital stay were prospect ively recorded . Cure of SUI was defined as no leakage of urine during the stress test at urodynamic testing at the 12-mo evaluation . The Wilcoxon signed rank sum test , Mann-Whitney U test , McNemar test , and Fisher exact test were used to verify statistical significance , set at p<0.05 . RESULTS All patients were evaluable at the 12-mo follow-up . The characteristics of patients were well balanced between groups after r and omisation . The mean operative time was significantly shorter in the TVT-O group . Perioperative complications were significantly more common after the retropubic approach ( 5 % and 27 % in TVT-O and TVT groups , respectively , p<0.04 ) . The groups did not differ significantly in intraoperative blood loss , hospital stays , and time to return to normal activities . Sixty-five patients ( 90 % ) were successfully treated for SUI 12 mo after the operation ( 89 % and 91 % for TVT-O and TVT groups , respectively ) . CONCLUSIONS Both techniques appear to be equally effective in the surgical treatment of SUI . However , TVT-O had a shorter operative time and lower overall perioperative complication rate OBJECTIVES To describe a new , simple surgical technique for the treatment of female stress urinary incontinence ( SUI ) and to evaluate its feasibility . METHODS We have developed a novel surgical treatment of SUI , the transobturator inside-out tension-free urethral suspension , which uses specifically design ed surgical tools , and in which a synthetic tape is passed from underneath the urethra , through the obturator foramens , towards the thigh folds , without entering the pelvic region at any time during the procedure . The tape is positioned without tension under the junction between mid and distal urethra . RESULTS The procedure was carried out in 107 consecutive patients ( mean age : 62 years ) using the same operative protocol in all case subjects , independently of the patient 's size and weight . Mean operative time was 14 min ( range : 7 - 20 ) in case of isolated SUI treatment . No bladder or urethral injuries and no vascular ( hematoma or bleeding ) or neurological complications were encountered . CONCLUSIONS The results of this study indicate that our novel transobturator inside-out surgical technique for treating SUI is feasible , accurate , and quick . This technique avoids damage to the urethra and bladder and , therefore , makes cystoscopy not necessary . Further prospect i ve studies are currently ongoing to determine the efficacy of our new surgical approach for treating SUI Introduction and hypothesisThis is a r and omized multicenter study comparing two mid-urethra tape procedures , the tension-free vaginal tape ( TVT ) with the tension-free vaginal tape-obturator ( TVT-O ) in terms of cure rate and complication rate . Methods Seven Finnish hospitals participated . Power calculations required 130 women in each group to detect a 10 % difference in cure rate . A total of 267 underwent the allocated operation . Follow-up was scheduled at 2 , 12 , 36 and 60 months . A cough stress test was used as an objective outcome measure . Subjective outcome was assessed by five different condition-specific quality of life question naires . Results At 36 months of follow-up , 96 % of the patients were evaluated . Objective cure rate was 94.6 % in the TVT group and 89.5 % in the TVT-O group ( p = 0.131 ) . Subjective cure rates were significant with no difference between the groups . Conclusion The TVT and the TVT-O are equally effective in the treatment of stress urinary incontinence after 36-month follow-up with no difference in complication rates Introduction and hypothesisIn a r and omised trial comparing transobturator tape ( TOT ) to retropubic tension-free vaginal tape ( TVT ) for women with stress urinary incontinence ( SUI ) , vaginal examination at 12 months showed that tapes were palpable for 80.0 % of the TOT group versus 26.7 % of the TVT group . We hypothesized that this difference would lead to more women in the TOT group experiencing vaginal mesh erosion or other serious adverse events compared to women in the TVT group 5 years after surgery . Methods All participants were invited to join the follow-up study after being r and omised to receive TOT or TVT for SUI . Consenting women had a vaginal examination , a pad test for urinary incontinence ( UI ) and completed Health-related Quality of Life Question naires ( HRQOL ) . Women unable to attend the clinic completed question naires only . The primary composite outcome incorporated mesh exposure , urinary retention , repeat incontinence surgery and moderate to severe pelvic pain . Assuming 80 % follow-up , our study would have 67 % power to detect a difference in primary outcome ( two-sided 5 % level of significance ) . Comparisons between groups used chi-square tests and t tests . Results One hundred and seventy-six ( 88.4 % ) women participated in the 5-year follow-up ( 83 TOT , 93 TVT ) . The primary composite outcome occurred in 21.8 % of the TOT and 27.6 % of the TVT groups [ difference = −5.8 % , 95 % confidence interval ( CI ) −18.9 % to 7.3 % , p value 0.39 ) ] Vaginal examination found more women with palpable tapes in the TOT versus the TVT group ( 48.5 % versus 22.4 % , p value 0.001 ) . There were no other significant differences between groups . Conclusions Serious adverse events and tape effectiveness did not differ between groups at 5 years . Palpable tape remains a concern for women who receive TOT for treating SUI OBJECTIVE To compare the safety and efficacy of an inexpensive-modified transobturator vaginal tape procedure with the transobturator tension-free vaginal tape ( TVT-O ) procedure for the surgical treatment of female stress urinary incontinence ( SUI ) . MATERIAL S AND METHODS Patients with SUI were r and omly allocated to either the test group receiving the inexpensive-modified transobturator vaginal tape procedure or the control group receiving the GYNECARE TVT-O procedure . Treatment outcomes and Quality -of-life scores were recorded and analyzed between two groups . RESULTS A total of 156 patients were enrolled in this trial . Eighty patients underwent the modified transobturator vaginal tape procedure . Among them 75(93.8 % ) were cured and 5(6.2 % ) were improved . The rest of the 76 patients underwent the GYNECARE TVT-O procedure with a 92 % ( 70 of 76 ) cure rate and an 8 % ( 6 of 76 ) improvement rate . No inefficient or aggravated cases occurred in both groups . The success rates between groups had no significant statistic difference ( p > 0.05 ) . The operative time , blood loss , hospital stay , and medical cost were significantly lower in the test group ( p < 0.01 ) ; the increases in Quality -of-life scores were comparable between groups . CONCLUSIONS The modified transobturator vaginal tape procedure is an efficacious and economic surgical treatment for female SUI OBJECTIVE To compare the efficacy and safety of the tension-free vaginal tape ( TVT ) and inside-out transobturator tape ( TVT-O ) procedures for the treatment of stress urinary incontinence ( SUI ) . METHODS A total of 315 women with or without concomitant pelvic organ prolapse repairs were r and omly allocated to undergo a TVT or TVT-O procedure . Demographic data , intra- and postoperative complications , and surgical outcomes were analyzed . RESULTS Fifteen patients were lost to follow-up . There were no significant differences in cure rates between the 2 groups at 6 , 12 , 24 , and 36 months ' follow-up . Hematomas occurred in 4 patients and there were 6 vaginal tape erosions . Urinary retention and de novo urinary urgency were similar in both groups . The operative time was significantly shorter for TVT-O than for TVT without other procedures ( P<0.001 ) and postoperative groin/thigh pain was higher ( P<0.05 ) in the TVT-O group . CONCLUSION Both techniques appear equally effective for the treatment of SUI . However , TVT-O had a shorter operative time and a higher rate of groin/thigh pain OBJECTIVE : To compare the safety and efficacy of the transobturator tape to tension-free vaginal tape ( TVT ) in the treatment of stress urinary incontinence in patients with and without concurrent pelvic organ prolapse . METHODS : One-hundred seventy women with urodynamic stress incontinence , including those with and those without pelvic organ prolapse , from three academic medical centers were r and omized to receive TVT or transobturator tape . Subjects with detrusor overactivity or previous sling surgery were excluded . The primary outcome was the presence or absence of abnormal bladder function , a composite outcome defined as the presence of any the following : incontinence symptoms of any type , a positive cough stress test , or retreatment for stress incontinence or postoperative urinary retention assessed 1 year after surgery . This study is a noninferiority study design . RESULTS : Of 180 women who enrolled in the study , 170 underwent surgery and 168 returned for follow-up , with a mean follow-up of 18.2±6 months . Mean operating time , length of stay , and postoperative pain scores were similar between the two groups . Bladder perforations occurred more frequently in the TVT group ( 7 % compared with 0 % , P=.02 ) ; otherwise , the incidence of perioperative complications was similar . Abnormal bladder function occurred in 46.6 % of TVT patients and 42.7 % of transobturator tape patients , with a mean absolute difference of 3.9 % favoring transobturator tape ( 95 % confidence interval –11.0 % to 18.6 % . ) . The P value for the one-sided noninferiority test was .006 , indicating that transobturator tape was not inferior to TVT . CONCLUSION : The transobturator tape is not inferior to TVT for the treatment of stress urinary incontinence and results in fewer bladder perforations . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00475839 LEVEL OF EVIDENCE :

Conclusion This review identified emergence of potential ART-resistance mediating k13 mutations in the African region . Diversity of mutations in pfkelch13 gene is highest in African region compared to SEA . Mutations outside the pfkelch13 propeller region associated with increased ART parasite clearance half-life occur in malaria-affected regions

Background Efficacy of artemisinin ( ART ) agents , a critical element of current malaria control efforts is threatened by emergence and spread of resistance . Mutations in pfkelch13 gene associated with ART-resistance evolved in Southeast Asia ( SEA ) . k13 mutations whose role in ART-resistance remains unknown , have subsequently emerged independently across all malaria-affected regions . The aim of this systematic review was to determine the prevalence and identify risk factors of Plasmodium falciparum k13 mutations in malaria-endemic countries .

Abstract Background Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria . Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker , most of the mutations need to be vali date d. In this study , artemisinin resistance was assessed by clinical and molecular analysis , including k13 and recently reported markers , pfarps10 , pffd and pfmdr2 . Methods A prospect i ve cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy ( ACT ) , in 6 sentinel sites in Myanmar from 2009 to 2013 . Therapeutic efficacy of ACT was assessed by longitudinal follow ups . Molecular markers analysis was done on all available day 0 sample s. Results True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites . Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10 , pffd , and pfmdr2 were observed in western Myanmar . K13 mutations , V127 M of pfarps10 , D193Y of pffd , and T448I of pfmdr2 were significantly associated with day 3 positivity ( OR : 6.48 , 3.88 , 2.88 , and 2.52 , respectively ) . Conclusions Apart from k13 , pfarps10 , pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported . Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar . Trial registration This study was registered with Clinical Trials.gov , identifier NCT02792816 Background Artemisinin-based combination therapy has been first-line treatment for falciparum malaria in Myanmar since 2005 . The wide extent of artemisinin resistance in the Greater Mekong sub-region and the presence of mefloquine resistance at the Myanmar-Thail and border raise concerns over resistance patterns in Myanmar . The availability of molecular markers for resistance to both drugs enables assessment even in remote malaria-endemic areas . Methods A total of 250 dried blood spot sample s collected from patients with Plasmodium falciparum malarial infection in five malaria-endemic areas across Myanmar were analysed for kelch 13 sequence ( k13 ) and pfmdr1 copy number variation . K13 mutations in the region corresponding to amino acids 210–726 ( including the propeller region of the protein ) were detected by nested PCR amplification and sequencing , and pfmdr1 copy number variation by real-time PCR . In two sites , a sub-set of patients were prospect ively followed up for assessment of day-3 parasite clearance rates after a st and ard course of artemether-lumefantrine . Results K13 mutations and pfmdr1 amplification were successfully analysed in 206 and 218 sample s , respectively . Sixty-nine isolates ( 33.5 % ) had mutations within the k13 propeller region with 53 of these ( 76.8 % ) having mutations already known to be associated with artemisinin resistance . F446I ( 32 isolates ) and P574L ( 15 isolates ) were the most common examples . K13 mutation was less common in sites in western border regions ( 29 of 155 isolates ) compared to sample s from the east and north ( 40 of 51 isolates ; p < 0.0001 ) . The overall proportion of parasites with multiple pfmdr1 copies ( greater than 1.5 ) was 5.5 % . Seven sample s showed both k13 mutation and multiple copies of pfmdr1 . Only one of 36 patients followed up after artemether-lumefantrine treatment still had parasites at day 3 ; molecular analysis indicated wild-type k13 and single copy pfmdr1 . Conclusion The proportion of P. falciparum isolates with mutations in the propeller region of k13 indicates that artemisinin resistance extends across much of Myanmar . There is a low prevalence of parasites with multiple pfmdr1 copies across the country . The efficacy of artemisinin-based combination therapy containing mefloquine and lumefantrine is , therefore , expected to be high , although regular monitoring of efficacy will be important Background Intensified efforts are urgently needed to contain and eliminate artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion . Médecins Sans Frontières plans to support the Ministry of Health in eliminating P. falciparum in an area with artemisinin resistance in the north-east of Cambodia . As a first step , the prevalence of Plasmodium spp . and the presence of mutations associated with artemisinin resistance were evaluated in two districts of Preah Vihear Province . Methods A cross-sectional population -based study using a two-stage cluster sampling was conducted in the rural districts of Chhaeb and Chey Saen , from September to October 2013 . In each district , 30 clusters of 10 households were r and omly selected . In total , blood sample s were collected for 1,275 participants in Chhaeb and 1,224 in Chey Saen . Prevalence of Plasmodium spp . was assessed by PCR on dried blood spots . Plasmodium falciparum positive sample s were screened for mutations in the K13-propeller domain gene ( PF3D7_1343700 ) . Result The prevalence of Plasmodium spp . was estimated at 1.49 % ( 95 % CI 0.71–3.11 % ) in Chhaeb and 2.61 % ( 95 % CI 1.45–4.66 % ) in Chey Saen . Twenty-seven sample s were positive for P. falciparum , giving a prevalence of 0.16 % ( 95 % CI 0.04–0.65 ) in Chhaeb and 2.04 % ( 95 % CI 1.04–3.99 % ) in Chey Saen . Only 4.0 % of the participants testing positive presented with fever or history of fever . K13-propeller domain mutant type alleles ( C580Y and Y493H ) were found , only in Chey Saen district , in seven out of 11 P. falciparum positive sample s with enough genetic material to allow testing . Conclusion The overall prevalence of P. falciparum was low in both districts but parasites presenting mutations in the K13-propeller domain gene , strongly associated with artemisinin-resistance , are circulating in Chey Saen . The prevalence might be underestimated because of the absentees – mainly forest workers - and the workers of private companies who were not included in the study . These results confirm the need to urgently develop and implement targeted interventions to contain and eliminate P. falciparum malaria in this district before it spreads to other areas BACKGROUND Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease . There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border , historically a site of emerging antimalarial-drug resistance . METHODS In two open-label , r and omized trials , we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin , western Cambodia , and Wang Pha , northwestern Thail and : oral artesunate given at a dose of 2 mg per kilogram of body weight per day , for 7 days , and artesunate given at a dose of 4 mg per kilogram per day , for 3 days , followed by mefloquine at two doses totaling 25 mg per kilogram . We assessed in vitro and in vivo Plasmodium falciparum susceptibility , artesunate pharmacokinetics , and molecular markers of resistance . RESULTS We studied 40 patients in each of the two locations . The overall median parasite clearance times were 84 hours ( interquartile range , 60 to 96 ) in Pailin and 48 hours ( interquartile range , 36 to 66 ) in Wang Pha ( P<0.001 ) . Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients ( 30 % ) receiving artesunate monotherapy and 1 of 20 ( 5 % ) receiving artesunate-mefloquine therapy in Pailin , as compared with 2 of 20 ( 10 % ) and 1 of 20 ( 5 % ) , respectively , in Wang Pha ( P=0.31 ) . These markedly different parasitologic responses were not explained by differences in age , artesunate or dihydroartemisinin pharmacokinetics , results of isotopic in vitro sensitivity tests , or putative molecular correlates of P. falciparum drug resistance ( mutations or amplifications of the gene encoding a multidrug resistance protein [ PfMDR1 ] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [ PfSERCA ] ) . Adverse events were mild and did not differ significantly between the two treatment groups . CONCLUSIONS P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thail and . Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing . Containment measures are urgently needed . ( Clinical Trials.gov number , NCT00493363 , and Current Controlled Trials number , IS RCT N64835265 . ABSTRACT Imported malaria has been a great challenge for public health in China due to decreased locally transmitted cases and frequent exchange worldwide . Plasmodium falciparum has been mainly responsible for the increasing impact . Currently , artesunate plus amodiaquine , one of the artemisinin combination therapies recommended by the World Health Organization , has been mainly used against uncomplicated P. falciparum malaria in China . However , drug resistance marker polymorphism in returning migrant workers has not been demonstrated . Here , we have evaluated the prevalence of pfmdr1 and pfcrt polymorphisms , as well as the K13 propeller gene , a molecular marker of artemisinin resistance , in migrant workers returned from Ghana to Shanglin County , Guangxi Province , China , in 2013 . A total of 118 blood sample s were r and omly selected and used for the assay . Mutations of the pfmdr1 gene that covered codons 86 , 184 , 1034 , and 1246 were found in 11 isolates . Mutations at codon N86Y ( 9.7 % ) were more frequent than at others , and Y86Y184S1034D1246 was the most prevalent ( 63.6 % ) of the four haplotypes . Mutations of the pfcrt gene that covered codons 74 , 75 , and 76 were observed in 17 isolates , and M74N75T76 was common ( 70.6 % ) in three haplotypes . Eight different genotypes of the K13 propeller were first observed in 10 sample s in China , 2 synonymous mutations ( V487V and A627A ) and 6 nonsynonymous mutations . C580Y was the most prevalent ( 2.7 % ) in all the sample s. The data presented might be helpful for enrichment of molecular surveillance of antimalarial resistance and will be useful for developing and updating antimalarial guidance in China The emergence of resistance to artemisinin derivatives in Southeast Asia , manifested as delayed clearance of Plasmodium falciparum following treatment with artemisinins , is a major concern . Recently , the artemisinin resistance phenotype was attributed to mutations in portions of a P. falciparum gene ( PF3D7_1343700 ) encoding kelch ( K13 ) propeller domains , providing a molecular marker to monitor the spread of resistance . The P. falciparum cysteine protease falcipain-2 ( FP2 ; PF3D7_1115700 ) has been shown to contribute to artemisinin action , as hemoglobin degradation is required for potent drug activity , and a stop mutation in the FP2 gene was identified in parasites selected for artemisinin resistance . Although delayed parasite clearance after artemisinin-based combination therapy ( ACT ) has not yet been noted in Ug and a and ACTs remain highly efficacious , characterizing the diversity of these genes is important to assess the potential for resistance selection and to provide a baseline for future surveillance . We therefore sequenced the K13-propeller domain and FP2 gene in P. falciparum isolates from children previously treated with ACT in Ug and a , including sample s from 2006–7 ( n = 49 ) and from 2010–12 ( n = 175 ) . Using 3D7 as the reference genome , we identified 5 non-synonymous polymorphisms in the K13-propeller domain ( 133 isolates ) and 35 in FP2 ( 160 isolates ) ; these did not include the polymorphisms recently associated with resistance after in vitro selection or identified in isolates from Asia . The prevalence of K13-propeller and FP2 polymorphisms did not increase over time , and was not associated with either time since prior receipt of an ACT or the persistence of parasites ≥2 days following treatment with an ACT . Thus , the K13-propeller and FP2 polymorphisms associated with artemisinin resistance are not prevalent in Ug and a , and we did not see evidence for selection of polymorphisms in these genes Systematic review s have become very popular . A recent estimate suggests that 22 new systematic review s are published daily [ 1 ] . One reason for this interest is that they serve many purpose s. For example , the influential Institute of Medicine has indicated that a systematic review is an essential component when developing clinical practice guidelines within the USA [ 2 ] . Some granting agencies are now advocating for the use of systematic review s as an evidence -based rationale for the conduct of a proposed r and omized trial [ 3 ] . And journals are now dem and ing the use of systematic review s to provide readers with context of the results of a clinical trial [ 4 ] . For systematic review s to be useful , they need to be reported in the highest possible quality thus facilitating their accurate use across a wide spectrum of stakeholders , including patients . Unfortunately , surveys of the published literature indicate that the quality of reporting is not optimal . For example , there is evidence indicating that reporting biases , particularly selective outcome reporting , is prevalent . An early example of differences between outcomes reported in protocol s and the paired completed review was an examination of 47 Cochrane review s in which 43 ( 91 % ) contained a major change , such as the addition or deletion of outcomes , between the protocol and the full publication [ 5 ] . More recently , in an examination of 485 Cochrane protocol - review pairs , 38 % ( 95 % CI 23 to 54 % ) were found to have discrepant outcomes ( i.e. , added , omitted , or changed the priority ) between the protocol and completed review [ 6 ] . The vast majority of these discrepancies were without attribution with more significant outcomes being up grade d or added . Whether or not , and to what extent , these examples reflect reporting biases is not clear . However , they represent inconsistencies that should be avoided by authors . The gold st and ard for identifying reporting biases is a comparison of the completed review with its paired protocol . Such an examination is difficult with systematic review s as too few of them report working from a protocol , although a growing number of funders are now requiring them . Perhaps , systematic review ers do not report or use protocol s because there has been little guidance on how to report them until recently . To help facilitate the use of reporting systematic review protocol s , the three of us and several colleagues developed Preferred Reporting Items for Systematic Review and Meta- Analysis Protocol s ( PRISMA -P ) [ 7 ] . This is a reporting guideline consisting of a 17-item checklist , to help prospect i ve authors in the preparation and reporting of a scientifically rigorous systematic review protocol . We also prepared a pedagogical explanation and elaboration document to facilitate its use [ 8 ] . Readers appear interested in the guidance . Since its publication a little more than a year ago , it has been downloaded about 45,000 times and cited ( Google scholar ) nearly 100 times . This journal and others have endorsed PRISMA -P. Here , we describe how the journal intends to implement it . All protocol su bmi ssions to the journal should use continuous line numbering in their manuscript . Authors should also include a completed PRISMA -P checklist indicating whether or not the requested item information is reported ( by completing the check mark ) . If the item is checked , authors should then specify the line number ( or range of line numbers ) where this information is described . Manuscripts accepted for publication will have the completed PRIMSA-P checklist ( on su bmi ssion ) included as an Appendix to their publication , which must be referenced within the main text ( Additional file 1 ) . Prospect i ve authors can download a Word version of the PRISMA -P checklist , which includes the two added columns , from the journal ’s website ( URL to be added)or the PRISMA website ( ttp://www . prisma -statement.org/Extensions/ Protocol s.aspx ) . If PRISMA -P was used to help report the protocol , it should be cited or the PRISMA -P URL ( http://www . prisma -statement.org/Extensions/ Protocol s.aspx ) on the PRISMA website should be reported . About half of what the journal publishes are protocol s of systematic review s. We want to ensure they are published to the highest possible quality . Endorsement and implementation of reporting guidelines appears to improve the completeness of reporting . For example , a systematic review examining the completeness of reporting in more than 16,000 r and omized trials in journals that endorsed the CONSORT statement , compared to journals that did not , found more complete reporting [ 9 ] . Similarly , examining 300 systematic review s published in February 2014 found that mention of PRISMA was associated with better reporting [ 1 ] . There is always a tension between an optimal implementation strategy and ensuring minimal barriers to su bmi ssion for prospect i ve authors . We believe the journal has achieved a good balance with this strategy . Protocol s su bmi tted for publication consideration from now on that do not include a completed checklist , including the two aforementioned columns , will be returned to the authors with instructions about the journal ’s systematic review protocol implementation strategy and invited to resu bmi t their continuously line numbered manuscript and appropriately completed checklist ABSTRACT Western Cambodia is recognized as the epicenter of Plasmodium falciparum multidrug resistance . Recent reports of the efficacy of dihydroartemisinin (DHA)-piperaquine ( PP ) , the latest of the artemisinin-based combination therapies ( ACTs ) recommended by the WHO , have prompted further investigations . The clinical efficacy of dihydroartemisinin-piperaquine in uncomplicated falciparum malaria was assessed in western and eastern Cambodia over 42 days . Day 7 plasma piperaquine concentrations were measured and day 0 isolates tested for in vitro susceptibilities to piperaquine and mefloquine , polymorphisms in the K13 gene , and the copy number of the Pfmdr-1 gene . A total of 425 patients were recruited in 2011 to 2013 . The proportion of patients with recrudescent infections was significantly higher in western ( 15.4 % ) than in eastern ( 2.5 % ) Cambodia ( P < 10−3 ) . Day 7 plasma PP concentrations and median 50 % inhibitory concentrations ( IC50 ) of PP were independent of treatment outcomes , in contrast to median mefloquine IC50 , which were found to be lower for isolates from patients with recrudescent infections ( 18.7 versus 39.7 nM ; P = 0.005 ) . The most significant risk factor associated with DHA-PP treatment failure was infection by parasites carrying the K13 mutant allele ( odds ratio [ OR ] , 17.5 ; 95 % confidence interval [ CI ] , 1 to 308 ; P = 0.04 ) . Our data show evidence of P. falciparum resistance to PP in western Cambodia , an area of widespread artemisinin resistance . New therapeutic strategies , such as the use of triple ACTs , are urgently needed and must be tested . ( This study has been registered at the Australian New Zeal and Clinical Trials Registry under registration no. ACTRN12614000344695 . OBJECTIVE To determine the efficacy of artemether-lumefantrine malaria treatment , as an alternative to artesunate + mefloquine , which is becoming ineffective in some areas of the Thai-Cambodian border . METHODS Two studies were conducted to monitor the efficacy of artemether-lumefantrine in Sampov Lun referral hospital , Battambang Province , in 2002 and 2003 , and one study was conducted to assess the efficacy of mefloquine + artesunate in 2003 for comparison . The studies were performed according to the WHO st and ardized protocol with a follow-up of 28 days . The therapeutic efficacy tests were complemented with in vitro tests and in 2003 , with the measurement of lumefantrine plasma concentration at day 7 for the patients treated with artemether-lumefantrine . RESULTS A total of 190 patients were included : 55 were treated with artemether-lumefantrine in 2002 ( AL2002 ) , 80 with artemether-lumefantrine and food supplementation in 2003 ( AL2003 ) and 55 with artesunate + mefloquine in 2003 ( AM2003 ) . With the per- protocol analysis , the cure rate was 71.1 % in study AL2002 , 86.5 % in study AL2003 and 92.4 % in study AM2003 . All the data were PCR corrected . The artemether-lumefantrine cure rate was unexpectedly low in 2002 , but it increased with food supplementation in 2003 . There was a significant difference ( P = 0.02 ) in lumefantrine plasma concentrations between adequate clinical and parasitological responses and treatment failure cases . In vitro susceptibility to lumefantrine was reduced for isolates sample d from patients presenting with treatment failure , but the difference was not statistically different from isolates sample d from patients who were successfully treated . CONCLUSION Treatment failure cases of artemether-lumefantrine are most probably because of low levels of lumefantrine blood concentration . Further investigations are necessary to determine whether resistance of Plasmodium falciparum isolates to lumefantrine is present in the region We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin , the frontline antimalarial drug . Across 15 locations in Southeast Asia , we identified at least 20 mutations in kelch13 ( PF3D7_1343700 ) affecting the encoded propeller and BTB/POZ domains , which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives . Nonsynonymous polymorphisms in fd ( ferredoxin ) , arps10 ( apicoplast ribosomal protein S10 ) , mdr2 ( multidrug resistance protein 2 ) and crt ( chloroquine resistance transporter ) also showed strong associations with artemisinin resistance . Analysis of the fine structure of the parasite population showed that the fd , arps10 , mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance . These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population Background In the absence of an effective vaccine , malaria treatment and eradication is still a challenge in most endemic areas globally . This is especially the case with the current reported emergence of resistance to artemisinin agents in Southeast Asia . This study therefore explored the prevalence of K13-propeller gene polymorphisms among Plasmodium falciparum parasites in northern Ug and a. Methods Adult patients ( ≥18 years ) presenting to out- patients department of Lira and Gulu regional referral hospitals in northern Ug and a were r and omly recruited . Laboratory investigation for presence of plasmodium infection among patients was done using Plasmodium falciparum exclusive rapid diagnostic test , histidine rich protein-2 ( HRP2 ) ( Pf ) . Finger prick capillary blood from patients with a positive malaria test was spotted on a filter paper Whatman no. 903 . The parasite DNA was extracted using chelex resin method and sequenced for mutations in K13-propeller gene using Sanger sequencing . PCR DNA sequence products were analyzed using in DNAsp 5.10.01software , data was further processed in Excel spreadsheet 2007 . Results A total of 60 parasite DNA sample s were sequenced . Polymorphisms in the K13-propeller gene were detected in four ( 4 ) of the 60 parasite DNA sample s sequenced . A non-synonymous polymorphism at codon 533 previously detected in Cambodia was found in the parasite DNA sample s analyzed . Polymorphisms at codon 522 ( non-synonymous ) and codon 509 ( synonymous ) were also found in the sample s analyzed . The study found evidence of positive selection in the Plasmodium falciparum population in northern Ug and a ( Tajima ’s D = −1.83205 ; Fu and Li ’s D = −1.82458 ) . Conclusions Polymorphism in the K13-propeller gene previously reported in Cambodia has been found in the Ug and an Plasmodium falciparum parasites . There is need for continuous surveillance for artemisinin resistance gene markers in the country BACKGROUND Dihydroartemisinin-piperaquine has been adopted as first-line artemisinin combination therapy ( ACT ) for multidrug-resistant Plasmodium falciparum malaria in Cambodia because of few remaining alternatives . We aim ed to assess the efficacy of st and ard 3 day dihydroartemisinin-piperaquine treatment of uncomplicated P falciparum malaria , with and without the addition of primaquine , focusing on the factors involved in drug resistance . METHODS In this observational cohort study , we assessed 107 adults aged 18 - 65 years presenting to Anlong Veng District Hospital , Oddar Meanchey Province , Cambodia , with uncomplicated P falciparum or mixed P falciparum/Plasmodium vivax infection of between 1000 and 200,000 parasites per μL of blood , and participating in a r and omised clinical trial in which all had received dihydroartemisinin-piperaquine for 3 days , after which they had been r and omly allocated to receive either primaquine or no primaquine . The trial was halted early due to poor dihydroartemisinin-piperaquine efficacy , and we assessed day 42 PCR-corrected therapeutic efficacy ( proportion of patients with recurrence at 42 days ) and evidence of drug resistance from the initial cohort . We did analyses on both the intention to treat ( ITT ) , modified ITT ( withdrawals , losses to follow-up , and those with secondary outcomes [ eg , new non-recrudescent malaria infection ] were censored on the last day of follow-up ) , and per- protocol population s of the original trial . The original trial was registered with Clinical Trials.gov , number NCT01280162 . FINDINGS Between Dec 10 , 2012 , and Feb 18 , 2014 , we had enrolled 107 patients in the original trial . Enrolment was voluntarily halted on Feb 16 , 2014 , before reaching planned enrolment ( n=150 ) because of poor efficacy . We had r and omly allocated 50 patients to primaquine and 51 patients to no primaquine groups . PCR-adjusted Kaplan-Meier risk of P falciparum 42 day recrudescence was 54 % ( 95 % CI 45 - 63 ) in the modified ITT analysis population . We found two kelch13 propeller gene mutations associated with artemisinin resistance -- a non-synonymous Cys580Tyr substitution in 70 ( 65 % ) of 107 participants , an Arg539Thr substitution in 33 ( 31 % ) , and a wild-type parasite in four ( 4 % ) . Unlike Arg539Thr , Cys580Tyr was accompanied by two other mutations associated with extended parasite clearance ( MAL10:688956 and MAL13:1718319 ) . This combination triple mutation was associated with a 5·4 times greater risk of treatment failure ( hazard ratio 5·4 [ 95 % CI 2·4 - 12 ] ; p<0·0001 ) and higher piperaquine 50 % inhibitory concentration ( triple mutant 34 nM [ 28 - 41 ] ; non-triple mutant 24 nM [ 1 - 27 ] ; p=0·003 ) than other infections had . The drug was well tolerated , with gastrointestinal symptoms being the most common complaints . INTERPRETATION The dramatic decline in efficacy of dihydroartemisinin-piperaquine compared with what was observed in a study at the same location in 2010 was strongly associated with a new triple mutation including the kelch13 Cys580Tyr substitution . 3 days of artemisinin as part of an artemisinin combination therapy regimen might be insufficient . Strict regulation and monitoring of antimalarial use , along with non-pharmacological approaches to malaria resistance containment , must be integral parts of the public health response to rapidly accelerating drug resistance in the region . FUNDING Armed Forces Health Surveillance Center/Global Emerging Infections Surveillance and Response System , Military Infectious Disease Research Program , National Institute of Allergy and Infectious Diseases , and American Society of Tropical Medicine and Hygiene/Burroughs Wellcome Fund

We did not find evidence that a single dose of 200,000 IU of vitamin A per day , given in oil-based formulation in areas with low case fatality , was associated with reduced mortality among children with measles . However , there was evidence that the same dose given for two days was associated with a reduced risk of overall mortality and pneumonia specific mortality . REVIEW ER 'S CONCLUSIONS Although we did not find evidence that a single dose of 200,000 IU of vitamin A per day was associated with reduced mortality among children with measles , there was evidence that the same dose given for two days was associated with a reduced risk of overall mortality and pneumonia specific mortality . The effect was greater in children under the age of two years .

BACKGROUND Measles is a leading cause of childhood morbidity and mortality . Vitamin A deficiency is a recognised risk factor for severe measles . The World Health Organization ( WHO ) recommends administration of an oral dose of 200,000 IU ( or 100,000 IU in infants ) of vitamin A per day for two days to children with measles in areas where vitamin A deficiency may be present . OBJECTIVES The purpose of this review is to determine whether vitamin A when commenced after measles has been diagnosed , is beneficial in preventing mortality , pneumonia and other complications in children .

OBJECTIVES --To determine whether a single high dose of vitamin A given to all children in communities with high mortality and malnutrition could affect mortality and to assess whether periodic community wide supplementation could be readily incorporated into an ongoing primary health programme . DESIGN --Opportunistic controlled trial . SETTING --Jumla district , Nepal . SUBJECTS -- All children aged under 5 years ; 3786 in eight subdistricts given single dose of vitamin A and 3411 in remaining eight subdistricts given no supplementation . MAIN OUTCOME MEASURES --Mortality and cause of death in the five months after supplementation . RESULTS --Risk of death for children aged 1 - 59 months in supplemented communities was 26 % lower ( relative risk 0.74 , 95 % confidence interval 0.55 to 0.99 ) than in unsupplemented communities . The reduction in mortality was greatest among children aged 6 - 11 months : death rate ( deaths/1000 child years at risk ) was 133.8 in supplemented children and 260.8 in unsupplemented children ( relative risk 0.51 , 0.30 to 0.89 ) . The death rate from diarrhoea was also reduced ( 63.5 supplemented v 97.5 unsupplemented ; relative risk 0.65 , 0.44 to 0.95 ) . The extra cost per death averted was about $ 11 . CONCLUSION --The results support a role for Vitamin A in increasing child survival . The supplementation programme was readily integrated with the ongoing community health programme at little extra cost The authors assessed the efficacy of the World Health Organization ( WHO ) recommendation of 200,000 IU of vitamin A in oil to treat acute non-xerophthalmic measles patients . Acute measles patients who did not require hospitalization were enrolled in a r and omized , double-masked , clinical trial of vitamin A ( n=90 ) versus placebo ( n=110 ) carried out in Ndola , Zambia , in 1991 . Measles-associated morbidity was defined by the presence of signs and symptoms of acute respiratory infection . Daily evaluations for the first 3 days were followed by weekly visits for a month at urban health centers . Baseline demographic , clinical , and biochemical characteristics were similar in both groups . Cross-sectional analysis of morbidity status , by group , at each weekly evaluation showed no significant differences until week 4 , when more placebo-treated patients had cough or pneumonia ( p=0.005 ) . However , longitudinal analysis , which looked at changes among individuals and controlled for initial health status , showed more equivocal results . The odds ratio for the development of pneumonia in patients with measles cough in vitamin A-treated subjects was 0.73 ( 95 % confidence interval ( Cl ) 0.30 - 1.80 ) . The odds ratio for the development of measles-associated cough or pneumonia in asymptomatic measles patients was 0.52 ( 95 % Cl 0.24 - 1.13 ) , in favor of vitamin A , but the odds ratio for failing to improve from pneumonia in vitamin A-treated subjects was 1.23 ( 95 % Cl 0.68 - 2.3 ) , a result in favor of placebo . These results suggest that the evidence for the efficacy of one dose of vitamin A in oil to prevent measles complications is not as strong as that previously shown for two 200,000 IU doses of water-miscible vitamin A , and that the WHO recommendation may need to be reexamined A prospect i ve study was conducted in slum children to determine the incidence of post-measles corneal disease and to clarify its relationship with nutritional status . A total of 318 cases of measles were identified over a period of 15 mo ; maximum incidence was observed for children between 1 - 2 yr . Most of the children showed weight loss and serum proteins decrease during the acute stage of measles . Corneal lesions were observed in 3 % of the children , and the lesions responded well to treatment . Serum vitamin A and RBP levels were significantly depressed during the acute stage of measles but were restored to normal 8 wk after recovery . There were no significant differences in the serum levels for those with and without eye lesions , which suggests that these lesions may not be mediated simply through the effect of infection on serum concentration of vitamin Incidence , duration , and severity of diarrhea and respiratory symptoms were monitored weekly for 1 y in 15,419 children 6 - 60 mo of age in a r and omized , placebo-controlled , masked clinical trial conducted in southern India . Half the children received weekly doses of 8.7 mumol ( 2500 microgram ) vitamin A and 46 mumol ( 20 mg ) vitamin E ( treated ) and the other half , 46 mumol vitamin E ( control ) . Medical and ocular examinations and anthropometric measurements were obtained before and after 52 wk of intervention . Ocular examinations also were obtained after 26 wk . Supplements were delivered weekly from calibrated dispenser bottles by community health volunteers who also recorded each mother 's recall of daily morbidity of her child during the previous week . Baseline characteristics of treated and control subjects were similar and documented a prevalence of 11 % xerophthalmia and 72 % undernutrition . Weekly treatment with the low-dose vitamin A supplement did not influence the incidence , severity , or duration of diarrhea or respiratory infections and did not influence linear or ponderal growth 450 villages in northern Sumatra were r and omly assigned to either participate in a vitamin A supplementation scheme ( n = 229 ) or serve for 1 year as a control ( n = 221 ) . 25 939 preschool children were examined at baseline and again 11 to 13 months later . Capsules containing 200 000 IU vitamin A were distributed to preschool children aged over 1 year by local volunteers 1 to 3 months after baseline enumeration and again 6 months later . Among children aged 12 - 71 months at baseline , mortality in control villages ( 75/10 231 , 7.3 per 1000 ) was 49 % greater than in those where supplements were given ( 53/10 919 , 4.9 per 1000 ) ( p less than 0.05 ) . The impact of vitamin A supplementation seemed to be greater in boys than in girls . These results support earlier observations linking mild vitamin A deficiency to increased mortality and suggest that supplements given to vitamin A deficient population s may decrease mortality by as much as 34 % Micronutrients ( zinc , vitamins A and E ) and related proteins ( retinol binding protein ( RBP ) , prealbumin , albumin ) were measured in the serum of African children with measles , and the changes induced in these by vitamin A supplementation ( offered in a r and omised , double blind , placebo controlled trial ) were studied . All these substances were significantly reduced early in the exanthem in measles patients as compared to controls ; they attained control values by day 8 after the rash , except for serum albumin which became normal by day 42 . Vitamin A and prealbumin levels on day 8 were significantly increased in the supplemented over the placebo group . Vitamin A levels in serum correlated with those of RBP , prealbumin and zinc . These findings strengthen the hypothesis that hyporetinemia during measles is the consequence of impaired mobilisation . Our results indicate that our patients did not have pre-existing low liver stores . Accordingly , the results obtained here provide rational support for the recommendation that vitamin A should be given to all children with severe measles , even in communities where vitamin A deficiency is not a recognised public health problem A cross-sectional study , a follow-up study , and an intervention trial were carried out to investigate the association between mild vitamin A deficiency and the occurrence of diarrhea and respiratory diseases . Cross-sectional analysis was performed among 1,772 children , aged 1 - 8 years , in the Sakon Nakhon province of northeastern Thail and . Children with a history of diarrhea or respiratory disease had lower levels of serum retinol and retinol-binding protein . Adjusted for age , sex , nutritional status , and level of urbanization , logistic regression using data for 877 children showed a negative association between serum retinol and both diarrhea and respiratory diseases . A follow-up three months later ( n = 146 children ) showed that children with deficient serum retinol ( less than 0.35 mumol/liter ) had a fourfold greater risk of respiratory disease ( p less than 0.01 ) . No relation was found for diarrhea . An intervention trial ( n = 166 children aged 1 - 5 years ) showed that , during 2 months of follow-up after administration of oral vitamin A ( 200,000 IU ) , the control group ( aged 3 - 5 years ) had a higher incidence of respiratory disease ( 2.9 times ) as well as diarrhea ( 3.1 times ) . Between 2 and 4 months , a significantly ( p less than 0.025 ) higher incidence of respiratory diseases ( 2.5 times ) could be observed in children aged 1 - 2 years . This study supports earlier reports on a greater risk of respiratory diseases and of diarrhea in mild vitamin A deficiency . Supplementation reduced the incidence of both diarrhea and respiratory disease for a period of at least 2 months Recently , the efficacy of oral vitamin A supplementation for measles and respiratory syncytial ( RSV ) infection has been evaluated in developing countries . However , in developed countries where vitamin A deficiency is little worth consideration , few studies have been conducted on the effect of vitamin A supplementation . The effect of oral vitamin A ( 100,000 IU ) supplementation was evaluated in 105 children with measles ( age 5 months to 4 years ) and in 96 children with RSV infection ( ages a month to 2.5 years ) in Fukushima , Japan . Comparisons were made of clinical signs , duration of hospitalization and complications between treated groups and non-treated groups . Treated group ( measles n = 47 , RSV n = 54 ) and non-treated groups ( measles n = 58 , RSV n = 42 ) had similar baseline characteristics . Patients with measles given a vitamin A supplementation had a shorter duration of cough ( 7.2 + /- 1.6 vs 9.2 + /- 1.8 days , p < 0.05 ) and patients with severe RSV infection given a vitamin A supplementation had a shorter duration of retraction ( 3.6 + /- 1.4 vs 5.3 + /- 0.8 days , p < 0.05 ) and wheezing ( 4.4 + /- 1.7 vs 6.3 + /- 1.5 days , p < 0.05 ) . Toxicities , including excess vomiting and bulging fontanel were not observed . Our findings may suggest the efficacy of oral vitamin A supplementation for measles and severe RSV infection , in children who have no malnutrition The effect of vitamin A supplementation on preschool child morbidity and mortality was assessed in a prospect i ve double-blind placebo-controlled study around Hyderabad , India . Every six months 200,000 IU vitamin A was given to 7691 children ( treatment group ) whereas 8084 children received a placebo ( control group ) . Morbidity and mortality data were collected every three months . Risk of respiratory infection was higher in children with mild xerophthalmia than in children with normal eyes . Vitamin A supplementation had no effect on morbidity status . Mortality rates were similar in the two groups ; it was highest in children who did not receive either vitamin A or placebo . The findings suggest that vitamin A supplementation alone may not reduce child mortality The effect of vitamin A supplementation on selected factors of immunity was tested in African children ( ages 4 to 24 months with complicated measles ) during a r and omized doubleblind intervention trial . Placebo ( n = 31 ) and treated groups ( n = 29 ) had similar baseline characteristics . The supplemented group had significant reductions in morbidity ( expressed as integrated morbidity scores ) during the acute ( Day 8 , P = 0.006 ) and chronic ( Day 42 , P = 0.02 ; 6 months ; P = 0.002 ) phases . In the treated group there was an increase in total number of lymphocytes ( Day 42 , P = 0.05 ) and measles IgG antibody concentrations ( Day 8 , P = 0.02 ) , both of which have consistently been previously shown to correlate more closely with outcome in measles than other immunologic , clinical and radiologic factors . Interleukin 2 and plasma complement values were unaffected by vitamin A supplementation . These findings reinforce results from animal studies that show that the pathways of vitamin A activity in decreasing morbidity and mortality are partly founded on selective immunopotentiation Although most studies on the effect of vitamin A supplementation have reported reductions in childhood mortality , the effects on morbidity are less clear . We have carried out two double-blind , r and omised , placebo-controlled trials of vitamin A supplementation in adjacent population s in northern Ghana to assess the impact on childhood morbidity and mortality . The Survival Study included 21,906 children aged 6 - 90 months in 185 geographical clusters , who were followed for up to 26 months . The Health Study included 1455 children aged 6 - 59 months , who were monitored weekly for a year . Children were r and omly assigned either 200,000 IU retinol equivalent ( 100,000 IU under 12 months ) or placebo every 4 months ; r and omisation was by individual in the Health Study and by cluster in the Survival Study . There were no significant differences in the Health Study between the vitamin A and placebo groups in the prevalence of diarrhoea or acute respiratory infections ; of the symptoms and conditions specifically asked about , only vomiting and anorexia were significantly less frequent in the supplemented children . Vitamin-A-supplemented children had significantly fewer attendances at clinics ( rate ratio 0.88 [ 95 % CI 0.81 - 0.95 ] , p = 0.001 ) , hospital admissions ( 0.62 [ 0.42 - 0.93 ] , p = 0.02 ) , and deaths ( 0.81 [ 0.68 - 0.98 ] , p = 0.03 ) than children who received placebo . The extent of the effect on morbidity and mortality did not vary significantly with age or sex . However , the mortality rate due to acute gastroenteritis was lower in vitamin-A-supplemented than in placebo clusters ( 0.66 [ 0.47 - 0.92 ] , p = 0.02 ) ; mortality rates for all other causes except acute lower respiratory infections and malaria were also lower in vitamin A clusters , but not significantly so . Improving the vitamin A intake of young children in population s where xerophthalmia exists , even at relatively low prevalence , should be a high priority for health and agricultural services in Africa and elsewhere One hundred and eighty children admitted with measles were r and omly allocated to receive routine treatment alone or with additional large doses of vitamin A ( 200,000 IU orally immediately and again the next day ) . Baseline characteristics of the two groups were virtually identical for age , severity of measles , and vitamin A and general nutritional states . In 91 % of the children serum vitamin A concentrations were less than 0.56 mumol/l . Of the 88 subjects given vitamin A supplements , six ( 7 % ) died ; of the 92 controls , 12 ( 13 % ) died ( p = 0.13 ) . This difference in mortality was most obvious for children aged under 2 years ( one death out of 46 children receiving supplements versus seven deaths out of 42 controls ; p less than 0.05 ) and for cases complicated by croup or laryngotracheobronchitis . Mortality was several times higher in marasmic than in better nourished children , regardless of study allocation ( p less than 0.01 ) The effects of vitamin A supplementation on measles morbidity are unclear . Sixty hospitalized children aged 4 - 24 mo with complicated measles received a World Health Organization--(WHO ) recommended dose of vitamin A or placebo . The two groups were comparable in known covariants of measles severity : weight-for-age percentiles , overcrowding , rash , total lymphocytes , and serum concentrations of zinc , albumin , prealbumin , retinol-binding protein , and vitamins A and E. Ninety percent of the patients had hyporetinemia . Integrated morbidity scores , determined by severity of condition ( eg , diarrhoea , herpes , and respiratory-tract infection ) were assigned on day 8 and 6 wk and 6 mo ; these were reduced by 82 % , 61 % , and 85 % , respectively , in the supplemented group , which was mainly due to reduced respiratory-tract infection . There was one death in the placebo group . At 6 wk weight gain was significant in the supplemented group . Despite the selected sample , attention to multiple covariates enhances the validity of the data obtained and supports the current WHO recommendations for vitamin A supplementation during measles

Ketamine was associated with transient psychotomimetic effects , but no persistent psychosis or affective switches . CONCLUSION Our meta- analysis suggests that single administrations ketamine are efficacious in the rapid treatment of unipolar and bipolar depression .

BACKGROUND There is growing interest in glutamatergic agents in depression , particularly ketamine , a glutamate N-methyl-d-aspartate ( NMDA ) receptor antagonist . We aim ed to assess the efficacy of ketamine in major depressive episodes .

CONTEXT Existing therapies for major depression have a lag of onset of action of several weeks , result ing in considerable morbidity . Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care . Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders . OBJECTIVE To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression . DESIGN A r and omized , placebo-controlled , double-blind crossover study from November 2004 to September 2005 . SETTING Mood Disorders Research Unit at the National Institute of Mental Health . Patients Eighteen subjects with DSM-IV major depression ( treatment resistant ) . INTERVENTIONS After a 2-week drug-free period , subjects were given an intravenous infusion of either ketamine hydrochloride ( 0.5 mg/kg ) or placebo on 2 test days , a week apart . Subjects were rated at baseline and at 40 , 80 , 110 , and 230 minutes and 1 , 2 , 3 , and 7 days postinfusion . Main Outcome Measure Changes in scores on the primary efficacy measure , the 21-item Hamilton Depression Rating Scale . RESULTS Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection , which remained significant throughout the following week . The effect size for the drug difference was very large ( d = 1.46 [ 95 % confidence interval , 0.91 - 2.01 ] ) after 24 hours and moderate to large ( d = 0.68 [ 95 % confidence interval , 0.13 - 1.23 ] ) after 1 week . Of the 17 subjects treated with ketamine , 71 % met response and 29 % met remission criteria the day following ketamine infusion . Thirty-five percent of subjects maintained response for at least 1 week . CONCLUSIONS Robust and rapid antidepressant effects result ed from a single intravenous dose of an N-methyl-D-aspartate antagonist ; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week BACKGROUND The high-affinity N-methyl-D-aspartate ( NMDA ) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties . AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects . This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder ( MDD ) . METHODS In this double-blind , r and omized , crossover , placebo-controlled study , 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 ( 150 mg ) or placebo on 2 test days 1 week apart . The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale , which was used to rate overall depressive symptoms at baseline and 60 , 80 , 110 , and 230 min postinfusion and on Days 1 , 2 , 3 , and 7 postinfusion . Several secondary outcome measures were also used , including the Hamilton Depression Rating Scale . RESULTS Within 80 min , Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo ; this improvement remained significant only through 110 min ( d = .40 ) . On the Hamilton Depression Rating Scale , a drug difference was found at 80 and 110 min and at Day 2 ( d = .49 ) . Overall , 32 % of subjects responded to AZD6765 , and 15 % responded to placebo at some point during the trial . No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects . CONCLUSIONS In patients with treatment-resistant MDD , a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects ; no psychotomimetic effects were observed Antagonism of N-methyl-D-aspartate glutamatergic receptors ( NMDAR ) may represent an effective antidepressant mechanism . D-cycloserine ( DCS ) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist . Twenty-six treatment-resistant major depressive disorder patients participated in a double blind , placebo-controlled , 6-wk parallel group trial with a gradually titrated high dose ( 1000 mg/d ) of DCS added to their antidepressant medication . DCS treatment was well tolerated , had no psychotomimetic effects and led to improvement in depression symptoms as measured by Hamilton Depression Rating Scale ( HAMD ; p = 0.005 ) and Beck Depression Inventory ( p = 0.046 ) . Of the 13 subjects treated with DCS , 54 % had a ≥ 50 % HAMD score reduction vs. 15 % of the 13 patients r and omized to placebo ( p = 0.039 ) . A significant ( p = 0.043 ) treatment × pre-treatment glycine serum levels interaction was registered . These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants . Larger-sized DCS trials are warranted Accumulating evidence suggests that N-methyl-d-aspartate receptor ( NMDAR ) antagonists ( e.g. ketamine ) may exert rapid antidepressant effects in MDD patients . In the present study , we evaluated the rapid antidepressant effects of ketamine compared with the electroconvulsive therapy ( ECT ) in hospitalized patients with MDD . In this blind , r and omized study , 18 patients with DSM-IV MDD were divided into two groups which received either three intravenous infusions of ketamine hydrochloride ( 0.5 mg/kg over 45 min ) or ECT on 3 test days ( every 48 h ) . The primary outcome measure was the Beck Depression Inventory ( BDI ) and Hamilton Depression Rating Scale ( HDRS ) , which was used to rate overall depressive symptoms at baseline , 24 h after each treatment , 72 h and one week after the last ( third ) ketamine or ECT . Within 24 h , depressive symptoms significantly improved in subjects receiving the first dose of ketamine compared with ECT group . Compared to baseline level , this improvement remained significant throughout the study . Depressive symptoms after the second dose ketamine was also lower than the second ECT . This study showed that ketamine is as effective as ECT in improving depressive symptoms in MDD patients and have more rapid antidepressant effects compared with the ECT 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 We investigated whether ketamine is suitable for depressed patients who had undergone orthopedic surgery . We studied 70 patients with major depression and 25 patients as the control ( Group C ) . The depressed patients were divided r and omly into two groups ; patients in Group A ( n = 35 ) were induced with propofol , fentanyl , and ketamine and patients in Group B ( n = 35 ) were induced with propofol and fentanyl , and all patients were maintained with 1.5%–2.0 % isoflurane plus nitrous oxide . The mean Hamilton Depression Rating ( HDR ) score was 12.7 ± 5.4 for Group A and 12.3 ± 6.0 for Group B 2 days before surgery and 9.9 ± 4.1 for Group A and 14.4 ± 3.8 for Group B 1 day after surgery . The HDR score in Group A 1 day after surgery was significantly ( P < 0.05 ) lower than that in Group B. The HDR score in Group C was 4.2 ± 1.7 2 days before surgery and 4.8 ± 1.6 1 day after surgery . Depressed mood , suicidal tendencies , somatic anxiety , and hypochondriasis significantly decreased in Group A as compared with Group B. Postoperative pain scores in Group A at 8 and 16 h after the end of anesthesia were 26.6 ± 8.7 and 24.9 ± 8.2 , respectively , which were significantly ( P < 0.05 ) lower than 34.3 ± 12.0 and 31.1 ± 8.8 in Group B. In conclusion , small-dose ketamine improved the postoperative depressive state and relieved postoperative pain in depressed patients OBJECTIVE Ketamine , a glutamate N-methyl-d-aspartate ( NMDA ) receptor antagonist , has shown rapid antidepressant effects , but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion . The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression . METHOD This was a two-site , parallel-arm , r and omized controlled trial of a single infusion of ketamine compared to an active placebo control condition , the anesthetic midazolam . Patients with treatment-resistant major depression experiencing a major depressive episode were r and omly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio ( N=73 ) . The primary outcome was change in depression severity 24 hours after drug administration , as assessed by the Montgomery-Åsberg Depression Rating Scale ( MADRS ) . RESULTS The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment . After adjustment for baseline scores and site , the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points ( 95 % confidence interval [ CI ] , 3.20 to 12.71 ) . The likelihood of response at 24 hours was greater with ketamine than with midazolam ( odds ratio , 2.18 ; 95 % CI , 1.21 to 4.14 ) , with response rates of 64 % and 28 % , respectively . CONCLUSIONS Ketamine demonstrated rapid antidepressant effects in an optimized study design , further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression . More information on response durability and safety is required before implementation in clinical practice BACKGROUND Currently , no pharmacological treatments for bipolar depression exist that exert rapid ( within hours ) antidepressant or antisuicidal effects . We previously reported that intravenous administration of the N-methyl-D-aspartate antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression . The present study sought to replicate this finding in an independent sample . METHODS In this double-blind , r and omized , crossover , placebo-controlled study , 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride ( .5 mg/kg ) or placebo on 2 test days 2 weeks apart . The primary outcome measure was the Montgomery-Asberg Depression Rating Scale , which was used to rate overall depressive symptoms at baseline ; at 40 , 80 , 110 , and 230 minutes postinfusion ; and on days 1 , 2 , 3 , 7 , 10 , and 14 postinfusion . RESULTS Within 40 minutes , depressive symptoms , as well as suicidal ideation , significantly improved in subjects receiving ketamine compared with placebo ( d = .89 , 95 % confidence interval = .61 - 1.16 , and .98 , 95 % confidence interval = .64 - 1.33 , respectively ) ; this improvement remained significant through day 3 . Seventy-nine percent of subjects responded to ketamine and 0 % responded to placebo at some point during the trial . The most common side effect was dissociative symptoms , which occurred only at the 40-minute time point . CONCLUSIONS This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response . In addition , we found that ketamine rapidly improved suicidal ideation in these patients The purpose of this study was to develop an instrument for the measurement of present-state dissociative symptoms , the Clinician Administered Dissociative States Scale ( CADSS ) . Reported here are interrater reliability and internal consistency of the CADSS , validity as assessed by comparisons with other instruments for the assessment of dissociation , and sensitivity of the CADSS to discriminate patients with dissociative disorders from patients with other psychiatric disorders and healthy subjects . Initial analyses indicated good interrater reliability and construct validity for the CADSS . Scores on the CADSS discriminated patients with dissociative disorders from the other groups Ketamine produces rapid antidepressant effects in treatment-resistant depression ( TRD ) , but the magnitude of response varies considerably between individual patients . Brain-derived neurotrophic factor ( BDNF ) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine . We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a r and omized controlled trial of ketamine compared to an anaesthetic control ( midazolam ) . Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion , and Montgomery-Åsberg Depression Rating Scale ( MADRS ) scores were negatively correlated with BDNF ( r=-0.701 , p = 0.008 ) . Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min ( r = -0.897 , p=.002 ) , 24 h ( r = -0.791 , p = 0.038 ) , 48 h ( r = -0.944 , p = 0.001 ) and 72 h ( r = -0.977 , p = 0.010 ) . No associations with BDNF were found for patients receiving midazolam . These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response Ketamine , an N-methyl-D-aspartate receptor ( NMDAR ) channel blocker , has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients . However , the marked acute psychological side effects of ketamine complicate the interpretation of both pre clinical and clinical data . Moreover , the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question . Using quantitative electroencephalography ( qEEG ) to objective ly align doses of a low-trapping NMDA channel blocker , AZD6765 ( lanicemine ) , to that of ketamine , we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects . Furthermore , using placebo-controlled data , we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration . Together , these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders BACKGROUND Ketamine is reported to have rapid antidepressant effects ; however , there is limited underst and ing of the time-course of ketamine effects beyond a single infusion . A previous report including 10 participants with treatment-resistant major depression ( TRD ) found that six ketamine infusions result ed in a sustained antidepressant effect . In the current report , we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample , inclusive of the original . METHODS Participants with TRD ( n = 24 ) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine ( .5 mg/kg ) administered open-label three times weekly over a 12-day period . Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion . RESULTS The overall response rate at study end was 70.8 % . There was a large mean decrease in Montgomery-Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion ( 18.9 ± 6.6 , p < .001 ) , and this decrease was largely sustained for the duration of the infusion period . Response at study end was strongly predicted by response at 4 hours ( 94 % sensitive , 71 % specific ) . Among responders , median time to relapse after the last ketamine infusion was 18 days . CONCLUSIONS Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect . Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine BACKGROUND A single subanesthetic ( intravenous ) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression ( TRD ) . Here we tested the tolerability , safety , and efficacy of repeated-dose open-label IV ketamine ( six infusions over 12 days ) in 10 medication-free symptomatic patients with TRD who had previously shown a meaningful antidepressant response to a single dose . METHODS On day 1 , patients received a 40-min IV infusion of ketamine ( .5 mg/kg ) in an inpatient setting with continuous vital-sign monitoring . Psychotomimetic effects and adverse events were recorded repeatedly . The primary efficacy measure was change from baseline in the Montgomery-Asberg Depression Rating Scale ( MADRS ) score . If patients showed a > or = 50 % reduction in MADRS scores on day 2 , they received five additional infusions on an outpatient basis ( days 3 , 5 , 8 , 10 , and 12 ) . Follow-up visits were conducted twice-weekly for > or = 4 weeks or until relapse . RESULTS Ketamine elicited minimal positive psychotic symptoms . Three patients experienced significant but transient dissociative symptoms . Side effects during and after each ketamine infusion were generally mild . The response criterion was met by nine patients after the first infusion as well as after the sixth infusion . The mean ( SD ) reduction in MADRS scores after the sixth infusion was 85 % ( 12 % ) . Postketamine , eight of nine patients relapsed , on average , 19 days after the sixth infusion ( range 6 days-45 days ) . One patient remained antidepressant-free with minimal depressive symptoms for > 3 months . CONCLUSIONS These pilot findings suggest feasibility of repeated-dose IV ketamine for the acute treatment of TRD OBJECTIVE This study was conducted to determine the efficacy and safety of riluzole , a glutamate-modulating agent , in patients with recurrent major depression . METHOD After a 1-week drug-free period , subjects 18 years or older with a diagnosis of recurrent major depression and a Montgomery-Asberg Depression Rating Scale score > or = 20 received riluzole monotherapy ( 100 - 200 mg/day ) openly for 6 weeks . RESULTS Nineteen treatment-resistant depressed patients , 53 % of whom were classified as having stage 2 treatment resistance or greater , received riluzole at a mean dose of 169 mg/day . Significant improvement occurred during weeks 3 through 6 for all patients and weeks 2 through 6 for completers . CONCLUSIONS Although preliminary , these results indicate that riluzole may have antidepressant properties in some patients BACKGROUND Antidepressants , aim ing at monoaminergic neurotransmission , exhibit delayed onset of action , limited efficacy , and poor compliance . Glutamatergic neurotransmission is involved in depression . However , it is unclear whether enhancement of the N-methyl-D-aspartate ( NMDA ) subtype glutamate receptor can be a treatment for depression . METHODS We studied sarcosine , a glycine transporter-I inhibitor that potentiates NMDA function , in animal models and in depressed patients . We investigated its effects in forced swim test , tail suspension test , elevated plus maze test , novelty-suppressed feeding test , and chronic unpredictable stress test in rats and conducted a 6-week r and omized , double-blinded , citalopram-controlled trial in 40 patients with major depressive disorder . Clinical efficacy and side effects were assessed biweekly , with the main outcomes of Hamilton Depression Rating Scale , Global Assessment of Function , and remission rate . The time course of response and dropout rates was also compared . RESULTS Sarcosine decreased immobility in the forced swim test and tail suspension test , reduced the latency to feed in the novelty-suppressed feeding test , and reversed behavioral deficits caused by chronic unpredictable stress test , which are characteristics for an antidepressant . In the clinical study , sarcosine substantially improved scores of Hamilton Depression Rating Scale , Clinical Global Impression , and Global Assessment of Function more than citalopram treatment . Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out . Sarcosine was well tolerated without significant side effects . CONCLUSIONS Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression . Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies BACKGROUND Depression and anxiety are prevalent and undertreated in patients receiving hospice care . St and ard antidepressants do not work rapidly or often enough to benefit most of these patients . Ketamine has many properties that make it an interesting c and i date for rapidly treating depression and anxiety in patients receiving hospice care . To test this hypothesis , a 28-day , open-label , proof-of-concept trial of daily oral ketamine administration was conducted in order to evaluate the tolerability , potential efficacy , and time to potential efficacy in treating depression and anxiety in patients receiving hospice care . METHODS In this open-label study , 14 subjects with symptoms of depression or depression mixed with anxiety warranting psychopharmacological intervention received daily oral doses of ketamine hydrochloride ( 0.5 mg/kg ) over a 28-day period . The primary outcome measure was the Hospital Anxiety and Depression Scale ( HADS ) , which was used to rate overall depression and anxiety symptoms at baseline , and on days 3 , 7 , 14 , 21 , and 28 . RESULTS Over the 28-day trial there was significant improvement in both depressive symptoms ( F5,35=8.03 , p=0.002 , η(2)=0.534 ) and symptoms of anxiety ( F5,35=14.275 , p<0.001 , η(2)=0.67 ) for the eight subjects that completed the trial . One hundred percent of subjects completing the trial responded to ketamine for both anxiety and depression . A significant response in depressive symptoms occurred by day 14 for depression ( mean Δ=3.5 , d=1.14 , 95 % CI=1.09 - 5.9 , p=0.01 ) and day 3 for anxiety ( mean Δ=2.4 , d=0.67 , 95 % CI=1.0 - 3.7 , p=0.004 ) . These improvements remained significant through day 28 for both depression ( mean Δ=4.0 , d=1.34 , 95 % CI=2.3 - 5.9 , p=0.001 ) and anxiety ( mean Δ=6.09 , d=1.34 , 95 % CI=3.6 - 8.6 , p<0.001 ) . Side effects were rare , the most common being diarrhea , trouble sleeping , and trouble sitting still . CONCLUSIONS Patients who received daily oral ketamine experienced a robust antidepressant and anxiolytic response with few adverse events . The response rate for depression is similar to those found with IV ketamine ; however , the time to response is more protracted . The findings of the potential efficacy of oral ketamine for depression and the response of anxiety symptoms are novel . Further investigation with r and omized , controlled clinical trials is necessary to firmly establish the efficacy and safety of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care or other subject population BACKGROUND The N-methyl-D-aspartate glutamate receptor antagonist ketamine , delivered via an intravenous route , has shown rapid antidepressant effects in patients with treatment-resistant depression . The current study was design ed to test the safety , tolerability , and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial . METHODS In a r and omized , double-blind , crossover study , 20 patients with major depression were r and omly assigned , and 18 completed 2 treatment days with intranasal ketamine hydrochloride ( 50 mg ) or saline solution . The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo , measured using the Montgomery-Åsberg Depression Rating Scale . Secondary outcomes included persistence of benefit , changes in self-reports of depression , changes in anxiety , and proportion of responders . Potential psychotomimetic , dissociative , hemodynamic , and general adverse effects associated with ketamine were also measured . RESULTS Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo ( t = 4.39 , p < .001 ; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7 ; 95 % confidence interval , 3.9 - 11.3 ) . Response criteria were met by 8 of 18 patients ( 44 % ) 24 hours after ketamine administration compared with 1 of 18 ( 6 % ) after placebo ( p = .033 ) . Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinical ly significant changes in hemodynamic parameters . CONCLUSIONS This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine . Treatment was associated with minimal adverse effects . If replicated , these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression Background : Single infusions of ketamine have been used successfully to achieve improvement in depressed patients . Side effects during the infusions have been common . It is not known whether serial infusions or lower infusion rates result in greater efficacy . Methods : Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0.5 mg/kg administered over 100 min until either remission was achieved or four infusions were given . Side effects were assessed with the Young Mania Rating Scale ( YMRS ) and the Brief Psychiatric Rating Scale ( BPRS ) . Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions . Results : Five of 10 patients achieved remission status . There were no significant increases on the BPRS or YMRS . Two of the remitting patients sustained their improvement throughout the four week follow-up period . Conclusions : Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care . Serial ketamine infusions appear to be more effective than a single infusion . Further research to test relapse prevention strategies with continuation ketamine infusions is indicated BACKGROUND Residual depressive symptomatology constitutes a substantial risk for relapse in depression . Treatment until full remission is achieved is therefore implicated . However , there is a lack of knowledge about the prevalence of ( 1 ) residual symptoms in general and ( 2 ) the individual residual symptoms in particular . METHOD In a 3-year prospect i ve study of 267 initially depressed primary care patients we established per week the presence/absence of the individual DSM-IV depressive symptoms during subsequent major depressive episodes ( MDEs ) and episodes of ( partial ) remission . This was accomplished by means of 12 assessment s at 3-monthly intervals with the Composite International Diagnostic Interview ( CIDI ) . RESULTS In general , residual depressive symptomatology was substantial , with on average two symptoms present during remissions . Three individual symptoms ( cognitive problems , lack of energy and sleeping problems ) dominated the course of depression and were present 85 - 94 % of the time during depressive episodes and 39 - 44 % of the time during remissions . CONCLUSIONS Residual symptoms are prevalent , with some symptoms being present for almost half of the time during periods of remission . Treatment until full remission is achieved is not common practice , yet there is a clear need to do so to prevent relapse . Several treatment suggestions are made BACKGROUND A growing body of pre clinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants . This is the first placebo-controlled , double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate ( NMDA ) receptor antagonist in patients with depression . METHODS Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride ( .5 mg/kg ) or saline solutions under r and omized , double-blind conditions . RESULTS Subjects with depression evidence d significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion ( i.e. , mean 25-item Hamilton Depression Rating Scale scores decreased by 14 + /- SD 10 points vs. 0 + /- 12 points , respectively during active and sham treatment ) . CONCLUSIONS These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression CONTEXT Existing therapies for bipolar depression have a considerable lag of onset of action . Pharmacological strategies that produce rapid antidepressant effects-for instance , within a few hours or days-would have an enormous impact on patient care and public health . OBJECTIVE To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression . DESIGN A r and omized , placebo-controlled , double-blind , crossover , add-on study conducted from October 2006 to June 2009 . SETTING Mood Disorders Research Unit at the National Institute of Mental Health , Bethesda , Maryl and . Patients Eighteen subjects with DSM-IV bipolar depression ( treatment-resistant ) . INTERVENTIONS Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride ( 0.5 mg/kg ) or placebo on 2 test days 2 weeks apart . The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40 , 80 , 110 , and 230 minutes and on days 1 , 2 , 3 , 7 , 10 , and 14 postinfusion . MAIN OUTCOME MEASURES Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores . RESULTS Within 40 minutes , depressive symptoms significantly improved in subjects receiving ketamine compared with placebo ( d = 0.52 , 95 % confidence interval [ CI ] , 0.28 - 0.76 ) ; this improvement remained significant through day 3 . The drug difference effect size was largest at day 2 ( d = 0.80 , 95 % CI , 0.55 - 1.04 ) . Seventy-one percent of subjects responded to ketamine and 6 % responded to placebo at some point during the trial . One subject receiving ketamine and 1 receiving placebo developed manic symptoms . Ketamine was generally well tolerated ; the most common adverse effect was dissociative symptoms , only at the 40-minute point . CONCLUSION In patients with treatment-resistant bipolar depression , robust and rapid antidepressant effects result ed from a single intravenous dose of an N-methyl-D-aspartate antagonist

Conclusions Current data confirms that PP is an independent risk factor for stroke but is not a predictor of mortality

Background Recent evidence suggests that pulse pressure ( PP ) is a strong cardiovascular diseases ’ risk factor . We systematic ally evaluated all relevant studies to determine whether PP can be used as an independent predictor of stroke and mortality .

BACKGROUND Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events . Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure . METHODS In the Cardiovascular Health Study , 5888 adults 65 years and older were recruited from 4 US centers . At baseline in 1989 - 1990 , participants underwent an extensive examination , and all subsequent cardiovascular events were ascertained and classified . RESULTS At baseline , 1961 men and 2941 women were at risk for an incident myocardial infa rct ion or stroke . During follow-up that averaged 6.7 years , 572 subjects had a coronary event , 385 had a stroke , and 896 died . After adjustment for potential confounders , systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , and pulse pressure were directly associated with the risk of incident myocardial infa rct ion and stroke . Only SBP was associated with total mortality . Importantly , SBP was a better predictor of cardiovascular events than DBP or pulse pressure . In the adjusted model for myocardial infa rct ion , a 1-SD change in SBP , DBP , and pulse pressure was associated with hazard ratios ( 95 % confidence intervals ) of 1.24 ( 1.15 - 1.35 ) , 1.13 ( 1.04 - 1.22 ) , and 1.21 ( 1.12 - 1.31 ) , respectively ; and adding pulse pressure or DBP to the model did not improve the fit . For stroke , the hazard ratios ( 95 % confidence intervals ) were 1.34 ( 1.21 - 1.47 ) with SBP , 1.29 ( 1.17 - 1.42 ) with DBP , and 1.21 ( 1.10 - 1.34 ) with pulse pressure . The association between blood pressure level and cardiovascular disease risk was generally linear ; specifically , there was no evidence of a J-shaped relationship . In those with treated hypertension , the hazard ratios for the association of SBP with the risks for myocardial infa rct ion and stroke were less pronounced than in those without treated hypertension . CONCLUSION In this population -based study of older adults , although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events , SBP was the best single predictor of cardiovascular events Background In patients with cardiovascular disease , a high pulse pressure is related to an increased risk of cardiovascular events but in patients with advanced heart failure , a low pulse pressure is predictive of adverse ( cardiovascular ) events . Aim We studied the prognostic importance of pulse pressure in a group of post-myocardial infa rct ion patients , with and without signs and symptoms of heart failure . Subjects had been r and omised in the CAPRICORN clinical trial , and followed up for a mean of 1.3 years . Methods Blood pressure was measured in 1,955 patients with a left ventricular ejection fraction ≤40 % , between 3 and 21 days post myocardial infa rct ion . Cox proportional survival models were reproduced for those with Killip Class I ( n = 1342 ) versus classes II/III/IV heart failure ( n = 613 ) . Results Overall mean ( SD ) age was 63 ( 12 ) years , mean ( SD ) left ventricular ejection fraction 33(6)% , mean ( SD ) baseline blood pressure was 121 (17)/74 ( 10 ) mmHg and most ( 73 % ) were male . In patients with Killip Class 1 , pulse pressure was not predictive for any outcome . However , in patients with Killip Class II – IV , a low pulse pressure independently predicted all cause mortality ( HR 0.83 per 10 mmHg , CI 0.71–0.98 , p = 0.025 ) , cardiovascular mortality ( HR 0.83 per 10 mmHg , CI 0.70–0.98 , p = 0.025 ) and sudden death ( HR 0.77 per 10 mmHg , CI 0.60–1.00 , p = 0.047 ) . A lower pulse pressure did not predict hospitalisation for worsening heart failure . Conclusion A low pulse pressure is an independent predictor of mortality in subjects with depressed left ventricular ejection fraction after a recent myocardial infa rct ion and evidence of Killip Class II – IV heart failure Abstract Objective : This study aims to develop and vali date a stroke risk model incorporating pulse pressure ( PP ) as a potential risk factor . Recent evidence suggests that PP , defined as the difference between systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) , could be an incremental risk factor beyond SBP . Methods : Electronic health records ( EHRs ) of hypertensive patients from a US integrated health delivery system were analyzed ( January 2004 to May 2012 ) . Patients with ≥1 PP reading and ≥6 months of observation prior to the first diagnosis of hypertension were r and omly split into development ( two-thirds of sample ) and validation ( one-third of sample ) data sets . Stroke events were identified using ICD-9-CM 433.xx–436.xx . Cox proportional hazards models assessed time to first stroke event within 3 years of first hypertension diagnosis based on baseline risk factors , including PP , age , gender , diabetes , and cardiac comorbidities . The optimal model was selected using the least absolute shrinkage and selection operator ( LASSO ) ; performance was evaluated by the c-statistic . Results : Among 34,797 patients selected ( mean age 59.3 years , 48 % male ) , 4272 patients ( 12.3 % ) had a stroke . PP was higher among patients who developed stroke ( mean [ SD ] PP , stroke : 02.0 [ 15.3 ] mmHg ; non-stroke : 58.1 [ 14.0 ] mmHg , p < 0.001 ) . The best performing risk model ( c-statistic , development : 0.730 ; validation : 0.729 ) included PP ( hazard ratio per mmHg increase : 1.0037 , p < 0.001 ) as a significant risk factor . Limitations : This study was subject to limitations similar to other studies using EHRs . Only patient encounters occurring within the single healthcare network were captured in the data source . Though the model was tested internally , external validation ( using a separate data source ) would help assess the model ’s generalizability and calibration . Conclusions : This stroke risk model shows that greater PP is a significant predictive factor for increased stroke risk , even in the presence of known risk factors . PP should be considered by practitioners along with established risk factors in stroke treatment strategies Objective Although pulse pressure has been recognized a risk factor for coronary heart disease in both middle-aged and elderly , and for stroke in the elderly , the contribution of pulse pressure to the risk of stroke among the middle-aged is uncertain . Methods A total of 33 372 participants ( 11 684 men and 21 688 women aged 40–69 years ) living in communities , free of prior diagnosis of cardiovascular disease and cancer , completed health check-up examination . They were followed from 1990–1992 to the end of 2004 in the Japan public health center-based prospect i ve study on cancer and cardiovascular disease . After 422 864 person-years of follow-up , 1081 incident strokes ( 559 men and 522 women ) were documented . Results Pulse pressure was positively associated with risk of stroke as was systolic and diastolic blood pressures . The multivariable hazard ratio of total stroke associated with a 1-SD increment ( 13.2 mmHg ) of pulse pressure was 1.14 ( 1.05–1.24 ) . The excess risk was observed for the stratum of systolic blood pressure below 140 mmHg , but not of higher systolic blood pressure levels after adjustment for diastolic blood pressure and other potential confounding factors ; the multivariable hazard ratio of stroke associated with a 1-SD increment of pulse pressure was 1.32 ( 1.07–1.64 ) among persons with normal systolic blood pressure levels . Conclusions Pulse pressure is a risk factor for stroke among normotensive individuals with systolic blood pressure below 140 mmHg , which suggests that pulse pressure may be useful to predict the risk of stroke among middle-aged nonsystolic hypertensive patients Objective : To evaluate which blood pressure measure is the best predictor of risk of total , ischemic , and hemorrhagic stroke . Methods : The authors used a prospect i ve cohort study among 11,466 men followed for incident stroke during a median of 19.4 years in the Physicians ' Health Study . Systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) were self-reported . They calculated relative risks ( RRs ) and 95 % CIs for total , ischemic , and hemorrhagic stroke using Cox proportional hazards models . Model fit was compared using the χ2 test statistic from likelihood ratio tests . Results : During follow-up , 508 strokes occurred ( 411 ischemic , 89 hemorrhagic , and eight of unknown etiology ) . For each 10-mm Hg increase in SBP , the multivariable RRs were 1.31 ( 95 % CI : 1.20 to 1.42 ) for total stroke , 1.28 ( 95 % CI : 1.16 to 1.40 ) for ischemic stroke , and 1.38 ( 95 % CI : 1.13 to 1.68 ) for hemorrhagic stroke . Although DBP , pulse pressure , and mean arterial pressure were all significant predictors of stroke risk , none was a significantly better predictor than SBP alone . Adding DBP did not significantly improve the model fit of SBP alone for any stroke type . Conclusion : In this large cohort of initially healthy men , systolic blood pressure was a consistent and significant predictor of total , ischemic , and hemorrhagic stroke . Systolic blood pressure alone was the only measure necessary to predict risk of total stroke or its major subtypes Background and Purpose — The purpose of this prospect i ve cohort study was to investigate associations between stroke and blood pressure ( BP ) indices ( systolic BP [ SBP ] , diastolic BP [ DBP ] , mean BP , and pulse pressure [ PP ] ) determined by home BP measurement . Methods — Associations between stroke and BP indices were examined in a rural Japanese population . Home BP data of 2369 subjects ( 40 % men ) ≥35 years of age ( mean , 59 years ) without a history of stroke were obtained . Associations between stroke and each index were determined using Cox proportional hazards regression and the likelihood ratio ( LR ) test . Results — During follow-up ( mean , 11.7 years ) , 238 strokes occurred . The LR test showed that SBP and mean BP were significantly more strongly associated with total and ischemic stroke than DBP and PP ( LR & khgr;2 ≥9.3 , P<0.01 for SBP/mean BP , LR & khgr;2 ≤3.8 , P≥0.05 for DBP/PP ) . SBP tended to be more strongly associated with total/ischemic stroke than mean BP ( LR & khgr;2=3.8 , P=0.05 for SBP , LR & khgr;2 ≤0.2 , P>0.6 for mean BP ) . PP tended to be slightly more strongly associated with ischemic stroke than DBP ( LR & khgr;2=7.5 , P<0.01 for DBP , LR & khgr;2=9.3 , P<0.01 for PP ) , whereas DBP was significantly more strongly associated with hemorrhagic stroke than PP ( LR & khgr;2=9.2 , P<0.01 for DBP , LR & khgr;2=2.5 , P=0.01 for PP ) . Conclusion — PP obtained from home BP measurements was weakly associated with stroke , whereas SBP showed the strongest association . Additionally , DBP and PP may be associated with different stroke types Background Our objective was to test the hypothesis that elevated blood pressure ( BP ) is associated with increased risk of stroke , bleeding and death in patients with incident heart failure ( HF ) . Methods We conducted a prospect i ve cohort study among subjects who were participants in the Diet , Cancer and Health study , born in Denmark , aged 50–64 years at recruitment . We assessed stroke ( ischemic stroke or systemic embolic events ) , major bleeding , death and the composite endpoint according to degree of BP control in patients with incident HF . BP was assessed prior to HF at cohort entry . Results Of the whole cohort of 55,748 subjects , n = 2159 ( 35 % female ) had incident HF , of which 12 % had treatment for hypertension . Median follow-up after incident HF was 3.5 years . High systolic ( SBP ) , diastolic ( DBP ) and pulse ( PP ) pressures were associated with an increased risk of stroke , major bleeding and the composite endpoint . For death and stroke/death , the relation appeared U-shaped for SBP and DBP . When comparing the highest quartile group ( Q4 ) to first quartile group ( Q1 ) , SBP ( Q4 : SBP > 163 mmHg ) was associated with significantly higher adjusted hazard rate ratio ( HR ) for stroke ( HR 1.46 , 95 % CI 1.00–2.14 ) and major bleeding ( HR 1.68 , 95 % CI 1.12–2.53 ) . For DBP ( Q4 : DBP > 94 mmHg ) , adjusted HR was significantly higher for major bleeding ( HR 1.63 , 95 % CI 1.13–2.38 ) . The highest quartile of pulse pressure ( Q4 : PP > 74 mmHg ) was associated with non-significantly higher risk of stroke ( HR 1.40 , 95 % CI 0.94–2.06 ) . Conclusion We have shown for the first time that amongst a population with incident HF , higher baseline systolic , diastolic and pulse pressure levels were associated with a higher rate of adverse events . Our data support the importance for optimised BP control , as part of the holistic management of HF patients Pulse pressure has been related to higher risk of cardiovascular events in older persons . Isolated systolic hypertension is common among the elderly and is accompanied by elevated pulse pressure . Treatment of isolated systolic hypertension may further increase pulse pressure if diastolic pressure is lowered to a greater extent than systolic pressure . Little is known regarding pulse pressure as a predictor of cardiovascular outcomes in elderly persons with isolated systolic hypertension , and the influence of treatment on the pulse pressure effect . We assessed the relation between pulse pressure , measured throughout the follow-up period , and the incidence of coronary heart disease ( CHD ) , heart failure ( HF ) , and stroke in 4,632 participants in the Systolic Hypertension in the Elderly Program , a 5-year r and omized , placebo-controlled clinical trial of treatment of isolated systolic hypertension in older adults . In the treatment group , a 10-mm Hg increase in pulse pressure was associated with a statistically significant 32 % increase in risk of HF and a 24 % increase in risk of stroke after controlling for systolic blood pressure and other known risk factors , as well as with a 23 % increase in risk of HF and a 19 % increase in risk of stroke after controlling for diastolic blood pressure and other risk factors . Pulse pressure was not significantly associated with HF or stroke in the placebo group , nor with incidence of CHD in either the placebo or treatment group . These results suggest that pulse pressure is a useful marker of risk for HF and stroke among older adults being treated for isolated systolic hypertension OBJECTIVES The aim of this study was to determine whether pulse pressure is a risk factor for coronary artery disease using data from the MRC trial of treatment of mild hypertension , and whether the effect of anti-hypertensive drug therapy on pulse pressure may be a determinant of outcome in treated patients . METHODS Logistic regression and Cox regression analyses were used to compare systolic and diastolic blood pressure , pulse pressure and mean blood pressure as predictors of coronary events and stroke in the MRC Mild Hypertension Trial . The effects of anti-hypertensive drug treatment with bendrofluazide and propranolol on pulse pressure were assessed using 1-year follow-up data . Event rates in the placebo-treated group and responses to anti-hypertensive treatment were measured in quartiles of age-adjusted entry pulse pressure . A ' four-corners ' analysis was performed , with subjects divided into the upper and lower halves of the distributions of systolic and diastolic blood pressure at entry . RESULTS Pulse pressure was a stronger predictor of coronary events than systolic , diastolic or mean blood pressure in males by logistic regression . Pulse pressure was similar to systolic pressure as a coronary event predictor on Cox regression . Stroke was predicted most strongly by mean blood pressure . Fatal and non-fatal coronary event rates increased progressively in ascending quartiles of age-adjusted pulse pressure , but there was also a strong correlation with systolic blood pressure . The values of partial logistic regression coefficients in models containing both systolic and diastolic blood pressure also supported a role for pulse pressure in predicting coronary events and for mean blood pressure in predicting stroke . Coronary risk , but not stroke , was inversely related to diastolic blood pressure in the four-corners analysis . In a Cox model , regressions of coronary event probability on systolic blood pressure at entry were significantly and inversely related to diastolic blood pressure categorized in quartiles . Bendrofluazide but not propranolol decreased pulse pressure significantly and was associated with a reduction in cardiovascular events overall , but no definite relationship between the effect of drugs on pulse pressure and specific responses to treatment was seen . CONCLUSION Pulse pressure is a strong risk factor for coronary events in untreated hypertensive male subjects in the MRC Mild Hypertension Trial , whereas stroke is best predicted by mean blood pressure . Bendrofluazide and propranolol have different effects on pulse pressure which may be related to their relative efficacy in the treatment of hypertension , but this possibility requires further study in more suitable population Objective Increased arterial stiffness is a determinant of cardiovascular mortality . Pulse wave velocity ( PWV ) is a direct measure of arterial stiffness . Aortic augmentation index ( AI ) and pulse pressure ( PP ) are surrogate measures of arterial stiffness . Both PWV , AI and PP increase with cardiovascular risk factors . The aim of this study was to test the validity of AI and PP as surrogate measures of arterial stiffness compared with PWV , during beta-adrenergic stimulation with Isoprenaline ( Iso ) . Design and methods A total of 41 healthy volunteers entered a r and omized , double-blind , placebo-controlled , cross-over study . In r and om order , subjects were given intravenous infusion in equal volume of Iso 8 μg/kg per min ( dissolved in glucose 5 % ) and placebo ( glucose 5 % ) . A wash-out period of 25 min was observed between the infusions . Measurements included blood pressure ( BP ) , heart rate ( HR ) , PWV , and AI . PWV were determined using complior ( Complior , Artech-Medical , Paris , France ) . AI and aortic PP were obtained from pulse wave analysis of radial applanation tonometry , using transfer function ( SphygmoCor Windows software ) . Results Baseline AI increased ( P < 0.05 ) with aging , a lower height and a larger diastolic BP ( DBP ) . Iso increased ( P < 0.0001 ) HR , brachial SBP , brachial and aortic PP as compared with placebo . In contrast , Iso decreased ( P < 0.05 ) AI , brachial DBP , peripheral PWV , but not aortic PWV . Decrease of AI induced by Iso was not related to PWV . In stepwise multiple regression changes in HR , brachial SBP and DBP were independent determinants of AI response to Iso ( r = 0.78 , P < 0.0001 ) . Conclusions Our findings show that AI and PP fail as surrogate measures of arterial stiffness during beta-adrenergic stimulation Objective An age-dependent relationship between aortic and left ventricular ( LV ) stiffening has been observed in community-based adults . Our aim was to compare the performances of wave reflection-dependent ( pulse pressure ) and independent [ carotid-femoral pulse wave velocity ( PWV ) ] indexes of aortic stiffness to detect pre clinical LV diastolic dysfunction . Methods In this case – control study , a stratified sub sample of participants of a population -based echocardiographic survey with LV ejection fraction higher than 45 % and without overt heart failure was r and omly selected to undergo assessment of brachial blood pressure , LV diastolic function by Doppler echocardiography , and estimation of central aortic pressures and PWV by applanation tonometry . Results Of the 233 subjects ( mean age 73 ± 6 years , 54 % men ) , 84 had normal diastolic function , 99 had mild diastolic dysfunction , and 50 had moderate or severe diastolic dysfunction . Brachial pulse pressure , central pulse pressure , and PWV progressively increased according to the severity of diastolic dysfunction , independent of age and sex . The overall performance of PWV was superior to brachial pulse pressure [ area under receiver operating characteristic curve ( AUC ) : 0.70 versus 0.59 , respectively ; P = 0.005 ] and central pulse pressure ( AUC : 0.70 versus 0.56 , respectively ; P = 0.001 ) for the detection of any diastolic dysfunction . Conclusion PWV appeared to be superior to central and brachial pulse pressure for the detection of diastolic dysfunction in older adults with ‘ preserved ’ LV ejection fraction AIM The purpose of this study was to assess the relationship between pulse pressure ( PP ) and cardiovascular outcomes in a large , elderly , coronary artery disease ( CAD ) population with hypertension , and compare the predictive power of PP with other blood pressure measures . METHODS AND RESULTS In INternational VErapamil-tr and olapril STudy , 22,576 CAD patients with hypertension ( mean age 66 years ) were r and omized to verapamil-SR or atenolol-based strategies and followed for 2.7 years ( mean ) . Primary outcome ( PO ) was time to first occurrence of death ( all-cause ) , non-fatal myocardial infa rct ion ( MI ) , or non-fatal stroke . Mean follow-up PP was summarized by 5 mmHg subgroups for association with incidence of PO . Stepwise Cox proportional hazards models were used to estimate adjusted relative hazard ratios ( HR ) for the risk of PO with follow-up PP as a continuous variable , with linear and quadratic terms . Similar models were constructed for follow-up systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , and mean arterial pressures ( MAP ) . A -2 log-likelihood statistic was used to assess the predictive power of PP compared with SBP , DBP , and MAP . For follow-up PP , the incidence and adjusted HR for the PO formed a J- or U-shaped curve . After adjusting for baseline covariates , both linear and quadratic terms for PP were significant ( P < 0.0001 for both ) , with a nadir of 54 mmHg ( bootstrapping 95 % CI 42 - 60 mmHg ) . Similar quadratic relationships were found between PP and all-cause mortality or MI ; the relationship between PP and stroke was linear . Pulse pressure was a predictor of PO even after including SBP ( P = 0.007 linear term ) or DBP ( P < 0.0001 for both linear and quadratic terms ) or MAP ( P < 0.01 for both liner and quadratic terms ) in the model . Using -2 log-likelihood differences , SBP ( -2 log-likelihood difference 77.1 vs. 7.3 for PP ) , DBP ( -2 log-likelihood difference 138.5 vs. 44.6 for PP ) , and MAP ( -2 log-likelihood difference 125.0 vs. 13.4 for PP ) were stronger predictors of PO than PP . CONCLUSION In CAD patients with hypertension , PP ( on anti-hypertensive treatment ) is a weaker predictor of cardiovascular outcomes than SBP , DBP , or MAP Summary The latter was due to a reduction in cardiac mortality ( −38 % , p=0.036 ) and a nonsignificant decrease in cerebrovascular mortality ( −32 % , p=0.16 ) . In the double-blind part of the trial , the total mortality rate was not significantly reduced ( −26 % , p=0.077 ) . However , cardiovascular mortality was reduced in the actively treated group ( −38 % , p=0.023 ) , owing to a reduction in cardiac deaths ( −47 % , p=0.048 ) and a non-significant decrease in cerebrovascular mortality ( −43 % , p=0.15 ) . Deaths from myocardial infa rct ion were reduced ( −60 % , p=0.043 ) , and study -terminating morbid cardiovascular events were significantly reduced by active treatment ( −60 % , p=0.0064 ) . Non-terminating cerebrovascular events were reduced ( −52 % , p=0.026 ) , but the non-terminating cardiac events were not ( + 3 % , p=0.98 ) . In the patients r and omised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial . A double-blind r and omised placebo-controlled trial of antihypertensive treatment was conducted in patients over the age of 60 . Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90 to 119 mm Hg and a systolic pressure in the range 160 to 239 mm Eg . 840 patients were r and omised either to active treatment ( hydrochlorothiazide and triamterene ) or to matching placebo . If the blood pressure remained raised , methyldopa was added to the active regimen and matching placebo in the placebo group . An overall intention-to-treat analysis , combining the double-blind part of the trial and all subsequent follow-up , revealed a non-significant change in total mortality rate ( −9 % , p=0.41 ) but a significant reduction in cardiovascular mortality rate ( −27 % , p=0.037 ) Background A poor outcome after stroke is associated independently with high blood pressure during the acute phase ; however , relationships with other haemodynamic measures [ heart rate ( HR ) , pulse pressure ( PP ) , rate – pressure product ( RPP ) ] remain less clear . Methods The Tinzaparin in Acute Ischaemic Stroke Trial is a r and omised , controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke . Systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) and HR measurements taken immediately prior to r and omization were averaged , and the mid-blood pressure ( MBP ) , PP , mean arterial pressure ( MAP ) , pulse pressure index , and RPP were calculated . The relationship between these haemodynamic measures and functional outcome ( death or dependency , modified Rankin Scale > 2 ) and early recurrent stroke , were studied with adjustment for baseline prognostic factors and treatment group . Odds ratios ( OR ) and 95 % confidence intervals ( CI ) refer to a change in haemodynamic measure by 10 points . Results A poor functional outcome was associated with SBP ( adjusted OR ; 1.11 ; 95 % CI , 1.03–1.21 ) , HR ( adjusted OR ; 1.15 ; 95 % CI , 1.00–1.31 ) , MBP ( adjusted OR ; 1.15 , 95 % CI , 1.03–1.29 ) , PP ( adjusted OR ; 1.14 ; 95 % CI , 1.02–1.26 ) , MAP ( adjusted OR ; 1.15 ; 95 % CI , 1.02–1.31 ) and RPP ( adjusted OR ; 1.01 ; 95 % CI , 1.00–1.02 ) . Early recurrent stroke was associated with SBP , DBP , MBP and MAP . Conclusions A poor outcome is independently associated with elevations in blood pressure , HR and their derived haemodynamic variables , including PP and the RPP . Agents that modify these measures may improve functional outcome after stroke The current guidelines for the detection and management of high blood pressure depend exclusively on the measurement of systolic and diastolic blood pressure , although these are only two specific points on the arterial pressure wave form [ 1,2 ] . However , it may be more appropriate to describe the cardiac cycle as consisting of a pulsatile ( pulse pressure ) and a steady ( mean pressure ) component . Pulse pressure is defined as the difference between systolic and diastolic pressures and primarily reflects the stiffness of large arteries , especially the aorta . Elevated pulse pressure increases the stretch of arteries , induces fatigue and fracture of elastic elements , and accelerates the development of aneurysms , and ultimately their rupture . Similarly , an increased pulse pressure is more likely to contribute to intimal damage , the prelude to atherosclerosis and arterial thrombotic events . Increased pulse pressure has also been associated with thickening of the carotid intima and media [ 3,4 ] . Systolic blood pressure increases across all age groups , whereas diastolic blood pressure increases until the sixth decade of life and then declines thereafter . As a result , pulse pressure increases as age rises , especially in older people as systolic and diastolic blood pressure move in opposite directions . Hence , pulse pressure may become the key blood pressure measure in older individuals and increase in importance as a risk factor for cerebrovascular diseases and death [ 5,6 ] . Several observational studies have found that pulse pressure is an independent predictor of cardiovascular risk in middle aged and older people , in subjects with high blood pressure , in survivors of myocardial infa rct ion and in patients with left ventricular dysfunction [ 7–11 ] . A meta analysis based on individual patient data from three large trials ( Syst-Eur , SystChina and EWPHE [ 12–14 ] ) showed that isolated systolic hypertension and pulse pressure were the major determinants of cardiovascular risk in elderly hypertensives [ 7 ] . A further meta- analysis of individual patient data in control groups of seven r and omized clinical trials ( SHEP , Syst-Eur , MRC 1 , HEP , MRC 2 , EWPHE and STOP ) in the INDANA project [ 8 ] also reported that pulse pressure , rather than mean pressure , was the major risk factor for adverse cardiovascular events . A 10-mmHg increase in pulse pressure at baseline was associated independently with a 6 % rise in total mortality , a 7 % rise in cardiovascular mortality and a 7 % rise in fatal coronary events . A similar rise in fatal stroke was present , although this was statistically nonsignificant due to the limited number of events . However , the relationship between pulse pressure and fatal stroke became significant ( p = 0.04 ) at higher age [ 8 ] . Importantly , pulse pressure calculated from 24 h ambulatory blood pressure recordings is a better predictor of adverse events than if derived from officemeasured blood pressure in older patients with isolated systolic hypertension [ 15 ] Abstract Background . The relationship between pulse pressure ( PP ) and stroke has been described in population s outside Japan . Here , we investigated the relationship between PP and stroke incidence in Japan . Methods . Study subjects were 11,097 people ( 4315 men and 6782 women ) in 12 rural areas of Japan enrolled in the Jichi Medical School Cohort Study , a population -based prospect i ve study . The subjects were divided into quintiles of PP . Baseline data were obtained by question naire and health checkups between April 1992 and July 1995 , and the incidence of all strokes and stroke subtypes was monitored . Results . A total of 412 strokes were observed during a mean follow-up period of 10.7 years . After adjusting for age , smoking status , drinking status , total cholesterol , low-density lipoprotein-cholesterol , high-density lipoprotein-cholesterol , body mass index and diabetes mellitus , hazard ratios [ HRs ] in the second to fifth quintiles of PP for all strokes were 1.06 ( 95 % confidence interval [ CI ] 0.69–1.64 ) , 1.53 ( CI 1.02–2.28 ) , 2.02 ( CI 1.38–2.96 ) and 2.22 ( CI 1.53–3.20 ) compared with the first quintile using Cox 's proportional hazard model , respectively . Conclusion . Our findings suggest high PP is at an increased risk of stroke

Patient characteristics may be important predictors of AMI readmission ; however , few variables were consistently identified .

BACKGROUND Readmission after acute myocardial infa rct ion ( AMI ) has been targeted for public reporting because it is a common , costly , and often preventable outcome . To assist in ongoing efforts to risk-stratify patients and profile hospitals through public reporting of performance measures , we conducted a systematic review to identify models design ed to compare hospital rates of readmission or predict patients ' risk of readmission after AMI and to identify studies evaluating patient characteristics associated with AMI readmission .

BACKGROUND Whether there is an association between depression at the time of acute myocardial infa rct ion and subsequent risk of cardiac complications and death remains controversial . Most studies of this risk factor have been limited to patients of single institutions , and this might account for the varying results . We prospect ively evaluated patients admitted to 5 tertiary care and 5 community hospitals and followed them for 1 year to measure the prevalence and prognostic impact of depressive symptoms after acute myocardial infa rct ion . METHODS Patients were recruited for the study by trained nurse interviewers who had documented acute myocardial infa rct ion within 2 - 3 days of admission . The nurses collected information from the medical records and asked study subjects to complete the Beck Depression Inventory question naire during their stay in hospital and using a mailed question naire 30 days , 6 months and 1 year later . We obtained information on vital status for patients lost to follow-up from a central death registry . RESULTS Of the 587 study subjects , 550 ( 94 % ) completed the Beck Depression Inventory at baseline and 191 ( 35 % ) had a score of 10 or more , indicating at least mild depression . Rates of depression did not vary over the follow-up period and were similar among patients admitted to tertiary care or community hospitals . Depressed patients were more likely to undergo catheterization ( 57 % v. 47 % , 95 % confidence interval [ CI ] around the difference 0.1%-19.6 % ) and were more likely to undergo percutaneous coronary intervention ( 32 % v. 24 % , 95 % CI around the difference 0.1%-16.2 % ) within 30 days of first admission to hospital . Patients with depression on admission had higher rates of a composite of cardiac complications , including recurrent ischemia , infa rct ion or congestive heart failure during their first stay in hospital or readmission for angina , recurrent acute myocardial infa rct ion , congestive heart failure or arrhythmia ( adjusted hazard ratio 1.4 , 95 % CI 1.05 - 1.86 ) , compared with patients who were not depressed on admission . After 1 year , death rates were higher among patients who were depressed at admission ( 30 patients , 16 % ) compared with nondepressed patients ( 28 patients , 8 % ) , although the difference was not statistically significant ( hazard ratio 1.3 , 95 % CI 0.59 - 3.05 ) . INTERPRETATION Depressive symptoms are common after acute myocardial infa rct ion and are associated with a slight increase in risk of in-hospital catheterization and angiography and readmission because of cardiac complications . Death was infrequent , with no statistically significant difference between the 2 groups Background —Few data are available on the impact of heart failure ( HF ) across all types of acute coronary syndromes ( ACS ) . Methods and Results —The Global Registry of Acute Coronary Events ( GRACE ) is a prospect i ve study of patients hospitalized with ACS . Data from 16 166 patients were analyzed : 13 707 patients without prior HF or cardiogenic shock at presentation were identified . Of these , 1778 ( 13 % ) had an admission diagnosis of HF ( Killip class II or III ) . HF on admission was associated with a marked increase in mortality rates during hospitalization ( 12.0 % versus 2.9 % [ with versus without HF ] , P < 0.0001 ) and at 6 months after discharge ( 8.5 % versus 2.8 % , P < 0.0001 ) . Of note , HF increased mortality rates in patients with unstable angina ( defined as ACS with normal biochemical markers of necrosis ; mortality rates : 6.7 % with versus 1.6 % without HF at admission , P < 0.0001 ) . By logistic regression analysis , admission HF was an independent predictor of hospital death ( odds ratio , 2.2 ; P < 0.0001 ) . Admission HF was associated with longer hospital stay and higher readmission rates . Patients with HF had lower rates of catheterization and percutaneous cardiac intervention , and fewer received & bgr;-blockers and statins . Hospital development of HF ( versus HF on presentation ) was associated with an even higher in-hospital mortality rate ( 17.8 % versus 12.0 % , P < 0.0001 ) . In patients with HF , in-hospital revascularization was associated with lower 6-month death rates ( 14.0 % versus 23.7 % , P < 0.0001 ; adjusted hazard ratio , 0.5 ; 95 % CI , 0.37 to 0.68 , P < 0.0001 ) . Conclusions —In this observational registry , heart failure was associated with reduced hospital and 6-month survival across all ACS subsets , including patients with normal markers of necrosis . More aggressive treatment of these patients may be warranted to improve prognosis CONTEXT The prevalence and consequences of financial barriers to health care services and medications are not well documented for patients with an acute myocardial infa rct ion ( AMI ) . OBJECTIVE To measure the baseline prevalence of self-reported financial barriers to health care services or medication ( as defined by avoidance due to cost ) among individuals following AMI and their association with subsequent health care outcomes . DESIGN , SETTING , AND PARTICIPANTS The Prospect i ve Registry Evaluating Myocardial Infa rct ion : Event and Recovery ( PREMIER ) , an observational , multicenter US study of patients with AMI over 12 months in 2498 individuals enrolled from January 2003 through June 2004 . MAIN OUTCOME MEASURES Health status symptoms ( Seattle Angina Question naire [ SAQ ] ) , overall health status function ( Short Form-12 ) , and rehospitalization . RESULTS The prevalence of self-reported financial barriers to health care services or medication was 18.1 % and 12.9 % , respectively . Among individuals who reported financial barriers to health care services or medication , 68.9 % and 68.5 % , respectively , were insured . At 1-year follow-up , individuals with financial barriers to health care services were more likely to have lower SAQ quality -of-life score ( 77.9 vs 86.2 ; adjusted mean difference= -4.0 ; 95 % confidence interval [ CI ] , -6.3 to -1.8 ) , and increased rates of all-cause rehospitalization ( 49.3 % vs 38.1 % ; adjusted hazard ratio [ HR ] , 1.3 ; 95 % CI , 1.1 - 1.5 ) and cardiac rehospitalization ( 25.7 % vs 17.7 % ; adjusted HR , 1.3 ; 95 % CI , 1.0 - 1.6 ) . At 1-year follow-up , individuals with financial barriers to medication were more likely to have angina ( 34.9 % vs 17.9 % ; adjusted odds ratio , 1.55 ; 95 % CI , 1.1 - 2.2 ) , lower SAQ quality -of-life score ( 74.0 vs 86.1 ; adjusted mean difference = -7.6 ; 95 % CI , -10.2 to -4.9 ) , and increased rates of all-cause rehospitalization ( 57.0 % vs 37.8 % ; risk-adjusted HR , 1.5 ; 95 % CI , 1.2 - 1.8 ) and cardiac rehospitalization ( 33.7 % vs 17.3 % ; adjusted HR , 1.7 ; 95 % CI , 1.3 - 2.2 ) . CONCLUSION Financial barriers to health care services and medications are associated with worse recovery after AMI , manifested as more angina , poorer quality of life , and higher risk of rehospitalization Background — The role of the vasopressin system after acute myocardial infa rct ion is unclear . Copeptin , the C-terminal part of the vasopressin prohormone , is secreted stoichiometrically with vasopressin . We compared the prognostic value of copeptin and an established marker , N-terminal pro-B-type natriuretic peptide ( NTproBNP ) , after acute myocardial infa rct ion . Methods and Results — In this prospect i ve single-hospital study , we recruited 980 consecutive post – acute myocardial infa rct ion patients ( 718 men , median [ range ] age 66 [ 24 to 95 ] years ) , with follow-up over 342 ( range 0 to 764 ) days . Plasma copeptin was highest on admission ( n=132 , P<0.001 , day 1 versus days 2 to 5 ) and reached a plateau at days 3 to 5 . In the 980 patients , copeptin ( measured at days 3 to 5 ) was elevated in patients who died ( n=101 ) or were readmitted with heart failure ( n=49 ) compared with survivors ( median [ range ] 18.5 [ 0.6 to 441.0 ] versus 6.5 [ 0.3 to 267.0 ] pmol/L , P<0.0005 ) . With logistic regression analysis , copeptin ( odds ratio , 4.14 , P<0.0005 ) and NTproBNP ( odds ratio , 2.26 , P<0.003 ) were significant independent predictors of death or heart failure at 60 days . The area under the receiver operating characteristic curves for copeptin ( 0.75 ) and NTproBNP ( 0.76 ) were similar . The logistic model with both markers yielded a larger area under the curve ( 0.84 ) than for NTproBNP ( P<0.013 ) or copeptin ( P<0.003 ) alone , respectively . Cox modeling predicted death or heart failure with both biomarkers ( log copeptin [ hazard ratio , 2.33 ] , log NTproBNP [ hazard ratio , 2.70 ] ) . In patients stratified by NTproBNP ( above the median of ≈900 pmol/L ) , copeptin above the median ( ≈7 pmol/L ) was associated with poorer outcome ( P<0.0005 ) . Findings were similar for death and heart failure as individual end points . Conclusions — The vasopressin system is activated after acute myocardial infa rct ion . Copeptin may predict adverse outcome , especially in those with an elevated NTproBNP ( more than ≈900 pmol/L ) BACKGROUND Disease management programs ( DMPs ) that use multidisciplinary teams and specialized clinics reduce hospital admissions and improve quality of life and functional status . Evaluations of cardiac DMPs delivered by home health nurses are required . METHODS Between August 1999 and August 2000 we identified consecutive patients admitted to hospital with elevated cardiac enzymes . Patients who agreed were r and omly assigned to participate in a DMP or to receive usual care . The DMP included 6 home visits by a cardiac-trained nurse , a st and ardized nurses ' checklist , referral criteria for specialty care , communication with the family physician and patient education . We measured readmission days per 1000 follow-up days for angina , congestive heart failure ( CHF ) and chronic obstructive pulmonary disease ( COPD ) ; all-cause readmission days ; and provincial cl aims for emergency department visits , physician visits , diagnostic or therapeutic services and laboratory services . RESULTS We screened 715 consecutive patients admitted with elevated cardiac markers between August 1999 and August 2000 . Of those screened 71 DMP and 75 usual care patients met the diagnostic criteria for myocardial infa rct ion , were eligible for visits from a home health nurse and consented to participate in the study . Readmission days for angina , CHF and COPD per 1000 follow-up days were significantly higher for usual care patients than for DMP patients ( incidence density ratio [ IDR ] = 1.59 , 95 % confidence interval [ CI ] 1.27 - 2.00 , p < 0.001 ) . All-cause readmission days per 1000 follow-up days were significantly higher for usual care patients than for DMP patients ( IDR = 1.53 , 95 % CI 1.37 - 1.71 , p < 0.001 ) . The difference in emergency department encounters per 1000 follow-up days was significant ( IDR = 2.08 , 95 % CI 1.56 - 2.77 , p < 0.001 ) . During the first 25 days after discharge , there were significantly fewer provincial cl aims su bmi tted for DMP patients than for usual care patients for emergency department visits ( p = 0.007 ) , diagnostic or therapeutic services ( p = 0.012 ) and laboratory services ( p = 0.007 ) . INTERPRETATION The results provide evidence that an appropriately developed and implemented community-based inner-city DMP delivered by home health nurses has a positive impact on patient outcomes Although chronic obstructive pulmonary disease ( COPD ) is common in patients with myocardial infa rct ion ( MI ) , its association with long-term mortality after MI is controversial and little is known about its influence on patients ' health status ( symptoms , function , and quality of life ) . We prospect ively enrolled 2,481 patients presenting with MI at 19 United States centers to examine the relations between COPD and patients ' long-term mortality , rehospitalization rates , and health status after MI . Patients were administered the disease-specific Seattle Angina Question naire and the generic Short Form 12 at baseline and 1 year later . COPD was common ( 15.6 % of patients ) and was associated with a substantially greater risk of 1-year mortality ( 15.8 % vs 5.7 % , p < 0.001 ) and rehospitalization ( 48.7 % vs 38.6 % , p < 0.001 ) . After extensive adjustment for baseline differences , patients with COPD had a twofold greater 1-year mortality rate ( hazard ratio 2.00 , 95 % confidence interval [ CI ] 1.44 to 2.79 ) and higher rehospitalization rates ( hazard ratio 1.22 , 95 % CI 1.01 to 1.48 ) . Similarly , adjusted 1-year health status was worse in patients with COPD , with lower 1-year Seattle Angina Question naire quality -of-life score ( -2.53 points , 95 % CI -0.25 to -4.81 ) and Short Form 12 physical component score ( -1.83 points , 95 % CI -0.43 to -3.24 ) . In addition , COPD was associated with a trend toward a greater prevalence of angina at 1 year ( risk ratio 1.12 , 95 % CI 0.89 to 1.41 ) . In conclusion , patients with COPD have greater mortality , higher rehospitalization rates , and poorer health status 1 year after a MI . Although additional research is needed , clinicians should recognize that patients with COPD are at high risk for poor outcomes after MI Previous reports indicate that patients who do not develop Q waves after thrombolytic therapy are a different population with a better long-term survival than those who do develop Q waves . However , the use of re sources , quality of life , and health status of this population have not been fully evaluated . Using data from the Economics and Quality of Life subset of the Global Utilization of Streptokinase and tPA for Occluded Arteries study , we examined 30-day and 1-year mortality , use of re sources , and quality -of-life measures among 1,830 of 3,000 patients with acute myocardial infa rct ion and ST-segment elevation treated with thrombolytic therapy . At hospital discharge , 555 patients ( 30.2 % ) had not developed Q waves . These patients had lower mortality than patients with Q waves at 30 days ( 1.6 % vs 4.5 % , p < 0.01 ) and at 1 year ( 4.7 % vs 6.8 % , p < 0.04 ) . Recurrent chest pain and dyspnea were similar at 30 days and 1 year . Patients without Q waves had significantly more angiography and trends toward higher readmission , revascularization , and use of calcium antagonists at 30 days . Angiography , revascularization , readmission , and quality of life were equivalent from 30 days to 1 year , with no sign of late instability . Logistic regression analysis showed an association between in-hospital revascularization and better survival and quality of life at 1 year . Conversely , there was no association between in-hospital use of calcium antagonists and outcome to explain the lower mortality in non-Q-wave patients . The absence of Q waves after thrombolytic therapy is a marker of success , implying better prognosis and equivalent quality of life , use of re sources , and health status than for patients with Q-wave acute myocardial infa rct ion and no sign of long-term unstable clinical course BACKGROUND During the last 5 years , many studies have produced conflicting results concerning the survival of women hospitalized with acute myocardial infa rct ion ( AMI ) . OBJECTIVE To determine if gender is associated with hospital mortality and long-term survival in individuals with AMI . METHODS This prospect i ve study included 4255 consecutive women ( 34 % ) and 8076 ( 66 % ) men who developed AMI in 19 Seattle , Wash , area hospitals between January 1988 and June 1994 . Key information was abstract ed from hospital records and entered in the Myocardial Infa rct ion Triage and Intervention registry data base . In addition , data concerning survival and rehospitalization were obtained from the state of Washington and linked to the Myocardial Infa rct ion Triage and Intervention registry . RESULTS In comparison with men , women were 8 years older , more often had history of congestive heart failure , hypertension , or diabetes mellitus , and less often had history of myocardial infa rct ion or coronary surgery . During hospitalization , women were less likely to undergo coronary angiography , thrombolytic therapy , coronary angioplasty , or bypass surgery . After adjustment for covariates , women were 20 % more likely to die in the hospital ( odds ratio , 1.22 ; 95 % confidence interval , 1.06 - 1.39 ) , yet long-term survival was similar in the 2 groups ( hazard ratio , 0.97 ; 95 % confidence interval , 0.90 - 1.05 ) . The use of thrombolytic therapy or revascularization during the index hospitalization did not change the association between gender and survival . CONCLUSIONS All things being equal , women with AMI were more likely to die in the hospital , yet survival after hospital discharge did not differ according to gender . Appropriate treatment to reduce hospital mortality in women is needed Objective To determine the safety and prognostic value of dipyridamole thallium-201 scintigraphy performed in patients within three to five days of acute myocardial infa rct ion , including those receiving thrombolytic treatment . Design A prospect i ve study of dipyridamole thallium-201 scintigraphy in patients early after acute myocardial infa rct ion . Setting University hospital . Patients 200 patients who were clinical ly uncomplicated at day 3 after infa rct ion , 92 ( 46 % ) of whom had received thrombolysis . Main outcome measures Incidence of cardiac death , non-fatal reinfa rct ion , readmission to hospital for unstable angina , or non-elective revascularisation procedure within six months ’ follow up . Results No patient had a serious complication from the dipyridamole study . At six month follow up , 55 patients ( 28 % ) had suffered a defined cardiac event . Patients who received thrombolysis had the same extent of thallium-201 redistribution and the same occurrence of subsequent cardiac events as those not receiving thrombolysis . Patients who subsequently had an event had more myocardial segments showing thallium-201 redistribution than event free patients : 2.7 ( SD 1.9 ) v 1.2 ( 1.4 ) , respectively ( p < 0.001 ) . Among all clinical and scintigraphic variables , multivariate analysis identified the extent of thallium-201 redistribution as the only independent predictor of outcome ( p < 0.001 ) . Among 63 patients ( 32 % ) of the study cohort who showed more than two myocardial segments with thallium-201 redistribution , the adjusted risk ratio for a cardiac event was 7.5 ( 95 % confidence interval 2.9 to 19.1 ) compared with patients without any redistribution . Conclusions Dipyridamole thallium-201 scintigraphy can be performed safely within a few days of the event in patients with uncomplicated myocardial infa rct ion , including those who received thrombolysis , and can identify a subgroup of patients at high risk of future ischaemic events Background : After the cardiovascular events of myocardial infa rct ion ( MI ) and coronary artery bypass surgery ( CABS ) , unpartnered older adults are a vulnerable group that may benefit from interventions to improve health outcomes . The purpose of this analysis is to determine if a community-based collaborative peer advisor/advanced practice nurse intervention increased participation in cardiac rehabilitation programs and reduced hospital readmissions after MI and CABS and determine whether the type of cardiovascular event influenced rehospitalization . Subjects and Methods : This study was a r and omized clinical trial that enrolled 247 unpartnered older adults who were single , widowed , or divorced . Subjects were r and omized into 4 groups : st and ard of care group for MI and for CABS and st and ard of care plus the treatment groups for MI and for CABS , for 12 weeks after discharge . There were 163 women/84 men , with a mean age of 76.4 years , who were admitted for MI ( n = 93 ) or CABS ( n = 154 ) and who were enrolled from 5 academic medical centers . The treatment consisted of a community-based intervention of a home visit within 72 hours and telephone calls at 2 , 6 , and 10 weeks from an advanced practice nurse and 12 weekly telephone calls from a peer advisor . Participation in a cardiac rehabilitation program and rehospitalizations were collected at 6 weeks and 3 , 6 , and 12 months by telephone interview . Results and Conclusions : There were significantly more participants in cardiac rehabilitation programs after 3 months in the treatment group , and this increase was seen up to 1 year after MI and CABS . There were no statistical differences , although there were fewer rehospitalizations between 3 and 6 months after MI and CABS in the treatment group compared with the st and ard of care group . Overall , the evidence from this study suggests that a community-based collaborative peer advisor/advanced practice nurse intervention can play a role in promoting active participation in cardiac rehabilitation programs and fewer rehospitalizations in unpartnered older adults after MI and CAGS BACKGROUND Current methods for risk stratification after acute myocardial infa rct ion ( MI ) include several noninvasive studies . In this cost-containment era , the development of low-cost means should be encouraged . We assessed the ability of an electrocardiogram ( ECG ) MI-sizing score to predict outcomes in patients enrolled in the Economics and Quality of Life ( EQOL ) sub study of the Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries -I ( GUSTO-I ) trial . METHODS We classified patients by electrocardiographic Selvester QRS score at hospital discharge : those with a score 0 - 9 versus > or = 10 . Endpoints were 30-day and 1-year mortality , re source use , and quality -of-life measures . RESULTS Patients with a QRS score < 10 were well-matched with those with QRS score > or = 10 with the exception of a trend to more anterior MI in the higher scored group . Patients with QRS score > or = 10 had increased risk of death at 30-days ( 8.9 % vs. 2.9 % P < .001 ) , and this difference persisted at 1 year ( 12.6 % vs. 5.4 % , P = .001 ) . Recurrent chest pain , use of angiography , and angioplasty were similar during follow-up . However , there was a trend toward less coronary bypass surgery in patients with a QRS score > or = 10 . Readmission rates were higher at 30 days but similar at 1 year . CONCLUSIONS Stratification of patients after acute MI by a simple measure of MI size identifies population s with different long-term prognoses ; patients with a QRS score > or = 10 ( approximately 30 % of the left ventricle infa rct ed ) at discharge have poorer outcomes in both the short- and long-term . The st and ard 12-lead ECG provides a simple , economical means of risk stratification at discharge The risk of progression to ESRD among individuals with cardiovascular disease and chronic kidney disease ( CKD ) is not well defined . The purpose of this study was to describe the risk of ESRD among patients with cardiovascular disease . Charts were abstract ed for r and omly selected hospitalized Medicare beneficiaries with a diagnosis of either congestive heart failure ( CHF ) or acute myocardial infa rct ion ( AMI ) . The prevalence of CKD , based on the estimated modified diet in renal disease GFR of < 60 ml/min per m2 , was 60.4 % of CHF patients and 51.7 % of AMI patients . When compared with patients without CKD , the 30-d readmission rate was higher for CHF patients with CKD ( odds ratio [ OR ] , 1.70 ; 95 % confidence interval [ CI ] , 1.18 to 2.44 ) and for AMI patients with CKD ( OR , 1.78 ; 95 % CI , 1.17 to 2.70 ) . CHF patients ( OR , 1.62 ; 95 % CI , 1.15 to 2.30 ) and AMI patients ( OR , 3.10 ; 95 % CI , 1.98 to 4.84 ) with CKD were more likely to die during the year after discharge from the hospital . ESRD after discharge occurred in nine of 517 patients with AMI and 24 of 640 patients with CHF . CKD increased the risk of ESRD among CHF patients ( OR , 34.5 ; 95 % CI , 4.23 to 279.43 ) and AMI patients ( 0 and 3 % for those without and with CKD , respectively ) . At discharge , 18 % of AMI patients and 21 % of CHF patients with CKD were discharged with a diagnosis of renal disease . CKD is highly prevalent among patients with cardiovascular disease and is associated with increased risk of adverse outcomes , including progression to ESRD . This study suggests that opportunities may exist to improve the detection of CKD in these patients who are hospitalized with cardiovascular disease To assess the association between color M-mode flow propagation velocity and the early diastolic mitral annular velocity ( E(m ) ) obtained with tissue Doppler echocardiography and to assess the prognostic implication s of the indexes , echocardiography was performed on days 1 and 5 , and 1 and 3 months after a first myocardial infa rct ion in 67 consecutive patients . Flow propagation velocity correlated well with E(m ) ( r = 0.72 , P < .0001 ) . The ratio of peak E-wave velocity ( E ) to flow propagation velocity also correlated well with E/E(m ) ( r = 0.87 , P < .0001 ) . The positive predictive value of E/FPV > or = 1.5 to identify patients with Killip class > or = II was 90 % , and the negative predictive value 92 % . The corresponding values for E/E(m ) > or = 10 were 70 % and 90 % . Cox proportional hazards analysis identified E/flow propagation velocity > or = 1.5 ( relative risk , 12.4 [ 95 % confidence interval , 4.1 - 37.3 ] ) , E/E(m ) > or = 10 ( relative risk , 11.5 [ 95 % confidence interval , 3.8 - 34.7 ] ) , and Killip class > or = II ( relative risk , 7.8 [ 95 % confidence interval , 1.6 - 40.4 ] ) to be predictors of the composite end point of cardiac death and readmission because of heart failure . Thus flow propagation velocity and E(m ) are closely related after myocardial infa rct ion and appear to have similar prognostic information

Conclusion With the performed statistical approach , a clear benefit in terms of an enhanced chance for pocket closure by co-administration of the combination of amoxicillin and metronidazole as an adjunct to non-surgical mechanical periodontal therapy has been shown . However , data calculation failed to show a benefit regarding the possible avoidance of surgical interventions

Background Relevant benefits of adjunctive medication of antibiotica after conventional root surface debridement in terms of enhanced pocket depth ( PD ) reduction have been shown . However , means and st and ard deviations of enhanced reductions are difficult to translate into clinical relevant treatment outcomes such as pocket resolution or avoidance of additional surgical interventions . Accordingly , the aim of this systematic review was to calculate odds ratios for relevant cut-off values of PD after mechanical periodontal treatment with and without antibiotics , specifically the combination of amoxicilline and metronidazol , from published studies . As clinical relevant cut-off values “ pocket closure ” for PD ≤ 3 mm and “ avoidance of surgical intervention ” for PD ≤ 5 mm were determined .

AIM The aim of this study was to evaluate the clinical and microbiological effects of scaling and root planing ( SRP ) alone or combined with metronidazole ( MTZ ) or with MTZ and amoxicillin ( AMX ) in the treatment of smokers with chronic periodontitis . METHODS A double-blind , placebo-controlled , r and omized clinical trial was conducted in 43 subjects who received SRP alone ( n=15 ) or combined with MTZ ( 400 mg 3 x per day , n=14 ) or with MTZ+AMX ( 500 mg 3 x per day , n=14 ) for 14 days . Clinical and microbiological examinations were performed at baseline and 3 months post-therapy . Subgingival sample s were analysed by checkerboard DNA-DNA hybridization . RESULTS Subjects receiving MTZ+AMX showed the greatest improvements in mean probing depth and clinical attachment level . Both antibiotic therapies led to additional clinical benefits over SRP alone in initially shallow , intermediate , and deep sites . The SRP+MTZ+AMX therapy led to the most beneficial changes in the subgingival microbial profile . These subjects showed significant reductions in the mean counts and proportions of periodontal pathogens such as Tannerella forsythia , Porphyromonas gingivalis and Treponema denticola , and the greatest increase in proportions of host-compatible species . CONCLUSION Significant advantages are observed when systemic antibiotics are combined with SRP in the treatment of smokers with chronic periodontitis . The greatest benefits in clinical and microbiological parameters are achieved with the use of SRP+MTZ+AMX The aim of the present study was to analyze the effect of systemic antimicrobial therapy and mechanical plaque control in patients with recurrent periodontal disease . 9 patients volunteered for the combined therapy . At a baseline examination they were r and omly distributed into 2 groups , one given tetracycline therapy for 2 weeks and the other metronidazole therapy for 1 week . A mechanical plaque control program comprising oral hygiene training , professional cleaning of all teeth and subgingival debridement at diseased sites was carried out at the baseline examination and at all recall visits , i.e. once every month during the first 6 months and then after 9 , 12 , and 18 months . The results demonstrated clinical ly and microbiologically that a combination of an initial antimicrobial and a continuous systematic mechanical plaque control program may be a valuable therapeutic approach in a strictly selected group of refractory patients . Recurrent periodontal lesions which still displayed severe inflammation despite renewed conventional therapy showed a marked reduction in probing depths , bleeding and suppuration from the pockets , and further , a reduced presence of spirochetes and motile rods during the trial . The results indicate that the level and longevity of success is also related to whether or not self-performed oral hygiene measures are sufficiently carried out . No superior effect of the combined program could be observed in cooperating patients receiving tetracycline as compared with those given metronidazole Aim Find the periodontal treatment that best maintained clinical results over time evaluated by changes in pocket depth ( PD ) and clinical attachment level ( CAL ) . Methods 229 patients with chronic periodontitis from USA ( n=134 ) and Sweden ( n=95 ) were r and omly assigned to eight groups receiving 1 scaling+root planing ( SRP ) alone or combined with 2 surgery (SURG)+systemic amoxicillin (AMOX)+systemic metronidazole ( MET ) ; 3 SURG+local tetracycline ( TET ) ; 4 SURG ; 5 AMOX+MET+TET ; 6 AMOX+MET ; 7 TET ; and 8 SURG+AMOX+MET+TET . Antibiotics were given immediately after SRP . Plaque , gingival redness , bleeding on probing , suppuration , PD , and CAL were recorded at baseline and after 3 , 6 , 12 , 18 , and 24 months . Treatment effects were evaluated by linear multilevel regression and logistic multilevel regression models . We considered only data from sites with a baseline PD of at least 5 mm of 187 patients completing the study . Results Surgically treated patients experienced most CAL loss . Adjunctive therapy including SURG was most effective in reducing PD . Combining SURG with AMOX , MET , and TET gave significant clinical benefits . Past and current smoking habits were significant predictors of deeper PD . Only current smoking was a significant predictor of CAL loss . Bleeding , accumulation of plaque , gingival redness , and suppuration were significant predictors of further CAL loss and deeper PD . Conclusions Both surgical and non-surgical therapies can be used to arrest chronic periodontitis . SURG+AMOX+MET+TET gave best maintenance of clinical results Periodontitis , a common cause of tooth loss in adult population s , is an inflammatory response to the overgrowth of anaerobic organisms such as spirochetes and bacteroides and , in some cases , micro-aerophilic organisms in the subgingival plaque . In the present investigation , using a double-blind clinical design , we sought to determine whether 1 week of metronidazole treatment plus debridement of the tooth surfaces was superior to 1 week of placebo treatment plus debridement ( positive control ) in reducing the subsequent amount of periodontal surgery given to the patients . Thirty-nine patients were r and omly assigned to either the metronidazole or placebo ( positive control ) groups . All patients were given the necessary scaling and root planing and were unsupervised in their usage of the medication . After the completion of this treatment , they were reexamined and it was found that the metronidazole regimen caused a significant reduction in surgical needs of about 5 teeth per patient compared to the positive control ( difference before and after treatment 8.3 + /- 6.8 teeth metronidazole versus 2.9 + /- 4.8 positive control , P = 0.007 ) . The difference between groups was maintained during the 2 to 3 years ' recall period . Metronidazole had a significant effect on the site specific reduction of spirochetes : 90 % of the sites in the metronidazole group versus 64 % in the positive-control group had a decrease in the percentage of spirochetes ( P less than 0.05 ) . We conclude that systemic metronidazole given 250 mg tid for 7 days in conjunction with debridement of the tooth surfaces can significantly reduce the need for periodontal surgery compared to the st and ard regimen which included only debridement BACKGROUND AND OBJECTIVE The periodontal region is a source of gram-negative bacterial infection . The pathogens involved have recently also been demonstrated in atheromatous plaques . They may increase the risk of myocardial infa rct ion . In this study a strategy for eradicating periodontal bacteria and thus healing in patients with periodontal pockets and advanced destruction of alveolar bone was examined . PATIENTS AND METHODS Initial periodontal status was documented in 36 patients with periodontitis ( 24 women , 12 men ) who were then r and omly assigned to one of three groups . Those in two of the groups were given either metronidazole or doxycycline orally as adjuvant treatment , while the third group received no antibiotics . Patients in all groups were treated according to a two-step procedure . In step 1 , extensive supra- and subgingival plaques and concrements were removed . In step 2 , root debridement and /or closed curettage of all pockets was undertaken in one visit , and the antibiotic given to the patients in groups 1 and 2 . Results were assessed 3 weeks after the first step and 6 months , 2 and 4 years after step 2 . RESULTS The initial examination at 3 weeks revealed significant changes in all three groups with regard to the incidence of plaque and sulcus bleeding , but not regarding probing depth and attachment level . However , there were significant changes in probing depth and attachment level in all groups after step 2 . Periodontal attachment was significantly improved at 2 and 4 years in the patients on metronidazole , but not those on doxycycline or no antibiotics . The greatest decrease in bleeding tendency was recorded in the metronidazole group . This group also had the greatest gain of new alveolar bone compared with the other two groups . Complete eradication of Porphyromonas gingivalis and Actinobacillus ( Hemophilus ) actinomycetemcomitans , important pathogenic bacteria that may have an atherogenic action , was obtained only in patients on metronidazole . CONCLUSION The tissue-sparing two-step procedure brought about good clinical and radiological results , which can be significantly bettered by the addition of metronidazole , achieving eradication of pathogens involved in periodontal disease AIMS The objective of this study was to investigate the effect of the systemic administration of metronidazole and amoxicillin as an adjunct to initial periodontal therapy in patients with moderate to severe chronic periodontitis . METHODS AND MATERIAL S This r and omized , double blind , placebo controlled parallel study involved 50 adult patients with untreated periodontitis who were r and omly assigned to receive either a full-mouth scaling and root planing along with systemic metronidazole and amoxicillin ( T group ) or scaling and root planing with a placebo ( P group ) . Clinical measurements including probing depth ( PD ) , clinical attachment levels ( CAL ) , Plaque Index ( PI ) , and Bleeding Index ( BI ) were recorded at baseline and six to eight weeks after therapy . The deepest pocket was selected and sample s for microbiological testing were taken . Patients received coded study medications of either 500 mg amoxicillin in combination with 250 mg metronidazole or an identical placebo every eight hours for seven days following scaling and root planing . RESULTS There was a significant change in PD ( P=0.0001 ) , CAL ( P=0.00001 ) , PI ( P<0.05 ) , and BI ( P<0.05 ) in the T group compared to the placebo group after therapy . Parallel to the clinical changes , treatment significantly reduced the number of Actinobacillus actinomycetemcomitans ( Aa ) , Porphyromonas gingivalis ( Pg ) , and P. intermedia ( Pi ) compared with baseline in the T group ( P=0.003 , 0.021 and 0.0001 , respectively ) . However , in the P group only the Pi colony count was reduced significantly ( P=0.0001 ) . After therapy , there was a significant difference between the T and P groups in the number of patients negative for Aa , Pg , and Pi ( Pv = 0.033 ) . CONCLUSIONS The significant differences between treatment and placebo groups are in line with other studies and support the considerable adjunctive benefits of the combination of amoxicillin and metronidazole in the treatment of chronic periodontitis BACKGROUND AND AIM Several studies have reported adjunctive benefits to scaling and root planing ( SRP ) of systemic amoxycillin and metronidazole in the treatment of periodontal diseases . To date no comparisons have been made of these antimicrobials alone or in combination . The aim of this study was to compare the adjunctive benefits to SRP of amoxycillin and metronidazole alone and combined . METHODS 66 subjects < 46 years of age with advanced chronic periodontal disease participated in this r and omised , double blind , 4 parallel treatment group design ed study . All subjects received quadrant SRP and then were prescribed amoxycillin capsules ( 250 mg ) and metronidazole tablets ( 200 mg ) ( AM ) or lactate capsules and metronidazole ( PM ) or amoxycillin and calcium lactate tablets ( AP ) or lactate and calcium lactate ( PP ) . All medication was 3 of each per day for 7 days . Subgingival plaque sample s were obtained and probing depth ( PD ) , loss of attachment ( LOA ) , bleeding on probing ( BOP ) , suppuration ( SUPP ) and plaque ( DEP ) were recorded pre-treatment , 1 , 3 and 6 months post-treatment . RESULTS Final group sizes were : AM=15 , PM=16 , AP=16 and PP=15 . PD improved in all groups . Treatment effects were highly significantly different and always greatest in the AM and least in the PP groups . Benefits of PM and AP over PP were also noted . LOA improved in all groups and showed the same highly significant treatment differences , again favouring AM . BOP improved in all groups , particularly in AM compared to the other groups . SUPP improved in all groups and was virtually eradicated in AM with differences among treatments highly significant . DEP changed little in any group and there were no significant differences among groups . Microbiological data showed significant differences in favour of AM compared to PP and PM for total aerobes and anaerobes at 1 month . P. intermedia counts were always lower in active groups compared to PP and reached significance for AM and AP at 1 month and AM and PM at 3 months . CONCLUSION The significant differences among treatment groups and the overall trend in the data , in line with other studies , support the considerable adjunctive benefits to SRP of amoxycillin and metronidazole combined in the treatment of advanced chronic periodontal disease Considerable data have accumulated which suggest that some or most forms of periodontal disease are specific , albeit chronic , bacteriological infections ( 1 , 2 ) . In most instances the plaque flora removed from infiamed sites are dominated by anaerobic organisms such as spi-rochetes , bacteroides and eubacterium species ( 1^ ) . In some instances , the microaerophilic organism Actinobacil-lus actinomycetemcomitans ( Aa ) has been associated with periodontal pathology ( 5 , 6 ) . These findings indicate that treatments aim ed at controlling peri-odontal disease could contain an anti-microbial component directed to the reduction , if not the elimination of the above periodontopathic organisms in or from the plaque . The choice of which antimicrobial agent to use would depend on the bacterial nature of the plaque infection and as to whether the agent is to be delivered systemically and /or locally ( 1 ) . Agents such as metronidazole and clindamycin would seem to be indicated when an anaerobic infection has been documented , whereas tetracyclines would be indicated where an Aa infection has been established ( 6 , 7 ) . Alternatively , broad spectrum antiseptics such as chlorhex-idine can be delivered locally to the pocket either via irrigation ( 8) or slow release delivery systems ( 9 ) . The efficacy of antimicrobial agents can best be evaluated by the inclusion of placebo groups and the use of a double blind design . In a double blind ( DB ) design all patients could receive the required mechanical debridement , so as to fulfill the ethical considerations for treatment , and then r and omly receive either placebo ( positive control ) or anti-microbial medications ( experimental ) . The antimicrobial treatments need only be of short duration , say 1 or 2 wk , because this length of treatment , provided an appropriate dose is prescribed and taken by the patient , is sufficient to change the composition of the plaque fiora in most instances ( 1 , 10 ) . Tetracyclines and metronidazole ( Met ) have been the agents most widely studied in the treatment of periodon-titis , but only metronidazole has been evaluated using a DB design ( 8 , 10 ) . In these studies . Met significantly increased apparent attachment gain and reduced probing depths in the deepest probing sites relative to mechanical de-bridement ( 10 ) , or irrigation with chlor-hexidine ( 8) . This suggested that the sy-stemically delivered Met was able to reduce or eliminate the anaerobic infection at the base of the pocket in ways that were not routinely achievable with mechanical debridement or chlor-hexidine irrigation . The success of Met in both reducing probing depth and in increasing apparent attachment raised the possibility that Met therapy could BACKGROUND This study assessed the long-term effects of adjunctive antimicrobial therapy on periodontal disease progression and oral colonization . METHODS Patients with previously untreated chronic periodontitis and subgingival Actinobacillus actinomycetemcomitans and /or Porphyromonas gingivalis were r and omly assigned to subgingival scaling without ( control group ) or with systemic amoxicillin plus metronidazole and CHX irrigation ( test group ) . Relative attachment levels were determined and subgingival and mucosal plaque sample s were taken at baseline , at 10 days ( plaque only ) and at 3 , 6 , 9 , 12 , 18 , and 24 months following initial therapy . During maintenance therapy , patients received supragingival debridement only . RESULTS After 24 months , the 18 test group patients showed at sites with initial probing depths ( PD ) > or = 7 mm a significantly ( P < 0.05 ) higher frequency of 2 mm or more attachment gain ( 37.3 % + /- 4.6 % ) and lower frequency of attachment loss ( 7.2 % + /- 3.1 % ) compared to the 17 controls ( 8.2 % + /- 3.9 % and 19.1 % + /- 13.1 % , respectively ) . Compared to controls , the intraoral prevalence of A. actinomycetemcomitans ( up to 18 months ) and P. gingivalis ( up to 3 months ) decreased and that of Eikenella corrodens ( at 10 days ) increased in test patients ( P < 0.05 ) . In both treatment groups , the detection frequency of Tannerella forsythensis decreased transiently , while an overall increase was recorded for Treponema ssp . CONCLUSIONS Over the 24-month period , a single course of the administered adjunctive antimicrobial therapy led to a relative risk reduction of 62 % for attachment loss at deep sites . However , with the exception of A. actinomycetemcomitans , it failed to induce long-term changes in the prevalence profiles of oral colonization BACKGROUND The purpose of this study was to evaluate the adjunctive clinical , microbiologic , and immunologic effects of the systemic administration of amoxicillin and metronidazole in the full-mouth ultrasonic debridement of patients with severe chronic periodontitis . METHODS Twenty-five patients presenting at least eight teeth with probing depth ( PD ) > or = 5 mm and bleeding on probing ( BOP ) were selected and r and omly assigned to full-mouth ultrasonic debridement + placebo ( control group ) or full-mouth ultrasonic debridement + amoxicillin and metronidazole ( test group ) . The clinical outcomes evaluated were visible plaque index , BOP , position of the gingival margin , relative attachment level ( RAL ) , and PD . Real-time polymerase chain reaction ( PCR ) was used for quantitative analysis of Aggregatibacter actinomycetemcomitans ( previously Actinobacillus actinomycetemcomitans ) , Porphyromonas gingivalis , and Tannerella forsythia ( previously T. forsythensis ) . The enzyme-linked immunosorbent assay ( ELISA ) technique permitted the detection of prostagl and in E(2 , ) interleukin-1beta , and interferon-gamma levels in gingival crevicular fluid . All parameters were evaluated at baseline and at 3 and 6 months post-treatment . RESULTS At 6 months , the test treatment result ed in lower BOP and an additional reduction ( 0.83 mm ) in PD ( P < 0.05 ) . Data also showed RAL gain > or = 2 mm at 43.52 % of sites in control patients compared to 58.03 % of sites in test patients ( P < 0.05 ) . However , both groups had similar mean RAL gain ( 1.68 and 1.88 mm for the control and test groups , respectively ) . Real-time PCR and ELISA failed to identify significant differences between the groups . CONCLUSIONS Both treatments result ed in significant clinical improvements ; however , there was a slight , but significantly greater , improvement in BOP and the percentage of sites with PD > or = 5 mm exhibiting RAL gain > or = 2 mm in the test group . Nevertheless , no improvement in the microbiologic or immunologic outcome was observed with the adjunctive use of systemic amoxicillin and metronidazole Patient compliance with the unsupervised usage of prescription medication can be poor . In the treatment of periodontal infections with systemic antimicrobial agents , in situations where the efficacy of the antimicrobial agent is being evaluated , non-compliance could underestimate the true efficacy of the agent . Metronidazole is an agent with reported success in the treatment of anaerobic periodontal infections . Metronidazole is particularly effective in vitro against spirochetes , and this efficacy was investigated as a means of measuring patient compliance with metronidazole usage . Patients who had high proportions of spirochetes , i.e. , > 20 % , in plaques removed from diseased periodontal sites , were given metronidazole ( 500 mg bid ) under supervision . In all individuals who received the metronidazole , there was a significant and rapid decline and /or disappearance of spirochetes from the plaque during the time interval that metronidazole was detectable in the saliva . This observed decline in spirochetes was then used to determine which patients had been compliant in a double-blind clinical trial involving the unsupervised usage of metronidazole . Only 10 of 18 patients ( 56 % ) were considered compliant in their usage of metronidazole . These 10 patients experienced a significantly greater benefit from the metronidazole than did the 8 patients who were considered noncompliant , i.e. , a reduction of surgical needs of 8.3 teeth per compliant patient versus 3.6 teeth per non-compliant patient . A test for the hydrolysis of the synthetic peptide ( BANA ) was also able to identify most non-compliant patients . Clinical trials involving the unsupervised usage of systemic medication need to take into account patient non-compliance BACKGROUND It has been suggested that scaling and root planing of all pockets within a few hours and chlorhexidine treatments ( full-mouth disinfection ) may reduce the need for supplementary therapies . The aim of this study was to evaluate the clinical benefit of amoxicillin and metronidazole administered immediately after completion of full-mouth periodontal debridement in patients with chronic periodontitis . METHODS This was a single-center , double-masked , placebo-controlled , r and omized longitudinal study of 6 months ' duration . Fifty-one patients received full-mouth periodontal debridement , performed within 48 hours . Twenty-five subjects received metronidazole , 500 mg , and amoxicillin , 375 mg , three times a day for 7 days ; 26 subjects received a placebo . RESULTS Forty-seven patients could be followed up to month 6 . No differences in clinical parameters were noted before treatment . The overall mean probing depth decreased from 4.3 + /- 0.4 mm to 3.0 + /- 0.2 mm in the test group and from 4.4 + /- 0.4 mm to 3.1 + /- 0.3 mm in the control group ( P = 0.05 , difference between groups ) . More importantly , test subjects had a significantly lower mean number of persisting pockets > 4 mm and bleeding on probing that required further treatment ( P = 0.005 ) : 6 months after full-mouth debridement plus antibiotics , only 0.4 + /- 0.8 persisting pockets were still present , whereas 3.0 + /- 4.3 persisting pockets were still present in the control group . The protective risk of the antibiotics for having more than one pocket deeper than 4 mm and bleeding on probing per subject after 6 months was 8.85 . CONCLUSION Systemic metronidazole and amoxicillin significantly improved the 6-month clinical outcomes of full-mouth non-surgical periodontal debridement , thus significantly reducing the need for additional therapy This study investigated two variables associated with scaling and planning ( S&RP ) : operator experience level and root surface access . One hundred and fourteen periodontally involved , single-rooted teeth design ated for extraction were r and omly distributed among four operators of various experience levels for either an open or closed session of S&RP . Immediately after treatment , the teeth were extracted , washed , and scored for residual calculus in a blind manner . Results showed that there was no difference in S&RP effectiveness for experience level or type of procedure in shallow ( 1 - 3 mm ) pockets . However , in moderate ( 4 - 6 mm ) and deep ( greater than 6 mm ) periodontal pockets , S&RP combined with an open flap procedure was more effective than S&RP alone for both experience levels . Also , the more experienced operators produced a significantly greater number of calculus-free root surfaces than the less experienced operators in periodontal pockets with moderate and deep probing depths . Clinical application of these results suggests that surgical access is associated with thorough surface debridement in periodontal pockets with moderate-to-advanced probing depths . However , more experienced operators could be expected to render more effective soft surface debridement BACKGROUND The objective of this study was to assess the adjunctive clinical effect of the administration of systemic amoxicillin and metronidazole in the non-surgical treatment of generalized aggressive periodontitis ( GAP ) . METHODS Forty-one systemically healthy subjects with GAP were included in this 6-month double-blind , placebo-controlled , r and omized clinical trial . Patients received a course of full-mouth non-surgical periodontal treatment delivered over a 24 h period using machine-driven and h and instruments . Test subjects received an adjunctive course of systemic antibiotic consisting of 500 mg amoxicillin and 500 mg metronidazole three times a day for 7 days . Clinical parameters were collected at baseline , and at 2 and 6 months post-treatment . RESULTS In both the test and the placebo groups , all clinical parameters improved at 2 and 6 months . In deep pockets ( > or = 7 mm ) , the test treatment result ed in an additional 1.4 mm ( 95 % confidence interval 0.8 , 2.0 mm ) in full-mouth probing pocket depth ( PPD ) reduction and 1 mm ( 0.7 , 1.3 mm ) of life cumulative attachment loss ( LCAL ) gain at 6 months . In moderate pockets ( 4 - 6 mm ) , the adjunctive benefit was smaller in magnitude : PPD reduction was 0.4 mm ( 0.1 , 0.7 mm ) and LCAL gain was 0.5 mm ( 0.2 , 0.8 mm ) . In addition , the 6-month data showed LCAL gains > or = 2 mm at 25 % of sites in test patients compared with 16 % in placebo ( p=0.028 ) . Similarly , PPD reductions of 2 mm or more were observed in 30 % of sites in test and 21 % of sites in placebo patients . Seventy-four percent of pockets with PPD > or = 5 mm at baseline were 4 mm or shallower at 6 months in the test group . This compared with 54 % in the placebo group ( p=0.008 ) . Disease progression at 6 months was observed at 1.5 % of test and 3.3 % of sites in test and placebo , respectively ( p=0.072 ) . CONCLUSIONS These data indicate that a 7-day adjunctive course of systemic metronidazole and amoxicillin significantly improved the short-term clinical outcomes of full-mouth non-surgical periodontal debridement in subjects with GAP OBJECTIVE The current investigation evaluated the clinical effects of scaling and root planing ( SRP ) alone or in combination with systemic metronidazole and /or repeated professional removal of supragingival plaque in subjects with chronic periodontitis . METHODS Fourty-four adult subjects ( mean age : 45+/-6 years ) with periodontitis were r and omly assigned to four treatment groups ; a control ( C , n=10 ) that received SRP and placebo and three test groups treated as follows : Test 1 ( T1 ) ( n=12 ) received SRP and metronidazole ( 400 mg t.i.d . , M ) for 10 days ; Test 2 ( T2 ) ( n=12 ) received SRP , weekly professional supragingival plaque removal for three months ( professional cleaning ( PC ) ) and placebo ; and Test 3 ( T3 ) ( n=10 ) received SRP , M and PC . Pocket depth ( PD ) , attachment level ( AL ) , bleeding on probing ( BOP ) and presence of visible plaque and suppuration were measured at six sites per tooth at baseline and at 90 days post-therapy . Significance of differences over time was determined using the Wilcoxon test , and among groups using ancova . RESULTS A reduction in full-mouth mean clinical parameters was observed at 90 days after all therapies . Sites with baseline PD<4 mm showed an increase in mean PD in the control group and in mean AL in all treatment groups . Sites with baseline PD of 4 - 6 mm in subjects who received PC as part of therapy ( T2 , T3 ) showed a marked reduction in PD , AL and in the % of sites with BOP . Subjects who received metronidazole ( T1 and T3 ) showed the best clinical response at sites with an initial PD of > 6 mm . The major clinical benefit occurred when the combination of SRP , M and PC was used . Group T3 showed the least attachment loss in initially shallow pockets . This group also exhibited the greatest reduction in the % of sites with BOP and suppuration as well as in mean PD and AL at sites with baseline PD>4 mm . CONCLUSION The data suggest a significant clinical benefit in combining SRP , systemic metronidazole and weekly professional supragingival plaque removal for the treatment of chronic periodontitis BACKGROUND The purpose of this study is to compare the additional benefit of systemic antimicrobials versus placebos to a repeated mechanical instrumentation combined with comprehensive local chemical plaque control for the periodontal treatment of generalized aggressive periodontitis ( GAgP ) . METHODS This was a 6-month r and omized , double-masked , placebo-controlled clinical trial . All GAgP patients received full-mouth disinfection followed by staged scaling and root planing without ( placebo group ; n = 17 ) or with ( test group ; n = 18 ) systemic antimicrobials ( 500 mg amoxicillin [ AMX ] + 250 mg metronidazole [ MET ] ; three times a day for 10 days ) . Clinical parameters were measured at baseline and 3 and 6 months post-therapy . Significant differences between groups at baseline were sought by using the Mann-Whitney U test , whereas comparisons over time were examined by using a general linear model repeated measures procedure . RESULTS Both groups demonstrated similar improvements in most parameters over time . The test group presented a greater mean probing depth ( PD ) reduction and clinical attachment level ( CAL ) gain at sites with initially moderate PD at 6 months ( P < 0.03 ) . No differences were seen between groups regarding mean reductions and mean gains , respectively , for PD and CAL initially ≥7 mm . The test group presented a higher percentage of sites that improved ≥2 mm and ended up with PD ≤4 mm or a lower percentage of sites that worsened ≥2 mm and remained with PD > 4 mm at 3 months ( P < 0.01 ) . No differences were noticed between groups for these parameters at 6 months . CONCLUSION AMX + MET brought additional clinical effects to the repeated mechanical and antiseptic treatment of GAgP in a very short time ( 3 months ) , which tended to fade away over time ( 6 months ) The present clinical trial was performed to study the effect of systemic administration of metronidazole and amoxicillin as an adjunct to mechanical therapy in patients with advanced periodontal disease . 16 individuals , 10 female and 6 male , aged 35 - 58 years , with advanced periodontal disease were recruited . A baseline examination included assessment of clinical , radiographical , microbiological and histopathological characteristics of periodontal disease . The 16 patients were r and omly distributed into 2 different sample s of 8 subjects each . One sample of subjects received during the first 2 weeks of active periodontal therapy , antibiotics administered via the systemic route ( metronidazole and amoxicillin ) . During the corresponding period , the 2nd sample of subjects received a placebo drug ( placebo sample ) . In each of the 16 patients , 2 quadrants ( 1 in the maxilla and 1 in the m and ible ) were exposed to non-surgical subgingival scaling and root planing . The contralateral quadrants were left without subgingival instrumentation . Thus , 4 different treatment groups were formed ; group 1 : antibiotic therapy but no scaling , group 2 : antibiotic therapy plus scaling , group 3 : placebo therapy but no scaling , group 4 : placebo therapy plus scaling . Re-examinations regarding the clinical parameters were performed , sample s of the subgingival microbiota harvested and 1 soft tissue biopsy from 1 scaled and 1 non-scaled quadrant obtained 2 months and 12 months after the completion of active therapy . The teeth included in groups 1 and 3 were following the 12-month examination exposed to non-surgical periodontal therapy , and subsequently exited from the study . Groups 2 and 4 were also re-examined 24 months after baseline . The findings demonstrated that in patients with advanced periodontal disease , systemic administration of metronidazole plus amoxicillin result ed in ( i ) an improvement of the periodontal conditions , ( ii ) elimination/suppression of putative periodontal pathogens such as A. actinomycetemcomitans , P. gingivalis , P. intermedia and ( iii ) reduction of the size of the inflammatory lesion . The antibiotic regimen alone , however , was less effective than mechanical therapy with respect to reduction of BoP - positive sites , probing pocket depth reduction , probing attachment gain . The combined mechanical and systemic antibiotic therapy ( group 2 ) was more effective than mechanical therapy alone in terms of improvement of clinical and microbiological features of periodontal disease OBJECTIVE The use of antibiotics as an adjunctive therapy in the management of periodontal diseases has always been of interest for dental practitioners . Although studies have demonstrated the importance of different antibiotics as adjunct in the treatment of periodontitis , few studies have reported comparative results of antibiotics in localized aggressive periodontitis ( LAP ) . The aim of the present study was to evaluate the comparative effects of systemic tetracycline derivative doxycycline versus a combination of metronidazole and amoxicillin in the elimination/suppression of Actinobacillus actinomycetemcomitans and their clinical effects during 90 days of follow-up in patients with LAP . METHOD AND MATERIAL S Thirty patients with untreated LAP participated in the study . Patients were r and omly divided into 2 groups and given doxycycline or metronidazole plus amoxicillin , and periodontal clinical parameters were achieved at baseline and 10 , 30 , 60 , and 90 days after microbiologic sampling . Patients were also given mechanical debridement after measurement at baseline . RESULTS Both groups of patients demonstrated improvement in clinical parameters , and microbiologic sample s did not show any A actinomycetemcomitans at days 30 , 60 , and 90 . CONCLUSION Systemic use of doxycycline or metronidazole plus amoxicillin as an adjunct to conventional therapy may be used for the treatment of patients with LAP OBJECTIVE To evaluate the short term clinical results of scaling and root planning ( SRP ) only , SRP combined with amoxicillin ( AMX ) and metronidazole ( MTZ ) after supragingival scaling or after SRP in the treatment of aggressive periodontitis ( AgP ) . METHODS A total of 45 patients with AgP were r and omly divided into SRP group , SRP with AMX + MTZ after supragingival scaling group and AMX + MTZ after SRP group . Subgingival scaling and root planning were performed one week after supragingival scaling and finished within 1 month . AMX and MTZ were given for 7 days immediately after supragingival scaling or the last time of SPR . Clinical examinations including probing depth ( PD ) , attachment level ( AL ) and bleeding index ( BI ) were performed at baseline and 8 weeks after non-surgical periodontal treatment by the same examiner . RESULTS There were more PD reduction and AL gain in both AMX + MTZ after supragingival scaling group and AMX + MTZ after SRP group compared with SRP group [ 2.5 ( 1.8 , 3.3 ) mm , 2.3 ( 1.9 , 2.7 ) mm vs. 1.8 ( 1.3 , 2.1 ) mm , P < 0.05 ] ; [ 0.9 ( 0.5 , 1.4 ) mm , 0.8 ( 0.4 , 1.3 ) mm vs. 0.4 ( 0.2 , 1.0 ) mm , P < 0.05 ] . In sites PD ≥ 7 mm , PD reduction was more in AMX + MTZ after supragingival scaling group than AMX + MTZ after SRP group [ 4.0 ( 3.0 , 5.0 ) mm vs. 4.0 ( 3.0 , 4.0 ) mm , P < 0.05 ) ] . CONCLUSIONS The combined use of AMX and MTZ during non-surgical periodontal treatment for patients with AgP was effective in short term . In patients with most sites PD ≥ 7 mm , AMX and MTZ could be taken after supragingival scaling , but the long-term clinical effects needs further investigation The purpose of this study was to assay the concentration of metronidazole in gingival fluid , to correlate clinical and microbiologic parameters of periodontal disease to each other and to the gingival fluid concentration of the drug . Ten subjects with a minimum of two contralateral pairs of periodontal pockets of greater than or equal to 5 mm were utilized . One side of the mouth was selected to serve as the root-planed site while the other was left untreated . On day 0 , plaque and bleeding-time indexes and probing depths were recorded . Subgingival plaque was analyzed using phase contrast microscopy . When root planing was completed , the subjects were prescribed either metronidazole or placebo three times daily for seven days . Within 24 hours of the last dose , and thereafter at intervals of 1 , 2 and 3 weeks , fluid sample s were assayed for metronidazole . Clinical and bacterial data were likewise recorded . The results indicate that root planing with metronidazole appears to be more effective in promoting periodontal health than root planing alone . Concentrations of metronidazole ranging from 5 to 20 micrograms/ml were detectable in fluid sample s obtained within 24 hours of administration of the last dose . No discernible levels could be found in sample s taken at the longer intervals OBJECTIVES The purpose of the present study was to evaluate the clinical effects of non-surgical periodontal treatment , supplemented with enamel matrix derivative ( EMD ) and /or systemic antibiotics , in deep periodontal pockets of patients with chronic periodontitis . METHODS This was a r and omized , placebo-controlled longitudinal clinical trial of 12 months duration . Using a split-mouth design , 16 subjects were r and omly assigned to scaling and root planing ( SRP ) with EMD or placebo in contra-lateral dentition areas . One half of the subjects received 250 mg metronidazole and 375 mg amoxicillin three times a day for 7 days and the other half received a placebo . One inter-proximal periodontal lesion was chosen as study site in each of the contra-lateral quadrants . RESULTS Subjects treated with systemic antibiotics yielded significantly better clinical results than those treated with placebo . In these cases , probing pocket depth was reduced significantly more after 6 months ( 3.0+/-2.1 mm versus 1.6+/-1.4 mm , p=0.05 ) , and the mean clinical attachment gain was significantly greater after 6 months ( 2.3+/-1.9 mm versus 0.7+/-1.6 mm , p=0.02 ) and 12 months ( 2.3+/-3.5 mm versus 0.4+/-3.8 mm , p=0.02 ) . Sites treated with the antibiotics plus EMD gained the largest amount of clinical attachment . There was no significant benefit of EMD adjunctive to SRP in subjects not treated with antibiotics . CONCLUSIONS The present study supports the notion that optimal repair and regeneration of the periodontium requires suppression of the microbiota causing periodontal disease BACKGROUND Periodontitis consists of a mixture of diseases , most of which respond favorably to traditional mechanical therapy . It is now recognized that advanced periodontitis does not always respond to conventional management with scaling , periodontal surgery , and oral hygiene measures . However , various types of antibiotics given systemically or locally improve the success rate of periodontal therapy . In short-term studies , it has been shown that metronidazole , when systemically administered after debridement , result ed in treatment benefits including less need for surgical intervention . METHODS In this double-blind study , we evaluated periodontal treatment involving initial non-surgical treatment , systemic administration of metronidazole for 1 week , and then follow-ups for scaling and root planing every 6 months , for 5 years . The study population consisted of 64 subjects ( 37 smokers and 27 non-smokers ) , mean age 36.3 ( + /-3.0 SD ) years , with severe periodontal disease . After initial scaling and root planing , patients were r and omly assigned to the intervention or placebo groups : 400 mg metronidazole or a placebo administered at 8-hour intervals for 1 week . The participants underwent an extensive clinical periodontal examination . Gingival crevicular fluid ( GCF ) was analyzed for spirochetes and granulocytes . Sample s were cultured for Actinobacillus actinomycetemcomitans ( A.a . ) , Porphyromonas gingivalis ( Pg . ) , and Prevotella intermedia ( Pi . ) . RESULTS The number of patients infected with A.a . , Pg . , Pi . , and spirochetes decreased during the study . Most patients who harbored spirochetes at the end of the study had these microorganisms at the beginning . Smokers responded less favorably to periodontal therapy than non-smokers . Non-smoking patients who required only non-surgical therapy in the intervention group showed statistically significant improvement in the clinical parameters after 5 years . Patients with complete healing , defined as the absence of inflamed sites > or = 5 mm , after 5 years were found only in the intervention group . The patients considered healthy after 5 years were the same patients found to be healthy after 6 months . CONCLUSIONS Decisive factors in the sustained long-term improvement of patients who respond satisfactorily to treatment are probably initial scaling and root planing ; a brief course of metronidazole ; and regular follow-up examinations at 6-month intervals for oral hygiene and scaling and root planing In a previous study , a double-blind between subject comparison of the effects of metronidazole and placebo tablets was completed over 22 weeks in 45 subjects with chronic periodontal disease ranging in severity from moderate ( PI = 2.0 - 3.9 ) to high ( PI = 4.0 - 6.0 ) . The results showed a significantly greater reduction in the mean probing depth of pockets with the use of metronidazole , but this reduction was apparent only in subjects with severe periodontal disease ( PI = 4.0 - 6.0 ) . 3 years later , 28 subjects attended . All groups still showed statistically significant improvements in all parameters when compared with those at the first visit . However , when compared with those at the end of the trial , there were statistically significant increases in gingival bleeding and calculus scores . An increase in plaque levels was also observed but this was not statistically significant . When subjects with moderate and severe periodontal disease were grouped together , there were no significant differences in any of the parameters between test and control groups . Moreover , the significantly greater reductions in mean probing depth of pockets , achieved with the use of metronidazole in the severe group at the end of the trial , had disappeared after 3 years . However , in subjects with mild disease , statistically significant reductions in pocket probing depth , not originally apparent , were observed 3 years later AIM To compare the effects of systemic amoxicillin ( AMX ) plus metronidazole ( MET ) or placebos combined with anti-infective mechanical debridement on the sub-gingival microbiota of generalized aggressive periodontitis ( GAP ) . MATERIAL AND METHODS The study was a 6-month r and omized , double-blinded , placebo-controlled clinical trial . Thirty-one subjects received full-mouth ultrasonic debridement followed by scaling and root planing with chlorhexidine rinsing , brushing and irrigation . During mechanical therapy , subjects received systemic AMX (500mg)+MET ( 250 mg ) or placebo , t.i.d . for 10 days . Sub-gingival sample s were obtained from each patient and analysed for their composition by checkerboard at baseline , 3 and 6 months post-therapy . Significant differences between groups over time were examined by General Linear Model of Repeated Measures . RESULTS High levels of periodontal pathogens , as well as some " non-periodontal " species were observed . Most of the periodontal pathogens decreased significantly over time ( p<0.05 ) , whereas " non-periodontal " bacteria tended to increase in both groups . Sites that showed attachment loss and probing depth increase harboured higher levels of Dialister pneumosintes , Campylobacter rectus , Fusobacterium necrophorum , Prevotella tannerea and Peptostreptococcus anaerobius than sites that improved after both therapies ( p<0.05 ) . CONCLUSIONS Systemic AMX+MET or placebos adjunctive to anti-infective mechanical debridement were comparable in lowering periodontal pathogens up to 6 months after treatment . Species not commonly associated with GAP were less affected by both therapies BACKGROUND In the last few years knowledge about periodontal infections has increased enormously , nevertheless practitioners are still seeking guidelines for suitable treatment concepts . METHODS The aim of this study was to examine the effect of doxycycline , metronidazole , and clindamycin used adjunctively in a 2-step nonsurgical procedure in patients with rapidly progressive periodontitis ( RPP ) . The first step included scaling , root planing , and polishing ( SRP ) in each quadrant using 4 to 5 visits . The second step included full-mouth enhanced root planing ( RP ) and wound dressing in 1 or 2 visits after SRP and the beginning of antibiotic therapy . Forty-eight patients ( mean age 32.4 years ) with generalized RPP , with an average of 16 sites with probing depths ( PD ) deeper than 8 mm , and high counts of Porphyromonas gingivalis were r and omly assigned to 4 different groups : group 1 ( doxycycline ) n = 12 , group 2 ( metronidazole ) n = 15 , group 3 ( clindamycin ) n = 11 , and group 4 ( control group ; no antibiotic treatment ) n = 10 . Clinical evaluations , including plaque index ( PI ) , sulcus bleeding index ( SBI ) , probing depth ( PD ) , clinical attachment level ( CAL ) , and bacteriological and crevicular cell sampling , were done at baseline ( BL ) , 3 weeks after SRP , and 6 and 24 months after RP . RESULTS After the first step ( SRP ) , we observed an improvement of PI and SBI in all 4 groups , but did not see any statistically significant PD reduction 3 weeks after SRP compared to baseline . However , 6 and 24 months after the second step ( RP ) we observed a significantly greater reduction of PD in groups 2 and 3 and a significantly greater CAL gain in comparison to groups 1 and 4 . After 24 months , the attachment level gain in group 1 and group 4 was less than 1.5 mm , and less than 1.0 mm in PD site categories 6 to 9 mm and > 9 mm . PI showed no significant difference between the groups throughout the period after SRP until 24 months , compared to 3 weeks after SRP . SBI decreased most in the metronidazole and clindamycin groups . P. gingivalis and Actinobacillus actinomycetemcomitans were almost completely eradicated in these 2 groups 24 months after RP . In addition , the phagocytotic capacity of crevicular polymorphonuclear neutrophils was increased in groups 2 and 3 after the second step . CONCLUSIONS The present results show that metronidazole and clindamycin are effective antibiotics when used adjunctively in a 2-step nonsurgical procedure of scaling and root planing in RPP patients The effect of adjunctive systemic metronidazole was studied in patients with moderate and advanced periodontitis recalcitrant to comprehensive non-surgical treatment . The material originated from a r and omly selected part of the population aged 31 to 40 years . After non-surgical treatment of 149 patients , 98 with persisting pathological pockets greater than or equal to 5 mm ( 52 men and 46 women ) became the subjects for the study . Clinical parameters were registered and pocket contents subjected to laboratory analysis . The subjects were r and omized into two groups according to a code list known only by the manufacturer and the statistician . The test group took three 400 mg metronidazole tablets daily for 1 week and the control group took placebo tablets . Re assessment 6 months later showed statistically significant clinical improvement , with a reduction in the number of sites greater than or equal to 5 mm in both test and control groups . Complete healing , with no pockets greater than or equal to 5 mm , was noted in 30 % of the test group and 9 % of the control group . The difference is statistically significant and shows the supplementary effect of adjunctive metronidazole in non-surgical treatment of moderate and advanced periodontitis The aim of the present parallel , double-blind investigation was to evaluate the effect of using systemic metronidazole alone or associated to scaling and root planing on adult chronic periodontal disease , monitored at baseline , 30 , 60 and 90 days . Twelve subjects were divided into three groups : the first group ( Group I - 22 sites ) was su bmi tted to scaling and root planing ( SRP ) alone ; the second group ( Group II - 30 sites ) received SRP and 250 mg of metronidazole ( 3 times a day for 10 days ) , and the third group ( Group III - 31 sites ) was treated with metronidazole alone . The clinical parameters evaluated were probing depth ( PD ) , clinical attachment level ( CAL ) , plaque index ( PlI ) , gingival index ( GI ) and bleeding upon probing ( BP ) . Microbiological ( BANA test ) and enzymatic ( Pocket Watch ) tests were also performed . All three proposed treatments produced significant improvements in clinical conditions of subjects , from baseline , 30 , 60 and 90-day period , except for clinical attachment level . The results obtained by microbiological and enzymatic tests did not show statistical differences among the groups for the 90-day period ( r = 0.7924 and r = 0.7757 , respectively ) . In relation to clinical parameters , statistical differences among groups were observed only for the gingival index ( p = 0.0261 ) between Groups I and II , and probing depth ( p = 0.0124 ) between Group I and the others . We conclude that the use of systemic metronidazole did not produce additional effects on the microbiological conditions of these patients with chronic periodontal disease AIM To evaluate and compare the effects of adjunctive metronidazole plus amoxicillin , doxycycline and metronidazole on clinical and microbiological parameters in patients with generalized aggressive periodontitis . MATERIAL AND METHODS Forty-three patients participated in this r and omized clinical trial divided into four groups . Six weeks after scaling and root planning ( SRP ) , groups 1 - 3 received adjunctive metronidazole , plus amoxicillin , doxycycline and metronidazole respectively , and group 4 acted as controls . Clinical recordings concerning probing depth , probing attachment level and bleeding on probing were performed at baseline , 6 weeks after SRP and 6 months from baseline . Subgingival sample s were analysed using the ' checkerboard ' DNA-DNA hybridization for Porphyromonas gingivalis , Actinobacillus actinomycetemcomitans , Tannerella forsythia and Treponema denticola . RESULTS All treatments result ed in improvement of clinical parameters ( ANOVA p > 0.05 ) . Systemic administration of metronidazole plus amoxicillin or metronidazole result ed in statistically significant greater reduction of the proportion of sites > 6 mm than SRP ( z-test , p < 0.05 ) . These antimicrobials yielded a significant effect on levels of important periodontal pathogens for 6 months . CONCLUSION Adjunctive metronidazole plus amoxicillin or metronidazole alone ( when A.actinomycetemcomitans is not involved ) is effective in deep pockets of aggressive periodontitis patients OBJECTIVE The current investigation evaluated changes in levels and proportions of 39 bacterial species in subgingival plaque sample s after scaling and root planing ( SRP ) alone or in combination with systemic metronidazole and /or professional cleaning in subjects with chronic periodontitis . METHODS Forty-four adult subjects ( mean age 45+/-6 years ) with periodontitis were r and omly assigned in four treatment groups , a control ( C , n=10 ) that received SRP and placebo and three test groups treated as follows : T1 ( n=12 ) : SRP and metronidazole ( M , 400 mg tid ) for 10 days ; T2 ( n=12 ) : SRP , weekly professional supragingival plaque removal for 3 months ( PC ) and placebo ; and T3 ( n=10 ) : SRP , M and PC . Subgingival plaque sample s were taken from seven sites per subject at baseline and 90 days post-therapy . Counts of 39 subgingival species were determined using checkerboard DNA-DNA hybridization . Significance of differences over time was determined using the Wilcoxon signed ranks test and among groups using ancova . RESULTS The mean counts of the majority of the species were reduced post-therapy in the 4 treatment groups . Counts ( x 10(5)+/-SEM ) of Porphyromonas gingivalis , Tannerella forsythensis and Treponema denticola were significantly reduced in groups T2 and T3 . Levels of beneficial species , such as some Actinomyces species , Veillonella parvula , Streptococcus sanguis , Streptococcus oralis and Streptococcus gordonii were minimally affected in levels when the combined therapy was applied ( T3 ) . Mean proportions of red complex species decreased from 18.4 % at baseline to 3 % at 90 days post-therapy in group T3 ( p<0.01 ) , from 25.8 % to 2.3 % in group T2 ( p<0.01 ) , from 17.7 % to 5.6 % in group T1 ( p<0.05 ) and from 19.4 % to 8.8 % in group C ( NS ) . Proportions of the suspected periodontal pathogens from the orange complex were also markedly reduced in groups T2 and T3 . CONCLUSIONS All treatments reduced counts and proportions of red complex species . Adjunctive therapy appeared to have a greater effect and also affected members of the orange complex BACKGROUND The aim of this study was to test the hypothesis that there are no differences in clinical parameters in generalized aggressive periodontitis patients after full-mouth scaling and root planing ( FRP ) or quadrant-wise basic periodontal therapy ( BPT ) when combined with an antibiotic regimen . METHODS Patients were allocated r and omly to BPT ( N = 15 ; mean age : 29.5 + /- 5.7 years ) or FRP ( N = 15 ; mean age : 28.4 + /- 5.7 years ) . All subjects received oral hygiene instructions including the use of a 0.12 % chlorhexidine mouthrinse solution twice a day for 2 months . Patients also received amoxicillin , 500 mg , and metronidazole , 250 mg , three times a day for 7 days . Probing depth ( PD ) , clinical attachment level , visible plaque , and bleeding on probing were recorded at baseline and at 2 , 4 , and 6 months post-therapy . Statistically significant changes within and between groups were determined using the general linear model repeated measures procedure . RESULTS Both groups showed a significant improvement in all clinical parameters post-therapy , which was particularly evident at 2 months in the sites that had been deepest at baseline . For instance , the mean PD at sites with mean PD > or = 7 mm at baseline had decreased 3.9 mm in the BPT group and 3.6 mm in the FRP group . At 6 months , the percentage of sites with PD > or = 7 mm decreased from 13.2 % + /- 3.2 % to 0 % in the BPT group and from 13.3 % + /- 3.5 % to 0.2 % + /- 0.1 % in the FRP group . No statistically significant differences were observed between groups for most clinical parameters . CONCLUSION Within the limits of the present investigation , FRP and BPT caused comparable clinical effects in aggressive periodontitis patients when an adjunctive combined antibiotic regimen was included 48 adult patients with untreated periodontitis harboring subgingival Actinobacillus actinomycetemcomitans and /or Porphyromonas gingivalis as assessed by PCR were r and omly assigned to receive full-mouth scaling alone ( control ) or scaling with systemic metronidazole plus amoxicillin and supragingival irrigation with chlorhexidine digluconate ( test ) . In patients harboring A. actinomycetemcomitans intraorally at baseline , the adjunctive antimicrobial therapy result ed in a significantly higher incidence of probing attachment level ( PAL ) gain of 2 mm or more compared to scaling alone over 12 months ( p<0.05 ) . In addition , suppression of A. actinomycetemcomitans in subgingival plaque below detectable levels was associated with an increased incidence of PAL gain . In contrast , patients initially harboring P. gingivalis but not A. actinomycetemcomitans in the oral cavity showed a significantly higher incidence of PAL loss following adjunctive antimicrobial therapy compared to scaling alone ( p<0.05 ) . When the presence of pathogens at baseline was disregarded in the analysis , adjunctive antimicrobial therapy did not significantly enhance clinical treatment outcome . The results indicated that adults with untreated periodontitis harboring A. actinomycetemcomitans may benefit from the adjunctive antimicrobial therapy for a minimum of 12 months , whereas , the regimen may adversely affect the clinical treatment outcome of patients harboring P. gingivalis but not A. actinomycetemcomitans The effect of operator experience level and root surface access on instrumentation of multirooted teeth was investigated . Fifty molars design ated for extraction were r and omly distributed among four operators of two different experience levels for scaling and root planing with or without surgical access . Following treatment the teeth were extracted and scored in a blind manner for residual calculus . Teeth were sectioned to allow assessment of the furcal aspects . Results show that operators of both experience levels obtained calculus-free root surfaces significantly more often with flap access than with a non-surgical approach . Additionally , operators with more experience achieved calculus-free root surfaces significantly more often than operators of lesser experience with both an open and closed procedure . However , when furcation aspects alone were assessed , it was found that the more experienced operators obtained a calculus-free surface only 68 % of the time with an open approach . Results suggest that , although both surgical access and a more experienced operator significantly enhance calculus removal in molars with furcation invasion , total calculus removal in furcations utilizing conventional instrumentation may be limited BACKGROUND Short-term clinical observations suggest an anti-inflammatory effect of enamel matrix derivative ( EMD ) . The purpose of this study was to evaluate the anti-inflammatory capacity of EMD , used as an adjunct to non-surgical periodontal treatment of deep lesions in chronic periodontitis patients , by monitoring inflammatory markers in gingival crevicular fluid ( GCF ) . METHODS Sixteen subjects were r and omly assigned to treatment with EMD or placebo in contralateral dentition areas . Half of the subjects received 250 mg metronidazole and 375 mg amoxicillin three times a day for 7 days ; the other half received a placebo . GCF sample s were collected from one interproximal lesion in each of the contralateral quadrants before treatment and after 10 days and 2 , 6 , and 12 months . Total protein content was determined according to the Bradford method . Myeloid-related protein ( MRP ) 8/14 and interleukin (IL)-1beta were analyzed quantitatively by enzyme-linked immunosorbent assay ( ELISA ) , and elastase activity was determined using a low molecular weight fluorogenic substrate . RESULTS No significant differences were observed between sites treated with or without EMD for any biochemical parameter . Two months after treatment , subjects treated with antibiotics exhibited less clinical signs of inflammation . Furthermore , these subjects had lower MRP 8/14 levels only at day 10 compared to those receiving the placebo . For total protein , IL-1beta , and elastase , no statistically significant differences were noted for subjects with or without antibiotic therapy at any time point . CONCLUSIONS Improved healing of the soft tissues has been noted clinical ly in non-surgically treated sites in subjects treated with antibiotics . The expression of inflammatory mediators in GCF corroborated this finding only in part . EMD did not seem to further affect the expression of inflammatory mediators BACKGROUND , AIMS The aim of this double-blind , parallel study was to evaluate the adjunctive effects of systemically administered amoxicillin and metronidazole in a group of adult periodontitis patients who also received supra- and subgingival debridement . METHODS 49 patients with a diagnosis of generalised severe periodontitis participated in the study . R and om assignment result ed in 26 patients in the placebo ( P ) group with a mean age of 40 years and 23 patients in the test ( T ) group which had a mean age of 45 years . Clinical measurements and microbiological assessment s were taken at baseline and 3 months after completion of initial periodontal therapy with additional placebo or antibiotic treatment . Patients received coded study medication of either 375 mg amoxicillin in combination with 250 mg metronidazole or identical placebo tablets , every 8 hours for the following 7 days . RESULTS At baseline , no statistically significant differences between groups were found for any of the clinical parameters . Except for the plaque , there was a significantly larger change in the bleeding , probing pocket depth ( PPD ) and clinical attachment level ( CAL ) in the T-group as compared to the P-group after therapy . The greatest reduction in PPD was found at sites with initial PPD of > or = 7 mm , 2.5 mm in the P-group and 3.2 mm in the T-group . The improvement in CAL was most pronounced in the PPD category > or = 7 mm and amounted to 1.5 mm and 2.0 mm in the P- and T-groups , respectively . No significant decrease was found in the number of patients positive for any of the test species in the P-group . The number of patients positive for Porphyromonas gingivalis , Bacteroides forsythus and Prevotella intermedia in the T-group showed a significant decrease . After therapy there was a significant difference between the P- and the T- group in the remaining number of patients positive for P. gingivalis , B. forsythus and Peptostreptococcus micros . 4 subgroups were created on the basis of the initial microbiological status for P. gingivalis positive ( Pg-pos ) and negative patients ( Pg-neg ) in the P- and the T-groups . The difference in reduction of PPD between Pg-pos and Pg-neg patients was particularly evident with respect to the changes in % of sites with a probing pocket depth > or = 5 mm . This % decreased from 45 % at baseline to 23 % after treatment in the Pg-pos placebo subgroup and decreased from 46 % to 11 % in the Pg-pos test subgroup ( p < or = 0.005 ) . In contrast , the changes in the proportions of sites with a probing pocket depth > or = 5 mm in the Pg-neg placebo and Pg-neg test subgroup were similar , from 43 % at baseline to 18 % after treatment versus 40 % to 12 % respectively . CONCLUSIONS This study has shown that systemic usage of metronidazole and amoxicillin , when used in conjunction with initial periodontal treatment in adult periodontitis patients , achieves significantly better clinical and microbiological results than initial periodontal treatment alone . Moreover , this research suggests that especially patients diagnosed with P. gingivalis benefit from antibiotic treatment The present study describes results on selected clinical and microbiological parameters obtained by treatment with local ( Elyzol ) and systemic ( Flagyl ) use of metronidazole alone and /or mechanical subgingival debridement in adult periodontitis . Patients were r and omly divided into local and systemic treatment groups each comprising 5 individuals in each of whom 4 sites ( one site/ quadrant ) with a probing depth of > or = 5 mm were selected and treated with separate treatment modalities . The overall treatment design provided 6 different test groups . Groups of quadrants received : ( 1 ) scaling and root planing ; ( 2 ) local metronidazole treatment ; ( 3 ) systemic metronidazole treatment ; ( 4 ) local metronidazole combined with scaling and root planing ; ( 5 ) systemic metronidazole combined with scaling and root planing ; ( 6 ) no treatment . The microbiological and clinical effects of treatment modalities were monitored over a period of 42 days . All treatments result ed in clinical improvements ( gingivitis , probing pocket depth , attachment level ) except for the untreated group . Parallel to the clinical changes , all treatments reduced the number of total bacteria and proportions of obligately anaerobic microorganisms . Although both of the combined treatment groups responded to therapy with better resolution of infection that the pure mechanical and pure metronidazole treatments , local metronidazole in combination with scaling and root planing seems to be more effective in terms of producing both clinical and microbial improvements BACKGROUND / AIMS To examine subgingival microbiological changes in chronic periodontitis subjects receiving scaling and root planing ( SRP ) alone or with systemically administered azithromycin , metronidazole or a sub-antimicrobial dose of doxycycline . METHODS Ninety-two periodontitis subjects were r and omly assigned to receive SRP alone or combined with azithromycin , metronidazole or sub-antimicrobial dose doxycycline . Subgingival plaque sample s taken at baseline , 2 weeks , and 3 , 6 , and 12 months were analyzed for 40 bacterial species using checkerboard DNA-DNA hybridization . Percentage of resistant species and percentage of sites harboring species resistant to the test antibiotics were determined at each time-point . RESULTS All treatments reduced counts of red complex species at 12 months , although no significant differences were detected among treatment groups for most species at all time-points . Both antibiotics significantly reduced counts of red complex species by 2 weeks . Percentage of resistant isolates increased in plaque sample s in all adjunctive treatment groups , peaking at the end of administration , but returned to pretreatment levels by 12 months . CONCLUSION The significant reduction of red and orange complex species at 2 weeks in the subjects receiving SRP plus azithromycin or metronidazole may have contributed to a better clinical response in these treatment groups . Therapy did not appear to create lasting changes in the percentage of resistant isolates or sites harboring resistant species OBJECTIVE To compare clinical changes occurring in chronic periodontitis subjects receiving SRP alone or with systemically administered azithromycin , metronidazole or a sub-antimicrobial dose of doxycycline . MATERIAL AND METHODS 92 chronic periodontitis subjects were r and omly assigned to receive SRP alone ( N=23 ) or combined with 500 mg azithromycin per day for 3 days ( N=25 ) , 250 mg metronidazole tid for 14 days ( N=24 ) or 20 mg doxycycline bid for 3 months ( N=20 ) . Gingival redness , bleeding on probing , suppuration , pocket depth and attachment level were measured at baseline and 3 , 6 and 12 months post therapy . The significance of changes in clinical parameters within groups over time was sought using the Friedman test and among groups using ANCOVA or the Kruskal Wallis test . RESULTS All groups showed clinical improvements at 12 months , with subjects receiving adjunctive agents showing a somewhat better response . Sites with initial pocket depth > 6 mm showed significantly greater pocket depth reduction and greater attachment gain in subjects receiving metronidazole or azithromycin than subjects in the other groups . Some subjects showed attachment loss at 12 months in each group ranging from 15 % to 39 % of subjects in the SDD and SRP only groups respectively . CONCLUSION This study , demonstrated that periodontal therapy provides clinical benefits and that antibiotics provide a clinical benefit over SRP alone , particularly at initially deeper periodontal pockets BACKGROUND The benefit of full-mouth disinfection ( FDIS ) over traditional scaling and root planing ( SRP ) remains equivocal , and it is not known whether the use of adjunctive antibiotics may enhance the effect of FDIS . The aim of the present study is to test the hypothesis that there is no difference in the 1-year clinical outcome of therapy among groups of patients treated with conventional SRP performed over 2 to 3 weeks , or same-day FDIS , with or without adjunctive metronidazole . METHODS A total of 184 patients with moderate-to-severe periodontitis were r and omly allocated to one of four treatment groups : 1 ) FDIS+metronidazole ; 2 ) FDIS+placebo ; 3 ) SRP+metronidazole ; or 4 ) SRP+placebo . Recordings of plaque , bleeding on probing , probing depth ( PD ) , and clinical attachment level ( CAL ) were carried out in four sites per tooth at baseline and at 3 and 12 months after treatment . RESULTS No differences were observed in the mean CAL or PD values between the four experimental groups at baseline and 3 or 12 months post-treatment . All four groups displayed significant improvements in all parameters . However , using absence of pockets ≥5 mm as the criterion for treatment success , the two groups receiving adjunctive metronidazole performed significantly better than the two placebo groups . CONCLUSION Metronidazole had a significant , adjunctive effect in patients with a metronidazole-sensitive subgingival microbiota on the clinical parameters of CAL , PD , and absence of pockets ≥5 mm The aim of this study was to assess the clinical and microbiologic effects of the combination of amoxicillin and metronidazole therapy as an adjunct to mechanical treatment in the management of localized juvenile periodontitis . Twenty-five localized juvenile periodontitis ( LJP ) patients from a Brazilian population were r and omly allocated into an experimental group receiving mechanical treatment and antibiotics , and a control group receiving mechanical treatment and placebo . Clinical and radiographic assessment s , as well as microbiologic sampling for Actinobacillus actinomycetemcomitans , were performed at baseline and one year after the end of the treatment . At the termination of the study A. actinomycetemcomitans could be isolated from the oral cavity of all patients in the control group who harbored the bacterium at baseline and in 4 out of 8 patients in the experimental group . Both treatment modalities result ed in significant benefit on an individual basis . The experimental group , however , displayed better results than did the control group regarding gingival index ( GI ) , probing depth ( PD ) , clinical attachment level ( CAL ) , and radiographic analysis of crestal alveolar bone mass , but not with respect to plaque index ( PI ) . No serious adverse effects of the antibiotic treatment were observed in the present study A double blind between subject comparison of the effect of metronidazole and placebo tablets was completed over 22 weeks in 45 subjects with chronic periodontal disease ranging in severity from moderate ( PI = 2.0 - 3.9 ) to high ( PI = 4.0 - 6.0 ) . All subjects used a topically applied chlorhexidine gel for the first 10 weeks . Throughout the trial plaque , bleeding and calculus were assessed on the buccal , lingual , mesial and distal surfaces of teeth 16 , 21 , 24 , 36 , 41 and 44 and their supporting tissues . The pocket depths on the same 4 aspects of all teeth present were measured . The regime employed consisted of oral hygiene instruction ( OHI ) at the initial visit followed by scaling and further OHI at visits 1 and 2 weeks later . After the third visit 16 X 200 mg metronidazole or placebo tablets were issued with instructions to take 1 that evening and 3 per day at 5-h intervals for the next 5 days . 4 weeks later , scaling and OHI were carried out and the course of test or placebo tablets was repeated . The subjects returned for further scaling and OHI 4 weeks later and the chlorhexidine gel was withdrawn . Final assessment s were made 12 weeks later . The results showed that metronidazole had no effect on plaque levels and gingival bleeding beyond the effect of OHI , scaling and chlorhexidine gel . On the other h and , significantly greater reductions in pocket depths were achieved with the use of metronidazole . A surprising and interesting finding was that these reductions were apparent only in the subjects with severe periodontal disease ( PI = 4.0 - 6.0 ) The aim of the present study was to investigate the clinical and microbiological effects of initial periodontal therapy in conjunction with systemic amoxicillin plus clavulanic acid in adult periodontitis patients using a double-blind , parallel-group , and placebo-controlled protocol . 21 patients with a clinical diagnosis of generalised adult periodontitis were recruited . Clinical measurements and microbiological assessment s were carried out at baseline , 3 , and 12 months post-treatment . Approximately 6 weeks after initial periodontal treatment ( 3 - 6 h ) , patients were r and omly assigned to receive coded study medication of 500 mg amoxicillin plus 125 mg clavulanic acid ( Augmentin ) or placebo , every 8 h for 10 days . Patients returned for follow-up visits 3 , 6 , 9 , and 12 months after completion of the medication . The mean plaque index ( PI ) at baseline was 1.1 for placebo group and 0.9 for the test group . At 3 months , the PI had dropped to 0.3 in both groups , and was maintained during the rest of the study . The changes in bleeding on probing ( BOP ) and gingival index ( GI ) in the course of the study were similar in both groups . The mean whole mouth probing pocket depth ( PPD ) in the placebo group was 3.8 mm at baseline and 3.9 mm in the test group . A mean reduction of 1.0 mm in the placebo group and 0.9 mm in the test group was observed during the first 3 months . No further reduction in PPD was noticed during the study period in either group . There was no statistically significant difference in the PPD reduction between the 2 groups . The change in clinical attachment level ( CAL ) from baseline to 3 months amounted to 0.5 mm in both groups . Between 3 and 12 months , the CAL changed in neither group . In both groups , treatment result ed in a decrease in the number of spirochetes and motile rods in positive patients , but no significant differences between either group were noted in any of the dark field microscopy observations . At baseline , 1 patient in the placebo group and 2 patients in the test group were culture positive for Actinobacillus actinomycetemcomitans ( Aa ) . After therapy , Aa was not detectable in the placebo group and 1 patient remained positive in the test group . In the placebo group , the number of patients positive for Porphyromonas gingivalis ( Pg ) decreased from 7 to 2 after therapy . In the test group , the 4 patients positive for Pg at baseline remained positive after therapy . In both groups , all subjects were positive for Prevotella intermedia ( Pi ) and Fusobacterium nucleatum ( Fn ) at baseline . At 12 months , all subjects had detectable subgingival Fn . 9 out of the 11 placebo and 8 of the 10 test patients remained positive for Pi . There were no differences in detection frequency of Peptostreptococcus micros ( Pm ) and Bacteroides forsythus ( Bf ) in both groups between baseline , 3 , and 12 months post-treatment . The findings demonstrated that , in comparison to placebo , systemic amoxicillin plus clavulanic acid provided no additional clinical and microbiological effects in the treatment of adult periodontitis patients AIM To evaluate the clinical effects of the adjunctive use of metronidazole ( MTZ ) and amoxicillin ( AMX ) in the treatment of generalized aggressive periodontitis ( GAgP ) . METHODS Thirty subjects were r and omly assigned to receive scaling and root planing ( SRP ) alone or combined with MTZ ( 400 mg/TID ) and AMX ( 500 mg/TID ) for 14 days . Subjects were clinical ly monitored at baseline , 6 months and 1 year post-therapies . RESULTS Both therapies led to a statistically significant improvement in all clinical parameters at 1 year post-therapy ( p < 0.05 ) . Subjects receiving MTZ plus AMX exhibited the deepest reductions in mean probing depth ( PD ) and gain in clinical attachment between baseline and 1 year post-therapy in the full-mouth analysis and in initially intermediate ( PD 4 - 6 mm ) and deep ( PD ≥ 7 mm ) sites ( p < 0.01 ) . In addition , the antibiotic group presented lower mean number of residual sites with PD ≥ 5 or 6 mm as well as fewer subjects still presenting nine or more sites with PD ≥ 5 mm or three or more sites with PD ≥ 6 mm at the end of the study period . CONCLUSION The non-surgical treatment of GAgP is markedly improved by the adjunctive use of MTZ+AMX , up to 1 year post-treatment A considerable amount of circumstantial evidence indicates that most forms of periodontitis are due to the presence or dominance of a finite number of bacterial species in the subgingival plaque . Almost all of the putative pathogens are anaerobic species , indicating that most forms of periodontitis could be diagnosed as anaerobic infections . In this double-blind investigation , patients with elevated proportions or levels of spirochetes in 2 or more plaque sample s , i.e. , 60 % spirochetes , were r and omly assigned to receive either metronidazole , 250 mg 3 x a day for 1 week , or placebo ( positive-control ) after the completion of all debridement procedures . When the patients were re-examined 4 to 6 weeks later , the patients in the metronidazole group ( n = 15 ) exhibited a highly significant ( p less than 0.01 ) reduction in probing depth and apparent gain in attachment levels relative to the patients ( n = 18 ) in the positive-control group about those teeth that initially had probing depths of 4 to 6 mm . This pattern was also observed about teeth that initially had probing depths greater than or equal to 7 mm . This reduction in probing depths and apparent gain in attachment was associated with a significant reduction in the need for periodontal surgery in the metronidazole-treated patients ( difference 8.4 teeth per patient ) compared to the positive-control patients ( 2.6 teeth per patient ) . These clinical improvements in the metronidazole group were associated with significantly lower proportions of spirochetes , selenomonads , motile rods , and P. intermedius , and a significantly higher proportion of cocci in the plaques . These findings indicate that systemic metronidazole , when given after all the root surface debridement is completed , leads to additional treatment benefits , including a reduced need for surgery , beyond that which can be achieved by debridement alone Objective : To compare clinical and microbiological responses following non-surgical treatment of moderate to advanced adult periodontitis using subgingival scaling with and without adjunctive topical or systemic metronidazole . Design : A single blind r and omised clinical trial of 90 subjects , stratified for periodontitis disease severity and smoking status , divided into three treatment groups : 1 . Subgingival scaling using ultrasonic scalers and local anaesthesia ; 2 . Subgingival scaling using ultrasonic scalers and local anaesthesia plus seven days of systemic metronidazole ( 200 mg tds ) ; 3 . Subgingival scaling using ultrasonic scalers and local anaesthesia plus two applications of 25 % metronidazole gel one week apart in all sites with probing depths more than 4 mm . Evaluations were made before treatment , and 8 weeks and 24 weeks post treatment . Main outcome measures : Probing depths , probing attachment levels and bleeding on probing were measured using a Florida probe . Bacterial morphotypes were evaluated with darkfield microscopy . Results were analysed for all sites with baseline probing depths equal to or greater than Florida probe recordings of 4.6 mm using analysis of variance . Results : 84 subjects completed the trial and the three treatment groups did not differ at baseline for any clinical parameter . Mean probing depths were reduced following treatment by greater than 1.6 mm ( Group 1 = 1.68 mm , Group 2 = 1.62 mm , Group 3 = 1.74 mm at six months post treatment ) but no significant differences were detected between treatment groups at any time point . Similarly , no significant differences were detectable between treatments for changes in mean probing attachment levels , bleeding on probing , plaque scores or proportions of bacterial morphotypes . Conclusions : This study does not support the routine use of adjunctive metronidazole in the non-surgical treatment of OBJECTIVE To compare the treatment outcome of scaling and root planing ( SRP ) in combination with systemic antibiotics , local antibiotic therapy and /or periodontal surgery . MATERIAL AND METHODS One hundred and eighty-seven patients were assigned to eight groups treated by SRP plus none , one , two or three adjunctive treatments and monitored for 24 months in a r and omized controlled clinical trial using a 2 × 2 × 2 factorial design . Systemic amoxicillin + metronidazole ( SMA ) , local tetracycline delivery ( LTC ) and periodontal surgery ( SURG ) were evaluated as adjuncts . Changes in clinical attachment level ( CAL ) and probing pocket depth ( PPD ) were statistically evaluated by ancova of main effects . RESULTS Effects of adjunctive therapy to SRP were minimal at 3 months . Between 3 and 6 months PPD reduction occurred particularly in patients receiving periodontal surgery . After 6 months , both CAL gain and PPD reduction reached a plateau that was maintained at 24 months in all groups . The 24-month CAL gain was improved by SMA ( 0.50 mm ) while PPD was reduced by SMA ( 0.51 mm ) and SURG ( 0.36 mm ) . Smoking reduced CAL gain and PPD reduction . CONCLUSION Patients receiving adjunctive therapies generally exhibited improved CAL gain and /or PPD reduction when compared with the outcome of SRP alone . Only additive , not synergistic effects of the various adjunctive therapies were observed BACKGROUND It has been suggested that use of systemic antibiotics should be limited to patients with specific microbiologic profiles . The main purpose of the present analysis was to study whether microbiologic testing before therapy was of value in predicting which patients would specifically benefit from adjunctive amoxicillin and metronidazole , given in the context of full-mouth scaling and root planing ( SRP ) within 48 hours . METHODS This was a 6-month , single-center , double-masked , placebo-controlled , r and omized longitudinal study . Fifty-one patients received full-mouth periodontal debridement , performed within 48 hours ; then , 25 subjects received metronidazole , 500 mg , and amoxicillin , 375 mg , three times a day for 7 days , and 26 received a placebo ( control group ) . Pooled microbiologic sample s were taken from the deepest pocket at baseline in each quadrant before and 6 months after treatment . Six periodontal pathogens were quantified by real-time polymerase chain reaction . RESULTS Forty-seven patients were followed for 6 months . After treatment , test subjects had a substantially lower mean number of persisting sites with probing depth > 4 mm and bleeding on probing than did control subjects ( 0.4 versus 3.0 ; P = 0.005 ; month 6 ) . Aggregatibacter actinomycetemcomitans ( previously Actinobacillus actinomycetemcomitans ) could not be detected in the antibiotic group after treatment . However , in the placebo group , three of six subjects positive for A. actinomycetemcomitans continued to be positive . Lower frequencies were also noted in the test group for Porphyromonas gingivalis ( P = 0.013 ) and Tannerella forsythia ( previously T. forsythensis ) ( P = 0.007 ) . However , even subjects testing negative for A. actinomycetemcomitans at baseline had a significantly better primary clinical outcome if they received the active drugs . The presence of six putative periodontal pathogens ( A. actinomycetemcomitans , Fusobacterium nucleatum spp . , P. gingivalis , Prevotella intermedia , Treponema denticola , and T. forsythia ) quantified prior to therapy was not correlated with the outcome of full-mouth SRP with or without amoxicillin and metronidazole . CONCLUSION Excellent clinical results in the antibiotics group were obtained regardless of the presence or absence of six classic periodontal periopathogens prior to treatment BACKGROUND It has been suggested that prescription of amoxicillin plus metronidazole in the context of periodontal therapy should be limited to patients with specific microbiologic profiles , especially those testing positive for Aggregatibacter actinomycetemcomitans . The main purpose of this analysis is to determine if patients positive for A. actinomycetemcomitans with moderate to advanced periodontitis benefit specifically from amoxicillin plus metronidazole given as an adjunct to full-mouth scaling and root planing . METHODS This is a double-masked , placebo-controlled , r and omized longitudinal study including 41 participants who were positive for A. actinomycetemcomitans and 41 participants who were negative for A. actinomycetemcomitans . All 82 patients received full-mouth periodontal debridement performed within 48 hours . Patients then received either systemic antibiotics ( 375 mg amoxicillin and 500 mg metronidazole , three times daily ) or placebo for 7 days . The primary outcome variable was persistence of sites with a probing depth ( PD ) > 4 mm and bleeding on probing ( BOP ) at the 3-month reevaluation . Using multilevel logistic regression , the effect of the antibiotics was analyzed according to the following factors ( interaction effect ) : A. actinomycetemcomitans-positive or -negative at baseline , sex , age , smoking , tooth being a molar , and interdental location . RESULTS At reevaluation , participants in the test group had significantly fewer sites with a persisting PD > 4 mm and BOP than control patients ( P < 0.01 ) . Being A. actinomycetemcomitans-positive or -negative did not change the effect of the antibiotics . Patients benefited from the antibiotics irrespective of sex , age , or smoking status . Molars benefited significantly more from the antibiotics than non-molars ( P for interaction effect = 0.03 ) . CONCLUSIONS Patients who were positive for A. actinomycetemcomitans had no specific benefit from amoxicillin plus metronidazole . Sites on molars benefited significantly more from the antibiotics than non-molar sites

Conclusions All exercise modalities improve EF significantly and there was a significant , positive relationship between aerobic exercise intensity and EF . Greater frequency , rather than intensity , of resistance exercise training enhanced EF

Background Regular exercise is associated with enhanced nitric oxide ( NO ) bioavailability . Flow-mediated dilation ( FMD ) is used widely to assess endothelial function ( EF ) and NO release . Objectives The aims of this systematic review and meta- analysis were to ( i ) investigate the effect of exercise modalities ( aerobic , resistance or combined ) on FMD ; and ( ii ) determine which exercise and participant characteristics are most effective in improving FMD .

It is well established that endothelial dysfunction is present in coronary artery disease ( CAD ) , although few studies have determined the effect of training on peripheral conduit vessel function in patients with CAD . A r and omized , crossover design determined the effect of 8 wk of predominantly lower limb , combined aerobic and resistance training , in 10 patients with treated CAD . Endothelium-dependent dilation of the brachial artery was determined , by using high-resolution vascular ultrasonography , from flow-mediated vasodilation ( FMD ) after ischemia . Endothelium-independent vasodilation was measured after administration of glyceryl trinitrate ( GTN ) . Baseline function was compared with that of 10 control subjects . Compared with matched healthy control subjects , FMD and GTN responses were significantly impaired in the untrained CAD patients [ 3.0 + /- 0.8 ( SE ) vs. 5.8 + /- 0.8 % and 14.5 + /- 1.9 vs. 20.4 + /- 1.5 % , respectively ; both P < 0.05 ] . Training significantly improved FMD in the CAD patients ( from 3.0 + /- 0.8 to 5.7 + /- 1.1 % ; P < 0.05 ) but not responsiveness to GTN ( 14.5 + /- 1.9 vs. 12.1 + /- 1.4 % ; P = not significant ) . Exercise training improves endothelium-dependent conduit vessel dilation in subjects with CAD , and the effect , evident in the brachial artery , appears to be generalized rather than limited to vessels of exercising muscle beds . These results provide evidence for the benefit of exercise training , as an adjunct to routine therapy , in patients with a history of CAD The aim of this study was to investigate the effects of very high intensity sprint interval training ( SIT ) on metabolic and vascular risk factors in overweight/obese sedentary men . Ten men ( age , 32.1 ± 8.7 years ; body mass index , 31.0 ± 3.7 kg m(-2 ) ) participated . After baseline metabolic , anthropometric , and fitness measurements , participants completed a 2-week SIT intervention , comprising 6 sessions of 4 to 6 repeats of 30-second Wingate anaerobic sprints on an electromagnetically braked cycle ergometer , with 4.5-minute recovery between each repetition . Metabolic , anthropometric , and fitness assessment s were repeated post-intervention . Both maximal oxygen uptake ( 2.98 ± 0.15 vs 3.23 ± 0.14 L min(-1 ) , P = .013 ) and mean Wingate power ( 579 ± 24 vs 600 ± 19 W , P = .040 ) significantly increased after 2 weeks of SIT . Insulin sensitivity index ( 5.35 ± 0.72 vs 4.34 ± 0.72 , P = .027 ) and resting fat oxidation rate in the fasted state ( 0.13 ± 0.01 vs 0.11 ± 0.01 g min(-1 ) , P = .019 ) were significantly higher and systolic blood pressure ( 121 ± 3 vs 127 ± 3 mm Hg , P = .020 ) and resting carbohydrate oxidation in the fasted state ( 0.03 ± 0.01 vs 0.08 ± 0.02 g min(-1 ) , P = .037 ) were significantly lower 24 hours post-intervention compared with baseline , but these changes were no longer significant 72 hours post-intervention . Significant decreases in waist ( 98.9 ± 3.1 vs 101.3 ± 2.7 cm , P = .004 ) and hip ( 109.8 ± 2.2 vs 110.9 ± 2.2 cm , P = .017 ) circumferences compared with baseline were also observed after the intervention . Thus , 2 weeks of SIT substantially improved a number of metabolic and vascular risk factors in overweight/obese sedentary men , highlighting the potential for this to provide an alternative exercise model for the improvement of vascular and metabolic health in this population Aerobic exercise training combined with resistance training ( RT ) might prevent the deterioration of vascular function . However , how aerobic exercise performed before or after a bout of RT affects vascular function is unknown . The present study investigates the effect of aerobic exercise before and after RT on vascular function . Thirty-three young , healthy subjects were r and omly assigned to groups that ran before RT ( BRT : 4 male , 7 female ) , ran after RT ( ART : 4 male , 7 female ) , or remained sedentary ( SED : 3 male , 8 female ) . The BRT and ART groups performed RT at 80 % of one repetition maximum and ran at 60 % of the targeted heart rate twice each week for 8 wk . Both brachial-ankle pulse wave velocity ( baPWV ) and flow-mediated dilation ( FMD ) after combined training in the BRT group did not change from baseline . In contrast , baPWV after combined training in the ART group reduced from baseline ( from 1,025 + /- 43 to 910 + /- 33 cm/s , P < 0.01 ) . Moreover , brachial artery FMD after combined training in the ART group increased from baseline ( from 7.3 + /- 0.8 to 9.6 + /- 0.8 % , P < 0.01 ) . Brachial artery diameter , mean blood velocity , and blood flow in the BRT and ART groups after combined training increased from baseline ( P < 0.05 , P < 0.01 , and P < 0.001 , respectively ) . These values returned to the baseline during the detraining period . These values did not change in the SED group . These results suggest that although vascular function is not improved by aerobic exercise before RT , performing aerobic exercise thereafter can prevent the deteriorating of vascular function Background — Exercise training reduces the symptoms of chronic heart failure . Which exercise intensity yields maximal beneficial adaptations is controversial . Furthermore , the incidence of chronic heart failure increases with advanced age ; it has been reported that 88 % and 49 % of patients with a first diagnosis of chronic heart failure are > 65 and > 80 years old , respectively . Despite this , most previous studies have excluded patients with an age > 70 years . Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfa rct ion heart failure . Methods and Results — Twenty-seven patients with stable postinfa rct ion heart failure who were undergoing optimal medical treatment , including & bgr;-blockers and angiotensin-converting enzyme inhibitors ( aged 75.5±11.1 years ; left ventricular [ LV ] ejection fraction 29 % ; & OV0312;o2peak 13 mL · kg−1 · min−1 ) were r and omized to either moderate continuous training ( 70 % of highest measured heart rate , ie , peak heart rate ) or aerobic interval training ( 95 % of peak heart rate ) 3 times per week for 12 weeks or to a control group that received st and ard advice regarding physical activity . & OV0312;o2peak increased more with aerobic interval training than moderate continuous training ( 46 % versus 14 % , P<0.001 ) and was associated with reverse LV remodeling . LV end-diastolic and end-systolic volumes declined with aerobic interval training only , by 18 % and 25 % , respectively ; LV ejection fraction increased 35 % , and pro-brain natriuretic peptide decreased 40 % . Improvement in brachial artery flow-mediated dilation ( endothelial function ) was greater with aerobic interval training , and mitochondrial function in lateral vastus muscle increased with aerobic interval training only . The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups . No changes occurred in the control group . Conclusions — Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity , endothelial function , and quality of life in patients with postinfa rct ion heart failure . These findings may have important implication s for exercise training in rehabilitation programs and future studies Although high-intensity resistance training increases central arterial stiffness , moderate-intensity resistance training does not . However , the effects of low-intensity resistance training on arterial stiffness are unknown . The aim of this study was to investigate the effect of low-intensity resistance training with short inter-set rest period ( LSR ) on arterial stiffness . Twenty-six young healthy subjects were r and omly assigned to training ( 10 males , 3 females ) and control groups ( 9 males , 4 females ) . The subjects performed LSR twice a week at 50 % of one repetition maximum for 10 weeks . Training consisted of five sets of ten repetitions with an inter-set rest period of 30 s. Changes in brachial-ankle pulse wave velocity ( baPWV ) and brachial flow-mediated dilation ( FMD ) were assessed before and after the intervention period . After the intervention period , one repetition maximum strength increased ( by 9–38 % , P < 0.05 to < 0.001 ; increases varied among the exercise types ) , baPWV decreased ( from 1,093 ± 148 to 1,020 ± 128 cm/s , P < 0.05 ) , and brachial FMD increased ( from 9.7 ± 1.3 to 11.8 ± 1.9 % , P < 0.05 ) . These values did not change in the control group . These results suggest that LSR reduced arterial stiffness and improved vascular endothelial function OBJECTIVES The aim of this study was to assess the efficacy of exercise and antidepressant medication in reducing depressive symptoms and improving cardiovascular biomarkers in depressed patients with coronary heart disease . BACKGROUND Although there is good evidence that clinical depression is associated with poor prognosis , optimal therapeutic strategies are currently not well defined . METHODS One hundred one out patients with coronary heart disease and elevated depressive symptoms underwent assessment of depression , including a psychiatric interview and the Hamilton Rating Scale for Depression . Participants were r and omized to 4 months of aerobic exercise ( 3 times/week ) , sertraline ( 50 - 200 mg/day ) , or placebo . Additional assessment s of cardiovascular biomarkers included measures of heart rate variability , endothelial function , baroreflex sensitivity , inflammation , and platelet function . RESULTS After 16 weeks , all groups showed improvement on Hamilton Rating Scale for Depression scores . Participants in both the aerobic exercise ( mean -7.5 ; 95 % confidence interval : -9.8 to -5.0 ) and sertraline ( mean -6.1 ; 95 % confidence interval : -8.4 to -3.9 ) groups achieved larger reductions in depressive symptoms compared with those receiving placebo ( mean -4.5 ; 95 % confidence interval : -7.6 to -1.5 ; p = 0.034 ) ; exercise and sertraline were equally effective at reducing depressive symptoms ( p = 0.607 ) . Exercise and medication tended to result in greater improvements in heart rate variability compared with placebo ( p = 0.052 ) ; exercise tended to result in greater improvements in heart rate variability compared with sertraline ( p = 0.093 ) . CONCLUSIONS Both exercise and sertraline result ed in greater reductions in depressive symptoms compared to placebo in patients with coronary heart disease . Evidence that active treatments may also improve cardiovascular biomarkers suggests that they may have a beneficial effect on clinical outcomes as well as on quality of life . ( Exercise to Treat Depression in Individuals With Coronary Heart Disease ; NCT00302068 ) Objectives The aim of this study was to examine the effect of three different doses of aerobic exercise training ( corresponding to approximately 50 % , 100 % and 150 % of the National Institutes of Health consensus guidelines ) on endothelial function in sedentary obese postmenopausal women with elevated blood pressure . Aerobic exercise training improves endothelial function in individuals with cardiovascular risk ; however , it is unknown whether these adaptations occur in a dose-dependent manner . Methods Obese postmenopausal women ( n=155 ) with elevated blood pressure ( systolic blood pressure between 120 and 159.0 mm Hg ) were r and omly assigned to one of four groups : 4 , 8 or 12 kilocalories per kilogram of energy expenditure per week ( kcal/kg/week ) or a non-exercise control group for 6 months . Endothelial function was assessed via flow-mediated dilation ( FMD ) at baseline and post-intervention . Results After exercise training , there was a similar improvement ( 1.02–1.5 % ) in FMD in all three exercise groups ( p<0.05 ) compared with control ( –0.5 % ) . Change in FMD after exercise training was significantly correlated with FMD at baseline ( r= –0.35 , p<0.001 ) . Post hoc analyses found a significant improvement in FMD in exercisers ( all exercise groups combined ) with endothelial dysfunction ( FMD < 5.5 % ) at baseline ( 1.8 % , 95 % CI : 1.17 to 2.38 ; p<0.001 ) compared with exercisers with normal endothelial function ( FMD ≥ 5.5 % ) ( –1.2 % ; 95 % CI : –1.17 to 0.69 ; p=0.60 ) . Conclusions Aerobic exercise training was associated with improved FMD in postmenopausal women with elevated blood pressure . In addition , exercise training may be more efficacious in improving endothelial function in postmenopausal women with endothelial dysfunction than individuals with normal endothelial function at baseline OBJECTIVE To investigate the effect of an exercise intervention on flow-mediated dilation ( FMD ) and circulating endothelial biomarkers in adults with type 2 diabetes ( T2DM ) . METHODS Sedentary adults ( n = 140 ) , aged 40 - 65 , with T2DM and untreated pre or Stage I hypertension or treated hypertension were r and omized to a 6-month , supervised , exercise program ( 3 × week ) or a sedentary control . Assessment s included BMI , body and visceral fat , blood pressure , lipids , HbA1c , insulin sensitivity ( QUICKI ) , fitness , FMD , E-selectin , P-selectin , intracellular and vascular cellular adhesion molecules ( ICAM , VCAM ) , and tissue plasminogen activator ( tPA ) . Intervention effects were compared by t-tests . Pearson 's correlations were calculated between changes in cardiovascular risk factors and endothelial outcomes . RESULTS Exercisers significantly improved BMI ( -0.6 kg/m(2 ) ) , body fat % ( -1.4 % ) , HbA1c ( -0.5 % ) , and fitness ( 2.9 mL/kg min ) vs. controls ( p < 0.05 ) . However , there were no differences between groups in changes in FMD , E-selectin , P-selectin , ICAM , VCAM , or tPA . Among exercisers , changes in cardiovascular risk factors correlated with several biomarkers . Decreased P-selectin correlated with decreased BMI ( r = 0.29 , p = 0.04 ) and increased HDL cholesterol ( r = -0.36 , p = 0.01 ) . Decreased ICAM correlated with decreased triglycerides and HbA1c ( r = 0.30 , p = 0.04 ; r = 0.31 , p = 0.03 ) and increased QUICKI ( r = - 0.28 , p = 0.05 ) . Decreased tPA correlated with decreased total body and visceral fat ( r = 0.28 , p = 0.05 ; r = 0.38 , p = 0.008 ) and increased QUICKI ( r = -0.38 , p = 0.007 ) . CONCLUSIONS While exercise result ed in improved fitness , body composition , and glycemic control , there were no changes in FMD or circulating endothelial biomarkers . The associations of changes in cardiovascular risk factors and endothelial biomarkers suggest that improvement in risk factors could mediate the exercise-induced improvements in endothelial function seen in prior studies BACKGROUND Regular exercise and consuming long-chain n-3 fatty acids ( FAs ) from fish or fish oil can independently improve cardiovascular and metabolic health , but combining these lifestyle modifications may be more effective than either treatment alone . OBJECTIVE We examined the individual and combined effects of n-3 FA supplements and regular exercise on body composition and cardiovascular health . DESIGN Overweight volunteers [ body mass index ( BMI ; in kg/m(2 ) ) : > 25 ] with high blood pressure , cholesterol , or triacylglycerols were r and omly assigned to one of the following interventions : fish oil ( FO ) , FO and exercise ( FOX ) , sunflower oil ( SO ; control ) , or SO and exercise ( SOX ) . Subjects consumed 6 g tuna FO/d ( approximately 1.9 g n-3 FA ) or 6 g SO/d . The exercise groups walked 3 d/wk for 45 min at 75 % age-predicted maximal heart rate . Plasma lipids , blood pressure , and arterial function were assessed at 0 , 6 , and 12 wk . Body composition was assessed by dual-energy X-ray absorptiometry at 0 and 12 wk only . RESULTS FO supplementation lowered triacylglycerols , increased HDL cholesterol , and improved endothelium-dependent arterial vasodilation ( P<0.05 ) . Exercise improved arterial compliance ( P<0.05 ) . Both fish oil and exercise independently reduced body fat ( P<0.05 ) . CONCLUSIONS FO supplements and regular exercise both reduce body fat and improve cardiovascular and metabolic health . Increasing intake of n-3 FAs could be a useful adjunct to exercise programs aim ed at improving body composition and decreasing cardiovascular disease risk AIMS Despite the importance of both lipid metabolism and physical activity to cardiovascular health , few studies have examined the effect of exercise training on vascular function in hypercholesterolaemic humans . METHODS AND RESULTS A r and omized , cross-over design investigated the effect of 8 weeks of combined aerobic and resistance exercise training on conduit and resistance vessel function in 11 untreated subjects with hypercholesterolaemia and 11 subjects taking lipid-lowering medication . High-resolution vascular ultrasonography following forearm ischaemia and glyceryl trinitrate administration determined conduit vessel endothelium-dependent and independent function . Strain-gauge plethysmography , with intra-aerial infusions of acetylcholine , sodium nitroprusside and N(G)-monomethyl-L-arginine , determined resistance vessel function . Flow-mediated dilation and the forearm blood flow response to acetylcholine improved significantly following training in the treated subgroup ( both P<0.05 ) but not the untreated , although the blood flow response to N(G)-monomethyl-L-arginine was augmented following training in the untreated subjects ( P<0.05 ) , indicating greater basal nitric oxide bioactivity . Training did not alter responsiveness to glyceryl trinitrate or sodium nitroprusside . CONCLUSIONS Combined aerobic and resistance training improves endothelium-dependent conduit and resistance vessel function in hypercholesterolaemic subjects taking lipid-lowering medications and basal nitric oxide bioactivity in untreated hypercholesterolaemic subjects . Exercise training may provide additional cardiovascular benefits for hypercholesterolaemic patients including those taking lipid-lowering medication CONTEXT Observational studies have shown that psychosocial factors are associated with increased risk for cardiovascular morbidity and mortality , but the effects of behavioral interventions on psychosocial and medical end points remain uncertain . OBJECTIVE To determine the effect of 2 behavioral programs , aerobic exercise training and stress management training , with routine medical care on psychosocial functioning and markers of cardiovascular risk . DESIGN , SETTING , AND PATIENTS R and omized controlled trial of 134 patients ( 92 male and 42 female ; aged 40 - 84 years ) with stable ischemic heart disease ( IHD ) and exercise-induced myocardial ischemia . Conducted from January 1999 to February 2003 . INTERVENTIONS Routine medical care ( usual care ) ; usual care plus supervised aerobic exercise training for 35 minutes 3 times per week for 16 weeks ; usual care plus weekly 1.5-hour stress management training for 16 weeks . MAIN OUTCOME MEASURES Self-reported measures of general distress ( General Health Question naire [ GHQ ] ) and depression ( Beck Depression Inventory [ BDI ] ) ; left ventricular ejection fraction ( LVEF ) and wall motion abnormalities ( WMA ) ; flow-mediated dilation ; and cardiac autonomic control ( heart rate variability during deep breathing and baroreflex sensitivity ) . RESULTS Patients in the exercise and stress management groups had lower mean ( SE ) BDI scores ( exercise : 8.2 [ 0.6 ] ; stress management : 8.2 [ 0.6 ] ) vs usual care ( 10.1 [ 0.6 ] ; P = .02 ) ; reduced distress by GHQ scores ( exercise : 56.3 [ 0.9 ] ; stress management : 56.8 [ 0.9 ] ) vs usual care ( 53.6 [ 0.9 ] ; P = .02 ) ; and smaller reductions in LVEF during mental stress testing ( exercise : -0.54 % [ 0.44 % ] ; stress management : -0.34 % [ 0.45 % ] ) vs usual care ( -1.69 % [ 0.46 % ] ; P = .03 ) . Exercise and stress management were associated with lower mean ( SE ) WMA rating scores ( exercise : 0.20 [ 0.07 ] ; stress management : 0.10 [ 0.07 ] ) in a subset of patients with significant stress-induced WMA at baseline vs usual care ( 0.36 [ 0.07 ] ; P = .02 ) . Patients in the exercise and stress management groups had greater mean ( SE ) improvements in flow-mediated dilation ( exercise : mean [ SD ] , 5.6 % [ 0.45 % ] ; stress management : 5.2 % [ 0.47 % ] ) vs usual care patients ( 4.1 % [ 0.48 % ] ; P = .03 ) . In a subgroup , those receiving stress management showed improved mean ( SE ) baroreflex sensitivity ( 8.2 [ 0.8 ] ms/mm Hg ) vs usual care ( 5.1 [ 0.9 ] ms/mm Hg ; P = .02 ) and significant increases in heart rate variability ( 193.7 [ 19.6 ] ms ) vs usual care ( 132.1 [ 21.5 ] ms ; P = .04 ) . CONCLUSION For patients with stable IHD , exercise and stress management training reduced emotional distress and improved markers of cardiovascular risk more than usual medical care alone Background — Higher levels of physical activity are associated with fewer cardiovascular disease ( CVD ) events . Although the precise mechanisms underlying this inverse association are unclear , differences in several cardiovascular risk factors may mediate this effect . Methods and Results — In a prospect i ve study of 27 055 apparently healthy women , we measured baseline levels of hemoglobin A1c , traditional lipids ( total , low-density lipoprotein , and high-density lipoprotein cholesterol ) , novel lipids [ lipoprotein(a ) and apolipoprotein A1 and B-100 ] , creatinine , homocysteine , and inflammatory/hemostatic biomarkers ( high-sensitivity C-reactive protein , fibrinogen , soluble intracellular adhesion molecule-1 ) and used women 's self-reported physical activity , weight , height , hypertension , and diabetes . Mean follow-up was 10.9±1.6 years , and 979 incident CVD events occurred . The risk of CVD decreased linearly with higher levels of activity ( P for linear trend < 0.001 ) . Using the reference group of < 200 kcal/wk of activity yielded age- and treatment-adjusted relative risk reductions associated with 200 to 599 , 600 to 1499 , and ≥1500 kcal/wk of 27 % , 32 % , and 41 % , respectively . Differences in known risk factors explained a large proportion ( 59.0 % ) of the observed inverse association . When sets of risk factors were examined , inflammatory/hemostatic biomarkers made the largest contribution to lower risk ( 32.6 % ) , followed by blood pressure ( 27.1 % ) . Novel lipids contributed less to CVD risk reduction compared with traditional lipids ( 15.5 % and 19.1 % , respectively ) . Smaller contributions were attributed to body mass index ( 10.1 % ) and hemoglobin A1c/diabetes ( 8.9 % ) , whereas homocysteine and creatinine had negligible effects ( < 1 % ) . Conclusions — The inverse association between physical activity and CVD risk is mediated in substantial part by known risk factors , particularly inflammatory/hemostatic factors and blood pressure Background Aerobic exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension . Several hypertensive patients , however , are limited by musculoskeletal complaints or vascular occlusive disease from lower-limb exercise such as jogging or cycling . In the present r and omized-controlled study , we evaluate whether an aerobic arm-cycling program provides a measurable cardiovascular benefit . Methods Twenty-four prob and s were r and omly assigned to sedentary activity or a heart rate controlled 12 week exercise program , consisting of arm-cycling at target lactate concentrations of 2.0 ± 0.5 mmol/l . Endothelial function was assessed by flow-mediated dilation of the brachial artery . Augmentation index and large/small artery compliance ( C1 and C2 ) were measured by computerized pulse-wave analysis of the radial artery . Results The exercise program led to a significant reduction in systolic ( 134.0 ± 20.0 to 127.0 ± 16.4 mmHg ; P = 0.03 ) and diastolic blood pressure ( 73.0 ± 21.6 to 67.1 ± 8.2 mmHg ; P = 0.02 ) accompanied by a significant improvement in C2 ( 3.5 ± 1.6 to 4.8 ± 2.0 ml/mmHg × 100 ; P = 0.004 ) . Flow-mediated dilation , augmentation index , and C2 were not significantly affected ( P > 0.05 ) . Physical performance as derived from lactate and heart rate curves of lower-limb stress tests was unchanged , whereas maximal workload in an upper-limb ergometry significantly increased ( P = 0.005 ) . Blood pressure and vascular parameters remained unchanged in the control group . Conclusion Regular arm aerobic exercise leads to a marked reduction in systolic and diastolic blood pressures and an improvement in small artery compliance . Arm-cycling is a reasonable option for hypertensive patients who want to support blood pressure control by sports despite having coxarthrosis , gonarthrosis , or intermittent claudication Abstract Habitual exercise provides repeated episodes of elevated vascular shear stress ( SS ) , which may be a mechanism for repair of endothelial dysfunction in disease . Our aim was to determine the brachial artery SS during the 3–hour period following single bouts of low , moderate , and high-intensity walking exercise . In a r and omized crossover design , 14 men walked for 45 minutes on a treadmill at 25 % , 50 % and 75 % of VO2peak separated by 2–7 days . Using Doppler ultrasonography , brachial artery SS was assessed immediately after exercise and then hourly for 3 hours . High-intensity walking elicited greater ( p < 0.05 ) post-exercise SS compared with low and moderate intensity . In addition , a 3 x 4 ( intensity x time ) ANOVA indicated an absence of interaction ( p = 0.369 ) and a decline in post-exercise SS over time ( p < 0.0001 ) which was abolished after 2 hours . Thus , we found that brachial artery SS is greatest following high-intensity walking and that the rate of decline in SS is similar across all walking intensities Background — In coronary artery disease , exercise training ( ET ) is associated with an improvement in endothelial function , but little is known about the relative effect of different types of training . The purpose of this study was to prospect ively evaluate the effect of different types of ET on endothelial function in 209 patients after a first recent acute myocardial infa rct ion . Methods and Results — Endothelial function was evaluated before and after 4 weeks of different types of ET and after 1 month of detraining by measuring flow-mediated dilation and von Willebr and factor levels at baseline and after ET . Patients were r and omized into 4 groups : group 1 , aerobic ET ( n=52 ) ; group 2 , resistance training ( n=54 ) ; group 3 , resistance plus aerobic training ( n=53 ) ; and group 4 , no training ( n=50 ) . At baseline , flow-mediated dilation was 4.5±2.6 % in group 1 , 4.01±1.6 % in group 2 , 4.4±4 % in group 3 , and 4.3±2.3 % in group 4 ( P = NS ) . After ET , flow-mediated dilation increased to 9.9±2.5 % in group 1 , 10.1±2.6 % in group 2 , and 10.8±3 % in group 3 ( P<0.01 versus baseline for all groups ) ; it also increased in group 4 but to a much lesser extent ( to 5.1±2.5 % ; P<0.01 versus trained groups ) . The von Willebr and factor level after ET decreased by 16 % ( P<0.01 ) similarly in groups 1 , 2 , and 3 but remained unchanged in group 4 . Detraining returned flow-mediated dilation to baseline levels ( P<0.01 versus posttraining ) . Conclusion — In patients with recent acute myocardial infa rct ion , ET was associated with improved endothelial function independently of the type of training , but this effect disappeared after 1 month of detraining OBJECTIVES The aim of this study was to analyze whether L-arginine ( L-arg . ) has comparable or additive effects to physical exercise regarding endothelium-dependent vasodilation in patients with chronic heart failure ( CHF ) . BACKGROUND Endothelial dysfunction in patients with CHF can be corrected by both dietary supplementation with L-arg . and regular physical exercise . METHODS Forty patients with severe CHF ( left ventricular ejection fraction 19 + /- 9 % ) were r and omized to an L-arg . group ( 8 g/day ) , a training group ( T ) with daily h and grip training , L-arg . and T ( L-arg . + T ) or an inactive control group ( C ) . The mean internal radial artery diameter was determined at the beginning and after four weeks in response to brachial arterial administration of acetylcholine ( ACh ) ( 7.5 , 15 , 30 microg/min ) and nitroglycerin ( 0.2 mg/min ) with a transcutaneous high-resolution 10 MHz A-mode echo tracking system coupled with a Doppler device . The power of the study to detect clinical ly significant differences in endothelium-dependent vasodilation was 96.6 % . RESULTS At the beginning , the mean endothelium-dependent vasodilation in response to ACh , 30 microg/min was 2.54 + /- 0.09 % ( p = NS between groups ) . After four weeks , internal radial artery diameter increased by 8.8 + /- 0.9 % after ACh 30 microg/min in L-arg . ( p < 0.001 vs. C ) , by 8.6 + /- 0.9 % in T ( p < 0.001 vs. C ) and by 12.0 + /- 0.3 % in L-arg . + /- T ( p < 0.005 vs. C , L-arg . and T ) . Endothelium-independent vasodilation as assessed by infusion of nitroglycerin was similar in all groups at the beginning and at the end of the study . CONCLUSIONS Dietary supplementation of L-arg . as well as regular physical exercise improved agonist-mediated , endothelium-dependent vasodilation to a similar extent . Both interventions together seem to produce additive effects with respect to endothelium-dependent vasodilation UNLABELLED Erectile dysfunction ( ED ) is a major adverse effect of radical prostatectomy ( RP ) . We conducted a r and omized controlled trial to examine the efficacy of aerobic training ( AT ) compared with usual care ( UC ) on ED prevalence in 50 men ( n=25 per group ) after RP . AT consisted of five walking sessions per week at 55 - 100 % of peak oxygen uptake ( VO2peak ) for 30 - 60 min per session following a nonlinear prescription . The primary outcome was change in the prevalence of ED , as measured by the International Index of Erectile Function ( IIEF ) , from baseline to 6 mo . Secondary outcomes were brachial artery flow-mediated dilation ( FMD ) , VO2peak , cardiovascular ( CV ) risk profile ( eg , lipid profile , body composition ) , and patient-reported outcomes ( PROs ) . The prevalence of ED ( IIEF score ≤ 21 ) decreased by 20 % in the AT group and by 24 % in the UC group ( difference : p=0.406 ) . There were no significant between-group differences in any erectile function subscale ( p>0.05 ) . Significant between-group differences were observed for changes in FMD and VO2peak , favoring AT . There were no group differences in other markers of CV risk profile or PROs . In summary , nonlinear AT does not improve ED in men with localized prostate cancer in the acute period following RP . TRIAL REGISTRATION Clinical trials.gov identifier NCT00620932 BACKGROUND Heart transplantation normalizes central hemodynamics , but endothelial dysfunction persists after transplantation . METHODS To investigate the effects of aerobic exercise on arterial function , oxidative stress , lipid profile , and sympathetic nervous system activity , 20 heart transplant recipients ( age , 54.3 + /- 9.1 years ; 17 men , 3 women ) were r and omly assigned to 12 weeks of supervised treadmill exercise ( Trained ; n = 10 ) or st and ard medical care ( Control ; n = 10 ) . Supervised exercise was initiated at 8 weeks after transplant . Brachial artery reactivity was assessed using flow-mediated dilation . RESULTS The VO2 peak increased 26 % in the Trained patients ( 15.4 + /- 4.3 vs 19.4 + /- 5.5 ml/kg/min ; p < or = 0.05 ) but did not change in the Controls ( 16.2 + /- 5.2 vs 16.8 + /- 2.8 ml/kg/min ; p > or = 0.05 ) . Brachial artery flow-mediated dilation ( 10.1 % + /- 6.1 % vs 9.6 % + /- 6.2 % ) and absolute brachial diameter ( 0.48 + /- 0.22 vs 0.42 + /- 0.24 mm ) did not change in Trained patients , but brachial flow-mediated dilation ( 10.5 % + /- 2.8 % vs 7.9 % + /- 5.1 % ) and the absolute change in brachial diameter ( 0.48 + /- 0.16 vs 0.36 + /- 0.24 mm ) decreased significantly ( p < or = 0.05 ) in the Control patients . Resting norepinephrine decreased significantly ( p < or = 0.05 ) after training ( 0.32 + /- 0.19 vs 0.22 + /- 0.22 ng/ml ) , but there was a nonsignificant trend toward increased norepinephrine in the Controls ( 0.26 + /- 0.17 vs 0.53 + /- 0.41 ng/ml ; p = 0.07 ) . The lipid profile and marker of oxidative stress did not differ between the groups before or after the intervention . CONCLUSIONS To our knowledge , this is the first prospect i ve , r and omized study to investigate the effects of heart transplantation and aerobic exercise on peripheral artery function in the same cohort of heart transplant recipients . Brachial artery flow-mediated dilation increased early in the post-operative period . Aerobic exercise preserved but did not improve brachial artery flow-mediated dilation . Heart transplant recipients who did not participate in supervised exercise showed a progressive decline in brachial artery flow-mediated dilation Background —Attenuated peripheral perfusion in patients with advanced chronic heart failure ( CHF ) is partially the result of endothelial dysfunction . This has been causally linked to an impaired endogenous regenerative capacity of circulating progenitor cells ( CPC ) . The aim of this study was to eluci date whether exercise training ( ET ) affects exercise intolerance and left ventricular ( LV ) performance in patients with advanced CHF ( New York Heart Association class IIIb ) and whether this is associated with correction of peripheral vasomotion and induction of endogenous regeneration . Methods and Results —Thirty-seven patients with CHF ( LV ejection fraction 24±2 % ) were r and omly assigned to 12 weeks of ET or sedentary lifestyle ( control ) . At the beginning of the study and after 12 weeks , maximal oxygen consumption ( Vo2max ) and LV ejection fraction were determined ; the number of CD34+/KDR+ CPCs was quantified by flow cytometry and CPC functional capacity was determined by migration assay . Flow-mediated dilation was assessed by ultrasound . Capillary density was measured in skeletal muscle tissue sample s. In advanced CHF , ET improved Vo2max by + 2.7±2.2 versus −0.8±3.1 mL/min/kg in control ( P=0.009 ) and LV ejection fraction by + 9.4±6.1 versus −0.8±5.2 % in control ( P<0.001 ) . Flow-mediated dilation improved by + 7.43±2.28 versus + 0.09±2.18 % in control ( P<0.001 ) . ET increased the number of CPC by + 83±60 versus −6±109 cells/mL in control ( P=0.014 ) and their migratory capacity by + 224±263 versus −12±159 CPC/1000 plated CPC in control ( P=0.03 ) . Skeletal muscle capillary density increased by + 0.22±0.10 versus −0.02±0.16 capillaries per fiber in control ( P<0.001 ) . Conclusions —Twelve weeks of ET in patients with advanced CHF is associated with augmented regenerative capacity of CPCs , enhanced flow-mediated dilation suggestive of improvement in endothelial function , skeletal muscle neovascularization , and improved LV function . Clinical Trial Registration —http://www . clinical trials.gov . Unique Identifier : NCT00176384 Muscle contractions in normal resistance training are performed by eccentric ( ECC , lowering phase ) and concentric ( CON , lifting phase ) muscle contractions . However , the difference in effects of timing of muscle contraction during resistance training on arterial stiffness is unknown . This study investigated the effect of muscle contraction timing during resistance training on vascular function in healthy young adults . Thirty healthy men were r and omly assigned to group of resistance training with quick lifting and slow lowering ( ERT , n=10 ) , group of resistance training with slow lifting and quick lowering ( CRT , n=10 ) and sedentary groups ( SED , n=10 ) . The ERT and CRT groups underwent two supervised resistance-training sessions per week for 10 weeks . The ERT group performed the on set of 8–10 repetitions with 3 s ECC and 1 s CON muscle contractions . In contrast , the CRT group performed the on set of 8–10 repetitions with 1 s ECC and 3 s CON muscle contractions . Brachial – ankle pulse wave velocity ( baPWV ) after ERT did not change from baseline . In contrast , baPWV after CRT increased from baseline ( from 1049±37 to 1153±30 cm s−1 , P<0.05 ) . No significant changes in flow-mediated dilation were observed in the ERT and CRT groups . These values did not change in the SED group . These findings suggest that although both training does not deteriorate a vascular endothelial function , resistance training with quick lifting and slow lowering ( that is , ERT ) prevent the stiffening of arterial stiffness OBJECTIVES We sought to analyze the systemic effects of lower-limb exercise training ( ET ) on radial artery endothelial function in patients with chronic heart failure ( CHF ) . BACKGROUND Local ET has the potential to improve local endothelial dysfunction in patients with CHF . However , it remains unclear whether the systemic effects can be achieved by local ET . METHODS Twenty-two male patients with CHF were prospect ively r and omized to either ET on a bicycle ergometer ( ET group , n = 11 ; left ventricular ejection fraction [ LVEF ] 26 + /- 3 % ) or an inactive control group ( group C , n = 11 ; LVEF 24 + /- 2 % ) . At the beginning of the study and after four weeks , endothelium-dependent and -independent vasodilation of the radial artery was determined by intra-arterial infusion of acetylcholine ( ACh-7.5 , 15 and 30 microg/min ) and nitroglycerin ( 0.2 mg/min ) . The mean internal diameter ( ID ) of the radial artery was assessed using a high resolution ultrasound system ( NIUS-02 , Asulab Research Laboratories , Neuchâtel , Switzerl and ) with a 10-MHz probe . RESULTS After four weeks of ET , patients showed a significant increase in the baseline-corrected mean ID in response to ACh ( 30 microg/min ) , from 33 + /- 10 to 127 + /- 25 microm ( p < 0.001 vs. control group at four weeks ) . In the control group , the response to ACh ( 30 microg/min ) remained unchanged . Endothelium-independent vasodilation was similar in both groups at the beginning of the study and at four weeks . In the training group , increases in agonist-mediated , endothelium-dependent vasodilation correlated to changes in functional work capacity ( r = 0.63 , p < 0.05 ) . CONCLUSIONS In patients with stable CHF , bicycle ergometer ET leads to a correction of endothelial dysfunction of the upper extremity , indicating a systemic effect of local ET on endothelial function BACKGROUND High-intensity interval training has been shown to be superior to moderate continuous exercise training in improving exercise capacity and endothelial function in patients with coronary artery disease . The objective of this study was to evaluate this training model on in-stent restenosis following percutaneous coronary intervention for stable or unstable angina . METHODS AND RESULTS We prospect ively r and omized 40 patients after percutaneous coronary intervention with implantation of a bare metal stent ( n = 30 ) or drug eluting stent ( n = 32 ) to a 6-month supervised high-intensity interval exercise training program ( n = 20 ) or to a control group ( n = 20 ) . At six months , restenosis , measured as in-segment late luminal loss of the stented coronary area , was smaller in the training group 0.10 ( 0.52 ) mm compared to the control group 0.39 ( 0.38 ) mm ( P = .01 ) . Reduction of late luminal loss in the training group was consistent with both stent types . Peak oxygen uptake increased in the training and control group by 16.8 % and 7.8 % , respectively ( P < .01 ) . Flow-mediated dilation improved 5.2 % ( 7.6 ) in the training group and decreased -0.1 % ( 8.1 ) in the control group ( P = .01 ) . Levels of high-sensitivity C-reactive protein decreased by -0.4 ( 1.1 ) mg/L in the training group and increased by 0.1 ( 1.2 ) mg/L in the control group ( P = .03 for trend ) . CONCLUSIONS Regular high-intensity interval exercise training was associated with a significant reduction in late luminal loss in the stented coronary segment . This effect was associated with increased aerobic capacity , improved endothelium function , and attenuated inflammation AIM Nitroglycerin-mediated vasodilatation ( NMD ) provides insight into the NTG-induced bioactivity of smooth muscle . It is plausible that in dysfunctional smooth muscle cells , the response to nitroglycerin may become blunted . The relationship between impaired brachial artery NMD and subsequent cardiovascular events is not well established . METHODS We examined brachial artery flow-mediated dilatation ( FMD ) and NMD using ultrasound in 93 subjects ( 71±7 years , including 26 with peripheral artery disease ( PAD ) , 37 with aortic aneurysms , 10 with PAD complicated with aneurysms , and 20 without evident arterial disease ) . Brachial artery responses to hyperemia and nitroglycerin were measured every minute after cuff deflation and nitroglycerin administration . Time courses of vasodilatation were assessed and maximal FMD and NMD were measured . RESULTS The time courses in response to NTG were sigmoidal and maximal diameter reached 7.2±1.6 minutes after NTG was administered sublingually . The mean FMD was 2.3±2.0 % and the mean NMD was 17.6±7.1 % . Subjects were prospect ively followed for an average of 47±13 months . Eighteen subjects had an event during follow-up ; events included myocardial infa rct ion ( five ) , unstable angina pectoris ( four ) , stroke ( two ) , aortic dissection ( one ) , ruptured aortic aneurysm ( three ) , symptomatic abdominal aortic aneurysm ( two ) , and lower limb ischemia requiring revascularization ( one ) . NMD and FMD were significantly lower in subjects with events than in those without an event . In a Cox proportional-hazards model , lower FMD as well as lower NMD independently predicted future cardiovascular events . CONCLUSION Brachial artery nitroglycerin-mediated vasodilatation may add information to conventional risk stratification Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension . Beta-blockade interacts with heart rate , sympathetic tone , maximal workload and local lactate production . In the present r and omized-controlled study , we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade . Fifty-two patients ( 23 with beta-blocker , 29 without beta-blocker ) ⩾60 years with systolic 24-h ambulatory blood pressure ( ABP ) ⩾140 mm Hg and /or antihypertensive treatment were r and omly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme ( lactate 2.0 mmol/l ) . In the exercise group , the training significantly decreased systolic and diastolic 24-h ABP , blood pressure on exertion ( 100 W ) and increased endothelium-dependent vasodilation ( flow-mediated vasodilation , FMD ) and physical performance both in the presence and absence of beta-blockade ( P<0.05 each ) . The extent of ABP reduction did not significantly differ in the presence or absence of beta-blockade ( Δ systolic ABP 10.6±10.5 vs 10.6±8.8 mm Hg , Δ diastolic ABP 5.7±8.6 vs 5.8±4.0 mm Hg ) . Mean training heart rate was significantly lower in the patients on beta-blockers ( 97.2±7.7 vs 118.3±7.5/min , P<0.001 ) . Lactate-based aerobic endurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function . In the present study , target training heart rate with beta-blockers is about 18 % lower than without BACKGROUND Peripheral conduit artery endothelium-dependent dilatation decreases with aging in humans . Lactotripeptides ( LTPs ) and regular exercise can improve endothelium-dependent dilatation , but combining these lifestyle modifications may be more effective than either treatment alone . We conducted a r and omized , place-controlled trial with four different intervention arms . METHODS A total of 43 postmenopausal women ( 50 - 65 years old ) were r and omly divided into placebo , LTP , exercise and placebo ( Ex+placebo ) , or exercise and LTP ( Ex+LTP ) groups . LTP or placebo was administered orally for 8 weeks . The exercise groups completed an 8-week moderate aerobic exercise ( walking or cycling ) intervention . RESULTS There were no statistically significant differences in baseline flow-mediated dilatation ( FMD ) and most other key dependent variables among the groups . FMD significantly increased in the LTP , Ex+placebo , and Ex+LTP groups whereas no such changes were observed in the placebo control group . The magnitude of increases in FMD was significantly greater in the Ex+LTP group than other intervention groups . CONCLUSION We concluded that LTP ingestion combined with regular aerobic exercise improves endothelium-dependent dilatation to a greater extent than monotherapy with either intervention alone in postmenopausal women BACKGROUND There is evidence that aerobic exercise improves endothelial function in healthy subjects as well as in patients with chronic heart failure . However , it is unknown whether this effect occurs in patients with recent myocardial infa rct ion ( AMI ) . METHODS Fifty-two patients with a recent first uncomplicated AMI underwent endothelial function evaluation before and after 3 months of moderate aerobic exercise training . We measured brachial artery vasomotor reactivity using flow-mediated dilation ( FMD ) , a cold pressor ( CP ) test , and sublingual nitroglycerin . Patients were r and omized into 2 groups : 28 patients ( G1 ) underwent training , while 24 patients ( G2 ) served as controls . Brachial artery vasomotor reactivity was reassessed after 1 month of detraining ( DT ) . RESULTS At baseline the FMD was 1.66 % + /- 4.11 % in G1 and 2.04 % + /- 3.4 % in G2 ( P = NS ) and vasoconstriction was evident after a CP test . The diameter reduction was -4.1 % + /- 3.89 % in G1 and -4.39 % + /- 5.67 % in G2 ( P = NS ) . At follow-up the FMD had increased to 9.39 % + /- 4.87 % in G1 ( P < .01 ) and to 4.4 % + /- 3.9 % in G2 ( P < .01 vs G1 ) . Vasoconstriction during a CP test was observed only in G2 . Endothelium-independent vasodilation was unchanged in both groups . Effort tolerance increased by 32 % in G1 patients ( P < .01 versus G2 ) and was correlated with FMD change ( R = 0.51 , P < .01 ) . After detraining the FMD was significantly reduced in G1 ( P < .01 ) and a further vasoconstriction was evident after CP testing . CONCLUSIONS Exercise training improves endothelium-dependent vasodilation in post-AMI patients . This improvement is associated with a significant increase in exercise tolerance . These benefits disappeared after detraining Background Impaired glucose tolerance ( IGT ) is associated with endothelial dysfunction and upregulation of inflammatory markers , which is potentially reversible by adequate treatment . It was our aim to compare the impact of exercise training with that of rosiglitazone on endothelial function and inflammatory markers in patients with IGT and coronary artery disease ( CAD ) . Methods Patients with IGT and CAD were r and omly assigned to either exercise training ( n = 13 ) , rosiglitazone ( 8 mg ; n = 11 ) , or a control group ( n = 10 ) . During the first week , exercise training consisted of 6 × 15 min/d followed by three weeks of 30 min/d submaximal ergometer exercise . In addition , group exercise training of 1 h was performed twice per week . Results After 4 weeks , triglycerides and uric acid were significantly lower in the exercise group whereas fasting glucose , HbA1c , low-density lipoprotein-cholesterol , high-density lipoprotein-cholesterol , C-reactive protein , fibrinogen , and body mass index did not differ between groups . In the exercise group , exercise capacity ( 123 ± 33 vs. 144 ± 31 W ; P = 0.006 ) and endothelium-dependent , flow-mediated vasodilatation ( P < 0.01 ) increased significantly , whereas in the rosiglitazone group and in the control group ( P = n.s . ) no changes were seen . Conclusion In patients with IGT and CAD , 4 weeks of exercise training exert significant and superior improvement of endothelium-dependent vasodilatation as compared with rosiglitazone therapy or usual care . This finding should be seen as an even further encouragement to recommend and , where available , prescribe exercise training to our patients . Eur J Cardiovasc Prev Rehabil 15:473 - 478 © 2008 The European Society of AIM The effects of exercise intervention and to assess its long-term efficacy in preventing subsequent cardiovascular events in patients with type 2 diabetes were little known on r and omized controlled trial . METHODS Thirty-eight type 2 diabetic patients ( 21 men and 17 women ) were assigned to either the exercise group ( n=21 ) or the control group without exercise training ( n=17 ) by simple r and omization . The exercise training group was scheduled for aerobic and resistance exercise programs for 3 months . After the 3-month , we investigated endothelial function , insulin resistance , adipocytokines and inflammatory markers . The endothelial function was evaluated by examining a flow-mediated endothelium-dependent vasodilatation ( FMD ) . Furthermore , we followed the incidence of cardiovascular events for 24 months . RESULTS After 3-month , HbA1C was decreased significantly in both groups . FMD was increased from 7.3+/-4.7 % to 10.9+/-6.2 % only in the exercise group ( p<0.05 ) . Long-term follow-up data showed that the control group developed cardiovascular events more frequently than did the exercise group ( p<0.05 ) . CONCLUSIONS Exercise improves endothelial dysfunction independently of glycemic control and insulin sensitivity in patients with type 2 diabetes . The beneficial effects of 3-month exercise to reduce cardiovascular events persist for 24 months The present study investigates whether lower-limb dominant exercise training in patients with chronic heart failure ( CHF ) improves endothelial function primarily in the trained lower extremities or equally in the upper and lower extremities . Twenty-eight patients with CHF were r and omized to the exercise or control group . The exercise group underwent cycle ergometer training for 3 months while controls continued an inactive sedentary lifestyle . Exercise capacity ( 6-min walk test ) and flow-mediated vasodilation in the brachial and posterior tibial arteries were evaluated . After 3 months , walking performance increased only in the exercise group ( 488+/-16 to 501+/-14 m [ control ] ; 497+/-23 to 567+/-39 m [ exercise , p<0.05 ] ) . The flow-mediated vasodilation in the brachial arteries did not change in either group ( 4.2+/-0.5 to 4.5+/-0.4 % [ control ] ; 4.3+/-0.5 to 4.6+/-0.4 % [ exercise ] ) , but that in the posterior tibial arteries increased only in the exercise group ( 4.1+/-0.5 to 4.1+/-0.3 % [ control ] ; 3.6+/-0.3 to 6.4+/-0.6 % [ exercise , p<0.01 ] ) . Cycle ergometer training improved flow-mediated vasodilation in the trained lower limbs , but not in the untrained upper limbs . Exercise training appears to correct endothelial dysfunction predominantly by a local effect in the trained extremities CONTEXT Neither supervised treadmill exercise nor strength training for patients with peripheral arterial disease ( PAD ) without intermittent claudication have been established as beneficial . OBJECTIVE To determine whether supervised treadmill exercise or lower extremity resistance training improve functional performance of patients with PAD with or without claudication . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled clinical trial performed at an urban academic medical center between April 1 , 2004 , and August 8 , 2008 , involving 156 patients with PAD who were r and omly assigned to supervised treadmill exercise , to lower extremity resistance training , or to a control group . MAIN OUTCOME MEASURES Six-minute walk performance and the short physical performance battery . Secondary outcomes were brachial artery flow-mediated dilation , treadmill walking performance , the Walking Impairment Question naire , and the 36-Item Short Form Health Survey physical functioning ( SF-36 PF ) score . RESULTS For the 6-minute walk , those in the supervised treadmill exercise group increased their distance walked by 35.9 m ( 95 % confidence interval [ CI ] , 15.3 - 56.5 m ; P < .001 ) compared with the control group , whereas those in the resistance training group increased their distance walked by 12.4 m ( 95 % CI , -8.42 to 33.3 m ; P = .24 ) compared with the control group . Neither exercise group improved its short physical performance battery scores . For brachial artery flow-mediated dilation , those in the treadmill group had a mean improvement of 1.53 % ( 95 % CI , 0.35%-2.70 % ; P = .02 ) compared with the control group . The treadmill group had greater increases in maximal treadmill walking time ( 3.44 minutes ; 95 % CI , 2.05 - 4.84 minutes ; P < .001 ) ; walking impairment distance score ( 10.7 ; 95 % CI , 1.56 - 19.9 ; P = .02 ) ; and SF-36 PF score ( 7.5 ; 95 % CI , 0.00 - 15.0 ; P = .02 ) than the control group . The resistance training group had greater increases in maximal treadmill walking time ( 1.90 minutes ; 95 % CI , 0.49 - 3.31 minutes ; P = .009 ) ; walking impairment scores for distance ( 6.92 ; 95 % CI , 1.07 - 12.8 ; P = .02 ) and stair climbing ( 10.4 ; 95 % CI , 0.00 - 20.8 ; P = .03 ) ; and SF-36 PF score ( 7.5 ; 95 % CI , 0.0 - 15.0 ; P = .04 ) than the control group . CONCLUSIONS Supervised treadmill training improved 6-minute walk performance , treadmill walking performance , brachial artery flow-mediated dilation , and quality of life but did not improve the short physical performance battery scores of PAD participants with and without intermittent claudication . Lower extremity resistance training improved functional performance measured by treadmill walking , quality of life , and stair climbing ability . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00106327 BACKGROUND Patients with chronic heart failure ( CHF ) have sexual dysfunction that impairs quality of life . Recent trials have demonstrated that exercise training ( ET ) improves quality of life ( QOL ) of CHF patients , but it is not established whether this benefit may be associated with an improvement in sexual dysfunction . OBJECTIVE To determine whether ET can improve sexual dysfunction in patients with CHF . METHODS We prospect ively studied 59 male patients ( 57+/-9 years ) with stable CHF in sinus rhythm and without prostatic disease . Patients were r and omized into two groups . A group ( T , n = 30 ) underwent supervised cycle ergometer ET at 60 % of peak VO2 , three times a week , 60 min each session , for 8 weeks . A group ( NT , n = 29 ) was not exercised . Medications were not changed during the study . On study entry and at 8 weeks all patients underwent a symptom-limited cardiopulmonary exercise testing , brachial artery endothelium-dependent ( ED ) and endothelium-independent ( EI ) vasomotor responses , QOL and sexual activity profile assessment ( SAP ) by question naire . RESULTS At 8 weeks , no changes were observed in control patients . In trained patients , however , peak VO2 improved by 18 % ( P < 0.005 ) and was correlated with QOL ( r = 0.80 ; P < 0.001 ) . Flow-mediated dilation improved in trained patients ( from 2.29+/-1.13 % to 5.04+/-1.7 % , P = 0.0001 ) , while EI dilation ( after 0.3 mg sublingual NTG ) did not . In group T , all three domains ( i.e. Domain 1=relationship with the partner ; Domain 2 = quality of penile erection ; Domain 3 = personal wellness ) were significantly improved from baseline ( total score patients : from 3.49+/-3.4 to 6.17+/-3.2 , P < 0.001 ; partners : from 2.47+/-2.7 to 4.87+/-2.5 , P < 0.001 ) . Pre-post training change in SAP total score was correlated with changes in coronary risk profile ( r = -0.49 ; P = 0.01 ) , peak VO2 ( r = 0.67 ; P < 0.001 ) and QOL ( r = 0.73 ; P = 0.01 ) . Multivariate analysis selected the improvement in ED-vasomotor response as the strongest independent predictor of SAP improvement ( r = 0.63 , P < 0.001 ) . CONCLUSIONS In stable CHF , cycle ergometer ET significantly improves brachial artery endothelial dysfunction , suggesting a systemic effect of leg exercise . This benefit was correlated with improvements in sexual activity Congestive heart failure ( CHF ) is associated with an impaired flow-mediated vasodilation that reflects an impaired endothelial function . Limited information is available , however , on whether and to what extent this impairment is improved by pharmacological or nonpharmacological treatment . We measured radial artery diameter and blood flow by an echo-tracking Doppler device both at baseline and after 4 minutes of h and ischemia , which increases diameter through NO secretion mediated by an increase in flow and shear stress . Data were collected from 44 CHF patients ( New York Heart Association class I to III ) under st and ard treatment ( diuretic , digitalis , and enalapril , 20 mg/d ) , in whom CHF severity was assessed by a cardiopulmonary stress test , and from 16 age- and sex-matched controls . CHF patients were then r and omized to maintain for ( A ) 2 months of st and ard treatment ( n=11 ) , ( B ) treatment with double the ACE inhibitor dose ( n=11 ) , ( C ) st and ard treatment with an angiotensin II antagonist ( losartan , 50 mg/d ; n=11 ) , or ( D ) st and ard treatment with bicycle training for 30 minutes , 3 times a week ( n=11 ) . At baseline , radial artery diameter and flow were similar in CHF patients and controls ; CHF patients had a modest although significant impairment in flow increase ( −36 % ) and a striking impairment ( −78 % ) in diameter increase following the 4 minutes of ischemia . After 2 months , baseline diameter and flow remained unaltered in the 4 groups . After the 4 minutes of ischemia , radial artery flow and diameter increased as before in the group under st and ard treatment ( A ) , whereas in the other 3 groups , the increase was significantly ( P < 0.05 ) and , for diameter , markedly ( B , 83 % ; C , 92 % ; and D , 95 % ) greater . The vasodilatation induced by trinitroglycerin was similar in CHF and control subjects and not affected by treatments . In CHF , radial artery shows a marked reduction in flow-mediated vasodilation , reflecting impairment of endothelial function . This impairment can be markedly improved by treatments that effectively block the renin-angiotensin system either at ACE or at ACE plus angiotensin receptor level . This is the case also with nonpharmacological treatment of CHF Brachial artery FMD ( flow-mediated dilation ) is impaired with aging and is associated with an increased risk of CVD ( cardiovascular disease ) . In the present study , we determined whether regular aerobic exercise improves brachial artery FMD in MA/O ( middle-aged/older ) men and post-menopausal women . In sedentary MA/O adults ( age , 55 - 79 years ) without CVD , 8 weeks of brisk walking ( 6 days/week for approx . 50 min/day ; r and omized controlled design ) increased treadmill time approx . 20 % in both MA/O men ( n=11 ) and post-menopausal women ( n=15 ) ( P<0.01 ) , without altering body composition or circulating CVD risk factors . Brachial artery FMD increased > 50 % in the MA/O men ( from 4.6±0.6 to 7.1±0.6 % ; P<0.01 ) , but did not change in the post-menopausal women ( 5.1±0.8 compared with 5.4±0.7 % ; P=0.50 ) . No changes occurred in the non-exercising controls . In a separate cross-sectional study ( n=167 ) , brachial artery FMD was approx . 50 % greater in endurance-exercise-trained ( 6.4±0.4 % ; n=45 ) compared with sedentary ( 4.3±0.3 % ; n=60 ) MA/O men ( P<0.001 ) , whereas there were no differences between endurance-trained ( 5.3±0.7 % , n=20 ) and sedentary ( 5.6±0.5 % , n=42 ) post-menopausal women ( P=0.70 ) . Brachial artery lumen diameter , peak hyperaemic shear rate and endothelium-independent dilation did not differ with exercise intervention or in the endurance exercise compared with sedentary groups . In conclusion , regular aerobic exercise is consistently associated with enhanced brachial artery FMD in MA/O men , but not in post-menopausal women . Some post-menopausal women without CVD may be less responsive to habitual aerobic exercise than MA/O men AIM To evaluate the effect of regular aerobic exercise on the endothelial function and cardiorespiratory fitness in pregnant women . METHOD This was a r and omized , double-blinded , controlled clinical trial of 64 healthy primigravid women between 16 and 20 weeks ' gestation . The experimental group took part in aerobic exercise at an intensity of 50 - 65 % of their maximum heart rate for 60 min , three times a week for 16 weeks . The control group undertook their usual physical activity . The outcomes were the endothelial function evaluated by flow-mediated dilatation and cardiorespiratory fitness evaluated by the maximum indirect oxygen consumption ( VO2max ) in a 6-min walk test . RESULTS Initially , no differences were found between the groups in any of the variables . At the end of the intervention , the participants that performed exercise showed a higher cardiorespiratory fitness , measured by the walked distance in the 6-min walk test ( P = 0.014 ) and by the VO2max ( P = 0.014 ) . Also , the exercise group showed a lower heart rate at rest and a higher flow-mediated dilatation than the control group ( P = 0.02 ) . CONCLUSIONS Regular aerobic exercise improves endothelium-dependent vasodilation in pregnancy . This intervention may be an early and effective alternative to strengthen the prevention of disorders associated to endothelial dysfunction Background The objective of this study was to determine the effects of a moderate exercise training program on functional capacity , quality of life , and hospital readmission rate in chronic heart failure patients with implantable cardioverter defibrillators and cardiac resynchronization therapy . Methods and results We studied 52 men ( mean age 55 ± 10 years , ejection fraction 31 ± 7 % ) in chronic heart failure II ( n = 29 ) and III ( n = 23 ) NYHA functional class with ischemic cardiomyopathy who received implantable cardioverter defibrillators with or without cardiac resynchronization therapy . Patients were r and omized into two groups . Group T ( n = 30 patients , 15 implantable cardioverter defibrillator , 15 implantable cardioverter defibrillator + cardiac resynchronization therapy ) underwent a supervised exercise training program at 60 % of peak Vo2 three times a week for 8 weeks . Group C ( n = 22 patients , 12 implantable cardioverter defibrillator , 10 implantable cardioverter defibrillator + cardiac resynchronization therapy ) avoided physical training . At 8 weeks , only trained patients had improvements in peak Vo2 ( P < 0.01 versus C ) , endothelium-dependent dilatation of the brachial artery ( P < 0.001 versus C ) and quality of life ( P < 0.001 versus C ) . Among trained patients , those with cardiac resynchronization therapy had greater improvements in peak Vo2 and quality of life . During the follow-up ( 24 ± 6 months ) , eight controls had sustained ventricular tachycardia requiring hospital readmission , while no trained patients had adverse events ( log rank 8.56 ; P < 0.001 ) . The improvement in peak Vo2 was correlated with the improvement in endothelium-dependent dilatation ( r=0.65 ) . Conclusion Moderate exercise training is safe and has beneficial effects after implantable cardioverter defibrillator implantation , especially when cardiac resynchronization therapy is present . These effects are associated with improvement in quality of life and outcome Prehypertensives exhibit marked endothelial dysfunction , a risk factor for future cardiovascular morbidity and mortality . However , the ability of exercise to ameliorate endothelial dysfunction in prehypertensives is grossly underinvestigated . This prospect i ve r and omized and controlled study examined the separate effects of resistance and endurance training on conduit artery endothelial function in young prehypertensives . Forty-three unmedicated prehypertensive ( systolic blood pressure [SBP]=120–139 mmHg ; diastolic blood pressure [DBP]=80–89 mmHg ) but otherwise healthy men and women and 15 normotensive matched time-controls ( NMTC ) ; n = 15 ) between 18 and 35 y of age met screening requirements and participated in the study . Prehypertensive subjects were r and omly assigned to either a resistance exercise training ( PHRT ; n = 15 ) , endurance exercise training ( PHET ; n = 13 ) or time-control group ( PHTC ; n = 15 ) . The treatment groups performed exercise training three days per week for eight weeks . The control groups did not initiate exercise programs throughout the study . Flow mediated dilation ( FMD ) of the brachial artery , biomarkers of enodothelial function and peripheral blood pressure were evaluated before and after exercise intervention or time-matched control . PHRT and PHET reduced resting SBP ( 9.6 ± 3.6 and 11.9 ± 3.4 mmHg , respectively ; P < 0.05 ) and DBP ( 8.0 ± 5.1 and 7.2 ± 3.4 mmHg , respectively ; P < 0.05 ) . Exercise training improved brachial artery FMD absolute diameter , percent dilation and normalized percent dilation by 30 % , 34 % and 19 % for PHRT , P < 0.05 ; and by 54 % , 63 % and 75 % for PHET , P < 0.05 ; respectively . PHRT and PHET increased plasma concentrations of 6-keto prostagl and in F1α ( 19 % and 22 % , respectively ; P < 0.05 ) , NO x ( 19 % and 23 % , respectively ; P < 0.05 ) , and reduced endothelin-1 by ( 16 % and 24 % , respectively ; P < 0.01 ) . This study provides novel evidence that resistance and endurance exercise separately have beneficial effects on resting peripheral blood pressure , brachial artery FMD and endothelial-derived vasoactive agents in young prehypertensives OBJECTIVES The purpose of this study was to examine whether exercise training stimulates a generalized improvement in vascular function in patients with type 2 diabetes mellitus . BACKGROUND Exercise is often recommended for patients with type 2 diabetes to improve physical conditioning and glycemic control . This study examined the effect of eight weeks of exercise training on conduit and resistance vessel function in patients with type 2 diabetes , using a r and omized crossover design . METHODS Both resistance vessel endothelium-dependent and -independent functions were determined by forearm plethysmography and intrabrachial infusions of acetylcholine ( ACh ) and sodium nitroprusside ( SNP ) , respectively , in 16 patients with type 2 diabetes . Conduit vessel endothelial function was assessed in 15 of these patients using high-resolution ultrasound and flow-mediated dilation of the brachial artery ; glyceryl trinitrate ( GTN ) was used as an endothelium-independent dilator . RESULTS Flow-mediated dilation increased from 1.7 + /- 0.5 % to 5.0 + /- 0.4 % following training ( p < 0.001 ) . The forearm blood flow ratio to ACh was significantly improved ( analysis of variance , p < 0.05 ) . Responses to SNP and GTN were unchanged . Endothelium-dependent vasodilation was enhanced in both conduit and resistance vessels . CONCLUSIONS If endothelial dysfunction is an integral component of the pathogenesis of vascular disease , as currently believed , this study supports the value of an exercise program in the management of type 2 diabetes The objective of this study was to investigate the effects of 12 weeks of st and ard cardiac rehabilitation on endothelial function , oxidative stress , and antioxidant defenses in patients with coronary artery disease . Twelve weeks of endurance exercise training led to an improvement in endothelial function as measured by brachial artery flow-mediated dilation ( 7.9 % at baseline vs 11.1 % at 12 weeks ) . Exercise training result ed in increased plasma nitrite and nitrate levels , increased plasma superoxide dismutase activity , and decreased oxidative stress Exercise training is an important adjunct to medical therapy in chronic heart failure , but the extent to which exercise impacts on conduit artery remodeling is unknown . The aim of this study was to evaluate the impact of aerobic and resistance exercise training modalities on arterial remodeling in patients with chronic heart failure . We r and omized 36 untrained subjects with chronic heart failure to resistance training ( 58.8±3.5 years ) , aerobic training ( 61.3±2.8 years ) , or an untrained control group ( 64.4±2.4 years ) . Peak oxygen consumption during cycle ergometry increased after 12 weeks in both the resistance and aerobic training ( P<0.001 ) groups , but not in controls , whereas leg strength only increased after resistance training ( P<0.05 ) . Brachial artery wall thickness decreased in the resistance training group ( 475±10 versus 443±13 & mgr;m ; P<0.01 ) , whereas no changes were apparent in the aerobic or control groups . Brachial diameter increased by ≈6 % and ≈5 % in the aerobic training and resistance training groups ( P<0.01 ) , with no change evident in the control group . The wall : lumen ratio consequently declined in the resistance training group at 12 weeks ( 0.121±0.004 versus 0.107±0.004 ; P<0.01 ) and increased in the control group ( 0.111±0.006 versus 0.121±0.009 ; P<0.05 ) . No wall : lumen change was evident in the aerobic training group . Our findings suggest that exercise has a systemic impact on remodeling of conduit arteries in humans and that resistance exercise training may be advantageous in subjects with chronic heart failure in this regard OBJECTIVES The study sought to evaluate the effects of endurance exercise training ( ET ) on endothelial-dependent flow-mediated arterial dilation ( FMD ) and carotid artery stiffness , and their potential contributions to the training-related increase in peak exercise oxygen consumption ( Vo2 ) in older patients with heart failure with preserved ejection fraction ( HFPEF ) . BACKGROUND Elderly HFPEF patients have severely reduced peak Vo2 , which improves with ET , however , the mechanisms of this improvement are unclear . FMD and arterial distensibility are critical components of the exercise response and are reduced with aging . However , it is unknown whether these improve with ET in elderly HFPEF or contribute to the training-related improvement in peak Vo2 . METHODS A total of 63 HFPEF patients ( age 70 ± 7 years ) were r and omized to 16 weeks of ET ( walking , arm and leg ergometry , n = 32 ) or attention control ( CT ) ( n = 31 ) . Peak Vo2 , brachial artery FMD in response to cuff ischemia , carotid artery distensibility by high-resolution ultrasound , left ventricular function , and quality of life were measured at baseline and follow-up . RESULTS ET increased peak Vo2 ( ET : 15.8 ± 3.3 ml/kg/min vs. CT : 13.8 ± 3.1 ml/kg/min , p = 0.0001 ) and quality of life . However , brachial artery FMD ( ET : 3.8 ± 3.0 % vs. CT : 4.3 ± 3.5 % , p = 0.88 ) , and carotid arterial distensibility ( ET : 0.97 ± 0.56 vs. CT : 1.07 ± 0.34 × 10(-3 ) mm·mm Hg(-2 ) ; p = 0.65 ) were unchanged . Resting left ventricular systolic and diastolic function were unchanged by ET . CONCLUSIONS In elderly HFPEF patients , 16 weeks of ET improved peak Vo2 without altering endothelial function or arterial stiffness . This suggests that other mechanisms , such as enhanced skeletal muscle perfusion and /or oxygen utilization , may be responsible for the ET-mediated increase in peak Vo2 in older HFPEF patients . ( Prospect i ve Aerobic Reconditioning Intervention Study [ PARIS ] ; NCT01113840 ) The aim of this study was to examine the effects of 12 weeks of supervised aerobic and strength training ( SET ) versus no‐training ( NT ) on peak aerobic power ( VO2peak ) , submaximal exercise left ventricular ( LV ) systolic function , peripheral vascular function , lean tissue mass and maximal strength in clinical ly stable heart transplant recipients ( HTR ) . Forty‐three HTR were r and omly assigned to 12 weeks of SET ( n = 22 ; age : 57 ± 10 years ; time posttransplant : 5.4 ± 4.9 years ) or NT ( n = 21 ; age : 59 ± 11 years ; time posttransplant : 4.4 ± 3.3 years ) . The change in VO2peak ( 3.11 mL/kg/min , 95 % CI : 1.2–5.0 mL/kg/min ) , leg and total lean tissue mass ( 0.78 kg , 95 % CI : 0.31–1.3 kg and 1.34 kg , 95 % CI : 0.34–2.3 kg , respectively ) , chest‐press ( 10.4 kg , 95 % CI : 5.2–15.5 kg ) and leg‐press strength ( 34.7 kg , 95 % CI : 3.7–65.6 kg ) were significantly higher after SET versus NT . No significant change was found for submaximal exercise LV systolic function or brachial artery endothelial‐dependent or ‐independent vasodilation . Supervised exercise training is an effective intervention to improve VO2peak , lean tissue mass and muscle strength in HTR . This training regimen did not improve exercise LV systolic function or brachial artery endothelial function Coronary allograft vasculopathy is a well‐known long‐term complication after cardiac transplantation . Endothelial dysfunction is involved and may be prevented by aerobic exercise . The purpose of this study was to examine whether high intensity aerobic exercise improves peak oxygen uptake ( VO2 peak ) and endothelial function in heart transplant ( HT ) recipients . Twenty‐seven long‐term HT recipients were r and omized to either 8‐weeks high intensity aerobic exercise or no training . Flow mediated dilation of the brachial artery ( FMD ) was measured by ultrasound and VO2 peak by the analysis of expired air . Blood pressure and biomarkers were measured before and after 8 weeks . VO2 peak increased significantly in the exercise group ( VO2 peak 23.9 ± 1.79 to 28.3 ± 1.63 mL/kg/min compared to controls ( VO2 peak 24.6 ± 1.38 to 23.4 ± 1.58 , p < 0.001 exercise vs. control).FMD increased in the exercise group compared to controls ( 8.3 ± 1.1 % to 11.4 ± 1.2 % vs. 5.6 ± 1.0 % to 5.3 ± 1.7 % , p = 0.024 ) . No increase in nitroglycerin‐induced vasodilation was observed . Systolic blood pressure fell in the exercise group ( 142 ±4.2 mmHg to127 ± 3.4 mmHg , p = 0.01 ) and was unchanged in controls ( 141 ± 4.2 mmHg to 142 ±6.4 mmHg , NS ) . High intensity aerobic exercise reduces systolic blood pressure and improves endothelial function in HT recipients Background : We aim to investigate the effect of exercise training on endothelial function and exercise capacity in patients with coronary artery disease . Methods and results : A r and omized , controlled trial was conducted to determine the effects of an 8-week exercise training programme ( n = 32 ) vs. controls ( n = 32 ) on brachial flow-mediated dilation ( FMD ) in patients with stable CAD . After 8 weeks , patients received exercise training had significant improvements in FMD ( 1.84 % , p = 0.002 ) and exercise capacity ( 2.04 metabolic equivalents , p < 0.001 ) compared with controls . The change in FMD correlated inversely with baseline FMD ( r = −0.41 , p = 0.001 ) and positively with the increase in exercise capacity ( r = 0.35 , p = 0.005 ) . After adjusting for confounders , every 1 metabolic equivalent increase in exercise capacity was associated with 0.55 % increase in FMD . Furthermore , patients received exercise training had significantly increased high-density lipoprotein cholesterol and decreased diastolic blood pressure and resting heart rate compared with controls . However , exercise training did not alter high-sensitivity C-reactive protein , oxidative stress measured as superoxide dismutase and 8-isoprostane , and CD34/KDR + endothelial progenitor cell count . Subgroup analysis showed that FMD was significantly improved only in CAD patients with baseline low exercise capacity ( < median value of 7.65 metabolic equivalents , p = 0.004 ) but not in those with normal exercise capacity . Conclusion : Exercise training improved FMD and exercise capacity in stable CAD patients independent of the changes in inflammation , oxidative stress , or endothelial progenitor cells . The beneficial effects of exercise training on FMD and exercise capacity are inter-related , and more pronounced in those with baseline impaired exercise capacity

The recommendation for the use of oral cryotherapy to prevent oral mucositis in patients receiving bolus fluorouracil ( 5-FU ) was maintained , in agreement with the 2007 guidelines . Conclusions The evidence continues to support the use of oral cryotherapy for prevention of oral mucositis in patients receiving bolus 5-FU chemotherapy or high-dose melphalan . This intervention is consistent with the MASCC/ISOO guidelines published in 2007 .

Purpose This systematic review analyzed the strength of the literature and defined clinical practice guidelines for the use of oral cryotherapy for the prevention and /or treatment of oral mucositis caused by cancer therapy .

Severe oral mucositis is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation ( AHSCT ) . Cryotherapy , that is , the application of ice chips on the mucosa of the oral cavity during the administration of antineoplastic agents , may reduce the incidence and severity of chemotherapy-related oral mucositis . In this multicenter r and omized study , we addressed whether cryotherapy during MTX administration is effective in the prevention of severe oral mucositis in patients undergoing myeloablative AHSCT . One hundred and thirty patients undergoing myeloablative AHSCT and MTX-containing GVHD prophylaxis were enrolled and r and omized to receive or not receive cryotherapy during MTX administration . The incidence of severe ( grade 3–4 ) oral mucositis , the primary end point of the study , was comparable in patients receiving or not cryotherapy . Moreover , no difference was observed in the incidence of oral mucositis grade 2–4 and the duration of oral mucositis grade 3–4 or 2–4 , or in the kinetics of mucositis over time . In univariate and multivariate analysis , severe oral mucositis correlated with TBI in the conditioning regimen and lack of folinic acid rescue following MTX administration . Thus , cryotherapy during MTX administration does not reduce severe oral mucositis in patients undergoing myeloablative allogeneic HSCT . Future studies will assess cryotherapy before allogeneic HSCT Purpose : Edatrexate ( 10-Edam ) is a methotrexate analog with improved intracellular transport , polyglutamation , and antitumor activity compared to the parent compound . Edatrexate shows schedule-dependent synergism with platinum compounds in pre clinical studies . We performed a phase I trial to determine toxicities and establish the maximum tolerated dose ( MTD ) of edatrexate in combination with carboplatin . Based on the short initial plasma half-life of edatrexate , prophylactic ice chip cryotherapy was used to reduce the severity of mucositis . Patients and methods : Forty-six chemotherapy-naive patients with advanced solid tumors were treated . Edatrexate was given weekly for 5 doses ( 50 % on day 8) , and then every other week , followed by carboplatin at a fixed dose of 350 mg/m2 on day 1 and then every 4 weeks for 8 cycles . Edatrexate dose was increased at increments of 10 mg/m2/dose level beginning at 60 mg/m2/week ( range 60–120 mg/m2 ) . Results : All patients were assessable for toxicity and response analysis . The median number of cycles administered per patients was 4 . This combination chemotherapy regimen was well tolerated . Using ice chip cryotherapy , no grade IV mucositis was observed . Grade III mucositis occurred in only 7/46 pts and was not dose-related . Protocol -defined dose-limiting toxicity occurred at a edatrexate dose level of 120 mg/m2 , yielding an MTD of 110 mg/m2 . Responding tumor types included non-small cell and small lung cancer , head and neck cancer , and bladder cancer . Conclusions : 1 ) This phase I study demonstrated the safety and tolerability of this edatrexate and carboplatin combination . 2 ) Dose-limiting mucositis did not occur allowing escalation of edatrexate dose above levels previously achieved with this edatrexate dose schedule . This was most likely a result of prophylactic ice chip cryotherapy . 3 ) An edatrexate dose of 110 mg/m2 with ice chip cryotherapy is recommended for Phase II trials of this combination AIM AND OBJECTIVE To investigate if oral cryotherapy during myeloablative therapy may influence frequency and severity of mucositis , nutritional status and infection rate after bone marrow transplantation . BACKGROUND Patients treated with intensive myeloablative treatment before bone marrow transplantation are all at risk to develop mucositis . Oral mucositis causes severe pain and oral dysfunction , which can contribute to local and systemic infections and bleeding ; it may even interrupt cancer therapy . Oral mucositis also decreases the oral food intake , which increases the risk for malnutrition and infection . Reduced food intake , loss of fat and muscles , alterations in energy and substrate metabolism leads to malnutrition . DESIGN A r and omised controlled trial with a r and om assignment to experimental or control group . METHOD A stratified r and omisation was used with regard to the type of transplantation . Mucositis was measured on WHO mucositis scale . Number of days of total parenteral nutrition , infection rate , weight , albumin levels and days at hospital was compared . RESULTS There were significantly fewer patients in the experimental group with mucositis grade 3 - 4 than in the control group and significantly lower number of days in the hospital ( allogeneic patients ) . Less total parenteral nutrition was needed in the experimental group in both setting s , and the S-albumin level was significantly better preserved . No significant difference could be found with regard to infection rate . CONCLUSION Oral cryotherapy reduced mucositis , number of hospital days , the need for total parenteral nutrition and result ed in a better nutritional status . RELEVANCE TO CLINICAL PRACTICE Nurses caring for patients treated with myeloablative therapy should place high priority to prevent oral mucositis and hereby reduce its side effects AIMS AND OBJECTIVES The study aim ed to compare the use of plain ice , flavoured ice and st and ard care , to evaluate the effect on mucositis and to determine patients ' perceptions of the two forms of oral cryotherapy . BACKGROUND Despite evidence that oral cryotherapy is useful in preventing mucositis in patients receiving 5-fluorouracil , concerns have been expressed about its clinical utility , due to potential side effects and negative perceptions . DESIGN A r and omized , controlled , crossover trial was conducted in the outpatient chemotherapy department of an acute care teaching hospital in Perth , Western Australia . Patients were r and omized to receive each of three interventions across three cycles of chemotherapy : st and ard care alone ; st and ard care plus plain ice ; and st and ard care plus flavoured ice . METHODS Oral mucositis was assessed by nurses prior to each of the three chemotherapy cycles and 15 days after each intervention . Two assessment tools were used , the Oral Assessment Guide , and the Western Consortium Cancer Nursing Research Scale . Participants completed a question naire to determine their comfort and satisfaction with oral cryotherapy , as well as factors affecting compliance . RESULTS Findings from 67 patients revealed that when participants used st and ard care alone , they were significantly more likely to experience symptoms of mucositis than when they used either plain or flavoured ice . Odds ratios were at least threefold higher for st and ard care alone , varying according to the instrument used . The two main concerns reported were the taste of flavoured ice and the time required to complete the cryotherapy interventions . Side effects such as nausea , sensitivity and headache were reported more frequently for flavoured ice ( n = 11 ) compared with plain ice ( n = 5 ) and st and ard care ( n = 1 ) . CONCLUSIONS Both forms of oral cryotherapy were effective in reducing the severity of oral mucositis after chemotherapy and were more effective than st and ard care alone . Flavoured ice was associated with the highest frequency of side effects . RELEVANCE TO CLINICAL PRACTICE The benefits of cryotherapy appear to outweigh the problems in this sample of patients . The intervention should be tailored to individual patients , based on preferences for plain versus flavoured ice and small chips vs. larger blocks . Unsweetened frozen fruit juices should be evaluated . Time constraints could be addressed by providing transportable containers of ice Recently , a r and omised study demonstrated the utility of oral cooling ( cryotherapy ) in the prevention of 5-fluorouracil (5FU)-induced stomatitis . In order to verify these results a confirmatory study , using identical treatment regimen , was initiated . 84 patients treated with a 5-FU-containing regimen were r and omised to a control arm or to receive oral cryotherapy . End point evaluation was obtained by a global assessment of the physician 's judgement and patients ' description of mucositis severity grade d 0 - 4 . Mucositis was significantly reduced by cryotherapy considering both the first cycle of therapy ( the mean toxicity score for cryotherapy was 0.59 and it was 1.1 for the control group , P < or = 0.05 ) and all the chemotherapeutic courses ( the mean toxicity score for cryotherapy was 0.36 when it was 0.69 for the control group , P < or = 0.05 ) . In conclusion , the present study confirms that cryotherapy can decrease 5FU-induced stomatitis and should be recommended for patients receiving bolus 5FU-containing regimens Mucositis is a significant dose-limiting toxicity associated with fluorouracil ( 5FU ) , particularly when it is combined with leucovorin . We hypothesized that oral cryotherapy would cause local vasoconstriction and would temporarily decrease blood flow to the oral mucous membranes . If cryotherapy were used during the time of peak serum 5FU levels , then the oral mucous membranes would have less exposure to 5FU and thus develop less mucositis . To test this hypothesis , 95 patients scheduled to receive their first cycle of 5FU plus leucovorin were r and omized to have oral cryotherapy at the time of chemotherapy administration or to serve as a control group . Subsequent mucositis was significantly reduced in the group assigned to receive cryotherapy as judged by the attending physicians ( P = .0002 ) and by the patients themselves ( P = .0001 ) . We now routinely recommend this cryotherapy procedure for our patients receiving daily bolus 5FU plus leucovorin Stomatitis is a common adverse effect of intravenously infused 5-fluorouracil ( 5FU ) . Although there are encouraging studies about the preventive role of oral cryotherapy in stomatitis induced by intravenous administration of 5FU , this simple and cost-effective method is not part of clinical practice . This prospect i ve r and omized study investigates whether oral cryotherapy alleviates 5FU-induced stomatitis . Thirty six patients , included in the cryotherapy group , were instructed to hold ice cubes in their oral cavity , shortly before , during and shortly after the infusion of 5FU . Both mean physician and patient- grade d stomatitis of our cryotherapy group were compared with those of a control group ( 40 patients ) and were found significantly reduced for all three chemotherapy cycles . The percentage of patients who were free from oral toxicity was significantly higher in the cryotherapy group in all three chemotherapy cycles , as judged both by patients and physicians . The results of this study encourage the use of cryotherapy in patients receiving 5FU in alleviating stomatitis by using a side-effect-free , easy to perform and inexpensive measure , which does not interfere with the efficacy of antineoplastic agents Mucosal toxicity is an incapacitating complication of intensive chemo-radiotherapy for children with malignant disorders , and is physically and psychologically distressful . It is therefore important to minimize mucosal toxicity in those patients . In this report , the effects of the combined prophylaxis of oral cooling ( cryotherapy ) and administration of propantheline , an anticholinergic drug , were studied in patients ( aged 2 - 16 year ) with acute leukemias or solid tumors , who underwent myeloablative chemo-radiotherapy and autologous peripheral blood stem cell rescue from 1993 to 1997 . Patients were pretreated with the combined prophylaxis ( n = 12 ) or single prophylaxis ( n = 5 ) , or left untreated ( n = 7 ) . The combined prophylaxis significantly reduced the severe mucositis ( combined , 8.3 % ; single , 20.0 % ; and untreated , 42.9 % ) and severe diarrhea ( combined , 16.7 % ; single , 60.0 % ; and untreated , 57.1 % ) . Moreover , the combined prophylaxis tended to shorten the periods of febrile episodes defined as temperature > 38 degrees C ( combined , 3.8 days ; single , 4.6 days ; and untreated , 5.6 days ) . Therefore , the combination of propantheline and oral cryotherapy may be feasible and effective for reduction of mucosal toxicity in patients with malignancy who undergo high-dose chemotherapy Background . The authors previously reported that 30 minutes of oral cryotherapy inhibits 5‐fluorouracil (5‐FU)‐induced stomatitis . The current trial was design ed to determine whether a longer duration of cryotherapy would provide additional protection Introduction Mucositis is a major complication in myeloablative therapy , which often necessitates advanced pharmacological pain treatment , including i.v . opioids . Attempts to prevent oral mucositis have included oral cryotherapy , which has been shown to reduce mucositis , but there is a lack of knowledge concerning the effect of oral cryotherapy on opioid use by reducing the mucositis for patients treated with myeloablative therapy before bone marrow transplantation ( BMT ) . Aim The aim of the present study was to evaluate if oral cryotherapy could delay or alleviate the development of mucositis and thereby reduce the number of days with i.v . opioids among patients who receive myeloablative therapy before BMT . Material s and methods Eighty patients 18 years and older , scheduled for BMT , were included consecutively and r and omised to oral cryotherapy or st and ard oral care . A stratified r and omisation was used with regard to type of transplantation . Intensity of pain , severity of mucositis and use of opioids were recorded using pain visual analogue scale ( VAS ) scores , mucositis index scores and medical and nursing charts . Results This study showed that patients receiving oral cryotherapy had less pronounced mucositis and significantly fewer days with i.v . opioids than the control group . In the autologous setting , cryotherapy patients also needed significantly lower total dose of opioids . Conclusion Oral cryotherapy is an effective and well-tolerated therapy to alleviate mucositis and consequently reduce the number of days with i.v . opioids among patients treated with myeloablative therapy before BMT We performed a Phase II trial of edatrexate in 44 chemotherapy-naive patients with advanced renal cell carcinoma . Prior therapy with one biological-response modifier was permitted . Most patients had multiple sites of metastatic disease and were considered to have a poor prognosis using Eastern Cooperative Oncology Group criteria . Edatrexate was administered intravenously at a dose of 80 mg/m2 weekly with 5 weeks of therapy considered one cycle . Oral cryotherapy using ice chips was administered before each edatrexate dose . Thirty-seven patients were eligible and evaluable for toxicity and response . Two patients obtained a partial response , for an overall response rate of 5.4 % ( 95 % confidence interval of 0.6 % , 18.2 % ) ; one patient remained in remission at 26 + months . Three treatment-related deaths occurred . Toxicity was severe , with stomatitis , myelosuppression , and other gastrointestinal side effects most prominent . Edatrexate in this dose and schedule has minimal activity in advanced renal cell carcinoma and is toxic This article describes the system for rating the quality of medical evidence developed and used during creation of the Agency for Health Care Policy and Research -sponsored heart failure guideline . Previous approaches to rating evidence were not design ed for use in the setting of clinical practice guidelines . The present system is based on the tenet that flaws in research design are serious to the extent they threaten the validity of the results of studies . A taxonomy of major and minor flaws based on that tenet was developed for r and omized controlled trials and for cohort and medical registry studies . The use of the system is described in the context of two difficult clinical issues considered by the Panel : the role of coronary artery revascularization and the use of metoprolol BACKGROUND Stomatitis in cancer chemotherapy manifests with pronounced subjective symptoms , lowers the patient 's quality of life ( QOL ) and may necessitate the discontinuation of chemotherapy . There have been few effective therapies established to date for chemotherapy-induced stomatitis . PATIENTS AND METHODS We used frozen allopurinol solution ( allopurinol ice balls ) in the prevention of stomatitis associated with leucovorin (LV)/5-fluorouracil ( 5-FU ) therapy for colon cancer . RESULTS Among 32 patients undergoing LV/5-FU therapy , without the use of the allopurinol ice balls , 15 patients developed stomatitis . On the other h and , only 3 patients developed stomatitis among 20 patients receiving the chemotherapy in conjunction with allopurinol ice balls ( p=0.0187 ) . Seven patients who developed stomatitis during a course of chemotherapy without allopurinol ice balls were administered the ice balls in the subsequent course ; 6 of these patients responded with lessened severity of stomatitis . In 2 of these responders , stomatitis of comparable severity recurred on discontinuation of the medication . CONCLUSION Concomitant use of allopurinol ice balls is effective in preventing stomatitis in patients undergoing LV/5-FU therapy

There is a lack of evidence for the efficacy of relaxation therapies in the management of asthma . There is some evidence that muscular relaxation improves lung function of patients with asthma but no evidence for any other relaxation technique

BACKGROUND Emotional stress can either precipitate or exacerbate both acute and chronic asthma . There is a large body of literature available on the use of relaxation techniques for the treatment of asthma symptoms . The aim of this systematic review was to determine if there is any evidence for or against the clinical efficacy of such interventions .

Asthma patients pose special problems as far as the medical supervision , danger of symptoms and the course of the disease are concerned . Some 90 asthma patients were registered for the treatment in the Heidelberg Medical Clinic . 31 patients who were interested in taking part were r and omized into 3 groups : two treatment group consisted of the exchange of information , discussion sessions on the illness as well as ' autogenic training ' or ' functional relaxation ' . The third group was the control group . Before and after treatment the patients were su bmi tted to a thorough examination both of lungs and other internal organs as well as from the psychodiagnostical point of view . The average age of the patients was 43.5 years and the average duration of illness 16.8 years . Nevertheless , the treatment group 's sympathomimetics use was significantly reduced by 1 year of treatment ( p less than 0.05 ) ; the use of steroids decreased as well . The number of visits of the general practitioner also decreased . These results support the conclusion that psychosomatic group therapy can make an important contribution to the treatment of asthma patients . Body therapy practised in ' autogenic training ' and ' functional relaxation ' seems to be another important healing factor for the treatment in addition to the discussion sessions and the exchange of information Stress , unpleasant emotions and autonomic imbalance may play a main role in precipitating asthmatic attacks . In this study two homogeneous groups of asthmatic patients ( N = 24 ) are treated over an eight-month period . The experimental group was treated with autogenic therapy and the control group with supportive group psychotherapy . Respiratory function parameters measured were Forced Vital Capacity ( FVC ) , Forced Expiratory Volume in the first sec ( FEV1 ) , Forced Expiratory Flow between 25 % and 75 % of the FVC ( FEF25 - 75 % ) , and Mesoexpiratory Flow ( MEF50 % ) . The group under Autogenic Therapy obtained a relevant clinical improvement ( > 15 % of pretreatment values ) in respiratory function . No significant changes were observed in the control group . These results suggest that autogenic therapy could be an effective adjunctive treatment in bronchial asthma One hundred six asthmatic subjects were medically prestabilized , then assigned to eight sessions of progressive relaxation , music , or a waiting-list . Seventy-two subjects completed treatment , of which 37 were evaluated in the laboratory with measures of forced expiratory flow . Relaxation-group subjects reported feeling the most deeply relaxed and produced the greatest improvement in forced expiratory flow during the last presession assessment period . All groups evidence d decreases in asthma symptoms . All groups showed decreases in pulmonary function immediately after relaxation sessions . None of the changes in pulmonary function reached levels that are accepted in drug trials to be of clinical significance , and the therapeutic changes occurred only in the situation where training was rendered . Listening to music produced greater decreases in peaks of tension than progressive relaxation , and it produced greater compliance with relaxation practice , but it did not produce any specific therapeutic effects on asthma BACKGROUND High levels of stress have been shown to predict the onset of asthma in children genetically at risk , and to correlate with higher asthma morbidity . Our study set out to examine whether stressful experiences actually provoke new exacerbations in children who already have asthma . METHODS A group of child patients with verified chronic asthma were prospect ively followed up for 18 months . We used continuous monitoring of asthma by the use of diaries and daily peak-flow values , accompanied by repeated interview assessment s of life events and long-term psychosocial experiences . The key measures included asthma exacerbations , severely negative life events , and chronic stressors . FINDINGS Severe events , both on their own and in conjunction with high chronic stress , significantly increased the risk of new asthma attacks . The effect of severe events without accompanying chronic stress involved a small delay ; they had no effect within the first 2 weeks , but significantly increased the risk in the subsequent 4 weeks ( odds ratio 1.71 [ 95 % CI 1.04 - 2.82 ] , p < or = 0.05 for weeks 2 - 4 and 2.17 [ 1.32 - 3.57 ] , p < or = 0.01 for weeks 4 - 6 ) . When severe events occurred against the backdrop of high chronic stress , the risk increased sharply and almost immediately within the first fortnight ( 2.98 [ 1.20 - 7.38 ] , p < or = 0.05 ) . The overall attack frequency was affected by several factors , some related to asthma and some to child characteristics . Female sex , higher baseline illness severity , three or more attacks within 6 months , autumn to winter season , and parental smoking were all related to increased risk of new exacerbations ; social class and chronic stress were not . INTERPRETATION Severely negative life events increase the risk of children 's asthma attacks over the coming few weeks . This risk is magnified and brought forward in time if the child 's life situation is also characterised by multiple chronic stressors Abstract To assess the role of the autonomic nervous system in the bronchospasm which occurs in asthmatic children following exercise , β-adrenergic , α-adrenergic , or cholinergic blockade was induced by the intravenous injection of propranolol , phentolamine , or atropine , respectively , with saline as a control . Treatments were given by r and om assignment once to each of 10 asthmatic children on each of four successive afternoons , with each child acting as his own control . Measurement of peak expiratory flow rates ( PEFR ) before injections , 15 minutes later before st and ard treadmill exercise , and 10 minutes after completion of 8 minutes of exercise disclosed a significant decrease in PEFR following injection with propranolol only . Pulse rate alterations were consistent with the various kinds of blockade sought . None of the treatments affected the decrease in PEFR induced by exercise . It seems unlikely , therefore , that exercise-induced bronchospasm is mediated in major fashion by the autonomic nervous system Abstract Twelve patients with chronic bronchial asthma were matched in pairs and r and omly assigned to two treatment groups , one group received mental and muscular relaxation , the second group received muscular relaxation alone . Treatment consisted of 4 weekly treatment sessions . Pre , post and follow-up phases each consisted of 3 weekly sessions . Respiratory function was measured by the forced expiratory volume in 1 second ( FEV 1 ) . Two self-report inventories were used to measure change in the symptoms and signs of the patient 's asthma . Following factor analysis , 3 factors were used — Psychological , Physical and Bronchoconstriction . Results showed that for each of these 3 factors and for FEV 1 , there was no overall mean significant difference between results in either treatment group . In addition , patients showed no significant trend of improvement in respiratory function . No significant difference was shown between respiratory function recorded before and after relaxation treatment in each of the individual treatment sessions . There was a moderate correlation between objective recordings and the patient 's subjective assessment of asthma severity Thirty-two children with asthma ( 16 4- to 8-year-olds and 16 9- to 14-year-olds ) were r and omly assigned to receive either massage therapy or relaxation therapy . The children 's parents were taught to provide one therapy or the other for 20 minutes before bedtime each night for 30 days . The younger children who received massage therapy showed an immediate decrease in behavioral anxiety and cortisol levels after massage . Also , their attitude toward asthma and their peak air flow and other pulmonary functions improved over the course of the study . The older children who received massage therapy reported lower anxiety after the massage . Their attitude toward asthma also improved over the study , but only one measure of pulmonary function ( forced expiratory flow 25 % to 75 % ) improved . The reason for the smaller therapeutic benefit in the older children is unknown ; however , it appears that daily massage improves airway caliber and control of asthma

In the studies analyzed , considering symptomatic venous thromboembolism , rivaroxaban result ed in higher benefits when compared to enoxaparin

Total knee arthroplasty is an elective procedure performed on relatively healthy individuals . However , due to the inherent risk of venous thromboembolism , drugs are used for its prophylaxis . The objective of the present study was to conduct a systematic review of the literature to compare the efficacy of enoxaparin and rivaroxaban in preventing this complication and the risk of intraoperative bleeding .

Post-operative complications after total hip or knee replacement can delay recovery , prolong hospitalisation , increase rates of re-admission and , in the most severe cases , lead to long-term disability or even death . In this analysis of pooled data from four large , r and omised , phase III clinical trials that compared the oral , direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement ( n = 12,729 ) , the incidence of complications , including bleeding and adverse events related to surgery ( such as wound infection , wound dehiscence and haemarthrosis ) are reported . Interventions and procedures relating to surgery are also compared between the groups . Bleeding events , including excessive wound haematoma and surgical-site bleeding , occurred at similar rates in the rivaroxaban and enoxaparin groups . Over the total study duration , adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement ( 2.26 % vs. 2.69 % , respectively ) and total hip replacement ( 1.48 % vs. 1.65 % , respectively ) . Blood loss , wound drainage and transfusion requirements were also similar between the two groups . This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin Rivaroxaban has been recommended for routine use as a thromboprophylactic agent in patients undergoing lower-limb arthroplasty . However , trials supporting its use have not fully evaluated the risks of wound complications . This study of 1048 total hip/knee replacements records the rates of return to theatre and infection before and after the change from a low molecular weight heparin ( tinzaparin ) to rivaroxaban as the agent of chemical thromboprophylaxis in patients undergoing lower-limb arthroplasty . During a period of 13 months , 489 consecutive patients undergoing lower-limb arthroplasty received tinzaparin and the next 559 consecutive patients received rivaroxaban as thromboprophylaxis . Nine patients in the control ( tinzaparin ) group ( 1.8 % , 95 % confidence interval 0.9 to 3.5 ) returned to theatre with wound complications within 30 days , compared with 22 patients in the rivaroxaban group ( 3.94 % , 95 % confidence interval 2.6 to 5.9 ) . This increase was statistically significant ( p = 0.046 ) . The proportion of patients who returned to theatre and became infected remained similar ( p = 0.10 ) . Our study demonstrates the need for further r and omised controlled clinical trials to be conducted to assess the safety and efficacy of rivaroxaban in clinical practice , focusing on the surgical complications as well as the potential prevention of venous thromboembolism Background This study aim ed to assess whether the efficacy of tranexamic acid ( TXA ) would be altered when rivaroxaban or enoxaparin was used for thromboprophylaxis in primary total knee replacement ( TKR ) . It was hypothesized that the hemostatic effect of TXA would be better with the use of enoxaparin . Material / Methods A r and omized clinical trial was conducted on 194 patients undergoing primary TKR for osteoarthritis . An intravenous dose of 15 mg/kg ( TXA ) and 1 g topical TXA were used . Patients r and omly received enoxaparin or rivaroxaban prophylaxis when the drainage was less than 30 ml/h 6–8 h postoperatively . The primary endpoint was hidden blood loss ( HBL ) . Indexes of total blood loss drainage , hemoglobin drop , transfusion , range of motion ( ROM ) , HSS score , VAS pain score , knee swelling , length of hospital stay ( LOHS ) , incidence of venous thromboembolism , major/minor bleeding , and wound complications were also compared between the groups . Results More than 80 % of patients initiated anticoagulation within 6 h postoperatively . No statistically significance difference was detected in terms of HBL ( 679.0±205.6 vs. 770.5±206.1 , p=.062 ) or other bleeding index , ROM , or LOHS . The motion VAS pain score and knee swelling ( 16.7 % vs. 6.1 % , p=.021 ) were significantly lower , and HSS score at discharge was higher in the enoxaparin group . The rivaroxaban group had less asymptomatic deep venous ( 4.1 % vs. 0 % , p=.121 ) and muscular venous thrombosis ( 2.1 % vs. 9.2 % , p=.033 ) ; more ecchymosis ( 13.5 % vs. 10.2 % , p=.472 ) , and wound complications ( 13.5 % vs. 6.1 % , p=.082 ) . No episodes of transfusion , pulmonary embolism , or major bleeding occurred in either group . Conclusions More attention should be paid to the increased risk of wound complications and knee swelling associated with rivaroxaban , although the hidden blood loss was similar in both groups Purpose Venous thromboembolism is a common complication after major orthopedic surgery . When prescribing anticoagulant prophylaxis , clinicians weigh the benefits of thromboprophylaxis against bleeding risk and other adverse events . Previous benefit – risk analyses of the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism ( RECORD ) r and omized clinical studies of rivaroxaban versus enoxaparin after total hip ( THA ) or knee ( TKA ) arthroplasty generally used pooled THA and TKA results , counted fatal bleeding as both an efficacy and a safety event , and included the active and placebo-controlled portions of RECORD2 , which might confound benefit – risk assessment s. We conducted a post hoc analysis without these constraints to assess benefit – risk for rivaroxaban versus enoxaparin in the RECORD studies . Patients and methods Data from the safety population of the two THA and two TKA studies were pooled separately . The primary analysis compared the temporal course of event rates and rate differences between rivaroxaban and enoxaparin prophylaxis for symptomatic venous thromboembolism plus all-cause mortality ( efficacy events ) versus nonfatal major bleeding ( safety events ) . Additionally , these rates were used to derive measures of net clinical benefit , number needed to treat ( NNT ) , and number needed to harm ( NNH ) for these two end points . Results After THA or TKA , and compared with enoxaparin , rivaroxaban therapy result ed in more efficacy events prevented than safety events caused , with benefits exceeding harms early and throughout treatment and follow-up . Relative to enoxaparin , rivaroxaban treatment prevented six efficacy events per harm event caused for THA , with NNT = 262/NNH = 1,711 . For TKA , rivaroxaban treatment prevented four to five efficacy events per harm event caused , with NNT = 102/NNH = 442 . Sensitivity analysis that included surgical-site bleeding result ed in NNH = 345 for THA and NNH = 208 for TKA . Conclusion In the RECORD studies , considering death , symptomatic venous thromboembolism , and major bleeding , rivaroxaban result ed in greater benefits than harms compared with enoxaparin . When incorporating surgical-site bleeding , rivaroxaban also results in greater benefit than harm for TKA and is balanced with enoxaparin for THA OBJECTIVES To compare the main efficacy and safety endpoints of the pivotal r and omised clinical trials ( RCTs ) on venous thromboembolism ( VTE ) prevention after total hip ( THR ) or knee ( TKR ) replacement with the new oral anticoagulants ( NAs ) versus enoxaparin . METHODS A pool- analysis of 10 RCTs that included 32.144 r and omised patients was performed . Efficacy outcomes were total VTE and all-cause mortality , major VTE , and proximal DVT . Safety outcomes were major bleeding , and clinical ly relevant ( major or non-major ) bleeding . RESULTS Overall , a significant effect favouring NAs was found for the primary efficacy outcome ( RR 0.71 ; 95%CI 0.56 - 0.90 ) , major VTE ( RR 0.59 ; 95%CI 0.41 - 0.84 ) , and proximal DVT ( RR 0.51 ; 95%CI 0.35 - 0.76 ) . Compared to enoxaparin 40 mg QD , rivaroxaban showed superiority ( RR 0.50 ; 95%CI 0.34 - 0.73 ) , followed by apixaban ( RR 0.63 ; 95%CI 0.36 - 1.01 ) and dabigatran ( RR 1.02 ; 95%CI 0.86 - 1.20 ) . There was significant heterogeneity among trials and subgroups analysed for these efficacy outcomes . Major bleeding ( RR 1.04 ; 95 % CI 0.74 - 1.46 ) and clinical ly relevant bleeding ( RR 1.03 ; 95%CI 0.88 - 1.21 ) was similar with NAs or enoxaparin . Rivaroxaban showed a trend toward more major bleeding episodes than enoxaparin ( RR 1.88 ; 95%CI 0.92 - 3.82 ) and apixaban showed the lowest clinical ly relevant bleeding risk ( RR 0.81 ; 95%CI 0.64 - 1.01 ) . CONCLUSIONS Overall , NAs showed more efficacy and same safety when compared to the recommended dose of enoxaparin after THR and TKR . There are little differences in efficacy and bleeding risk among NAs and the type of prophylaxis that should be analysed further This study aim ed to compare the efficacy and safety of aspirin , rivaroxaban and low-molecular-weight heparin ( LMWH ) for post total knee arthroplasty ( TKA ) deep vein thrombosis ( DVT ) prophylaxis . Between July 2011 and July 2013 , a prospect i ve r and omized controlled trial was performed on 324 patients with osteoarthritis who underwent primary unilateral TKA . Twelve hours after the surgery , Group A was given oral rivaroxaban at a dose of 10 mg/day . Group B was given subcutaneous LMWH at a dose of 4000 AxaIU ( 0.4 ml)/day and Group C was given oral aspirin at a dose of 100 mg/day . All three groups were treated for 14 days , and all of the patients were followed for 4 weeks . The incidence of DVT , dominant/hidden blood loss , the incidence of wound complications and the incidence of subcutaneous ecchymosis in the affected extremities were compared between the three groups . The incidence of DVT was lower in Group A compared with the other two groups [ 3 ( 2.94 % ) vs. 14 ( 12.50 % ) , P = 0.029 ; 3 ( 2.94 % ) vs. 18 ( 16.36 % ) , P = 0.017 ] . However , hidden blood loss [ 1.71 ( 1.19–2.97 ) vs. 1.18 ( 0.77–2.31 ) , P = 0.009 ; 1.71 ( 1.19–2.97 ) vs. 1.30 ( 0.61–2.43 ) , P = 0.004 ] and wound complications [ 5 ( 4.90 ) vs. 3 ( 2.67 ) , P = 0.027 ; 5 ( 4.90 ) vs. 2 ( 1.82 ) , P = 0.014 ] were more common in Group A than in the other groups . There were no significant differences between Group B and Group C in the incidence of DVT [ 14 ( 12.50 % ) vs. 18 ( 16.36 % ) , P = 0.831 ] , hidden blood loss [ 1.18 ( 0.77–2.31 ) vs. 1.30 ( 0.61–2.43 ) , P = 0.327 ] or wound complications [ 3 ( 2.67 ) vs. 2 ( 1.82 ) , P = 0.209 ] . No significant differences in the incidence of limb swelling were found between the three groups [ 38 ( 37.25 % ) vs. 28 ( 25.00 % ) vs. 24 ( 21.82 % ) , P = 0.247 ] . Group A had a higher incidence of subcutaneous ecchymosis in the affected extremities than Group C [ 74 ( 72.55 % ) vs. 54 ( 49.09 % ) , P = 0.039 ] , but there were no significant differences between Groups A and B [ 74 ( 72.55 % ) vs. 62 ( 55.36 % ) , P = 0.193 ] or between Groups B and C [ 62 ( 55.36 % ) vs. 54 ( 49.09 % ) , P = 0.427 ] . Rivaroxaban has a positive anticoagulation effect but leads to increases in both postoperative blood loss and wound complications in patients . Hence , clinicians using rivaroxaban for anticoagulant therapy should closely monitor the changes in the hemoglobin level and wound healing and promptly supplement blood volume and provide other symptomatic and supportive treatments . No significant difference in post-TKA DVT prophylaxis was found between aspirin and LMWH , and the former can be used as part of a multimodal anticoagulation therapy BACKGROUND Prophylaxis for venous thromboembolism is recommended for at least 10 days after total knee arthroplasty ; oral regimens could enable shorter hospital stays . We aim ed to test the efficacy and safety of oral rivaroxaban for the prevention of venous thromboembolism after total knee arthroplasty . METHODS In a r and omised , double-blind , phase III study , 3148 patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily , beginning 6 - 8 h after surgery , or subcutaneous enoxaparin 30 mg every 12 h , starting 12 - 24 h after surgery . Patients had m and atory bilateral venography between days 11 and 15 . The primary efficacy outcome was the composite of any deep-vein thrombosis , non-fatal pulmonary embolism , or death from any cause up to day 17 after surgery . Efficacy was assessed as non-inferiority of rivaroxaban compared with enoxaparin in the per- protocol population ( absolute non-inferiority limit -4 % ) ; if non-inferiority was shown , we assessed whether rivaroxaban had superior efficacy in the modified intention-to-treat population . The primary safety outcome was major bleeding . This trial is registered with Clinical Trials.gov , number NCT00362232 . FINDINGS The primary efficacy outcome occurred in 67 ( 6.9 % ) of 965 patients given rivaroxaban and in 97 ( 10.1 % ) of 959 given enoxaparin ( absolute risk reduction 3.19 % , 95 % CI 0.71 - 5.67 ; p=0.0118 ) . Ten ( 0.7 % ) of 1526 patients given rivaroxaban and four ( 0.3 % ) of 1508 given enoxaparin had major bleeding ( p=0.1096 ) . INTERPRETATION Oral rivaroxaban 10 mg once daily for 10 - 14 days was significantly superior to subcutaneous enoxaparin 30 mg given every 12 h for the prevention of venous thromboembolism after total knee arthroplasty . FUNDING Bayer Schering Pharma AG , Johnson & Johnson Pharmaceutical Research & Development BACKGROUND We investigated the efficacy of rivaroxaban , an orally active direct factor Xa inhibitor , in preventing venous thrombosis after total knee arthroplasty . METHODS In this r and omized , double-blind trial , 2531 patients who were to undergo total knee arthroplasty received either oral rivaroxaban , 10 mg once daily , beginning 6 to 8 hours after surgery , or subcutaneous enoxaparin , 40 mg once daily , beginning 12 hours before surgery . The primary efficacy outcome was the composite of any deep-vein thrombosis , nonfatal pulmonary embolism , or death from any cause within 13 to 17 days after surgery . Secondary efficacy outcomes included major venous thromboembolism ( i.e. , proximal deep-vein thrombosis , nonfatal pulmonary embolism , or death related to venous thromboembolism ) and symptomatic venous thromboembolism . The primary safety outcome was major bleeding . RESULTS The primary efficacy outcome occurred in 79 of 824 patients ( 9.6 % ) who received rivaroxaban and in 166 of 878 ( 18.9 % ) who received enoxaparin ( absolute risk reduction , 9.2 % ; 95 % confidence interval [ CI ] , 5.9 to 12.4 ; P<0.001 ) . Major venous thromboembolism occurred in 9 of 908 patients ( 1.0 % ) given rivaroxaban and 24 of 925 ( 2.6 % ) given enoxaparin ( absolute risk reduction , 1.6 % ; 95 % CI , 0.4 to 2.8 ; P=0.01 ) . Symptomatic events occurred less frequently with rivaroxaban than with enoxaparin ( P=0.005 ) . Major bleeding occurred in 0.6 % of patients in the rivaroxaban group and 0.5 % of patients in the enoxaparin group . The incidence of drug-related adverse events , mainly gastrointestinal , was 12.0 % in the rivaroxaban group and 13.0 % in the enoxaparin group . CONCLUSIONS Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty , with similar rates of bleeding . ( Clinical Trials.gov number , NCT00361894 . A prospect i ve , r and omized trial was done to evaluate the prevalence of deep venous thrombosis following primary unilateral or bilateral total hip arthroplasty with use of hypotensive epidural anesthesia , external pneumatic-compression boots , and aspirin ( Group I ) and with use of hypotensive epidural anesthesia and aspirin ( Group II ) . All operations were performed by two of us ( E. A. S. and T. P. S. ) through a posterolateral approach . Two hundred and thirty-one patients who were more than thirty-nine years old and who had a total of 250 primary total hip arthroplasties were included in the study . There were 113 patients ( 124 hips ) in Group I and 118 patients ( 126 hips ) in Group II . All patients had venography on the sixth , seventh , or eighth postoperative day . Group I had no proximal thrombi , seven distal thrombi ( 6 per cent ) , and one late pulmonary embolus ( 1 per cent ) . Group II had one proximal thrombus ( popliteal ) ( 1 per cent ) , eight distal thrombi ( 6 per cent ) , and one late pulmonary embolus ( 1 per cent ) . The difference was not significant ( p = 0.65 ) . However , a significant difference may have been noted if the study population had been larger . The combination of hypotensive epidural anesthesia and aspirin is effective prophylaxis against deep venous thrombosis in patients who have a primary total hip arthroplasty . The extremely low rate of deep venous thrombosis in the present study may be attributed to the use of hypotensive epidural anesthesia and the associated decrease in blood loss and transfusion requirements . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND This phase 3 trial compared the efficacy and safety of rivaroxaban , an oral direct inhibitor of factor Xa , with those of enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty . METHODS In this r and omized , double-blind study , we assigned 4541 patients to receive either 10 mg of oral rivaroxaban once daily , beginning after surgery , or 40 mg of enoxaparin subcutaneously once daily , beginning the evening before surgery , plus a placebo tablet or injection . The primary efficacy outcome was the composite of deep-vein thrombosis ( either symptomatic or detected by bilateral venography if the patient was asymptomatic ) , nonfatal pulmonary embolism , or death from any cause at 36 days ( range , 30 to 42 ) . The main secondary efficacy outcome was major venous thromboembolism ( proximal deep-vein thrombosis , nonfatal pulmonary embolism , or death from venous thromboembolism ) . The primary safety outcome was major bleeding . RESULTS A total of 3153 patients were included in the superiority analysis ( after 1388 exclusions ) , and 4433 were included in the safety analysis ( after 108 exclusions ) . The primary efficacy outcome occurred in 18 of 1595 patients ( 1.1 % ) in the rivaroxaban group and in 58 of 1558 patients ( 3.7 % ) in the enoxaparin group ( absolute risk reduction , 2.6 % ; 95 % confidence interval [ CI ] , 1.5 to 3.7 ; P<0.001 ) . Major venous thromboembolism occurred in 4 of 1686 patients ( 0.2 % ) in the rivaroxaban group and in 33 of 1678 patients ( 2.0 % ) in the enoxaparin group ( absolute risk reduction , 1.7 % ; 95 % CI , 1.0 to 2.5 ; P<0.001 ) . Major bleeding occurred in 6 of 2209 patients ( 0.3 % ) in the rivaroxaban group and in 2 of 2224 patients ( 0.1 % ) in the enoxaparin group ( P=0.18 ) . CONCLUSIONS A once-daily , 10-mg oral dose of rivaroxaban was significantly more effective for extended thromboprophylaxis than a once-daily , 40-mg subcutaneous dose of enoxaparin in patients undergoing elective total hip arthroplasty . The two drugs had similar safety profiles . ( Clinical Trials.gov number , NCT00329628 . BACKGROUND The risk of venous thromboembolism is high after total hip arthroplasty and could persist after hospital discharge . Our aim was to compare the use of rivaroxaban for extended thromboprophylaxis with short-term thromboprophylaxis with enoxaparin . METHODS 2509 patients scheduled to undergo elective total hip arthroplasty were r and omly assigned , stratified according to centre , with a computer-generated r and omisation code , to receive oral rivaroxaban 10 mg once daily for 31 - 39 days ( with placebo injection for 10 - 14 days ; n=1252 ) , or enoxaparin 40 mg once daily subcutaneously for 10 - 14 days ( with placebo tablet for 31 - 39 days ; n=1257 ) . The primary efficacy outcome was the composite of deep-vein thrombosis ( symptomatic or asymptomatic detected by m and atory , bilateral venography ) , non-fatal pulmonary embolism , and all-cause mortality up to day 30 - 42 . Analyses were done in the modified intention-to-treat population , which consisted of all patients who had received at least one dose of study medication , had undergone planned surgery , and had adequate assessment of thromboembolism . This study is registered at Clinical Trials.gov , number NCT00332020 . FINDINGS The modified intention-to-treat population for the analysis of the primary efficacy outcome consisted of 864 patients in the rivaroxaban group and 869 in the enoxaparin group . The primary outcome occurred in 17 ( 2.0 % ) patients in the rivaroxaban group , compared with 81 ( 9.3 % ) in the enoxaparin group ( absolute risk reduction 7.3 % , 95 % CI 5.2 - 9.4 ; p<0.0001 ) . The incidence of any on-treatment bleeding was much the same in both groups ( 81 [ 6.6 % ] events in 1228 patients in the rivaroxaban safety population vs 68 [ 5.5 % ] of 1229 patients in the enoxaparin safety population ; p=0.25 ) . INTERPRETATION Extended thromboprophylaxis with rivaroxaban was significantly more effective than short-term enoxaparin plus placebo for the prevention of venous thromboembolism , including symptomatic events , in patients undergoing total hip arthroplasty Rivaroxaban demonstrated superior efficacy and a similar safety profile to enoxaparin for the prevention of venous thromboembolism in the phase III RECORD programme in patients undergoing elective hip or knee replacement surgery . The XAMOS study investigated adverse events , including bleeding and thromboembolic events , in patients receiving rivaroxaban for thromboprophylaxis in routine clinical practice . XAMOS was a non-interventional , open-label cohort study in patients undergoing major orthopaedic surgery of the hip or knee ( predominantly elective arthroplasty ) , in which rivaroxaban was compared with other pharmacological thromboprophylaxis . All adverse events were documented , including symptomatic thromboembolic and bleeding events . Crude and adjusted incidences based on propensity score subclasses were calculated and compared between the rivaroxaban and st and ard-of-care groups . A total of 17,701 patients were enrolled from 252 centres in 37 countries . Crude incidences of symptomatic thromboembolic events three months after surgery in the safety population were 0.89 % in the rivaroxaban group ( n=8,778 ) and 1.35 % in the st and ard-of-care group ( n=8,635 ; odds ratio [ OR ] 0.65 ; 95 % confidence interval [ CI ] 0.49 - 0.87 ) , and 0.91 % and 1.31 % ( weighted ) in the propensity score-adjusted analysis ( OR 0.69 ; 95 % CI 0.56 - 0.85 ) , respectively . Treatment-emergent major bleeding events ( as defined in the RECORD studies ) occurred in 0.40 % and 0.34 % of patients in the rivaroxaban and st and ard-of-care groups in the safety population ( OR 1.19 ; 95 % CI 0.73 - 1.95 ) , and in 0.44 % versus 0.33 % ( weighted ) in the propensity score-adjusted analysis ( OR 1.35 ; 95 % CI 0.94 - 1.93 ) , respectively . This study in unselected patients confirmed the favourable benefit-risk profile of rivaroxaban seen in the RECORD programme

Do patients need continuous passive motion for their post-surgery rehabilitation ? At the same time , it is becoming apparent that a meticulous operative technique , respecting the soft tissue envelope and knowing the principles of alignment and soft tissue balancing , are some of the parameters that might contribute more to achieving the optimal results for the patients

Total knee replacement ( TKR ) is a widely used operation that has radically improved the quality of life of millions of people during the last few decades . However , some technical details , concerning the surgical procedure and the rehabilitation following total knee arthroplasty , are still a matter of a strong debate . In this review of the literature , we have included the best evidence available of the last decade , in an effort to shed light on some of the most controversial subjects related to TKR surgery . Posterior-stabilized or cruciate-retaining prosthesis ? To use a tourniquet during operation or not ? To resurface patella or not ? These are some of the most controversial topics that until now have been persistent dilemmas for the orthopedic surgeon .

Background The primary purpose of this r and omized controlled trial ( RCT ) was to compare knee-specific outcomes ( stiffness , pain , function ) between patellar retention and resurfacing up to 10 years after primary total knee arthroplasty ( TKA ) . Secondarily , we compared re-operation rates . Methods 38 subjects with non-inflammatory arthritis were r and omized at primary TKA surgery to receive patellar resurfacing ( n = 21 ; Resurfaced group ) or to retain their native patella ( n = 17 ; Non-resurfaced group ) . Evaluations were performed preoperatively , one , five and 10 years postoperatively by an evaluator who was blinded to group allocation . Self-reported knee-specific stiffness , pain and function , the primary outcomes , were measured by the Western Ontario McMaster Osteoarthritis Index ( WOMAC ) . Revision rate was determined at each evaluation and through hospital record review . Results 30 ( 88 % ) and 23 ( 72 % ) of available subjects completed the five and 10-year review respectively . Knee-specific scores continued to improve for both groups over the 10-years , despite diminishing overall health with no significant group differences seen . All revisions occurred within five years of surgery ( three Non-resurfaced subjects ; one Resurfaced subject ) ( p = 0.31 ) . Two revisions in the Non-resurfaced group were due to persistent anterior knee pain . Conclusions We found no differences in knee-specific results between groups at 5–10 years postoperatively . The Non-resurfaced group had two revisions due to anterior knee pain similar to rates reported in other studies . Knee-specific results provide useful postoperative information and should be used in future studies comparing patellar management strategies . Clinical Trials.gov The superiority between the posterior cruciate-retaining and the posterior cruciate-substituting design s still remains controversial . We performed a prospect i ve , r and omized control study for evaluation of the superiority of these design s. This study investigated 58 knees in 29 patients with simultaneous bilateral total knee arthroplasty , in which the high-flex CR design was r and omly implanted in one knee and the high-flex PS design was implanted in the other knee . The follow-up duration averaged 5.0 years , with a minimum duration of 3 years . Postoperatively , Knee Score and pain points in Knee Score result ed in no significant differences between the 2 design s. However , postoperative arc of range of motion , patient satisfaction , and posterior knee pain at passive flexion in the PS design were significantly superior to that of the CR design Background Total knee arthroplasty with the use of a tourniquet during the entire operation has not been shown to improve the performance of the operation and may increase the risk of complications . Questions / purpose sWe asked whether the limited use of a tourniquet for cementation only would affect ( 1 ) surgical time ; ( 2 ) postoperative pain and motion of the knee ; ( 3 ) blood loss ; or ( 4 ) complications such as risk of nerve injuries , quadriceps dysfunction , and drainage compared with use of a tourniquet throughout the procedure . Methods Seventy-one patients ( 79 knees ) were r and omized to either use of a tourniquet from the incision through cementation of the implants and deflated for closure ( operative tourniquet group ) or tourniquet use only during cementation ( cementation tourniquet group ) . The initial study population was a minimum of 30 knees in each group as suggested for r and omized studies by American Society for Testing and Material s st and ards ; termination of the study was determined by power analysis performed after 40 knees in each group showed any statistical solution to our questions would require a minimum of 260 more cases . Patients were excluded who were considered in previous r and omized studies as high risk for complications , which might be attributed to the tourniquet . Results There were no differences in terms of surgical time , pain scores , pain medicine requirements , range of motion , hemoglobin change , or total blood loss . One major complication ( compartmental syndrome ) occurred in a patient with tourniquet inflation until closure . No other complications were attributed to the use of a tourniquet . Conclusions With the numbers available , our results suggest that there are no important clinical differences between patients who had a tourniquet inflated throughout the procedure compared with those who had it inflated only during cementation . Tourniquet inflation for cementation only provides the benefit of bloodless bone for fixation and may eliminate the risks associated with prolonged tourniquet use . Level of Evidence Level I , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence BACKGROUND Anterior knee pain is still a major problem in total knee arthroplasty ( TKA ) . Although the most widely accepted opinion is that anterior knee pain is often associated with a patellofemoral etiology , there is no clear consensus as to etiology or treatment . Disabling pain receptors by electrocautery could theoretically achieve denervation of the anterior knee region . The present prospect i ve r and omized controlled study aim ed to evaluate results after patellar denervation with electrocautery in TKA at a minimum follow-up of 2 years . HYPOTHESIS Patellar denervation provides some benefit in terms of pain and clinical outcomes after TKA without patellar resurfacing . PATIENTS AND METHODS Clinical and radiological results for 35 patients with single-stage bilateral TKA ( 70 knees ; 26 women , nine men ; mean age , 68 years [ range , 58 to 77 years ] ) were review ed . In addition to removal of all osteophytes , patellar denervation by electrocautery was performed on one patella ; and debridement alone , removing all osteophytes , was performed on the contralateral patella , as a control . KSS score and a visual analog scale ( VAS ) were used to assess pre- and postoperative anterior knee pain . RESULTS Mean follow-up was 36 months ( 24 to 60 months ) . No revisions or re-operations were performed . There were no patellar fractures . On all parameters ( KSS score , range of motion and VAS ) , there was a statistically significant pre- to postoperative difference in favor of the denervation group . DISCUSSION Patellar denervation with electrocautery can reduce anterior knee pain , with satisfactory clinical and radiological outcome , in TKA without patellar resurfacing . LEVEL OF EVIDENCE Level II : low-powered prospect i ve r and omized trial We r and omized 126 consecutive patients undergoing primary total knee arthroplasty into group 1 : patella denervation ( n = 63 ) and group 2 : no patella denervation ( n = 63 ) . Assessment was performed preoperatively and at 3 , 12 and 24 months post-operatively . Average follow-up of patients was 26.5 months for denervation group and 26.3 months for no denervation group ( P = 0.84 ) . Pain scores for anterior knee pain were significantly better in the denervation group at 3 months but not at 12 and 24 months . Patient satisfaction was higher in the denervation group . Flexion range was higher in the denervation group at 3 , 12 and 24 months review ( P < 0.01 ) . There were , however , no statistically significant differences with other vali date d knee scores Background Adequate and intensive rehabilitation is an important requirement for successful total knee arthroplasty . Although research suggests that Continuous Passive Motion ( CPM ) should be implemented in the first rehabilitation phase after surgery , there is substantial debate about the duration of each session and the total period of CPM application . A Cochrane review on this topic concluded that short-term use of CPM leads to greater short-term range of motion . It also suggested , however , that future research should concentrate on the treatment period during which CPM should be administered . Methods In a r and omised controlled trial we investigated the effectiveness of prolonged CPM use in the home situation as an adjunct to st and ardised PT . Efficacy was assessed in terms of faster improvements in range of motion ( RoM ) and functional recovery , measured at the end of the active treatment period , 17 days after surgery . Sixty patients with knee osteoarthritis undergoing TKA and experiencing early postoperative flexion impairment were r and omised over two treatment groups . The experimental group received CPM + PT for 17 consecutive days after surgery , whereas the usual care group received the same treatment during the in-hospital phase ( i.e. about four days ) , followed by PT alone ( usual care ) in the first two weeks after hospital discharge . From 18 days to three months after surgery , both groups received st and ardised PT . The primary focus of rehabilitation was functional recovery ( e.g. ambulation ) and regaining RoM in the knee . Results Prolonged use of CPM slightly improved short-term RoM in patients with limited RoM at the time of discharge after total knee arthroplasty when added to a semi-st and ard PT programme . Assessment at 6 weeks and three months after surgery found no long-term effects of this intervention Neither did we detect functional benefits of the improved RoM at any of the outcome assessment s. Conclusion Although results indicate that prolonged CPM use might have a small short-term effect on RoM , routine use of prolonged CPM in patients with limited RoM at hospital discharge should be reconsidered , since neither long-term effects nor transfer to better functional performance was detected . Trial Registration IS RCT Minimally invasive surgery has recently been introduced in TKA surgery . The purpose of this study was to evaluate the effect of eversion of the patella , on safety and functional result after TKA . In a prospect i ve , r and omised , double blinded trial , 60 patients were divided in two groups : group A underwent TKA through a st and ard medial parapatellar arthrotomy , with patellar eversion . Group B underwent the same exposure , except for the fact that the patella was subluxed laterally . All other treatment protocol s were identical . Outcomes were measured until 1 year postoperatively . Radiographic evaluation included AP , lateral , skyline and full leg st and ing radiographs . VAS , WOMAC score , Knee Society Knee and Function score were performed . Active and passive range of motion ( ROM ) and knee proprioception was measured . All patients underwent isokinetic strength testing . The mean passive ROM changed from 121 ° preoperatively to 121 ° postoperatively in group A , compared to 118 ° –131 ° respectively in group B at 1 year ( P = 0.003 ) . The mean active ROM changed from 112 ° to 115 ° in group A , and from 108 ° to 125 ° in group B ( P = 0.005 ) . All other parameters were not significantly different . Patellar dislocation without eversion for exposing the knee during TKA is a safe procedure and improves ROM at 1 year postoperatively BACKGROUND There is conflicting evidence regarding the merits of patellar resurfacing during total knee arthroplasty , as many of the previous r and omized controlled trials have not been adequately powered . METHODS A pragmatic , multicenter , r and omized controlled trial was initiated in 1999 in the United Kingdom . Within a partial factorial design , 1715 patients were r and omly allocated to receive or not receive patellar resurfacing during total knee arthroplasty . The primary outcome measure was the Oxford Knee Score ; secondary measures included the Short Form-12 , the EuroQoL 5D , cost , cost-effectiveness , and the need for subsequent knee surgery . RESULTS The mean Oxford Knee Score was 35 points at five years postoperatively in both groups . There was no significant difference between the groups with respect to the mean Oxford Knee Score ( difference , 0.59 point ; 95 % confidence interval , -0.58 to 1.76 points ) or any other outcome measure at five years postoperatively . The outcome was not affected by whether the patella was domed or anatomic . There was no significant difference between the two groups with respect to the prevalence of knee-related readmission , of minor or intermediate reoperation , or of subsequent patella-related surgery . The total health care cost for the primary arthroplasty , subsequent monitoring , and any revision surgery did not differ significantly between the two groups . CONCLUSIONS In the largest r and omized controlled trial of patellar resurfacing reported to date , the functional outcome , reoperation rate , and total health care cost five years after primary total knee arthroplasty were not significantly affected by the addition of patellar resurfacing to the surgical procedure Background and purpose Although a tourniquet may reduce bleeding during total knee replacement ( TKA ) , and thereby possibly improve fixation , it might also cause complications . Migration as measured by radiostereometric analysis ( RSA ) can predict future loosening . We investigated whether the use of a tourniquet influences prosthesis fixation measured with RSA . This has not been investigated previously to our knowledge . Methods 50 patients with osteoarthritis of the knee were r and omized to cemented TKA with or without tourniquet . RSA was performed postoperatively and at 6 months , 1 year , and 2 years . Pain during hospital stay was registered with a visual analog scale ( VAS ) and morphine consumption was measured . Overt bleeding and blood transfusions were registered , and total bleeding was estimated by the hemoglobin dilution method . Range of motion was measured up to 2 years . Results RSA maximal total point motion ( MTPM ) differed by 0.01 mm ( 95 % CI –0.13 to 0.15 ) . Patients in the tourniquet group had less overt bleeding ( 317 mL vs. 615 mL ) , but the total bleeding estimated by hemoglobin dilution at day 4 was only slightly less ( 1,184 mL vs. 1,236 mL ) with a mean difference of –54 mL ( 95 % CI –256 to 152 ) . Pain VAS measurements were lower in the non-tourniquet group ( p = 0.01 ) . There was no significant difference in morphine consumption . Range of motion was 11 ° more in the non-tourniquet group ( p = 0.001 at 2 years ) . Interpretation Tourniquet use did not improve fixation but it may cause more postoperative pain and less range of motion Patellar resurfacing in total knee arthroplasty remains controversial . This study compared the long-term clinical outcomes of total knee arthroplasties performed with and without the patella resurfaced and is an up date of a previous report . Eighty-six patients ( 118 knees ) underwent primary total knee replacement and were r and omized into two groups : those treated with and those treated without resurfacing of the patella . Outcomes included the scores according to the Knee Society clinical rating system , the scores according to a forty-one- question patellofemoral-specific patient question naire , patient satisfaction , global and anterior knee pain scores , radiographic findings , and complications and revisions . Fifty-seven patients ( seventy-eight knees ) were followed for a minimum of ten years . No significant differences were identified between the two groups in terms of the range of motion , Knee Society scores , satisfaction , global knee pain , or anterior knee pain . The overall revision rates in the original series of 118 knees were 12 % in the nonresurfacing group and 9 % in the resurfacing group . Seven patients ( 12 % ) in the nonresurfacing group and two patients ( 3 % ) in the resurfacing group underwent revision for a reason related to a patellofemoral problem . On the basis of these findings , we concluded that , with the type of total knee arthroplasty used in our patients , similar results may be achieved with and without patellar resurfacing Continuous passive motion ( CPM ) , though of doubtful value , is yet routinely practice d post-total knee arthroplasty ( TKA ) . We prospect ively distributed 84 patients with TKA to 1 of the 3 st and ard rehabilitation regimes : no-CPM , 1-day-CPM , and 3-day-CPM . We recorded a unique " Timed up and go " test besides pain , Western Ontario and McMaster Universities ( WOMAC ) , short form-12 ( SF-12 ) , range of motion , knee and calf swelling , and wound healing parameters . Our st and ardized and elaborate measurements preoperatively and on postoperative days 3 , 5 , 14 , 42 , and 90 showed no statistically significant difference among the 3 groups in each parameter . We concluded that CPM gives no benefit in immediate functional recovery post-TKA , and in fact , the postoperative knee swelling persisted longer . We have since then discontinued its use in our patients without any untoward effect BACKGROUND Proponents of minimally invasive total knee arthroplasty cl aim that patellar eversion and anterior tibial translation during total knee arthroplasty have a deleterious effect on early patient rehabilitation and the early clinical outcome . Our purpose was to identify differences in knee preference and clinical outcome measures in a series of patients who had undergone bilateral total knee arthroplasty with each knee r and omized to one of two different surgical approaches : patellar eversion and anterior tibial translation , or patellar subluxation and no tibial translation . METHODS The knees of forty patients were prospect ively r and omized to one of two treatment groups , patellar eversion or patellar subluxation , with each patient having one knee treated with each type of approach . Three patients were withdrawn , leaving a final study group of thirty-seven patients . The patients and physical therapists were blinded to the type of treatment . Clinical outcomes , including the Knee Society scores , range of motion , quadriceps strength as tested with a dynamometer , and the patient 's preferred knee on the basis of pain , motion , and strength , were collected preoperatively and at six weeks , twelve weeks , and six months postoperatively and were analyzed . RESULTS At six weeks after the surgery , there were no significant differences between the two groups with regard to the range of motion , quadriceps strength , or Knee Society scores . With regard to the patient 's knee preference at six weeks , the two knees were rated as being the same in terms of pain , whereas a higher percentage preferred the knee treated with eversion in terms of motion ( 43 % compared with 35 % who preferred the knee treated with subluxation ) and strength ( 43 % compared with 22 % ) . The mean arc of motion in both groups was approximately 113 degrees . At twelve weeks and six months after the surgery , we found no significant differences between the treatment groups in terms of the range of motion , quadriceps strength , or Knee Society scores , and there was no difference with regard to the patient 's knee preference . CONCLUSIONS We found no significant differences between the two treatment groups ( patellar eversion and anterior tibial translation compared with patellar subluxation and no tibial translation ) at six weeks , twelve weeks , or six months after the surgery . We concluded that patellar eversion and anterior tibial translation appear to have no adverse effects on the range of motion , quadriceps strength , or patient 's knee preference during the early postoperative recovery period after total knee arthroplasty A prospect i ve , r and omized , blinded study was design ed to investigate the impact of patellar eversion on early quadriceps function after total knee arthroplasty . One hundred twenty-two consecutive patients were r and omized by 2 surgeons to receive one of 2 different surgical approaches . Surgeon A r and omized patients to receive a mid-vastus split with or without patellar eversion . Surgeon B r and omized patients to receive a median parapatellar arthrotomy or a mid-vastus split , both without patellar eversion . For surgeon A , a significantly earlier return of straight leg raise was noted when patellar eversion was avoided . Significant correlation existed between an earlier return of straight leg raise and decreased length of stay . Avoiding patellar eversion enhanced the return of quadriceps function and led to a decreased length of stay in the hospital BACKGROUND Although tourniquets are widely used in total knee arthroplasty , their effectiveness in reducing blood loss and their influence on the postoperative course remain unclear . Tourniquet-related soft-tissue damage is a related concern . We performed a prospect i ve , r and omized , controlled trial to clarify the effect of tourniquets in total knee arthroplasty . METHODS Seventy-two patients undergoing total knee arthroplasty were r and omly allocated to a tourniquet or non-tourniquet group . Blood loss and changes in C-reactive protein , creatine phosphokinase , and other indicators of soft-tissue damage were monitored preoperatively and postoperatively on Days 1 , 2 , and 4 . Thigh pain , knee pain , limb swelling , rehabilitation progress , and hospital stays were also recorded for comparison . RESULTS Patients in the tourniquet group showed smaller decreases in hemoglobin ( mean and st and ard deviation , 2.6 ± 0.9 versus 3.7 ± 1.3 g/dL ) and hematocrit ( 7.6 % ± 2.8 % versus 10.4 % ± 4.0 % ) , less calculated blood loss ( 303 ± 119 versus 423 ± 197 mL ) , and smaller increases in C-reactive protein ( peak value , 175 ± 55 versus 139 ± 75 mg/dL ) and creatine phosphokinase ( peak value , 214 ± 89 versus 162 ± 104 U/L ) compared with those in the non-tourniquet group . There was slightly less postoperative pain in the non-tourniquet group . There were no significant differences between the groups in terms of swelling , rehabilitation progress , or hospital stays . CONCLUSIONS The use of a tourniquet during total knee arthroplasty was effective for reducing blood loss and avoiding excessive postoperative inflammation and muscle damage . The use of a tourniquet was related to slightly more postoperative pain but did not affect postoperative recovery OBJECTIVE To compare the results of primary total knee arthroplasty with patellar reshaping or resurfacing . METHODS One hundred thirty-three patients were r and omized into patellar reshaping group and patellar resurfacing group . Patellar reshaping includes resecting the partial lateral facet of the patella and the osteophytes surrounding the patella , trimming the patella to match the trochlea of the femoral component . The minimum follow-up time was 7 years . The outcome was measured by anterior knee pain rate , Knee Society clinical score , and radiographs . RESULTS Eight patients in the reshaping group ( 12.5 % ) and 10 patients in the resurfacing group ( 14.7 % ) complained of anterior knee pain ( P=0.712 ) . Meanwhile , there were no significant differences between the two groups in terms of total Knee Society score , Knee Society pain score , Knee Society function score , as well as anterior knee pain rate . CONCLUSIONS With the numbers available , there was no significant difference between the groups treated with patellar reshaping or patellar resurfacing with regard to the KSS , anterior knee pain rate and radiographs . We prefer reshaping the patella to resurfacing the patella because the former preserves sufficient patellar bone stock and can easily be converted to patellar replacement if patients complain of recurrent anterior knee pain BACKGROUND The impact of posterior cruciate ligament-substituting and posterior cruciate ligament-retaining devices on the range of motion of the knee following primary total knee arthroplasty is unclear . The primary objective of our study was to compare the range of motion of the knee over the first two postoperative years between subjects who had received the ligament-substituting design and those who had received the ligament-retaining design . Secondarily , pain , function , and health-related quality of life were compared between the two groups . METHODS We undertook a prospect i ve r and omized study of 100 patients with noninflammatory osteoarthritis who were undergoing primary total knee arthroplasty . Patients were r and omized at the time of surgery to receive one of the two study prosthesis design s. They were evaluated preoperatively , at the time of hospital discharge , at three months postoperatively , and at up to two years postoperatively by a physical therapist who was blinded to the group allocation . Active knee flexion and extension , measured with a goniometer , were the primary outcome measures . Self-reported pain , function , and health-related quality of life were measured with the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the R AND 36-Item Health Survey ( R AND -36 ) . Complications and revision rates were determined through hospital record review and at each patient evaluation . RESULTS Eighty percent ( seventy-eight ) of the ninety-eight available patients returned for the final assessment . At two years postoperatively , the mean difference between the groups with regard to knee flexion was 0.03 degrees ( 95 % confidence interval , -5.9 degrees to 6.0 degrees ) and the mean difference in knee extension was 1.0 degrees ( 95 % confidence interval , -0.36 degrees to 2.4 degrees ) . Ninety-one ( 93 % ) of the ninety-eight available patients completed question naires at the time of the final assessment . The two treatment groups had similar pain , function , and quality -of-life scores and complication rates . One subject in the cruciate-retaining group required revision , secondary to a deep joint infection , and one subject in the cruciate-substituting group required manipulation to address poor knee flexion . CONCLUSIONS Overall , the two treatment groups had a similar range of motion of the knee over the initial two-year postoperative time period . A satisfactory range of motion was achieved by three months postoperatively and was maintained at the final assessment We have carried out a prospect i ve r and omised , single blind clinical trial to investigate the effect of continuous passive motion on range of knee flexion , lack of extension , pain levels and analgesic use after total knee replacement surgery . 85 subjects were r and omly allocated to control or study group . All subjects followed the existing rehabilitation protocol , which permits immediate active range of motion exercises and mobilisation with the study group using continuous passive motion for 1 h , twice a day . Outcome measures employed were range of motion , pain assessed on a visual analogue scale and analgesic use according to the WHO ladder . Blinded evaluation was carried out preoperatively , at time of discharge from hospital , 6 weeks , 6 and 12 months postoperation . No significant difference was observed between groups at all time intervals for each outcome variable using Wilcoxon Rank sum tests . The results substantiate previous findings that short duration continuous passive motion following total knee arthroplasty does not influence outcome of range of motion or reported pain Although avoiding patellar eversion during a total knee arthroplasty ( TKA ) has theoretical benefit in quadriceps recovery , there has been paucity of supportive objective clinical results . We prospect ively design ed the study whether TKA without patellar eversion has better quadriceps recovery in an objective , dynamometer study . Seventy-two knees undergoing TKA with midvastus approach were r and omized into two groups according to patellar eversion or not . Clinical data and objective quadriceps recovery using a dynamometer were investigated preoperatively and postoperative at 6weeks , 3months , 6months and 1year . There were no statistical differences between two groups throughout the follow-up periods in recovery of quadriceps force or power and clinical data . Choosing to evert patella during TKA using midvastus approach would not adversely affect postoperative quadriceps recovery The control of perioperative blood loss is a major concern in cementless knee arthroplasty surgery . We r and omized retrospectively 55 patients ( 60 knees in total ) who had undergone cementless total knee arthroplasty and determined the efficacy of tourniquet release either " before " ( 30 knees ) or " after " ( 30 knees ) wound closure . Measurements of total blood loss showed significant differences between the groups ( " Before " group , 906 + /- 238 mL ; " After " group , 731 + /- 332 mL ; P = .0225 ) . The levels of red blood cells , hemoglobin , and hematocrit recovered to the preoperative levels by 3 months after surgery in both groups . In summary , we recommend that the tourniquet be released after wound closure and that a compressive dressing be applied with the aim of limiting or reducing perioperative blood loss without significant effects of the transfer requirement in the 2 groups , provided that tourniquet time is kept below 60 minutes to avoid ill effects of the tourniquet BACKGROUND Measurement of limb occlusion pressure before surgery might lead to the use of a lower tourniquet cuff pressure during surgery and thereby reduce the risk of postoperative pain and complications . The primary aim of this study was to investigate whether the limb-occlusion-pressure method reduces the tourniquet cuff pressure used during total knee arthroplasty and if this leads to less postoperative pain compared with that experienced by patients on whom this method is not used . The secondary aim was to investigate whether there were any differences regarding the quality of the bloodless field , range of motion , and postoperative wound complications . METHODS One hundred and sixty-four patients scheduled to be treated with a total knee arthroplasty were r and omized to a control group or to undergo the intervention under study ( the limb-occlusion-pressure [ LOP ] group ) . In the control group , the tourniquet cuff pressure was based on the patient 's systolic blood pressure and a margin decided by the surgeon ( the routine method ) . In the LOP group , the tourniquet cuff pressure was based on the measurement of the limb occlusion pressure . The primary outcome measure was postoperative pain , and the secondary outcome measures were the quality of the bloodless field , knee motion , and wound-related complications at discharge and two months after surgery . RESULTS The tourniquet cuff pressure was significantly lower in the LOP group than in the control group ( p < 0.001 ) . We could not demonstrate any differences between the groups regarding postoperative pain or complications , although the number of postoperative complications was relatively high in both groups . However , at discharge forty of the forty-seven patients with a wound complication had had a cuff pressure above 225 mm Hg and at the two-month follow-up evaluation fourteen of the sixteen patients with a wound complication had had a cuff pressure above 225 mm Hg . CONCLUSIONS The limb-occlusion-pressure method reduces the cuff pressure without reducing the quality of the bloodless field , but there were no differences in outcomes between the groups . An important secondary finding was that patients with a cuff pressure of ≤225 mm Hg had no postoperative infections and a lower rate of wound complications We conducted a r and omized clinical trial to determine long-term outcome differences of patella resurfacing versus non-resurfacing in patients undergoing bilateral total knee arthroplasty . We question ed whether there were differences with respect to the operative procedure , anterior knee pain , Knee Society scores , patellofemoral-related revision rates , patient satisfaction and preference , and patellofemoral functional activities . Thirty-two patients ( 64 knees ) underwent primary bilateral single-stage total knee arthroplasty for osteoarthritis . All patients received the same cruciate-retaining total knee arthroplasty . Patients were r and omized to resurfacing or nonresurfacing of the patella for the first total knee arthroplasty , and the second knee received the opposite treatment . All living patients were followed to a minimum of 10 years . We found no differences with regard to range of motion , Knee Society Clinical Rating Score , satisfaction , revision rates , or anterior knee pain . Thirty-seven percent of patients preferred the resurfaced knee , 22 % the nonresurfaced knee , and 41 % had no preference . Two patients ( 7.4 % ) in the nonresurfaced group and one patient ( 3.5 % ) in the resurfaced group underwent revision for a patellofemoral-related complication . Equivalent clinical results for resurfaced and nonresurfaced patellae in total knee arthroplasty were demonstrated in this 10-year r and omized clinical trial . Level of Evidence : Level I , therapeutic study . See the Guide lines for Authors for a complete description of levels of evidence BACKGROUND A concern that arises with any change in technique is whether it affects the long-term implant stability . The objective of this study was to evaluate the early migration , measured by radiostereometric analysis ( RSA ) , and the functional outcome of the Triathlon ™ cemented knee prosthesis , operated on with or without a tourniquet . During the last decades RSA has emerged as a way to assess prosthetic fixation and long time prognosis . The method has been used extensively in both hip and knee arthroplasty . METHOD This was a single centre prospect i ve study including 60 patients r and omized into two groups operated on either with or without tourniquet . RSA investigation was done within 2 - 3 days postoperatively after full weight bearing , and then at 3 months , 1 year and 2 years postoperatively . RESULTS There were no differences between the groups regarding the translation along or rotation around the three coordinal axes , or in maximum total point motion ( MTPM ) . At 2 years the mean MTPM ( SD ) was 0.71 mm ( 0.64 ) for the tourniquet-group and 0.53 mm ( 0.21 ) for the non-tourniquet-group . CONCLUSIONS The tibial tray of the Triathlon ™ cemented knee prosthesis showed similar early stability whether operated on with or without tourniquet . LEVEL OF EVIDENCE Level I. ARTICLE SUMMARY Article focus : A safety study for total knee replacement operated on with or without perioperative tourniquet regarding the prosthetic fixation . Strengths and limitations : Strength of this study is that it is a r and omized prospect i ve trial using an objective measuring tool . The sample size of 25 - 30 patients is reportedly sufficient for the screening of implants using RSA ( 1 - 3 ) . TRIAL REGISTRATION Clinical trials NCT01604382 , Ethics Committee approval D-nr : 144/20085 The purpose of the current study was to compare midterm outcomes of posterior cruciate-retaining ( CR ) versus posterior cruciate-substituting ( PS ) procedures using the Genesis II total knee arthroplasty ( TKA ) system ( Smith and Nephew , Memphis , TN ) . Ninety-nine ( 99 ) CR and 93 PS TKA 's were analyzed in this prospect i ve , r and omized clinical trial . Surgeries were performed at seven medical centers by participating surgeons . Clinical outcomes ( Knee Society Score , Range of Motion , WOMAC , SF-12 , and Radiographic Findings ) , in addition to postoperative complications , were evaluated with a minimum follow-up of 5 years . Following data analysis , there were no significant differences in patient demographics or preoperative clinical measures between the two groups . At the latest follow-up interval , no significant differences were found between the CR and PS groups with regards to functional assessment , patient satisfaction , or postoperative complication . However , the PS group did display statistically significant improvements in range of motion when compared with the CR group . The results of this investigation would suggest that , while comparable in regards to supporting good clinical outcomes , the PS Genesis II design does appear to support significantly improved postoperative range of motion when compared with the CR design

In conclusion , in this systematic review and meta- analysis involving studies , the use of epinephrine result ed in a significantly higher likelihood of survival to hospital discharge and ROSC than the non-epinephrine administration , but , there was no significant between group difference in the rate of a favorable neurologic outcome

AIM Our objective is to assess the effects of epinephrine for out of hospital cardiac arrest . BACKGROUND Cardiac arrest was the most serious medical incidents with an estimated incidence in the United States of 95.7 per 100,000 person years . Though epinephrine improved coronary and cerebral perfusion , improving a return of spontaneous circulation , potentially harmful effects on the heart lead to greater myocardial oxygen dem and . Concerns about the effect of epinephrine for out-of-hospital cardiac arrest were controversial and called for a higher argument to determine whether the effects of epinephrine is safe and effective for shor and long terms outcomes .

CONTEXT Epinephrine is widely used in cardiopulmonary resuscitation for out-of-hospital cardiac arrest ( OHCA ) . However , the effectiveness of epinephrine use before hospital arrival has not been established . OBJECTIVE To evaluate the association between epinephrine use before hospital arrival and short- and long-term mortality in patients with cardiac arrest . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , nonr and omized , observational propensity analysis of data from 417 188 OHCAs occurring in 2005 - 2008 in Japan in which patients aged 18 years or older had an OHCA before arrival of emergency medical service ( EMS ) personnel , were treated by EMS personnel , and were transported to the hospital . MAIN OUTCOME MEASURES Return of spontaneous circulation before hospital arrival , survival at 1 month after cardiac arrest , survival with good or moderate cerebral performance ( Cerebral Performance Category [ CPC ] 1 or 2 ) , and survival with no , mild , or moderate neurological disability ( Overall Performance Category [ OPC ] 1 or 2 ) . RESULTS Return of spontaneous circulation before hospital arrival was observed in 2786 of 15,030 patients ( 18.5 % ) in the epinephrine group and 23,042 of 402,158 patients ( 5.7 % ) in the no-epinephrine group ( P < .001 ) ; it was observed in 2446 ( 18.3 % ) and 1400 ( 10.5 % ) of 13,401 propensity-matched patients , respectively ( P < .001 ) . In the total sample , the numbers of patients with 1-month survival and survival with CPC 1 or 2 and OPC 1 or 2 , respectively , were 805 ( 5.4 % ) , 205 ( 1.4 % ) , and 211 ( 1.4 % ) with epinephrine and 18,906 ( 4.7 % ) , 8903 ( 2.2 % ) , and 8831 ( 2.2 % ) without epinephrine ( all P < .001 ) . Corresponding numbers in propensity-matched patients were 687 ( 5.1 % ) , 173 ( 1.3 % ) , and 178 ( 1.3 % ) with epinephrine and 944 ( 7.0 % ) , 413 ( 3.1 % ) , and 410 ( 3.1 % ) without epinephrine ( all P < .001 ) . In all patients , a positive association was observed between prehospital epinephrine and return of spontaneous circulation before hospital arrival ( adjusted odds ratio [ OR ] , 2.36 ; 95 % CI , 2.22 - 2.50 ; P < .001 ) . In propensity-matched patients , a positive association was also observed ( adjusted OR , 2.51 ; 95 % CI , 2.24 - 2.80 ; P < .001 ) . In contrast , among all patients , negative associations were observed between prehospital epinephrine and long-term outcome measures ( adjusted ORs : 1-month survival , 0.46 [ 95 % CI , 0.42 - 0.51 ] ; CPC 1 - 2 , 0.31 [ 95 % CI , 0.26 - 0.36 ] ; and OPC 1 - 2 , 0.32 [ 95 % CI , 0.27 - 0.38 ] ; all P < .001 ) . Similar negative associations were observed among propensity-matched patients ( adjusted ORs : 1-month survival , 0.54 [ 95 % CI , 0.43 - 0.68 ] ; CPC 1 - 2 , 0.21 [ 95 % CI , 0.10 - 0.44 ] ; and OPC 1 - 2 , 0.23 [ 95 % CI , 0.11 - 0.45 ] ; all P < .001 ) . CONCLUSION Among patients with OHCA in Japan , use of prehospital epinephrine was significantly associated with increased chance of return of spontaneous circulation before hospital arrival but decreased chance of survival and good functional outcomes 1 month after the event CONTEXT Intravenous access and drug administration are included in advanced cardiac life support ( ACLS ) guidelines despite a lack of evidence for improved outcomes . Epinephrine was an independent predictor of poor outcome in a large epidemiological study , possibly due to toxicity of the drug or cardiopulmonary resuscitation ( CPR ) interruptions secondary to establishing an intravenous line and drug administration . OBJECTIVE To determine whether removing intravenous drug administration from an ACLS protocol would improve survival to hospital discharge after out-of-hospital cardiac arrest . DESIGN , SETTING , AND PATIENTS Prospect i ve , r and omized controlled trial of consecutive adult patients with out-of-hospital nontraumatic cardiac arrest treated within the emergency medical service system in Oslo , Norway , between May 1 , 2003 , and April 28 , 2008 . INTERVENTIONS Advanced cardiac life support with intravenous drug administration or ACLS without access to intravenous drug administration . MAIN OUTCOME MEASURES The primary outcome was survival to hospital discharge . The secondary outcomes were 1-year survival , survival with favorable neurological outcome , hospital admission with return of spontaneous circulation , and quality of CPR ( chest compression rate , pauses , and ventilation rate ) . RESULTS Of 1183 patients for whom resuscitation was attempted , 851 were included ; 418 patients were in the ACLS with intravenous drug administration group and 433 were in the ACLS with no access to intravenous drug administration group . The rate of survival to hospital discharge was 10.5 % for the intravenous drug administration group and 9.2 % for the no intravenous drug administration group ( P = .61 ) , 32 % vs 21 % , respectively , ( P<.001 ) for hospital admission with return of spontaneous circulation , 9.8 % vs 8.1 % ( P = .45 ) for survival with favorable neurological outcome , and 10 % vs 8 % ( P = .53 ) for survival at 1 year . The quality of CPR was comparable and within guideline recommendations for both groups . After adjustment for ventricular fibrillation , response interval , witnessed arrest , or arrest in a public location , there was no significant difference in survival to hospital discharge for the intravenous group vs the no intravenous group ( adjusted odds ratio , 1.15 ; 95 % confidence interval , 0.69 - 1.91 ) . CONCLUSION Compared with patients who received ACLS without intravenous drug administration following out-of-hospital cardiac arrest , patients with intravenous access and drug administration had higher rates of short-term survival with no statistically significant improvement in survival to hospital discharge , quality of CPR , or long-term survival . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00121524 IMPORTANCE Among patients with cardiac arrest , preliminary data have shown improved return of spontaneous circulation and survival to hospital discharge with the vasopressin-steroids-epinephrine ( VSE ) combination . OBJECTIVE To determine whether combined vasopressin-epinephrine during cardiopulmonary resuscitation ( CPR ) and corticosteroid supplementation during and after CPR improve survival to hospital discharge with a Cerebral Performance Category ( CPC ) score of 1 or 2 in vasopressor-requiring , in-hospital cardiac arrest . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled , parallel-group trial performed from September 1 , 2008 , to October 1 , 2010 , in 3 Greek tertiary care centers ( 2400 beds ) with 268 consecutive patients with cardiac arrest requiring epinephrine according to resuscitation guidelines ( from 364 patients assessed for eligibility ) . INTERVENTIONS Patients received either vasopressin ( 20 IU/CPR cycle ) plus epinephrine ( 1 mg/CPR cycle ; cycle duration approximately 3 minutes ) ( VSE group , n = 130 ) or saline placebo plus epinephrine ( 1 mg/CPR cycle ; cycle duration approximately 3 minutes ) ( control group , n = 138 ) for the first 5 CPR cycles after r and omization , followed by additional epinephrine if needed . During the first CPR cycle after r and omization , patients in the VSE group received methylprednisolone ( 40 mg ) and patients in the control group received saline placebo . Shock after resuscitation was treated with stress-dose hydrocortisone ( 300 mg daily for 7 days maximum and gradual taper ) ( VSE group , n = 76 ) or saline placebo ( control group , n = 73 ) . MAIN OUTCOMES AND MEASURES Return of spontaneous circulation ( ROSC ) for 20 minutes or longer and survival to hospital discharge with a CPC score of 1 or 2 . RESULTS Follow-up was completed in all resuscitated patients . Patients in the VSE group vs patients in the control group had higher probability for ROSC of 20 minutes or longer ( 109/130 [ 83.9 % ] vs 91/138 [ 65.9 % ] ; odds ratio [ OR ] , 2.98 ; 95 % CI , 1.39 - 6.40 ; P = .005 ) and survival to hospital discharge with CPC score of 1 or 2 ( 18/130 [ 13.9 % ] vs 7/138 [ 5.1 % ] ; OR , 3.28 ; 95 % CI , 1.17 - 9.20 ; P = .02 ) . Patients in the VSE group with postresuscitation shock vs corresponding patients in the control group had higher probability for survival to hospital discharge with CPC scores of 1 or 2 ( 16/76 [ 21.1 % ] vs 6/73 [ 8.2 % ] ; OR , 3.74 ; 95 % CI , 1.20 - 11.62 ; P = .02 ) , improved hemodynamics and central venous oxygen saturation , and less organ dysfunction . Adverse event rates were similar in the 2 groups . CONCLUSION AND RELEVANCE Among patients with cardiac arrest requiring vasopressors , combined vasopressin-epinephrine and methylprednisolone during CPR and stress-dose hydrocortisone in postresuscitation shock , compared with epinephrine/saline placebo , result ed in improved survival to hospital discharge with favorable neurological status . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00729794 BACKGROUND There is little evidence from clinical trials that the use of adrenaline ( epinephrine ) in treating cardiac arrest improves survival , despite adrenaline being considered st and ard of care for many decades . The aim of our study was to determine the effect of adrenaline on patient survival to hospital discharge in out of hospital cardiac arrest . METHODS We conducted a double blind r and omised placebo-controlled trial of adrenaline in out-of-hospital cardiac arrest . Identical study vials containing either adrenaline 1:1000 or placebo ( sodium chloride 0.9 % ) were prepared . Patients were r and omly allocated to receive 1 ml aliquots of the trial drug according to current advanced life support guidelines . Outcomes assessed included survival to hospital discharge ( primary outcome ) , pre-hospital return of spontaneous circulation ( ROSC ) and neurological outcome ( Cerebral Performance Category Score - CPC ) . RESULTS A total of 4103 cardiac arrests were screened during the study period of which 601 underwent r and omisation . Documentation was available for a total of 534 patients : 262 in the placebo group and 272 in the adrenaline group . Groups were well matched for baseline characteristics including age , gender and receiving byst and er CPR . ROSC occurred in 22 ( 8.4 % ) of patients receiving placebo and 64 ( 23.5 % ) who received adrenaline ( OR=3.4 ; 95 % CI 2.0 - 5.6 ) . Survival to hospital discharge occurred in 5 ( 1.9 % ) and 11 ( 4.0 % ) patients receiving placebo or adrenaline respectively ( OR=2.2 ; 95 % CI 0.7 - 6.3 ) . All but two patients ( both in the adrenaline group ) had a CPC score of 1 - 2 . CONCLUSION Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC CONTEXT The health and policy implication s of regional variation in incidence and outcome of out-of-hospital cardiac arrest remain to be determined . OBJECTIVE To evaluate whether cardiac arrest incidence and outcome differ across geographic regions . DESIGN , SETTING , AND PATIENTS Prospect i ve observational study ( the Resuscitation Outcomes Consortium ) of all out-of-hospital cardiac arrests in 10 North American sites ( 8 US and 2 Canadian ) from May 1 , 2006 , to April 30 , 2007 , followed up to hospital discharge , and including data available as of June 28 , 2008 . Cases ( aged 0 - 108 years ) were assessed by organized emergency medical services ( EMS ) personnel , did not have traumatic injury , and received attempts at external defibrillation or chest compressions or resuscitation was not attempted . Census data were used to determine rates adjusted for age and sex . MAIN OUTCOME MEASURES Incidence rate , mortality rate , case-fatality rate , and survival to discharge for patients assessed or treated by EMS personnel or with an initial rhythm of ventricular fibrillation . RESULTS Among the 10 sites , the total catchment population was 21.4 million , and there were 20,520 cardiac arrests . A total of 11,898 ( 58.0 % ) had resuscitation attempted ; 2729 ( 22.9 % of treated ) had initial rhythm of ventricular fibrillation or ventricular tachycardia or rhythms that were shockable by an automated external defibrillator ; and 954 ( 4.6 % of total ) were discharged alive . The median incidence of EMS-treated cardiac arrest across sites was 52.1 ( interquartile range [ IQR ] , 48.0 - 70.1 ) per 100,000 population ; survival ranged from 3.0 % to 16.3 % , with a median of 8.4 % ( IQR , 5.4%-10.4 % ) . Median ventricular fibrillation incidence was 12.6 ( IQR , 10.6 - 5.2 ) per 100,000 population ; survival ranged from 7.7 % to 39.9 % , with a median of 22.0 % ( IQR , 15.0%-24.4 % ) , with significant differences across sites for incidence and survival ( P<.001 ) . CONCLUSION In this study involving 10 geographic regions in North America , there were significant and important regional differences in out-of-hospital cardiac arrest incidence and outcome This trial compared blinded 10 mg aliquots of adrenaline with placebo in 194 cardiac arrest patients treated in hospital using American Heart Association guidelines . In-hospital and out-of-hospital arrests were included . Of the 339 eligible patients a large proportion ( 145 ( 45 % ) ) were not r and omised and received open 1 mg aliquots of adrenaline . This group is also analysed . Supervising physicians gave significant preference for males , patients with no previous cardiac history and without multiple organ disease to be given open 1 mg adrenaline . Patients in asystole at the time of consideration for entry were preferentially placed in the trial group ( 114 ( 69 % ) vs. 170 ( 88 % ) ) and patients in ventricular fibrillation were preferentially given open 1 mg adrenaline ( 31 ( 21 % ) vs. 24 ( 12 % ) P < 0.03 ) . The most beneficial rhythm changes which led to survival were sinus rhythm and ventricular tachycardia . Analysis of rhythm changes result ing from the dosing showed a significant ( P = 0.01 ) change to a beneficial rhythm with 10 mg adrenaline but not for 1 mg adrenaline or placebo . This was not reflected by an improvement in immediate survival . No significant differences in immediate survival ( IS ) or hospital discharge ( HD ) exists between open 1 mg adrenaline ( IS 14 ( 9.7 % ) , HD 3 ( 2 % ) ) or the 10 mg adrenaline ( IS 9 ( 9.6 % ) , HD 0 ) vs. placebo ( IS 7 ( 7 % ) , HD 0 ) trial arms . Patients reaching the point of use of adrenaline have a uniformly poor immediate survival ( 8.8 % ) and hospital discharge rate ( 0.9 % ) . Dosing with 10 mg or 1 mg adrenaline does not influence outcome compared with placebo BACKGROUND In cardiac arrest , pulseless electrical activity ( PEA ) is a challenging clinical syndrome . In a r and omized study comparing intravenous ( i.v . ) access and drugs versus no i.v . access or drugs during advanced life support ( ALS ) , adrenaline ( epinephrine ) improved return of spontaneous circulation ( ROSC ) in patients with PEA . Originating from this study , we investigated the time-dependent effects of adrenaline on clinical state transitions in patients with initial PEA , using a non-parametric multi-state statistical model . METHODS AND RESULTS Patients with available defibrillator recordings were included , of whom 101 received adrenaline and 73 did not . There were significantly more state transitions in the adrenaline group than in the no-adrenaline group ( rate ratio = 1.6 , p<0.001 ) . Adrenaline markedly increased the rate of transition from PEA to ROSC during ALS and slowed the rate of being declared dead ; e.g. by 20 min 20 % of patients in the adrenaline group had been declared dead and 25 % had obtained ROSC , whereas 50 % in the no-adrenaline group have been declared dead and 15 % had obtained ROSC . The differential effect of adrenaline could be seen after approx . 10 min of ALS for most transitions . For both groups the probability of deteriorating from PEA to asystole was highest during the first 15 min . Adrenaline increased the rate of transition from PEA to ventricular fibrillation or -tachycardia ( VF/VT ) , and from ROSC to VF/VT . CONCLUSIONS Adrenaline has notable clinical effects during ALS in patients with initial PEA . The drug extends the time window for ROSC to develop , but also renders the patient more unstable . Further research should investigate the optimal dose , timing and mode of adrenaline administration during ALS BACKGROUND Cardiac arrest outside the hospital is common and has a poor outcome . Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome , but there have been no conclusive studies in humans . In a r and omized , controlled trial , we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest . METHODS The study subjects were 77 patients who were r and omly assigned to treatment with hypothermia ( with the core body temperature reduced to 33 degrees C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours ) or normothermia . The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility . RESULTS The demographic characteristics of the patients were similar in the hypothermia and normothermia groups . Twenty-one of the 43 patients treated with hypothermia ( 49 percent ) survived and had a good outcome --that is , they were discharged home or to a rehabilitation facility -- as compared with 9 of the 34 treated with normothermia ( 26 percent , P=0.046 ) . After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation , the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 ( 95 percent confidence interval , 1.47 to 18.76 ; P=0.011 ) . Hypothermia was associated with a lower cardiac index , higher systemic vascular resistance , and hyperglycemia . There was no difference in the frequency of adverse events . CONCLUSIONS Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest To determine if clinical ly accessible hemodynamic and blood gas measurements are of value in predicting outcome of countershock after prolonged ventricular fibrillation ( VF ) and artificial cardiopulmonary support , 14 dogs were studied during 30 minutes of VF using two r and omly assigned closed-chest techniques . Seven dogs underwent conventional CPR ; the other seven were supported with a pneumatic thoracic vest and abdominal binder , which were inflated synchronously with the airway . Ascending aortic ( Ao ) , right atrial ( RA ) , and instantaneous coronary perfusion pressures ( Ao - RA ) were measured at five-minute intervals . Ao and RA blood sample s were analyzed at 10 , 20 , 25 and 30 minutes for PO2 , PCO2 , and pH. After 25 minutes , 1 mg epinephrine was given intravenously , and five minutes later defibrillation was attempted . If unsuccessful , repeated countershocks , conventional pharmacologic therapy , and artificial support were continued . If a perfusing spontaneous cardiac rhythm did not result within an additional 30 minutes , the experiment was terminated . Six animals developed a perfusing cardiac rhythm after one or more countershocks ( Group 1 ) ; eight failed to develop a perfusing rhythm after repeated countershocks and an additional 30 minutes of resuscitative effort ( Group 2 ) . Five Group 1 dogs received vest/binder artificial support . When measured values were averaged over the study period , Group 1 was found to have a significantly greater Ao end-diastolic pressure ( AoEDP ) and peak diastolic coronary perfusion pressure ( CPP ) when compared to Group 2 ( 23 + /- 6 vs 14 + /- 8 mm Hg , P less than .05 ; and 22 + /- 6 vs 5 + /- 10 mm Hg , P less than .01 , respectively ) . ( ABSTRACT TRUNCATED AT 250 WORDS We studied the effect of st and ard and high doses of epinephrine on coronary perfusion pressure during cardiopulmonary resuscitation in 32 patients whose cardiac arrest was refractory to advanced cardiac life support . Simultaneous aortic and right atrial pressures were measured and plasma epinephrine levels were sample d. Patients remaining in cardiac arrest after multiple 1-mg doses of epinephrine received a high dose of 0.2 mg/kg . The increase in the coronary perfusion pressures was 3.7 + /- 5.0 mm Hg following a st and ard dose , not a statistically significant change . The increase after a high dose was 11.3 + /- 10.0 mm Hg ; this was both statistically different than before administration and larger than after a st and ard dose . High-dose epinephrine was more likely to raise the coronary perfusion pressure above the previously demonstrated critical value of 15 mm Hg . The highest arterial plasma epinephrine level after a st and ard dose was 152 + /- 162 ng/mL , and after a high dose , 393 + /- 289 ng/mL. Because coronary perfusion pressure is a good predictor of outcome in cardiac arrest , the increase after high-dose epinephrine may improve rates of return of spontaneous circulation STUDY OBJECTIVE The benefit of epinephrine in cardiac arrest is controversial and has not been conclusively shown in any human clinical study . We seek to assess the effect of introducing intravenous epinephrine on the survival outcomes of out-of-hospital cardiac arrest patients in an emergency medical services ( EMS ) system that previously did not use intravenous medications . METHODS This observational , prospect i ve , before-after clinical study constitutes phase II of the Cardiac Arrest and Resuscitation Epidemiology project . Included were all patients who are older than 8 years , with nontraumatic out-of-hospital cardiac arrest conveyed by the national emergency ambulance service . The comparison between the 2 intervention groups for survival to discharge was made with logistic regression and expressed in terms of the odds ratio ( OR ) and the corresponding 95 % confidence interval ( CI ) . RESULTS From October 1 , 2002 , to October 14 , 2004 , 1,296 patients were enrolled into the study , with 615 in the pre-epinephrine and 681 in the epinephrine phase . Demographic and EMS characteristics were similar in both groups . Forty-four percent of patients received intravenous epinephrine in the epinephrine phase . There was no significant difference in survival to discharge ( pre-epinephrine 1.0 % ; epinephrine 1.6 % ; OR 1.7 [ 95 % CI 0.6 to 4.5 ] ; adjusted for rhythm OR 2.0 [ 95 % CI 0.7 to 5.5 ] ) ; return of circulation ( pre-epinephrine 17.9 % ; epinephrine 15.7 % ; OR 0.9 [ 95 % CI 0.6 to 1.2 ] ) , or survival to admission ( pre-epinephrine 7.5 % ; epinephrine 7.5 % ; OR 1.0 [ 95 % CI 0.7 to 1.5 ] ) . There was a minimal increase in scene time in the epinephrine phase ( 10.3 minutes versus 10.7 minutes ; 95 % CI of difference 0.02 to 0.94 minutes ) . CONCLUSION We were unable to establish a significant survival benefit with the introduction of intravenous epinephrine to an EMS system . More research is needed to determine the effectiveness of drugs such as epinephrine in resuscitation INTRODUCTION Early administration of epinephrine ( Epi ) improves outcomes in animal models of cardiac arrest , but there is limited time-dependent clinical data regarding its benefit . OBJECTIVE Our objective was to assess whether timing of Epi administration was associated with improved outcomes after out of hospital cardiac arrest ( OHCA ) . METHODS We performed a retrospective analysis of a cardiac arrest data base from a suburban EMS system from November 2005 to April 2011 . Data was abstract ed from EMS run sheets , including drug treatment , route and timing of drug administration , and other Utstein variables . Our primary outcome was return of spontaneous circulation ( ROSC ) . Secondary outcomes measured were survival to hospital admission and discharge . For analysis , data were dichotomized according to timing of Epi administration : early Epi group ( defined as 911 call to Epi administration of ≤10 min ) and late Epi group ( > 10 min ) . Further , exploratory analyses were conducted looking at subgroups sorted by initial rhythm and whether the arrest was witnessed . Wilcoxon rank sum tests , chi-square tests , 95 % confidence intervals , and multi-variable regression were used for statistical analysis . RESULTS We review ed 809 patients from study communities : 123 patients were excluded , leaving a sample size of 686 for study analysis . The mean time from 911-Epi was 14.3±5.5 min , with 155 ( 22.6 % ) receiving early Epi . Key arrest and treatment characteristics were similar between groups . Patients who received early Epi were more likely to have ROSC ( 32.9 % vs. 23.4 % , OR 1.59 ( 1.07 , 2.38 ) ) , however , no significant increase in survival to admission or discharge was observed . Patients with an initial rhythm of PEA had an increased rate of ROSC ( 48.6 % vs. 21.5 % , OR 3.45 ( 1.56 , 7.62 ) ) but not survival to discharge ( 5.9 % vs. 2.6 % ) , OR 2.35 ( 0.38 , 14.7 ) with early Epi . In a multivariable analysis of byst and er witnessed arrests , early Epi was associated with a higher rate of ROSC ( OR 3.20 ( 1.75 , 5.88 ) but not survival to discharge ( OR 1.48 ( 0.50 , 4.36 ) ) . No improvement in ROSC or secondary outcomes was noted in patients with other arrest rhythms or un-witnessed arrest with Early Epi . CONCLUSIONS Within the limitations of our study , this data suggests improved rates of ROSC with early Epi administration during OHCA resuscitation , but this study lacks adequate sample size to demonstrate impact on survival to discharge . Large prospect i ve trials are needed to further delineate the benefit of early Epi administration in OHCA Objectives : Both epinephrine and vasopressin increase aortic and carotid arterial pressure when administered during cardiopulmonary resuscitation . However , we recently demonstrated that epinephrine reduces cerebral cortical microcirculatory blood flow . Accordingly , we compared the effects of nonadrenergic vasopressin with those of epinephrine on cerebral cortical microvascular flow together with cortical tissue Po2 and Pco2 as indicators of cortical tissue ischemia . Design : R and omized , prospect i ve animal study . Setting : University-affiliated research laboratory . Subjects : Domestic pigs . Measurements and Main Results : The tracheae of ten domestic male pigs , weighing 40 ± 2 kg , were noninvasively intubated , and the animals were mechanically ventilated . A frontoparietal bilateral craniotomy was created . Microcirculatory blood flow was quantitated with orthogonal polarization spectral imaging . Blood flow velocity in pial and cortical penetrating vessels measuring < 20 μm was grade d from 0 ( no flow ) to 3 ( normal ) . Cerebral cortical tissue carbon dioxide and oxygen tensions ( Pbco2 and Pbo2 ) were measured concurrently using miniature optical sensors . Ventricular fibrillation , induced with an alternating current delivered to the right ventricular endocardium , was untreated for 3 mins . Animals were then r and omized to receive central venous injections of equipressor doses of epinephrine ( 30 μg/kg ) or vasopressin ( 0.4 units/kg ) at 1 min after the start of cardiopulmonary resuscitation . After 4 mins of cardiopulmonary resuscitation , defibrillation was attempted . Spontaneous circulation was restored in each animal . However , postresuscitation microvascular flows and Pbo2 were greater and Pbco2 less after vasopressin when compared with epinephrine . We observed that a significantly greater number of cortical microvessels were perfused after vasopressin . Conclusions : Cortical microcirculatory blood flow was markedly reduced after epinephrine , result ing in a greater severity of brain ischemia after the restoration of spontaneous circulation in contrast to the more benign effects of vasopressin Fewer than 8 % of adult out-of-hospital cardiac arrest ( OOH-CA ) victims survive to hospital discharge despite public education of event recognition , early notification of 9 - 1 - 1 , byst and er cardiopulmonary resuscitation , automated external defibrillator ( AED ) use , therapeutic hypothermia , and improvements in emergency medical service delivery.1 Densely populated urban areas such as New York , NY , and Chicago , Ill , where a large number of cardiac arrests occur , report even lower ( 1.4 % to 2 % ) survival rates.2,3 Unlike other areas of cardiovascular health such as myocardial infa rct ion , which has demonstrated a 3-fold decrease in acute mortality,4 the improvements in outcome from OOH-CA have remained modest over the last 25 years.5 Is this dismal survival and lack of progress a result of the biological lethality of the condition , or has inadequate research been done to define its pathogenesis , pathophysiology , and prevention and the optimal implementation of effective treatments ? OOH-CA is obviously a life-threatening condition , yet it is a “ treatable disease ” in the sense that medical interventions can improve survival significantly.6,–,8 Moreover , a nearly 500 % difference in survival rates exists across communities in the United States , suggesting that variability in the quality of resuscitation care is driving large differences in community survival rates.9 Collectively , these data suggest the potential for a major improvement in community survival rates that could save tens of thous and s of lives . So where is the problem ? Improving care and survival requires a commitment to sustained , high- quality , basic scientific and clinical research . Despite the devastating public health consequences of OOH-CA , the r and omized clinical trial ( RCT ) base from which evidence -based resuscitation guidelines are derived is limited compared with that used to derive evidence -based guidelines for other cardiovascular diseases . Table 1 lists the number of MEDLINE English language citations of resuscitation RCTs compared with ST-elevation myocardial infa rct ion ,

Adequacy and appropriateness of external support , functionality of quality improvement teams , leadership characteristics and alignment with national systems and priorities may influence outcomes of quality improvement collaboratives , but the strength and quality of the evidence is weak . Participation in quality improvement collaborative activities may improve health professionals ’ knowledge , problem-solving skills and attitude ; teamwork ; shared leadership and habits for improvement . Interaction across quality improvement teams may generate normative pressure and opportunities for capacity building and peer recognition .

Quality improvement collaboratives are widely used to improve health care in both high-income and low and middle-income setting s. Teams from multiple health facilities share learning on a given topic and apply a structured cycle of change testing . Previous systematic review s reported positive effects on target outcomes , but the role of context and mechanism of change is underexplored .

Background Multiorganisational quality improvement ( QI ) collaborative networks are promoted for improving quality within healthcare . Recently , several large-scale QI initiatives have been conducted in the intensive care unit ( ICU ) environment with successful quantitative results . However , the mechanisms through which such networks lead to QI success remain uncertain . We aim to underst and ICU staff perspectives on collaborative QI based on involvement in a multiorganisational improvement network and hypothesise about theoretical constructs that might explain the effect of collaboration in such networks . Methods Qualitative study using a modified grounded theory approach . Key informant interviews were conducted with staff from 12 community hospital ICUs that participated in a cluster r and omized control trial ( RCT ) of a QI intervention using a collaborative approach between 2006 and 2008 . Data analysis followed the st and ard procedure for grounded theory using constant comparative methodology . Results The collaborative network was perceived to promote increased intrateam cooperation over interorganisational cooperation , but friendly competition with other ICUs appeared to be a prominent driver of behaviour change . Bedsides , clinicians reported that belonging to a collaborative network provided recognition for the high- quality patient care that they already provided . However , the existing communication structure was perceived to be ineffective for staff engagement since it was based on a hierarchical approach to knowledge transfer and project awareness . Conclusions QI collaborative networks may promote behaviour change by improving intrateam communication , fostering competition with other institutions , and increasing recognition for providing high- quality care . Other commonly held assumptions about their potential impact , for instance , increasing interorganisational legitimisation , communication and collaboration , may be less important BACKGROUND The adherence to evidence -based treatment guidelines for acute myocardial infa rct ion ( AMI ) is still suboptimal . Therefore , we design ed a study to evaluate the effects of a collaborative quality improvement ( QI ) intervention on the adherence to AMI guidelines . The intervention used a national web-based quality registry to generate local and regular real-time performance feedback . METHODS A 12-month baseline measurement of the adherence rates was retrospectively collected , comprising the period July 1 , 2001 , through June 30 , 2002 . During the intervention period of November 1 , 2002 , through April 30 , 2003 , multidisciplinary teams from 19 nonr and omized intervention hospitals were subjected to a multifaceted QI-oriented intervention . Another 19 hospitals , unaware of their status as controls , were matched to the intervention hospitals . During the postintervention measurement period of May 1 , 2003 , through April 30 , 2004 , a total of 6726 consecutive patients were included at the intervention ( n = 3786 ) and control ( n = 2940 ) hospitals . The outcome measures comprised 5 Swedish national guideline -derived quality indicators , compared between baseline and postintervention levels in the control and QUICC intervention hospitals . RESULTS In the control and QI intervention hospitals , the mean absolute increase of patients receiving angiotensin-converting enzyme inhibitors was 1.4 % vs 12.6 % ( P = .002 ) , lipid-lowering therapy 2.3 % vs 7.2 % ( P = .065 ) , clopidogrel 26.3 % vs 41.2 % ( P = .010 ) , heparin/low-molecular weight heparin 5.3 % vs 16.3 % ( P = .010 ) , and coronary angiography 6.2 % vs 16.8 % ( P = .027 ) , respectively . The number of QI intervention hospitals reaching a treatment level of at least 70 % in 4 or 5 of the 5 indicators was 15 and 5 , respectively . In the control group , no hospital reached 70 % or more in just 4 of the 5 indicators . CONCLUSIONS By combining a systematic and multidisciplinary QI collaborative with a web-based national quality registry with functionality allowing real-time performance feedback , major improvements in the adherence to national AMI guidelines can be achieved Background Quality improvement collaboratives ( QIC ) have proliferated internationally , but there is little empirical evidence for their effectiveness . Method We search ed Medline , Embase , CINAHL , PsycINFO and the Cochrane Library data bases from January 1995 to December 2014 . Studies were included if they met the criteria for a QIC intervention and the Cochrane Effective Practice and Organisation of Care ( EPOC ) minimum study design characteristics for inclusion in a review . We assessed study bias using the EPOC checklist and the quality of the reported intervention using a subset of SQUIRE 1.0 st and ards . Results Of the 220 studies meeting QIC criteria , 64 met EPOC study design st and ards for inclusion . There were 10 cluster r and omised controlled trials , 24 controlled before-after studies and 30 interrupted time series studies . QICs encompassed a broad range of clinical setting s , topics and population s ranging from neonates to the elderly . Few reports fully described QIC implementation and methods , intensity of activities , degree of site engagement and important context ual factors . By care setting , an improvement was reported for one or more of the study ’s primary effect measures in 83 % of the studies ( 32/39 ( 82 % ) hospital based , 17/20 ( 85 % ) ambulatory care , 3/4 nursing home and a sole ambulance QIC ) . Eight studies described persistence of the intervention effect 6 months to 2 years after the end of the collaborative . Collaboratives reporting success generally addressed relatively straightforward aspects of care , had a strong evidence base and noted a clear evidence - practice gap in an accepted clinical pathway or guideline . Conclusions QICs have been adopted widely as an approach to shared learning and improvement in healthcare . Overall , the QICs included in this review reported significant improvements in targeted clinical processes and patient outcomes . These reports are encouraging , but most be interpreted cautiously since fewer than a third met established quality and reporting criteria , and publication bias is likely Background : Continuous Quality Improvement ( CQI ) is a process where health teams systematic ally collect and regularly reflect on local data to inform decisions and modify local practice s and so improve delivery of services . We implemented a cluster r and omized trial to examine the effects of CQI interventions on Prevention of Mother-to-Child Transmission ( PMTCT ) services . Here , we report our experiences and challenges establishing CQI in 2 high HIV prevalence states in northern Nigeria . Methods : Facility-based teams were trained to implement CQI activities , including structured assessment s , developing change packages , and participation in periodic collaborative learning sessions . Locally evolved solutions ( change ideas ) were tested and measured using process data and intermediate process indicators were agreed including overall time spent accessing services , client satisfaction , and quality of data . Results : Health workers actively participated in clinic activities and in the collaborative learning sessions . During the study , the mean difference in time spent accessing services during clinic visits increased by 40 minutes ( SD = 93.4 ) in the control arm and decreased by 44 minutes ( SD = 73.7 ) in the intervention arm . No significant difference was recorded in the mean client satisfaction assessment score by study arm . The quality of data was assessed using a st and ardized tool scored out of 100 ; compared with baseline data , quality at the end of study had improved at intervention sites by 6 points ( 95 % CI : 2.0 to 10.1 ) . Conclusions : Health workers were receptive to CQI process . A compendium of “ change ideas ” compiled into a single change package can be used to improve health care delivery Background Maternal , perinatal and neonatal mortality remains high in low-income countries . We evaluated community and facility-based interventions to reduce deaths in three districts of Malawi . Methods We evaluated a rural participatory women ’s group community intervention ( CI ) and a quality improvement intervention at health centres ( FI ) via a two-by-two factorial cluster r and omized controlled trial . Consenting pregnant women were followed-up to 2 months after birth using key informants . Primary outcomes were maternal , perinatal and neonatal mortality . Clusters were health centre catchment areas assigned using stratified computer-generated r and omization . Following exclusions , including non-birthing facilities , 61 clusters were analysed : control ( 17 clusters , 4912 births ) , FI ( 15 , 5335 ) , CI ( 15 , 5080 ) and FI + CI ( 14 , 5249 ) . This trial was registered as International St and ard R and omised Controlled Trial [ IS RCT N18073903 ] . Outcomes for 14 576 and 20 576 births were recorded during baseline ( June 2007–September 2008 ) and intervention ( October 2008–December 2010 ) periods . Results For control , FI , CI and FI + CI clusters neonatal mortality rates were 34.0 , 28.3 , 29.9 and 27.0 neonatal deaths per 1000 live births and perinatal mortality rates were 56.2 , 55.1 , 48.0 and 48.4 per 1000 births , during the intervention period . Adjusting for clustering and stratification , the neonatal mortality rate was 22 % lower in FI + CI than control clusters ( OR = 0.78 , 95 % CI 0.60–1.01 ) , and the perinatal mortality rate was 16 % lower in CI clusters ( OR = 0.84 , 95 % CI 0.72–0.97 ) . We did not observe any intervention effects on maternal mortality . Conclusions Despite implementation problems , a combined community and facility approach using participatory women ’s groups and quality improvement at health centres reduced newborn mortality in rural Malawi Background The Medical Research Councils ’ framework for complex interventions has been criticized for not including theory-driven approaches to evaluation . Although the framework does include broad guidance on the use of theory , it contains little practical guidance for implementers and there have been calls to develop a more comprehensive approach . A prospect i ve , theory-driven process of intervention design and evaluation is required to develop complex healthcare interventions which are more likely to be effective , sustainable and scalable . Methods We propose a theory-driven approach to the design and evaluation of complex interventions by adapting and integrating a programmatic design and evaluation tool , Theory of Change ( ToC ) , into the MRC framework for complex interventions . We provide a guide to what ToC is , how to construct one , and how to integrate its use into research projects seeking to design , implement and evaluate complex interventions using the MRC framework . We test this approach by using ToC within two r and omized controlled trials and one non-r and omized evaluation of complex interventions . Results Our application of ToC in three research projects has shown that ToC can strengthen key stages of the MRC framework . It can aid the development of interventions by providing a framework for enhanced stakeholder engagement and by explicitly design ing an intervention that is embedded in the local context . For the feasibility and piloting stage , ToC enables the systematic identification of knowledge gaps to generate research questions that strengthen intervention design . ToC may improve the evaluation of interventions by providing a comprehensive set of indicators to evaluate all stages of the causal pathway through which an intervention achieves impact , combining evaluations of intervention effectiveness with detailed process evaluations into one theoretical framework . Conclusions Incorporating a ToC approach into the MRC framework holds promise for improving the design and evaluation of complex interventions , thereby increasing the likelihood that the intervention will be ultimately effective , sustainable and scalable . We urge research ers developing and evaluating complex interventions to consider using this approach , to evaluate its usefulness and to build an evidence base to further refine the methodology .Trial registration Clinical trials.gov : Deficiencies in the quality and safety of health care remain a significant concern in the United States and abroad as evidence documenting gaps between actual and recommended clinical practice s continues to accumulate ( 1 , 2 ) . The significance of the well-recognized health care quality chasm has been acknowledged by a broad array of stakeholders , who have responded with efforts to identify , underst and , and correct specific shortcomings in health care delivery . The quality improvement collaborative ( QIC ) examined by L and on and colleagues in this issue ( 3 ) is arguably the health care delivery industry 's most important response to quality and safety gaps ; it represents substantial investments of time , effort , and funding . Largely developed and popularized by the Boston-based Institute for Healthcare Improvement ( IHI ) and best exemplified by IHI 's Breakthrough Series collaborative program , the QIC method has been adopted on a large scale by the U.S. Health Re sources and Services Administration ( HRSA ) ( 4 ) and the United Kingdom 's National Health Service ( NHS ) ( 5 ) . The Veterans Health Administration ( 6 ) and numerous smaller health care systems and individual hospitals and clinics worldwide have adopted the method on a smaller scale ( 7 ) . The QIC method brings together a group of participating ( collaborating ) health care delivery organizations ( typically between 20 and 40 ) and guides them in study ing a specific health care quality problem , design ing and implementing specific solutions , evaluating and refining these solutions , and disseminating findings to other organizations . Each participating organization is represented by a 3- or 4-person team ; all teams meet together with a small faculty of experts in a series of 2 or 3 multiday collaborative learning session meetings , which take place over several months . During the meetings , the team members learn improvement techniques , exchange insights and advice , and generate enthusiasm and a shared sense of commitment to achieving common improvement goals and outcomes . Teams return to their organizations between learning sessions to apply their new knowledge and ideas in a Pl anD o Study Act framework ( 8) . They conduct repeated cycles of quality problem diagnosis , development and implementation of small-scale improvement efforts , assessment of effects , and refinement and expansion of effective actions until desired outcomes are achieved . The QIC method is described in detail elsewhere ( 7 , 9 , 10 ) . Although estimates of total investment and applications of the QIC method are not available , IHI reports that Since 1995 , IHI has sponsored over 50 [ Breakthrough Collaborative ] projects on several dozen topics involving over 2,000 teams from 1,000 healthcare organizations ( 11 ) . The IHI tally includes a large series of collaboratives conducted under HRSA sponsorship but excludes NHS-sponsored collaboratives and numerous other collaborative efforts conducted without IHI 's direct involvement . The widespread acceptance and application of the QIC method are often question ed by observers citing the modest quantity and quality of published evidence that supports its effectiveness ( 12 , 13 ) . Although numerous reports of collaboratives have been published , they consist primarily of subjective or self-report assessment s of QIC effects and qualitative summaries of key lessons learned by collaborative leaders and participants . Such first-h and reports offer important insights into the black box of improvement methods and processes ( information generally absent from published evaluations of other quality improvement methods ) . However , they are incomplete without complementary , objective impact evaluations and are probably biased in favor of positive findings . This bias results from dem and and supply factors . Dem and -induced bias occurs because much of the published information is concentrated in management- and practitioner-oriented journals , such as The Joint Commission Journal on Quality and Safety and Quality Management in Health Care , whose mission and readership attract articles offering practical guidance and insights from only the successful quality improvement efforts . Supply-induced bias occurs when authors pursue quality improvement rather than research goals and document only successful collaboratives . Method ologic weaknesses in the individual studies exacerbate distortion in the published QIC evidence base caused by publication bias . Published assessment s of collaboratives generally use uncontrolled pretestpost-test design s that can not rule out plausible alternative explanations for observed improvements , such as secular trends . ( A detailed table listing published assessment s of collaboratives and describing key features of the evaluation design , methods , and measures in each published article is available from the author upon request . ) Although QIC authors routinely acknowledge design limitations and suggest cautious interpretation of positive findings ( 14 ) , such caution s are easily overlooked . Probable errors in measurement are also pervasive . They include outcome measures that rely on participants ' unvali date d self-reports or collaborative leaders ' subjective ratings of readily observed phenomena ( such as team enthusiasm , commitment , and adherence to the collaborative process ) rather than objective measures of clinical practice or outcome change . Participants ' self-reported outcome measures are typically derived from nonrigorous , highly variable measurement efforts , which often focus on short-term effects measured during or immediately following the intensive collaborative period . This results in the capture of positive effects that may be temporary and driven by Hawthorne effects rather than fundamental , lasting change . Furthermore , subjective ratings provided by collaborative participants and leaders are subject to unintentional and unrecognized biases generated by common human decision and judgment heuristics . For example , expectation biases and the phenomenon of belief perseverance combine to produce systematic overweighting of evidence and observations that confirm a priori expectations and beliefs and underweighting or discounting of evidence that does not support the effectiveness of the QIC method ( 15 ) . These phenomena reinforce faith and belief in the effectiveness of the QIC method , which contributes to further accumulation of published positive findings and an escalating cycle of belief and confirmatory evidence ( 12 , 16 ) . The apparent inconsistency between widespread belief in and use of the QIC method and the available supporting evidence heightens the importance of the study by L and on and colleagues . The authors reported on a large HRSA-sponsored collaborative that addresses the care of patients with HIV infection or AIDS . The HRSA has embraced the QIC method and has recently encouraged or m and ated the participation of grantee clinics in a series of QIC projects ( 4 ) . L and on and colleagues studied 44 HRSA-contracted clinics participating in the collaborative ( some on a voluntary basis and some to meet contract requirements ) and 25 comparison clinics . Although clinics were not r and omly assigned , the authors selected comparison clinics through a careful matching process , which provided a basis for ruling out secular trends and other possible explanations of the positive effects often observed in uncontrolled pretestpost-test evaluations of collaboratives . Outcome measures were defined consistently across all sites , and comparable measures were obtained through chart review for representative patient sample s from all sites . Although medical record review ers were selected from the participating sites and the authors provide no information about chart review er training ( or about reliability , validity checks , or other efforts to minimize measurement error ) , the level of rigor in the study by L and on and colleagues exceeds that of earlier evaluations of collaboratives . Any remaining bias seems more likely to produce false-positive rather than false-negative findings . L and on and colleagues ' study demonstrates small and generally insignificant prepost improvements among both intervention and control sites in most of the 8 quality indicators measured . For the 2 indicators showing the greatest improvement ( 11 % and 7.3 % ) among intervention clinics , comparable improvements were seen among control clinics as well . The small differences between the intervention and control clinics did not reach statistical significance and therefore did not preclude the attribution of observed improvement to secular trends . Several supplementary analyses compared subgroups of clinics ( for example , newly funded vs. more established HRSA-funded clinics and clinics with low quality -of-care indicator scores at baseline vs. those with higher baseline scores ) and subgroups of patients ( for example , patients already receiving highly active antiretroviral therapy ) . The authors consider and rule out numerous potential explanations for their null findings , including the possibility that control clinics conducted their own improvement initiatives . They summarize many of the key design shortcomings in the existing evidence base and note that their own study would have reported ( and attributed to the intervention ) statistically significant improvements in 2 key measures in the absence of comparison group data . L and on and colleagues thoroughly discuss the limitations of their study but note that most seem unlikely to have produced their null results . Unfortunately , the data collected do not provide the information needed to underst and and explain their findings . For example , the intervention sites may not have correctly diagnosed and understood the causes of targeted quality problems and may not have developed or fully implemented appropriate corrective actions . In addition , corrections may not have been sufficient to overcome the full spectrum of barriers to improvement . Thus , although the study by L and on and ABSTRACT Background : The collaborative quality improvement approach proposed by the Institute for Healthcare Improvement has the potential to improve coverage of evidence -based maternal and newborn health practice s. The Safe Care , Saving Lives initiative supported the implementation of 20 evidence -based maternal and newborn care practice s , targeting labour wards and neonatal care units in 85 public and private hospitals in Telangana and And hra Pradesh , India . Objective : We present a protocol for the evaluation of this programme which aims to ( a ) estimate the effect of the initiative on evidence -based care practice s and mortality ; ( b ) evaluate the mechanisms leading to changes in adherence to evidence -based practice s , and their relationship with context ual factors ; ( c ) explore the feasibility of scaling-up the approach . Methods : The mixed- method evaluation is based on a plausibility design nested within a phased implementation . The 29 non-r and omly selected hospitals comprising wave II of the programme were compared to the 31 remaining hospitals where the quality improvement approach started later . We assessed mortality and adherence to evidence -based practice s at baseline and endline using abstract ion of registers , checklists , observations and interviews in intervention and comparison hospitals . We also explored the mechanisms and drivers of change in adherence to evidence -based practice s. Qualitative methods investigated the mechanisms of change in purpose fully selected case study hospitals . A readiness assessment complemented the analysis of what works and why . We used a difference-in-difference approach to estimate the effects of the intervention on mortality and coverage . Thematic analysis was used for the qualitative data . Discussion : This is the first quality improvement collaborative targeting neonatal health in secondary and tertiary hospitals in a middle-income country linked to a government health insurance scheme . Our process evaluation is theory driven and will refine hypotheses about how this quality improvement approach contributes to institutionalization of evidence -based practice BACKGROUND Emergency abdominal surgery is associated with poor patient outcomes . We studied the effectiveness of a national quality improvement ( QI ) programme to implement a care pathway to improve survival for these patients . METHODS We did a stepped-wedge cluster-r and omised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery . Eligible UK National Health Service ( NHS ) hospitals ( those that had an emergency general surgical service , a substantial volume of emergency abdominal surgery cases , and contributed data to the National Emergency Laparotomy Audit ) were organised into 15 geographical clusters and commenced the QI programme in a r and om order , based on a computer-generated r and om sequence , over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period . Patients were masked to the study group , but it was not possible to mask hospital staff or investigators . The primary outcome measure was mortality within 90 days of surgery . Analyses were done on an intention-to-treat basis . This study is registered with the IS RCT N registry , number IS RCT N80682973 . FINDINGS Treatment took place between March 3 , 2014 , and Oct 19 , 2015 . 22 754 patients were assessed for elegibility . Of 15 873 eligible patients from 93 NHS hospitals , primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group . Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data . The primary outcome of 90-day mortality occurred in 1210 ( 16 % ) patients in the QI group compared with 1393 ( 16 % ) patients in the usual care group ( HR 1·11 , 0·96 - 1·28 ) . INTERPRETATION No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery . Future QI programmes should ensure that teams have both the time and re sources needed to improve patient care . FUNDING National Institute for Health Research Health Services and Delivery Research Programme

Our cumulative , cross-sectional data suggest a similar virological efficacy of abacavir/lamivudine and tenofovir/emtricitabine regardless of the baseline VL

OBJECTIVES The efficacy of abacavir/lamivudine has been reported to be inferior to tenofovir/emtricitabine . Several r and omized clinical trials ( RCTs ) investigated the effectiveness and safety of abacavir/lamivudine and tenofovir/emtricitabine combined antiretroviral treatment ( cART ) and we have review ed the available evidence .

CONTEXT Abacavir , a nucleoside analogue , has demonstrated suppression of human immunodeficiency virus ( HIV ) replication alone and in combination therapy . However , the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a st and ard protease inhibitor-containing regimen for initial antiretroviral treatment . OBJECTIVE To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen . DESIGN AND SETTING A multicenter , phase 3 , r and omized , double-blind trial with an enrollment period from August 1997 to June 1998 , with follow-up through 48 weeks at 73 clinical research units in the United States , Canada , Australia , and Europe . PATIENTS Five hundred sixty-two antiretroviral-naive , HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L. INTERVENTIONS Patients were stratified by baseline HIV RNA level and r and omly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo . After 16 weeks , patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving r and omized treatment or receive open-label therapy . MAIN OUTCOME MEASURE Virologic suppression , defined as HIV RNA concentration of 400 copies/mL or less at week 48 . RESULTS The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group ( 51 % [ 133/262 ] ) and in the indinavir group ( 51 % [ 136/265 ] ) with a treatment difference of -0.6 % ( 95 % confidence interval [ CI ] , -9 % to 8 % ) . In patients with baseline HIV RNA levels greater than 100 000 copies/mL , the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45 % ( 45/100 ) vs 31 % ( 30/96 ) and a treatment diference of -14 % ( 95 % CI , -27 % to 0 % ) . The 2 treatments were comparable with respect to their effects on CD4 cell count . There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities . One death in the abacavir group was attributed to hypersensitivity reaction , which occurred following rechallenge with abacavir , approximately 3 weeks after initiating study treatment . CONCLUSIONS In this study of antiretroviral-naive HIV-infected adults , the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks Patients with sustained virological suppression on protease inhibitor (PI)-based therapy were r and omly assigned to switch the PI to nevirapine ( n = 155 ) , efavirenz ( n = 156 ) , or abacavir ( n = 149 ) and were followed for at least 3 years regardless of the discontinuation of assigned therapy . There was a higher probability of maintaining virological suppression after 3 years of follow-up with nevirapine or efavirenz than with abacavir . In contrast , abacavir showed a lower incidence of adverse effects leading to drug discontinuation BACKGROUND Evidence from r and omized controlled trials supports the use of triple therapy . Research is required on the effectiveness of quadruple therapy in comparison to this and the relative effectiveness of specific highly active antiretroviral therapy ( HAART ) combinations . METHODS Antiretroviral-naive individuals ( n = 53 ) with an HIV-1 viral load > 100 000 copies/mL were r and omized to receive three-drug HAART with zidovudine/lamivudine ( Combivir ) and efavirenz or quadruple therapy with zidovudine/lamivudine/abacavir ( Trizivir ) and efavirenz ( quad regimen ) . Patients continued on HAART for 48 weeks with regular clinical and immunological assessment . St and ard and ultrasensitive ( < 5 copies/mL ) viral load testing was carried out . RESULTS A DAVG ( difference in averages ) analysis of the fall in viral load and increase in CD4 count showed no significant differences between regimens . Triple therapy result ed in a -4.17 log change ( 95 % CI , -4.48 to -3.85 ) and quadruple therapy in a -4.36 log change ( 95 % CI , -4.68 to -4.03 ) in viral load . For CD4 counts , the triple therapy arm increased by 164 cells/mm(3 ) ( 95 % CI 112 - 217 ) and the quadruple arm by 185 ( 95 % CI , 133 - 237 ) . In an intent-to-treat analysis , 77 % of patients in the triple therapy group reached an undetectable viral load ( < 50 copies/mL ) compared with 84.2 % of the quadruple therapy group . For ultrasensitive viral load testing , 23 % and 18 % of each group , respectively , reached undetectable viral loads . The hazard ratio for attaining a viral load of < 5 copies/mL was 0.59 ( 95 % CI , 0.26 - 1.33 ) for quadruple versus triple therapy . Three individuals in the triple therapy arm and nine in the quadruple therapy arm discontinued treatment . CONCLUSIONS No differences in any analyses were observed between a st and ard of care regimen ( zidovudine/lamivudine and efavirenz ) and the quad regimen ( zidovudine/lamivudine/abacavir and efavirenz ) BACKGROUND The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors ( NRTIs ) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 ( HIV-1 ) infection , but which NRTI combination has greater efficacy and safety is not known . METHODS In a r and omized , blinded equivalence study involving 1858 eligible patients , we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection : abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir . The primary efficacy end point was the time from r and omization to virologic failure ( defined as a confirmed HIV-1 RNA level > or = 1000 copies per milliliter at or after 16 weeks and before 24 weeks , or > or = 200 copies per milliliter at or after 24 weeks ) . RESULTS A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy , according to the NRTI combination , among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more . At a median follow-up of 60 weeks , among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more , the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group ( hazard ratio , 2.33 ; 95 % confidence interval , 1.46 to 3.72 ; P<0.001 ) , with 57 virologic failures ( 14 % ) in the abacavir-lamivudine group versus 26 ( 7 % ) in the tenofovir DF-emtricitabine group . The time to the first adverse event was also shorter in the abacavir-lamivudine group ( P<0.001 ) . There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48 . CONCLUSIONS In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more , the times to virologic failure and the first adverse event were both significantly shorter in patients r and omly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine . ( Clinical Trials.gov number , NCT00118898 . OBJECTIVE To compare the efficacy and safety of fixed-dose abacavir/lamivudine ( ABC/3TC ) and tenofovir/emtricitabine ( TDF/FTC ) with ritonavir-boosted atazanavir ( ATV/r ) in treatment-naïve Japanese patients with HIV-1 infection . METHODS A 96-week multicenter , r and omized , open-label , parallel group pilot study was conducted . The endpoints were times to virologic failure , safety event and regimen modification . RESULTS 109 patients were enrolled and r and omly allocated ( 54 patients received ABC/3TC and 55 patients received TDF/FTC ) . All r and omized subjects were analyzed . The time to virologic failure was not significantly different between the two arms by 96 weeks ( HR , 2.09 ; 95 % CI , 0.72 - 6.13 ; p=0.178 ) . Both regimens showed favorable viral efficacy , as in the intention-to-treat population , 72.2 % ( ABC/3TC ) and 78.2 % ( TDF/FTC ) of the patients had an HIV-1 viral load < 50 copies/mL at 96 weeks . The time to the first grade 3 or 4 adverse event and the time to the first regimen modification were not significantly different between the two arms ( adverse event : HR 0.66 ; 95 % CI , 0.25 - 1.75 , p=0.407 ) ( regimen modification : HR 1.03 ; 95 % CI , 0.33 - 3.19 , p=0.964 ) . Both regimens were also well-tolerated , as only 11.1 % ( ABC/3TC ) and 10.9 % ( TDF/FTC ) of the patients discontinued the allocated regimen by 96 weeks . Clinical ly suspected abacavir-associated hypersensitivity reactions occurred in only one ( 1.9 % ) patient in the ABC/3TC arm . CONCLUSION Although insufficiently powered to show non-inferiority of viral efficacy of ABC/3TC relative to TDF/FTC , this pilot trial suggested that ABC/3TC with ATV/r is a safe and efficacious initial regimen for HLA-B*5701-negative patients , such as the Japanese population Background : Long-term antiretroviral therapy , while dramatically reducing HIV-related morbidity and mortality , is associated with metabolic and morphological changes . Peripheral fat loss , lipoatrophy , appears most associated with prolonged therapy with thymidine nucleoside analogues . Methods : A r and omized , open-label , comparative study of switching from a thymidine nucleoside analogue to either tenofovir disoproxil fumarate ( DF ) or abacavir in 105 individuals on successful antiretroviral therapy with clinical ly evident moderate to severe lipoatrophy . Results : Individuals were r and omized to tenofovir DF ( 52 ) or abacavir ( 53 ) . The switch was well tolerated and the majority of patients completed 48 weeks of study . One individual in the tenofovir DF group and three in the abacavir group discontinued due to drug-related adverse events . Both groups similarly maintained virological control . Limb fat mass increased similarly in both groups : mean increases by week 48 of 329 and 483 g in tenofovir DF and abacavir groups , respectively [ mean 95 % confidence interval for difference , −154.3 ( range −492.8 to 184.3 ) ] . This change from baseline was statistically significant in both groups ( tenofovir DF , P = 0.01 ; abacavir , P = 0.0001 ) . Mean total cholesterol , low density lipoprotein cholesterol and triglycerides improved modestly with switching to tenofovir DF but were unchanged with abacavir . The changes in these parameters were significantly greater in the tenofovir DF arm relative to abacavir . Conclusions : Switching from a thymidine nucleoside analogue to either tenofovir DF or abacavir leads to significant improvement in limb fat mass over 48 weeks . Tenofovir DF may have modest advantages over abacavir for changes in lipids . Peripheral lipoatrophy , when clinical ly apparent , resolves slowly following treatment switching Background Hyperlipidemia secondary to protease inhibitors ( PI ) may abate by switching to anti-HIV medications without lipid effects . Method An open-label , r and omized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia ( fasting serum total cholesterol > 200 mg/dL ) who were r and omized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily ( n = 52 ) or a regimen in which their PI was continued ( n = 52 ) for 28 weeks . All patients had undetectable viral loads ( HIV-1 RNA < 50 copies/mL ) at baseline and were naïve to abacavir and non-nucleoside reverse transcriptase inhibitors . Results At baseline , the mean total cholesterol was 243 mg/dL , low density lipoprotein (LDL)-cholesterol 149 mg/dL , high density lipoprotein (HDL)-cholesterol 41 mg/dL , and triglycerides 310 mg/dL. Mean CD4 + cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms , respectively . At week 28 , the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol ( -42 vs -10 mg/dL , P < 0.001 ) , LDL-cholesterol ( -14 vs + 5 mg/dL , P = 0.016 ) , and triglycerides ( -134 vs -36 mg/dL , P = 0.019 ) than the PI-continuation arm , with no differences in HDL-cholesterol ( + 0.2 vs + 1.3 mg/dL , P = 0.583 ) . A higher proportion of patients in the abacavir-switch arm had decreases in protocol -defined total cholesterol and triglyceride toxicity grade s , whereas a smaller proportion had increases in these toxicity grade s. At week 28 , an intent-to treat : missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA < 400 or < 50 copies/mL or adjusted mean change from baseline in CD4 + cell count . Two possible abacavir-related hypersensitivity reactions were reported . No significant changes in glucose , insulin , insulin resistance , C-peptide , or waist-to-hip ratios were observed in either treatment arm , nor were differences in these parameters noted between treatments . Conclusion In hyperlipidemic , antiretroviral-experienced patients with HIV-1 RNA levels < 50 copies/mL and CD4 + cell counts > 500 cells/mm3 , substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period , and it simplifies treatment Objective : To assess the effects of initiating abacavir-containing therapy on plasma lipids and cardiovascular biomarkers . Design : Sub- study of the BICOMBO study in which participants were r and omized to switch their nucleoside backbone to either abacavir/lamivudine or tenofovir/emtricitabine . Methods : We assessed 48-week changes in fasting lipids and several biomarkers including serum high-sensitivity C-reactive protein ( hsCRP ) , monocyte chemoattractant protein-1 ( MCP-1 ) , osteoprotegerin , interleukin (IL)-6 , IL-10 , tumor necrosis factor alpha ( TNF-alpha ) , intercellular adhesion molecule-1 ( ICAM-1 ) , vascular adhesion molecule-1 ( VCAM-1 ) , selectin E and P , adiponectin , insulin , and D-dimer in otherwise healthy , virologically suppressed HIV-infected patients r and omly switched to abacavir/lamivudine or tenofovir/emtricitabine with no history of cardiovascular disease , no prior abacavir or tenofovir use , and no virological failure or AIDS during follow-up . Results : Eighty ( 46 abacavir/lamivudine and 34 tenofovir/emtricitabine ) patients were included . Baseline characteristics were similar between groups and between patients in the sub- study vs. those not . There were no significant differences in baseline lipids and markers between groups . Although total ( 6.5 vs. −6.7 % , P < 0.0001 ) and low-density lipoprotein ( LDL ) ( 8.6 vs. −9.1 % , P = 0.004 ) cholesterol increased significantly in the abacavir/lamivudine group relative to the tenofovir/emtricitabine group , we found no significant changes in the biomarkers : CRP ( −3.9 vs. 0.0 % ) , MCP-1 ( 5.9 vs. 4.0 % ) , osteoprotegerin ( 5.1 vs. −2.8 % ) , IL−6 ( 0.0 vs. 0.0 % ) , IL-10 ( 0.0 vs. 0.0 % ) , TNF-alpha ( 0.0 vs. 0.0 % ) , ICAM-1 ( 6.6 vs. 5.2 % ) , VCAM-1 ( 0.02 vs. −0.01 % ) , selectin E ( −0.4 vs. 7.8 % ) , selectin P ( 4.6 vs. 12.6 % ) , insulin ( −2.5 vs. 8.8 % ) , adiponectin ( −2.2 vs. 15.4 % ) , and D-dimer ( 0.0 vs. 0.0 % ) ( P ≥ 0.12 for all comparisons ) . Conclusion : Abacavir/lamivudine increased total and LDL cholesterol compared with tenofovir/emtricitabine , but it did not cause inflammation , endothelial dysfunction , insulin resistance , or hypercoagulability in virologically suppressed HIV-infected patients BACKGROUND There are 2 once-daily , fixed-dose-combination , dual-nucleoside analogue tablets : tenofovir 300 mg-emtricitabine 200 mg ( TDF-FTC ) and abacavir 600 mg-lamivudine 300 mg ( ABC-3TC ) . Which fixed-dose-combination tablet is more effective and safe is uncertain . METHODS We compared TDF-FTC and ABC-3TC in a r and omized , open-label , 96-week trial in which either fixed-dose-combination was substituted for current nucleoside treatments in human leukocyte antigen-B*5701-negative adults with human immunodeficiency virus loads < 50 copies/mL. The primary end point was virological failure ( consecutive viral load measurements > 400 copies/mL , by intention-to-treat ) . Secondary end points included death , AIDS , adverse events , serious non-AIDS events , metabolic parameters , and body composition . We used exact statistics for differences in proportions , T tests to compare means , and Cox regression for hazard ratios . RESULTS Of 441 patients who were screened , 357 were treated ; 98 % were men , the mean age was 45 years , 30 % were receiving TDF , 20 % were receiving ABC , and 24 % were receiving a protease inhibitor . Virological failure was uncommon ( 5.6 % for ABC-3TC and 3.9 % for TDF-FTC ; difference , 1.7 % ; 95 % confidence interval [ CI ] , -2.8 % to 6.1 % ; P = .62 ) . No participant developed AIDS , whereas 18 ( 5 % ) participants developed a serious non-AIDS event ( rate , 2.79 events per 100 person-years ; 95 % CI , 1.76 - 4.43 ) , of which 4 were fatal . TDF-FTC was associated with significantly fewer serious non-AIDS events than ABC-3TC ( 1.2 vs 4.8 events per 100 patient-years ; hazard ratio [ HR ] , 0.24 ; 95 % CI , 0.08 - 0.73 ; P = .012 ) , influenced mostly by a lower rate of cardiovascular events ( 0.3 vs 2.2 events per 100 patient-years ; HR , 0.12 ; 95 % CI , 0.02 - 0.98 ; P = .048 ) . TDF-FTC result ed in significantly lower bone mineral density ( mean difference in hip t score , 0.16 ; 95 % CI , 0.08 - 0.23 ; P < .001 ) but not in more fractures . CONCLUSIONS In this population , TDF-FTC and ABC-3TC had similar virological efficacy , but ABC-3TC was associated with more serious non-AIDS events , particularly cardiovascular events . Clinical trials registration . NCT00192634 BACKGROUND Observational and retrospective clinical trial cohorts have reported conflicting results for the association of abacavir use with risk of myocardial infa rct ion ( MI ) , possibly related to issues that may bias estimation of treatment effects , such as time-varying confounders , informative dropout , and cohort loss due to competing events . METHODS We analyzed data from 5056 individuals initiating r and omized antiretroviral treatment ( ART ) in AIDS Clinical Trials Group studies ; 1704 started abacavir therapy . An intent-to-treat analysis adjusted for pretreatment covariates and weighting for informative censoring was used to estimate the hazard ratio ( HR ) of MIs after initiation of a regimen with or without abacavir . RESULTS Through 6 years after ART initiation , 36 MI events were observed in 17,404 person-years of follow-up . No evidence of an increased hazard of MI in subjects using abacavir versus no abacavir was seen ( over a 1-year period : P=.50 ; HR , 0.7 [ 95 % confidence interval { CI } , 0.2 - 2.4 ] ) ; over a 6-year period : P=.24 ; HR , 0.6 [ 95 % CI , 0.3 - 1.4 ] ) ; these results were robust over as-treated and sensitivity analyses . Although the risk of MI decreased over time , there was no evidence to suggest a time-dependent abacavir effect . Classic cardiovascular disease ( CVD ) risk factors were the strongest predictors of MI . CONCLUSION We find no evidence to suggest that initial ART containing abacavir increases MI risk over short-term and long-term periods in this population with relatively low MI risk . Traditional CVD risk factors should be the main focus in assessing CVD risk in individuals with human immunodeficiency virus infection BACKGROUND Abacavir/lamivudine ( ABC/3TC ) and tenofovir disoproxil fumarate/emtricitabine ( TDF/FTC ) are widely used as first-line antiretroviral therapies . However , there are limited data comparing the safety of these therapies with long-term use . The objective of this study was to assess the long-term safety of these commonly used first-line nucleoside/nucleotide combinations each administered with efavirenz ( EFV ) . METHODS This open-label , 96-week , r and omized study compared the safety ( renal , bone and metabolic ) and efficacy of ABC/3TC and TDF/FTC plus EFV in HLA-B*5701-negative antiretroviral-naive adults . RESULTS A total of 385 subjects were enrolled , and 249 ( 65 % ) subjects completed the study . The difference in changes from baseline in estimated glomerular filtration rate ( calculated by the Modified Diet in Renal Disease equation ) between treatment arms was not significant . There was a significant difference between the arms ( P < 0.0001 ) for markers of tubular dysfunction ( retinol-binding protein and ß-2 microglobulin ) favouring ABC/3TC . Hip bone mineral density decreased from baseline in both arms , with a significantly greater decline with TDF/FTC ( ABC/3TC -2.2 % and TDF/FTC -3.5 % ; P < 0.001 at week 96 ) . Subjects in the ABC/3TC arm had greater increases from baseline in median total cholesterol , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol and triglycerides . Adverse events were similar between arms . The virological failure rate was low in both arms . CONCLUSIONS ABC/3TC and TDF/FTC in combination with EFV minimally affected estimated glomerular filtration rate over 96 weeks . TDF/FTC was associated with greater increases in tubular dysfunction and bone turnover marker levels , greater decreases in hip bone mineral density , and smaller increases in serum lipid levels Background Traditional first line regimens containing a non-nucleoside reverse transcriptase inhibitor or protease inhibitor may not be suitable for a subset of antiretroviral-naïve patients such as those with certain co-morbidities , women of child-bearing potential , and intolerability to components of st and ard first line therapy . This study was conducted to determine if alternate treatment options may meet the needs of both general and special patient population s. The ACTION study was a r and omized , open-label , multicenter , 48-week trial that compared the safety and efficacy of a triple nucleoside regimen versus a protease inhibitor plus a dual nucleoside regimen in HIV-1 treatment-naïve subjects . Results 279 HIV-infected subjects with HIV-1 RNA ( VL ) > 5000 but < 200,000 copies/mL ( c/mL ) and CD4 + count ≥ 100 cells/mm3 were r and omized ( 1:1 ) to receive abacavir sulfate/lamivudine/zidovudine ( ABC/3TC/ZDV ) twice-daily or atazanavir ( ATV ) once-daily plus lamivudine/zidovudine ( 3TC/ZDV ) twice-daily . Protocol -defined virologic failure was based on multiple failure criteria .Non-inferiority of ABC/3TC/ZDV to ATV+3TC/ZDV was established with 62 % vs. 59 % of subjects achieving a VL < 50 c/mL at week 48 , [ ITT(E ) , M/S = F , 95 % CI : -5.9 , 10.4 ] . Similar results were observed in the 230 ( 82 % ) subjects with baseline VL<100,000 c/mL ( ABC/3TC/ZDV vs. ATV+3TC/ZDV ) , 66 % vs. 59 % ; 95 % CI : -5.6 , 19.5 . However , ABC/3TC/ZDV did not meet the non-inferiority criterion compared to ATV+3TC/ZDV in the 48 subjects with baseline VL ≥ 100,000 c/mL , 39 % vs. 60 % ; 95 % CI : -49.2 , 7.4 , respectively . Protocol -defined virologic failure was similar between groups . Conclusion ABC/3TC/ZDV demonstrated comparable virologic efficacy to ATV+3TC/ZDV in this population over 48 weeks . In those with a baseline VL ≥ 100,000 c/mL , subjects in the ATV+3TC/ZDV showed better virologic efficacy . Both regimens offer benefits in select therapy-naïve subjects . Trial Registration [ Clinical Trials Identifier , NCT00082394 ] This r and omized study evaluated the efficacy and tolerability of continued treatment with protease inhibitor plus nucleoside-analogue combination regimens ( n=79 ) or a change to the simplified regimen of abacavir-lamivudine-zidovudine ( n=84 ) in patients with suppressed human immunodeficiency virus type 1 ( HIV-1 ) RNA for > or = 6 months who did not have the reverse transcriptase 215 mutation . After a median follow-up of 84 weeks , virologic failure was 6 % in the continuation and 15 % in the simplified group ( P=.081 ) . Previous zidovudine monotherapy or dual therapy and archived reverse transcriptase resistance mutations in HIV-1 DNA at baseline were significant predictors of failure . Study treatment was discontinued because of adverse events in 20 % of the continuation and 7 % of the simplified group ( P=.021 ) . Simplification to abacavir-lamivudine-zidovudine significantly decreased nonfasting cholesterol and triglyceride levels ; however , this switch strategy carries a risk of virologic failure when treatment history or resistance testing suggest the presence of archived resistance mutations to the simplified regimen BACKGROUND AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine ( ABC/3TC ) to tenofovir DF/emtricitabine ( TDF/FTC ) with efavirenz ( EFV ) or atazanavir/ritonavir ( ATV/r ) in human immunodeficiency virus (HIV)-infected treatment-naive patients , stratified by screening HIV RNA ( < or ≥ 10(5 ) copies/mL ) . Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum , blinded treatment was stopped in this group , but study follow-up continued for all patients . METHODS Primary endpoints were times to virologic failure , regimen modification , and safety event . RESULTS In the low HIV RNA stratum , time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r ( hazard ratio [ HR ] 1.25 , 95 % confidence interval [ CI ] 0.76 , 2.05 ) or EFV ( HR 1.23 , 95 % CI 0.77 , 1.96 ) , with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV . Prior to stopping blinded treatment in the high stratum , higher virologic failure rates were seen with ABC/3TC with EFV ( HR 2.46 , 95 % CI 1.20 , 5.05 ) or ATV/r ( HR 2.22 , 95 % CI 1.19 , 4.14 ) . CONCLUSIONS In the low HIV RNA stratum , times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r . In the high stratum , virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r OBJECTIVE To compare the efficacy and safety of a triple nucleoside combination to a protease inhibitor-containing triple regimen as first-line antiretroviral therapy ( ART ) in HIV-1-infected patients . DESIGN Open-label study in HIV-1-infected ART-naive adults , r and omized to receive either Combivir ( lamivudine 150 mg/zidovudine 300 mg twice daily ) + abacavir ( 300 mg twice daily ) , or Combivir + nelfinavir ( 750 mg every 8 h ) for 48 weeks . Plasma HIV-1 RNA , CD4 cell count and adverse events were assessed at baseline and weeks 4 , 8 , 16 , 24 , 32 , 40 and 48 . RESULTS 195 subjects ( 131 men , 64 women ) , median age 34 years , were r and omized : 98 received combivir/abacavir and 97 combivir/nelfinavir . Baseline median plasma HIV-1 RNA was 4.2 log10 copies/ml [ Interquartile range ( IQR ) : 3.7 - 4.5.2 ] and 4.1 log10 copies/ml ( IQR : 3.8 - 4.6 ) , respectively . Baseline median CD4 cell count was 387 cells/mm3 ( IQR : 194 - 501 ) and 449 cells/mm3 ( IQR : 334 - 605 ) , respectively . Nine patients ( 3 vs 6 , respectively ) did not start treatment or did not have any available efficacy data . At week 48 , using the intent to treat analysis ( switch/missing equals failure ) , plasma HIV-1 RNA was < 50 copies/ml in 54/95 ( 57 % ) and 53/91 ( 58 % ) of subjects , respectively . Median CD4 increase was + 110 and + 120 cells/mm3 , respectively . Possible hypersensitivity reactions to abacavir were reported in four subjects ( 4 % ) . CONCLUSION The triple nucleoside combination combivir/abacavir is well tolerated as a first-line ART regimen in HIV-1-infected adults , with comparable antiviral activity to a nelfinavir-containing regimen at week 48 In a prospect i ve , open-label , 104-week study , patients who were infected with human immunodeficiency virus type 1 ( virus load , < 50 copies/mL ) and who were receiving protease inhibitor-based therapy were r and omly assigned to continue treatment with a protease inhibitor or to replace it with abacavir or efavirenz . Treatment failure , defined as virological failure ( virus load , > 500 copies/microL ) or any clinical or biochemical adverse event with a grade of > or=3 ( on the basis of the World Health Organization [ WHO ] or American Heart Association [ AHA ] scales ) , was the primary outcome measurement . Failure rates were more frequent in the group treated with protease inhibitors ( P<.01 ) , and there were no significant differences in the rate of treatment failure between the group treated with efavirenz and the group treated with abacavir . Tolerability was better in the groups treated with abacavir or with efavirenz versus those treated with protease inhibitors . Fewer patients who received efavirenz experienced viral rebound . Among all groups , the mean increase in the CD4 cell count was 131 cells/microL ( P<.001 ) , with no significant difference between groups . This switching strategy maintains optimal levels of virological suppression and may improve lipid profiles in most patients Objective To assess the antiviral efficacy , safety and adherence in patients switched to an abacavir-containing nucleoside reverse transcriptase inhibitor ( NRTI ) regimen after long-term HIV-1 RNA suppression with a dual NRTI/protease inhibitor ( PI ) combination . Methods In an open-label , multicentre study , patients receiving 2NRTI plus PI for at least 6 months , with a history of undetectable plasma HIV-1 RNA since the initiation of therapy and plasma HIV-1 RNA < 50 copies/ml at screening , were r and omly assigned to replace the PI with abacavir ( n = 105 ) or continue the same treatment ( n = 106 ) . Clinical assessment s included plasma HIV-1 RNA , chemistry , haematology , lymphocyte counts , and adverse event reports . Adherence to treatment was assessed by patient self-report . Results A significantly longer time to treatment failure was demonstrated in the abacavir arm compared with the PI arm ( P = 0.03 ) while treatment failure was experienced by significantly more patients in the PI arm : 24 ( 23 % ) versus 12 ( 12 % ) ( P = 0.03 ) . Therapy-limiting toxicity led to treatment failure in eight versus 14 cases in the abacavir and PI arms , respectively , whereas virological rebound was the cause in four versus two cases . Significant reductions in cholesterol and non-fasting triglyceride plasma levels at 48 weeks were observed in the abacavir arm ( P < 0.001 and P = 0.035 , respectively ) . The number of patients reporting no difficulty in taking their therapy showed a marked increase from baseline in the abacavir arm . Conclusion The replacement of PI by abacavir in a triple combination regimen following prolonged suppression of plasma HIV-1 RNA provides continued virological suppression , significant improvements in lipid abnormalities and enhanced ease of dosing Background : Recently , the Data collection of Adverse events of Anti-HIV Drugs Group ( D : A : D ) described results from their international observational cohort of 33,347 HIV-1-infected individuals , suggesting unexpected increased risk of myocardial infa rct ion ( MI ) associated with abacavir ( ABC ) therapy [ relative rate 1.9 , 95 % confidence interval ( CI ) : 1.47 to 2.45 ; P = 0.0001 ] . To contribute to the scientific question , we summarized GlaxoSmithKline HIV clinical trial data to determine if a similar signal emerged . Methods : We compiled data from GlaxoSmithKline-sponsored clinical trials with ≥24 weeks of combination antiretroviral therapy comprising 14,174 HIV-infected adults who received ABC ( n = 9502 ; 7641 person-years ) or not ( n = 4672 ; 4267 person-years ) . Findings : Baseline demographics and HIV disease characteristics , including lipids and glucose values , were similar . MI rates were comparable among subjects exposed [ n = 16 ( 0.168 % ; CI : 0.096 to 0.273 ; 2.09 per 1000 person-years ) ] or not [ n = 11 ( 0.235 % ; CI : 0.118 to 0.421 ; 2.57 per 1000 person-years ) ] to ABC-containing therapy . Results of 12 trials with r and omization to ABC or not were consistent ( 2.15 per 1000 person-years vs. 4.10 per 1000 person-years ) . Interpretations : In this pooled summary , we observed few MI events overall and no excess risk of MI with ABC therapy . It is unclear why results from this data set seem discrepant to the Data collection of Adverse events of Anti-HIV Drugs data set , particularly , as the non-ABC MI event rate is similar . Further data are needed to evaluate any association between ABC and increased risk of MI BACKGROUND The role of exposure to specific antiretroviral drugs on risk of myocardial infa rct ion in human immunodeficiency virus (HIV)-infected patients is debated in the literature . METHODS To assess whether we confirmed the association between exposure to abacavir and risk of myocardial infa rct ion ( MI ) and to estimate the impact of exposure to other nucleoside reverse transcriptase inhibitors ( NRTIs ) , protease inhibitors ( PIs ) , and non-NRTIs on risk of MI , we conducted a case-control study nested within the French Hospital Data base on HIV . Cases ( n = 289 ) were patients who , between January 2000 and December 2006 , had a prospect ively recorded first definite or probable MI . Up to 5 controls ( n = 884 ) , matched for age , sex , and clinical center , were selected at r and om with replacement among patients with no history of MI already enrolled in the data base when MI was diagnosed in the corresponding case . Conditional logistic regression models were used to adjust for potential confounders . RESULTS Short-term/recent exposure to abacavir was associated with an increased risk of MI in the overall sample ( odds ratios [ ORs ] , 2.01 ; 95 % confidence interval [ CI ] , 1.11 - 3.64 ) but not in the subset of matched cases and controls ( 81 % ) who did not use cocaine or intravenous drugs ( 1.27 ; 0.64 - 2.49 ) . Cumulative exposure to all PIs except saquinavir was associated with an increased risk of MI significant for amprenavir/fosamprenavir with or without ritonavir ( OR , 1.53 ; 95 % CI , 1.21 - 1.94 per year ) and lopinavir with ritonavir ( 1.33 ; 1.09 - 1.61 per year ) . Exposure to all non-NRTIs was not associated with risk of MI . CONCLUSION The risk of MI was increased by cumulative exposure to all the studied PIs except saquinavir and particularly to amprenavir/fosamprenavir with or without ritonavir and lopinavir with ritonavir , whereas the association with abacavir can not be considered causal BACKGROUND Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor ( NNRTI ) . In FLAMINGO , we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy . METHODS In this multicentre , open-label , phase 3b , non-inferiority study , HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were r and omly assigned ( 1:1 ) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily , with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine . R and omisation was stratified by screening HIV-1 RNA ( ≤100,000 or > 100,000 copies per mL ) and nucleoside reverse transcriptase inhibitor ( NRTI ) selection . The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL ( Food and Drug Administration [ FDA ] snapshot algorithm ) at week 48 with a 12 % non-inferiority margin . This trial is registered with Clinical Trials.gov , NCT01449929 . FINDINGS Recruitment began on Oct 31 , 2011 , and was completed on May 24 , 2012 , in 64 research centres in nine countries worldwide . Of 595 patients screened , 484 patients were included in the analysis ( 242 in each group ) . At week 48 , 217 ( 90 % ) patients receiving dolutegravir and 200 ( 83 % ) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL ( adjusted difference 7·1 % , 95 % CI 0·9 - 13·2 ) , non-inferiority and on pre-specified secondary analysis dolutegravir was superior ( p=0·025 ) . Confirmed virological failure occurred in two ( < 1 % ) patients in each group ; we recorded no treatment-emergent resistance in either group . Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir ( four [ 2 % ] patients ) than for darunavir plus ritonavir ( ten [ 4 % ] patients ) and contributed to the difference in response rates . The most commonly reported ( ≥10 % ) adverse events were diarrhoea ( dolutegravir 41 [ 17 % ] patients vs darunavir plus ritonavir 70 [ 29 % ] patients ) , nausea ( 39 [ 16 % ] vs 43 [ 18 % ] ) , and headache ( 37 [ 15 % ] vs 24 [ 10 % ] ) . Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher ( 11 [ 2 % ] vs 36 [ 7 % ] ; p=0·0001 ) . INTERPRETATION Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir . Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected , treatment-naive patients . FUNDING ViiV Healthcare and Shionogi & Background : Abacavir/lamivudine and tenofovir/emtricitabine fixed-dose combinations are commonly used first-line antiretroviral therapies , yet few studies have comprehensively compared their safety profiles . Methods : Forty-eight-week data are presented from this multicenter , r and omized , open-label study comparing the safety profiles of abacavir/lamivudine and tenofovir/emtricitabine , both administered with efavirenz , in HLA-B*5701-negative HIV-1-infected adults . Results : Three hundred eighty-five subjects were enrolled in the study . The overall rate of withdrawal was high ( 28 % ) . Changes in estimated glomerular filtration rate from baseline were similar between arms [ difference 0.953 mL·min−1·1.73 m−2 ( 95 % confidence interval : −1.445 to 3.351 ) , P = 0.435 ] . Urinary excretion of retinol-binding protein and β-2 microglobulin increased significantly more in the tenofovir/emtricitabine arm ( + 50 % ; + 24 % ) compared with the abacavir/lamivudine arm ( no change ; −47 % ) ( P < 0.0001 ) . A lower proportion achieved viral load < 50 copies per milliliter in the abacavir/lamivudine arm ( 114 of 192 , 59 % ) compared with the tenofovir/emtricitabine arm ( 137 of 193 , 71 % ) [ difference 11.6 % ( 95 % confidence interval : 2.2 to 21.1 ) ] . The overall virological failure rate was low . The adverse event rate was similar between arms ( except drug hypersensitivity , reported more in the abacavir/lamivudine arm ) . Conclusions : The study showed no difference in estimated glomerular filtration rate between the arms , however , increases in markers of tubular dysfunction were observed in the tenofovir/emtricitabine arm , the long-term consequence of which is unclear . A significant difference in efficacy favoring tenofovir/emtricitabine was observed Background : Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial . We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression . Methods : We r and omly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with < 200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine ( n = 167 ) or tenofovir/emtricitabine ( n = 166 ) . The primary outcome was treatment failure [ “ switching = failure ” intention to treat ( ITT ) analysis , noninferiority margin 12.5 % ] . Secondary outcomes were time to treatment failure , virological failure , adverse events , and changes in CD4 count , fasting plasma lipids , lipodystrophy , body fat , bone mineral density , and renal function . Results : Treatment failure occurred in 32 patients ( 19 % ) on abacavir/lamivudine and 22 patients ( 13 % ) on tenofovir/emtricitabine [ difference 5.9 % ; ( 95 % confidence interval −2.1 % to 14.0 % ) , P = 0.06 ] . Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [ difference 2.4 ; ( 95 % confidence interval 0.05 to 6.0 ) , P = 0.04 ] . Twenty-three patients ( 14 % ) assigned to abacavir/lamivudine and 10 ( 6 % ) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects ( P = 0.03 ) . CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group . Conclusions : In HIV-1-infected patients with virological suppression , abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine BACKGROUND In the primary analysis of SPRING-2 at week 48 , dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment . We present the 96 week results . METHODS SPRING-2 is an ongoing phase 3 , r and omised , double-blind , active-controlled , non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19 , 2010 . We present results for the safety cutoff date of Jan 30 , 2013 . Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more . Patients were r and omly assigned ( 1:1 ) to receive either dolutegravir ( 50 mg once daily ) or raltegravir ( 400 mg twice daily ) , plus investigator-selected tenofovir-emtricitabine or abacavir-lamivudine . Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL , CD4 cell count changes from baseline , safety , tolerability , and genotypic or phenotypic resistance . We used an intention-to-treat exposed population ( received at least one dose of study drug ) for the analyses . Sponsor staff were masked to treatment assignment until primary analysis at week 48 ; investigators , site staff , and patients were masked until week 96 . FINDINGS Of 1035 patients screened , 827 were r and omly assigned to study group , and 822 received at least one dose of the study drug ( 411 patients in each group ) . At week 96 , 332 ( 81 % ) of 411 patients in the dolutegravir group and 314 ( 76 % ) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL ( adjusted difference 4∙5 % , 95 % CI -1∙1 % to 10∙0 % ) confirming non-inferiority . Secondary analyses of efficacy such as per protocol ( HIV RNA < 50 copies per mL : 83 % for dolutegravir and 80 % for raltegravir ) and treatment-related discontinuation equals failure ( 93 % without failure for dolutegravir ; 91 % for raltegravir ) supported non-inferiority . Virological non-response occurred less frequently in the dolutegravir group ( 22 [ 5 % ] patients for dolutegravir vs 43 [ 10 % ] patients for raltegravir ) . Median increases in CD4 cell count from baseline were similar between groups ( 276 cells per μL for dolutegravir and 264 cells per μL for raltegravir ) . Ten patients ( 2 % ) in each group discontinued because of adverse events , with few such events between weeks 48 and 96 ( zero in the dolutegravir group and one in the raltegravir group ) . No study -related serious adverse events occurred between week 48 and week 96 . At virological failure , no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir . INTERPRETATION At week 96 , once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive , patients with HIV-1 . Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients Objective : The Simplification of antiretroviral therapy with Tenofovir-Emtricitabine or Abacavir-Lamivudine trial ( STEAL ) study r and omized HIV participants to switch existing nucleoside reverse transcriptase inhibitors ( NRTI ) to either abacavir/lamivudine ( ABC/3TC ; n = 179 ) or tenofovir/emtricitabine ( TDF/FTC ; n = 178 ) . An increased risk in cardiovascular disease ( CVD ) was reported ( hazard ratio 7.7 , P = 0.048 ) in ABC/3TC recipients compared with TDF/FTC in the STEAL study . The impact of ABC/3TC treatment on a range of CVD and inflammatory biomarkers was explored . Design and methods : Biomarkers were assessed at 0 , 12 , 24 , and 48 weeks to examine : inflammation – high sensitive C-reactive protein , amyloid-P , amyloid-A , interleukin 6 , interleukin 10 , interferon α , and macrophage migration inhibitory factor ; coagulation – D-dimer and fibrinogen ; platelet function – soluble P-selectin ; endothelial function – vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 ; renal function – cystatin C. The primary endpoint was the difference between arms for mean change from baseline to week 12 . Secondary analyses were differences between groups for mean change from baseline to weeks 24 and 48 , time-weighted change from baseline to week 48 , and changes to week 12 stratified by Framingham CVD risk score at baseline . Results : Sera were available from 330 ( 92 % ) of 357 participants . At baseline , all biomarkers were similar between treatment arms and when stratified for baseline NRTI exposure . There were no significant differences between treatment arms in the mean change from baseline to week 12 for any biomarkers . No consistent between-group differences were seen in the secondary analyses that could suggest one pathophysiological pathway . Conclusion : A thorough examination of selected biomarkers associated with cardiovascular morbidity and mortality did not reveal associations with the use of ABC/3TC relative to use of TDF/FTC BACKGROUND Dolutegravir ( S/GSK1349572 ) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile . We compared dolutegravir with HIV integrase inhibitor raltegravir , as initial treatment for adults with HIV-1 . METHODS SPRING-2 is a 96 week , phase 3 , r and omised , double-blind , active-controlled , non-inferiority study that began on Oct 19 , 2010 , at 100 sites in Canada , USA , Australia , and Europe . Treatment-naive adults ( aged ≥ 18 years ) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were r and omly assigned ( 1:1 ) via a computer-generated r and omisation sequence to receive either dolutegravir ( 50 mg once daily ) or raltegravir ( 400 mg twice daily ) . Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine . R and omisation was stratified by screening HIV-1 RNA ( ≤ 100,000 copies per mL or > 100,000 copies per mL ) and nucleoside reverse transcriptase inhibitor backbone . Investigators were not masked to HIV-1 RNA results before r and omisation . The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks , with a 10 % non-inferiority margin . Main secondary endpoints were changes from baseline in CD4 cell counts , incidence and severity of adverse events , changes in laboratory parameters , and genotypic or phenotypic evidence of resistance . Our primary analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT01227824 . FINDINGS 411 patients were r and omly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug . At 48 weeks , 361 ( 88 % ) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 ( 85 % ) in the raltegravir group ( adjusted difference 2·5 % ; 95 % CI -2·2 to 7·1 ) . Adverse events were similar between treatment groups . The most common events were nausea ( 59 [ 14 % ] patients in the dolutegravir group vs 53 [ 13 % ] in the raltegravir group ) , headache ( 51 [ 12 % ] vs 48 [ 12 % ] ) , nasopharyngitis ( 46 [ 11 % ] vs 48 [ 12 % ] ) , and diarrhoea ( 47 [ 11 % ] in each group ) . Few patients had drug-related serious adverse events ( three [ < 1 % ] vs five [ 1 % ] ) , and few had adverse events leading to discontinuation ( ten [ 2 % ] vs seven [ 2 % ] in each group ) . CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of grade d laboratory toxic effects were similar . We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir , whereas of the patients with virologic failure who received raltegravir , one ( 6 % ) had integrase treatment-emergent resistance and four ( 21 % ) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance . INTERPRETATION The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved , combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients . FUNDING ViiV Healthcare Objectives : To assess the virologic noninferiority of an antiretroviral treatment simplification with coformulated zidovudine/lamivudine/abacavir ( group 1 ) vs. coformulated zidovudine/lamivudine plus nevirapine ( group 2 ) in HIV-1-infected patients receiving successful first-line highly active antiretroviral therapy . Methods : This is a prospect i ve , multicenter , open-label , comparative , r and omized , noninferiority study . A delta of 15 % for differences in virologic suppression < 200 copies/mL between groups was prespecified with a 1-sided 0.025 significance level . Results : A total of 134 patients were included into this study : 68 were allocated to group 1 and 66 to group 2 . By intention-to-treat analysis ( switch equals failure ) , the percentage of virologic suppression < 200 copies/mL ( < 50 copies/mL ) at week 48 was 71.0 % ( 65.1 % ) and 73.0 % ( 63.3 % ) in groups 1 and 2 , respectively ( estimate for differences [ < 200 copies/mL ] : −2.1 , 95 % CI : −17.4 - 13.1 , P = 0.783 ) . Thirteen and 14 patients in groups 1 and 2 , respectively , discontinued therapy due to adverse events . Dyslipidemia improved in both groups , with a higher improvement in low-density lipoprotein cholesterol ( P = 0.049 ) in group 1 . Conclusions : Group 1 is not inferior to group 2 regarding virologic suppression < 200 copies/mL. Both strategies improve lipid profile OBJECTIVE To assess the antiviral efficacy , safety , and adherence in subjects who switched to Trizivir following long-term HIV-1 RNA suppression . STUDY DESIGN A r and omized , open-label , multicentre , 48-week comparative study in subjects who have received two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or an nonnucleoside reverse transcriptase inhibitor or three nucleoside reverse transcriptase inhibitors for at least 6 months , with a history of undetectable plasma HIV-1 RNA since initiation of therapy and plasma viral load of < 50 HIV-1 RNA copies/mL at screening . METHODS Subjects were r and omized 1:1 to continue their current treatment or to switch to a simplified treatment with Trizivir administered twice daily . Assessment s included plasma HIV-1 RNA , lymphocyte counts , clinical laboratory evaluations , adverse events , and adherence to treatment ( obtained via subject self-report ) . Treatment failure was defined as a plasma viral load of > /= 400 HIV-1 RNA copies/mL on two consecutive occasions or premature discontinuation of r and omized treatment . RESULTS At week 48 , the proportion of treatment failures in Trizivir arm ( 23/106 , 22 % ) was noninferior to that observed in continued arm ( 23/103 , 22 % ) with a treatment difference stratified by prior ART of 1.2%[-10.1 ; 12.5 ] . Incidence of adverse events was similar in both treatment groups . The incidence of possible hypersensitivity reaction in the Trizivir trade mark arm was 10 % . Significant reductions in cholesterol and triglyceride plasma levels were observed in the Trizivir arm ( P < 0.001 and P = 0.006 , respectively ) . CONCLUSION Switching to Trizivir offers a potent and simplified regimen with equivalent efficacy and significant improvement in lipid abnormalities compared to continued triple therapy SUMMARY Objective : An equivalence ( non-inferiority ) trial comparing antiviral response , tolerability , and adherence with a triple nucleoside regimen containing abacavir 300 mg ( ABC ) plus a lamivudine 150-mg/zidovudine 300-mg combination tablet ( COM ) twice daily vs. a regimen containing the protease inhibitor indinavir ( IDV ) 800 mg three times daily plus COM twice daily ( IDV/COM ) in antiretroviral-naïve , HIV-infected patients . Methods : Adult patients with plasma HIV-1 RNA levels ≥ 5000 copies/mL and CD4 + cell counts ≥ 100 cells/mm3 were r and omized to receive open-label ABC/COM ( n = 169 ) or IDV/COM ( n = 173 ) for 48 weeks . The intent-to-treat ( ITT ) population was the primary population evaluated . ITT : switch/missing equals failure ( ITT : S/M = F ) and as-treated ( AT ) analyses were used for assessing the proportion of patients achieving plasma HIV-1 RNA level < 400 and < 50 copies/mL at each clinic visit . In the ITT : S/M = F analysis , patients who switched treatment or had missing values were considered treatment failures ; the AT analysis examined virologic data only while patients received study treatment . ABC/COM was considered equivalent ( non-inferior ) to IDV/COM if the lower limit of the 95 % confidence intervals ( CIs ) about the difference in proportions of ABC/COM- vs. IDV/COM-treated patients attaining plasma HIV-1 RNA < 400 copies/mL exceeded –15 % at week 48 . Results : The study population was diverse with respect to ethnicity ( 38 % Asian , 27 % Hispanic , 28 % white , 3 % black , 4 % other ) and gender ( 39 % women , 61 % men ) . Baseline median HIV-1 RNA was 4.80 log10 copies/mL and CD4 + cell count was 315 cells/mm3 . ABC/COM met the criterion of equivalence to IDV/COM . In the ITT : S/M = F analysis at Week 48 , a greater proportion of ABC/COM-treated patients achieved HIV-1 RNA < 400 copies/mL ( 66 % [ 109/164 ] vs. 50 % [ 82/165 ] ; treatment difference 16.6 % , 95 % CI ( 6.0 , 27.2 ) , p = 0.002 ) and HIV-1 RNA < 50 copies/mL ( 60 % [ 99/164 ] vs. 50 % [ 83/165 ] ; treatment difference 9.6 % , 95 % CI [ –1.1 , 20.2 ] ) , whereas the AT analysis showed similar proportions achieving these endpoints ( < 400 copies/mL : 85 vs. 83 % ; < 50 copies/mL : 79 vs 81 % ) . Comparable proportions of patients with screening HIV-1 RNA values > 100 000 copies/mL achieved HIV-1 RNA < 400 copies/mL ( ABC/COM : 60 % [ 35/58 ] ; IDV/COM : 51 % [ 33/65 ] ; treatment difference 9.6 % , 95 % CI [ –7.9 , 27.1 ] ; ITT : S/M = F analysis ) . A significantly greater proportion taking ABC/COM were ≥ 95 % adherent ( 72 % [ 109/151 ] vs. 45 % [ 70/154 ] with IDV/COM , p < 0.001 ) . Median increases from baseline in CD4 + cell counts were similar in the two treatment groups ( + 148 vs. + 152 cells/mm3 ) . Significantly more patients on IDV/COM reported drug-related adverse events ( 87 % [ 142/165 ] vs. 65 % [ 108/164 ] with ABC/COM , p < 0.001 ) , similar proportions discontinued treatment due to adverse events ( 13 vs. 10 % ) , and a slightly greater proportion in the ABC/COM group reported serious adverse events ( 13 vs. 8 % ) . About half of the latter comprised suspected ABC-related hypersensitivity reactions ( overall rate , 6 % ) . Most adverse events were gastrointestinal in nature in both treatment groups . Conclusion : ABC/COM was at least equivalent to IDV/COM over 48 weeks in the treatment of antiretroviral-naïve patients . ABC/COM was associated with a significantly higher adherence rate and lower incidence of drug-related adverse events than IDV/COM . The study was limited in that it was not powered to determine equivalence of treatments within high vs. low viral load strata , adherence was not monitored electronically , and bias could not be ruled out due to the open-label study design Background : Abacavir sulfate/lamivudine ( ABC/3TC ) and tenofovir DF/emtricitabine ( TDF/FTC ) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment . This is the first completed , r and omized clinical trial to directly compare the efficacy , safety , and tolerability of these agents , each in combination with lopinavir/ritonavir in antiretroviral-naive patients . Methods : Six hundred and eighty-eight antiretroviral-naive , HIV-1-infected patients were r and omized in this double-blind , placebo-matched , multicenter , noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg , both with lopinavir/ritonavir 800 mg/200 mg . Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 ( missing = failure , switch included analysis ) and the proportion of patients experiencing adverse events over 96 weeks . Results : At week 48 , 68 % in the ABC/3TC group vs. 67 % in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml ( intent-to-treat exposed missing = failure , 95 % confidence interval on the difference −6.63 to 7.40 , P = 0.913 ) , demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48 . Noninferiority of the two regimens was sustained at week 96 ( 60 % vs. 58 % , respectively , 95 % confidence interval −5.41 to 9.32 , P = 0.603 ) . In addition , efficacy of both regimens was similar in patients with baseline HIV-1 RNA ≥ 100 000 copies/ml or CD4 + cell counts below 50 cells/μl . Median CD4 + recovery ( ABC/3TC vs. TDF/FTC , cells/μl ) was + 250 vs. + 247 by week 96 . Premature study discontinuation due to adverse events occurred in 6 % of patients in both groups . Protocol -defined virologic failure occurred in 14 % of patients in both groups . Conclusion : Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy , safety , and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients

In the absence of large , comparative r and omized clinical trials , the minimally invasive techniques appear to be at least as effective as surgery in the treatment of lower extremity varicose veins

BACKGROUND Minimally invasive techniques such as endovenous laser therapy , radiofrequency ablation , and ultrasound-guided foam sclerotherapy are widely used in the treatment of lower extremity varicosities . These therapies have not yet been compared with surgical ligation and stripping in large r and omized clinical trials .

Background Twenty subjects were treated with either polidocanol ( POL ) or sodium tetradecyl sulfate ( STS ) to compare the efficacy and adverse sequelae of each agent . Objective To determine the safety and efficacy of two widely used sclerosing agents . Methods After the exclusion of saphenofemoral junction incompetency , each subject 's leg veins were categorized by size ( < 1 , 1–3 , and 3–6 mm in diameter ) . Each leg was then r and omized to be treated with 0.5 % , 1 % , or 1 % foam of POL or 0.25 % , 0.5 % , or 0.5 % foam of STS according to vein size . An independent panel of four physicians , blinded to treatment , performed r and omized photographic evaluations obtained pretreatment and 12 weeks post-treatment . Subject satisfaction index and overall clinical improvement assessment were also obtained . Results An average 83 % improvement was noted for all vein sizes in all subjects with both POL and STS after a single treatment . Subjects were satisfied with treatment , regardless of the sclerosing agent used or the vein size treated . There was no statistically significant difference in adverse effects between each group . Conclusion Both POL and STS are safe and effective sclerosing agents in the treatment of varicose and telangiectatic leg veins . Both are very tolerable and demonstrate similar post-treatment sequelae OBJECTIVE The aim of this r and omized study was to compare a new method of endovenous saphenous vein obliteration ( Closure System , VNUS Medical Technologies , Inc , Sunnyvale , Calif ) with the conventional stripping operation in terms of short-term recovery and costs . METHODS Twenty-eight selected patients for operative treatment of primary greater saphenous vein tributary varicose veins were r and omly assigned to endovenous obliteration ( n = 15 ) or stripping operation ( n = 13 ) . Postoperative pain was daily assessed during the 1st week and on the 14th postoperative day . The length of sick leave was determined . The R AND -36 health survey was used to assess the patient health-related quality of life . The patient conditions were controlled 7 to 8 weeks after surgery , and patients underwent examination with duplex ultrasonography . The comparison of costs included both direct medical costs and costs result ing from lost of productivity of the patients . Costs that were similar in the study groups were not considered in the analysis . RESULTS All operations were successful , and the complication rates were similar in the two groups . Postoperative average pain was significantly less severe in the endovenous obliteration group as compared with the stripping group ( at rest : 0.7 , st and ard deviation [ SD ] 0.5 , versus 1.7 , SD 1.3 , P = .017 ; on st and ing : 1.3 , SD 0.7 , versus 2.6 , SD 1.9 , P = .026 ; on walking : 1.8 , SD 0.8 , versus 3.0 , SD 1.8 , P = .036 ; with t test ) . The sick leaves were significantly shorter in the endovenous obliteration group ( 6.5 days , SD 3.3 days , versus 15.6 days , SD 6.0 days ; 95 % CI , 5.4 to 12.9 ; P < .001 , with t test ) . Physical function was also restored faster in the endovenous obliteration group . The estimated annual investment costs of the closure operation were US $ 3360 . The other direct medical costs of the Closure operation were about $ 850 , and those of the conventional treatment were $ 360 . With inclusion of the value of the lost working days , the Closure treatment was cost-saving for society , and when 40 % of the patients are retired ( or 60 % of the productivity loss was included ) , the Closure procedure became cost-saving at a level of 43 operations per year . CONCLUSION Endovenous obliteration may offer advantages over the conventional stripping operation in terms of reduced postoperative pain , shorter sick leaves , and faster return to normal activities , and it appears to be cost-saving for society , especially among employed patients . Because the procedure is also associated with shorter convalescence , this new method may potentially replace conventional varicose vein surgery STUDY OBJECTIVE : To determine the prevalence of varicose veins and chronic venous insufficiency ( CVI ) in the general population . DESIGN : Cross sectional survey . SETTING : City of Edinburgh . PARTICIPANTS : Men and women aged 18 - 64 years selected r and omly from age-sex registers of 12 general practice s. MAIN RESULTS : In 1566 subjects examined , the age adjusted prevalence of trunk varices was 40 % in men and 32 % in women ( p < or = 0.01 ) . This sex difference was mostly a result of higher prevalence of mild trunk varices in men . More than 80 % of all subjects had mild hyphenweb and reticular varices . The age adjusted prevalence of CVI was 9 % in men and 7 % in women ( p < or = 0.05 ) . The prevalence of all categories of varices and of CVI increased with age ( p < or = 0.001 ) . No relation was found with social class . CONCLUSIONS : Approximately one third of men and women aged 18 - 64 years had trunk varices . In contrast with the findings in most previous studies , mainly conducted in the 1960s and 1970s , chronic venous insufficiency and mild varicose veins were more common in men than women . No evidence of bias in the study was found to account for this sex difference . Changes in lifestyle or other factors might be contributing to an alteration in the epidemiology of venous disease BACKGROUND Endovascular radiofrequency obliteration has been used as an alternative to conventional vein-stripping surgery for elimination of saphenous vein insufficiency . A clinical registry was established in 1998 , and its mid-term results have been reported previously . This study is to demonstrate the long-term treatment outcomes and to determine the risk factors that affect treatment efficacy . METHODS Data were collected in an ongoing multicenter , prospect i ve registry . Patients were treated before October 2004 . Clinical and duplex ultrasound follow-up was performed 1 week , 6 months , 1 year , and yearly thereafter to 5 years . Treatment efficacy and clinical improvement after the procedure were analyzed . Three types of anatomical failure were identified . Logistic regression analysis was performed to determine the existence of any significant risk factors associated with anatomical failure . Risk factors considered were age , gender , body mass index , vein diameter , and pullback speed . The impact of anatomical failure on clinical symptoms and varicose vein recurrence was also analyzed . RESULTS There were 1,006 patients ( 1,222 limbs ) treated , their mean age was 47.4 + /- 12.1 years , and 78.1 % were female . Veins treated included 89.1 % great saphenous vein above-knee segments , 1.2 % great saphenous vein below-knee segments , 4.1 % great saphenous vein groin-to-ankle , 4.3 % small saphenous veins , and 1.3 % accessory saphenous veins . Mean vein diameter was 7.5 mm , with a maximum of 24 mm . Vein occlusion rates were 87.1 % , 88.2 % , 83.5 % , 84.9 % , and 87.2 % , and reflux-free rates were 88.2 % , 88.2 % , 88.0 % , 86.6 % , and 83.8 % at each annual follow-up . Clinical symptom improvement was seen in 70 % to 80 % of limbs with anatomical failures and in 85 % to 94 % of limbs with anatomical success from 6 months to 5 years after the radiofrequency obliteration . Logistic regression analysis showed that catheter pullback speed ( P < .0001 ) and body mass index ( P < .0333 ) were risk factors for anatomical failure . Limbs that had type II and type III anatomical failures were found to be more prone to varicose vein recurrence . CONCLUSIONS Endovascular radiofrequency obliteration of saphenous vein reflux exhibits enduring efficacy . Adequate pullback speed during the procedure should be emphasized to ensure the proper thermal dose delivery . A whole treatment strategy to address hemodynamically significant tributaries and perforators can further improve treatment outcomes . Body mass index is a risk factor for anatomical failure , indicating the impact of hemodynamic factors on disease progression and recurrence AIM The innovations for disease management need to be thoroughly evaluated so that their benefits and potential downsides can be compared with the already existing approaches . Endovascular laser ( EVL ) treatment for varicose veins offers today several advantages over surgical st and ard stripping . The Italian Endovenous-laser Working Group ( IEWG ) is a homogeneous group of surgeons and phlebologists who have been using EVL since 1999 and has undertaken to examine EVL in a multicenter study starting from a well defined rationale , with the benefit of a single protocol to use . METHODS In a cooperative , multicenter , clinical study , 1076 limbs in 1050 patients , mean age of 54.5 years , 241 males and 809 females affected by chronic venous insufficiency ( CVI ) were considered eligible for surgery and stratified by CEAP classification in a four-year period ( January 1999 December 2003 ) . Inclusion criteria were insufficiency of the great and /or small saphenous vein at various levels , beyond those accessory saphenous trunks with incompetence in the saphenofemoral junction . In all cases truncular reflux apparead up on duplex scan examination , with or without associated varicosities . All the patients underwent a surgery on the basis of the clinical assessment . All the centres involved performed treatment in conformity with the Food and Drug Administration ( FDA ) vali date d procedure , using an endo-laser venous system kit with a 810 - 980 nm diode . Duplex scan was performed in all patients after 36 months with very few lost to follow-up cases . RESULTS In the immediate postoperative period the results have been impressive , with a very effective closure of incompetent great saphenous vein and the other treated varicose veins ( the early occlusion rate has been 99 % ) . Major complications have not been detected : in particular , no deep venous thrombosis ( DVT ) evaluated duplex ultrasound . The patients ' acceptability and satisfaction regarding the procedure , have been measured by means of a question naire on the quality of life , and the result was 96.7 % . After 36 months , the total occusion rate of saphenous trunks has been 97 % . CONCLUSIONS The first important Italian experience with EVL based on preoperative , perioperative and postoperative duplex control and which is also based on the patients ' satisfaction at mid/long-term has indicated some advantages over the st and ard treatment with the stripping method . In terms of reduced postoperative pain , shorter sick leave , a faster resumption of the normal activities , and , in particular , the total absence of DVT , we can conclude that EVL is a good solution for all patients with anatomic and hemodinamic patterns for saphenous vein surgery The study was planned to evaluate efficacy and costs of endovascular sclerotherapy ( ES ) in comparison with surgery and surgery associated with sclerotherapy in a prospect i ve ( 10-year follow-up ) , good- clinical - practice study . Patients with varicose veins and pure , superficial venous incompetence were included . Of the patients r and omized into the three groups 39 ( group A ) were treated with ES , 40 ( B ) with surgery + sclerotherapy , and 42 with surgery only ( C ) . Surgery consisted of ligation of the SFJ ( saphenofemoral junction ) and of incompetent veins detected with color duplex . Of the preselected 150 patients , 121 subjects entered the study ; 96 completed the 10-year follow-up ( mean age 52.6 ±6 years ; 51 men , 45 women ) . Dropouts were due to nonmedical problems . At 10 years no incompetence was observed in subjects treated with SPJ ligation ( B and C ) . In the ES group 18.8 % of the SFJs were patent and incompetent and in 43.8 % of limbs the distal ( below-knee ) venous system was still incompetent [ 16.1 % in the surgery + scle rotherapy group ( p < 0.05 ) and 36 % in the group treated with surgery only ( p < 0.05 vs B and 0.05 vs A ) ] . Color duplex of the long saphenous vein indicated atrophy or obstruc tion of a segment ( average 6.7 cm ) after SFJ ligation ( 4.2 cm after ES ) . The cost of ES was 68 % of surgery while the cost of surgery and sclerotherapy was 122 % of surgery only . Endovascular sclerotherapy is an effective , cheaper treatment option , but surgery after 10 years is superior OBJECTIVE The purpose of this study was to investigate the possible long-term clinical advantages of stripping the long saphenous vein during routine primary varicose vein surgery . METHODS The study was design ed as a 5-year , clinical and duplex scan follow-up examination of a group of patients who were r and omized to stripping of the long saphenous vein during varicose vein surgery versus saphenofemoral ligation alone . The study was conducted in the vascular unit of a district general hospital . One hundred patients ( 133 legs ) with uncomplicated primary long saphenous varicose veins originally were r and omized . After invitation 5 years later , 78 patients ( 110 legs ) underwent clinical review and duplex scan imaging . RESULTS Sixty-five patients remained pleased with the results of their surgery ( 35 of 39 stripped vs 30 of 39 ligated ; P = .13 ) . Reoperation , either done or awaited , for recurrent long saphenous veins was necessary for three of 52 of the legs that underwent stripping versus 12 of 58 ligated legs . The relative risk was 0.28 , with a 95 % confidence interval of 0.13 to 0.59 ( P = .02 ) . Neovascularization at the saphenofemoral junction was responsible for 10 of 12 recurrent veins that underwent reoperation and also was the cause of recurrent saphenofemoral incompetence in 12 of 52 stripped veins versus 30 of 58 ligated legs . The relative risk was 0.45 , with a 95 % confidence interval of 0.26 to 0.78 ( P = .002 ) . CONCLUSION Stripping reduced the risk of reoperation by two thirds after 5 years and should be routine for primary long saphenous varicose veins PURPOSE This study was design ed as a prospect i ve multicenter r and omized comparison of procedure-related complications , patient recuperation , and quality -of-life outcomes between patients undergoing vein stripping with high ligation and patients undergoing great saphenous vein ( GSV ) obliteration with temperature-controlled radiofrequency ablation without adjunctive high ligation ( Closure procedure ) . METHODS Eighty-five patients ( 86 limbs ) from five sites ( France , 2 ; Austria , 1 ; United States , 2 ) were r and omly allocated to undergo radiofrequency obliteration ( RFO ) or stripping and high ligation ( S&L ) . Final analysis included data for 44 limbs in the RFO group and 36 limbs in the S&L group . Follow-up examinations were performed at 72 hours , 1 week , 3 weeks , and 4 months . All patients completed the CIVIQ2 quality -of-life ( QOL ) question naire and underwent clinical and ultrasound examinations at each follow-up visit . RESULTS Immediate success on the day of treatment was reported for 95 % ( 42 of 44 ) of limbs in the RFO group and 100 % ( 36 of 36 ) of limbs in the S&L group . In seven RFO limbs ( 16.3 % ) a scan obtained 72 hours after the procedure showed flow in the proximal GSV . Five of these segments had reflux in the open segment . At 1 week two of these closed , and an additional segment closed at 3 weeks . In no cases did flow reappear after complete occlusion of the GSV . Time to return to normal activities was significantly less in the RFO group ( mean , 1.15 days ; 95 % confidence interval [ CI ] , 0.05 - 2.34 ) compared with the S&L group ( mean , 3.89 days ; CI , 2.67 - 5.12 ; P = .02 ) . In the RFO group , 80.5 % of patients returned to routine activities of daily living within 1 day , compared with 46.9 % of patients in the S&L group ( P < .01 ) . Patients in the RFO group were able to return to work in 4.7 days ( CI , 1.16 - 8.17 ) , compared with 12.4 days ( CI , 8.66 - 16.23 ) for the S&L group ( P < .05 ) . Analysis of the QOL surveys showed statistically significant differences in favor of the RFO group for global score and pain score during follow-up . The magnitude of the difference , however , progressively decreased between 1 week and 4 months . CONCLUSIONS In the absence of significant complications , such as deep vein thrombosis and pulmonary embolism , severe neuritic sequelae , and skin burns , there are significant early advantages to endovascular obliteration of the GSV compared with conventional vein stripping BACKGROUND Foamed sclerosing agents have been used with enthusiasm by phlebologists for more than 5 decades . Any type of varicose veins can and has been treated with this technique . Numerous publications have stressed the advantages of foamed sclerosing agents on the basis of empiric and experimental criteria and have described various individual techniques to prepare foams . Until now , however , no comparative study for the treatment of large varicose veins with foam or liquid exists . OBJECTIVE The purpose of this first r and omized , prospect i ve , multicenter trial was to study the elimination of reflux , the rate of recanalization , and possible side effects of foam sclerotherapy ( FS ) compared with conventional liquid sclerotherapy for the greater saphenous vein ( GSV ) . METHODS Eighty-eight patients were r and omized into two groups : One group was treated with sclerosing foam ( 45 patients ) and the other with sclerosing liquid ( 43 cases ) . Sclerotherapy was performed with direct puncture of the vessel under duplex guidance . The reference sclerosing agent was polidocanol in a 3 % solution . The foam was prepared using the Double Syringe System ( DSS ) method . Only one injection of 2.0 or 2.5 mL liquid or foam was allowed , depending on the diameter of the GSV . Results were assessed according to the protocol . RESULTS Follow-up after 3 weeks showed 84 % elimination of reflux in the GSV with DSS foam versus 40 % with liquid sclerosant ( P < 0.01 ) . At 6 months , six recanalizations were found in the liquid group versus two in the foam group . After 1 year , no additional recanalization was observed with either foam or liquid . Longer term studies are underway . Side effects did not differ between both groups . CONCLUSION The efficacy of sclerosing foam ( DSS ) compared with sclerosing liquid in therapy of the GSV is superior , a finding that had already gained empirical recognition but for which there has not been any clinical evidence to date OBJECTIVE The objective of this r and omized , prospect i ve , blinded study was to determine the relative effects of two laser wavelengths in the treatment of great saphenous vein ( GSV ) insufficiency . METHODS Fifty-one male and female patients scheduled for routine laser treatment of GSV insufficiency provided signed informed consent for the procedure . Patients were r and omized to receive endovenous laser treatment with a wavelength of 810 or 980 nm . The same surgeon , blinded to the wavelength , performed all procedures . Nonoperating study staff , blinded to the laser wavelengths , evaluated patients before and after the procedure regarding physical signs and symptoms . Patients were monitored within 72 hours after the procedure ( via duplex ultrasonography ) , at 1 week ( by procedural site photos scored for bruising , as well as a pain score ) , at 3 weeks , and at 4 months for bruising , physical and emotional effects of the procedure ( scored by patients on a five-point visual analogue scale ) , and symptoms ( scored by the physician ) , along with adverse events . Patients were followed up for a year to determine the long-term efficacy of the procedure . RESULTS The 51 patients ( 38 women and 13 men ; mean age , 52.4 + /- 11.7 years ) completed treatment and follow-up examination ( 30 legs for each wavelength ) . At 72 hours after the procedure , no significant differences were noted between patient outcomes , physical conditions , and symptoms and or possible adverse events . At 1 week after the procedure , bruising scores were significantly different ( P < .005 ) : patients in the 980-nm group showed less bruising of the procedure site than the patients in the 810-nm group . Only three physical or symptom parameters presented with significant differences ( P < .05 ) over time-less itching was noted by 810 nm-treated patients at 3 weeks after the procedure , lower levels of pain intensity were seen in the 980 nm-treated patients at the 4-month follow-up visit , and lower varicose vein ratings were seen for the 980 nm-treated patients at the 4-month follow-up visit . Thirteen legs were phlebitic at 7 days after the procedure ( 10 in the 810-nm group and 3 in the 980-nm group ) . Two treatment failures occurred ( one patient in each treatment group ) ; both patients exhibited flow in the treated venous segment at the 4-month follow-up visit . Two other patients ( one in each group ) had treatment failure at the 1-year follow-up , demonstrating venous insufficiency in the treated segment . CONCLUSIONS Both laser wavelengths were effective in treating GSV insufficiency , with no major complications and a paucity of adverse outcomes Endovenous laser therapy ( EVLT ) is a minimally invasive treatment for varicose veins . This study compares early quality -of-life ( QoL ) outcomes following EVLT and surgery . Two nonr and omized groups were studied : an EVLT group with 70 patients , median age 49 ( interquartile range [ IQR ] 35 - 58 ) years , and a surgery group with 62 patients , median age 49 ( IQR 35 - 61 ) years . Patients were assessed prior to and at 1 , 6 , and 12 weeks following the procedure using the Short Form 36 ( SF-36 ) , the Aberdeen Varicose Veins Question naire ( AVVQ ) , and the Venous Clinical Severity Score ( VCSS ) . Follow-up at 1 , 6 , and 12 weeks was 100 % , 77 % , and 70 % following EVLT and 100 % , 85 % , and 47 % following surgery . SF-36 scores were significantly better in the EVLT group at 1 week ( Physical Functioning , Role Physical , Bodily Pain , Vitality , and Social Functioning domains ) and at 6 weeks ( Physical Functioning and Role Physical ) . At 12 weeks , no significant differences were evident between the groups . AVVQ scores were significantly better in the EVLT group at 6 and 12 weeks . VCSS scores were significantly improved in both groups at 12 weeks . EVLT and surgery provide similar QoL improvements in patients with varicose veins . EVLT , however , removes the QoL limitations experienced by patients in the early postoperative period To find out whether the usual total stripping of the long saphenous vein in operations for varicose veins could be replaced by a less traumatic removal of only the femoral part of the vein , a r and omised prospect i ve study was carried out in 163 consecutive patients , of whom 157 were evaluable . Group A ( n = 80 ) had total stripping and group B ( n = 77 ) had partial stripping ( extraction of the long saphenous vein from the groin to immediately below the knee ) . The two groups , which were comparable , were assessed three months after operation when 75 in group A ( 94 % ) and 75 in group B ( 97 % ) had excellent or good relief of symptoms and comparable absence of residual varicosities . Lesions of the saphenous nerve were found in 31 in group A ( 39 % ) and 5 in group B ( 7 % ) ( p less than 0.001 ) . There were few other complications . We conclude that preservation of the distal long saphenous vein not only reduces nerve damage , but also retains enough vein for use should coronary artery bypass or peripheral vascular grafting be necessary in future BACKGROUND Endovenous laser ( EVL ) ablation of the great saphenous vein ( GSV ) is thought to minimize postoperative morbidity and reduce work loss compared with high ligation and stripping ( HL/S ) . However , the procedures have not previously been compared in a r and omized trial with parallel groups where both treatments were performed in tumescent anesthesia on an out-patient basis . METHODS Patients with varicose veins due to GSV insufficiency were r and omized to either EVL ( 980 nm ) or HL/S in tumescent anesthesia . Miniphlebectomies were also performed . Patients were examined preoperatively and at 12 days , and 1 , 3 , and 6 months postoperatively . Sick leave , time to normal physical activity , pain score , use of analgesics , Aberdeen score , Medical Outcomes Study Short Form-36 quality -of-life score , Venous Clinical Severity Score ( VCSS ) , and complication rates were investigated . The total cost of the procedures , including lost wages and equipment , was calculated . Cost calculations were based on the st and ard fee for HL/S with the addition of laser equipment and the st and ard salary and productivity level in Denmark . RESULTS A follow-up of 6 months was achieved in 121 patients ( 137 legs ) . The groups were well matched for patient and GSV characteristics . Two HL/S procedures failed , and three GSVs recanalized in the EVL group . The groups experienced similar improvement in quality -of-life scores and VCSS score at 3 months . Only one patient in the HL/S group had a major complication , a wound infection that was treated successfully with antibiotics . The HL/S and EVL groups did not differ in mean time to resume normal physical activity ( 7.7 vs 6.9 calendar days ) and work ( 7.6 vs 7.0 calendar days ) . Postoperative pain and bruising was higher in the HL/S group , but no difference in the use of analgesics was recorded . The total cost of the procedures , including lost wages , was euro 3084 ( $ 3948 US ) in the HL/S and euro 3396 ( $ 4347 US ) in the EVL group . CONCLUSIONS This study suggests that the short-term efficacy and safety of EVL and HL/S are similar . Except for slightly increased postoperative pain and bruising in the HL/S group , no differences were found between the two treatment modalities . The treatments were equally safe and efficient in eliminating GSV reflux , alleviating symptoms and signs of GSV varicosities , and improving quality of life . Long-term outcomes , particularly with respect to recurrence rates , shall be investigated in future studies , including the continuation of the present Background Patients with varicose veins seek medical assistance for many reasons , including esthetic ones . The development of suitable and more flexible instruments , along with less invasive techniques , enables the establishment of new therapeutic procedures . Objective To compare endovenous great saphenous vein photocoagulation with an 810 nm diode laser and the conventional stripping operation in the same patient . Methods Twenty patients selected for operative treatment of primary great saphenous vein insufficiency on duplex scanning were assigned to a bilateral r and om comparison . In all cases , both techniques were performed , one on each lower limb . Clinical ly , evaluation was assessed on the seventh , thirtieth , and sixtieth postoperative days . Patients underwent examination with duplex ultrasonography and air plethysmography during the follow-up . Results Patients who received endovenous photocoagulation presented with the same pain but fewer swellings and less bruising than the stripping side . Most patients indicated that the limb operated on by laser received more benefits than the other . There was only one recanalization and no adverse effects . The venous filling time showed better hemodynamics in both techniques . Conclusion The endovenous great saphenous vein photocoagulation is safe and well tolerated and presents results comparable to those of conventional stripping We evaluated the 3-year outcome of a series of patients with primary varicose veins who were r and omized to radiofrequency endovenous obliteration vs. stripping of the long saphenous vein ( LSV ) . Twenty-eight patients were included in the study : 15 were r and omized to the radiofrequency endovenous obliteration procedure and 13 to LSV stripping . At 3-year follow-up , five patients ( 33.3 % ) of the endovenous group had recurrent or residual varices and in three of them a reflux in the thigh veins was detected . None of the primarily occluded LSV segments was recanalized . In the stripping group , three patients ( 23.1 % , p = 0.68 ) showed varicosities at clinical and duplex examinations . In one patient , a patent duplicate LSV trunk was detected . In the remaining two patients , no reflux in the thigh region was detected . According to the present results , radiofrequency endovenous obliteration of the LSV is associated with somewhat poorer short-term results compared with the stripping operation This prospect i ve r and omized study compared the treatment of greater saphenous vein insufficiency by stripping and local avulsions of varicose veins with high ligation of the saphenofemoral junction ( crossectomy ) combined with sclerocompression therapy . Of 156 consecutive patients , 89 legs were r and omly allocated to stripping and 92 to high ligation . At follow-up of 3 months and 1 , 2 , and 3 years after treatment , clinical and Doppler ultrasound results , and complaints and cosmetic results , as judged by the patient and the surgeon , were scored . At 3 years , 69 limbs in the stripping group ( 78 % ) and 73 limbs in the ligation group ( 79 % ) were available to follow-up . The cosmetic results , both judged by the patient and the surgeon , were significantly better ( P < 0.05 ) in the stripped limbs than in the limbs with high ligation and sclerotherapy . Clinical and Doppler ultrasound evidence of reverse flow in the saphenous vein was significantly less ( P < 0.001 ) after the stripping operation . The results of treatment of isolated saphenous vein insufficiency by stripping operation , therefore , were superior to those obtained by high ligation combined with sclerotherapy Sensory impairment in the cutaneous distribution of the saphenous nerve was measured in 30 patients after bilateral stripping of the long saphenous vein . The vein was stripped upwards in one leg and downwards in the other . Three months after operation a significantly greater incidence of sensory loss was found in those legs in which the vein was stripped upwards ( 13 out of 26 ) compared with those which had been stripped downwards ( 6 out of 26 ) . We recommend that the long saphenous vein should be stripped downwards

Furthermore , compared with the placebo group , adverse events in the orlistat group were more severe . In the orlistat trials , we identified important disparities in the reporting of adverse events between protocol s , clinical study reports , and published papers . Reports of these trials seemed to have systematic ally understated adverse events .

BACKGROUND Little is known about how adverse events are summarised and reported in trials , as detailed information is usually considered confidential . We have acquired clinical study reports ( CSRs ) from the European Medicines Agency through the Freedom of Information Act . The CSRs describe the results of studies conducted as part of the application for marketing authorisation for the slimming pill orlistat . The purpose of this study was to study how adverse events were summarised and reported in study protocol s , CSRs , and published papers of orlistat trials .

BACKGROUND Long-term maintenance of weight loss remains a therapeutic challenge in obesity treatment . OBJECTIVE This multicenter , double-blind , placebo-controlled study was design ed to test the hypothesis that orlistat , a gastrointestinal lipase inhibitor , is significantly more effective than a placebo in preventing weight regain . DESIGN Obese subjects who lost > or = 8 % of their initial body weight during a 6-mo lead-in of a prescribed hypoenergetic diet ( 4180-kJ/d deficit ) with no adjunctive pharmacotherapy were r and omly assigned to receive placebo , 30 mg orlistat , 60 mg orlistat , or 120 mg orlistat 3 times daily for 1 y in combination with a maintenance diet to help prevent weight regain . Of 1313 recruited subjects [ body mass index ( in kg/m2 ) : 28 - 43 ] , 729 subjects lost > or = 8 % of their initial body weight during the 6-mo weight-loss lead-in period and were enrolled in the double-blind phase . RESULTS After 1 y , subjects treated with 120 mg orlistat 3 times daily regained less weight than did placebo-treated subjects ( 32.8 + /- 4.5 % compared with 58.7 + /- 5.8 % regain of lost weight ; P < 0.001 ) . Moreover , more subjects in the 120-mg orlistat group than in the placebo group regained < or = 25 % of lost weight ( 47.5 % of subjects compared with 29.9 % ) . In addition , orlistat treatment ( 120 mg 3 times daily ) was associated with significantly greater reductions in total and LDL-cholesterol concentrations than was placebo ( P < 0.001 ) . CONCLUSION The use of orlistat during periods of attempted weight maintenance minimizes weight readjustment and facilitates long-term improvement in obesity-related disease risk factors OBJECTIVE To evaluate the long-term efficacy and tolerability within primary care setting s of orlistat , a gastrointestinal lipase inhibitor , for the treatment of obesity . DESIGN R and omized , double-blind , placebo-controlled , multicenter study . PARTICIPANTS A group of 796 obese patients ( body mass index , 30 - 44 kg/m2 ) , treated with placebo 3 times a day ( TID ) , 60 mg of orlistat TID , or 120 mg of orlistat TID , in conjunction with a reduced-energy diet for the first year and a weight-maintenance diet during the second year . SETTING Seventeen primary care centers in the United States . MAIN OUTCOME MEASURES Changes in body weight and obesity-related disease risk factors . RESULTS Patients treated with orlistat lost significantly more weight ( 7.08 + /- 0.54 and 7.94 + /- 0.57 kg for the 60-mg and 120-mg orlistat groups , respectively ) than those treated with placebo ( 4.14 + /- 0.56 kg ) in year 1 ( P<.001 ) and sustained more of this weight loss during year 2 ( P<.001 ) . More patients treated with orlistat lost 5 % or more of their initial weight in year 1 ( 48.8 % and 50.5 % of patients in the 60-mg and 120-mg groups , respectively ) compared with placebo ( 30.7 % ; P<.001 ) , and approximately 34 % of patients in the orlistat groups sustained weight loss of 5 % or greater over 2 years compared with 24 % in the placebo group ( P<.001 ) . Orlistat produced greater improvements than placebo in serum lipid levels and blood pressure and was well tolerated , although treatment result ed in a higher incidence of gastrointestinal events . CONCLUSIONS This long-term study indicates that orlistat is an effective adjunct to dietary intervention in the treatment of obesity in primary care setting Reporting harms may cause more trouble and discredit than the fame and glory associated with successful reporting of benefits ( 1 ) . The CONSORT ( Consoli date d St and ards of Reporting Trials ) statement , a checklist ( Table 1 ) flow diagram first published in 1996 and revised 5 years later ( 2 , 3 ) , is an effort to st and ardize , and thereby improve , published reports of r and omized , controlled trials ( RCTs ) . One of the additions to the 2001 revision was an item about reporting adverse events . This single item did not do full justice to the importance of harms-related issues . The CONSORT Group met in September 2001 to discuss how to correct this deficiency . We aim ed to provide evidence -based guidance on the reporting of harms in RCTs . First , we search ed MEDLINE , EMBASE , Web of Science , and the Cochrane Library using a wide array of terms related to harms and identified pertinent evidence . We also communicated with experts and review ed bibliographies of identified articles to find additional studies . At a meeting in Montebello , Quebec , Canada , in May 2003 , CONSORT Group members , including several journal editors and additional experts in related fields , held a structured discussion of recommendations about reporting of harms-related issues in RCTs . The discussion s led to a written document that we circulated among the team members for comment . The present manuscript describes our recommendations on the appropriate reporting of harms in RCTs . Table 1 . Original CONSORT Checklist The terminology of harms-related issues in RCTs is confusing and often misleading or misused ( see Glossary ) ( 4 , 5 ) . Safety is a reassuring term that may obscure the real and potentially major harms that drugs and other interventions may cause . We encourage authors to use the term harms instead of safety . In addition to misused terminology , reporting of harms in RCTs has received less attention than reporting of efficacy and effectiveness and is often inadequate ( 6 - 14 ) . In short , both scientific evidence and ethical necessity call for action to improve the quality of reporting of harms in RCTs ( 15 , 16 ) . Here , we present a set of recommendations and accompanying explanations for the proper reporting of harms in RCTs . These recommendations should complement the existing CONSORT statement ( Table 2 ) . Examples are presented on the Annals and CONSORT ( www.consort-statement.org ) Web sites . Table 2 . Checklist of Items To Include When Reporting Harms in R and omized , Controlled Trials Recommendations Title and Abstract Recommendation 1 . If the study collected data on harms and benefits , the title or abstract should so state . The title should mention harms if the study of harms was a key trial objective . Many phase I and phase II trials , some phase II/III trials , and most phase IV trials ( 17 , 18 ) target harms as primary outcomes . Yet , the title and abstract seldom contain the word harm . Among 375143 entries in the Cochrane Central Register of Controlled Trials ( Cochrane Library , issue 3 , 2003 ) , search ing titles with the search terms harm or harms yielded 337 references ( compared with 55374 for efficacy and 23415 for safety ) . Of the 337 , excluding several irrelevant articles on self-harm or harm reduction , only 3 trial reports and 2 abstract s contained the word harm in their titles . Authors should present information on harms in the abstract . If no important harms occurred , authors should so state . Explicit reference to the reporting of adverse events in the title or abstract is also important for appropriate data base indexing and information retrieval ( 19 ) . Introduction Background Recommendation 2 . If the trial addresses both harms and benefits , the introduction should so state . The introduction states the scientific background and rationale of an RCT . This requires a balanced presentation whereby the possible benefits of the intervention under investigation are outlined along with the possible harms associated with the treatment . R and omized , controlled trials that focus primarily on harms should clearly state this interest when describing the study objectives in the Introduction and in defining these objectives in the Methods . Methods Outcomes Recommendation 3 . List addressed adverse events with definitions for each ( with attention , when relevant , to grading , expected vs. unexpected events , reference to st and ardized and vali date d definitions , and description of new definitions ) . The Methods section should succinctly define the recorded adverse events ( clinical and laboratory ) . Authors should clarify whether the reported adverse events encompass all the recorded adverse events or a selected sample . They should explain how , why , and who selected adverse events for reporting . In trials that do not mention harms-related data , the Methods section should briefly explain the reason for the omission ( for example , the design did not include the collection of any information on harms ) . Authors should also be explicit about separately reporting anticipated and unexpected adverse events . Expectation may influence the incidence of reported or ascertained adverse events . Making participants aware in the consent form of the possibility of a specific adverse event ( priming ) may increase the reporting rate of the event ( 20 ) . Another example of priming is the finding that the rates of withdrawals due to adverse events and the rates of specific adverse events were significantly higher in trials of aspirin , diclofenac , or indomethacin with comparator drugs compared with placebo-controlled trials ( 21 ) . Presumably , participants were more eager to come forth and report an adverse event or to withdraw from treatment when they knew they could not be receiving inactive placebo . Authors should report whether they used st and ardized and vali date d measurement instruments for adverse events . Several medical fields have developed st and ardized scales ( 22 - 32 ) . Use of nonvali date d scales is common . The source document for well-established definitions and scales should be referenced . New definitions for adverse events should be explicit and clear . Authors should describe how they developed and vali date d new scales . For interventions that target healthy individuals ( for example , many preventive interventions ) , any harm , however minor , may be important to capture and report because the balance of harms and benefits may easily lean toward harms in a low-risk population . For other population s and for interventions that improve major outcomes ( for example , survival ) , severe and life-threatening adverse events may be the only ones that are important in the balance of benefits and harms . Recommendation 4 . Clarify how harms-related information was collected ( mode of data collection , timing , attribution methods , intensity of ascertainment , and harms-related monitoring and stopping rules , if pertinent ) . It is important to describe the question naires , interviews , and tests used to collect information on harms , as well as their timing during follow-up . Passive surveillance of harms leads to fewer recorded adverse events than active surveillance ( 4 ) . Open-ended questions may yield different information , both quantitatively and qualitatively , than structured question naires ( 33 ) . Studies of nonsteroidal , anti-inflammatory drugs ( NSAIDs ) exemplify how data collection methods can affect the detection and reporting of harms . When selective NSAIDs with fewer gastrointestinal adverse events became available , trials reported more than 10 times as many ulcers when comparing these drugs with older NSAIDs as when older NSAIDs were compared with placebo . In the newer trials , more ulcers were detected because participants had regular endoscopy , and the case definition of ulcers was more sensitive ( 34 ) . Authors should specify the time frame of surveillance for adverse events . Some investigators stop recording adverse events at the end of the intervention period or a certain number of days afterward ( for example , 30 days after discontinuation of drug therapy ) and miss events with long latency ( 35 ) . Surgical trials often capture only the adverse events that occur intraoperatively . Several important surgical complications are likely to occur later . Finally , in crossover trials , delayed events might occur while the patient is taking a subsequent assigned treatment . Attribution is the process of deciding whether an adverse event is related to the intervention . Whenever authors filter events through an attribution process , they should state who makes the attribution ( investigators , participants , sponsors , or combinations ) , whether the process is blinded to assigned treatment , and what definitions of adverse events they use ( 4 ) . Discontinuations and withdrawals due to adverse events are especially important because they reflect the ultimate decision of the participant and /or physician to discontinue treatment . Although treatment may occasionally be discontinued for mild or moderate adverse events , attributing discontinuation to a specific reason ( to toxicity , lack of efficacy , other reasons , or combinations of reasons ) may be difficult . For example , in psychopharmacology , dropouts may reflect treatment ineffectiveness as much as toxicity-related intolerance ( 36 ) . Trial reports should specify who gave the reasons for discontinuation ( participants or physicians ) and whether attribution was blinded to the assigned treatment . For example , even in blinded trials , participants and their clinicians are often unblinded before they decide whether to discontinue the intervention . It is important to report participants who are nonadherent or lost to follow-up because their actions may reflect their inability to tolerate the intervention . Moreover , authors should specify how they h and led withdrawals in the analyses of the data . R and omized , controlled trials should report any plan for monitoring for harms and rules for stopping the trial because of harms ( 37 ) . They should clarify whether stopping guidelines examine benefits and harms BACKGROUND Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30 % , promotes weight loss , and may reduce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects . OBJECTIVE To test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes status more effectively than placebo . METHODS We pooled data from 675 obese ( body mass index , 30 - 43 kg/m2 ) adults at 39 US and European research centers in 3 r and omized , double-blind , placebo-controlled multicenter clinical trials . Subjects received placebo plus a low-energy diet during a 4-week lead-in period . On study day 1 , the diet was continued , and subjects were r and omized to receive placebo 3 times a day ( n=316 ) or treatment with orlistat , 120 mg 3 times a day ( n=359 ) , for 104 weeks . A st and ard 3-hour oral glucose tolerance test was performed on day 1 and at the end of treatment . MAIN OUTCOME MEASURES The categorical assessment of glucose tolerance status ( normal , impaired , diabetic ) and changes in status from r and omization to end of treatment were the primary efficacy measures . The secondary measures were fasting and postchallenge glucose and insulin levels . RESULTS The mean length of follow-up was 582 days . Subjects who were treated with orlistat lost more weight ( mean + /- SEM , 6.72 + /- 0.41 kg from initial weight ) than subjects who received placebo ( 3.79+/-0.38 kg ; P<.001 ) . A smaller percentage of subjects with impaired glucose tolerance at baseline progressed to diabetic status in the orlistat ( 3.0 % ) vs placebo ( 7.6 % ) group . Conversely , among subjects with impaired glucose tolerance at baseline , glucose levels normalized in more subjects after orlistat treatment ( 71.6 % ) vs placebo ( 49.1 % ; P=.04 ) . CONCLUSIONS The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of impaired glucose tolerance and type 2 diabetes This study describes the changes in risk factors for coronary heart disease in obese persons with syndrome X after orlistat-assisted weight loss . Data were available for 1,700 patients who completed 52 weeks of weight loss ; 128 were defined as having syndrome X by being in the quintile with the highest plasma triglyceride levels ( > 2.2 mM/L ) and the lowest high-density lipoprotein cholesterol ( HDL , < 1.0 mM/L ) concentrations . Initial characteristics of those with syndrome X were similar to the 119 subjects ( non-syndrome X ) in the lowest quintile of plasma triglyceride ( < 0.975 mM/L ) and highest quintile of HDL cholesterol ( > 1.5 mM/L ) . Subjects were placed on a calorie-restricted diet , and r and omized to receive orlistat or placebo . Initial values were higher in those with syndrome X for diastolic blood pressure ( p = 0.03 ) , plasma insulin ( p = 0.0001 ) , triglyceride ( p = 0.0001 ) concentrations , and ratio of low-density lipoprotein cholesterol to HDL cholesterol ( p = 0.0001 ) , and were lower for HDL cholesterol ( p = 0.001 ) concentrations . Weight loss was greater in both groups of orlistat-treated patients ( p = 0.026 ) ; in those with syndrome X , it was associated with a significant reduction in plasma insulin ( p = 0.019 ) and triglyceride ( p = 0.0001 ) concentrations , an increase in HDL cholesterol concentration , and a decrease in low-density lipoprotein/HDL cholesterol ratio ( p = 0.0001 ) . There were no significant changes in plasma insulin , triglycerides , or HDL cholesterol concentration in the non-syndrome X group . In conclusion , weight loss attenuates coronary heart disease risk factors in obese persons with syndrome X , and the risk factor reduction is enhanced with administration of orlistat OBJECTIVE To determine the effect of orlistat , a new lipase inhibitor , on long-term weight loss , to determine the extent to which orlistat treatment minimizes weight regain in a second year of treatment , and to assess the effects of orlistat on obesity-related risk factors . RESEARCH METHODS AND PROCEDURES This was a 2-year , multicenter , r and omized , double-blind , placebo-controlled study . Obese patients ( body mass index 28 to 43 kg/m2 ) were r and omized to placebo or orlistat ( 60 or 120 mg ) three times a day , combined with a hypocaloric diet during the first year and a weight maintenance diet in the second year of treatment to prevent weight regain . Changes in body weight , lipid profile , glycemic control , blood pressure , quality of life , safety , and tolerability were measured . RESULTS Orlistat-treated patients lost significantly more weight ( p<0.001 ) than placebo-treated patients after Year 1 ( 6.6 % , 8.6 % , and 9.7 % for the placebo , and orlistat 60 mg and 120 mg groups , respectively ) . During the second year , orlistat therapy produced less weight regain than placebo ( p = 0.005 for orlistat 60 mg ; p<0.001 for orlistat 120 mg ) . Several obesity-related risk factors improved significantly more with orlistat treatment than with placebo . Orlistat was generally well tolerated and only 6 % of orlistat-treated patients withdrew because of adverse events . Orlistat leads to predictable gastrointestinal effects related to its mode of action , which were generally mild , transient , and self-limiting and usually occurred early during treatment . DISCUSSION Orlistat administered for 2 years promotes weight loss and minimizes weight regain . Additionally , orlistat therapy improves lipid profile , blood pressure , and quality of life CONTEXT Orlistat , a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30 % , may promote weight loss and reduce cardiovascular risk factors . OBJECTIVE To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years . DESIGN R and omized , double-blind , placebo-controlled study conducted from October 1992 to October 1995 . SETTING AND PARTICIPANTS Obese adults ( body mass index [ weight in kilograms divided by the square of height in meters ] , 30 - 43 kg/m2 ) evaluated at 18 US research centers . INTERVENTION Subjects received placebo plus a controlled-energy diet during a 4-week lead-in . On study day 1 , the diet was continued and subjects were r and omized to receive placebo 3 times a day or orlistat , 120 mg 3 times a day , for 52 weeks . After 52 weeks , subjects began a weight-maintenance diet , and the placebo group ( n = 133 ) continued to receive placebo and orlistat-treated subjects were rer and omized to receive placebo 3 times a day ( n = 138 ) , orlistat , 60 mg ( n = 152 ) or 120 mg ( n = 153 ) 3 times a day , for an additional 52 weeks . MAIN OUTCOME MEASURES Body weight change and changes in blood pressure and serum lipid , glucose , and insulin levels . RESULTS A total of 1187 subjects entered the protocol , and 892 were r and omly assigned on day 1 to double-blind treatment . For intent-to-treat analysis , 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated . During the first year orlistat-treated subjects lost more weight ( mean + /- SEM , 8.76+/-0.37 kg ) than placebo-treated subjects ( 5.81+/-0.67 kg ) ( P<.001 ) . Subjects treated with orlistat , 120 mg 3 times a day , during year 1 and year 2 regained less weight during year 2 ( 3.2+/-0.45 kg ; 35.2 % regain ) than those who received orlistat , 60 mg ( 4.26+/-0.57 kg ; 51.3 % regain ) , or placebo ( 5.63+/-0.42 kg ; 63.4 % regain ) in year 2 ( P<.001 ) . Treatment with orlistat , 120 mg 3 times a day , was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels . CONCLUSIONS Two-year treatment with orlistat plus diet significantly promotes weight loss , lessens weight regain , and improves some obesity-related disease risk factors Objective To study the efficacy of orlistat , as an adjunct to dietary modification , in weight reduction and modification of cardiovascular risk factors in obese patients after 1 year of treatment . Design A total of 3132 obese patients ( body mass index 28–43 kg/m2 ) were evaluated in an analysis of pooled data from five r and omized , double-blind , placebocontrolled trials of orlistat in conjunction with a hypocaloric diet . All studies included a 4-week , single-blind , placebo lead-in period during which patients followed a mildly hypocaloric diet , after which they were r and omized to double-blind treatment with orlistat 120 mg three times a day ( tid ) or placebo for 1 year . Results After 1 year , orlistat 120 mg tid produced significantly more weight loss than placebo ( 9.2 % vs 5.8 % ; P < 0.001 ) . Furthermore , a greater proportion of orlistat-treated patients lost > 5 % or > 10 % of their initial body weight compared to placebo ( 69.6 % vs 51.9 % ; P < 0.001 and 42.1 % vs 22.7 % ; P < 0.001 , respectively ) . Improvements in cardiovascular risk factors were observed during a 4-week placebo lead-in period . However , following r and omization , orlistat-treated patients had significantly greater improvements than placebo-treated patients in several lipid parameters including total cholesterol , low-density lipoproteincholesterol , triglycerides , and apolipoprotein B. In addition , orlistat had a beneficial effect on oral glucose tolerance tests status , waist circumference and systolic and diastolic blood pressure . Orlistat was well tolerated and had a similar safety profile to placebo OBJECTIVE Obesity is an important risk factor for type 2 diabetes . Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors , but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise . The purpose of this study was to assess the impact of treatment with orlistat , a pancreatic lipase inhibitor , on weight loss , glycemic control , and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications . RESEARCH DESIGN AND METHODS In a multicenter 57-week r and omized double-blind placebo-controlled study , 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years , had a BMI of 28–40 kg/m2 , and were clinical ly stable on oral sulfonylureas . Changes in body weight , glycemic control , lipid levels , and drug tolerability were measured . RESULTS After 1 year of treatment , the orlistat group lost 6.2 ± 0.45 % ( mean ± SEM ) of initial body weight vs. 4.3 ± 0.49 % in the placebo group ( P < 0.001 ) . Twice as many patients receiving orlistat ( 49 vs. 23 % ) lost ≥ 5 % of initial body weight ( P < 0.001 ) . Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control , as reflected in decreases in HbA1c ( P < 0.001 ) and fasting plasma glucose ( P < 0.001 ) and in dosage reductions of oral sulfonylurea medication ( P < 0.01 ) . Orlistat therapy also result ed in significantly greater improvements than placebo in several lipid parameters , namely , greater reductions in total cholesterol , ( P < 0.001 ) , LDL cholesterol ( P < 0.001 ) , triglycerides ( P < 0.05 ) , apolipoprotein B ( P < 0.001 ) , and the LDL-to-HDL cholesterol ratio ( P < 0.001 ) . Mild to moderate and transient gastrointestinal events were reported with orlistat therapy , although their association with study withdrawal was low . Fat-soluble vitamin levels generally remained within the reference range , and vitamin supplementation was required in only a few patients . CONCLUSIONS Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinical ly meaningful weight loss and maintenance of weight loss , improved glycemic control , and improved lipid profile OBJECTIVE : To examine the effect of orlistat ( Xenical ™ ) treatment on body composition and resting energy expenditure ( REE ) during a 2 y weight-reduction programme in obese Finns . SUBJECTS : Of initially 96 obese subjects who participated in the weight-reduction programme , those 72 subjects ( 13 men , 59 women , body mass index ( BMI ) 35.9±3.9 kg/m2 , age 43.4±6.0 y , mean±s.d . ) with the complete set of data for 2 y were included in the study . DESIGN : After a 4-week lead-in period , subjects were r and omized with either orlistat 120 mg t.i.d . or placebo t.i.d . in conjunction with a mildly hypoenergetic balanced diet for 1 y. This was followed by 1 y double-blind period with the subjects within each treatment group re-assigned to receive orlistat 120 mg t.i.d . or placebo t.i.d . in conjunction with a weight maintenance diet . MEASUREMENTS : Body composition and REE were measured after an overnight fast by a bioelectrical impedance method and indirect calorimeter , respectively . The measurements were performed at the beginning and at 3 , 6 , 12 and 24 months . RESULTS : During the first year , the orlistat-treated group had greater reduction of body weight and fat mass but not of fat-free mass or REE as compared to placebo . During the second year , orlistat treatment was associated with smaller regain of body weight and fat mass with no significant differences in the changes of fat-free mass or REE as compared to placebo . CONCLUSION : In addition to better weight loss and maintenance of reduced weight , orlistat treatment is associated with beneficial changes in body composition but with no excess decrease in resting energy expenditure as compared to that achieved during placebo with a dietary therapy alone Objective : Orlistat and sibutramine are widely prescribed antiobesity agents that are approved for 2 years of continuous use . Previous 1–4-year r and omized , placebo-controlled trials of these drugs have reported average weight losses of < 5 kg , significant adverse effects and attrition rates of up to 60 % . The objective of this study was to determine the long-term persistence with orlistat and sibutramine therapy outside a clinical trial setting . Design , setting and patients : Population -based administrative data from British Columbia , Canada , were used to create an inception cohort of orlistat and sibutramine users and determine the 2-year persistence with therapy . Main outcome measure : Persistence with therapy at 2 years . Drug discontinuation was defined as the failure to refill a prescription within 120 days . Patients discontinuing therapy were censored at the 60-day mark . Results : Nearly 17 000 users of orlistat and 3500 users of sibutramine were identified . For both orlistat and sibutramine , 1-year persistence rates were < 10 % and 2-year persistence rates were 2 % . Conclusion : This population -based , retrospective cohort analysis demonstrated very poor long-term persistence rates with orlistat and sibutramine and discontinuation rates that were much higher than those reported in clinical trials Objective To explore the structure and content of a non-r and om sample of clinical study reports ( CSRs ) to guide clinicians and systematic review ers . Search strategy We search ed public sources and lodged Freedom of Information requests for previously confidential CSRs primarily written by the industry for regulators . Selection criteria CSRs reporting sufficient information for extraction ( ‘ adequate ’ ) . Primary outcome measures Presence and length of essential elements of trial design and reporting and compression factor ( ratio of page length for CSRs compared to its published counterpart in a scientific journal ) . Data extraction Data were extracted on st and ard forms and crosschecked for accuracy . Results We assembled a population of 78 CSRs ( covering 90 r and omised controlled trials ; 144 610 pages total ) date d 1991–2011 of 14 pharmaceuticals . Report synopses had a median length of 5 pages , efficacy evaluation 13.5 pages , safety evaluation 17 pages , attached tables 337 pages , trial protocol 62 pages , statistical analysis plan 15 pages and individual efficacy and safety listings had a median length of 447 and 109.5 pages , respectively . While 16 ( 21 % ) of CSRs contained completed case report forms , these were accessible to us in only one case ( 765 pages representing 16 individuals ) . Compression factors ranged between 1 and 8805 . Conclusions Clinical study reports represent a hitherto mostly hidden and untapped source of detailed and exhaustive data on each trial . They should be consulted by independent parties interested in a detailed record of a clinical trial , and should form the basic unit for evidence synthesis as their use is likely to minimise the problem of reporting bias . We can not say whether our sample is representative and whether our conclusions are generalisable to an undefined and undefinable population of CSRs OBJECTIVE : To assess the clinical usefulness of published guidelines for the use of orlistat , by study ing whether weight loss ≥2.5 kg during a 4 week dietary lead-in period , and weight losses of ≥5 % after 12 weeks and ≥10 % after 6 months of drug therapy predict weight loss and risk factor changes after 2 years . DESIGN : A retrospective analysis of pooled data from 2 multicentre , r and omised , placebo-controlled clinical trials with similar design . SETTING : Twenty-nine centres throughout Europe . PARTICIPANTS : Two hundred and twenty men and women ( BMI 28–43 kg/m2 ) who completed 2 years of treatment . INTERVENTION : After a 4 week hypocaloric diet plus placebo , 2 years of treatment with orlistat 120 mg tid , plus a hypocaloric diet for the first year and a weight maintenance diet in year two . MAIN OUTCOME MEASURES : Weight loss and obesity-related risk factor changes . RESULTS : Weight loss ≥5 % body weight after 12 weeks of diet plus orlistat therapy was a good indicator of 2 year weight loss , whereas weight loss of ≥2.5 kg during the 4 week lead-in and ≥10 % after 6 months did not add significantly to the prediction of 2 year outcomes . Patients who lost ≥5 % of their weight at 12 weeks ( n=104 , 47.3 % ) lost significantly more weight after 2 years than others : −11.9 % ( 95 % confidence interval ( CI ) −13.4 % to −10.3 % ) vs −4.7 % ( −5.7 % to −3.7 % ) ( P=0.0001 ) , and had significantly greater reductions in total cholesterol , LDL-cholesterol , triglycerides , glucose , insulin , and blood pressure . Among those who achieved ≥5 % weight loss at 12 weeks , the overall health benefits were not significantly greater in patients who went on to lose ≥10 % body weight at 6 months compared with those who did not achieve ≥10 % weight loss by month 6 . CONCLUSIONS : Of the criteria currently suggested for assessing response to orlistat treatment , weight loss of ≥5 % at 12 weeks accurately predicts sustained improvements in weight and major risk factors at 2 years , while other suggested criteria are less useful BACKGROUND We undertook a r and omised controlled trial to assess the efficacy and tolerability of orlistat , a gastrointestinal lipase inhibitor , in promoting weight loss and preventing weight regain in obese patients over a 2-year period . METHODS 743 patients ( body-mass index 28 - 47 kg/m2 ) , recruited at 15 European centres , entered a 4-week , single-blind , placebo lead-in period on a slightly hypocaloric diet ( 600 kcal/day deficit ) . 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg ( three times a day ) or placebo for 1 year in conjunction with the hypocaloric diet . In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance ( eucaloric ) diet . FINDINGS From the start of lead-in to the end of year 1 , the orlistat group lost , on average , more bodyweight than the placebo group ( 10.2 % [ 10.3 kg ] vs 6.1 % [ 6.1 kg ] ; LSM difference 3.9 kg [ p<0.001 ] from r and omisation to the end of year 1 ) . During year 2 , patients who continued with orlistat regained , on average , half as much weight as those patients switched to placebo ( p<0.001 ) . Patients switched from placebo to orlistat lost an additional 0.9 kg during year 2 , compared with a mean regain of 2.5 kg in patients who continued on placebo ( p<0.001 ) . Total cholesterol , low-density lipoprotein ( LDL ) cholesterol , LDL/high-density lipoprotein ratio , and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group . Gastrointestinal adverse events were more common in the orlistat group . Other adverse symptoms occurred at a similar frequency during both treatments . INTERPRETATION Orlistat taken with an appropriate diet promotes clinical ly significant weight loss and reduces weight regain in obese patients over a 2-year period . The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events OBJECTIVES This paper describes the methodology of a multicentre study design ed to assess the efficacy and tolerability of orlistat 120 mg tid as therapy for inducing weight loss in excess of that achieved with a moderately calorie-restricted diet alone . The results from a single centre are presented to illustrate the nature of the response . DESIGN This was a double-blind , r and omized , parallel-group , placebo-controlled multicentre study . A four-week , single-blind , placebo run-in period preceded a 52 week double-blind treatment period during which patients received either orlistat or placebo three times a day . At the start of the run-in period , all patients were placed on a diet containing approximately 30 % of calories as fat and design ed to cause an energy deficit of approximately 600 kcal/d . SUBJECTS Patients of either sex , more than 18 y of age , with a body mass index ( BMI ) between 30 and 43 kg/m2 were eligible for enrolment . MEASUREMENTS Efficacy assessment s included : measurements of body weight ; anthropometry ; quality of life ; blood pressure ; serum lipids ; fasting serum glucose and insulin . Safety assessment s included : adverse events ; vital signs ; ECG ; renal and gallbladder ultrasound ; haematology ; serum biochemistry . OUTCOME In the single centre there was a reduction in body weight of 5.5 + /- 4.5 ( s.d . ) kg ( 5.7 % reduction ) in the placebo group and 8.6 + /- 5.4 kg in the orlistat-treated group ( 8.4 % reduction ) by six months . Thereafter , the placebo group tended to relapse whereas the orlistat group maintained their loss ( 2.6 % vs 8.4 % reduction from initial value at 52 weeks ) . Total and LDL cholesterol fell by 0.05 mmol/l ( 1.6 % ) and 0.14 mmol/l ( 4.2 % ) , respectively , in orlistat treated patients . The drop-out rate was 48 % in the placebo group and 39 % in the orlistat group . Intestinal symptoms related to orlistat were significantly increased compared to placebo but were well tolerated . Fat soluble vitamin levels remained within the normal range in the treatment group ; the reduction seen in alpha-tocopherol levels in patients receiving orlistat was normalized by the decrease in plasma cholesterol concentrations . Beta-carotene and vitamin D concentrations also decreased in orlistat-treated patients . CONCLUSIONS This preliminary analysis suggests that orlistat , when used with a health-promoting low-fat and moderately energy-restricted diet , confers advantages in the long-term management of obesity BACKGROUND We undertook a r and omised controlled trial to assess the efficacy and tolerance of orlistat , a gastrointestinal lipase inhibitor , in promoting weight loss and preventing weight regain in obese patients over a 2-year period . METHODS 743 patients ( body-mass index 28 - 47 kg/m2 ) , recruited at 15 European centres , entered a 4-week , single-blind , placebo lead-in period on a slightly hypocaloric diet ( 600 kcal/day deficit ) . 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg ( three times a day ) or placebo for 1 year in conjunction with the hypocaloric diet . In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance ( eucaloric ) diet . FINDINGS From the start of lead-in to the end of year 1 , the orlistat group lost , on average , more bodyweight than the placebo group ( 10.2 % [ 10.3 kg ] vs 6.1 % [ 6.1 kg ] ; LSM difference 3.9 kg [ p < 0.001 ] from r and omisation to the end of year 1 ) . During year 2 , patients who continued with orlistat regained , on average , half as much weight as those patients switched to placebo ( p < 0.001 ) . Patients switched from placebo to orlistat lost an additional 0.9 kg during year 2 , compared with a mean regain of 2.5 kg in patients who continued on placebo ( p < 0.001 ) . Total cholesterol , low-density lipoprotein ( LDL ) cholesterol , LDL/high-density lipoprotein ratio , and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group . Gastrointestinal adverse events were more common in the orlistat group . Other adverse symptoms occurred at a similar frequency during both treatments . INTERPRETATION Orlistat taken with an appropriate diet promotes clinical ly significant weight loss and reduces weight regain in obese patients over a 2-year period . The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events OBJECTIVE : To assess the efficacy and tolerability of orlistat ( Xenical ® ) in producing and maintaining weight loss over a 12-month period . DESIGN : Patients were r and omized to double-blind treatment with either orlistat 120 mg or placebo three times daily , in conjunction with a low-energy diet , for 12 months . SETTING : Five centres in the UK.SUBJECTS : 228 obese adult patients with body mass index between 30 and 43 kg/m2 and mean weight 97 kg ( range 74–144 kg ) . INTERVENTIONS : All patients were prescribed a low-energy diet , providing 30 % of energy from fat , design ed to produce an individually tailored energy deficit of approximately 600 kcal/day , for a run-in period of 4 weeks and then 12 months , plus orlistat 120 mg or placebo three times daily . MAIN OUTCOME MEASURES : Change in body weight ( the primary efficacy parameter ) , waist circumference and adverse events were review ed regularly , together with serum lipids , insulin , glucose and plasma levels of fat-soluble vitamins and β carotene . RESULTS : Based on an intent-to-treat analysis , after 1 y of treatment patients receiving orlistat had lost an average of 8.5 % of their initial body weight compared with 5.4 % for placebo-treated patients ; 35 % of the orlistat group lost at least 5 % of body weight compared with 21 % of the placebo group ( P<0.05 ) , and 28 % and 17 % , respectively ( P=0.04 ) lost at least 10 % of body weight . Orlistat-treated patients showed significant decreases ( P<0.05 ) in serum levels of total cholesterol , low density lipoprotein cholesterol , and in the low density lipoprotein : high density lipoprotein ratio in comparison with placebo . Both groups had similar adverse-event profiles , except for gastrointestinal events , which were 26 % more frequent in the orlistat group but were mostly mild and transient . To maintain normal plasma levels of fat-soluble vitamins , supplements of vitamins A , D and E were given to 1.8 % , 8.0 % and 3.6 % , respectively , of orlistat-treated patients , compared with 0.9 % of placebo-treated patients for each vitamin type . After 1 y , the decrease in vitamin E and β carotene was significantly greater in orlistat-treated patients compared with those receiving placebo ( P<0.001 ) . No significant change was found in the mean vitamin E : total cholesterol ratio in either group after 52 weeks . Conclusions : Orlistat , in conjunction with a low-energy diet , produced greater and more frequent significant weight loss than placebo during 1 y of treatment . One-third of orlistat-treated patients achieved clinical ly relevant weight loss ( ≥5 % initial body weight ) . There was also an improvement in relevant serum lipid parameters . Fat-soluble vitamin supplements may be required during chronic therapy . Orlistat was well tolerated and offers a promising new approach to the long-term management of obesity

The circadian clock is reset in traditional-age college students leading to delayed sleep times . Newly realized autonomy and increased use of technology also prevent traditional-age college students from obtaining sufficient sleep . Insufficient sleep may result in poor academic performance influencing subsequent health outcomes .

Insufficient sleep experienced by these students has been linked to insulin resistance , hypertension , diabetes , weight gain , and stress . Sleep insufficiency increases the risk for pedestrian , motor vehicle , and domestic and occupational injuries .

Background Energy drink consumption has continued to gain in popularity since the 1997 debut of Red Bull , the current leader in the energy drink market . Although energy drinks are targeted to young adult consumers , there has been little research regarding energy drink consumption patterns among college students in the United States . The purpose of this study was to determine energy drink consumption patterns among college students , prevalence and frequency of energy drink use for six situations , namely for insufficient sleep , to increase energy ( in general ) , while study ing , driving long periods of time , drinking with alcohol while partying , and to treat a hangover , and prevalence of adverse side effects and energy drink use dose effects among college energy drink users . Methods Based on the responses from a 32 member college student focus group and a field test , a 19 item survey was used to assess energy drink consumption patterns of 496 r and omly surveyed college students attending a state university in the Central Atlantic region of the United States . Results Fifty one percent of participants ( n = 253 ) reported consuming greater than one energy drink each month in an average month for the current semester ( defined as energy drink user ) . The majority of users consumed energy drinks for insufficient sleep ( 67 % ) , to increase energy ( 65 % ) , and to drink with alcohol while partying ( 54 % ) . The majority of users consumed one energy drink to treat most situations although using three or more was a common practice to drink with alcohol while partying ( 49 % ) . Weekly jolt and crash episodes were experienced by 29 % of users , 22 % reported ever having headaches , and 19 % heart palpitations from consuming energy drinks . There was a significant dose effect only for jolt and crash episodes . Conclusion Using energy drinks is a popular practice among college students for a variety of situations . Although for the majority of situations assessed , users consumed one energy drink with a reported frequency of 1 – 4 days per month , many users consumed three or more when combining with alcohol while partying . Further , side effects from consuming energy drinks are fairly common , and a significant dose effect was found with jolt and crash episodes . Future research should identify if college students recognize the amounts of caffeine that are present in the wide variety of caffeine-containing products that they are consuming , the amounts of caffeine that they are consuming in various situations , and the physical side effects associated with caffeine consumption Objective : Several epidemiologic , longitudinal studies have reported that short sleep duration is a risk factor for the incidence of obesity . However , the vast majority of these studies used self-reported measures of sleep duration and did not examine the role of objective short sleep duration , subjective sleep disturbances and emotional stress . Design : Longitudinal , population -based study .Subjects : We studied a r and om sample of 815 non-obese adults from the Penn State Cohort in the sleep laboratory for one night using polysomnography ( PSG ) and followed them up for a mean of 7.5 years . Subjective and objective measures of sleep as well as emotional stress were obtained at baseline . Obesity was defined as a body mass index ( BMI ) ⩾30 kg/ m-2 . Results : The incidence of obesity was 15 % and it was significantly higher in women and in individuals who reported sleep disturbances , shorter sleep duration and higher emotional stress . Significant mediating effects showed that individuals with subjective sleep disturbances who developed obesity reported the shortest sleep duration and the highest emotional stress , and that subjective sleep disturbances and emotional stress were independent predictors of incident obesity . Further analyses revealed that the association between short sleep duration , subjective sleep disturbances and emotional stress with incident obesity was stronger in young and middle-age adults . Objective short sleep duration was not associated with a significantly increased risk of incident obesity . Conclusion : Self-reported short sleep duration in non-obese individuals at risk of developing obesity is a surrogate marker of emotional stress and subjective sleep disturbances . Objective short sleep duration is not associated with a significant increased risk of incident obesity . The detection and treatment of sleep disturbances and emotional stress should become a target of our preventive strategies against obesity Objective : The authors ' purpose in this study was to determine the sleep patterns of college students to identify problem areas and potential solutions . Participants : A total of 313 students returned completed surveys . Methods : A sleep survey was e-mailed to a r and om sample of students at a North Central university . Questions included individual sleep patterns , problems , and possible influencing factors . Results : Most students reported later bedtimes and rise times on weekends than they did on weekdays . More than 33 % of the students took longer than 30 minutes to fall asleep , and 43 % woke more than once nightly . More than 33 % reported being tired during the day . The authors found no differences between freshmen , sophomores , juniors , seniors , and graduate students for time to fall asleep , number of night wakings , or total time slept each night . Conclusions : Many students have sleep problems that may interfere with daily performance , such as driving and academics . Circadian rhythm management , sleep hygiene , and white noise could ameliorate sleep difficulties STUDY OBJECTIVES To describe the technology use and sleep quality of Americans , and the unique association between technology use and sleep disturbances . METHODS Interviews were conducted via r and om digit dialing ( N = 750 ) or the Internet ( N = 758 ) . 1,508 Americans ( 13 - 64 years old , 50 % males ) matched to 2009 U.S. Census data provided complete interviews . The sample was further divided into adolescents ( 13 - 18 years , N = 171 ) , young adults ( 19 - 29 years , N = 293 ) , middle-aged adults ( 30 - 45 years , N = 469 ) , and older adults ( 46 - 64 years , N = 565 ) to contrast different generations ' technology use . Participants answered a 47-item semi-structured survey , including questions about their sleep habits , and the presence and use of technology in the hour before bed in the past 2 weeks . RESULTS Nine of 10 Americans reported using a technological device in the hour before bed ( e.g. , TVs the most popular ; 60 % ) . However , those under 30 years of age were more likely to use cell phones ( 72 % of adolescents , 67 % of young adults ) than those over 30 years ( 36 % of middle-aged , and 16 % of older adults ) . Young adults ' sleep patterns were significantly later than other age groups on both weekdays and weekend nights . Unlike passive technological devices ( e.g. , TV , mp3 music players ) , the more interactive technological devices ( i.e. , computers/laptops , cell phones , video game consoles ) used in the hour before bed , the more likely difficulties falling asleep ( β = 9.4 , p < 0.0001 ) and unrefreshing sleep ( β = 6.4 , p < 0.04 ) were reported . CONCLUSIONS Technology use near bedtime is extremely prevalent in the United States . Among a range of technologies , interactive technological devices are most strongly associated with sleep complaints Objective : To examine the relationship between body mass index class , presenteeism , and prospect i ve registered sickness absence . Methods : Data were collected from 2983 Belgian workers . Presenteeism was assessed by a single question , evaluating the frequency of being at work , despite illness , during the preceding year . Sickness absence data were registered during 12 months ' follow-up . Multiple logistic regression analysis was conducted . Results : Body mass index class was positively and significantly associated with presenteeism ( at least two occasions of working despite illness ) in the male employees and was a significant predictor of high sickness absence ( at least 10 sick leave days ) in the female population . A final multivariate model demonstrated that these relations were only partly mediated by self-rated health . Conclusion : The results of this study suggest a gender difference concerning absenteeism and presenteeism in overweight and obese employees Background Young adults are at risk for weight gain . Little is known about how to design weight control programs to meet the needs of young adults and few theory-based interventions have been evaluated in a r and omized control trial . The Choosing Healthy Options in College Environments and Setting s ( CHOICES ) study was funded to create a technology-based program for 2-year community college students to help prevent unhealthy weight gain . The purpose of this article is to ( 1 ) provide a brief background on weight-related interventions in young adults ; ( 2 ) describe the study design for the CHOICES study , the conceptual model guiding the research and the CHOICES intervention ; and ( 3 ) discuss implication s of this research for health educators . Translation to Health Education Practice Our experiences from the CHOICES study will be useful in suggesting other theory-based models and intervention strategies that might be helpful in programs attempting to prevent unhealthy weight gain in young adults . In addition , this article discusses important considerations for working with 2-year colleges on this type of health promotion work Context Studies in animals and humans suggest that sleep duration is an important regulator of metabolism . Contribution In this study , 12 young , healthy , normal-weight men exhibited reductions in the satiety hormone leptin , increases in the hunger hormone ghrelin , and increases in hunger after 2 nights of only 4 hours of sleep compared with after 2 nights of 10 hours of sleep . Implication s Inadequate sleep seems to influence the hormones that regulate satiety and hunger in a way that could promote excess eating . The Editors Sleep plays an important role in energy balance . In rodents , food shortage or starvation results in decreased sleep ( 1 ) , and , conversely , total sleep deprivation leads to marked hyperphagia ( 2 ) . Leptin and ghrelin are peripheral signals that contribute to the central regulation of food intake . Leptin , a hormone released by the adipocytes , provides information about energy status to hypothalamic regulatory centers ( 3 ) . In humans , circulating leptin levels rapidly decrease or increase in response to acute caloric shortage or surplus , respectively ( 4 ) . These changes in leptin levels have been associated with reciprocal changes in hunger ( 4 ) . Ghrelin , a peptide produced predominantly by the stomach , is also involved in energy balance regulation , but , in contrast to the anorexigenic effects of leptin , ghrelin stimulates appetite ( 5 ) . It has been proposed that leptin and ghrelin represent the yinyang of one regulatory system that has developed to inform the brain about the current energy balance state ( 6 ) . Over the past 40 years , sleep duration in the U.S. population has decreased by 1 to 2 hours ( 7 - 10 ) . The proportion of young adults sleeping fewer than 7 hours per night has more than doubled between 1960 and 20012002 ( from 15.6 % to 37.1 % ) ( 7 - 10 ) . The effect of sleep curtailment on the control of appetite and food intake is not known . Because of the well-documented associations between sleep and food intake ( 1 , 2 ) , we sought to determine whether sleep duration influences the daytime profiles of leptin and ghrelin . Methods Participants Twelve healthy men(mean age [ SD ] , 22 2 years ] ; mean body mass index [ SD ] , 23.6 2.0 kg/m2 ) who did not smoke or take any medications participated in the study . All of the men were within 10 % of ideal body weight and had regular nocturnal time in bed of 7 to 9 hours . We excluded persons who had traveled across time zones less than 4 weeks before the study . Experimental Protocol The Institutional Review Board of the University of Chicago approved the protocol , and we obtained written informed consent from all participants . During the week preceding each study , we asked participants not to deviate from a fixed time in bed ( 11:00 p.m. to 7:00 a.m. ) by more than 30 minutes . Naps were not allowed . The men participated in 2 studies that were conducted in a r and omized order , were spaced at least 6 weeks apart , and were performed in the Clinical Research Center at the University of Chicago , Chicago , Illinois . Six of the 12 men first performed the study with restricted time in bed , and the remaining 6 men first performed the study with extended time in bed . Average weight did not change over the time period separating the 2 study conditions ( 75.2 kg in the sleep restriction condition vs. 75.4 kg in the sleep extension condition ; P > 0.2 ) . We obtained blood sample s at 20-minute intervals from 8:00 a.m. to 9:00 p.m. after 2 consecutive nights of 10 hours in bed ( 10:00 p.m. to 8:00 a.m. ; sleep extension ) and after 2 consecutive nights of 4 hours in bed ( 1:00 a.m. to 5:00 a.m. ; sleep restriction ) . Sleep was recorded every night . For both extension and restriction conditions , each overnight stay began at 7:00 p.m. with a st and ard hospital dinner , and the first overnight stay ended after breakfast , which was served at 8:00 a.m. We instructed the participants not to deviate from their usual eating habits between breakfast and dinner , but caloric intake was not otherwise monitored . Participants were readmitted in the early evening and , after receiving a st and ard hospital dinner at 7:00 p.m. , remained at bed rest . At 8:00 a.m. after the second night , the participants ' caloric intake was kept constant to avoid meal-related fluctuations of hunger and satiety and consisted of an intravenous glucose infusion at a constant rate of 5 g/kg of body weight every 24 hours . There was no other source of calories . Every hour from 9:00 a.m. to 9:00 p.m. , the men completed vali date d visual analogue scales ( 0 to 10 cm ) for hunger ( 11 ) and appetite for various food categories ( 12 ) . To assess hunger , we asked participants to mark their response to the question How hungry do you feel right now ? on a 10-cm scale ( with not at all hungry on the left and extremely hungry on the right ) . To assess appetite , we asked participants to mark their response to how much they would enjoy eating foods from 7 different food categories on a 10-cm scale ( with not at all on the left and very much on the right ) . They were asked to provide a score based only on their appetite at the moment , without concern for calories , fat , or a healthy diet . The food categories were sweets ( such as cake , c and y , cookies , ice cream , and pastry ) ; salty foods ( such as chips , salted nuts , pickles , and olives ) ; starchy foods ( such as bread , pasta , cereal , and potatoes ) ; fruits and fruit juices ; vegetables ; meat , poultry , fish , and eggs ; and dairy products ( such as milk , cheese , and yogurt ) . Assays We measured serum leptin levels in all sample s by using a human leptin radioimmunoassay kit ( Linco Research , St. Charles , Missouri ) with a sensitivity of 0.5 ng/mL and an intra-assay coefficient of variation of 8.3 % . In 9 of the 12 participants , we also measured total ghrelin levels at hourly intervals by radioimmunoassay ( Linco Research ) with a sensitivity of 0.5 ng/mL and an intra-assay coefficient of variation of 7.9 % . Statistical Analysis We performed paired comparisons by using the Wilcoxon matched-pairs signed-rank test . We calculated correlations by using the Spearman coefficient . The mean relative changes in leptin , ghrelin , hunger , and appetite between extended sleep ( the reference category ) and restricted sleep were calculated by using the ratios of the corresponding individual data and then deriving the mean across all individuals . Role of the Funding Sources This work was partially supported by grants from the National Institutes of Health , the European Sleep Research Society , the Belgian Fonds de la Recherche Scientifique Mdicale , the University of Chicago Diabetes Research and Training Grant , and The University of Chicago General Clinical Research Center . The funding sources had no role in the design , conduct , and reporting of the study or in the decision to su bmi t the manuscript for publication . Results Leptin levels were stable across the daytime period under both sleep conditions , which was consistent with the fact that calories were exclusively delivered in the form of a constant glucose infusion . Average total sleep time was 9 hours and 8 minutes when the men spent 10 hours in bed and 3 hours and 53 minutes when the men spent 4 hours in bed ( P < 0.01 ) . When spending 4 hours in bed , the participants had mean leptin levels that were 18 % lower ( 2.1 ng/mL vs. 2.6 ng/mL ; P= 0.04 ) ( Figure 1 , part A ) and mean ghrelin levels that were 28 % higher ( 3.3 ng/mL vs. 2.6 ng/mL ; P= 0.04 ) ( Figure 1 , part B ) than when the participants spent 10 hours in bed . The ratio of the concentrations of orexigenic ghrelin to anorexigenic leptin increased by 71 % ( CI , 7 % to 135 % ) with 4 hours in bed compared with 10 hours in bed . Sleep restriction relative to sleep extension was associated with a 24 % increase in hunger ratings on the 10-cm visual analogue scale ( P < 0.01 ) and a 23 % increase in appetite ratings for all food categories combined ( P= 0.01 ) ( Figure 1 , parts C and D , and Table 1 ) . The increase in appetite tended to be greatest for calorie-dense foods with high carbohydrate content ( sweets , salty foods , and starchy foods : increase , 33 % to 45 % ; P= 0.06 ) ( Table 1 ) . The increase in appetite for fruits and vegetables was less consistent and of lesser magnitude ( increase , 17 % to 21 % ) ( Table 1 ) . Appetite for protein-rich nutrients ( meat , poultry , fish , eggs , and dairy foods ) was not significantly affected by sleep duration ( Table 1 ) . When we considered the changes in ghrelin and leptin in an integrated fashion by calculating the ghrelin-to-leptin ratio , the increase in hunger was proportional to the increase in ghrelin-to-leptin ratio ( r= 0.87 ) ( Figure 2 ) . Almost 70 % of the variance in increased hunger could be accounted for by the increase in the ghrelin-to-leptin ratio . Figure 1 . Effect of sleep duration on daytime leptin levels , ghrelin levels , hunger , and appetite . A. B. C D C D Table . Average Ratings of Appetite after 2 Days of Sleep Restriction or Sleep Extension Figure 2 . Association between the change in hunger ratings and the change in ghrelin-to-leptin ratio during the 12:00 noon to 9:00 p.m. time period when sleep is restricted as compared with extended . P Discussion We observed that sleep duration may affect the circulating levels of neuroendocrine factors that regulate hunger and appetite . Two days with 4 hours of time in bed each night were associated with an 18 % decrease in the levels of the anorexigenic hormone leptin . By comparison , 3 days of underfeeding by approximately 900 calories per day in healthy lean volunteers has been reported to result in a decrease of leptin levels averaging 22 % ( 4 ) . Sleep curtailment was also associated with an almost 28 % increase in daytime levels of the orexigenic factor ghrelin . The reciprocal changes in leptin and ghrelin that we observed in response to sleep restriction were associated with a 24 % increase in hunger and a 23 % increase in appetite . Appetite for calorie-dense nutrients with high carbohydrate content , including sweets , salty snacks , and starchy foods , increased by 33 % to 45 % . In contrast ,

The overall rates of inappropriate use were 36.7 % ( 95 % CI [ 30.2 , 43.6 ] ) in major cities and 37.5 % ( 95 % CI [ 31.2 , 44.3 ] ) in other cities , respectively ; there was no statistically significant difference ( P > 0.05).In conclusion , China has suffered from a disadvantage in the clinical appropriateness of blood transfusion , especially in plasma and RBC use .

Abstract The issue of the clinical appropriateness of blood transfusion has become a focus of transfusion medicine worldwide . In China , irrational uses of blood have often been reported in recent years . However , to date there lacks a systematic review of the rational uses of blood . This study aim ed to determine the clinical appropriateness of blood transfusion in China .

BACKGROUND Unilateral total knee replacement ( TKR ) results in a substantial blood loss and 30 to 50 percent of patients receive allogeneic blood transfusion ( ABT ) . Therefore , the effectiveness of a restrictive transfusion trigger ( hemoglobin [ Hb ] level < 8 g/dL ) plus stimulation of erythropoiesis was evaluated , with or without blood salvage , for reducing ABT in TKR patients . STUDY DESIGN AND METHODS A series of 139 consecutive of primary TKR patients received perioperative iron sucrose ( 2 x 200 mg/48 hr , intravenously [ IV ] ) , plus preoperative erythropoietin ( EPO ; 1 x 40.000 UI , sc ) if preoperative Hb level was less than 130 g per L ( Group A ) . This protocol was applied to another series of 173 consecutive TKR patients who also received postoperative unwashed shed blood ( USB ) if preoperative Hb level was less than 130 g per L ( Group B ) . Perioperative clinical and laboratory data were gathered . RESULTS No adverse effects of iron sucrose , EPO , or USB administration were witnessed , and only 13 patients received ABT overall ( 4 % ) . No major differences in perioperative blood counts or iron metabolism variables were observed between groups , but stimulation of erythropoiesis seemed to be more pronounced in those patients receiving EPO ( p < 0.05 ) . There were no differences in postoperative complications between groups , but length of hospital stay for patients with a preoperative Hb level of less than 130 g per L was shorter in Group B ( p < 0.05 ) . CONCLUSION This blood saving protocol seems to be effective for reducing ABT in TKR patients . Which patients are more likely to benefit from either perioperative iron administration or selective addition of postoperative blood salvage to pharmacologic treatment , however , needs to be further evaluated BACKGROUND The decision to transfuse intra-operatively is based on preoperative haemoglobin ( Hb ) , estimated blood loss and physiological variables . The visual estimate of blood loss is notoriously unreliable especially with small volumes of blood losses in children . OBJECTIVES We sought therefore to determine the appropriateness of intra-operative blood transfusion in a sample of children METHODS All children requiring intra-operative blood transfusion between May and June 2008 were prospect ively studied . Neonates and children already on blood transfusion at induction were excluded . Transfusion was prescribed at the discretion of the attending anaesthetist . The Estimated blood volume ( EBV ) and estimated blood loss (EBL)were determined . Appropriate transfusion was defined as blood transfusion at EBL > 15 % of EBV , maximum allowable blood loss to PCV of 27 % and pre-transfusion Hb < 8g/dl . RESULTS Twenty-five patients were studied with a mean age of 4.16 + /- 3.59 years ( Range 0.33 - 11 years ) . The mean preoperative PCV was 31.14 + /- 3.53 % ( range 25 - 34 % ) . Twelve patients ( 48 % ) were appropriately transfused when MABL was calculated to PCV of 27 % . Nine patients ( 36 % ) had appropriate blood transfusion at an EBL greater or equal to 15 % of the EBV . Of the 12 patients that had pre-transfusion Hb measured , 2 ( 16.6 % ) were appropriately transfused at Hb < 8 g/dl . CONCLUSION The use of near patient monitoring devices should be encouraged as this will give an accurate assessment of Hb and appropriate indication for transfusion . Equipment should be made available to perform gravimetric estimation of blood loss as the visual method is notoriously unreliable BACKGROUND Transfusion thresholds for acute upper gastrointestinal bleeding are controversial . So far , only three small , underpowered studies and one single-centre trial have been done . Findings from the single-centre trial showed reduced mortality with restrictive red blood cell ( RBC ) transfusion . We aim ed to assess whether a multicentre , cluster r and omised trial is a feasible method to substantiate or refute this finding . METHODS In this pragmatic , open-label , cluster r and omised feasibility trial , done in six university hospitals in the UK , we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding , irrespective of comorbidity , except for exsanguinating haemorrhage . We r and omly assigned hospitals ( 1:1 ) with a computer-generated r and omisation sequence ( r and om permuted block size of 6 , without stratification or matching ) to either a restrictive ( transfusion when haemoglobin concentration fell below 80 g/L ) or liberal ( transfusion when haemoglobin concentration fell below 100 g/L ) RBC transfusion policy . Neither patients nor investigators were masked to treatment allocation . Feasibility outcomes were recruitment rate , protocol adherence , haemoglobin concentration , RBC exposure , selection bias , and information to guide design and economic evaluation of the phase 3 trial . Main exploratory clinical outcomes were further bleeding and mortality at day 28 . We did analyses on all enrolled patients for whom an outcome was available . This trial is registered , IS RCT N85757829 and NCT02105532 . FINDINGS Between Sept 3 , 2012 , and March 1 , 2013 , we enrolled 936 patients across six hospitals ( 403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy ) . Recruitment rate was significantly higher for the liberal than for the restrictive policy ( 62 % vs 55 % ; p=0·04 ) . Despite some baseline imbalances , Rockall and Blatchford risk scores were identical between policies . Protocol adherence was 96 % ( SD 10 ) in the restrictive policy vs 83 % ( 25 ) in the liberal policy ( difference 14 % ; 95 % CI 7 - 21 ; p=0·005 ) . Mean last recorded haemoglobin concentration was 116 ( SD 24 ) g/L for patients on the restrictive policy and 118 ( 20 ) g/L for those on the liberal policy ( difference -2·0 [ 95 % CI -12·0 to 7·0 ] ; p=0·50 ) . Fewer patients received RBCs on the restrictive policy than on the liberal policy ( restrictive policy 133 [ 33 % ] vs liberal policy 247 [ 46 % ] ; difference -12 % [ 95 % CI -35 to 11 ] ; p=0·23 ) , with fewer RBC units transfused ( mean 1·2 [ SD 2·1 ] vs 1·9 [ 2·8 ] ; difference -0·7 [ -1·6 to 0·3 ] ; p=0·12 ) , although these differences were not significant . We noted no significant difference in clinical outcomes . INTERPRETATION A cluster r and omised design led to rapid recruitment , high protocol adherence , separation in degree of anaemia between groups , and non-significant reduction in RBC transfusion in the restrictive policy . A large cluster r and omised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding . FUNDING NHS Blood and Transplant Research and Development BACKGROUND To determine whether a restrictive strategy of red-cell transfusion and a liberal strategy produced equivalent results in critically ill patients , we compared the rates of death from all causes at 30 days and the severity of organ dysfunction . METHODS We enrolled 838 critically ill patients with euvolemia after initial treatment who had hemoglobin concentrations of less than 9.0 g per deciliter within 72 hours after admission to the intensive care unit and r and omly assigned 418 patients to a restrictive strategy of transfusion , in which red cells were transfused if the hemoglobin concentration dropped below 7.0 g per deciliter and hemoglobin concentrations were maintained at 7.0 to 9.0 g per deciliter , and 420 patients to a liberal strategy , in which transfusions were given when the hemoglobin concentration fell below 10.0 g per deciliter and hemoglobin concentrations were maintained at 10.0 to 12.0 g per deciliter . RESULTS Overall , 30-day mortality was similar in the two groups ( 18.7 percent vs. 23.3 percent , P= 0.11 ) . However , the rates were significantly lower with the restrictive transfusion strategy among patients who were less acutely ill -- those with an Acute Physiology and Chronic Health Evaluation II score of < or = 20 ( 8.7 percent in the restrictive- strategy group and 16.1 percent in the liberal- strategy group ; P=0.03 ) -- and among patients who were less than 55 years of age ( 5.7 percent and 13.0 percent , respectively ; P=0.02 ) , but not among patients with clinical ly significant cardiac disease ( 20.5 percent and 22.9 percent , respectively ; P=0.69 ) . The mortality rate during hospitalization was significantly lower in the restrictive- strategy group ( 22.3 percent vs. 28.1 percent , P=0.05 ) . CONCLUSIONS A restrictive strategy of red-cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients , with the possible exception of patients with acute myocardial infa rct ion and unstable angina BACKGROUND Shrinkage of the donor pool coupled with an increasing dem and for blood presents a major challenge to maintaining an adequate blood supply . Consequently it has become even more important to reduce inappropriate blood use , including decisions about when and how much blood to prescribe . This study aim ed to ascertain the levels of inappropriate practice and factors associated with it . STUDY DESIGN AND METHODS The medical records of a r and omly selected sample of hospital patients in Northern Irel and who received a red blood cell transfusion during 2005 ( n = 1474 ) were review ed , and inappropriate transfusion and overtransfusion criteria were applied . Logistic regression models were used to identify factors associated with inappropriate practice and overtransfusion . RESULTS In this study 23 % of transfusions were considered inappropriate , occurring most commonly where the lowest hemoglobin ( Hb ) threshold for transfusion applied . Younger patients , those undergoing surgery , and those with lower comorbidity and higher Hb values were most likely to have an inappropriate transfusion . Among patients appropriately transfused , 19 % were overtransfused . Females and those of lower weight ( < 65 kg ) were most likely to be overtransfused . CONCLUSION While the choice of criteria used to judge decisions will influence the absolute level of inappropriate or overtransfusion reported , our findings suggest that a significant minority of clinicians are either unaware of or are reluctant to accept lower transfusion thresholds . To improve further improve transfusion practice we suggest that barriers to the implementation of recommended transfusion thresholds should be examined and guidance on an appropriate posttransfusion Hb level developed OBJECTIVE To evaluate the effectiveness of prospect i ve review of orders for fresh-frozen plasma ( FFP ) and platelets in reducing blood-product use , and of the effectiveness of preparing pathology residents to serve as clinical consultants . DESIGN At our 572-bed tertiary-care hospital , we developed guidelines for the use of blood products in collaboration with a variety of departments . For patients whose condition(s ) met generally accepted criteria , we identified trigger points to allow for quick release by blood bank staff of blood products . For patients whose condition(s ) did not meet the applicable criteria , the on-call pathology resident review ed the medical record of that patient to determine whether there were any extenuating circumstances ; consulted with the ordering physician and attending pathologist , as needed ; and advised the house staff on appropriate use of blood products . We evaluated the change in use of blood products between the years 2009 and 2012 to assess the effectiveness of the program . RESULTS We observed a decrease of 38.8 % and 31.4 % in the use of FFP and platelets , respectively ( 29.7 % and 21.1 % , respectively , when normalized for the number of discharges ) . If projected to the national level , this improvement would translate to an annual cost reduction of approximately $ 130 million . CONCLUSIONS Prospect i ve review of orders for blood products can significantly improve use of these products , thereby reducing risk to patients and avoiding unnecessary healthcare costs . The involvement of pathology residents in the prospect i ve review process provides an excellent opportunity for their training as laboratory consultants OBJECTIVES To assess the appropriateness of red blood cell ( RBC ) transfusions and the effectiveness of an intervention to reduce inappropriate RBC transfusions . DESIGN Medical record audit by hospital staff using a data form , before and after r and omly allocated interventions ( letter only or letter+visit ) . Criteria for assessing appropriateness of RBC transfusions were based on a systematic literature review . SETTING Ten major urban hospitals in Sydney , New South Wales , in 1998 and 1999 . SUBJECTS Medical records of up to 120 patients at each hospital ( n=1117 ) . INTERVENTIONS Letter-only ( 5 hospitals)-- results of first audit at the hospital mailed to chief executive officer of that hospital ; letter+visit ( 5 hospitals ) results of first audit at the hospital presented by the research team to a meeting of that hospital 's staff , and then mailed to the chief executive officer . MAIN OUTCOME MEASURE Proportion of RBC transfusions assessed as inappropriate . RESULTS At first audit , 35 % of RBC transfusions were assessed as inappropriate . Small reductions in inappropriate transfusions were found at the second audit , but the change was significant only for the hospitals receiving the letter-only intervention . About 5 % of patients received a single RBC unit ; 40 % of single-unit transfusions were inappropriate . More RBC transfusions were inappropriate in surgical patients than in those treated by other specialties . CONCLUSIONS About a third of RBC transfusions were assessed as inappropriate . The interventions had only a small effect on transfusion appropriateness BACKGROUND The objective was to investigate the impact of three national blood transfusion indicators ( NBTIs ) specifically design ed for critical care regarding the appropriate blood transfusion indications . STUDY DESIGN AND METHODS This was a prospect i ve , single-center study , carried out at a university hospital . A total of 1808 patients admitted to the intensive care unit ( ICU ) in 1 year were included . RESULTS The study consisted of four 90-day periods ( P ) . P1 was a control period with no intervention . P2 followed the inclusion of NBTIs into the ICU data base , aim ed at reinforcing NBTI knowledge . After presenting and discussing the results of P1 and P2 , the early ( P3 ) and late ( P4 ) impacts of NBTI knowledge were evaluated . All patients who were transfused with at least 1 unit of any blood component ( 33.3 % ) were included . Thirteen percent of red blood cell transfusions ( RBCTs ) were given outside of NBTI protocol s ( 13 % deviation of NBTIs for RBCTs ) without a significant change throughout the duration of the study . Most RBCTs ( 95 % ) were prescribed for a hemoglobin threshold of less than 90 g/L. There was a steady and significant improvement in the adherence to NBTI guidelines for platelet concentrate transfusions ( PCTs ) from 36 % ( P1 ) to 52 % ( P4 ; p < 0.01 ) . In contrast , the lack of adherence to NBTI guidelines for fresh-frozen plasma transfusions ( FFPTs ) remained high ( 74 % ) and stable throughout the study period . The most frequent reason for inappropriate use of FFPTs or PCTs was absence of severe bleeding . CONCLUSION The introduction of NBTI guidelines demonstrated a variable impact on the appropriateness of blood component transfusions in critically ill patients

Critical Flicker Frequency has a high specificity and moderate sensitivity for diagnosing minimal hepatic encephalopathy .

BACKGROUND Minimal hepatic encephalopathy ( MHE ) reduces quality of life , increases the risk of road traffic incidents and predicts progression to overt hepatic encephalopathy and death . Current psychometry-based diagnostic methods are effective , but time-consuming and a universal ' gold st and ard ' test has yet to be agreed upon . Critical Flicker Frequency ( CFF ) is a proposed language -independent diagnostic tool for MHE , but its accuracy has yet to be confirmed . AIM To assess the diagnostic accuracy of CFF for MHE by performing a systematic review and meta- analysis of all studies , which report on the diagnostic accuracy of this test .

UNLABELLED Patients with minimal hepatic encephalopathy ( MHE ) have impaired driving skills , but association of MHE with motor vehicle crashes is unclear . St and ard psychometric tests ( SPT ) or inhibitory control test ( ICT ) can be used to diagnose MHE . The aim was to determine the association of MHE with crashes and traffic violations over the preceding year and on 1-year follow-up . Patients with cirrhosis were diagnosed with MHE by ICT ( MHEICT ) and SPT ( MHESPT ) . Self and department-of-transportation (DOT)-reports were used to determine crashes and violations over the preceding year . Agreement between self and DOT-reports was analyzed . Patients then underwent 1-year follow-up for crash/violation occurrence . Crashes in those with/without MHEICT and MHESPT were compared . 167 patients with cirrhosis had DOT-reports , of which 120 also had self-reports . A significantly higher proportion of MHEICT patients with cirrhosis experienced crashes in the preceding year compared to those without MHE by self-report ( 17 % vs 0.0 % , P = 0.0004 ) and DOT-reports ( 17 % vs 3 % , P = 0.004 , relative risk : 5.77 ) . SPT did not differentiate between those with/without crashes . A significantly higher proportion of patients with crashes had MHEICT compared to MHESPT , both self-reported ( 100 % vs 50 % , P = 0.03 ) and DOT-reported ( 89 % vs 44 % , P = 0.01 ) . There was excellent agreement between self and DOT-reports for crashes and violations ( Kappa 0.90 and 0.80 ) . 109 patients were followed prospect ively . MHEICT patients had a significantly higher future crashes/violations compared to those without ( 22 % vs 7 % , P = 0.03 ) but MHESPT did not . MHEICT ( Odds ratio : 4.51 ) and prior year crash/violation ( Odds ratio : 2.96 ) were significantly associated with future crash/violation occurrence . CONCLUSION Patients with cirrhosis and MHEICT have a significantly higher crash rate over the preceding year and on prospect i ve follow-up compared to patients without MHE . ICT , but not SPT performance is significantly associated with prior and future crashes and violations . There was an excellent agreement between self- and DOT-reports AIM to determine the effect of L-ornithine-L-aspartate ( LOLA ) together with the nutritional improvement and branched chain amino acids ( BCAAs ) substitution , on encephalopathy in liver cirrhosis with malnutrition . METHODS liver cirrhosis patients visited Cipto mangunkusumo Hospital in June-October 2009 were evaluated by critical flicker frequency ( CFF ) test . Encephalopathy is defined when CFF < 39 Hz . Nutritional status is measured by the mid-arm muscle circumference ( MAMC ) and is stated as malnutrition when MAMC < 15 % . All subjects who fulfilled the inclusion criteria received education for adequate calories and protein intake , and then they were be divided into 2 groups by r and omization . One group was given LOLA granules 3 x 6 g/d for 2 weeks , while another group was not . Then their prealbumin and CFF test were measured again . Statistical analysis conducted for this double blind r and omized clinical trial was independent student t test . RESULTS there were 34 liver cirrhosis patients fit the inclusion criteria , and by r and omization 17 subjects were put into group A ( received LOLA ) and 17 subjects into group B ( without LOLA ) . Statistical analysis obtained the statistically significant ( p=0,016 ) of increasing of the mean CFF value in group A ( 2.41 ± 1.6 Hz ) compared to group B ( 0.67 ± 2.3 Hz ) . However , there was not significant increasing of prealbumin level in group A compared to group B ( 1 ± 1.3 mg/dL vs 1.2 ± 1.4 mg/dL , respectively ( p=0,59 ) . Furthermore , after 2 weeks of treatment there was no significant increase of ureum and creatinine level in both groups ( 4 ± 0.5 mg/dL vs 9.3 ± 1.3 mg/dL , ( p=0.4 ) for ureum , -0.1 ( 0.1 ) mg/dL vs 0.1 ± 0.1 mg/dL , ( p=0.3 ) for creatinine . CONCLUSION minimal hepatic encephalopathy with malnutrition can be given a diet of 35 - 40 cal/kgBW and 1.5 g protein/kgBW including BCAA substitution to improve nutritional status , and LOLA granules can be given to improve encephalopathy A representation and interpretation of the area under a receiver operating characteristic ( ROC ) curve obtained by the " rating " method , or by mathematical predictions based on patient characteristics , is presented . It is shown that in such a setting the area represents the probability that a r and omly chosen diseased subject is ( correctly ) rated or ranked with greater suspicion than a r and omly chosen non-diseased subject . Moreover , this probability of a correct ranking is the same quantity that is estimated by the already well-studied nonparametric Wilcoxon statistic . These two relationships are exploited to ( a ) provide rapid closed-form expressions for the approximate magnitude of the sampling variability , i.e. , st and ard error that one uses to accompany the area under a smoothed ROC curve , ( b ) guide in determining the size of the sample required to provide a sufficiently reliable estimate of this area , and ( c ) determine how large sample sizes should be to ensure that one can statistically detect differences in the accuracy of diagnostic techniques BACKGROUND AND AIMS : Minimal hepatic encephalopathy ( MHE ) is associated with poor quality of life and increased work disability in cirrhotic patients . Its prevalence in extrahepatic portal vein obstruction ( EHPVO ) is not known . We studied the prevalence of MHE in EHPVO patients and utility of critical flicker frequency ( CFF ) for diagnosing MHE . PATIENTS AND METHODS : Thirty-four EHPVO patients with a history of variceal bleed ( age 23.2 ± 11.2 yr , M : F 22:12 ) diagnosed by either Doppler US or MR angiography , which demonstrated portal vein obstruction and /or portal vein cavernoma , were evaluated by psychometry ( number connection tests A , B or figure connection tests A , B ) and P300 auditory event-related potential ( P300ERP ) . CFF was also evaluated . MHE was diagnosed by abnormal psychometry ( > 2 st and ard deviation [ SD ] ) and /or P300ERP ( > 2.5 SD ) . RESULTS : Prevalence of MHE ( N = 12 ) was 35.3 % . Of 34 patients , P300ERP was abnormal ( 380.0 ± 28.9 msec ) in 11 ( 32 % ) , psychometry in 9 ( 26.4 % ) , both P300ERP and psychometry in 8 ( 23.5 % ) , and CFF < 38 Hz in 7 ( 21 % ) patients . Six ( 67 % ) patients with abnormal psychometry and 7 ( 64 % ) with abnormal P300ERP had CFF below 38 Hz . CFF had sensitivity ( 75 % ) , specificity ( 96 % ) , positive predictive value ( 86 % ) , negative predictive value ( 93 % ) , and diagnosis accuracy of 91 % when compared to patients with both abnormal psychometry and P300ERP . The venous ammonia level was higher in patients with MHE ( 83.1 ± 29.7 vs 44.7 ± 16.1 μmol/L , P < 0.001 ) compared to patients without MHE . Spontaneous shunts were present in 67 % of patients with MHE compared to 14 % of non-MHE patients . MHE was more common in patients with spontaneous shunts ( 72.7 % vs 17.4 % , P= 0.001 ) than without spontaneous shunts . CONCLUSIONS : Prevalence of MHE in EHPVO patients is 35.3 % , and CFF alone can reliably diagnose 88 % of MHE patients with both abnormal psychometry and P300ERP . However , in view of the relatively low number of patients with MHE , the usefulness of CFF in this setting awaits confirmatory studies UNLABELLED The diagnosis of hepatic encephalopathy ( HE ) relies on clinical , neurophysiological , psychometric and laboratory variables . The relationships between such tests remain debated . The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis . Seventy-two patients and 14 healthy volunteers underwent EEG and paper- and -pencil psychometry ( PHES ) . Blood was obtained for C reactive protein ( CRP ) , interleukin 6 ( IL6 ) , tumor necrosis factor (TNF)α , ammonia and indole/oxindole . Patients were followed prospect ively for a median of 22 months in relation to the occurrence of death , transplantation and HE-related hospitalizations . Thirty-three patients had normal PHES and EEG , 6 had abnormal PHES , 18 abnormal EEG and 13 abnormal PHES and EEG . Patients with abnormal PHES had higher CRP ( 17 ± 22 vs 7 ± 6 , P < 0.01 ) , IL6 ( 32 ± 54 vs 12 ± 13 , P < 0.05 ) and TNFα ( 17 ± 8 vs 11 ± 7 , P < 0.001 ) levels than those with normal PHES . Patients with abnormal EEG had higher indole ( 430 ± 270 vs 258 ± 255 , P < 0.01 ) and ammonia ( 66 ± 35 vs 45 ± 27 , P < 0.05 ) levels than those with normal EEG . Psychometric test scores showed significant correlations with CRP , TNFα and IL6 ; EEG indices with ammonia and IL6 . CRP and TNFα concentrations were independent predictors of abnormal PHES , ammonia and indole of abnormal EEG on multivariate analysis . Seven patients were lost to follow-up ; of the remaining 65 , 20 died and 14 underwent transplantation ; 15 developed HE requiring hospitalization . PHES and EEG performance were independent predictors of HE and death ( P < 0.05 ) . CONCLUSION PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome OBJECTIVES : Cirrhotics with minimal hepatic encephalopathy ( MHE ) have a poor health-related quality of life ( HRQOL ) . Treatment of MHE is still evolving . The aim of this double-blind r and omized pilot study was to assess the efficacy of rifaximin in improving neuropsychometric ( NP ) test performance and HRQOL in patients with MHE . METHODS : MHE was diagnosed if any two NP tests ( number and figure connection tests , picture completion , digit symbol , and block design tests ) were deranged beyond 2 s.d . of normal . HRQOL was assessed using the sickness impact profile ( SIP ) question naire . RESULTS : A total of 486 patients with cirrhosis were screened and 284 were found eligible . Out of these 115 ( 40.9 % ) had MHE , of which 21 refused consent and 94 were r and omized to receive placebo ( n=45 ) and rifaximin ( n=49 ; 1200 mg/day ) for 8 weeks . At the end of treatment , significantly more number of patients in rifaximin group showed reversal of MHE ( 75.5 % ( 37/49 ) vs. 20 % ( 9/45 ) in placebo group ; P < 0.0001 ) . Rifaximin group also showed significant reduction in mean number of abnormal NP tests ( baseline , 2.35 ( 95 % confidence interval ( CI ) , 2.17–2.53 ) ; 2 weeks , 1.29 ( 95 % CI , 1.02–1.56 ) , P=0.002 ; 8 weeks , 0.81 ( 95 % CI , 0.61–1.02 ) , P=0.000 ) , compared with placebo group ( baseline , 2.31 ( 95 % CI , 2.03–2.59 ) ; 2 weeks , 2.03 ( 95 % CI , 1.74–2.31 ) ; 8 weeks , 1.97 ( 95 % CI , 1.69–2.25 ) , P>0.05 ) . The mean total SIP score also improved significantly in rifaximin group ( baseline , 11.67 ( 95 % CI , 10.31–13.03 ) ; 8 weeks , 6.45 ( 95 % CI , 5.59–7.30 ) ; P=0.000 ) compared with placebo group ( baseline , 9.86 ( 95 % CI , 8.66–11.06 ) ; 8 weeks , 8.51 ( 95 % CI , 7.35–9.67 ) ; P=0.82 ) . Improvement in HRQOL correlated with improvement in NP tests . Rifaximin was well tolerated . CONCLUSIONS : Rifaximin significantly improves both cognitive functions and HRQOL in patients with MHE Background : Minimal hepatic encephalopathy ( MHE ) is common in cirrhosis but its pathophysiologic basis remains undefined . We evaluated whether the presence of MHE was associated with severity of liver disease , ammonia levels or the presence of inflammation and assessed factors determining neuropsychological deterioration accompanying induction of hyperammonemia . Methods : Eighty four cirrhotics were studied . A neuropsychological test battery was performed and blood taken for ammonia , WCC , CRP , nitrate/nitrite , IL-6 and amino acids , before and after , induction of hyperammonemia by administration of a solution mimicking the amino acid composition of haemoglobin ( 60 ) or placebo ( 24 ) . Results : The presence and severity of MHE were independent of severity of liver disease and ammonia concentration but markers of inflammation were significantly higher in those with MHE compared with those without . Induction of hyperammonemia produced deterioration in one or more neuropsychological tests by ≥1 SD in 73.3 % . This was independent of the magnitude of change in plasma ammonia and severity of liver disease but was significantly greater in those with more marked inflammation . Conclusion : Our data show that inflammation is an important determinant of the presence and severity of MHE . The change in neuropsychological function following induced hyperammonemia is greater in those with more severe inflammation UNLABELLED Minimal hepatic encephalopathy ( MHE ) has a negative effect on patients ' daily functioning . Thus far , no study has investigated the effect of treatment-related improvement in cognitive functions on health-related quality of life ( HRQOL ) . We measured psychometric performance by number and figure connection tests parts A and B , picture completion , and block design tests and HRQOL by the Sickness Impact Profile ( SIP ) of 90 patients with cirrhosis on inclusion into the study and 3 months later . A Z score less than -2 on the neuropsychological ( NP ) tests was considered abnormal . Sixty-one ( 67.7 % ) patients had MHE . They were r and omly assigned in a 1:1 ratio to receive treatment ( lactulose ) for 3 months ( n=31 ) or no treatment ( n=30 ) in a nonblinded design . The mean number of abnormal NP tests decreased significantly in patients in the treated group ( baseline , 2.74 [ 95 % CI 2.40 - 3.08 ] ; after 3 months , .75 [ 95 % CI .36 - 1.16 ] ) compared with patients in the untreated group ( baseline , 2.47 [ 95 % CI 2.19 - 2.74 ] ; after 3 months , 2.55 [ 95 % CI 2.16 - 2.94 ] ) ; multivariate analysis of variance ( MANOVA ) for time and treatment , P=0.001 . The mean total SIP score improved among patients in the treated group ( baseline , 10.39 [ 95 % CI 9.36 - 11.43 ] ; after 3 months , 3.77 [ 95 % CI 2.52 - 5.02 ] ) compared with patients in the untreated group ( baseline , 10.36 [ 95 % CI 8.98 - 11.73 ] ; after 3 months , 10.39 [ 95 % CI 8.36 - 12.42 ] ) ; MANOVA for time and treatment , P=0.002 . Improvement in HRQOL was related to the improvement in psychometry . CONCLUSION Treatment with lactulose improves both cognitive function and HRQOL in patients with cirrhosis who have MHE OBJECTIVES : Minimal hepatic encephalopathy ( MHE ) , the pre clinical stage of overt hepatic encephalopathy ( OHE ) , is a significant condition affecting up to 60 % of cirrhotics . All MHE therapies modify gut microflora , but consensus regarding MHE treatment and long-term adherence studies is lacking . The aim was to determine the effect of probiotic supplementation in the form of a food item , probiotic yogurt , on MHE reversal and adherence . METHODS : Nonalcoholic MHE cirrhotics ( defined by a st and ard psychometric battery ) were r and omized with unblinded allocation to receive probiotic yogurt ( with proven culture stability ) or no treatment ( no Rx ) for 60 days in a 2:1 ratio . Quality of life ( short form [SF]-36 ) , adherence , venous ammonia , model of end-stage liver disease ( MELD ) scores , and inflammatory markers ( tumor necrosis factor [TNF]-α , interleukin [IL]-6 ) were also measured . Outcomes were MHE reversal using blinded scoring , OHE development , and adherence . RESULTS : Twenty-five patients ( 17 yogurt , 8 no Rx ; 84 % Child class A ) were enrolled . A significantly higher percentage of yogurt patients reversed MHE compared to no Rx patients ( 71 % vs 0 % , P= 0.003 , intention-to-treat ) . Yogurt patients demonstrated a significant improvement in number connection test-A ( NCT-A ) , block design test ( BDT ) , and digit symbol test ( DST ) compared to baseline/no Rx group . Twenty-five percent of no Rx versus 0 % of yogurt patients developed OHE during the trial . Eighty-eight percent of yogurt patients were adherent . No adverse effects or change in covariates were observed . All patients who completed the yogurt arm were agreeable to continue yogurt for 6 months if needed . CONCLUSIONS : This trial demonstrated a significant rate of MHE reversal and excellent adherence in cirrhotics after probiotic yogurt supplementation with potential for long-term adherence It has been suggested that the ability to drive a car is impaired in patients with cirrhosis of the liver and minimal hepatic encephalopathy ( MHE ) . However , the only study using an on‐road driving test did not reveal such an impairment . In a prospect i ve controlled study , we evaluated patients with cirrhosis of the liver for MHE and the ability to drive a car . MHE was diagnosed using three psychometric tests : Number Connection Test Part A , Digit Symbol Test , and a Complex Choice Reaction Test . In a st and ardized on‐road driving test ( 22 miles , 90 minutes ) , design ed for patients with brain impairment , a professional driving instructor blind to the subjects ' diagnosis and test results assessed the driving performance . Four global driving categories ( car h and ling , adaptation to traffic situation , cautiousness , maneuvering ) , 17 specific driving actions ( e.g. , changing lanes , overtaking , etc . ) , and a total score of driving performance were rated using a 6‐point scale . Of 274 consecutive patients with liver cirrhosis , 48 fulfilled the medical and driving inclusion criteria , 14 of them with and 34 without MHE . Forty‐nine subjects in a stable phase of chronic gastroenterological diseases and with normal liver findings served as controls . The total driving score of patients with MHE was significantly reduced in comparison to either cirrhotic patients without MHE or to controls ( P < .05 ) . Significant differences in ratings were found in the following driving categories : car h and ling , adaptation , and cautiousness . Significant differences were also found in specific driving actions . The instructor had to intervene in the driving of 5 of the 14 MHE patients to avoid an accident , significantly more than in cirrhotic patients without MHE and in controls . There was no significant difference in any driving category or specific driving action in cirrhotic patients without MHE compared to controls . In conclusion , fitness to drive a car can be impaired in patients with MHE . Therefore , patients with liver cirrhosis should be tested for MHE and informed in the case of abnormal test results . Therapy known to improve psychometric test results should be initiated . ( HEPATOLOGY 2004;39:739 –745 . BACKGROUND AND OBJECTIVE Publication bias and other sample size effects are issues for meta-analyses of test accuracy , as for r and omized trials . We investigate limitations of st and ard funnel plots and tests when applied to meta-analyses of test accuracy and look for improved methods . METHODS Type I and type II error rates for existing and alternative tests of sample size effects were estimated and compared in simulated meta-analyses of test accuracy . RESULTS Type I error rates for the Begg , Egger , and Macaskill tests are inflated for typical diagnostic odds ratios ( DOR ) , when disease prevalence differs from 50 % and when thresholds favor sensitivity over specificity or vice versa . Regression and correlation tests based on functions of effective sample size are valid , if occasionally conservative , tests for sample size effects . Empirical evidence suggests that they have adequate power to be useful tests . When DORs are heterogeneous , however , all tests of funnel plot asymmetry have low power . CONCLUSION Existing tests that use st and ard errors of odds ratios are likely to be seriously misleading if applied to meta-analyses of test accuracy . The effective sample size funnel plot and associated regression test of asymmetry should be used to detect publication bias and other sample size related effects BACKGROUND & AIMS Low- grade hepatic encephalopathy ( HE ) may impair fitness to drive . Driving deficits have not yet been characterized , and their relation to psychometric test results is unclear . METHODS Fifty-one cirrhotic patients and 48 age-matched controls underwent real driving in a multiple sensor and camera-equipped car , laboratory and " in-car " computer psychometry , and driving instructor 's assessment . RESULTS Ten cirrhotic patients had no hepatic encephalopathy ( HE0 ) ; 27 and 14 patients suffered from minimal HE ( mHE ) and overt HE grade I ( oHE ) , respectively . During real driving , mHE and oHE patients showed significantly more violations of in-lane keeping , reduced break use , prolonged reaction times , and diminished stress tolerance compared with control or cirrhotic HE0 patients . In a self-evaluation question naire , mHE and oHE , but not the HE0 , patients strongly overestimated their driving abilities . According to the driving instructor 's assessment , 75 % , 48 % , and 39 % of the patients with HE0 , mHE , and oHE , respectively , were fit to drive , compared with 87 % in the control group . Driving deficits in oHE patients were largely due to cognitive defects and prolonged reaction times , whereas , in mHE patients , mistakes and attention deficits predominated . Computer psychometric test results worsened with HE severity and age , whereas real driving was age independent . In 25 out of 94 patients , discordant results for driving fitness were obtained ( driving instructor 's assessment vs computer psychometry ) ; in mHE and oHE patients , the concordance rates were only 62 % and 64 % , respectively . CONCLUSIONS Despite significant driving deficits , HE patients overestimate their driving abilities . The presence of mHE does not necessarily predict driving unfitness , and computer-based testings can not reliably predict driving fitness

In conclusion , there is no significant evidence that aortic-only perfusion of the DBD liver compromises transplantation outcomes , and it may be favored because of its simplicity . However , there is currently insufficient evidence to advocate for the use of any particular perfusion/preservation fluid over the others .

The efficacy of cold in situ perfusion and static storage of the liver is a possible determinant of transplantation outcomes . The aim of this study was to determine whether there is evidence to substantiate a preference for a particular perfusion route ( aortic or dual ) or perfusion/preservation solution in donation after brain death ( DBD ) liver transplantation .

The effectiveness of liver preservation solutions remains in evidence . Cold ischemia time , steatosis , exp and ed criterion donors , operational cost , and survival represent important roles in its success . In a prospect i ve cohort study between August 2009 and April 2014 , 178 patients were allocated into an Institut Georges Lopez - 1 ( IGL-1 ) solution group ( 63.5 % ) or histidine-tryptophan-ketoglutarate ( HTK ) group ( 36.5 % ) . There were no differences among recipient 's characteristics including age , skin color , gender , Model for End-stage Liver Disease score , acute rejection , cholestasis , and reperfusion syndrome incidences . Also , donors , age average , skin color , donor risk index , time in intensive care unit , hemodynamic variables , infections , and steatosis incidences were similar . The average cold ischemia time was 494 minutes in the IGL-1 group and 489 minutes in the HTK group ( P = .77 ) . Alanine aminotransferase and aspartate aminotransferase serum levels on the first postoperative day were 707 and 1185 mg/dL , respectively , with IGL-1 and 1298 and 2291 mg/dL , respectively , with HTK ( P = .016 ) and similar at day 15 ( P > .88 ) . The incidence of delayed graft function was 4.5 % with IGL-1 and 4.6 % with HTK ( P = .90 ) . The incidence primary nonfunction was 2.7 % with IGL-1 and 3.1 % with HTK ( P = .71 ) . The incidence of perioperative death was 11.5 % with IGL-1 and 13.8 % with HTK ( P = .94 ) . The survival in 30 months was 86 % in IGL-1 group and 82 % in HTK group ( P = .66 ) . Both preservation solutions are efficient to liver transplantations with deceased donors . Major prospect i ve trials are necessary to evaluate each preservation solution 's particularities . The preservation solution availability in each transplantation center must guide its use at the present moment 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 ALTHOUGH University of Wisconsin ( UW ) solution remains the most commonly used for all intrabdominal organs , Celsior solution , widely utilized in clinical setting for the preservation of intrathoracic organs , has been recently proposed as a cold-storage solution for abdominal organs . One of the reasons for focusing on abdominal preservation with Celsior is to proceed with one solution for the preservation of all organs . Experimental studies have shown excellent results in kidney , liver , and tissue preservation in alternative to the U W. Celsior , due to its peculiar physical properties ( osmotic pressure ) , is able to limit the edema that develops rapidly after cold ischemia and able to prevent free-radical mediated tissue injury by its biochemical characteristics . Its clinical use in these organs is now under investigation in different centers . The only report about Celsior solution for human liver preservation experiences in a small , uncontrolled series , and the study suggested that this solution is appropriate for clinical use in liver preservation . A prospect i ve , r and omized , multicenter open clinical trial was instituted to compare preservation properties of the two solutions in liver transplantation , and a detailed report of the completed study will be made at a later date . This preliminary report contains the data collected from a single center to prove the equivalence of both solutions with regard to initial functioning and short and long-term graft and patient survival BACKGROUND To test the effectiveness of a simpler surgical technique for cadaveric liver procurement for liver transplantation , a prospect i ve r and omized study was carried out between August 1994 and December 1995 , to compare aortic perfusion only ( APO ) for flush-preservation of the liver with the conventional combined aortic and portal perfusion ( APP ) technique . METHODS Forty multiple organ donors were enrolled with 20 in each arm of the trial . Donor parameters ( age , bodyweight , liver function tests ) , surgeons performing the operations , the involvement of other procurement teams and the total ischaemic times were similar in the two groups . The liver recipients had a wide range of native liver pathology but were of similar age , sex and bodyweight in the two groups . RESULTS The mean procurement operation times for the APO and APP groups were 126.7+/-38.6 and 137.8+/-55.9 min , respectively ( P = ns ) . The perfusion took longer to complete in the APO group ( 10.2+/-1.7 vs 7.2+/-1.4 min ( APP ) , P < 0.001 ) . The liver temperature fell to its lowest level ( 12.5+/-3.4 degrees C ( APO ) vs 11+/-3 degrees C ( APP ) , P = ns ) in a similar time ( 11.9+/-3.8 min ( APO ) vs 9.3+/-3.4 mins ( APP ) , P = ns ) . There was no graft primary non-function or graft arterial injury in either group . There was no significant difference between the APO and APP initial graft outcomes . The 3-month patient survival rate was identical in the two groups ( 95 % ) ; 81 % of renal grafts from the APO donors functioned well from the time of transplantation as did 76 % of those from APP donors . CONCLUSIONS It is concluded that the APO procurement technique produces equivalent results to those achieved with the APP method . The simplicity of the APO technique makes it the preferred technique University of Wisconsin ( UW ) solution has been the st and ard for preservation of liver transplantation grafts since 1989 . However , some studies demonstrated that histidine-tryptophan-ketoglutarate ( HTK ) solution is also effective . The purpose of this study was to compare the efficacy of both solutions in liver transplantation . From January 2003 to August 2004 the livers of deceased donors were r and omized into HTK and UW groups . The 102 studied patients included 65 ( 63.7 % ) in the UW group and 37 ( 36.3 % ) in the HTK group . Sex , race , hemodynamic state , use of adrenergic drugs , and presence of steatosis in the donor were similarly distributed in the two groups ( P > .05 ) . The mean age of the donors was 38.1 years ( SD + /-14.4 ) in the UW group and 44.6 years ( SD + /-14.2 ) in the HTK cohort ( P = .036 ) . Sex , race , age , etiology of the cirrhosis , retransplant , acute liver failure , portal thrombosis , and Child-Pugh and MELD scores in the recipients were similarly distributed in the two recipient sample s ( P > .05 ) . Among 89 patients who completed 4 months of follow-up , the HTK group included eight cases ( 25.8 % ) of biliary complications versus five cases ( 8.6 % ) in the UW group ( P = .033 ; OR = 2.0 95 % CI = 1.2 - 3.5 ) . The incidence of graft dysfunction was 2.8 % in the HTK group and 9.4 % in the UW group ( P = .15 ) . In conclusion , UW and HTK solutions were equally effective for the preservation of the hepatic graft . The routine use of HTK solution can reduce the costs of liver transplantation Background Celsior solution ( CS ) is a high-sodium , low-potassium , low-viscosity extracellular solution that has been used for liver graft preservation in recent years , although experience with it is still limited . We performed an open-label r and omized active-controlled trial comparing CS with the University of Wisconsin solution ( UW ) for liver transplantation ( LT ) , with a follow-up period of 5 years . Methods Adult transplant recipients ( n = 102 ) were prospect ively r and omized to receive either CS ( n = 51 ) or UW ( n = 51 ) . The two groups were comparable with respect to donor and recipient characteristics . The primary outcome measure was the incidence of postreperfusion syndrome ( PRS ) . Secondary outcome measures included primary nonfunction ( PNF ) or primary dysfunction ( PDF ) , liver retransplantation , and graft and patient survival . Other secondary outcome measures were days in the intensive care unit ( ICU ) and the rates of acute rejection , chronic rejection , infectious complications , postoperative reoperations , and vascular and biliary complications . Results In all , 14 posttransplant variables revealed no significant differences between the groups . There were no cases of PNF or PDF . The incidence of PRS was 5.9 % in the CS group and 21.6 % in the UW group ( P = 0.041 ) . After reperfusion , CS revealed greater control of serum potassium ( P = 0.015 ) , magnesium levels ( P = 0.005 ) , and plasma glucose ( P = 0.042 ) than UW . Respective patient survivals at 3 , 12 , and 60 months were 95.7 , 87.2 , and 82.0 % for the CS group and 95.7 , 83.3 , and 66.6 % for the UW group ( P = 0.123 ) . Conclusions While retaining the same degree of safety and effectiveness as UW for LT , CS may yield postliver graft reperfusion benefits , as shown in this study by a significant reduction in the incidence of PRS and greater metabolic control University of Wisconsin solution ( UWS ) is the gold st and ard for graft preservation . Celsior solution ( CS ) is a new solution not as yet widely used in liver grafts . The aim of this study was to compare the liver function of transplanted grafts stored in these 2 preservation solutions . The primary endpoints were the rates of primary nonfunction ( PNF ) and primary dysfunction ( PDF ) . We performed a prospect i ve and pseudor and omized study that included 196 patients ( representing 104 and 92 livers preserved in UWS and CS , respectively ) at La Fe University Hospital ( Valencia , Spain ) between March 2003 and May 2005 . PNF and PDF rates , liver function laboratory parameters , postoperative bleeding , vascular and biliary complications , and patient and graft survival at 3 years were compared for the 2 groups . The 2 groups were similar in terms of donor variables , recipient variables , and surgical techniques . The PNF rates were 2.2 % and 1.9 % in the CS and UWS groups , respectively ( P = not significant ) , and the PDF rates were 15.2 % and 15.5 % in the CS and UWS groups , respectively ( P = not significant ) . There were no significant differences in the laboratory parameters for the 2 groups , except for alanine aminotransferase levels in month 3 , which were lower in the CS group ( P = 0.01 ) . No significant differences were observed in terms of complications . Three-year patient and graft survival rates were as follows for years 1 , 2 , and 3 : 83 % , 80 % , and 76 % ( patient ) and 80 % , 77 % , and 73 % ( graft ) for the UWS group and 83 % , 77 % , and 70 % ( patient ) and 81 % , 73 % , and 67 % ( graft ) for the CS group ( P = not significant ) . In conclusion , this study shows that CS is as effective as UWS in liver preservation Primary dysfunction ( PDF ) still occurs after orthotopic liver transplantation ( OLT ) . Celsior solution ( CS ) might offer some advantages over the conventional University of Wisconsin ( UW ) solution for organ preservation , but to date , this has not been prospect ively evaluated in the context of OLT . In this prospect i ve , r and omized , multicenter , pilot study , 215 potential liver donors were enrolled and r and omized . In 42 cases , the livers were unsuitable for transplantation ; therefore , 173 r and omized livers ultimately were implanted after perfusion and cold preservation with CS ( n = 83 ) or UW solution ( n = 90 ) . In accord with the indications of the CS manufacturing company , total CS infusion volume was 90 mL/kg , greater than that of UW solution ( 60 mL/kg ) . The main aim of the study is to compare the prevalence of PDF between the two groups . Donor and recipient variables were similar in the two groups . Episodes of PDF were numerically lower in the CS ( 2.4 % ) than UW group ( 7.8 % ) , but the difference was not statistically significant . There was a trend toward a lesser need for early re-OLT ( < 30 days ) in the CS group ( P = .0507 ) , but again , no statistically significant difference emerged . Overall and time-differentiated postoperative deaths also were similar . One-year actuarial patient ( UW , 89 % v CS , 87 % ) and graft ( UW , 83 % v CS , 85 % ) survival rates were similar . In conclusion , CS was similar to UW solution as a preservation solution in the clinical setting of OLT at the infusion volumes described , although some theoretical advantages of CS composition suggest that CS might prove a valid alternative to UW preservation solution in multiorgan harvesting , including the liver . A study on a larger patient basis is needed BACKGROUND Institut Georges Lopez-1 ( IGL-1 ) is a new preservation solution with lower potassium and lower viscosity than University Wisconsin solution ( UW ) . These characteristics which improve liver preservation lead us to evaluate clinical effects of IGL-1 in a r and omized controlled study with UW . MATERIAL / METHODS From June 2007 to July 2009 , after exclusion of partial graft , combined transplantation and fulminant hepatic failure , 140 deceased donor allografts were r and omly assigned to IGL-1 ( n=48 ) or UW ( n=92 ) solution . Variables concerning donors and recipients were collected including liver tests ( total serum bilirubin , prothrombin time and transaminases ) were analyzed until postoperative day 30 . Incidences of hepatic artery thrombosis ( HAT ) , primary non function ( PNF ) and biliary non anastomotic strictures ( NAS ) were analyzed . The comparative analysis of costs was realized . RESULTS Donor and recipients characteristics were similar in both groups . Volume of preservation solution utilized for harvesting was identical . Duration of cold ischemia ( 472±142 vs. 477±122 min ) , surgery ( 427±97 vs. 437±94 min ) and proportion of extended criteria donor was similar . Postoperative kinetic and level liver tests were similar . Rate of PNF ( 2 % vs. 4 % ) , early retransplantation ( 6 % vs. 7 % ) , incidence of biliary NAS ( 2 % vs. 3 % ) and HAT ( 6 % vs. 4 % ) were similar . Mean intensive care unit ( ICU ) stay was similar ( 5.6 vs. 6.1 days ) . However costs related to preservation solution for one liver procurement were 992.0 for IGL-1 vs. 1609.0 Euros for UW . CONCLUSIONS Results of this r and omized study shows that the efficacy and safety of IGL-1 are comparable to those of the reference UW with a lower cost In recent years , an increasing number of suboptimal grafts has been used to reduce the gap between the supply and dem and of organs for liver transplantation ( LT ) . In this r and omized prospect i ve study , we tested the impact of donor harvesting technique on the posttransplantation outcome of suboptimal donor livers . A modified double perfusion ( MDP ) technique ( aortic and portal cooling with tourniquet clamping of splenomesenteric vein inflow ) was compared with the single aortic perfusion ( SAP ) technique . Between February and November 2005 , 35 suboptimal grafts were r and omly assigned to either technique ( 18 MDP livers and 17 SAP livers ) . Donor and recipient variables were comparable in the 2 study groups . The SAP group had significantly higher blood transaminases and bilirubin levels after LT . The prevalence of graft primary dysfunction ( PDF ) was also significantly higher ( P=0.01 ) in the SAP group ( 35 % ) than in the MDP group ( 5 % ) . In 5 cases , all in the SAP group ( P=0.02 ) , early re-LT ( < 30 days ) was needed . The 6-month patient and graft survival rates were significantly higher in the MDP ( 100 % in both cases ) than in the SAP group ( 68 % and 58 % , respectively ) . The study was stopped in November 2005 , when the interim analysis revealed such markedly significant differences between the two groups . In conclusion , the present study showed a very low prevalence of PDF , death , and re-LT after transplantation with suboptimal liver when a MDP technique was used to harvest the donor graft INTRODUCTION A prospect i ve , r and omized , multicenter , open clinical trial was performed to compare the main liver function tests , postoperative complications , and early graft and patient survival of recipients transplanted with livers preserved in Celsior ( CEL ) versus histidine tryptophan ketoglutarate ( HTK ) solutions . METHODS We analyzed the data from a single center . Forty livers r and omized to CEL ( n = 20 ) or HTK ( n = 20 ) preservation solution were perfused in situ via the aorta and portal vein ( CEL , 30 mL/kg via portal vein and 60 mL/kg via aorta ; and HTK solution , 30 mL/kg via portal vein and 120 mL/kg via aorta ) . RESULTS The groups were comparable with regard to donor , graft , and recipient characteristics . The mean cold ischemia time was 458 minutes ( range : 203 - 667 minutes ) in CEL and 450 ( range : 310 - 684 minutes ) in HTK . The incidence of initial poor function and primary nonfunction in CEL and HTK were ( 0 vs 1 ) and ( 0 vs 1 ) , respectively . No differences were observed for acute rejection . No vascular or biliary complications were reported in either group . The 3-month graft and patient survival rates were 95 % and 95 % in CEL and 80 % and 90 % in HTK . The 12-month graft and patient survival rates were 90 % and 90 % in CEL and 75 % and 85 % in HTK . CONCLUSIONS To our knowledge , this is the first report comparing CEL and HTK preservation solutions in clinical liver preservation . Although a greater 1-year graft and patient survival was observed in the CEL group , a definitive evaluation comparing CEL and HTK solutions in clinical preservation must await completion of the trial INTRODUCTION We studied the evolution of the liver graft with preservation in Celsior ( CS ) compared with University of Wisconsin solution ( UW ) . MATERIAL AND METHODS A r and omized prospect i ve clinical study in 80 liver transplants ( OLTs ) from May 2001 to October 2003 , compared CS ( group I ; n = 40 ) and UW ( group II ; n = 40 ) . The characteristics of the donors were homogeneous , with no significant differences in 15 variables . CS was perfused with 4 L through the aorta , 2 L through the portal vein , and 1 L , through the portal vein on the back table ; and the UW , as 3 L , 2 L , and 1 L , respectively . All OLTs were performed using the piggyback technique . RESULTS Group I experienced reperfusion syndrome ( n = 2 ; 5.9 % ) , primary graft nonfunction ( n = 0 ) ; vascular complications ( n = 0 ) ; biliary anastomosis stenosis ( n = 8 ; 22.9 % ) , intensive care unit ( ICU ) days ( n = 4.1 + /- 1 ) , death within 30 days ( n = 1 ; 3.1 % ) . The patient and graft survivals at 1 , 3 , 6 , 12 , and 24 months were 93.7 % , 93.7 % , 90.2 % , 85.7 % , 85.7 % , and 94.3 % , 88.5 % , 85.2 % , 78 % , 78 % , respectively . For group II ; the reperfusion syndrome occured in 6 patients ( 17.6 % ) ; primary graft nonfunction ( n = 0 ) ; vascular complications ( n = 0 ) , biliary anastomosis stenosis ( n = 3 ; 8.6 % ) , ICU days ( n = 4.9 + /- 2.4 ) and death within 30 days ( n = 1 ; 3.1 % ) ; The patient and graft survival at 1 , 3 , 6 , 12 , and 24 months were 96.9 % , 93.5 % , 89.8 % , 79.8 % , 79.8 % and 94.3 % , 88.3 % , 84.9 % , 75.5 % , 66.1 % , respectively . CONCLUSIONS CS offers the similar safety to UW for preservation of liver grafts within these ischemia times

RESULTS Within the Body Structure and Function category , there was moderate evidence that exercise result ed in improvements in postural instability . Within the Activity category , there was moderate evidence that exercise was effective for improving balance task performance . In contrast , within the Participation category , there was limited evidence that exercise result ed in improvements in QOL measures or fall events . DISCUSSION AND CONCLUSIONS Regardless of the strength of the evidence , the studies review ed all report that exercise result ed in improvements in postural stability and balance task performance .

BACKGROUND AND PURPOSE Parkinson 's disease is a progressive neurodegenerative disorder that affects neurophysiologic function , movement abilities , and quality of life ( QOL ) . Research examining the effects of exercise has suggested benefits related to a variety of outcomes ; however , no review s have synthesized research findings across the spectrum of disability . This project sought to systematic ally review studies that examined the impact of exercise interventions on balance outcomes for people with Parkinson 's disease , within the categories defined by the World Health Organization in the International Classification of Functioning , Disability , and Health ( ICF ) model .

OBJECTIVES The effectiveness of an exercise intervention for people in early and midstage Parkinson 's disease ( stages 2 and 3 of Hoehn and Yahr ) in improving spinal flexibility and physical performance in a sample of community-dwelling older people is described . DESIGN AND SETTING Fifty-one men and women , aged 55 - 84 years , identified through advertisement , local support groups , and local neurologists were enrolled into a r and omized , controlled trial . Subjects were assigned r and omly to an intervention or a usual care arm ( i.e. , no specific exercise ) . Of the original 51 participants , 46 completed the r and omized , controlled trial . Participants in the exercise arm ( n = 23 ) received individual instruction three times per week for 10 weeks . Participants in the usual care arm ( n = 23 ) were " wait listed " for intervention . MEASUREMENTS Changes over 10 weeks in spinal flexibility ( i.e. , functional axial rotation ) and physical performance ( i.e. , functional reach , timed supine to st and ) were the primary outcome measures . RESULTS MANOVA conducted for the three primary outcome variables demonstrated significant differences ( P < or = .05 ) between the two groups . Further analysis using ANOVA demonstrated significant differences between groups in functional axial rotation and functional reach for the intervention compared with the control group . There was no significant difference in supine to sit time . CONCLUSION Study results demonstrate that improvements in axial mobility and physical performance can be achieved with a 10-week exercise program for people in the early and midstages of PD The impact of dyskinesias and motor fluctuations on quality of life ( QOL ) at various stages in the course of Parkinson 's disease ( PD ) is not well understood . In 301 subjects with early PD enrolled in a clinical trial ( CALM-PD ) , we quantified the impact of motor complications on QOL and investigated how this changes over time . We also compared QOL related to demographic and treatment characteristics . The presence of dyskinesias was associated with visual analogue scale ( VAS ) scores 3.0 of 100 points higher ( better ) than those without dyskinesias in years 1 to 2 , even when adjusting for Unified Parkinson 's Disease Rating Scale ( UPDRS ) motor scores . The positive association between dyskinesias and QOL scores was more marked in older patients . In years 3 to 4 , dyskinesias no longer had a significant relationship with QOL . Younger subjects had higher VAS scores . Gender , motor fluctuations , and treatment regimen had no significant association with QOL , although a trend was found toward a small negative effect of motor fluctuations on QOL . We conclude that motor complications that occur within the first 4 years of treatment of PD do not have a significant negative effect on quality of life as measured by a visual analogue scale for most patients 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 Objective : To detect the effectiveness of incremental speed-dependent treadmill training on postural instability , dynamic balance and fear of falling in patients with idiopathic Parkinson 's disease . Design : R and omized controlled trial . Setting : Ankara Education and Research Hospital , 2nd PM&R Clinic , Cardiopulmonary Rehabilitation Unit . Subjects : Fifty-four patients with idiopathic Parkinson 's disease in stage 2 or 3 of the Hoehn Yahr staging entered , and 31 patients ( 21 training , 10 control ) had outcome data . Interventions : Postural instability of patients with Parkinson 's disease was assessed using the motor component of the Unified Parkinson 's Disease Rating Scale ( UPDRS ) , Berg Balance Test , Dynamic Gait Index and Falls Efficacy Scale . Twenty-one patients with Parkinson 's disease participated in an eight-week exercise programme using incremental speed-dependent treadmill training . Before and after the training programme , balance , gait , fear of falling and walking distance and speed on treadmill were assessed in both Parkinson 's disease groups . Main measures : Walking distance and speed on treadmill , UPDRS , Berg Balance Test , Dynamic Gait Index and Falls Efficacy Scale . Results : Initial total walking distance of the training group on treadmill was 266.45 ± 82.14 m and this was progressively increased to 726.36 ± 93.1 m after 16 training session ( P < 0.001 ) . Tolerated maximum speed of the training group on treadmill at baseline was 1.9 ± 0.75 km/h and improved to 2.61 ± 0.77 km/h ( P < 0.001 ) . Berg Balance Test , Dynamic Gait Index and Falls Efficacy Scale scores of the training group were improved significantly after the training programme ( P < 0.01 ) . There was no significant improvement in any of the outcome measurements in the control group ( P > 0.05 ) . Conclusions : Specific exercise programmes using incremental speed-dependent treadmill training may improve mobility , reduce postural instability and fear of falling in patients with Parkinson 's disease The purpose of this study was to determine if individuals with Parkinson 's disease ( PD ) who completed an 8-week , supervised PoleStriding exercise program would undergo significant improvements in cognitive skills , activities of daily living , motor function , and quality of life . The Unified Parkinson 's Disease Rating Scale ( UPDRS ) and the Parkinson 's Disease Question naire ( PDQ-39 ) were used to measure functional independence . Six male volunteers ( 72.7+/-3.7 years of age ) performed PoleStriding exercise three times per week for 37+/-3 minutes . Differences in the participants ' pre- and post-training scores on the UPDRS and PDQ-39 were analyzed using the Wilcoxin Signed Ranks Test . A statistically significant improvement occurred in the UPDRS ( P<0.026 ) and PDQ-39 ( P<0.028 ) scores following the moderate-intensity exercise intervention . The results of this nonr and omized clinical trial indicate that an 8-week individualized PoleStriding exercise program increases perceived functional independence and quality of life in individuals with PD The aim of our study was to evaluate the influence of low-intensity exercise on levodopa absorption and levodopa motor effect . We studied the pharmacokinetics and pharmacodynamics of levodopa under resting conditions and under a workload of 50 watts for 2 hours on a cycle ergometer in 12 parkinsonian patients with predictable fluctuations of motor disability . The patients attended the hospital on both days in a provoked off state . After a baseline assessment of motor disability using the Columbia University rating scale ( CURS scale ) and a blood test for measurement of the baseline levodopa concentration in the plasma , 100 mg levodopa and 25 mg benserazide were administered as a single dose orally . Blood sample s for measurement of the levodopa concentration in the plasma were taken , and motor assessment s were conducted at 15-minute intervals for 240 minutes and at 30-minute intervals from 240 to 360 minutes . All patients were able to perform the exercise program . The baseline Columbia University rating scale score did not differ significantly between both days . The mean levodopa concentration in plasma at half-maximal motor effect tended to be higher during exercise and indicated that the patients needed a higher levodopa concentration in plasma to achieve the half-maximal motor effect . The maximal levodopa concentration in plasma tended to be higher with exercise . Both trends did not reach statistical significance . In summary , there was not a negative or a positive net effect of exercise on pharmacokinetics and pharmacodynamics of levodopa . However , there were two counteracting trends : a trend toward better levodopa absorption and a trend toward a deteriorated concentration-effect correlation Objective : To determine whether the Alex and er Technique , alongside normal treatment , is of benefit to people disabled by idiopathic Parkinson 's disease . Design : A r and omized controlled trial with three groups , one receiving lessons in the Alex and er Technique , another receiving massage and one with no additional intervention . Measures were taken pre and post-intervention , and at follow-up , six months later . Setting : The Polyclinic at the University of Westminster , Central London . Subjects : Ninety-three people with clinical ly confirmed idiopathic Parkinson 's disease . Interventions : The Alex and er Technique group received 24 lessons in the Alex and er Technique and the massage group received 24 sessions of massage . Main outcome measures : The main outcome measures were the Self- assessment Parkinson 's Disease Disability Scale ( SPDDS ) at best and at worst times of day . Secondary measures included the Beck Depression Inventory and an Attitudes to Self Scale . Results : The Alex and er Technique group improved compared with the no additional intervention group , pre-intervention to post-intervention , both on the SPDDS at best , p = 0.04 ( confidence interval ( CI ) –6.4 to 0.0 ) and on the SPDDS at worst , p = 0.01 ( CI –11.5 to –1.8 ) . The comparative improvement was maintained at six-month follow-up : on the SPDDS at best , p = 0.04 ( CI –7.7 to 0.0 ) and on the SPDDS at worst , p = 0.01 ( CI –11.8 to –0.9 ) . The Alex and er Technique group was comparatively less depressed post-intervention , p = 0.03 ( CI –3.8 to 0.0 ) on the Beck Depression Inventory , and at six-month follow-up had improved on the Attitudes to Self Scale , p = 0.04 ( CI –13.9 to 0.0 ) . Conclusions : There is evidence that lessons in the Alex and er Technique are likely to lead to sustained benefit for people with Parkinson 's disease Background and Purpose . The application of motor imagery practice in the treatment of Parkinson ’s disease ( PD ) is a novel treatment approach for improving motor function . The purpose of this study was to compare group treatment using a combination of physical and motor imagery practice with group treatment using only physical practice in subjects with PD . Methods . Of 23 patients with idiopathic PD , 12 received combined therapy , whereas 11 received physical therapy alone . Exercises for both groups were applied during 1-h sessions held twice a week for 12 weeks . Comparable motor tasks provided to both groups included callisthenic exercises , functional tasks , and relaxation exercises . However , the experimental group was treated with both imagery and real practice , whereas the control group received only physical exercises . Outcome measures included the time required to complete sequences of movements , the performance of balance tasks , impairment and functional scores on the Unified Parkinson ’s Disease Rating Scale ( UPDRS ) , and specific cognitive abilities ( Stroop and clock drawing tests ) . Results . Following the intervention , the combined treatment group exhibited significantly faster performance of movement sequences than the control group . In addition , the experimental subjects demonstrated higher gains in the mental and motor subsets of the UPDRS and in the cognitive tests . Both groups improved on the activities of daily living scale . Conclusions . The combination of motor imagery and real practice may be effective in the treatment of PD , especially for reducing bradykinesia . The implementation of this treatment regimen allows for the extension of practice time with negligible risk and low cost INTRODUCTION Frequent falls and risk of injury are evident in individuals with Parkinson 's disease ( PD ) as the disease progresses . There have been no reports of any interventions that reduce the incidence of falls in idiopathic PD . PURPOSE Assess the benefit of gait and step perturbation training in individuals with PD . DESIGN R and omized , controlled trial . SETTING Outpatient research , education and clinical center in a tertiary care Veterans Affairs Medical Center . OUTCOME MEASURES Gait parameters , 5-step test , report of falls . SUBJECTS Eighteen men with idiopathic PD in stage 2 or 3 of the Hoehn and Yahr staging . METHODS Subjects were r and omly assigned to a trained or control group . They were asked about any falls 2 weeks prior to and after an 8 week period . Gait speed , cadence , and step length were tested on an instrumented walkway . Subjects were timed while stepping onto and back down from an 8.8 cm step for 5 consecutive steps . Gait training consisted of walking on a treadmill at a speed greater than over ground walking speed while walking in 4 directions and while supported in a harness for safety . Step training consisted of suddenly turning the treadmill on and off while the subject stood in the safety harness facing either forwards , backwards , or sideways . Training occurred 1 hour per day , three times per week for 8 weeks . A two-factor ( time and group ) analysis of variance with repeated measures was used to compare the groups . RESULTS Substantial reduction occurred in falls in the trained group , but not in the control group . Gait speed increased in the trained group from 1.28+/-0.33 meters/sec to 1.45+/-0.37 meters/sec , but not in the control group ( from 1.26 to 1.27 m/s ) . The cadence increased for both groups : from 112.8 to 120.3 steps/min for the trained group and 117.7 to 124.3 steps/min for the control group . Stride lengths increased for the trained group , but not the control group . The 5-step test speed increased in the trained group from 0.40+/-0.08 steps/sec to 0.51+/-0.12 steps/sec , and in the control group ( 0.36+/-0.11 steps/sec to 0.42+/-0.11 steps/sec ) . CONCLUSION Gait and step perturbation training result ed in a reduction in falls and improvements in gait and dynamic balance . This is a promising approach to reduce falls for patients with PD The objectives of this study is to examine the effects of neuromuscular therapy ( NMT ) on motor and nonmotor symptoms in Parkinson 's disease ( PD ) . Thirty-six subjects with PD were r and omly assigned to NMT or music relaxation ( MR , or active control ) . Subjects received treatment twice a week for 4 weeks . Testing was conducted at baseline , after final treatment , and 8 days after final treatment . Primary outcome measures were the Motor subscale of the United Parkinson Disease Rating Scale ( UPDRS ) and the Clinical Global Impression scale ( CGI-Change ) . Secondary outcome measures included a PD-specific quality of life scale ( PDQ-39 ) , quantitative measures of motor function , and severity scales for anxiety and depression symptoms . NMT result ed in a significant and sustained improvement in the Motor subscale of the UPDRS ( P < or = 0.0001 ) , most notable in the tremor scores . Also improved 1 week after the last treatment were the CGI scores ( P = 0.007 ) and the finger-tapping speed ( P = 0.001 ) . The MR active control group had a slight improvement in tremor but evidence d no other change in motor function . Both groups exhibited a modest improvement in quality of life immediately after the last treatment . This effect was sustained for 8 days only in the MR group . In the nonmotor domains , the MR group evidence d improvements in mood ( P = 0.001 ) and anxiety ( P = 0.002 ) , whereas NMT had no effect on mood ( P = 0.09 ) , and its initial effect on anxiety ( P = 0.0009 ) dissipated after 8 days ( P = 0.40 ) . Group differences for UPDRS motor score and patient CGI-Change were superior in the NMT compared to the MR group . There was no group difference in PDQ-39 scores or in nonmotor measures . The findings suggest that NMT can improve motor and selected nonmotor symptoms in PD and that this effect is more durable for the motor symptoms . The results of this pilot study warrant larger controlled studies to examine dose range , durability , and mechanisms of NMT in PD function BACKGROUND Pulmonary and respiratory muscle function impairment are common in patients with Parkinson 's disease ( PD ) . Inspiratory muscle training may improve strength , dyspnea and functional capacity in healthy subjects and in those with chronic obstructive pulmonary disease . This study investigated the effect of specific inspiratory muscle training ( SIMT ) on pulmonary functions , inspiratory muscle performance , dyspnea and quality of life , in patients with PD . PATIENTS AND METHODS Twenty patients with PD ( stage II and III Hoehn and Yahr scale ) were recruited for the study and were divided into two groups : ( a ) ten patients who received SIMT and ( b ) ten patients who received sham training , for three months . Pulmonary functions , the respiratory muscle strength and endurance , the perception of dyspnea ( POD ) and the quality of life were studied before and within one week after the training period . All subjects trained daily , six times a week , each session consisting of 1/2 hour , for 12 weeks . RESULTS Following the training period , there was a significant improvement , in the training group but not in the control group , in the following parameters : inspiratory muscle strength , ( PImax , increased from 62.0 + /- 8.2 to 78.0 + /- 7.5 cm of H2O ( p < 0.05 ) , inspiratory muscle endurance ( increased from 20.0 + /- 2.8 to 29.0 + /- 3.0 cm of H2O ( p < 0.05 ) , and the POD ( decreased from 17.9 + /- 3.2 to 14.0 + /- 2.4 units ( p < 0.05 ) . There was a close correlation between the increase in the inspiratory muscle performance and the decrease in the POD . CONCLUSIONS The inspiratory muscle performance may be improved by SIMT in patients with PD . This improvement is associated with a significant decrease in their POD Recent research has shown that dance , specifically tango , may be an appropriate and effective strategy for ameliorating functional mobility deficits in people who are frail and elderly . Individuals with Parkinson 's disease ( PD ) experience declines in functional mobility that may be even more pronounced than those experienced by frail elderly individuals without PD . The purpose of this study was to compare the effects of two movement programs : tango classes or exercise classes . Nineteen subjects with PD were r and omly assigned to a tango group or a group exercise class representative of the current classes offered in our geographical area for individuals with PD . Subjects completed a total of 20 tango or exercise classes and were evaluated the week before and the week following the intervention . Both groups showed significant improvements in overall Unified Parkinson 's Disease Rating Scale ( UPDRS ) score and nonsignificant improvements in self-reported Freezing of Gait . In addition , the tango group showed significant improvements on the Berg Balance Scale . The exercise group did not improve on this measure . Finally , the tango group showed a trend toward improvement on the Timed Up and Go test that was not observed in the exercise group . Future studies with a larger sample are needed to confirm and extend our observation that tango may be an effective intervention to target functional mobility deficits in individuals with PD Background Modern management of Parkinson ’s disease ( PD ) aims to obtain symptom control , to reduce clinical disability , and to improve quality of life . Music acts as a specific stimulus to obtain motor and emotional responses by combining movement and stimulation of different sensory pathways . We explored the efficacy of active music therapy ( MT ) on motor and emotional functions in patients with PD . Methods This prospect i ve , r and omized , controlled , single-blinded study lasted 3 months . It consisted of weekly sessions of MT and physical therapy ( PT ) . Thirty-two patients with PD , all stable responders to levodopa and in Hoehn and Yahr stage 2 or 3 , were r and omly assigned to two groups of 16 patients each . We assessed severity of PD with the Unified Parkinson ’s Disease Rating Scale , emotional functions with the Happiness Measure , and quality of life using the Parkinson ’s Disease Quality of Life Question naire . MT sessions consisted of choral singing , voice exercise , rhythmic and free body movements , and active music involving collective invention . PT sessions included a series of passive stretching exercises , specific motor tasks , and strategies to improve balance and gait . Results MT had a significant overall effect on bradykinesia as measured by the Unified Parkinson ’s Disease Rating Scale ( p < .034 ) . Post – MT session findings were consistent with motor improvement , especially in bradykinesia items ( p < .0001 ) . Over time , changes on the Happiness Measure confirmed a beneficial effect of MT on emotional functions ( p < .0001 ) . Improvements in activities of daily living and in quality of life were also documented in the MT group ( p < .0001 ) . PT improved rigidity ( p < .0001 ) . Conclusions MT is effective on motor , affective , and behavioral functions . We propose active MT as a new method for inclusion in PD rehabilitation programs Background : Postural instability ( PI ) is a common and serious problem in Parkinson ’s disease ( PD ) . Dopaminergic medication is of negligible use and a positive effect of deep brain stimulation on this issue has not been reported . Objective : To develop a method of repetitive training of compensatory steps to enhance protective postural responses by using training strategies based on recent neurophysiological research . Methods : Fourteen patients with PD took part in a multiple baseline design study and were trained for 14 days in an ambulant setting consisting of two daily sessions . Results : After training , the length of compensatory steps increased and the step initiation shortened . In a gait analysis , the cadence and the step length increased , gait velocity improved , and the period of double support shortened . The “ mobility ” subscore of a quality of life question naire ( PDQ-39 ) also improved . All these changes were significant ( p < 0.05 ) . These effects were stable for two months without additional training . Conclusion : The repetitive training of compensatory steps is an effective approach in the treatment of PI and should be applied if PI is evident clinical ly or in a patient ’s history This study investigates the effects of parkinsonism and dopamine replacement therapy ( levodopa ) on central ly initiated postural activity preceding rising onto the toes . The electromyographic ( EMG ) and force magnitude , scaling , sequencing , and postural stabilization were compared when rising-to-toes under two conditions , slow/low versus fast/high , for parkinsonian patients and elderly control subjects . Parkinsonian subjects were tested after withholding their levodopa medication for 12 - 16 h and again 1 h after taking their medication when parkinsonian signs were diminished . Parkinsonian subjects showed reduced magnitudes and delayed timing of the postural and voluntary components of the rise-to-toes task , as if they had difficulty turning off the postural , tibialis anterior ( TIB ) component and initiating the voluntary , gastrocnemius ( GAS ) component . Dopamine improved the relative timing , as well as the magnitude of both postural and voluntary components of rise-to-toes . Although the magnitude of dorsiflexion torque was smaller for parkinsonian subjects ON and OFF than for healthy elderly controls , the parkinsonian subjects showed intact scaling of the magnitude of postural activity . Parkinsonian subjects do not perform the rise-to-toes task like normal subjects who are instructed to rise slowly ; the relative timing of TIB and GAS activation was different even at comparable speeds of performance . Parkinsonian subjects , both ON and OFF , exhibited greater risk of falling than elderly control subjects when rising to toes . This increased risk of falling was reflected in a smaller safety margin between the peak center of mass ( CoM ) and peak center of pressure ( CoP ) during the task . The magnitude of mean postural dorsiflexion torque in the rise-to-toes task was highly correlated with a clinical rating scale of gait and balance , suggesting that force control is a critical factor influencing postural control in patients with Parkinson 's disease 1 . This study investigates the effects of parkinsonism and of dopamine replacement therapy ( levodopa ) on scaling the magnitude of automatic postural responses based on sensory feedback and on predictive central set . Surface reactive torques and electromyographic ( EMG ) activity in response to backward surface translations were compared in patients with parkinsonism ON and OFF levodopa and in elderly control subjects . Correlations between the earliest postural responses [ initial rate of change of torque and integrated EMG ( IEMG ) ] and translation velocity provided a measure of postural magnitude scaling using somatosensory feedback . Correlations of responses with expected translation amplitude provided a measure of scaling dependent on predictive central set because the responses preceded amplitude completion . 2 . Parkinsonian EMG responses in six leg and trunk muscles were not later than in elderly control subjects . In fact , quadriceps antagonist latencies were earlier than normal , result ing in coactivation at the knee not present in control subjects . EMG activation was fragmented , with short burst duration s and high tonic levels that often returned to baseline with multiple bursts . In addition , parkinsonian responses showed smaller-than-normal agonist extensor bursts and larger-than-normal activation in tibialis and rectus femorus antagonist flexors . 3 . Although parkinsonian subjects scaled postural responses to both displacement velocities and amplitudes , their torque response were smaller than those of elderly controls , especially in response to the largest displacement amplitudes . The gain ( slope ) of postural response magnitude scaling to displacement velocity was similar for parkinsonian and control subjects , although parkinsonian subjects had smaller torques . Parkinsonian subjects were also able to use prediction to scale responses to small expected displacement amplitudes , but many patients did not generate the larger plantarflexion torques required at larger displacement amplitudes . Reduced torque at large amplitudes was associated with less agonist gastrocnemius IEMG , increased tibialis antagonist burst responses , and increased tibialis tonic background activity . 4 . Levodopa further reduced the already low magnitude of initial torque and IEMG responses to displacement velocities and amplitudes in parkinsonian patients . The ability to scale postural responses to velocity feedback was not affected by levodopa , but the ability to scale responses to large displacement amplitudes based on central set was worsened by levodopa . Levodopa also significantly reduced the tonic , background levels of EMG , particularly the distal gastrocnemius and tibialis activity . 5 . High baseline muscle tone was apparent in parkinsonian subjects from their high background EMG activity in quiet stance , especially in tibialis and quadriceps , and the slow initial velocity of center of mass falling in response to displacements . By reducing tone , levodopa reduced passive stiffness to perturbations without increasing EMG burst magnitudes , result ing in less resistance to external displacements and thus faster center of body mass ( COM ) displacements . 6 . The biggest postural deficit in parkinsonian subjects was not in response latency , pattern , or reactive or predictive scaling of response magnitude , but in quickly generating an adequate level of postural force . Dopamine improved tonic background postural tone but further weakened automatic postural responses to external displacements . Thus the basal ganglia may participate in postural control by regulating appropriate levels of background postural tone and by enabling adequate force generation for resisting external displacements BACKGROUND Parkinsonian signs in patients without Parkinson 's disease are often undetected but occur frequently in older people , and are often considered benign . We measured the association between parkinsonism and subsequent disability . METHODS We conducted a prospect i ve , longitudinal , community-based population study in East Boston , Massachusetts , using a stratified r and om sample of 455 community residents , aged 65 years and older . Four categories of parkinsonian signs were measured at baseline : bradykinesia , gait disturbance , rigidity , and tremor . Parkinsonism was defined as the presence of two or more categories of parkinsonian signs , and cases of Parkinson 's disease were excluded from analyses . Disability was assessed annually over a mean of 4.7 years using the Katz , Rosow-Breslau , and Nagi disability measures . RESULTS Parkinsonism at baseline strongly predicted subsequent disability as assessed with the three disability measures ( on the Katz measure , beta = -1.30 , p < .001 ) . On average , a person with parkinsonism had a disability level at follow-up equal to that of a comparable person approximately 16.7 years for men and 8 years for women . The rate of developing disability for persons with parkinsonism increased each year ; on the Katz measure , participants with parkinsonism declined on average 16.4 % faster than those without . Gait impairment and bradykinesia strongly predicted subsequent disability ; tremor and rigidity did not . The effect of parkinsonism was attenuated but still persistent in persons with coexistent moderate-to-severe cognitive impairment or stroke . CONCLUSIONS Parkinsonism strongly predicts progressive disability in the older community population and has a marked aging effect on disability level OBJECTIVE To investigate the effects of a physical therapy ( PT ) program in groups of people with Parkinson 's disease ( PD ) . DESIGN R and omized controlled trial with a crossover design . SETTING Two outpatient rehabilitation clinics in Boston and Amsterdam , respectively . PARTICIPANTS Sixty-eight subjects diagnosed with typical , idiopathic PD , Hoehn and Yahr stage II or III , and stable medication use . INTERVENTION Group A received PT and medication therapy ( MT ) for the first 6 weeks , followed by MT only for the second 6 weeks . Group B received only MT for the first 6 weeks and PT and MT for the second 6 weeks . MAIN OUTCOME MEASURES The Sickness Impact Profile ( SIP-68 ) , the mobility portion of the SIP-68 , the Unified Parkinson 's Disease Rating Scale ( UPDRS ) , and comfortable walking speed ( CWS ) at baseline , 6-week , 12-week , and 3-month follow-up . RESULTS At 6 weeks , differences between groups were significant for the SIP mobility ( P = .015 ; effect size [ES]=.55 ) , for CWS ( P = .012 ; ES=.49 ) , for the activities of daily living ( ADL ) section of the UPDRS ( P = .014 ; ES=.45 ) , and for the total UPDRS ( P = .007 ; ES=.56 ) . The total SIP and the mentation and motor sections of the UPDRS did not differ significantly between groups . Significant differences were found at 3 months compared with baseline for CWS , the UPDRS ADL , and total scores . CONCLUSIONS People with PD derive benefits in the short term from PT group treatment , in addition to their MT , for quality of life related to mobility , CWS , and ADLs ; long-term benefits were found in CWS , UPDRS ADL , and total scores but varied between groups Objective : To investigate the effect of home exercises on the motor performance of patients with Parkinson 's disease . Design : A prospect i ve blinded study with allocation of patients into their groups by alternate weeks . Setting : A University Hospital neurology and physiotherapy department . Subjects : Recruited from a movement disorders outpatient clinic of Cerrahpasa School of Medicine diagnosed with Parkinson 's disease , classified as Hoehn and Yahr Grade s I , II and III . Interventions : Patients who fulfilled the inclusion criteria were recruited to the study . Each patient was evaluated at the end of first and second month after the baseline evaluation . Patients were divided into two groups . Those in the first and third week were put in the exercise group and second and fourth week in the control group . Patients in the exercise group ( n=15 ) were given a schedule of exercises to undertake at home ; the others ( n=15 ) did not receive this instruction . Measures : Ten- and 20-m walking test , first pace length , pace number in 10 m , walking around a chair , Nine Hole Peg Board ( NHPB ) test . Results : Following the home exercise programme , patients in the exercise group showed improvement in walking 10 and 20 m , time elapsed to complete walking around a chair and length of the first pace length , and in the motor performance of both h and s ( p < 0.001 ) . Conclusions : A home-based rehabilitation programme for patients with Parkinson 's disease helped to improve motor performance compared to patients who did not take advantage of a regular , professionally design ed exercise programme PURPOSE To compare health-related quality of life ( HRQL ) and pain symptoms in patients with PD with a matched control group . To our knowledge , controlled studies of Parkinson 's disease ( PD ) patients within this area are rare . SCOPE Fifty-seven patients and 95 controls took part in a self-administered question naire study . The instruments were the SF-36 , visual analogue scales , pain drawing and pain-specific questions . CONCLUSIONS Pain problems are common in PD patients but also to a large extent in the normal population . HRQL was reduced ( p < or = 0.001 ) for the PD patients on all the scales on the SF-36 and consequently also in the pain dimension . The study indicates that even PD patients , who are optimally diagnosed and treated by a neurologist , might require additional rehabilitation treatment to improve their HRQL and pain problems Music therapy ( MT ) is an unconventional , multisensorial therapy poorly assessed in medical care but widely used to different ends in a variety of setting s. MT has two branches : active and passive . In active MT the utilisation of instruments is structured to correspond to all sensory organs so as to obtain suitable motor and emotional responses . We conducted a prospect i ve study to evaluate the effects of MT in the neurorehabilitation of patients with Parkinson 's Disease ( PD ) , a common degenerative disorder involving movement and emotional impairment . Sixteen PD patients took part in 13 weekly sessions of MT each lasting 2 hours . At the beginning and at the end of the session , every 2 weeks , the patients were evaluated by a neurologist , who assessed PD severity with UPDRS , emotional functions with Happiness Measures ( HM ) and quality of life using the Parkinson 's Disease Quality of Life Question naire ( PDQL ) . After every session a significant improvement in motor function , particularly in relation to hypokinesia , was observed both in the overall and in the pre-post session evaluations . HM , UPDRS-ADL and PDQL changes confirmed an improving effect of MT on emotional functions , activities of daily living and quality of life . In conclusion , active MT , operating at a multisensorial level , stimulates motor , affective and behavioural functions . Finally , we propose active MT as new method to include in PD rehabilitation programmes . This article describes the methods adopted during MT sessions with PD patients The quality of life in persons with Parkinson 's disease ( PD ) has increased significantly with improved medicines . However , as the disease progresses difficulty in performing activities of daily life occur and occupational therapy intervention is sought ( Deane et al. , 2001 ) . Review s describing the efficacy of occupational therapy intervention in PD are inconclusive ( Murphy and Tickle-Degnen , 2001 ; Gaudet , 2002 ) . The purpose of this study is to establish an occupational therapy protocol for PD based upon research on motor control , sensory feedback and bradykinesia . As a first stage , the present study investigated the contribution of sensory feedback in generating the most prevalent symptoms of PD , that is , bradykinesia . Fast reach-to-grasp movement without kinesthetic or visual dependence in PD patients under on-drug and off-drug conditions were investigated . Seven normal participants and 11 patients with PD voluntarily participated in the study . Movements of the upper arm as a measure of reach , and movements of the index finger as a measure of grasp were recorded using magnetic trackers . Compared to the normal participants , this index to upper arm movement relationship was severely disturbed in the patients with PD and was improved following medications . Inter-onset latency ( IOL ) , that is , the time lag between the initiation of upper arm movement and index movement , was significantly longer in PD patients compared to normal subjects . Medications reduced IOL which lead to improvement of the relationship of upper arm and index . The results suggest that bradykinesia is due to the breakdown of co-ordination between joint movements as a result of presumably slow executive processing of motor programmes . Individual joint movements are initiated out of sequence result ing in uncoordinated movements even with antiparkinsonian drugs . It is suggested that occupational therapy intervention in PD patients should be directed to occupations that require co-ordination of joint movements essential for successful completion of various activities of daily living tasks Objective : To evaluate the effectiveness of a personalised home programme of exercises and strategies for repeat fallers with Parkinson ’s disease ( PD ) . Method : Patients with a confirmed diagnosis of idiopathic PD , independently mobile , living at home in the community , experiencing more than one fall in the previous 12 months and with intact gross cognitive function were invited to participate in this r and omised controlled trial . Usual care was compared with a personalised 6 week , home based exercise and strategy programme . The primary outcomes were rates of falling at 8 weeks and 6 months . Whether participants had repeat fallen , nearly fallen or experienced injurious falls were also examined . Functional Reach , the Berg Balance Test , PD Self- assessment Scale and the Euro Quol were rated by a blinded assessor . Results : Participants were r and omised to the exercise ( n = 70 ) and control ( n = 72 ) groups . There was a consistent trend towards lower fall rates in the exercise group at both 8 weeks and 6 months and lower rates of injurious falls needing medical attention at 6 months . Lower rates of repeat near falling were evident for the exercise group at 8 weeks ( p = 0.004 ) and 6 months ( p = 0.007 ) . There was a positive effect of exercises at 6 months on Functional Reach ( p = 0.009 ) and quality of life ( p = 0.033 ) . No significant differences were found on other secondary outcomes measures . Conclusion : There was a trend towards a reduction in fall events and injurious falls with a positive effect of exercises on near falls and quality of life Abstract .The aim of this study was to evaluate the effects of prolonged physical therapy on disability in patients with Parkinson ’s disease . The study was design ed as an open long-term trial over 20 weeks . Twenty slightly to moderately affected parkinsonian patients were included ( Hoehn & Yahr stages : 1.5–3 ) . A comprehensive rehabilitation program was applied three times a week in all patients . Pharmacological treatment was kept stable . Evaluations were performed at baseline , at the end of treatment and after 3 months . Following physical rehabilitation , there was a significant improvement in UPDRS ( ADL and motor sections ) scores , Self- assessment Parkinson ’s disease Disability Scale , Ten-Meter Walk test and Zung scale for depression . At 3-month follow-up clinical improvements were largely maintained . A sustained improvement of motor skills in PD patients can be achieved with a long-term comprehensive rehabilitation program 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 The objective of this study was to define risk factors for depression in patients with idiopathic Parkinson 's disease ( PD ) and to evaluate the correlation of depression with cognitive function and the primary domains of parkinsonian motor dysfunction tremor , bradykinesia , rigidity , gait and balance impairment . The risk factors for depression in patients with PD remain controversial . Several investigators have demonstrated a significant association between cognitive dysfunction and depression , but motoric and disease variables can confound this evaluation and have shown an inconsistent relation to depression . A consecutive series of 88 patients with PD were examined using the motor subscale of the Unified Parkinson 's Disease Rating Scale ( UPDRSm ) , Hoehn-Yahr stage ( HY ) , and Hamilton Rating Scale for Depression ( HRSD ) . Major depression was diagnosed according to the criteria in the Diagnostic and Statistic Manual of Mental Disorders , 4th edition . Gender , age , h and edness , PD duration , side of PD onset , motor fluctuations , UPDRSm total score , daily Levodopa dose , and Mini-Mental State Examination score ( MMSE ) were analyzed using multivariate and univariate logistic regression , Fisher 's Exact test , and Pearson correlations . Major depression was diagnosed in 12 patients ( 7.3 % ) . Low MMSE score , axial bradykinesia , gait and balance impairment were strongly significant predictors of depression . In conclusion , depression and physical function are important factors impairing the quality of life for patients with PD , and regular depression screening and treatment should focus on patients with PD who have cognitive impairment , high axial bradykinesia , gait and balance impairment Objective : To determine whether a programme of multidisciplinary rehabilitation and group support achieves sustained benefit for people with Parkinson ’s disease or their carers . Methods : The study was a r and omised controlled crossover trial comparing patients and carers who had received rehabilitation four months before assessment with those who had not . Patients were recruited from a neurology clinic , attended a day hospital from home weekly for six weeks using private car or hospital transport , and received group educational activities and individual rehabilitation from a multidisciplinary team . Patients were assessed at entry and at six months using a 25 item self assessment Parkinson ’s disease disability question naire , Euroqol-5d , SF-36 , PDQ-39 , hospital anxiety and depression scale , and timed st and -walk-sit test . Carers were assessed using the carer strain index and Euroqol-5d . Results : 144 people with Parkinson ’s disease without severe cognitive losses and able to travel to hospital were registered ( seven were duplicate registration s ) ; 94 had assessment s at baseline and six months . Repeated measures analysis of variance comparing patients at the 24 week crossover point showed that those receiving rehabilitation had a trend towards better st and -walk-sit score ( p = 0.093 ) and worse general and mental health ( p = 0.002 , p = 0.019 ) . Carers of treated patients had a trend towards more strain ( p = 0.086 ) . Analysis comparing patients before and six months after treatment showed worsening in disability , quality of life , and carer strain . Conclusions : Patients with Parkinson ’s disease decline significantly over six months , but a short spell of multidisciplinary rehabilitation may improve mobility . Follow up treatments may be needed to maintain any benefit To study the feasibility of a large r and omised controlled trial ( RCT ) evaluating the effectiveness of physiotherapy in Parkinson 's disease ( PD ) , 173 patients were asked to participate in a study with r and om allocation to best practice physiotherapy , or to no physiotherapy . The primary outcome measures were the Parkinson 's disease question naire-39 , the Parkinson activity scale , and a patient preference outcome scale ( PPOS ) . Only 14 % of the patients could be included in the study . The PPOS showed the largest effect size ( 0.74 ) with a significant group effect ( p<0.05 ) . Specific alterations to the study design to ensure successful RCTs in this field are recommended Background and Purpose Exercise is advocated in the management of Parkinson disease ( PD ) , however , little is known regarding the potential benefits of complementary mind/body exercise for this clinical population . The purpose of this pilot program evaluation was to gain insight into participant and instructor perceptions of the perceived benefits and potential utility of a taiji exercise program . Program Evaluation Program participants ( N= 15 ) included 8 individuals with PD and 7 support partners with no history of PD . Group taiji instruction was offered in 45-minute weekly sessions , for 12 weeks at a community facility . Postprogram evaluation included administration of a survey question naire , thematic analysis of a focus group discussion , instructor reflections , and review of attendance records . Results Benefits were perceived by participants in physical , psychological , and social domains . Thirteen of the survey respondents , including 6 of the 8 respondents with PD reported perceiving a physical benefit attributed to taiji practice . Improved balance was reported most frequently . Instructor observations and participant testimony suggest movement capability for individuals with Parkinsons may also be improved by performing taiji . Conclusion This preliminary research provides support for further Taiji Buddy program examination and application OBJECTIVE To assess immediate and near-term effects of 2 exercise training programs for persons with idiopathic Parkinson 's disease ( IPD ) . DESIGN R and omized control trial . SETTING Public health facility and medical center . PARTICIPANTS Fifteen persons with IPD . INTERVENTION Combined group ( balance and resistance training ) and balance group ( balance training only ) underwent 10 weeks of high-intensity resistance training ( knee extensors and flexors , ankle plantarflexion ) and /or balance training under altered visual and somatosensory sensory conditions , 3 times a week on nonconsecutive days . Groups were assessed before , immediately after training , and 4 weeks later . MAIN OUTCOME MEASURES Balance was assessed by computerized dynamic posturography , which determined the subject 's response to reduced or altered visual and somatosensory orientation cues ( Sensory Orientation Test [ SOT ] ) . Muscle strength was assessed by measuring the amount of weight a participant could lift , by using a st and ardized weight- and -pulley system , during a 4-repetition-maximum test of knee extension , knee flexion , and ankle plantarflexion . RESULTS Both types of training improved SOT performance . This effect was larger in the combined group . Both groups could balance longer before falling , and this effect persisted for at least 4 weeks . Muscle strength increased marginally in the balance group and substantially in the combined group , and this effect persisted for at least 4 weeks . CONCLUSION Muscle strength and balance can be improved in persons with IPD by high-intensity resistance training and balance training OBJECTIVE To compare the effects of whole body vibration ( WBV ) and conventional physiotherapy ( PT ) on levodopa-resistant disturbances of balance and gait in idiopathic Parkinson 's disease ( PD ) . DESIGN R and omized controlled rater-blinded trial comparing 2 active interventions , final follow-up assessment 4 weeks after termination of active intervention . SETTING Specialized referral center , hospitalized care . PARTICIPANTS Patients with PD and dopa-resistant imbalance on stable dopamine replacement medication ( N=27 ) were r and omized ( intent-to-treat population ) to receive WBV ( n=13 ) or conventional PT ( controls , n=14 ) . Twenty-one patients ( per protocol population ) completed follow-up ( 14 men , 7 women ; mean age , 73.8 y ; age range , 62 - 84 y ; mean disease duration , 7.2 y ; mean dopa-equivalent dose , 768 mg/d ) . INTERVENTION Subjects were r and omized to receive 30 sessions ( two 15-min sessions a day , 5 days a week ) of either WBV on an oscillating platform or conventional balance training including exercises on a tilt board . Twenty-one subjects ( 10 with WBV , 11 controls ) were available for follow-up 4 weeks after treatment termination . MAIN OUTCOME MEASURES The primary measure was Tinetti Balance Scale score . Secondary clinical ratings included st and -walk-sit test , walking velocity , Unified Parkinson 's Disease Rating Scale ( section III motor examination ) score , performance in the pull test , and dynamic posturography . RESULTS The Tinetti score improved from 9.3 to 12.8 points in the WBV group and from 8.3 to 11.7 in the controls . All secondary measures , except posturography , likewise improved at follow-up compared with baseline in both groups . Quantitative dynamic posturography only improved in patients with WBV ( 1937 - 1467 mm ) whereas there was no significant change in controls ( 1832 - 2030 mm ) . CONCLUSIONS Equilibrium and gait improved in patients with PD receiving conventional WBV or conventional PT in the setting of a comprehensive rehabilitation program . There was no conclusive evidence for superior efficacy of WBV compared with conventional balance training We evaluated changes in different domains of quality of life ( QL ) for persons with Parkinson 's disease after a program of physical activity . Twenty subjects with a diagnosis of Parkinson 's disease classified as Stages 1 to 3 on the Hoehn and Yahr scale and with a mean age of 61.5 + /- 9.8 years participated in 36 group sessions of a combined group program of aerobic conditioning and muscular strengthening . QL was investigated by the Nottingham Health Profile , a generic question naire composed of six domains . Student 's paired t tests indicated significant gains associated with the program ( P < 0.05 ) on the total score and those related to emotional reactions ( ER ) , social interactions ( SI ) , and physical ability ( PA ) . SI was the domain that showed the greatest program gains ( 41.4 % ) . The program of physical activity performed with persons with Parkinson 's disease at light to moderate stages result ed in improvements in their perception of QL , mainly in the domains of ER , SI , and PA Objective : Freezing of gait is a frequently disabling symptom in Parkinson 's disease , poorly responding to dopaminergic treatment . We investigated the short-term effectiveness of a rehabilitation protocol in parkinsonian patients with freezing of gait . Design : Prospect i ve , uncontrolled pilot study with open label design . Setting : Outpatient service for rehabilitation of neurological disorders . Subjects : Twelve patients ( 8 male , 4 female ; aged 59 - 78 years ; Hoehn-Yahr stage : 2 - 3 ; mean disease duration : 14.29±SD 4.1 years ) . Interventions : Patients attended three ( 45 min ) sessions every week , over a six-week period , of physical therapy focused to improve balance , postural control and walking , and to learn new strategies for overcoming freezing of gait . Main outcome measures : Patients were evaluated before ( T0 ) , at the end ( T1 ) , and one month after ( T2 ) rehabilitation by means of clinical rating scales ( Unified Parkinson Disease Rating Scale-Motor Section ; Freezing of Gait Question naire ; Parkinson Disease Quality of Life Score ) and gait parameters ( number of strides , stride length and velocity ) during a st and ardized walking test . Results : The scores of Freezing of Gait Question naire and of Parkinson Disease Quality of Life Question naire ( but not of the Unified Parkinson Disease Rating Scale-Motor Section ) were significantly improved after treatment ( T1 ) . Gait parameters were significantly improved at T1 and T2 . Conclusions : We showed the potential short-term efficacy of a rehabilitative approach to freezing of gait in Parkinson 's disease . The positive outcome was documented by clinical rating scales and objective gait evaluation . The rapid reversibility of the clinical benefit suggests that further studies are needed to better define the optimal frequency and duration of treatment Background : The risk of people with Parkinson ’s disease ( PD ) falling is greater than that of the general population but to date , disease-specific predictors of falling have not been identified . Objectives : To identify one or more features , which would predict individuals at risk of falling during a 3-month prospect i ve follow-up study . Method : A battery of st and ardised tests administered in the home and the laboratory with a 3-month follow-up telephone interview . Results : Sixty-three people with PD were recruited from GP practice s. Eleven interview variables and six gait laboratory variables were used with sub sample s ( 55 and 44 subjects , respectively ) to fit predictive models for identifying future fallers . The number of falls in the previous year was the most important variable , without exception , to be selected as a predictor in various logistic regression models . A history of two or more falls had a sensitivity of 86.4 % ( 95 % CI 67.3–96.2 % ) and a specificity of 85.7 % ( 95 % CI 71.2–94.2 % ) in predicting falling in the next 3 months . Conclusion : Healthcare workers should be asking their patients with PD regularly and carefully about falling , and should consider instigating programmes of fall management for patients with PD who have fallen two or more times in the previous 12 months

Data for serious neonatal morbidity were not pooled due to high heterogeneity between the three studies that reported it ( 1098 babies ) ( evidence grade d very low).The use of Doppler to evaluate early and late changes in ductus venosus in early fetal growth restriction was not associated with significant differences in any perinatal death after r and omisation . However , there was an improvement in long-term neurological outcome in the cohort of babies in whom the trigger for delivery was either late changes in ductus venosus or abnormalities seen on computerised CTG . Current evidence suggests that the use of Doppler ultrasound on the umbilical artery in high-risk pregnancies reduces the risk of perinatal deaths and may result in fewer obstetric interventions .

BACKGROUND Abnormal blood flow patterns in fetal circulation detected by Doppler ultrasound may indicate poor fetal prognosis . It is also possible that false positive Doppler ultrasound findings could lead to adverse outcomes from unnecessary interventions , including preterm delivery . OBJECTIVES The objective of this review was to assess the effects of Doppler ultrasound used to assess fetal well-being in high-risk pregnancies on obstetric care and fetal outcomes .

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 ( enrolment , 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 OBJECTIVES We sought to document the pregnancy and neurodevelopmental outcome in monochorionic diamniotic twin pregnancies and to identify risk factors for death and impairment . STUDY DESIGN We conducted a prospect i ve cohort study of 136 monochorionic twins followed up from the first trimester until infancy . RESULTS A total of 122 ( 90 % ) pregnancies result ed in 2 survivors , 6 ( 4 % ) in 1 survivor and 8 ( 6 % ) in no survivor . In all , 230 ( 92 % ) of 250 surviving infants were assessed at a mean age of 24 months . Neurodevelopmental impairment was present in 22 ( 10 % ) infants . Death or impairment of 1 or both infants occurred in 28 ( 22 % ) of 126 pregnancies . Twin-to-twin transfusion syndrome and assisted conception increased the risk of both death and impairment , whereas early-onset discordant growth only increased the risk of death . CONCLUSION The mortality in this prospect i ve series was 8 % and neurodevelopmental impairment occurred in 10 % of infants After the adoption of the use of umbilical artery and middle cerebral artery peak systolic velocity in high-risk pregnancies and in pregnancies that are at risk of having an anemic fetus , the main focus of Doppler ultrasonography in obstetrics today is intrauterine growth-restricted fetuses . What is most needed at this time are ( 1 ) training of sonographers and sonologists on how to perform a Doppler study , ( 2 ) an international classification of intrauterine growth-restricted fetuses , and ( 3 ) a study of the natural history of intrauterine growth-restricted fetuses that might contribute to a better underst and ing of the intrauterine growth-restriction process and to st and ard treatment of intrauterine growth-restricted fetuses . Future investigations , which would include r and omized studies , could be design ed from the results of such studies We have done a r and omised controlled trial to assess the effect on primary management and outcome of routine doppler ultrasound examinations of the umbilical and uterine arteries during pregnancy . Over 9 months , 2600 women with singleton pregnancies were recruited from a general obstetric population . Of 2475 women who delivered in hospital after 20 weeks ' gestation , 1246 had been allocated at r and om to receive st and ard antenatal care with routine doppler examinations . The first doppler ultrasound was done at 19 - 22 weeks ' gestation , and thereafter examinations were monthly if the pregnancy was considered high risk ( 192 ) or once at 32 weeks if considered low risk ( 1054 ) . The control group of 1229 women received st and ard , antenatal care without doppler ultrasonography . The study groups did not differ in number of antenatal admissions or cardiotocographs , gestational age at delivery , method of delivery , frequency of deliveries with fetal distress , or need for resuscitation or admission to the neonatal intensive care unit . More perinatal deaths occurred in the doppler group ( 17 vs 7 , relative risk 2.4 , 95 % Cl 1.00 - 5.76 ) , but only 1 of 11 normally formed stillbirths and none of the 4 normally formed neonatal deaths after 24 weeks ' gestation had an abnormal umbilical-artery doppler examination . We did not demonstrate any improvement in neonatal outcome by routine doppler ultrasound screening of a general obstetric population One-hundred and eighty-seven single pregnancies , at full term determined accurately and confirmed by ultrasound before 17 weeks of amenorrhea and which were proceeding normally were monitored every 2 days after the expected end of term . This was done by conventional methods and in 132 cases by determining a placental resistance index ( R = D/S ) . All the deliveries were carried out under monitoring and the infants examined by a pediatrician . The umbilical index at 280 to 300 days of gestation was found to be constant and equal to R = 0.52 + /- 0.041 ( n + /- D ) and the signs of fetal distress and post-maturity increased beyond term . In the first 80 pregnancies studies in this way , the determination of the value of the index R was not included in the decision-making process . Twelve of the 14 cases of fetal heart rate arrhythmia during delivery and all recorded cases of post-mature clinical signs and neonatal acidosis occurred when the index was above RI = 0.54 . The next 107 pregnancies were r and omly divided into two groups . In the 52 pregnancies in which the Doppler revealed an index at two consecutive determinations in excess of 0.54 , this was taken to be a criterion for the induction of childbirth . In this group , some of the women gave birth earlier , without any increase in the number of Caesareans and this result ed in fewer post-mature infants . ( ABSTRACT TRUNCATED AT 250 WORDS BACKGROUND No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction . We aim ed to assess whether changes in the fetal ductus venosus Doppler waveform ( DV ) could be used as indications for delivery instead of cardiotocography short-term variation ( STV ) . METHODS In this prospect i ve , European multicentre , unblinded , r and omised study , we included women with singleton fetuses at 26 - 32 weeks of gestation who had very preterm fetal growth restriction ( ie , low abdominal circumference [ < 10th percentile ] and a high umbilical artery Doppler pulsatility index [ > 95th percentile ] ) . We r and omly allocated women 1:1:1 , with r and omly sized blocks and stratified by participating centre and gestational age ( < 29 weeks vs ≥29 weeks ) , to three timing of delivery plans , which differed according to antenatal monitoring strategies : reduced cardiotocograph fetal heart rate STV ( CTG STV ) , early DV changes ( pulsatility index > 95th percentile ; DV p95 ) , or late DV changes ( A wave [ the deflection within the venous waveform signifying atrial contraction ] at or below baseline ; DV no A ) . The primary outcome was survival without cerebral palsy or neurosensory impairment , or a Bayley III developmental score of less than 85 , at 2 years of age . We assessed outcomes in surviving infants with known outcomes at 2 years . We did an intention to treat study for all participants for whom we had data . Safety outcomes were deaths in utero and neonatal deaths and were assessed in all r and omly allocated women . This study is registered with IS RCT N , number 56204499 . FINDINGS Between Jan 1 , 2005 and Oct 1 , 2010 , 503 of 542 eligible women were r and omly allocated to monitoring groups ( 166 to CTG STV , 167 to DV p95 , and 170 to DV no A ) . The median gestational age at delivery was 30·7 weeks ( IQR 29·1 - 32·1 ) and mean birthweight was 1019 g ( SD 322 ) . The proportion of infants surviving without neuroimpairment did not differ between the CTG STV ( 111 [ 77 % ] of 144 infants with known outcome ) , DV p95 ( 119 [ 84 % ] of 142 ) , and DV no A ( 133 [ 85 % ] of 157 ) groups ( ptrend=0·09 ) . 12 fetuses ( 2 % ) died in utero and 27 ( 6 % ) neonatal deaths occurred . Of survivors , more infants where women were r and omly assigned to delivery according to late ductus changes ( 133 [ 95 % ] of 140 , 95 % , 95 % CI 90 - 98 ) were free of neuroimpairment when compared with those r and omly assigned to CTG ( 111 [ 85 % ] of 131 , 95 % CI 78 - 90 ; p=0.005 ) , but this was accompanied by a non-significant increase in perinatal and infant mortality . INTERPRETATION Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint , timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age . FUNDING ZonMw , The Netherl and s and Dr Hans Ludwig Geisenhofer Foundation , Germany OBJECTIVE To identify the temporal sequence of abnormal Doppler changes in the fetal circulation in a subset of early and severely growth-restricted fetuses . METHODS This was a prospect i ve observational study in a tertiary care/teaching hospital . Twenty-six women who were diagnosed with growth-restricted fetuses by local st and ards before 32 weeks ' gestation and who had abnormal uterine and umbilical artery Doppler velocimetry were enrolled onto the study . To compare Doppler changes as a function of time , pulsed-wave Doppler ultrasound was performed on five vessels in the fetal peripheral and central circulations . Doppler examinations were performed twice-weekly and on the day of delivery if the fetal heart rate tracing became abnormal . Doppler indices were scored as abnormal when their values were outside the local reference limits on two or more consecutive measurements . Biometry for assessment of fetal growth was performed every 2 weeks . Computerized fetal heart rates were obtained daily . Delivery was based on a non-reactive fetal heart rate tracing and not on Doppler information . Patients with a severely growth-restricted fetus who were delivered for maternal indications such as pre-eclampsia were excluded . Perinatal outcome endpoints included : intrauterine death , gestational age at delivery , newborn weight , central nervous system damage of grade 2 or greater , intraventricular hemorrhage and neonatal mortality . RESULTS Mean gestational age and newborn weight at delivery were 29 ( st and ard deviation ( SD ) , 2 ) weeks and 818 ( SD , 150 ) g , respectively . The sequence of Doppler velocimetric changes was described by onset time cumulative curves that showed two time-related events . First , for each vessel there was a progressive increase in the percent of fetuses developing a Doppler abnormality . Second , severely growth-restricted fetuses followed a progressive sequence of acquiring Doppler abnormalities which were categorized into ' early ' and ' late ' Doppler changes . Early changes occurred in peripheral vessels ( umbilical and middle cerebral arteries ; 50 % of patients affected 15 - 16 days prior to delivery ) . Late changes included umbilical artery reverse flow , and abnormal changes in the ductus venosus , aortic and pulmonary outflow tracts ( 50 % of patients affected 4 - 5 days prior to delivery ) . The time interval between the occurrence of early and late changes was significantly different ( P < 0.0001 ) and late changes were significantly associated with perinatal death ( P < 0.01 ) . CONCLUSIONS Doppler velocimetry abnormalities develop in different vessels of the severely growth-restricted fetus in a sequential fashion . Late changes in vascular adaptation by the severely growth-restricted fetus are the best predictor of perinatal death Abstract Despite widespread application of ultrasound imaging and Doppler blood flow studies , the effects of their frequent and repeated use in pregnancy have not been evaluated in controlled trials . From 2834 women with single pregnancies at 16 - 20 weeks gestation , 1415 were selected at r and om to receive ultrasound imaging and continuous-wave Doppler flow studies at 18 , 24 , 28 , 34 , and 38 weeks gestation ( the intensive group ) and 1419 to receive single ultrasound imaging at 18 weeks ( the regular group ) . Outcome data was obtained from 99 % of women who entered the study . The only difference between the two groups was significantly higher intrauterine growth restriction in the intensive group , when expressed both as birthweight 342 : The integrated power Doppler signal arising from blood flow is a r and om process . In this article , a general approach to model this r and om process is studied . Both the theoretical and experimental results show that the temporal autocorrelation function of the integrated power Doppler signals is directly related to properties of the insonified medium , such as the scattering strengths and velocities of all moving scatterers , and as well as the properties of the Doppler imaging system , such as the point spread function ( psf ) of the power Doppler images . Some initial experiments are performed to test the proposed model . Its potential application for flow measurement , such as perfusion evaluation , is also discussed OBJECTIVES Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction . Yet , the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching . The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery . METHODS We report cohort outcomes for a prospect i ve multicenter r and omized management study of fetal growth restriction ( Trial of R and omized Umbilical and Fetal Flow in Europe ( TRUFFLE ) ) performed in 20 European perinatal centers between 2005 and 2010 . Women with a singleton fetus at 26 - 32 weeks of gestation , with abdominal circumference < 10(th ) percentile and umbilical artery Doppler pulsatility index > 95(th ) percentile , were recruited . The main outcome measure was a composite of fetal or neonatal death or severe morbidity : survival to discharge with severe brain injury , bronchopulmonary dysplasia , proven neonatal sepsis or necrotizing enterocolitis . RESULTS Five-hundred and three of 542 eligible women formed the study group . Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g ; 12 ( 2.4 % ) babies died in utero . Gestational age at delivery was 30.7 ± 2.3 weeks , and birth weight was 1013 ± 321 g. Overall , 81 % of deliveries were indicated by fetal condition and 97 % were by Cesarean section . Of 491 liveborn babies , outcomes were available for 490 amongst whom there were 27 ( 5.5 % ) deaths and 118 ( 24 % ) babies suffered severe morbidity . These babies were smaller at birth ( 867 ± 251 g ) and born earlier ( 29.6 ± 2.0 weeks ) . Death and severe morbidity were significantly related to gestational age , both at study entry and delivery and also with the presence of maternal hypertensive morbidity . The median time to delivery was 13 days for women without hypertension , 8 days for those with gestational hypertension , 4 days for pre-eclampsia and 3 days for HELLP syndrome . CONCLUSIONS Fetal outcome in this study was better than expected from contemporary reports : perinatal death was uncommon ( 8 % ) and 70 % survived without severe neonatal morbidity . The intervals to delivery , death and severe morbidity were related to the presence and severity of maternal hypertensive conditions Objective To assess the addition value of umbilical artery Doppler ultrasound added to st and ard ultrasound biometry measurements in the management of twin pregnancies Objective To compare the effects of four methods of analysis on the results of r and omised controlled trials that recruit women with multiple pregnancies and measure outcomes on their babies BACKGROUND Although delivery is widely used for preterm babies failing to thrive in utero , the effect of altering delivery timing has never been assessed in a r and omised controlled trial . We aim ed to compare the effect of delivering early with delaying birth for as long as possible . METHODS 548 pregnant women were recruited by 69 hospitals in 13 European countries . Participants had fetal compromise between 24 and 36 weeks , an umbilical-artery doppler waveform recorded , and clinical uncertainty about whether immediate delivery was indicated . Before birth , 588 babies were r and omly assigned to immediate delivery ( n=296 ) or delayed delivery until the obstetrician was no longer uncertain ( n=292 ) . The main outcome was death or disability at or beyond 2 years of age . Disability was defined as a Griffiths developmental quotient of 70 or less or the presence of motor or perceptual severe disability . Analysis was by intention-to-treat . This trial has been assigned the International St and ard R and omised Controlled Trial Number IS RCT N41358726 . FINDINGS Primary outcomes were available on 290 ( 98 % ) immediate and 283 ( 97 % ) deferred deliveries . Overall rate of death or severe disability at 2 years was 55 ( 19 % ) of 290 immediate births , and 44 ( 16 % ) of 283 delayed births . With adjustment for gestational age and umbilical-artery doppler category , the odds ratio ( 95 % CrI ) was 1.1 ( 0.7 - 1.8 ) . Most of the observed difference was in disability in babies younger than 31 weeks of gestation at r and omisation : 14 ( 13 % ) immediate versus five ( 5 % ) delayed deliveries . No important differences in the median Griffiths developmental quotient in survivors was seen . INTERPRETATION The lack of difference in mortality suggests that obstetricians are delivering sick preterm babies at about the correct moment to minimise mortality . However , they could be delivering too early to minimise brain damage . These results do not lend support to the idea that obstetricians can deliver before terminal hypoxaemia to improve brain development A r and omized clinical trial was performed to test the hypothesis that if suspected intrauterine growth retardation ( IUGR ) is associated with normal umbilical artery Doppler ultrasound findings , hospitalization can safely be avoided . One hundred and fifty women with singleton pregnancies and suspected IUGR were r and omized between an intervention ( n = 74 ) and a control group ( n = 76 ) . In the intervention group , clinicians were strongly requested not to hospitalize for suspected IUGR if the Doppler findings were normal . In the control group , the Doppler results were not revealed and the participants received the st and ard management for suspected IUGR . Endpoints of the trial were : costs in terms of hospitalization , perinatal outcome , neurological development , and postnatal growth . Duration of hospitalization was significantly shorter in the intervention group than in the control group . Contrary to expectations , the hospitalization rate during pregnancy in the intervention group was not below that of the control group . This negative finding was partly due to the admission of patients in the intervention group despite their normal Doppler results . Moreover , the trial might have induced a more critical attitude towards hospitalization in suspected IUGR , decreasing admission in the control group . No clear differences were found in perinatal outcome , neurological development , or postnatal growth . The results suggest that normal umbilical artery Doppler findings in suspected cases of IUGR justify outpatient management Objective — To test whether the introduction of Doppler waveform analysis into the ultrasound department of a tertiary level hospital reduces neonatal morbidity and improves obstetric management OBJECTIVE To investigate whether pathological changes in the umbilical artery ( UA ) , ductus venosus ( DV ) and short-term fetal heart variation are related to perinatal outcome in severe , early intrauterine growth restriction ( IUGR ) . METHODS This multicenter , prospect i ve , longitudinal , observational study was carried out in the Departments of Fetal Medicine and Obstetrics in Hamburg , Amsterdam , Utrecht and London . In 70 singleton pregnancies with IUGR fetuses , delivered at 26 - 33 weeks of gestation because of antepartum fetal distress , short-term variation ( STV ) of fetal heart rate , pulsatility index of the fetal UA ( UA PI ) and DV pulsatility index for veins ( DV PIV ) were assessed at least weekly . The final measurement was performed within 24 h of delivery . St and ard cut-off levels ( 2 SD or 3 SD , absent flow or reversed flow ) were used and new cut-off levels were calculated by means of receiver-operating characteristics analysis . Adverse outcome was defined as perinatal death , cerebral hemorrhage ( > or = Grade II ) or bronchopulmonary dysplasia before discharge . The predictive value for adverse outcome was calculated for different cut-off levels of the monitoring parameters , adjusted for gestational age ( GA ) , by multivariate logistic regression analysis . Data were analyzed separately for three different time blocks , namely 8 - 14 , 2 - 7 and 0 - 1 days before delivery . RESULTS Adverse perinatal outcome occurred in 18/70 ( 26 % ) infants . During the last 24 h before delivery DV PIV and UA PI were significantly higher and STV lower in the adverse outcome group , while 2 - 7 days before delivery only DV PIV was significantly higher . Adverse perinatal outcome could be predicted at 0 - 1 days before delivery by DV PIV at a cut-off of three multiples of the SD ( odds ratio ( OR ) 11.3 ; 95 % CI 2.3 - 57 ) and GA ( OR 0.4 ; 95 % CI 0.3 - 0.8 ) , at 2 - 7 days by DV PIV at 2 SD ( OR 3.0 ; 95 % CI 0.8 - 12 ) and GA ( OR 0.5 ; 95 % CI 0.3 - 0.8 ) and at 8 - 14 days by DV PIV at 2 SD ( OR 3.9 ; 95 % CI 0.8 - 20 ) and GA ( OR 0.5 ; 95 % CI 0.3 - 0.8 ) . Other parameters did not contribute to the multivariate model . CONCLUSIONS DV PIV measurement is the best predictor of perinatal outcome . This measurement may be useful in timing the delivery of early IUGR fetuses and in improving perinatal outcome , even when delivery may be indicated at an earlier GA . However , as GA was also an important factor influencing outcome , with poorer outcome at earlier gestation at delivery , this hypothesis needs to be tested in a multicenter , prospect i ve , r and omized trial OBJECTIVE To determine whether knowledge of the result of Doppler velocimetry of the umbilical artery is beneficial to the management of a high risk pregnancy . DESIGN R and omised controlled trial . The trial was of the management type , design ed to assess benefit accruing from additional information supplied by Doppler velocimetry . SETTING Tygerberg Hospital , Cape Town , South Africa . The hospital serves a population from the lower socio-economic groups . SUBJECTS Women with pregnancies 28 or more weeks gestation with hypertensive diseases and /or suspected small for gestational age fetuses were referred for Doppler velocimetry . From this population , three subsets were formed : 1 . those with fetuses with absent end-diastolic velocities ( 20 fetuses ) ; 2 . those with hypertension but with fetuses with end-diastolic velocities ( 89 fetuses ) ; and 3 . those with fetuses suspected of being small for gestational age but with end-diastolic velocities ( 104 fetuses ) . INTERVENTIONS Doppler velocimetry on all subjects . The study group consisted of 10 cases with absent end-diastolic velocities , 47 cases with hypertensive diseases with end-diastolic velocities and 51 cases with suspected small for gestational age fetuses but with end-diastolic velocities in which the result was revealed to the clinician . The control group consisted of 10 , 42 and 53 cases , respectively , in which the Doppler results were not revealed . All other routine investigations ( sonar and antenatal fetal heart rate monitoring ) were available to the clinicians . St and ard management protocol s were followed in all groups . MAIN OUTCOME MEASURES Perinatal mortality and morbidity , antenatal hospitalisation , maternal intervention , admission to the neonatal intensive care unit and hospitalisation until discharge from the neonatal wards . RESULTS In the study and control groups the gestational age at entry to the study , maternal age , parity and various complications were not significantly different . In the subset with absent end-diastolic velocities , there was one neonatal death in the study group , but in the control group there were six deaths , five intrauterine and one perinatally related infant death ( P = 0.029 ) . Because of this significant finding , the study was stopped . There were no differences in outcome in the subset where there was hypertensive disease with end-diastolic velocities between the study and control groups . In the subset in which small for gestational age fetuses were suspected , but in which end-diastolic velocities were present , the women in the study group had significantly fewer days in hospital before delivery ( P < 0.001 ) and tended to have fewer maternal interventions ( study group = 27 % , control group = 43 % ; P = 0.07 ; odds ratio ( OR ) 0.49 , 95 % confidence limits ( CL ) 0.2 and 1.25 ) and caesarean sections ( study group = 13 % , control group = 27 % ; P = 0.08 ; OR 0.43 , 95 % CL 0.14 and 1.32 ) . The infants of the study group in this subset also spent significantly less time in the neonatal wards ( P = 0.029 ) The purpose of this investigation was to prospect ively determine the relationship between the umbilical artery systolic/diastolic ratio and the umbilical blood gases in sample s obtained from 165 fetuses during diagnostic cordocenteses . In each instance the sample was the umbilical vein . The systolic/diastolic ratio was measured in a midsection of the umbilical cord . Analyses used stepwise , multiple linear regression . The mean + /- SEM gestation was 29 + /- 0.4 weeks ; 72 % of fetuses were greater than or equal to 25 weeks and were considered potentially viable . There was no relationship between the umbilical artery systolic/diastolic ratio and pH , PCO2 , or PO2 in fetuses either less than 25 weeks ' gestation or greater than or equal to 25 weeks ' gestation but with systolic/diastolic ratios greater than or equal to the 95th percentile for control fetuses at 25 weeks ' gestation with normal blood gas values ( 3.5 ) . In fetuses greater than or equal to 25 weeks ' gestation with systolic/diastolic ratios that exceeded 3.5 ( n = 37 ) , there was a strong relationship between the systolic/diastolic ratio and the umbilical venous PO2 ( r = -0.68 , p less than 0.0001 ) , which was independent of gestational age . Each fetus with repetitively absent-reversed umbilical artery diastolic blood flow and a heart rate greater than 90 beats/min ( n = 6 ) had blood gas measurements consistent with hypoxia and acidosis . This investigation suggests that factors that lead to an increase in the umbilical artery systolic/diastolic ratio are associated with a progressive impairment of placental gas exchange and that by the time diastolic flow is lost , hypoxemia is present OBJECTIVE To describe the time sequence of changes in fetal monitoring variables in intrauterine growth restriction and to correlate these findings with fetal outcome at delivery . METHODS This was a prospect i ve longitudinal observational multicenter study on 110 singleton pregnancies with growth-restricted fetuses after 24 weeks of gestation . Short-term variation of fetal heart rate , pulsatility indices of fetal arterial and venous Doppler waveforms and amniotic fluid index were assessed at each monitoring session . The study population was divided into two groups : Group 1 comprised pregnancies with severely premature fetuses , which were delivered < or = 32 weeks and Group 2 included pregnancies delivered after 32 completed weeks . Logistic regression was used for modeling the probability for abnormality of a variable in relation to the time interval before delivery . Trends over time were analyzed for all variables by multilevel analysis . RESULTS Ninety-three ( 60 in Group 1 and 33 in Group 2 ) fetuses had at least three data sets ( median , 4 ; range , 3 - 27 ) and had the last measurements taken within 24 h of delivery or intrauterine death . The percentage of abnormal test results and the degree of abnormality were higher in Group 1 compared to Group 2 . Amniotic fluid index and umbilical artery pulsatility index were the first variables to become abnormal , followed by the middle cerebral artery , aorta , short-term variation , ductus venosus and inferior vena cava . In Group 1 , short-term variation and ductus venosus pulsatility index showed mirror images of each other in their trend over time . Perinatal mortality was significantly higher if both variables were abnormal compared to only one or neither being abnormal ( 13/33 ( 39 % ) vs. 4/60 ( 7 % ) ; P = 0.0002 ; Fisher 's exact test ) . CONCLUSION Ductus venosus pulsatility index and short-term variation of fetal heart rate are important indicators for the optimal timing of delivery before 32 weeks of gestation . Delivery should be considered if one of these parameters becomes persistently abnormal OBJECTIVE Meta- analysis of r and omized trials of Doppler ultrasonography in high-risk pregnancies has showed reduced mortality rates among normally formed fetuses . This trial addressed the impact on outcome of umbilical artery velocimetry in a nonselected population ( i.e. , as a screening test in low-risk and high-risk pregnancies ) . STUDY DESIGN A r and omized , controlled trial with Doppler ultrasonographic investigation was performed at two gestational age windows : 26 to 30 weeks and 34 to 36 weeks . The 2986 women were r and omly allocated to revealed or concealed groups in which the Doppler results were either made available or not made available to clinicians ; 1056 women were studied at only the first window , 544 at only the second , and 1386 at both . RESULTS There were no significant differences between groups in antenatal admissions to hospital , preterm deliveries , rates of cesarean section , admission to the neonatal unit , and need for assisted ventilation . There was , however , a trend toward fewer stillbirths in the " revealed " group ( three vs eight , odds ratio 0.34 , confidence interval 0.10 to 1.07 ) . CONCLUSIONS The incidence of stillbirths was reduced by more than half in the Doppler-revealed group , but the confidence intervals were wide and these findings could be compatible with chance OBJECTIVE Our aim was to assess the clinical value of umbilical Doppler velocimetry with regard to maternal hospitalization policy , obstetric management , and perinatal outcome . STUDY DESIGN We conducted a r and omized controlled trial in a university hospital population . A total of 1598 women participated , of whom 809 were allocated to the Doppler group and 789 to the control group . In the Doppler group umbilical Doppler studies were performed only when indicated . Abnormal pulsatility index values prompted intensified ( clinical ) fetal monitoring . In the control group Doppler velocimetry was not available . RESULTS The use of umbilical Doppler velocimetry did not show any clinical or economical benefit with regard to maternal admission rate and duration or neonatal admission policy and requirements of ventilatory support . Neither did the use of Doppler have any beneficial effect on obstetric management during labor and the occurrence of fetal distress during labor . In the control group a higher perinatal mortality rate was observed . In the Doppler group the risk ratio of perinatal mortality of fetuses and infants weighing > or = 500 gm was 0.45 ( 95 % confidence interval 0.21 to 0.94 ) , as compared with the control group . Neonatal mortality was equal in both groups ; therefore the reduction in perinatal mortality was not the result of a delay in timing of fetal death . CONCLUSION Selective use of umbilical Doppler velocimetry in pregnancies " at fetal risk " may be of benefit in antenatal care by a reduction of perinatal mortality and especially late fetal mortality Objective To compare the impact on use of re sources in the management of small for gestational age babies using Doppler ultrasound versus cardiotocography OBJECTIVES To compare the effect of delivering early to pre-empt terminal hypoxaemia with delaying for as long as possible to increase maturity . DESIGN A r and omized controlled trial . SETTING 69 hospitals in 13 European countries . PARTICIPANTS Pregnant women with fetal compromise between 24 and 36 weeks , an umbilical artery Doppler waveform recorded and clinical uncertainty whether immediate delivery was indicated . METHODS The interventions were ' immediate delivery ' or ' delay until the obstetrician is no longer uncertain ' . The data monitoring and analysis were Bayesian . MAIN OUTCOME MEASURES ' Survival to hospital discharge ' and ' developmental quotient at two years of age ' , this latter to be reported later . RESULTS Of 548 women ( 588 babies ) recruited , outcomes were available on 547 mothers ( 587 babies ) . The median time-to-delivery intervals were 0.9 days in the immediate group and 4.9 days in the delay group . Total deaths prior to discharge were 29 ( 10 % ) in the immediate group versus 27 ( 9 % ) in the delay group ( odds ratio 1.1 , 95 % CI 0.61 - 1.8 ) . Total caesarean sections were 249 ( 91 % ) in the immediate group versus 217 ( 79 % ) in the delay group : ( OR 2.7 ; 95 % CI 1.6 - 4.5 ) . These odds ratios were similar for those r and omized at gestational ages above or below 30 weeks . INTERPRETATION The lack of difference in overall mortality suggests that clinicians participating in this trial were on average prepared to r and omize at about the correct equivocal threshold between delivery and delay . However , there was insufficient evidence to convince enthusiasts for either immediate or delayed delivery that they were wrong OBJECTIVE The purpose of this study was to evaluate the ability of two different modes of antepartum fetal testing to screen for the presence of peripartum morbidity , as measured by the cesarean delivery rate for fetal distress in labor . STUDY DESIGN Over a 36-month period , all patients who were referred to the Fetal Assessment Unit at BC Women 's Hospital because of a perceived increased fetal antepartum risk at a gestational age of > or = 32 weeks of gestation were approached to participate in this study . Fetal surveillance of these women was allocated r and omly to either umbilical artery Doppler ultrasound testing or nonstress testing as a screening test for fetal well-being . If either the umbilical artery Doppler testing or the nonstress testing was normal , patients were screened subsequently with the same technique , according to study protocol . When the Doppler study showed a systolic/diastolic ratio of > 90th percentile or the nonstress testing was equivocal ( ie , variable decelerations ) , an amniotic fluid index was performed , as an additional screening test . When the amniotic fluid index was abnormal ( < 5th percentile ) , induction and delivery were recommended . When the Doppler study showed absent or reversed diastolic blood flow or when the nonstress test result was abnormal , induction and delivery were recommended to the attending physician . Statistical comparisons between groups were performed with an unpaired t test for normally distributed continuous variables and chi(2 ) test for categoric variables . RESULTS One thous and three hundred sixty patients were assigned r and omly to groups in the study ; 16 patients were lost to follow up . Six hundred forty-nine patients received Doppler testing and 691 received nonstress testing . The mean number of visits for the Doppler test and nonstress test groups was two versus two , respectively . The major indications for fetal assessment included post date s ( 43 % ) , decreased fetal movement ( 22 % ) , diabetes mellitus ( 11 % ) , hypertension ( 10 % ) , and intrauterine growth restriction ( 7 % ) . The incidence of cesarean delivery for fetal distress was significantly lower in the Doppler group compared with the nonstress testing group ( 30 [ 4.6 % ] vs 60 [ 8.7 % ] , respectively ; P < .006 ) . The greatest impact on the reduction in cesarean deliveries for fetal distress was seen in the subgroups in which the indication for testing was hypertension and suspected intrauterine growth restriction . CONCLUSION Umbilical artery Doppler as a screening test for fetal well-being in a high-risk population was associated with a decreased incidence of cesarean delivery for fetal distress compared to the nonstress testing , with no increase in neonatal morbidity Intrauterine growth retardation is associated with an increased risk of fetal asphyxia as well as greater perinatal morbidity and mortality . Ultrasound fetometry enables detection of fetuses that are small for gestational age . Doppler velocimetry of the umbilical artery has good predictive ability for fetal distress , but it is not yet clear whether it could replace cardiotocography in antenatal surveillance of small-for-gestational-age fetuses . We have done a r and omised comparison of the two methods . At four obstetric departments in Sweden , women with fetuses found to be small on ultrasound examination at 31 completed weeks of pregnancy or later were r and omly assigned to antenatal surveillance with either doppler velocimetry ( doppler ; 214 ) or cardiotocography ( CTG ; 212 ) . Pregnancies in the doppler group were managed according to a protocol based on blood-flow classes deriving from the semiquantitative evaluation of umbilical-artery velocity waveforms ; unless the pregnancy was complicated by any other disorder , no antenatal cardiotocography was done . By comparison with the CTG group , the doppler group had fewer monitoring occasions ( mean 4.1 [ SD 3.1 ] vs 8.2 [ 6.2 ] , p < 0.01 ) , antenatal hospital admissions ( 68 [ 31.3 % ] vs 97 [ 45.8 % ] , p < 0.01 ) , inductions of labour ( 22 [ 10.3 % ] vs 46 [ 21.7 % ] , p < 0.01 ) , emergency caesarean sections for fetal distress ( 11 [ 5.1 ] vs 30 [ 14.2 % ] , p < 0.01 ) , and admissions to neonatal intensive care ( 76 [ 35.5 % ] vs 92 [ 43.4 % ] , p = 0.10 ) . The groups did not differ in gestational age at birth , birthweight , Apgar scores , or total number of caesarean deliveries . Umbilical-artery doppler velocimetry of small-for-gestational-age fetuses allows antenatal monitoring and obstetric interventions to be aim ed more precisely than does cardiotocography OBJECTIVES The objective of this study was to determine whether the addition of the middle cerebral to umbilical artery systolic/diastolic velocity waveform ratio to the modified biophysical profile would improve perinatal outcome in patients at high risk . STUDY DESIGN A prospect i ve , r and omized outcome study of patients referred to the perinatal laboratory for antenatal surveillance was undertaken . Six hundred sixty-five patients were r and omized to two antenatal surveillance protocol s : group 1 , modified biophysical profile ; and group 2 , modified biophysical profile plus evaluation of the middle cerebral artery to umbilical artery systolic/diastolic ratio . Patients were followed up serially and neonatal outcome data including gestational age at delivery , birth weight , incidence of cesarean section delivery for fetal distress , admission to the neonatal intensive care unit , days in the neonatal intensive care unit , and the presence of significant neonatal morbidity were tabulated . RESULTS The total population showed no statistical difference in outcome parameters between groups 1 and 2 . However , a subgroup of patients evaluated for suspected uteroplacental insufficiency did show a significant reduction in caesarean section for fetal distress in group 2 patients . CONCLUSIONS In a subgroup of patients at risk for uteroplacental insufficiency , the addition of the middle cerebral/umbilical artery ratio to an antenatal surveillance protocol should be expected to improve perinatal outcome To determine whether the time taken for fetal assessment could safely be reduced by preliminary screening with Doppler ultrasound , 897 women having fetal assessment in the high-risk unit of the John Radcliffe Hospital , Oxford , were r and omly allocated to two groups . In the Doppler group , preliminary assessment was by umbilical artery resistance estimation , and in the fetal heart rate ( FHR ) group by computerized FHR analysis . To minimize the risk of failing to recognize fetal distress , the criteria for using the nonallocated method as well were deliberately conservative . Thus , 66 % of the 1869 Doppler studies done in the Doppler group and 39 % of the 2069 FHR tests done in the FHR group needed to be followed by the nonallocated tests . Trained nursing staff performed the Doppler studies as part of their routine duties . Doppler studies were unsuccessful in obtaining a result on 26 % of the occasions . Under the above clinical circumstances , preliminary Doppler screening did not reduce the time taken for fetal assessment . There were no significant differences in perinatal outcome between the groups , except that emergency as opposed to elective cesareans were less frequent in the Doppler group . As this finding was not predicted by previous hypothesis , it needs to be confirmed . ( Obstet Gynecol 78:359 , 1991 BACKGROUND Comparing the relative effectiveness of interventions on specific outcomes across trials can be problematic due to differences in the choice and definitions of outcome measures used by research ers . We sought to identify a minimum set of outcome measures for evaluating models of maternity care from the perspective of key stakeholders . METHODS A 3-round , electronic Delphi survey design was used . Setting was multinational , comprising a range of key stakeholders . Participants consisted of a single heterogeneous panel of maternity service users , midwives , obstetricians , pediatricians/neonatologists , family physicians/general practitioners , policy-makers , service practitioners , and research ers of maternity care . Members of the panel self-assessed their expertise in evaluating models of maternity care . RESULTS A total of 320 people from 28 countries expressed willingness to take part in this survey . Round 1 was completed by 218 ( 68.1 % ) participants , of whom 173 ( 79.4 % ) completed round 2 and 152 ( 87.9 % ) of these completed round 3 . Fifty outcomes were identified , with both a mean value greater than the overall group mean for all outcomes combined ( x=4.18 ) and rated 4 or more on a 5-point Likert-type scale for importance of inclusion in a minimum data set of outcome measures by at least 70 percent of respondents . Three outcomes were collapsed into a single outcome so that the final minimum set includes 48 outcomes . CONCLUSIONS Given the inconsistencies in the choice of outcome measures routinely collected and reported in r and omized evaluations of maternity care , it is hoped that use of the data set will increase the potential for national and international comparisons of models for maternity care . Although not intended to be prescriptive or to inhibit the collection of other outcomes , we hope that the core set will make it easier to assess the care of women and their babies during pregnancy and childbirth Objective To assess the effect on obstetric practice of clinician access to umbilical artery Doppler ultrasound results Objective To help answer the question : should Doppler ultrasound of the umbilical circulation be made available to all pregnant women as part of their routine antenatal care 300 patients at high fetal risk ( mean gestational age 34 wk ) were r and omised to a group for antenatal doppler umbilical artery waveform studies and a control group . The timing of delivery was similar in the control and doppler-report-available groups overall . However , in the report group obstetricians allowed the pregnancies of those not selected for elective delivery to continue longer . There was no difference in the rates for elective delivery ( induction of labour or caesarean section ) in the two groups , whereas among those who went into labour ( induced or spontaneous ) emergency caesarean section was more frequent in the control group ( 23 % ) than in the report group ( 13 % ) . Fetal distress in labour was also more common in the control group . Babies from the control group spent longer in neonatal intensive care ( level 3 ) and needed more respiratory support than did those in the report group . The findings indicate that the availability of doppler studies leads to better obstetrical decision making Background . In a previous prospect i ve r and omised trial on pregnancies complicated by small‐for‐gestational‐age fetuses fewer operative deliveries for fetal distress were found after antenatal surveillance with umbilical artery Doppler velocimetry ( Doppler group ) than after surveillance with cardiotocography ( CTG group ) . Despite that , the neonatal outcome was similar in both groups . This raised the question whether the knowledge of the antenatal Doppler results had influenced the obstetric management of labor 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

Conclusion The cytotoxic T-lymphocyte-associated protein-4 ( CTLA-4 ) inhibitors have a significantly higher risk of FAE ( P=0.01 ) , whereas programmed cell death protein 1 ( PD-1 ) inhibitors were not . The most common CTLA-4-related FAE was gastrointestinal toxicity , and the most common PD-1-related FAE was pulmonary toxicity . Moreover , we have shown that ipilimumab has significant dose-dependent lethal toxicity

Background Given the increasing use of immune checkpoint inhibitors ( ICIs ) , a concomitant rise in adverse events is inevitable . In a recent Phase III trial of ICIs versus placebo , we found the staggering difference of incidence of fatal adverse events ( FAEs ) . Hence , we should determine the risk of FAEs in ICIs . Objective To address the risks of FAEs associated with each ICI regimen , we performed a systematic review and meta- analysis of clinical trials with the Food and Drug Administration-approved ICI regimens in patients with advanced solid tumors .

BACKGROUND Blockade of programmed death 1 ( PD-1 ) , an inhibitory receptor expressed by T cells , can overcome immune resistance . We assessed the antitumor activity and safety of BMS-936558 , an antibody that specifically blocks PD-1 . METHODS We enrolled patients with advanced melanoma , non-small-cell lung cancer , castration-resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks . Response was assessed after each 8-week treatment cycle . Patients received up to 12 cycles until disease progression or a complete response occurred . RESULTS A total of 296 patients received treatment through February 24 , 2012 . Grade 3 or 4 drug-related adverse events occurred in 14 % of patients ; there were three deaths from pulmonary toxicity . No maximum tolerated dose was defined . Adverse events consistent with immune-related causes were observed . Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , melanoma , or renal-cell cancer . Cumulative response rates ( all doses ) were 18 % among patients with non-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with melanoma ( 26 of 94 patients ) , and 27 % among patients with renal-cell cancer ( 9 of 33 patients ) . Responses were durable ; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up . To assess the role of intratumoral PD-1 lig and ( PD-L1 ) expression in the modulation of the PD-1-PD-L1 pathway , immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients . Of 17 patients with PD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with PD-L1-positive tumors had an objective response ( P=0.006 ) . CONCLUSIONS Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer , melanoma , or renal-cell cancer ; the adverse-event profile does not appear to preclude its use . Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response . ( Funded by Bristol-Myers Squibb and others ; Clinical Trials.gov number , NCT00730639 . ) BACKGROUND Ipilimumab is an approved treatment for patients with advanced melanoma . We aim ed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma at high risk of recurrence . METHODS We did a double-blind , phase 3 trial in patients with stage III cutaneous melanoma ( excluding lymph node metastasis ≤1 mm or in-transit metastasis ) with adequate resection of lymph nodes ( ie , the primary cutaneous melanoma must have been completely excised with adequate surgical margins ) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries . Patients were r and omly assigned ( 1:1 ) , central ly by an interactive voice response system , to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses , then every 3 months for up to 3 years . Using a minimisation technique , r and omisation was stratified by disease stage and geographical region . The primary endpoint was recurrence-free survival , assessed by an independent review committee , and analysed by intention to treat . Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints . This trial is registered with EudraCT , number 2007 - 001974 - 10 , and Clinical Trials.gov , number NCT00636168 . FINDINGS Between July 10 , 2008 , and Aug 1 , 2011 , 951 patients were r and omly assigned to ipilimumab ( n=475 ) or placebo ( n=476 ) , all of whom were included in the intention-to-treat analyses . At a median follow-up of 2·74 years ( IQR 2·28 - 3·22 ) , there were 528 recurrence-free survival events ( 234 in the ipilimumab group vs 294 in the placebo group ) . Median recurrence-free survival was 26·1 months ( 95 % CI 19·3 - 39·3 ) in the ipilimumab group versus 17·1 months ( 95 % CI 13·4 - 21·6 ) in the placebo group ( hazard ratio 0·75 ; 95 % CI 0·64 - 0·90 ; p=0·0013 ) ; 3-year recurrence-free survival was 46·5 % ( 95 % CI 41·5 - 51·3 ) in the ipilimumab group versus 34·8 % ( 30·1 - 39·5 ) in the placebo group . The most common grade 3 - 4 immune-related adverse events in the ipilimumab group were gastrointestinal ( 75 [ 16 % ] vs four [ < 1 % ] in the placebo group ) , hepatic ( 50 [ 11 % ] vs one [ < 1 % ] ) , and endocrine ( 40 [ 8 % ] vs none ) . Adverse events led to discontinuation of treatment in 245 ( 52 % ) of 471 patients who started ipilimumab ( 182 [ 39 % ] during the initial treatment period of four doses ) . Five patients ( 1 % ) died due to drug-related adverse events . Five ( 1 % ) participants died because of drug-related adverse events in the ipilimumab group ; three patients died because of colitis ( two with gastrointestinal perforation ) , one patient because of myocarditis , and one patient because of multiorgan failure with Guillain-Barré syndrome . INTERPRETATION Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma . The adverse event profile was consistent with that observed in advanced melanoma , but at higher incidences in particular for endocrinopathies . The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value . FUNDING Bristol-Myers Squibb BACKGROUND Limited evidence exists to show that adding a third agent to platinum-doublet chemotherapy improves efficacy in the first-line advanced non-small-cell lung cancer ( NSCLC ) setting . The anti-PD-1 antibody pembrolizumab has shown efficacy as monotherapy in patients with advanced NSCLC and has a non-overlapping toxicity profile with chemotherapy . We assessed whether the addition of pembrolizumab to platinum-doublet chemotherapy improves efficacy in patients with advanced non-squamous NSCLC . METHODS In this r and omised , open-label , phase 2 cohort of a multicohort study ( KEYNOTE-021 ) , patients were enrolled at 26 medical centres in the USA and Taiwan . Patients with chemotherapy-naive , stage IIIB or IV , non-squamous NSCLC without targetable EGFR or ALK genetic aberrations were r and omly assigned ( 1:1 ) in blocks of four stratified by PD-L1 tumour proportion score ( < 1 % vs ≥1 % ) using an interactive voice-response system to 4 cycles of pembrolizumab 200 mg plus carboplatin area under curve 5 mg/mL per min and pemetrexed 500 mg/m2 every 3 weeks followed by pembrolizumab for 24 months and indefinite pemetrexed maintenance therapy or to 4 cycles of carboplatin and pemetrexed alone followed by indefinite pemetrexed maintenance therapy . The primary endpoint was the proportion of patients who achieved an objective response , defined as the percentage of patients with radiologically confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by masked , independent central review , in the intention-to-treat population , defined as all patients who were allocated to study treatment . Significance threshold was p<0·025 ( one sided ) . Safety was assessed in the as-treated population , defined as all patients who received at least one dose of the assigned study treatment . This trial , which is closed for enrolment but continuing for follow-up , is registered with Clinical Trials.gov , number NCT02039674 . FINDINGS Between Nov 25 , 2014 , and Jan 25 , 2016 , 123 patients were enrolled ; 60 were r and omly assigned to the pembrolizumab plus chemotherapy group and 63 to the chemotherapy alone group . 33 ( 55 % ; 95 % CI 42 - 68 ) of 60 patients in the pembrolizumab plus chemotherapy group achieved an objective response compared with 18 ( 29 % ; 18 - 41 ) of 63 patients in the chemotherapy alone group ( estimated treatment difference 26 % [ 95 % CI 9 - 42 % ] ; p=0·0016 ) . The incidence of grade 3 or worse treatment-related adverse events was similar between groups ( 23 [ 39 % ] of 59 patients in the pembrolizumab plus chemotherapy group and 16 [ 26 % ] of 62 in the chemotherapy alone group ) . The most common grade 3 or worse treatment-related adverse events in the pembrolizumab plus chemotherapy group were anaemia ( seven [ 12 % ] of 59 ) and decreased neutrophil count ( three [ 5 % ] ) ; an additional six events each occurred in two ( 3 % ) for acute kidney injury , decreased lymphocyte count , fatigue , neutropenia , and sepsis , and thrombocytopenia . In the chemotherapy alone group , the most common grade 3 or worse events were anaemia ( nine [ 15 % ] of 62 ) and decreased neutrophil count , pancytopenia , and thrombocytopenia ( two [ 3 % ] each ) . One ( 2 % ) of 59 patients in the pembrolizumab plus chemotherapy group experienced treatment-related death because of sepsis compared with two ( 3 % ) of 62 patients in the chemotherapy group : one because of sepsis and one because of pancytopenia . INTERPRETATION Combination of pembrolizumab , carboplatin , and pemetrexed could be an effective and tolerable first-line treatment option for patients with advanced non-squamous NSCLC . This finding is being further explored in an ongoing international , r and omised , double-blind , phase 3 study . FUNDING Merck & BACKGROUND This phase II study evaluated the safety and activity of ipilimumab , a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4 , in patients with advanced melanoma . PATIENTS AND METHODS Patients with previously treated , unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles ( induction ) followed by maintenance therapy every 3 months . The primary end point was best overall response rate ( BORR ) using modified World Health Organization ( WHO ) criteria . We also carried out an exploratory analysis of proposed immune-related response criteria ( irRC ) . RESULTS BORR was 5.8 % with a disease control rate ( DCR ) of 27 % ( N = 155 ) . One- and 2-year survival rates ( 95 % confidence interval ) were 47.2 % ( 39.5 % to 55.1 % ) and 32.8 % ( 25.4 % to 40.5 % ) , respectively , with a median overall survival of 10.2 months ( 7.6 - 16.3 ) . Of 43 patients with disease progression by modified WHO criteria , 12 had disease control by irRC ( 8 % of all treated patients ) , result ing in a total DCR of 35 % . Adverse events ( AEs ) were largely immune related , occurring mainly in the skin and gastrointestinal tract , with 19 % grade 3 and 3.2 % grade 4 . Immune-related AEs were manageable and generally reversible with corticosteroids . CONCLUSION Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population BACKGROUND Ipilimumab , an anti-CTLA4 monoclonal antibody , demonstrated survival benefit in melanoma with immune-related ( ir ) adverse events ( irAEs ) managed by the protocol -defined guidelines . This phase 2 study evaluated ipilimumab+paclitaxel (Taxol)/carboplatin in extensive-disease-small-cell lung cancer ( ED-SCLC ) . DESIGN Patients ( n=130 ) with chemotherapy-naïve ED-SCLC were r and omized 1 : 1 : 1 to receive paclitaxel ( 175 mg/m2)/carboplatin ( area under the curve=6 ) with either placebo ( control ) or ipilimumab 10 mg/kg in two alternative regimens , concurrent ipilimumab ( ipilimumab+paclitaxel/carboplatin followed by placebo+paclitaxel/carboplatin ) or phased ipilimumab ( placebo+paclitaxel/carboplatin followed by ipilimumab+paclitaxel/carboplatin ) . Treatment was administered every 3 weeks for a maximum of 18 weeks ( induction ) , followed by maintenance ipilimumab or placebo every 12 weeks . End points included progression-free survival ( PFS ) , irPFS , best overall response rate ( BORR ) ; irBORR , overall survival ( OS ) , and safety . RESULTS Phased ipilimumab , but not concurrent ipilimumab , improved irPFS versus control [ HR ( hazard ratio)=0.64 ; P=0.03 ] . No improvement in PFS ( HR=0.93 ; P=0.37 ) or OS ( HR=0.75 ; P=0.13 ) occurred . Phased ipilimumab , concurrent ipilimumab and control , respectively , were associated with median irPFS of 6.4 , 5.7 and 5.3 months ; median PFS of 5.2 , 3.9 and 5.2 months ; median OS of 12.9 , 9.1 and 9.9 months . Overall rates of grade 3/4 irAEs were 17 , 21 and 9 % for phased ipilimumab , concurrent ipilimumab and control , respectively . CONCLUSION These results suggest further investigation of ipilimumab in ED-SCLC PURPOSE Programmed cell death 1 ( PD-1 ) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory . PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma , but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued . PATIENTS AND METHODS Patients with advanced melanoma ( N = 107 ) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival , long-term safety , and response duration after treatment discontinuation . RESULTS Median overall survival in nivolumab-treated patients ( 62 % with two to five prior systemic therapies ) was 16.8 months , and 1- and 2-year survival rates were 62 % and 43 % , respectively . Among 33 patients with objective tumor regressions ( 31 % ) , the Kaplan-Meier estimated median response duration was 2 years . Seventeen patients discontinued therapy for reasons other than disease progression , and 12 ( 71 % ) of 17 maintained responses off-therapy for at least 16 weeks ( range , 16 to 56 + weeks ) . Objective response and toxicity rates were similar to those reported previously ; in an extended analysis of all 306 patients treated on this trial ( including those with other cancer types ) , exposure-adjusted toxicity rates were not cumulative . CONCLUSION Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient population s. Responses were durable and persisted after drug discontinuation . Long-term safety was acceptable . Ongoing r and omized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma BACKGROUND Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma . We aim ed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma . METHODS We undertook a r and omised , double-blind , phase 2 trial in 66 centres from 12 countries . 217 patients with previously treated stage III ( unresectable ) or stage IV melanoma were r and omly assigned a fixed dose of ipilimumab of either 10 mg/kg ( n=73 ) , 3 mg/kg ( n=72 ) , or 0.3 mg/kg ( n=72 ) every 3 weeks for four cycles ( induction ) followed by maintenance therapy every 3 months . R and omisation was done with a permuted block procedure , stratified on the basis of type of previous treatment . The primary endpoint was best overall response rate ( the proportion of patients with a complete or partial response , according to modified WHO criteria ) . Efficacy analyses were done by intention to treat , whereas safety analyses included patients who received at least one dose of ipilimumab . This study is registered with Clinical Trials.gov , number NCT00289640 . FINDINGS The best overall response rate was 11.1 % ( 95 % CI 4.9 - 20.7 ) for 10 mg/kg , 4.2 % ( 0.9 - 11.7 ) for 3 mg/kg , and 0 % ( 0.0 - 4.9 ) for 0.3 mg/kg ( p=0.0015 ; trend test ) . Immune-related adverse events of any grade arose in 50 of 71 , 46 of 71 , and 19 of 72 patients at doses of 10 mg/kg , 3 mg/kg , and 0.3 mg/kg , respectively ; the most common grade 3 - 4 adverse events were gastrointestinal immune-related events ( 11 in the 10 mg/kg group , two in the 3 mg/kg group , none in the 0.3 mg/kg group ) and diarrhoea ( ten in the 10 mg/kg group , one in the 3 mg/kg group , none in the 0.3 mg/kg group ) . INTERPRETATION Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma , lending support to further studies at a dose of 10 mg/kg . FUNDING Bristol-Myers Squibb BACKGROUND Patients with advanced gastric or gastro-oesophageal junction cancer refractory to , or intolerant of , two or more previous regimens of chemotherapy have a poor prognosis , and current guidelines do not recommend any specific treatments for these patients . We assessed the efficacy and safety of nivolumab , a fully human IgG4 monoclonal antibody inhibitor of programmed death-1 ( PD-1 ) , in patients with advanced gastric or gastro-oesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens . METHODS In this r and omised , double-blind , placebo-controlled , phase 3 trial done at 49 clinical sites in Japan , South Korea , and Taiwan , eligible patients ( aged ≥20 years with unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer refractory to , or intolerant of , st and ard therapy [ including two or more previous chemotherapy regimens ] , with an Eastern Cooperative Oncology Group [ ECOG ] performance status of 0 - 1 , and naive to anti-PD-1 therapy or other therapeutic antibodies and pharmacotherapies for the regulation of T cells ) were recruited . Patients were r and omly assigned ( 2:1 ) using an interactive web response system to receive 3 mg/kg nivolumab or placebo intravenously every 2 weeks , stratified by country , ECOG performance status , and number of organs with metastases . Study treatment was continued until progressive disease per investigator assessment or onset of toxicities requiring permanent discontinuation . Patients and investigators were masked to group assignment . The primary endpoint was overall survival in the intention-to-treat population . Safety was analysed in all patients who received at least one dose of study treatment . This study is ongoing but not recruiting new patients , and is registered with Clinical Trials.gov , number NCT02267343 . FINDINGS Between Nov 4 , 2014 , and Feb 26 , 2016 , we r and omly assigned 493 patients to receive nivolumab ( n=330 ) or placebo ( n=163 ) . At the data cutoff ( Aug 13 , 2016 ) , median follow-up in surviving patients was 8·87 months ( IQR 6·57 - 12·37 ) in the nivolumab group and 8·59 months ( 5·65 - 11·37 ) in the placebo group . Median overall survival was 5·26 months ( 95 % CI 4·60 - 6·37 ) in the nivolumab group and 4·14 months ( 3·42 - 4·86 ) in the placebo group ( hazard ratio 0·63 , 95 % CI 0·51 - 0·78 ; p<0·0001 ) . 12-month overall survival rates were 26·2 % ( 95 % CI 20·7 - 32·0 ) with nivolumab and 10·9 % ( 6·2 - 17·0 ) with placebo . Grade 3 or 4 treatment-related adverse events occurred in 34 ( 10 % ) of 330 patients who received nivolumab and seven ( 4 % ) of 161 patients who received placebo ; treatment-related adverse events led to death in five ( 2 % ) of 330 patients in the nivolumab group and two ( 1 % ) of 161 patients in the placebo group . No new safety signals were observed . INTERPRETATION In this phase 3 study , the survival benefits indicate that nivolumab might be a new treatment option for heavily pretreated patients with advanced gastric or gastro-oesophageal junction cancer . Ongoing trials that include non-Asian patients are investigating nivolumab for advanced gastric or gastro-oesophageal junction cancer in various setting s and earlier treatment lines . FUNDING Ono Pharmaceutical and Bristol-Myers Squibb BACKGROUND In a phase 1 dose-escalation study , combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response , including complete responses , among patients with advanced melanoma . METHODS In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment , we r and omly assigned patients in a 2:1 ratio to receive ipilimumab ( 3 mg per kilogram of body weight ) combined with either nivolumab ( 1 mg per kilogram ) or placebo once every 3 weeks for four doses , followed by nivolumab ( 3 mg per kilogram ) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects . The primary end point was the rate of investigator-assessed , confirmed objective response among patients with BRAF V600 wild-type tumors . RESULTS Among patients with BRAF wild-type tumors , the rate of confirmed objective response was 61 % ( 44 of 72 patients ) in the group that received both ipilimumab and nivolumab ( combination group ) versus 11 % ( 4 of 37 patients ) in the group that received ipilimumab and placebo ( ipilimumab-monotherapy group ) ( P<0.001 ) , with complete responses reported in 16 patients ( 22 % ) in the combination group and no patients in the ipilimumab-monotherapy group . The median duration of response was not reached in either group . The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy ( hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death , 0.40 ; 95 % confidence interval , 0.23 to 0.68 ; P<0.001 ) . Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors . Drug-related adverse events of grade 3 or 4 were reported in 54 % of the patients who received the combination therapy as compared with 24 % of the patients who received ipilimumab monotherapy . Select adverse events with potential immunologic causes were consistent with those in a phase 1 study , and most of these events resolved with immune-modulating medication . CONCLUSIONS The objective -response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy . Combination therapy had an acceptable safety profile . ( Funded by Bristol-Myers Squibb ; Clinical Trials.gov number , NCT01927419 . ) PURPOSE Nivolumab , a human immunoglobulin G4-blocking antibody against the T-cell programmed death-1 checkpoint protein , has activity against metastatic melanoma . Its safety , clinical efficacy , and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma . PATIENTS AND METHODS In this phase I study , 90 patients with unresectable stage III or IV melanoma who were ipilimumab naive and had experienced progression after at least one prior therapy ( cohorts 1 to 3 , 34 patients ) or experienced progression after prior ipilimumab ( cohorts 4 to 6 , 56 patients ) received nivolumab at 1 , 3 , or 10 mg/kg every 2 weeks for 24 weeks , then every 12 weeks for up to 2 years , with or without a multipeptide vaccine . RESULTS Nivolumab with vaccine was well tolerated and safe at all doses . The RECIST 1.1 response rate for both ipilimumab-refractory and -naive patients was 25 % . Median duration of response was not reached at a median of 8.1 months of follow-up . High pretreatment NY-ESO-1 and MART-1-specific CD8(+ ) T cells were associated with progression of disease . At week 12 , increased peripheral-blood T regulatory cells and decreased antigen-specific T cells were associated with progression . PD-L1 tumor staining was associated with responses to nivolumab , but negative staining did not rule out a response . Patients who experienced progression after nivolumab could respond to ipilimumab . CONCLUSION In patients with ipilimumab-refractory or -naive melanoma , nivolumab at 3 mg/kg with or without peptide vaccine was well tolerated and induced responses lasting up to 140 weeks . Responses to nivolumab in ipilimumab-refractory patients or to ipilimumab in nivolumab-refractory patients support combination or sequencing of nivolumab and ipilimumab

Rates of change were negative across age , sex and day type categories , but varied according to region , with Europe , the USA , Canada and Asia showing decreases and Australia , the UK and Sc and inavia showing increases . Over the last 103 years , there have been consistent rapid declines in the sleep duration of children and adolescents

BACKGROUND Sleep deficits are associated with a wide range of detrimental physical and mental health outcomes . There is concern that children are not getting enough sleep , and that sleep duration has been declining . However , evidence is sparse .

Learning of a procedural motor-skill task is known to progress through a series of unique memory stages . Performance initially improves during training , and continues to improve , without further rehearsal , across subsequent periods of sleep . Here , we investigate how this delayed sleep-dependent learning is affected when the task characteristics are varied across several degrees of difficulty , and whether this improvement differentially enhances individual transitions of the motor-sequence pattern being learned . We report that subjects show similar overnight improvements in speed whether learning a five-element unimanual sequence ( 17.7 % improvement ) , a nine-element unimanual sequence ( 20.2 % ) , or a five-element bimanual sequence ( 17.5 % ) , but show markedly increased overnight improvement ( 28.9 % ) with a nine-element bimanual sequence . In addition , individual transitions within the motor-sequence pattern that appeared most difficult at the end of training showed a significant 17.8 % increase in speed overnight , whereas those transitions that were performed most rapidly at the end of training showed only a non-significant 1.4 % improvement . Together , these findings suggest that the sleep-dependent learning process selectively provides maximum benefit to motor-skill procedures that proved to be most difficult prior to sleep OBJECTIVE To study the associations between sleep quality /quantity and performance in auditory/visual working memory tasks of different load levels . METHOD Sixty schoolchildren aged 6 to 13 years from normal school classes voluntarily participated . Actigraphy measurement was done during a typical school week for 72 consecutive hours . It was timed together with the working memory experiments to obtain information on children 's sleep during that period . The n-back task paradigm was used to examine auditory and visual working memory functions . RESULTS Lower sleep efficiency and longer sleep latency were associated with a higher percentage of incorrect responses in working memory tasks at all memory load levels ( partial correlations , controlling for age , all p values < .05 , except in visual 0-back and auditive 2-back tasks ) ; shorter sleep duration was associated with performing tasks at the highest load level only ( partial correlations , controlling for age , p < .05 ) . Also in general linear models ( controlling for age , gender , and socioeconomic status ) , sleep efficiency ( F = 11.706 , p = .050 ) and latency ( F = 3.588 , p = .034 ) were significantly associated with the mean incorrect response rate in auditory working memory tasks . CONCLUSIONS Sleep quality and quantity affect performance of working memory tasks in school-age children . In children with learning difficulties the possibility of underlying sleep problems should be excluded The endogenous circadian oscillator in mammals , situated in the suprachiasmatic nuclei , receives environmental photic input from specialized subsets of photoreceptive retinal ganglion cells . The human circadian pacemaker is exquisitely sensitive to ocular light exposure , even in some people who are otherwise totally blind . The magnitude of the re setting response to white light depends on the timing , intensity , duration , number and pattern of exposures . We report here that the circadian re setting response in humans , as measured by the pineal melatonin rhythm , is also wavelength dependent . Exposure to 6.5 h of monochromatic light at 460 nm induces a two-fold greater circadian phase delay than 6.5 h of 555 nm monochromatic light of equal photon density . Similarly , 460 nm monochromatic light causes twice the amount of melatonin suppression compared to 555 nm monochromatic light , and is dependent on the duration of exposure in addition to wavelength . These studies demonstrate that the peak of sensitivity of the human circadian pacemaker to light is blue-shifted relative to the three-cone visual photopic system , the sensitivity of which peaks at approximately 555 nm . Thus photopic lux , the st and ard unit of illuminance , is inappropriate when quantifying the photic drive required to reset the human circadian pacemaker BACKGROUND No prospect i ve studies exist on the relationship between sleep problems early in life and subsequent alcohol use . Stimulated by the adult literature linking sleep problems to the subsequent onset of alcohol use disorders in some adults , we examined whether sleep problems in early childhood predicted the onset of alcohol and other drug use in adolescence and whether such a relationship was mediated by other known predictors of this relationship , namely , attention problems , anxiety/depression , and aggression in late childhood . METHODS This study is part of an ongoing longitudinal study of the development of risk for alcohol and other substance use disorders . Study participants were 257 boys from a community-recruited sample of high-risk families . RESULTS Mothers ' ratings of their children 's sleep problems at ages 3 to 5 years significantly predicted an early onset of any use of alcohol , marijuana , and illicit drugs , as well as an early onset of occasional or regular use of cigarettes by age 12 to 14 . Additionally , although sleep problems in early childhood also predicted attention problems and anxiety/depression in later childhood , these problems did not mediate the relationship between sleep problems and onset of alcohol and other drug use . CONCLUSIONS This is , to our knowledge , the first study that prospect ively examines the relationship between sleep problems and early onset of alcohol use , a marker of increased risk for later alcohol problems and alcohol use disorders . Moreover , early childhood sleep problems seem to be a robust marker for use of drugs other than alcohol . Implication s for the prevention of early alcohol and other drug use are discussed OBJECTIVE To investigate the relationship between the presence of a television set , a gaming computer , and /or an Internet connection in the room of adolescents and television viewing , computer game playing , and Internet use on the one h and , and time to bed , time up , time spent in bed , and overall tiredness in first- and fourth-year secondary -school children on the other h and . METHODS A r and om sample of students from 15 schools in Fl and ers , Belgium , yielded 2546 children who completed a question naire with questions about media presence in bedrooms ; volume of television viewing , computer game playing , and Internet use ; time to bed and time up on average weekdays and average weekend days ; and questions regarding the level of tiredness in the morning , at school , after a day at school , and after the weekend . RESULTS Children with a television set in their rooms went to bed significantly later on weekdays and weekend days and got up significantly later on weekend days . Overall , they spent less time in bed on weekdays . Children with a gaming computer in their rooms went to bed significantly later on weekdays . On weekdays , they spent significantly less time in bed . Children who watched more television went to bed later on weekdays and weekend days and got up later on weekend days . They spent less time in bed on weekdays . They reported higher overall levels of being tired . Children who spent more time playing computer games went to bed later on weekdays and weekend days and got up later on weekend days . On weekdays , they actually got up significantly earlier . They spent less time in bed on weekdays and reported higher levels of tiredness . Children who spent more time using the Internet went to bed significantly later during the week and during the weekend . They got up later on weekend days . They spent less time in bed during the week and reported higher levels of tiredness . Going out was also significantly related to sleeping later and less . CONCLUSION Concerns about media use should not be limited to television . Computer game playing and Internet use are related to sleep behavior as well . Leisure activities that are unstructured seem to be negatively related to good sleep patterns . Imposing more structure ( eg , end times ) might reduce impact

Patients who received PEG were significantly less likely to require additional laxative therapies . Common adverse events in these studies included diarrhoea , abdominal pain , nausea , vomiting and pruritis ani . The pooled analyses suggest that PEG preparations may be superior to placebo , lactulose and milk of magnesia for childhood constipation . There is also evidence suggesting the efficacy of liquid paraffin ( mineral oil ) . There is no evidence to demonstrate the superiority of lactulose when compared to the other agents studied , although there is a lack of placebo controlled studies .

BACKGROUND Constipation within childhood is an extremely common problem . Despite the widespread use of osmotic and stimulant laxatives by health professionals to manage constipation in children , there has been a long st and ing paucity of high quality evidence to support this practice . OBJECTIVES We set out to evaluate the efficacy and safety of osmotic and stimulant laxatives used to treat functional childhood constipation .

CONTEXT The section of a research article most likely to be read is the abstract , and therefore it is particularly important that the abstract reflect the article faithfully . OBJECTIVE To assess abstract s accompanying research articles published in 6 medical journals with respect to whether data in the abstract could be verified in the article itself . DESIGN Analysis of simple r and om sample s of 44 articles and their accompanying abstract s published during 1 year(July 1 , 1996-June 30 , 1997 ) in each of 5 major general medical journals ( Annals of Internal Medicine , BMJ , JAMA , Lancet , and New Engl and Journal of Medicine ) and a consecutive sample of 44 articles published during 15 months ( July 1 , 1996-August 15 , 1997 ) in the CMAJ . MAIN OUTCOME MEASURE Abstract s were considered deficient if they contained data that were either inconsistent with corresponding data in the article 's body ( including tables and figures ) or not found in the body at all . RESULTS The proportion of deficient abstract s varied widely ( 18%-68 % ) and to a statistically significant degree ( P<.001 ) among the 6 journals studied . CONCLUSIONS Data in the abstract that are inconsistent with or absent from the article 's body are common , even in large-circulation general medical journals OBJECTIVE . Our aim was to compare 2 laxatives , namely , polyethylene glycol 3350 without electrolytes and milk of magnesia , evaluating the efficacy , safety , acceptance , and 1-year outcomes . METHODS . Seventy-nine children with chronic constipation and fecal incontinence were assigned r and omly to receive polyethylene glycol or milk of magnesia and were treated for 12 months in tertiary care pediatric clinics . Children were counted as improved or recovered depending on resolution of constipation , fecal incontinence , and abdominal pain after 1 , 3 , 6 , and 12 months . An intent-to-treat analysis was used . Safety was assessed with evaluation of clinical adverse effects and blood tests . RESULTS . Thirty-nine children were assigned r and omly to receive polyethylene glycol and 40 to receive milk of magnesia . At each follow-up visit , significant improvement was seen in both groups , with significant increases in the frequency of bowel movements , decreases in the frequency of incontinence episodes , and resolution of abdominal pain . Compliance rates were 95 % for polyethylene glycol and 65 % for milk of magnesia . After 12 months , 62 % of polyethylene glycol-treated children and 43 % of milk of magnesia-treated children exhibited improvement , and 33 % of polyethylene glycol-treated children and 23 % of milk of magnesia-treated children had recovered . Polyethylene glycol and milk of magnesia did not cause clinical ly significant side effects or blood abnormalities , except that 1 child was allergic to polyethylene glycol . CONCLUSIONS . In this r and omized study , polyethylene glycol and milk of magnesia were equally effective in the long-term treatment of children with constipation and fecal incontinence . Polyethylene glycol was safe for the long-term treatment of these children and was better accepted by the children than milk of magnesia Background Chronic constipation represents a common problem in children . The treatment of functional constipation is challenging . Some studies have investigated the effect of prokinetic agents as potential therapies for motility disorders of the lower gastrointestinal tract with paradoxical results . The present study aim ed to investigate the effect of oral domperidone in the treatment of chronic functional constipation in children . Method A total of 105 children with chronic functional constipation ( according to Rome III criteria ) who were referred to the Pediatric Gastroenterology Clinic were recruited in this double-blind r and omized clinical trial . The study subjects were r and omly divided into two groups , the first of which received polyethylene glycol ( PEG ) solution 0.6 g/kg/day two times a day for 6 months and domperidone syrup 0.15 mL/kg three times a day for 3 months ( case group ) while the second one received PEG with the same dose for 6 months and placebo for 3 months with the same dose ( control group ) . The two groups were compared regarding their symptoms and Rome III criteria through 1 , 3 , and 6 months following therapy . Primary outcome was response to treatment , and a response was defined as decrease in signs and symptoms that did not fulfill Rome III criteria . Secondary outcome measures were side effects during the course of treatment . Results A significant difference was observed both before and after PEG and domperidone treatment and before and after PEG and placebo treatment regarding Rome III criteria . There was no significant difference in response to treatment between the two study groups during 1 ( p = 1 ) , 3 ( p = 0.799 ) , and 6 ( p = 0.403 ) month follow up periods . Also , the two groups were not significantly different regarding the Rome III criteria during the mentioned follow up periods . There were no side effects during the course of treatment . Conclusion There was no additional effect of domperidone as adjunct to PEG in the treatment of children with constipation Background : Recently , polyethylene glycol ( PEG 3350 ) has been suggested as a good alternative laxative to lactulose as a treatment option in paediatric constipation . However , no large r and omised controlled trials exist evaluating the efficacy of either laxative . Aims : To compare PEG 3350 ( Transipeg : polyethylene glycol with electrolytes ) with lactulose in paediatric constipation and evaluate clinical efficacy/side effects . Patients : One hundred patients ( aged 6 months–15 years ) with paediatric constipation were included in an eight week double blinded , r and omised , controlled trial . Methods : After faecal disimpaction , patients < 6 years of age received PEG 3350 ( 2.95 g/sachet ) or lactulose ( 6 g/sachet ) while children ⩾6 years started with 2 sachets/day . Primary outcome measures were : defecation and encopresis frequency/week and successful treatment after eight weeks . Success was defined as a defecation frequency ⩾3/week and encopresis ⩽1 every two weeks . Secondary outcome measures were side effects after eight weeks of treatment . Results : A total of 91 patients ( 49 male ) completed the study . A significant increase in defecation frequency ( PEG 3350 : 3 pre v 7 post treatment/week ; lactulose : 3 pre v 6 post/week ) and a significant decrease in encopresis frequency ( PEG 3350 : 10 pre v 3 post/week ; lactulose : 8 pre v 3 post/week ) was found in both groups ( NS ) . However , success was significantly higher in the PEG group ( 56 % ) compared with the lactulose group ( 29 % ) . PEG 3350 patients reported less abdominal pain , straining , and pain at defecation than children using lactulose . However , bad taste was reported significantly more often in the PEG group . Conclusions : PEG 3350 ( 0.26 ( 0.11 ) g/kg ) , compared with lactulose ( 0.66 ( 0.32 ) g/kg ) , provided a higher success rate with fewer side effects . PEG 3350 should be the laxative of first choice in childhood constipation OBJECTIVE To investigate the efficacy and safety of polyethylene glycol ( PEG ) 3350 in the treatment of childhood fecal impaction . METHODS This was a prospect i ve , double-blind , parallel , r and omized study of 4 doses of PEG 3350 ; 0.25 g/kg per day , 0.5 g/kg per day , 1 g/kg per day , 1.5 g/kg per day , given for 3 days in children with constipation for > 3 months and evidence of fecal impaction . RESULTS Forty patients completed the study ( 27 boys , median age 7.5 , range 3.3 - 13.1 years ) . Disimpaction occurred in 75 % of children , with a significant difference between the two higher doses and the lower doses ( 95 % vs 55 % , P < .005 ) . All groups had an increased number of bowel movements during the 5-day study versus baseline , respectively : 6.5 versus 1.1 ( P < .005 ) , 8.0 versus 1.3 ( P < .005 ) , 10.9 versus 1.7 ( P < .005 ) , and 12.3 versus 1.4 ( P < .005 ) . Adverse effects included nausea ( 5 % ) , vomiting ( 5 % ) , bloating ( 18 % ) , cramping ( 5 % ) , and diarrhea ( 13 % ) . Diarrhea and bloating were more prevalent ( P < .02 ) in the higher-dose than in the lower-dose group . No clinical ly significant changes in electrolytes were noted . CONCLUSIONS The 3-day administration of PEG 3350 is safe and effective in the treatment of childhood fecal impaction at doses of 1 and 1.5 g/kg per day Background : Polyethylene glycol ( PEG ) is often considered as the first-line treatment for functional constipation in children . Descurainia sophia ( L. ) Webb et Berth ( D. sophia ) is a safe recommended medicine in Iranian folk and Traditional Persian Medicine for the treatment of constipation . Objectives : To clinical ly compare D. sophia with PEG 4000 ( without electrolyte ) in pediatric constipation and to assess its efficacy and side effects . Patients and Methods : 120 patients aged 2 - 12 years with constipation for at least 3 months were included in an 8 weeks lasting r and omized controlled trial within two parallel-groups . Children received either PEG , 0.4 g/kg/day , or D. sophia seeds , 2 grams ( for children aged 2 - 4 years ) and 3 grams ( for those aged > 4 years ) per day . Results : A total of 109 patients completed the study ( 56 in D. sophia and 53 in PEG group ) . At the end of the study , 36 ( 64.3 % ) patients in D. sophia group and 29 ( 54.7 % ) in PEG group were out of Rome III criteria ( P = 0.205 ) . Median weekly stool frequency in 0 , 1 , 2 , 3 weeks of the treatment was found to be 2 , 5 , 5 , 5 in D. sophia and 3 , 4 , 4 , 5 in PEG group ( P = 0.139 , 0.076 , 0.844 , 0.294 ) , respectively . The number of patients who suffered flatulence was less ( 5 , 8.9 % ) in D. sophia group as compared to PEG group ( 6 , 11.3 % ) at the end of the trial ( P = 0.461 ) . D. sophia taste was less tolerated . Conclusions : D. sophia is introduced as a cheap and available medication which can be applied as a safe alternative to conventional PEG in the management of pediatric chronic functional constipation Objectives : The aim of the study was to evaluate the effectiveness and safety of 2 different polyethylene glycol ( PEG ) doses for the maintenance treatment of functional constipation in children . Methods : Children with functional constipation according to the Rome III criteria were r and omly assigned to receive PEG 4000 at a dose of either 0.7 g/kg ( high-dose group ; n = 45 ) or 0.3 g/kg ( low-dose group ; n = 47 ) for 6 weeks . Adjustment of the therapy was recommended in the event of <3 bowel movements ( BM ) per week or ≥3 BM per day . The primary outcome measure was treatment success , defined as ≥3 BM per week with no fecal soiling during the last week of the intervention . Results : A total of 90 of 92 r and omized children , with a mean age of 3.7 ± 2.1 years , completed the study . In the analysis based on allocated treatment , treatment success was similar in both groups ( relative risk 0.9 , 95 % confidence interval 0.78–1.03 ) . Compared with the high-dose PEG group , the low-dose PEG group had an increased need for therapy adjustment of borderline significance ( relative risk 2.0 , 95 % confidence interval 1.0–4.2 ) , an increased risk of painful defecation , a lower number of stools per week , and lower parental satisfaction . Adverse events were similar in both groups . Conclusions : To achieve treatment success , both tested doses of PEG were equally safe and effective in the treatment of children with functional constipation Background Chronic constipation is frequent in children . The objective of this study is to compare the efficacy and safety of PEG 4000 and lactulose for the treatment of chronic constipation in young children . Methods This r and omised , double-blind study enrolled 88 young children aged 12 to 36 months , who were r and omly assigned to receive lactulose ( 3.3 g per day ) or PEG 4000 ( 8 g per day ) for four weeks . The primary efficacy variable was stool frequency during the fourth week of treatment . Secondary outcomes were the number and frequency of subjective symptoms associated with defecation at each visit . Results Stool frequency was comparable in the two groups at baseline ( lactulose : 0.7 ± 0.5 ; PEG 4000 : 0.5 ± 0.55 ) . Mean stool frequency increased from 0.70 ± 0.50 stools/day at baseline to 0.80 ± 0.41 at Week 4 in the lactulose group and from 0.50 ± 0.55 to 1.10 ± 0.55 stools/day in the PEG 4000 group . A significant difference was observed in the adjusted mean change from baseline , which was 0.15 stools/day in the lactulose group and 0.51 stools/day in the PEG 4000 group , with a least-squares mean difference of 0.36 stools/day [ 95 % CI : 0.16 to 0.56 ] . With respect to secondary outcome variables , stool consistency and ease of stool passage improved more in the PEG 4000 group ( p = 0.001 ) . The incidence of adverse events was similar in both groups , the majority of which were mild . Conclusions PEG 4000 has superior efficacy to lactulose for the treatment of chronic constipation in young children and is well tolerated . Trial registration US National Institute of Health Clinical Trials data base ; study NCT00255372 first registered 17th November 2005 OBJECTIVES To determine and compare efficacy , safety and optimal dose of two laxatives , liquid paraffin and lactulose , in 40 children with chronic functional constipation . METHODS A total of 20 children were treated with liquid paraffin and 20 with lactulose for 8 weeks and at an initial dose of 1 mL/kg per day for both drugs . The dose was adjusted every 3 days as required and a diary was kept to monitor dose , side-effects , stool frequency and consistency , and other symptoms . RESULTS During first 4 weeks , improvement in stool consistency and frequency was significantly higher in liquid the paraffin group ( P < 0.01 and P < 0.05 , respectively ) . Improvement in the number of stools per week was also significantly higher in the liquid paraffin group during the last 4 weeks of therapy ( P < 0.05 ) . Compliance rates averaged 95 % in the liquid paraffin group and 90 % in the lactulose group during the first 4 weeks of therapy and 90 % in the liquid paraffin group and 60 % in the lactulose group during the last 4 weeks of therapy ( chi(2 ) = 4.8 , SD = 1 , P = 0.02 ) . During the first 4 weeks of therapy and during the last 4 weeks of therapy , mostly side-effects and poor symptom control , respectively , influenced the compliance in the liquid paraffin group . CONCLUSIONS Liquid paraffin is more effective in the treatment of children with constipation . Patients treated with liquid paraffin responded more rapidly than patients responding to lactulose and showed fewer side-effect . It is considered that late response and side-effects in conjunction with poor symptom control influence the patient compliance and the successful treatment of childhood constipation OBJECTIVE : We hypothesized that enemas and polyethylene glycol ( PEG ) would be equally effective in treating rectal fecal impaction ( RFI ) but enemas would be less well tolerated and colonic transit time ( CTT ) would improve during disimpaction . METHODS : Children ( 4–16 years ) with functional constipation and RFI participated . One week before disimpaction , a rectal examination was performed , symptoms of constipation were recorded , and the first CTT measurement was started . If RFI was determined , then patients were assigned r and omly to receive enemas once daily or PEG ( 1.5 g/kg per day ) for 6 consecutive days . During this period , the second CTT measurement was started and a child 's behavior question naire was administered . Successful rectal disimpaction , defecation and fecal incontinence frequencies , occurrence of abdominal pain and watery stools , CTTs ( before and after disimpaction ) , and behavior scores were assessed . RESULTS : Ninety-five patients were eligible , of whom 90 participated ( male , n = 60 ; mean age : 7.5 ± 2.8 years ) . Forty-six patients received enemas and 44 PEG , with 5 dropouts in each group . Successful disimpaction was achieved with enemas ( 80 % ) and PEG ( 68 % ; P = .28 ) . Fecal incontinence and watery stools were reported more frequently with PEG ( P < .01 ) , but defecation frequency ( P = .64 ) , abdominal pain ( P = .33 ) , and behavior scores were comparable between groups . CTT normalized equally ( P = .85 ) in the 2 groups . CONCLUSION : Enemas and PEG were equally effective in treating RFI in children . Compared with enemas , PEG caused more fecal incontinence , with comparable behavior scores . The treatments should be considered equally as first-line therapy for RFI Background PEG-based laxatives are considered today the gold st and ard for the treatment of constipation in children . PEG formulations differ in terms of composition of inactive ingredients which may have an impact on acceptance , compliance and adherence to treatment . We therefore compared the efficacy , tolerability , acceptance and compliance of a new PEG-only formulation compared to a reference PEG-electrolyte ( PEG-EL ) formulation in resolving faecal impaction and in the treatment of chronic constipation . Methods Children aged 2–16 years with functional chronic constipation for at least 2 months were r and omized to receive PEG-only 0.7 g/kg/day in 2 divided doses or 6.9 g PEG-EL 1–4 sachets according to age for 4 weeks . Children with faecal impaction were r and omized to receive PEG-only 1.5/g/kg in 2 divided doses until resolution or for 6 days or PEG-EL with an initial dose of 4 sachets and increasing 2 sachets a day until resolution or for 7 days . Results Ninety-six children were r and omized into the study . Five patients withdrew consent before starting treatment . Three children discontinued treatment for refusal due to bad taste of the product ( 1 PEG-only , 2 PEG-EL ) ; 1 ( PEG-EL ) for an adverse effect ( abdominal pain ) . Intent-to-treat analysis was carried out in 49 children in the PEG-only group and 42 in the PEG-EL group . No significant differences were observed between the two treatment groups at baseline . Adequate relief of constipation in terms of normalized frequency and painless defecation of soft stools was achieved in all patients in both groups . The number of stools/week was 9.2 ± 3.2 ( mean ± SD ) in the PEG-only group and 7.8 ± 2.4 in the PEG-EL group ( p = 0.025 ) ; the number of days with stool was 22.4 ± 5.1 in the PEG-only group and 19.6 ± 7.2 in the PEG-EL group ( p = 0.034).In the PEG-only group faecaloma resolution was observed in 5 children on the second day and in 2 children on the third day , while in the PEG-EL group it was observed in 2 children on the second day , in 3 children on the third day and in 1 child on the fifth day . Only 2 patients reported mild treatment-related adverse events : 1 child in the PEG-only group had diarrhoea and vomiting and 1 child in the PEG-EL group had abdominal pain requiring treatment discontinuation . The PEG-only preparation was better tolerated as shown by the lower frequency of nausea than in the PEG-EL group . In the PEG-only group , 96 % of patients did not demonstrate any difficulties associated with treatment , as compared with 52 % of patients in the PEG-EL group ( p < 0.001 ) . Also , the PEG-only formulation taste was better than that of PEG-EL ( p < 0.001 ) . The difference between the percentage of subjects who took > 80 % of the prescribed dose was in favour of the PEG-only group ( 98 % vs. 88 % ) , though it did not reach a conventional statistical level ( p = 0.062 ) . Conclusion PEG-only was better tolerated and accepted than PEG-EL in children with chronic constipation . At the higher PEG doses recommended by the manufactures children in the PEG-only group had higher and more regular soft stool frequency than PEG-EL.Trial registration Clinical Trials.gov : Background and the purpose of the study Functional constipation is prevalent in children . Recently polyethylene glycol has been introduced as an effective and safe drug to treat chronic constipation . There are only a few clinical trials on comparison of PEG and liquid paraffin in childhood constipation . The purpose of this study was to evaluate clinical efficacy and safety of PEG 3350 solution and liquid paraffin in the treatment of children with functional constipation in Sari Toba clinic during the period of 2008–2009 . Methods Children with a history of functional constipation were subjects of this study . One hundred and sixty children of 2–12 years old with functional constipation were r and omized in two PEG and paraffin treatment groups . Patients received either 1.0–1.5 g/kg/day PEG 3350 or 1.0–1.5 ml/kg/day liquid paraffin for 4 months . Clinical efficacy was evaluated by stool and encopresis frequency/week and overall treatment success rate was compared in two groups . Results and major conclusion Compared with the baseline , defecation frequency/ week increased significantly and encopresis frequency meaningfully decreased in two groups during the period of the study . Patients using PEG 3350 had more success rate ( mean : 95.3%±3.7 ) compared with the patients in paraffin group ( mean : 87.2%±7.1 ) ( p=0.087 ) . Administration of PEG 3350 were associated with less adverse events than liquid paraffin . In conclusion in treatment of pediatric functional constipation , regarding clinical efficacy and safety , PEG 3350 were at least as effective as liquid paraffin and but less adverse drug events OBJECTIVE To determine the therapeutic effectiveness and safety of polyethylene glycol 4000 ( forlax ) in the treatment of constipation in children over 8 years old . METHODS This study was design ed as a r and omized , positive medicine ( lactulose ) controlled multicenter trial . A total of 216 children with constipation from 8 - 18 years old from 7 hospitals across China who were matched with a uniform entry criteria were enrolled in this study . The 216 patients were r and omized to receive either oral forlax ( 20 g/d , n=105 ) or lactulose ( 15 mL/d , n=111 ) for 2 weeks . The therapeutic effects , including bowel movement frequency , stool consistency , clinical complete remission rate of constipation and abdominal symptoms , and the safety of forlax and lactulose were evaluated at 1 and 2 weeks of treatment . RESULTS The median weekly frequency of bowel movement in the forlax group increased by 4 and 5 times respectively after 1 and 2 weeks of treatment , and increased by 3 and 4 times in the lactulose group ( P < 0.05 ) . The stool consistency of the two groups was both improved significantly after treatment . The Bristol score of stool consistency of the forlax and lactulose groups were 3.41+/-1.11 and 3.64+/-1.33 respectively ( P < 0.05 ) after 1 week of treatment , and were 4.26+/-0.89 and 3.63+/-1.33 respectively ( P < 0.05 ) after 2 weeks of treatment . The clinical complete remission rate of constipation in the forlax and lactulose groups was 70 % and 40 % respectively ( P < 0.05 ) by week 1 of treatment , and that was 72 % and 41 % respectively ( P < 0.05 ) by week 2 of treatment . Abdominal pain disappeared in 75 % of patients in the forlax group but in only 57 % in the lactulose group by week 2 of treatment ( P < 0.05 ) . No serious adverse events happened and no abnormalities were found in laboratory tests and physical examinations in the two groups after medication . CONCLUSIONS Forlax is safe and effective in the treatment of constipation in children over 8 years old OBJECTIVES To compare the effectiveness of a mixture of acacia fiber , psyllium fiber , and fructose ( AFPFF ) with polyethylene glycol 3350 combined with electrolytes ( PEG+E ) in the treatment of children with chronic functional constipation ( CFC ) ; and to evaluate the safety and effectiveness of AFPFF in the treatment of children with CFC . STUDY DESIGN This was a r and omized , open label , prospect i ve , controlled , parallel-group study involving 100 children ( M/F : 38/62 ; mean age ± SD : 6.5 ± 2.7 years ) who were diagnosed with CFC according to the Rome III Criteria . Children were r and omly divided into 2 groups : 50 children received AFPFF ( 16.8 g daily ) and 50 children received PEG+E ( 0.5 g/kg daily ) for 8 weeks . Primary outcome measures were frequency of bowel movements , stool consistency , fecal incontinence , and improvement of other associated gastrointestinal symptoms . Safety was assessed with evaluation of clinical adverse effects and growth measurements . RESULTS Compliance rates were 72 % for AFPFF and 96 % for PEG+E. A significant improvement of constipation was seen in both groups . After 8 weeks , 77.8 % of children treated with AFPFF and 83 % of children treated with PEG+E had improved ( P = .788 ) . Neither PEG+E nor AFPFF caused any clinical ly significant side effects during the entire course of the study period . CONCLUSIONS In this r and omized study , we did not find any significant difference between the efficacy of AFPFF and PEG+E in the treatment of children with CFC . Both medications were proved to be safe for CFC treatment , but PEG+E was better accepted by children Polyethylene glycol ( PEG ) 3350 and lactulose were compared in an unblinded , r and omized , crossover design for treatment of constipation in 37 children aged 2 to 16 years . Subjects received lactulose ( 1.3 g/kg/d divided twice daily up to 20 g ) or PEG 3350 ( 10 g/m2/day ) for 2 weeks . PEG 3350 significantly decreased the total colonic transit time compared to lactulose ( 47.6 + 2.7 vs 55.3 ±2.4 hours , mean ±SE , PEG 3350 vs lactulose , respectively , p = 0.038 ) . The stool frequency , form , and the ease of passage were similar for each laxative . Polyethylene glycol 3350 is an effective laxative for the treatment of chronic constipation in children OBJECTIVE To compare the effectiveness of two drugs , polyethylene glycol 4000 without electrolytes and magnesium hydroxide , in the treatment of chronic functional constipation in children . METHODS Thirty-eight children were r and omly assigned to either of two groups , polyethylene glycol 4000 without electrolytes or magnesium hydroxide . The children were followed through periodic appointments until they reached 6 months of treatment . In each medical appointment the following aspects were evaluated : stool consistency , frequency of bowel movements , fecal incontinence , abdominal pain , straining and acceptance of the drugs . RESULTS Seventeen children made use of polyethylene glycol and twenty-one received magnesium hydroxide . All variables analyzed improved for both groups , with no statistically significant differences . All children accepted polyethylene glycol , while 42.9 % refused magnesium hydroxide . CONCLUSION The two laxatives showed no difference in effectiveness for the treatment of constipation . However , due to its better acceptance , because it is odorless and tasteless , polyethylene glycol proved to be a better option for treating chronic functional constipation BACKGROUND / AIMS In the present study , we aim ed to investigate if partially hydrolyzed guar gum ( PHGG ) can be used safely as a fiber source for treatment of constipation in children and to compare its success with the most commonly used osmotic laxative , lactulose . METHODS A r and omized prospect i ve controlled study on 61 patients ( partially hydrolyzed guar gum group , n : 31 ; lactulose group , n : 30 ) was performed . Patients were given lactulose or partially hydrolyzed guar gum for four weeks . Using a st and ardized bowel diary , defecation frequency , stool consistency , and presence of flatulence and abdominal pain were recorded . Family question naires about the success , safety and side effect profile of both treatment arms were also obtained . RESULTS No significant differences were found in the baseline daily fiber ( fruits and vegetables ) intake between the two groups . Bowel movement frequency per week and stool consistency improved significantly in both treatment groups ( p<0.05 ) . The percent of children with abdominal pain and stool withholding also decreased eminently in both groups ( p<0.05 ) . Weekly defecation frequency increased from 4±0.7 to 6±1.06 and from 4±0.7 to 5±1.7 in the lactulose and partially hydrolyzed guar gum treated groups , respectively ( p<0.05 ) . According to the family question naire , the parents complained of bad taste , flatulence and necessity to ingest a high amount of drug in the lactulose treatment group . In the partially hydrolyzed guar gum treatment group , parents were satisfied with the defecation frequency of their children . CONCLUSIONS Treatment with partially hydrolyzed guar gum is as effective as lactulose treatment in relieving stool withholding and constipation-associated abdominal pain , and its use improves stool consistency . Lactulose seemed to have more side effects , including flatulence and sensation of bad taste The present multicenter double-blind placebo-controlled trial evaluates the therapeutic effectiveness of small-volume daily doses of an isosmotic polyethylene glycol ( PEG ) electrolyte solution in the treatment of chronic nonorganic constipation . After a complete diagnostic investigation , patients still constipated at the end of a four-week placebo-treatment run-in period were enrolled and r and omized to receive either placebo or PEG solution 250 ml twice a day for the following eight weeks . Patients were assessed at four and eight weeks of treatment , and they reported frequency and modality of evacuation , use of laxatives , and relevant symptoms daily on a diary card . Oroanal and segmental large-bowel transit times were assessed with radiopaque markers during the fourth week of the run-in period and the last week of the treatment period . During the study period , dietary fiber and liquids were st and ardized and laxatives were allowed only after five consecutive days without a bowel movement . Of the 55 patients enrolled , five dropped out , three because of adverse events and two for reasons unrelated to therapy ; another two were excluded from the efficacy analysis because of protocol violation . Of the remaining 48 patients ( 37 women , age 42±15 years , mean±sd ) , 23 were assigned to placebo and 25 to PEG treatment . In comparison to placebo , PEG solution induced a statistically significant increase in weekly bowel frequency at four weeks and at the end of the study ( PEG : 4.8±2.3 vs placebo : 2.8±1.6;P<0.002 ) and a significant decrease in straining at defecation ( P<0.01 ) , stool consistency ( P<0.02 ) , and use of laxatives ( P<0.03 ) . Oroanal , left colon , and rectal transit times were significantly shortened by PEG treatment . There was no difference between controls and PEG-treated patients as far as abdominal symptoms and side effects were concerned . In conclusion , PEG solution at 250 ml twice a day is effective in increasing bowel frequency , accelerating colorectal transit times , and improving difficult evacuation in patients with chronic nonorganic constipation and is devoid of significant side effects Objectives : To assess the efficacy and safety of polyethylene glycol 3350 plus electrolytes ( PEG+E ) for the treatment of chronic constipation in children . Design : R and omised , double blind , placebo controlled crossover trial , with two 2-week treatment periods separated by a 2-week placebo washout . Setting : Six UK paediatric departments . Participants : 51 children ( 29 girls , 22 boys ) aged 24 months to 11 years with chronic constipation ( lasting ⩾3 months ) , defined as ⩽2 complete bowel movements per week and one of the following : pain on defaecation on 25 % of days ; ⩾25 % of bowel movements with straining ; ⩾25 % of bowel movements with hard/lumpy stools . 47 children completed the double blind treatment . Main outcome measures : Number of complete defaecations per week ( primary efficacy variable ) , total number of complete and incomplete defaecations per week , pain on defaecation , straining on defaecation , faecal incontinence , stool consistency , global assessment of treatment , adverse events and physical examination . Results : The mean number of complete defaecations per week was significantly higher for children on PEG+E than on placebo ( 3.12 ( SD 2.05 ) v 1.45 ( SD 1.20 ) , respectively ; p<0.001 ) . Further significant differences in favour of PEG+E were observed for total number of defaecations per week ( p = 0.003 ) , pain on defaecation ( p = 0.041 ) , straining on defaecation ( p<0.001 ) , stool consistency ( p<0.001 ) and percentage of hard stools ( p = 0.001 ) . Treatment related adverse events ( all mild or moderate ) occurred in similar numbers of children on PEG+E ( 41 % ) and placebo during treatment ( 45 % ) . Conclusions : PEG+E is significantly more effective than placebo , and appears to be safe and well tolerated in the treatment of chronic constipation in children Objectives : To determine the doses of polyethylene glycol ( PEG ) 4000 without additional salts allowing normal bowel habits in childhood functional constipation . Methods : This multicenter noncomparative study allocated children to 4 groups : 6 - 12 months , 13 months-3 years , 4 - 7 years , and 8 - 15 years . Constipation was defined as < 1 stool/d for more than 1 month in children aged 6 - 12 months and <3 stools/w for more than 3 months in older children . Children r and omly received either a nominal or a double starting dose . Treatment scheduled for 3 months could be adapted . Data were collected daily by the parents and rated at each visit by the investigator . Results : In the 96 children included , the median ( interquartile ) effective daily doses were by groups ; 3.75 ( 2.50 - 5.00 ) g , 6.00 ( 4.00 - 7.43 ) g , 11.71 ( 7.00 - 16.00 ) g , and 16.00 ( 16.00 - 24.00 ) g , respectively , i.e. , around 0.50 g/day/kg with a potential increment of the maintenance dose with higher initial dosages . More children had a final dosage identical to the initial one when started on the nominal dose ( 73 % ) than with the double one ( 42 % , P < 0.003 ) . More than 90 % of children recovered normal bowel habits . Fecal soiling ceased in > 60 % of children with this symptom at enrolment . Fecal mass in the rectum and abdominal pain were markedly reduced and appetite improved . Conclusions : A daily dose of PEG 4000 around 0.50 g/day/kg in children aged 6 months to 15 years is effective in more than 90 % of constipated children and 60 % of those with fecal soiling Objectives : To assess the efficacy of polyethylene glycol 3350 plus electrolytes ( PEG + E ; Movicol ® ) as oral monotherapy in the treatment of faecal impaction in children , and to compare PEG + E with lactulose as maintenance therapy in a r and omised trial . Patients and Methods : An initial open-label study of PEG + E in the inpatient treatment of faecal impaction ( phase 1 ) , followed by a r and omised , double-blind comparison between PEG + E and lactulose for maintenance treatment of constipation over a 3-month period ( phase 2 ) in children aged 2 to 11 years with a clinical diagnosis of faecal impaction . Results : Disimpaction on PEG + E was achieved in 58 ( 92 % ) of 63 of children ( 89 % of 2 - 4 year olds and 94 % of 5 - 11 year olds ) without additional interventions . A maximum dose of 4 sachets ( for 2 - 4 year olds ) or 6 sachets ( for 5 - 11 year olds ) was required ; median time to disimpaction was 6 days ( range , 3 - 7 days ) . Seven children ( 23 % ) reimpacted whilst taking lactulose , whereas no children reimpacted while taking PEG + E ( P = 0.011 ) . The total incidence rate of adverse events seen was higher in the lactulose group ( 83 % ) than in the PEG + E group ( 64 % ) . Conclusions : PEG + E is safe and highly effective in the management of childhood constipation . It allows a single orally administered laxative to be used for disimpaction without recourse to invasive interventions . It is significantly more effective than lactulose as maintenance therapy , both in efficacy in treating constipation and efficacy in preventing the recurrence of faecal impaction Faecal impaction with or without encopresis is a very common problem . We performed a r and omized , open‐label , prospect i ve study to compare the efficacy and acceptability of the treatment of faecal impaction using either mineral oil or pineapple‐flavoured isotonic intestinal lavage solution containing polyethylene glycol‐3350 ( Colyte ) . Thirty‐six patients over 2 years of age were r and omized to receive either mineral oil or flavoured lavage solution . The dose of mineral oil was 2 to 8 tablespoons twice a day for two days ( 17 patients —Group I ) and of lavage solution was 20 ml/kg/h for 4 hours on two consecutive days ( 19 patients —Group II ) . The patients were assessed for the presence of abdominal faecal masses , presence and consistency of rectal mass , perineal soiling before and two days after either of the r and omly assigned treatment . The patients and parents were asked regarding the compliance with treatment , side‐effects , number of bowel movements after treatment and willingness to try similar treatment if faecal impaction recurred . Patients in the lavage group had more frequent bowel movements , and showed more effective clearance of abdominal and rectal lumps ( P < 0.01 ) at the time of repeat examination at two days . However , they had some vomiting and were less compliant ( P < 0.01 ) when compared to mineral oil patients . We conclude that balanced lavage solution effectively relieves faecal impaction , however , compliance with its use is poorer than that with mineral oil OBJECTIVE To establish the efficacy and best starting dose of polyethylene glycol (PEG)3350 in the short-term treatment of children with functional constipation . STUDY DESIGN Prospect i ve , r and omized , multicenter , double-blinded , placebo-controlled , dose-ranging study of PEG3350 in children with functional constipation . Patients were r and omly assigned to either placebo or 0.2 g/kg per day , 0.4 g/kg per day , or 0.8 g/kg per day of PEG3350 after a 1 week run-in period , followed by 2 weeks of treatment . All received behavior modification . The primary outcome was the proportion of patients with a successful treatment response : > or=3 bowel movements ( BM ) in the second week . RESULTS 103 children ( mean , 8.5 + /- 3.1 years ) were enrolled . 77 % , 74 % , and 73 % of the 0.2 , 0.4 , and 0.8 g/kg groups were successfully treated , as compared with 42 % receiving placebo ( P < .04 ) . There was a significant increase in BM ( P < .001 ) and straining improvement ( P < .05 ) with the different PEG3350 doses . Stool consistency improved significantly for doses 0.4 g/kg or higher ( P < .001 ) . There was more abdominal pain and fecal incontinence in patients receiving 0.8 g/kg . PEG3350 was well tolerated . CONCLUSIONS This placebo-controlled study confirms the efficacy and safety of PEG3350 for the short-term treatment of children with functional constipation . We recommend a starting dose of 0.4 g/kg per day The Authors investigated the effects of Allomin with admixture of 2 % and 4 % lactulose on constipation in infants aged 0 - 6 months reared on breast-milk substitutes . The investigation was r and omized and double-blind and was carried out during the period 1.4.1987 - 31.7.1988 on non-hospitalized infants in the counties of Funen and North Jutl and in cooperation with the health visitors in these regions . Constipation was defined as hard and difficult defaecation and the trial period lasted for 14 days . Parents of the infants who participated classified the infants ' motions according to consistence and degree of difficulty in defaecation on special forms . A total of 220 children participated and these received , after r and omizing , either Allomin-lactulose 2 % or 4 % as the only breast-milk substitute during the period of observation . The effect of treatment was defined as " no constipation " i.e. all motions during 24 hours described as easy and of normal or thin consistence . In addition , the effect was measured by the parents ' general impression of what the infant thrived best on . With both of the preparations , treatment was effective in over 90 % of the infants in both the groups without significant difference . The effect occurred gradually and , in some cases , up to 8 - 10 days after initiation of treatment without significant difference in the rate of effect between the groups . After the effect had commenced , significantly fewer thin motions occurred in the 2 % group than in the 4 % group . 92 % of the infants in the 2 % group and 91 % in the 4 % group wanted to continue the Allomin-lactulose preparation rather than the usual breast-milk substitute . A retrospective question naire to parents of 97 infants who had continued with Allomin-lactulose 2 % was answered by 84 . ( ABSTRACT TRUNCATED AT 250 WORDS A double-blind r and omly controlled trial of one particular laxative , Senokot , used in moderate dosage , was carried out on a group of 40 children with severe and persistent soiling and often with a history of faecal retention . Significant improvement occurred following three months of outpatient treatment using a behavioural approach and either Senokot , placebo or no medication . However , there was no evidence either during the trial or subsequently when Senokot was employed to supplement behavioural treatment in every child who continued with therapy that this laxative contributed in any way to relieving the problem in this group of cases Fifty-one children affected by chronic idiopathic constipation ( 23 males , 28 females ) , ranging in age from 8 months to 16 years were enrolled in the study ; 42 completed the trial . The patients were divided into two groups : Group A : 19 children treated with lactitol ( 250 - 400 mg/kg/day ) ; Group B:23 patients treated with lactulose ( 500 - 750 mg/kg/day ) . Parents filled a question naire concerning clinical response to therapy for a period of 30 days . In 17 Group A children and in 17 Group B children orocecal transit time using H2 Breath Test with lactulose was performed . A statistically significant increase of week stool frequency was found after treatment both with lactitol or lactulose ( p < 0.001 ) . Nevertheless Group B patients complained abdominal pain ( p < 0.005 ) and flatus ( p < 0.001 ) more frequently . Other adverse reactions , such as vomiting and meteorism , were more frequent in Group B patients ( n.s . ) . In addition patients treated with lactitol found that sugar as more palatable and had a better compliance to the therapy . Orocecal transit time did not show statistically significant differences after the therapy with both these sugars , indicating that the activity of lactulose and lactitol occurs in the colon and that small bowel functions are not affected by a previous therapy with these sugars . In conclusion , our study demonstrate that lactitol , because of the less number of side effects compared to lactulose , should be considered as an useful agent in the treatment of chronic idiopathic constipation in childhood 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 Twenty-one children under 15-years ' old with chronic constipation were treated in a crossover trial lasting 3 weeks . In the first week they received either lactulose or senna , in the next week no treatment , and in the third week the alternative treatment . Patient diaries were kept by parents on the number and character of stools passed , and of side-effects reported , during the 3 weeks . There was a significant difference , in favour of lactulose , in the number of days on which normal stools were passed during the treatment weeks . The number and frequency of the side-effects reported in the senna treatment week were very much higher ( p less than 0.001 ) than in the lactulose week . Lactulose is recommended as an effective and very well tolerated treatment for the constipated child Objectives : To assess the safety of a polyethylene glycol ( PEG ) 4000 laxative without additional salts in pediatric patients . Study Design : This was a 3-month multicenter , r and omized , double-blind , double-dummy , lactulose-controlled , parallel study enrolling 96 ambulatory constipated children aged 6 months to 3 years , treated daily with 4 - 8 g PEG or 3.33 g-6.66 g lactulose . Total protein , albumin , iron , electrolytes , and vitamins B9 ( folates ) , A and D ( 25OHD3 ) were measured in blood before and after treatment ( day 84 ) in a central laboratory . Results : The percentage of children with at least one value out of normal range at day 84 with respect to baseline status ( with or without at least one value out of normal range ) , i.e. the primary endpoint , was 87 % and 90 % in the PEG and lactulose groups , respectively , without any difference between groups . The whole blood parameters showed no qualitative or quantitative treatment-related changes . Vitamin A values were above normal range in 56 % and 41 % of children at baseline versus 33 % and 36 % at day 84 in the PEG and lactulose groups , respectively . Iron values were similarly under normal range in 47 % and 51 % at baseline versus 42 % and 51 % at day 84 . Clinical tolerance was similar for both treatments except for vomiting and flatulence , which were significantly higher with lactulose . Significantly higher improvements were evidence d with PEG regarding stool consistency , appetite , fecaloma and use of additional laxatives . Conclusion : This 3-month study in 96 constipated children aged 6 months to 3 years confirms the long-term tolerance of PEG 4000 in pediatrics and indicates a PEG efficacy similar to or greater than that of lactulose A multi-centre trial was carried out to compare the effectiveness in the treatment of chronic constipation of a lactulose preparation ( " Duphalac " ) and " irritant " laxatives containing senna , anthraquinone derivatives or bisacodyl . The results , in 164 patients , indicate that the lactulose prepartion was more effective than the " irritant " laxatives . By Day 7 , 58 % of the lactulose-treated group were passing a normal stool whereas only 42 % of the patients receiving an " irritant " laxative did so at the same stage in treatment . The lactulose preparation was shown to have a persistent CARRY-OVER " EFFECT , AND THIS EFFECT WAS SEEN IN SIGNIFICANTLY MORE PATIENTS RECEIVING " Duphalac " than in the " irritant " laxative group BACKGROUND & AIMS After 5 years of intensive oral laxative use , up to 30 % of constipated children still have an unsuccessful outcome . Children refractory to oral laxatives might benefit from regular rectal evacuation by enemas . This r and omized controlled trial compared the effects of additional treatment with rectal enemas ( intervention ) with conventional treatment alone ( oral laxatives , control ) in severely constipated children . METHODS In a tertiary hospital in the Netherl and s , 100 children , aged 8 - 18 years , with functional constipation for at least 2 years were r and omly assigned to intervention or control groups . The control group received education , behavioral strategies , and oral laxatives . The intervention group was also given 3 rectal enemas/week , reduced by 1 enema/week every 3 months . Outcome measures were defecation and fecal incontinence frequency and overall success at 12 , 26 , 39 , and 52 weeks . Overall success was defined as 3 or more defecations/week and less than 1 fecal incontinence episode/week , irrespective of laxative use . RESULTS Defecation frequency normalized in both groups but was significantly higher in the intervention group compared with controls at 26 and 52 weeks ( 5.6 vs 3.9/week , P = .02 , and 5.3 vs 3.9/week , P = .02 , respectively ) . There were no significant differences between groups in reduction of fecal incontinence episodes ( P = .49 ) and overall success rates ( P = .67 ) . After 1 year of treatment , the overall success rate was 47.1 % in the intervention group versus 36.1 % in the control group . CONCLUSIONS There is no additional effect of enemas compared with oral laxatives alone as maintenance therapy for severely constipated children Objective This study aim ed to compare efficacy of enema versus polyethylene glycol ( PEG ) 3350 for pediatric fecal impaction treatment . Methods We conducted a prospect i ve , r and omized comparison of treatments of fecal impaction in children in a pediatric emergency department ( ED ) . Treatment arms were a single milk and molasses enema in the ED or PEG 3350 for 3 days outpatient . Telephone follow-up was done on days 1 , 3 , and 5 . The primary outcome was main symptom improvement . Additional outcomes were stool frequency , consistency , and ease of stool passage . Treatment failures ( home enema , ED return , or hospital admission ) were tracked . Results Seventy-nine subjects participated ( 39 PEG ; 40 enema ) . At day 1 , PEG subjects were less likely to have improved main symptom ( odds ratio [ OR ] , 0.3 ; 95 % confidence interval [ CI ] , 0.1–0.8 ) but no difference in other outcomes . Half ( 54 % ) in enema arm were reported as upset by ED therapy , whereas no children in PEG arm were upset ( P < 0.05 ) . At day 3 , more patients in enema arm reported ideal stool consistency ( 74 % vs 38 % ; P < 0.05 ) . At day 5 , no difference between groups was noted . Most treatment failures were in PEG arm ( 83 % ; P = 0.08 ) . Conclusions This pilot study suggests that disimpaction by enema may be superior to PEG for immediate relief of symptoms . Larger trials are needed to assess any advantage AIM A Macrogol 3350-based , iso-osmotic laxative has become available for the treatment of chronic constipation in adults . This open-label , non-r and omised study aim ed to evaluate the safety and efficacy of this preparation in the treatment of chronic constipation in children . METHODS Seventy-eight children , aged 2 - 11 years , with chronic constipation for greater than 3 months were enrolled . All children received Macrogol 3350 plus electrolytes for 12 weeks . The primary efficacy variable was the number of spontaneous defaecations per week . Secondary efficacy variables were faecal form , abdominal pain , rectal bleeding , pain on defaecation , straining , soiling , amount of stool , stool withholding and assessment s of efficacy by the investigators and parents . Safety and compliance were also assessed . RESULTS The mean number of spontaneous defaecations per week increased from 1.4 + /- 0.55 ( SD ) at baseline to 6.8 + /- 3.45 after 14 days , and 7.1 + /- 3.45 at 12 weeks ( P < 0.001 ) . Similar improvements were found in the secondary efficacy variables . There was a significant reduction in reported abdominal pain from 53 ( 69 % ) children at baseline to 3 ( 4 % ) at the final visit ( P < 0.0001 ) . Similarly , 61 ( 79 % ) children had pain on defaecation at baseline , compared with 7 ( 9 % ) at the final visit ( P < 0.0001 ) . Treatment was well tolerated . Of 318 adverse events , 262 ( 82 % ) were considered mild , and 241 ( 76 % ) were deemed unrelated to treatment . Only 3 ( 4 % ) children were withdrawn because of poor compliance . CONCLUSIONS Macrogol 3350 plus electrolytes is a safe and effective treatment for constipation in children aged 2 - 11 years Results from a controlled clinical trial indicate that low doses of polyethylene glycol solutions are more effective and have fewer side-effects than lactulose . Large doses of polyethylene glycol are effective in the treatment of faecal impaction . Resolution of faecal impaction was obtained in all patients , and in 25/30 patients with three administrations in a three-day period

The primary results showed that preprocedural ultrasound increased the FPS rate in patients with predicted puncture difficulty but not in patients who were easily punctured . Preprocedural ultrasound reduced the number of redirections and punctures and decreased the incidence of vascular puncture and backache . There was no evidence of a reduction in failed punctures . We also noted that preprocedural ultrasound prolonged the identification time but not the procedure time . Thus , this systematic review provides evidence that preprocedural ultrasound does not improve the FPS rate of neuraxial anesthesia in patients who are easily palpated , although it increases the FPS rate in patients who are difficult to palpate

Neuraxial anesthesia is a common practice in obstetrics . Evidence suggests that preprocedural ultrasound versus the conventional l and mark location method accurately identifies a given intervertebral space and predicts the needle insertion depth required to reach the spinal canal . However , whether the preprocedural ultrasound examination improves the first-pass success ( FPS ) rate remains elusive .

Abstract Difficulties in the palpation of anatomical l and marks in pregnancy due to obesity may create problems in the regional anaesthesia . Objective of this study was to compare ultrasound examination carried out before the procedure with conventional spinal anaesthesia method with papation of bony l and marks in caesarean sections performed under spinal anaesthesia in obese pregnants . Ninety-seven obese pregnants having pre- and post-pregnancy body mass index > 30 kg/m2 were prospect ively examined . Patients were r and omised to two groups as l and mark group ( n = 49 ) and ultrasound group ( n = 48 ) . The needle insertion point was determined at L4–L5 level before the procedure through palpation in the l and mark group and with the examination in the ultrasound . The numbers of skin punctures and needle passes , total procedure time ( TPT ) and spinal block occurrence time ( SBOT ) were recorded . TPT was significantly longer in the ultrasound than in the l and mark group ( p < 0.001 ) ( 8 ± 2 and 5 ± 1 ; respectively ) . Whereas SBOT values were similar ( p = 0.063 ) . The numbers of skin punctures and needle passes were significantly fewer in the ultrasound than in the l and mark group ( p < 0.001 ) . We believe that , accurate determination of the needle introducing site before the procedure by viewing the vertebral structures through ultrasound examination in obese pregnants could increase the success rate Ultrasound assistance for neuraxial techniques may improve technical performance ; however , it is unclear which population s benefit most . Our study aim ed to investigate the efficacy of neuraxial ultrasound in women having caesarean section with combined spinal‐epidural anaesthesia , and to identify factors associated with improved technical performance . Two‐hundred and eighteen women were r and omly allocated to ultrasound‐assisted or control groups . All the women had a pre‐procedure ultrasound , but only women in the ultrasound group had this information conveyed to the anaesthetist . Primary outcomes were first‐pass success ( a single needle insertion with no redirections ) and procedure difficulty . Secondary outcomes were block quality , patient experience and complications . Exploratory sub‐group analysis and regression analysis were used to identify factors associated with success . Data from 215 women were analysed . First‐pass success was achieved in 67 ( 63.8 % ) and 42 ( 38.2 % ) women in the ultrasound and control groups , respectively ( adjusted p = 0.001 ) . Combined spinal‐epidural anaesthesia was ‘ difficult ’ in 19 ( 18.1 % ) and 33 ( 30.0 % ) women in the ultrasound and control groups , respectively ( adjusted p = 0.09 ) . Secondary outcomes did not differ significantly . Anaesthetists misidentified the intervertebral level by two or more spaces in 23 ( 10.7 % ) women . Sub‐group analysis demonstrated a benefit for ultrasound in women with easily palpable spinous processes ( adjusted p = 0.027 ) . Regression analysis identified use of ultrasound and easily palpable spinous processes to be associated with first‐pass success BACKGROUND Ultrasound imaging of the spine is thought to reduce failed and traumatic neuraxial procedures . Most of the evidence supporting this assumption has been produced in the context of an expert sonographer performing the ultrasound assessment , and it remains unknown whether this technique is useful when used by multiple individual operators . OBJECTIVE To invesstigate the impact of preprocedural spinal ultrasound on the ease of insertion of labour epidurals by a group of trainees . We hypothesised that the ultrasound-assisted technique would improve the ease of insertion when compared with the conventional palpation technique . DESIGN A r and omised controlled trial . SETTING Academic hospital in Toronto , Canada . PARTICIPANTS AND INTERVENTION A group of 17 second-year anaesthesia residents and five anaesthesia fellows underwent a training programme in ultrasound assessment of the spine . Parturients with easily palpable lumbar spines were r and omised to either ultrasound or palpation group . Residents and fellows performed both the assessment ( ultrasound or palpation ) and the epidural procedure . MAIN OUTCOME MEASURES Primary outcome : ease of insertion of epidural catheter composed of the time taken to insert the epidural catheter , number of interspace levels attempted and number of needle passes . Secondary outcomes : total procedural time ( assessment and insertion ) ; first pass success rate ; number of attempts required to thread the epidural catheter ; failure of epidural analgesia ; and patient satisfaction . RESULTS We analysed 128 epidural catheter insertions ( residents 84 , fellows 44 ) . There was no difference in median ( interquartile range , IQR ) epidural insertion time between the ultrasound and palpation groups [ 174 ( 120 to 241 ) versus 180 ( 130 to 322.5 ) s , respectively ; P = 0.14 ] . The number of interspace levels attempted and needle passes were also similar in both groups . The total procedural time was longer in the ultrasound group . CONCLUSION The use of preprocedural spinal ultrasound by a cohort of anaesthesia trainees did not improve the ease of insertion of labour epidural catheters in patients with easily palpable lumbar spines , as compared with the traditional palpation technique based on anatomical l and marks . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00996905 STUDY OBJECTIVE To assess the clinical use of ultrasonographic localization of the epidural space , and to evaluate the clinical efficacy of ultrasound diagnostics in obstetric anesthesia . DESIGN R and omized prospect i ve study . SETTING University Clinic of Obstetrics and Gynecology . PATIENTS 300 parturients , 85 of whom had conventional delivery and 65 who underwent cesarean section . INTERVENTIONS Patients underwent ultrasonography for the identification of the intervertebral structures . Puncture depth and angle were measured to improve the placement of the Tuohy needle . MEASUREMENTS In the ultrasound group , additional puncture data , optimized puncture point , expected puncture depth , and angle were used to optimize the puncture technique . To control for side effects , we compiled data on the number of puncture attempts and the number of necessary puncture levels , visual analog scale ( VAS ) scores , the rate of side effects , and the patient acceptance of the technique . MAIN RESULTS The two groups were similar regarding demographic data . Using ultrasound for structure detection , the rate of puncture attempts were significantly ( p < 0.013 ) reduced from 2.18 + /- 1.07 to 1.35 + /- 0.61 . The mean rate of necessary puncture levels was 1.30 + /- 0.55 and with ultrasound detection 1.136 + /- 0.36 ( p < 0.029 ) . Complete analgesia was achieved in 147 patients with ultrasound detection versus 138 patients in the Control group ( p < 0,03 ) . The maximum VAS pain score in the control group was 1.3 + /- 2.1 versus 0.8 + /- 1.5 in the Ultrasound group ( p < 0.006 ) . The rate of side effects were reduced significantly : 99 patients in the Control group had no side effects compared with 120 patients from the Ultrasound group who were free of side effects . Patient acceptance of the technique in the Ultrasound group was significantly higher than in the Control group . CONCLUSION The clinical use of ultrasound for epidural catheter placement may improve regional anesthesia . The use of ultrasound result ed in superior quality in all measured endpoints Palpation method is widely used in clinical practice to identify the puncture site during combined spinal-epidural ( CSE ) blocks . Tuffier ’s line , is an anatomical l and mark between two iliac crests ( inter-cristal ) , which is widely used to identify the puncture site during CSE blocks is not always an indicator for specific vertebral level or inter-vertebral space . One hundred and Ten ( 110 ) women were scheduled for normal vaginal delivery and were r and omized into two equal groups ; palpation group and an ultrasound guided group to detect the efficacy of puncture ultrasound before CSE blocks to increase chances of successful CSE procedure on the first attempt and to reduce the number of attempts or punctures during insertion of CSE catheter . There were no significant differences between two studied groups regarding ; maternal age , weight and height , while , there was a significant difference between two studied groups regarding ; parity . Percentage of successful CSE procedure on the first attempt was significantly higher ( 67.27 % ) in ultrasound compared to palpation group ( 40 % ) . Number of punctures ( attempts ) were significantly less in ultrasound ( 1.2 ± 0.6 ) compared to palpation group ( 2.3 ± 0.8 ) and the number of redirections was also significantly less in ultrasound ( 1.4 ± 0.5 ) compared to palpation group ( 2.8 ± 1.6 ) . Although , time to identify puncture site was significantly longer in ultrasound compared to palpation group and total procedure time was longer in ultrasound ( 9.1 ± 1.5 min ) compared to palpation group ( 6.2 ± 1.2 min ) , there was no significant difference between two studied groups regarding ; time to identify puncture site and total procedure time . Two cases of dural puncture in palpation versus no cases in ultrasound group and two cases of intravascular catheter placement ( one in each group ) , with no significant difference between two groups . Pre- puncture ultrasound guided epidural insertion before vaginal delivery , increases the chance of a successful CSE procedure on the first attempt and reduces the number of attempts during insertion of CSE catheter BACKGROUND Data are scarce on the advantage of ultrasound-guided spinal anaesthesia in patients with easily identifiable bony l and marks . In this study , we compared the use of ultrasound to the l and mark method in patients with no anticipated technical difficulty , presenting for caesarean delivery under spinal anaesthesia . METHODS A total of 150 pregnant women were recruited in this r and omized , controlled study . Ultrasound examination and spinal anaesthesia were performed by three anaesthetists with experience in ultrasound-guided neuraxial block . Patients were r and omized to either the Ultrasound Group ( n=75 ) or the L and mark Group ( n=75 ) . In both groups the level of L3 - 4 or L4 - 5 was identified by ultrasound ( transverse and longitudinal approach ) or palpation . The primary outcome was the procedure time , measured from the time of skin puncture by the introducer to the time of viewing cerebrospinal fluid at the hub of the spinal needle . Secondary outcomes were the number of skin punctures , number of passes , and incidence of successful spinal blockade . RESULTS The average procedure time , number of skin punctures and needle passes , were similar in both groups . The number of patients with successful spinal anaesthesia after one puncture was not statistically different between the groups . CONCLUSION The present results indicate that when performed by anaesthetists experienced in both ultrasound and l and mark techniques , the use of ultrasound does not appear to increase the success rate of spinal anaesthesia , or reduce the procedure time or number of attempts in obstetric patients with easily palpable spines Background and Aims : Identification of subarachnoid space in pregnant patients can pose a great challenge to anaesthesiologists . This study was design ed to compare conventional l and mark technique with pre-procedural ultrasonography-assisted midline approach for identification of the subarachnoid space in elective caesarean section . Methods : After institute ethics committee approval and written informed consent , 100 parturients scheduled for elective caesarean section under spinal anaesthesia were included in this prospect i ve r and omised control trial and divided into Group L ( n = 50 ) ( l and mark technique ) and Group U ( n = 50 ) ( ultrasound-guided technique ) . Parameters such as time taken for the identification of the interspace , distance between skin and dura mater , number of insertion attempts ( the primary outcome ) , number of passes and time taken were recorded in both the groups . Statistical analysis was done using SPSS software 16 . Results : Demographic profiles of both groups were comparable . The number of attempts for needle insertion ( 1.04 ± 0.19 vs. 1.97 ± 0.77 ) , number of passes in the same interspinous space ( 1.26 ± 0.44 vs. 1.90 ± 0.51 ) and the total time for successful lumbar puncture ( 31.90 ± 6.30 vs. 51.80 ± 12.28 s ) were significantly less in Group U as compared to Group L , but the time of identification of interspinous space was significantly more in Group U ( 56.70 ± 13.08 s ) as compared to Group L ( 47.10 ± 10.45 s ) . Conclusion : Pre-procedural ultrasound is a useful tool for successful lumbar puncture in parturients as it reduces the number of attempts with fewer side effects as compared to conventional l and mark technique STUDY OBJECTIVE This r and omized controlled trial was design ed to evaluate the efficacy of additional information from preprocedure ultrasound examination to aid anesthesiology trainees performing spinal anesthesia for obstetric patients . DESIGN Trainee residents were r and omly allocated to l and mark technique and anatomy demonstration via ultrasound examination or l and mark technique only for spinal anesthetic placement . SETTING Obstetric delivery suite . PATIENTS Eighty healthy obstetric patients undergoing elective cesarean delivery . INTERVENTION Ultrasound examination prior to spinal anesthetic placement . MEASUREMENTS The primary outcome was the number of attempts for the spinal anesthetic . Secondary outcomes included placement duration ; block height ; and the incidence of need for staff intervention , paresthesia , and bloody tap . Subjective ease of placement was rated on a 100-mm visual analog scale . MAIN RESULTS Baseline demographic data were similar between the patient groups . The median number of attempts with preprocedure ultrasound and l and mark was 3 ( interquartile range , 2 - 7 ) . This was not significantly different from the number of attempts with l and mark technique only of 3 ( 1 - 60 ) ( P=.69 ) . The median duration of spinal placement with ultrasound and l and mark was 92 ( 51 - 140 ) seconds vs 75 ( 53 - 126 ) seconds with l and mark only ( P=.57 ) . There was no statistical difference between the groups in spinal placement duration , need for staff intervention , paresthesia , bloody tap , lumbar interspace , or block height . There was no difference in subjective ease of spinal placement by the resident . CONCLUSIONS In this study of junior anesthesia trainees performing obstetrical spinal anesthesia with preprocedure ultrasound and l and mark technique or l and mark technique only , no significant difference was observed in the number of attempts , duration of spinal placement , subjective ease of spinal placement , or any other measured secondary outcome Background and Aims : Routine use of pre-procedural ultrasound guided midline approach has not shown to improve success rate in administering subarachnoid block . The study hypothesis was that the routine use of pre-procedural ( not real time ) ultrasound-guided paramedian spinals at L5-S1 interspace could reduce the number of passes ( i.e. , withdrawal and redirection of spinal needle without exiting the skin ) required to enter the subarachnoid space when compared to the conventional l and mark-guided midline approach . Methods : After local ethics approval , 120 consenting patients scheduled for elective total joint replacements ( Hip and Knee ) were r and omised into either Group C where conventional midline approach with palpated l and marks was used or Group P where pre-procedural ultrasound was used to perform subarachnoid block by paramedian approach at L5-S1 interspace ( real time ultrasound guidance was not used ) . Results : There was no difference in primary outcome ( difference in number of passes ) between the two groups . Similarly there was no difference in the number of attempts ( i.e. , the number of times the spinal needle was withdrawn from the skin and reinserted ) . The first pass success rates ( 1 attempt and 1 pass ) was significantly greater in Group C compared to Group P [ 43 % vs. 22 % , P = 0.02 ] . Conclusion : Routine use of paramedian spinal anaesthesia at L5-S1 interspace , guided by pre-procedure ultrasound , in patients undergoing lower limb joint arthroplasties did not reduce the number of passes or attempts needed to achieve successful dural puncture BACKGROUND The palpation method is widely used in clinical practice to identify the puncture site of combined spinal-epidural ( CSE ) blocks , but it is usually difficult to accurately locate the puncture site in obese parturients . Accurate identification of the puncture site is crucial for successful CSE block . The objective of this study was to evaluate the impact of ultrasound imaging on the success rate of CSE puncture in obese parturients . METHODS Sixty obese parturients with a body mass index ≥ 30 kg/m(2 ) who were scheduled for caesarean section were r and omized into two equal-sized groups for location of the puncture site : an ultrasound group and a palpation group . The success rate of puncture at the first puncture site , the number of puncture attempts , duration of CSE procedure , time taken to determine the puncture site , and the depth of the epidural space were compared between groups . The frequencies of complications such as puncture site hemorrhage , neurological damage , and inadvertent dural puncture were also studied . RESULTS There were no differences in age , body weight , height , body mass index , or gestational age between the two groups . The success rate of puncture at the first puncture site was significantly higher in the ultrasound group than the palpation group ( 100.00 % vs. 70.00 % , P = 0.004 ) . The number of puncture attempts was significantly lower in the ultrasound group than the palpation group ( χ(2 ) = 6.708 , P = 0.035 ) . The time taken for determining the puncture site was ( 0.30 ± 0.12 ) minutes in the palpation group and ( 2.60 ± 0.61 ) minutes in the ultrasound group ( P < 0.001 ) . The duration of CSE procedure was ( 7.67 ± 1.52 ) minutes in the palpation group and ( 9.37 ± 1.35 ) minutes in the ultrasound group ( P < 0.001 ) . The depth of the epidural space was similar in both groups ( P = 0.586 ) . Puncture site hemorrhage was observed in 6 ( 20.00 % ) patients in the palpation group and 2 ( 6.67 % ) patients in the ultrasound group ( P = 0.255 ) . CONCLUSIONS Ultrasound imaging improves the rate of successful puncture at the first puncture site and decreases the number of puncture attempts . It facilitates CSE puncture in obese parturients Background and objective : The quality of combined spinal-epidural anaesthesia mainly depends on accurate identification of the epidural space . The real-time ultrasound control of the procedure for puncture was therefore evaluated . Methods : Thirty parturients scheduled for Caesarean section were r and omized to three equal groups . Ten control patients received conventional combined spinal-epidural anaesthesia . Ten of the remaining patients received ultrasonic scans by an offline scan technique , and 10 received online imaging of the lumbar region during epidural puncture . The epidural space was identified and needle advancement was surveyed through the interspinal and flaval ligaments . The number of attempts to advance the needle to achieve a successful puncture was measured and compared , as well as the number of vertebral interspaces punctured before successful entry into the epidural space . Results : There was no difference between patient characteristics in the three groups . The visualization of the epidural structures and of the needle manipulations was very effective . In the ultrasound group , the reduction in the number of attempts at puncture was significant ( P < 0.036 ) . The number of interspaces necessary for puncture was reduced ( P < 0.036 ) in the ultrasound online group compared with controls . The number of spinal needle manipulations was significantly reduced ( P < 0.036 ) . Conclusions : Real-time ultrasonic scanning of the lumbar spine is an easy procedure . It provides an accurate reading of the location of the needle tip and facilitates the performance of combined spinal-epidural anaesthesia BACKGROUND Ultrasound can facilitate neuraxial blockade in patients with poorly defined anatomical surface l and marks , but there are no studies comparing an ultrasound-guided technique with l and mark palpation for spinal anaesthesia . The objective of this study was to compare pre-procedural lumbar ultrasonography with l and mark palpation to locate the needle insertion point in women with impalpable lumbar spinous processes presenting for caesarean delivery . METHODS After institutional ethics committee approval , 20 women with impalpable lumbar spinous processes presenting for elective caesarean delivery were recruited . Patients were r and omised to palpation or ultrasound . The primary outcome of the study was the number of needle passes to achieve lumbar puncture . Secondary outcomes were the overall procedural time and patient satisfaction score . RESULTS There was no difference in mean ( ±SD ) body mass index of both groups ( ultrasound 39.1 ± 5.02kg/m2 vs. palpation 38.3±3.77kg/m2 ) . There were significantly fewer needle passes in the ultrasound group ( median 3 [ IQR 1.8 - 3.2 ] ) compared to the palpation group ( median 5.5 [ IQR 3.2 - 7.2 ] ( P=0.03 ) ) . More time was required to locate the needle insertion point in the ultrasound group ( ultrasound 91.8±30.8s vs. palpation 32.6±11.4s , P<0.001 ) . There was no difference in the total procedural time between groups ( ultrasound 191.8±49.4s vs. palpation 192±110.9s , P=0.99 ) . CONCLUSION The use of ultrasonography to locate the needle insertion point reduced the number of needle passes in women with impalpable lumbar spinous processes undergoing elective caesarean delivery under spinal anaesthesia . Its use did not prolong overall procedural time BACKGROUND : Preprocedural ultrasound may improve the efficacy and safety of epidural catheterization , especially in difficult cases . Most studies of ultrasound-assisted epidural catheterization in the obstetric population are date d and nonblinded with inconsistent design s. This double-blind , r and omized controlled study aim ed to compare the ultrasound-assisted with the conventional palpation techniques for epidural catheterization in parturients undergoing cesarean delivery . We hypothesized that the use of preprocedural ultrasound would increase the success rate of epidural catheterization at the first needle pass . METHODS : Eligible subjects were American Society of Anesthesiologists physical status II parturients with full-term singleton pregnancy undergoing elective cesarean delivery using double-interspace combined spinal – epidural anesthesia . Exclusion criteria were age < 19 or > 40 years , body mass index ≥35 kg/m2 , women presenting in labor or having any contraindication to neuraxial anesthesia , marked spinal deformity , previous spinal surgery , or impalpable anatomical l and marks . One hundred ten patients were r and omly allocated into 2 equal groups ( palpation and ultrasound groups ) . All procedures were performed by a single experienced anesthesiologist . Patients and investigators assessing the outcome data were blinded to group allocation . A systematic spinal ultrasound assessment and a sham procedure were performed in the ultrasound and palpation groups , respectively , before attempting epidural catheterization . The primary outcome was the rate of successful epidural catheterization at the first needle pass . Secondary outcomes were the rate of successful epidural catheterization at the first skin puncture , number of performed needle passes and skin punctures , duration of the epidural procedure , patient satisfaction from the procedure , and complications of the procedure ( incidence of unintentional dural and vascular punctures , failed block , unilateral or patchy block , and backache ) . RESULTS : Data from 108 patients ( 55 patients in the palpation group and 53 patients in the ultrasound group ) were analyzed . The rate of successful epidural catheterization at the first needle pass was 60 % in the palpation group and 58.5 % in the ultrasound group ( 95 % confidence interval of the difference in proportions between groups is −18.5 % to 21.6 % ; P > 0.99 ) . There were no significant differences between the 2 groups in the success rate at the first skin puncture , the number of needle passes and skin punctures , or patient satisfaction . The median ( range ) duration of the epidural procedure was 185 ( 57–680 ) seconds in the ultrasound group and 215 ( 114–720 ) seconds in the palpation group ( P = 0.036 with the Mann-Whitney U test and P = 0.083 with the Student t test with unequal variances ) . The overall rate of complications of the procedure was low in both groups . CONCLUSIONS : For experienced anesthesiologists , it remains unclear whether preprocedural ultrasound improves the epidural catheterization technique in parturients with palpable anatomical l and marks undergoing cesarean delivery UNLABELLED Ultrasound ( US ) is widely used in rheumatology to study and guide injection of peripheral joints . It can also provide useful information about the anatomy of the lumbar spine . Studies have shown that US examination of the spine was a useful tool to help perform epidural anaesthesia . The purpose of the study was to determine if the selection of the optimum puncture level by US may facilitate epidural steroid injection in case of presumed difficult puncture ( BMI > 30 kg/m(2 ) , age>60 years or lumbar scoliosis ) . METHODS We performed a prospect i ve r and omized controlled study . Eighty patients were r and omized in two groups : US group ( n=40 ) which underwent a pre-procedure spinal US to determine the optimal lumbar level for injection or control group ( n=40 ) for which the level of injection was determined by palpation . Primary endpoint was the pain during the procedure assessed using the Visual Analogue Scale ( VAS ) . RESULTS We found a positive correlation between depth of the epidural space and BMI ( P<0.001 ) and a negative correlation between size of the interspinous spaces and age ( P<0.01 ) . Visibility of the epidural space was not altered by obesity or age . We observed a trend toward a reduction in pain intensity during the procedure in the US group compared to the control group with a mean difference at -0.94 [ -1.90 ; 0.02 ] but the difference was not significant ( P=0.054 ) . CONCLUSION US of the lumbar spine was feasible in patients with lumbar conditions even in obese and old ones and allowed the visualization of the epidural space . However , pre-procedure US examination did not reduce pain during the procedure Background : The efficacy of epidural anaesthesia depends on the accurate identification of the epidural space ( ES ) . Abnormal anatomical conditions may make the procedure difficult or impossible . The aim of this study was to investigate whether pre‐puncture ultrasound examination of the spinal anatomy might be beneficial in expected cases of difficult epidural anaesthesia Combined spinal and epidural analgesia ( CSE ) is widely used to provide analgesia for cesarean delivery . The success and quality of analgesia depend on correct cannulation of the epidural space ( ES ) . Epidural puncture is traditionally guided using surface l and marks and the loss-of-resistance ( LOR ) technique . However , difficulty in identifying surface l and marks ( e.g. , the obese patient ) and deviation of the needle trajectory from midline may lead to failed or asymmetric epidural block . To facilitate ES cannulation , additional information regarding puncture depth and axis from the skin ’s surface would be desirable . Diagnostic imaging including plain radiography , computed tomography , and magnetic resonance imaging ( MRI ) can provide accurate anatomic information regarding the location of the epidural space , but their use is impractical in most clinical setting s where epidural analgesia is used . In contrast , the safety and feasibility of bedside ultrasonography during pregnancy are well established . In the present study , we used ultrasonography to measure the ES depth ( i.e. , the distance from the skin to the ligamentum flavum ) and to gain additional information on neighboring anatomical structures before performing the epidural block . We assessed the usefulness of ultrasonography in facilitating successful localization of the epidural space compared with the LOR technique alone in a group of parturients undergoing CSE for elective cesarean delivery . Background : Poor surface anatomic l and marks are highly predictive of technical difficulty in neuraxial blockade . The authors examined the use of ultrasound imaging to reduce this difficulty . Methods : The authors recruited 120 orthopedic patients with one of the following : body mass index more than 35 kg/m2 and poorly palpable spinous processes ; moderate to severe lumbar scoliosis ; or previous lumbar spine surgery . Patients were r and omized to receive spinal anesthetic by the conventional surface l and mark-guided technique ( group LM ) or by an ultrasound-guided technique ( group US ) . Patients in group US had a preprocedural ultrasound scan to locate and mark a suitable needle insertion point . The primary outcome was the rate of successful dural puncture on the first needle insertion attempt . Normally distributed data were summarized as mean ± SD and nonnormally distributed data were summarized as median [ interquartile range ] . Results : The first-attempt success rate was twice as high in group US than in group LM ( 65 % vs. 32 % ; P < 0.001 ) . There was a twofold difference between groups in the number of needle insertion attempts ( group US , 1 [ 1–2 ] vs. group LM , 2 [ 1–4 ] ; P < 0.001 ) and number of needle passes ( group US , 6 [ 1–10 ] vs. group LM , 13 [ 5–21 ] ; P = 0.003 ) . More time was required to establish l and marks in group US ( 6.7 ± 3.1 ; group LM , 0.6 ± 0.5 min ; P < 0.001 ) , but this was partially offset by a shorter spinal anesthesia performance time ( group US , 5.0 ± 4.9 vs. group LM , 7.3 ± 7.6 min ; P = 0.038 ) . Similar results were seen in subgroup analyses of patients with body mass index more than 35 kg/m2 and patients with poorly palpable l and marks . Conclusion : Preprocedural ultrasound imaging facilitates the performance of spinal anesthesia in the nonobstetric patient population with difficult anatomic l and marks BACKGROUND : Multiple passes and attempts while administering spinal anesthesia are associated with a greater incidence of postdural puncture headache , paraesthesia , and spinal hematoma . We hypothesized that the routine use of a preprocedural ultrasound-guided paramedian technique for spinal anesthesia would reduce the number of passes required to achieve entry into the subarachnoid space when compared with the conventional l and mark-guided midline approach . METHODS : One hundred consenting patients scheduled for elective total joint replacements ( hip and knee ) were r and omized into group C ( conventional ) and group P ( preprocedural ultrasound-guided paramedian technique ) with 50 in each group . The patients were blinded to the study group . All spinal anesthetics were administered by a consultant anesthesiologist . In group C , spinal anesthetic was done via the midline approach using clinical ly palpated l and marks . In group P , a preprocedural ultrasound scan was used to mark the paramedian insertion site , and spinal anesthetic was performed via the paramedian approach . RESULTS : The average number of passes ( defined as the number of forward advancements of the spinal needle in a given interspinous space , i.e. , withdrawal and redirection of spinal needle without exiting the skin ) in group P was approximately 0.34 times that in group C , a difference that was statistically significant ( P = 0.01 ) . Similarly , the average number of attempts ( defined as the number of times the spinal needle was withdrawn from the skin and reinserted ) in group P was approximately 0.25 times that of group C ( P = 0.0021 ) . In group P , on an average , it took 81.5 ( 99 % confidence interval , 68.4–97 seconds ) seconds longer to identify the l and marks than in group C ( P = 0.0002 ) . All other parameters , including grading of palpated l and marks , time taken for spinal anesthetic injection , periprocedural pain scores , periprocedural patient discomfort visual analog scale score , conversion to general anesthetic , paresthesia , and radicular pain during needle insertion , were similar between the 2 groups . CONCLUSIONS : Routine use of paramedian spinal anesthesia in the orthopedic patient population undergoing joint replacement surgery , guided by preprocedure ultrasound examination , significantly decreases the number of passes and attempts needed to enter the subarachnoid space BACKGROUND Regional epidural analgesia is considered the gold st and ard for pain treatment in labor . However , epidural catheter placement may be a challenging procedure because of the difficulty in the palpation of anatomical l and marks , particularly in pregnant women . Pre-procedural neuroaxial ultrasound may facilitate the procedure . METHODS A prospect i ve r and omized controlled study was conducted in a labor ward . Two groups of women undergoing epidural analgesia were r and omized : Group A ( N.=28 ) , which was subjected to the loss of resistance technique , and Group B ( N.=30 ) which was subjected to an ultrasound (US)-assisted procedure . The real depth of epidural space was calculated in both groups by measuring the needle skin-to-tip distance , while the US depth was measured only in Group B. RESULTS The mean number of attempts in group A ( 3.43±3.8 ) was significantly higher than in Group B ( 1.70±0.87 , P=0.019 ) . Analysis of data from Group B revealed a strong positive correlation between the epidural real depth and US depth ( r=0.88 , P<0.0001 ) . CONCLUSIONS The US-assisted technique for epidural catheter placement for labor analgesia is safe , effective , easy to perform , and is a valuable aid to improve the identification of the epidural space compared with the palpation of anatomical l and marks and the loss of resistance technique . Pre-puncture ultrasound assessment shows the exact location of the intervertebral space , the optimal point of insertion and the tilt angle of the needle , the depth of the epidural space and any anatomical abnormalities of the spine , thereby increasing the success rate and reducing procedural complications of the blind approach BACKGROUND Spinal anesthesia , which is commonly used in cesarean deliveries , is often difficult to perform in obese parturients because of poorly palpable surface l and marks and positioning challenges . This study aim ed to evaluate the benefits of ultrasound-assisted technology for performing spinal anesthesia in obese parturients . METHODS Parturients with a body mass index ( BMI ) ≥30 kg/m scheduled for elective cesarean delivery were r and omized to undergo spinal anesthesia using the conventional l and mark location technique ( l and mark group , n = 40 ) or prepuncture ultrasound examination ( ultrasound group , n = 40 ) . All participants underwent spinal anesthesia in the lateral position . The primary outcome was the first-attempt success rate . Secondary outcomes were the number of skin punctures and needle passes , procedure times , patient satisfaction , changes in the intended interspace , and incidence of complications . RESULTS The ultrasound group had a significantly higher first-attempt success rate ( 87.5 % vs 52.5 % ; P = .001 ) , fewer cases requiring > 10 needle passes ( 1 vs 17 ; P < .001 ) , and fewer skin punctures and needle passes ( P < .001 for both ) . There was no statistically significant difference in the time taken to identify the needle insertion site between the 2 groups ( 202.5 vs 272.0 seconds ; P = .580 ) . Both the spinal injection time and total procedure time were significantly longer in the l and mark group ( P < .001 ) . Patient satisfaction scores were significantly higher in the ultrasound group ( P = .001 ) . Among patients with BMI between 30 and 34.9 kg/m , there was no statistically significant difference in the first-attempt success rate ( P = .407 ) , number of cases with > 10 needle passes ( P = .231 ) , spinal injection time ( P = .081 ) , or total procedure time ( P = .729 ) ; however , more time was required to identify the needle insertion site in the ultrasound group ( P < .001 ) . For patients with BMI between 35 and 43 kg/m , the ultrasound group had a significantly higher first-attempt success rate ( P ≤ .041 ) , fewer cases with > 10 needle passes ( P ≤ .01 ) , and shorter procedure times , including the time required to identify the needle insertion site ( P < .001 ) . CONCLUSIONS Prepuncture ultrasound examination can facilitate spinal anesthesia in the lateral position in obese parturients ( 35 kg/m ≤ BMI ≤ 43 kg/m ) by improving the first-attempt success rate , reducing the number of needle passes and puncture attempts , shortening the total procedure time , and improving patient satisfaction

The reported compliance rates did not differ by duration of EMA period among studies from either clinical or non clinical setting s. CONCLUSIONS The compliance rate among mobile-EMA studies in youth is moderate but suboptimal . Study design may affect protocol compliance differently between clinical and non clinical participants ; including additional wearable devices did not affect participant compliance .

BACKGROUND Mobile device-based ecological momentary assessment ( mobile-EMA ) is increasingly used to collect participants ' data in real-time and in context . Although EMA offers method ological advantages , these advantages can be diminished by participant noncompliance . However , evidence on how well participants comply with mobile-EMA protocol s and how study design factors associated with participant compliance is limited , especially in the youth literature .

OBJECTIVE The objective of this study was to compare the relationship between repeated momentary reports of stress and headaches in female adolescents with varying degrees of headache frequency . BACKGROUND Headaches are the most common form of pain reported by adolescents affecting more than a third of all adolescents . High levels of stress during adolescence may predispose an adolescent to experience headaches in adulthood . R and omized , momentary data collection of stress and headaches provides the most accurate data regarding the adolescent experience of these variables . METHODS The research methodology , ecological momentary assessment , is a valid approach to better underst and the relationship between stress and headaches in adolescence . Data were obtained by each participant 's use of an electronic diary ( ED ) , which captured repeated momentary reports of perceived stress , head pain , and stress-related symptoms in female adolescents with varying degrees of recurrent headache . Seven times per day for the 21-day study period , teen girls responded to ED questions about their current stress levels , head pain , and stress-related symptoms . Based on participants ' momentary reports of headaches , Low Headache , Moderate Headache , and Chronic Headache groups were created . General estimating equation models were used to analyze the relationship between momentary variables as well as the lag effect between stress and head pain . RESULTS Thirty-one participants , aged 14 - 18 years , completed 2841 r and omized ED reports and reported 674 occurrences of headache . The Chronic Headache and Moderate Headache groups reported significantly increased levels of stress , head pain , and headaches . The relationship between momentary stress and head pain was significantly strong both within and across participants . The strength of this relationship increased with increased headache activity . A significant lag effect was found between stress and headaches ; however , the effect of depression as a moderator of the stress and headache relationship remains unclear . CONCLUSION Perceived stress and head pain was highly correlated in these female adolescents . Given the large population of teens affected by headaches , a plausible next step would be to vali date these results in other sample s and to determine methods with which to identify teens who may be at risk for a pattern of increasing stress and headaches Background Research examining adolescent mood , stresses , and coping has tended to use retrospective question naires which are affected by recall biases . The aim of this study was to develop , pilot , and evaluate a youth-friendly mobile phone program to monitor , in real-time , young people ’s everyday experiences of mood , stress , and their coping behaviours . Method and design A momentary sampling program was design ed for mobile phones , and ran for 7 days , administering a brief question naire four r and om times each day , capturing information on current activity , mood , responses to negative mood , stresses , alcohol and cannabis use . Eleven high school students review ed the program in focus groups , and 18 students completed 7 days of monitoring . Results Engagement with the mobiletype program was high with 76 % of 504 possible entries completed and 94 % ( 17/18 ) of the participants reporting that the program adequately captured their moods , thoughts , and activities . The mobiletype program captured meaningful and analyzable data on the way young people ’s moods , stresses , coping strategies , and alcohol and cannabis use , vary both between and within individuals . Conclusions The mobiletype program captured a range of detailed and interesting qualitative and quantitative data about young people ’s everyday mood , stresses , responses , and general functioning INTRODUCTION AND AIMS Alcohol use during adolescence is associated with the onset of alcohol use disorders , mental health disorders , substance abuse as well as socially and physically damaging behaviours , the effects of which last well into adulthood . Nevertheless , alcohol use remains prevalent in this population . Underst and ing motivations behind adolescent alcohol consumption may help in developing more appropriate and effective interventions . This study aims to increase this underst and ing by exploring the temporal relationship between mood and different levels of alcohol intake in a sample of young people . DESIGN AND METHODS Forty-one secondary school students used a purpose - design ed mobile phone application to monitor their daily mood and alcohol use for 20 r and om days within a 31 day period . Generalised estimating equations were used to examine the relationship between differing levels of alcohol consumption ( light , intermediate and heavy ) and positive and negative mood three days before and after drinking episodes . RESULTS While there was no relationship between light and heavy drinking and positive mood , there was an increase in positive mood before and after the drinking event for those that drank intermediate amounts . No statistically significant relationships were found between negative mood and any of the three drinking categories . DISCUSSION AND CONCLUSION Adolescents who drank in intermediate amounts on a single drinking occasion experienced an increase in positive mood over the three days leading up to and three days following a drinking event . These findings contribute to an underst and ing of the motivations that underpin adolescent alcohol use , which may help inform future interventions The objective of this study was to identify physical , social , and intrapersonal cues that were associated with the consumption of sweetened beverages and sweet and salty snacks among adolescents from lower SES neighborhoods . Students were recruited from high schools with a minimum level of 25 % free or reduced cost lunches . Using ecological momentary assessment , participants ( N=158 ) were trained to answer brief question naires on h and held PDA devices : ( a ) each time they ate or drank , ( b ) when prompted r and omly , and ( c ) once each evening . Data were collected over 7days for each participant . Participants reported their location ( e.g. , school grounds , home ) , mood , social environment , activities ( e.g. , watching TV , texting ) , cravings , food cues ( e.g. , saw a snack ) , and food choices . Results showed that having unhealthy snacks or sweet drinks among adolescents was associated with being at school , being with friends , feeling lonely or bored , craving a drink or snack , and being exposed to food cues . Surprisingly , sweet drink consumption was associated with exercising . Watching TV was associated with consuming sweet snacks but not with salty snacks or sweet drinks . These findings identify important environmental and intrapersonal cues to poor snacking choices that may be applied to interventions design ed to disrupt these food-related , cue-behavior linked habits Computerized ecological momentary assessment ( EMA ) is widely accepted as a “ gold st and ard ” method for capturing momentary symptoms repeatedly experienced in daily life . Although many studies have addressed the within-individual temporal variations in momentary symptoms compared with simultaneously measured external criteria , their concurrent associations , specifically with continuous physiological measures , have not been rigorously examined . Therefore , in the present study , we first examined the variations in momentary symptoms by validating the associations among self-reported symptoms measured simultaneously ( depressive mood , anxious mood , and fatigue ) and then investigated covariant properties between the symptoms ( especially , depressive mood ) and local statistics of locomotor activity as the external objective criteria obtained continuously . Healthy subjects ( N = 85 ) from three different population s ( adolescents , undergraduates , and office workers ) wore a watch-type computer device equipped with EMA software for recording the momentary symptoms experienced by the subjects . Locomotor activity data were also continuously obtained by using an actigraph built into the device . Multilevel modeling analysis confirmed convergent associations by showing positive correlations among momentary symptoms . The increased intermittency of locomotor activity , characterized by a combination of reduced activity with occasional bursts , appeared concurrently with the worsening of depressive mood . Further , this association remained statistically unchanged across groups regardless of group differences in age , lifestyle , and occupation . These results indicate that the temporal variations in the momentary symptoms are not r and om but reflect the underlying changes in psychophysiological variables in daily life . In addition , our findings on the concurrent changes in depressive mood and locomotor activity may contribute to the continuous estimation of changes in depressive mood and early detection of depressive disorders BACKGROUND Variables that are thought to precipitate migraine or tension-type headache episodes in children hitherto have only been studied using retrospective reports . As such , there is little empirical evidence to support the actual predictive association between presumed headache triggers and actual headache occurrence in children . OBJECTIVE The present study sought to determine if fluctuations in weather , a commonly reported headache trigger in children , predict increased likelihood of headache occurrence when evaluated using rigorous prospect i ve methodology ( " electronic momentary assessment ") . METHODS Twenty-five children ( 21 girls , 4 boys ) between the ages of 8 - 17 years attending a new patient neurology clinic appointment and having a diagnosis of chronic migraine , chronic tension-type , or episodic migraine headache ( with or without aura ) participated in the study . Children completed baseline measures on headache characteristics , presumed headache triggers , and mood and subsequently were trained in the use of electronic diaries to record information on headaches . Children then completed thrice daily diaries on h and held computers for a 2-week time period ( 42 assessment s per child ) while data on weather variables ( temperature , dew point temperature , barometric pressure , humidity , precipitation , and sunlight ) in the child 's geographic location were recorded each time a diary was completed . Data were analyzed using multilevel models . RESULTS Of the weather variables , relative humidity and presence of precipitation were significantly predictive of new headache onset , with nearly a 3-fold increase in probability of headache occurrence during times of precipitation or elevated humidity in the child 's area , b = 0.38 , t(821 ) = 2.10 , P = .04 , and b = 0.02 , t(821 ) = 2.81 , P = .01 , respectively . These associations remained after accounting for fluctuations in mood , and associations were not significantly stronger in children who at baseline thought that weather was a headache trigger for them . Changes in temperature , dew point temperature , barometric pressure , and sunlight were not significantly predictive of new headache episode occurrence in this sample . CONCLUSIONS Results of the present study lend some support to the belief commonly held by children with recurrent headaches that weather changes may contribute to headache onset . Although electronic momentary assessment methodology was found to be feasible in this population and to have the potential to identify specific headache triggers for children , it remains to be determined how best ( or even whether ) to incorporate this information into treatment recommendations This study uses ecological momentary assessment ( EMA ) to simultaneously capture youths ' perceptions of peer affiliates and social context s to determine their association with youths ' current and future mood states . A sample of 82 seventh grade students ( 36 at risk for developing or escalating rule breaking and substance use and 46 r and omly selected ) from 4 schools participated . Using EMA methodology , we had students report their peer affiliations , perceptions of peer affiliates , moods , activities , location , and behaviors during their free time . Data from 3 assessment waves were collected ; each wave consisted of 27 r and omly prompted assessment s during a week . Youths spent a large portion of their free time watching television , on the computer , or playing video games . Being " out and about " increased over the school year , whereas adult supervision decreased , showing an increase in potentially risky situations . Happiness was associated with affiliating with peers who were perceived to be popular . Negative moods were associated with affiliating with peers by whom they were teased or treated meanly . Multilevel models found that both levels and lability of negative moods ( i.e. , sadness , anxiety ) were predicted by risk status and affiliation with peers who tease them . Compared with boys , girls who affiliated more with peers who teased them and were classified as at risk had more extreme negative moods and negative mood lability . EMA methodology has demonstrated the ways in which salient intrapersonal and peer processes are associated over time , which can inform efforts to prevent the development and escalation of behavior problems , substance use , and mood disorders in adolescence Paper diaries are commonly used in health care and clinical research to assess patient experiences . There is concern that patients do not comply with diary protocol s , possibly invalidating the benefit of diary data . Compliance with paper diaries was examined with a paper diary and with an electronic diary that incorporated compliance-enhancing features . Participants were chronic pain patients and they were assigned to use either a paper diary instrumented to track diary use or an electronic diary that time-stamped entries . Participants were instructed to make three pain entries per day at predetermined times for 21 consecutive days . Primary outcome measures were reported vs actual compliance with paper diaries and actual compliance with paper diaries ( defined by comparing the written times and the electronically-recorded times of diary use ) . Actual compliance was recorded by the electronic diary . Participants su bmi tted diary cards corresponding to 90 % of assigned times ( + /-15 min ) . However , electronic records indicated that actual compliance was only 11 % , indicating a high level of faked compliance . On 32 % of all study days the paper diary binder was not opened , yet reported compliance for these days exceeded 90 % . For the electronic diary , the actual compliance rate was 94 % . In summary , participants with chronic pain enrolled in a study for research were not compliant with paper diaries but were compliant with an electronic diary with enhanced compliance features . The findings call into question the use of paper diaries and suggest that electronic diaries with compliance-enhancing features are a more effective way of collecting diary information BACKGROUND Smartphone applications can potentially provide recovery monitoring and support in real-time , real-life context s. Study aims included determining feasibility of ( a ) adolescents completing ecological momentary assessment s ( EMAs ) and utilizing phone-based ecological momentary interventions ( EMIs ) ; and ( b ) using EMA and EMI data to predict substance use in the subsequent week . METHODS Twenty-nine adolescents were recruited at discharge from residential treatment , regardless of their discharge status or length of stay . During the 6-week pilot , youth were prompted to complete an EMA at 6 r and om times per day and were provided access to a suite of recovery support EMI . Youth completed 87 % of the 5580 EMAs . Based on use in the next 7 days , EMA observations were classified into 3 risk groups : " Current Use " in the past 30 minutes ( 3 % of observations ) , " Unrecognized Risk " ( 42 % ) , or " Recognized Risk " ( 55 % ) . All youth had observations in 2 or more risk groups and 38 % in all 3 . Youth accessed an EMI on average 162 times each week . RESULTS Participants were 31 % female , 48 % African American , 21 % Caucasian , 7 % Hispanic , and 24 % Mixed/Other ; average age was 16.6 years . During the 90 days prior to entering treatment , youth reported using alcohol ( 38 % ) , marijuana ( 41 % ) , and other drugs ( 7 % ) . When compared with the " Recognized Risk " group 's use in the following week ( 31 % ) , both the " Unrecognized Risk " ( 50 % , odds ratio [OR]=2.08 ) and " Current Use " ( 96 % , OR=50.30 ) groups reported significantly higher rates of use in the next week . When an EMI was accessed 2 or more times within the hour following an EMA , the rate of using during the next week was significantly lower than when EMIs were not accessed ( 32 % vs. 43 % , OR=0.62 ) . CONCLUSIONS Results demonstrate the feasibility of using smartphones for recovery monitoring and support with adolescents , with potential to reduce use INTRODUCTION Ecological momentary assessment s ( EMAs ) are increasingly used in smoking research to underst and context ual and individual differences related to smoking and changes in smoking . To date , there has been little detailed research into the predictors of EMA compliance . However , patterns or predictors of compliance may affect key relationships under investigation and introduce sources of bias in results . The purpose of this study was to investigate predictors of compliance to r and om prompts among a sample of adolescents who had ever smoked . METHODS Data for this study were drawn from a sample of 461 adolescents ( 9th and 10th grade rs at baseline ) participating in a longitudinal study of smoking escalation . We examined 2 outcomes : subject-level EMA compliance ( overall rate of compliance over a week-long EMA wave ) , and in-the-moment prompt-level compliance to the most proximal r and om prompt . We investigated several covariates including gender , race , smoking rate , alcohol use , psychological symptomatology , home composition , mood , social context , time in study , inter-prompt interval , and location . RESULTS At the overall subject level , higher mean negative affect , smoking rate , alcohol use , and male gender predicted lower compliance with r and om EMA prompts . At the prompt level , after controlling for significant subject-level predictors of compliance , increased positive affect , being outside of the home , and longer inter-prompt interval predicted lower momentary compliance . CONCLUSIONS This study identifies several factors associated with overall and momentary EMA compliance among a sample of adolescents participating in a longitudinal study of smoking . We also propose a conceptual framework for investigating the context ual and momentary predictors of compliance within EMA studies OBJECTIVE This study was design ed to examine context effects or provocation ecologies in the daily lives of children with ADHD . METHOD Across 7 days , mothers and children ( 27 children with attention-deficit/hyperactivity disorder [ ADHD ] taking stimulant medication ; 25 children without ADHD ; ages 7 - 12 years ) provided electronic diary reports every 30 + /- 5 minutes during non-school hours . Child and maternal perceptions of behaviors , moods , and interaction quality during preparatory and transitional ( " getting ready " ) activities were compared with those during other activities . RESULTS Maternal reports revealed that child symptomatic behaviors and negative moods , maternal negative moods , and parent-child disagreement were elevated in the ADHD but not in the comparison group while getting ready versus other activities . Children 's self-ratings also revealed situational effects , indicating that school-age children with ADHD can give meaningful self-reports using carefully structured electronic diaries . CONCLUSIONS Even when children with ADHD are receiving stimulant pharmacotherapy , the preparatory tasks of daily living are especially challenging and linked disproportionately to child behavior problems , parent negative affect , and contentious interactions . Treatment targeted on these transitional hurdles may improve child behavior patterns and enhance parent-child relationships and family harmony The risk of obesity during childhood can be significantly reduced through increased physical activity and decreased sedentary behavior . Recent technological advances have created opportunities for the real-time measurement of these behaviors . Mobile phones are ubiquitous and easy to use , and thus have the capacity to collect data from large numbers of people . The present study tested the feasibility , acceptability , and validity of an electronic ecological momentary assessment ( EMA ) protocol using electronic surveys administered on the display screen of mobile phones to assess children 's physical activity and sedentary behaviors . A total of 121 children ( ages 9 - 13 , 51 % male , 38 % at risk for overweight/overweight ) participated in EMA monitoring from Friday afternoon to Monday evening during children 's nonschool time , with 3 - 7 surveys/day . Items assessed current activity ( e.g. , watching TV/movies , playing video games , active play/sports/exercising ) . Children simultaneously wore an Actigraph GT2 M accelerometer . EMA survey responses were time-matched to total step counts and minutes of moderate-to-vigorous physical activity ( MVPA ) occurring in the 30 min before each EMA survey prompt . No significant differences between answered and unanswered EMA surveys were found for total steps or MVPA . Step counts and the likelihood of 5 + min of MVPA were significantly higher during EMA-reported physical activity ( active play/sports/exercising ) vs. sedentary behaviors ( reading/computer/homework , watching TV/movies , playing video games , riding in a car ) ( P < 0.001 ) . Findings generally support the acceptability and validity of a 4-day EMA protocol using mobile phones to measure physical activity and sedentary behavior in children during leisure time

RESULTS The data supported the current worldwide recommendation to use proton pump inhibitor (PPI)-based triple therapy with clarithromycin and either metronidazole or amoxycillin . There are , however , regional differences in success rates that are not completely explained by resistance to either metronidazole or amoxycillin . For second-line therapy , quadruple therapy using a PPI with bismuth , metronidazole and tetracycline ( PPI-BMT ) is superior to an alternative PPI-based triple therapy .

OBJECTIVE To perform a systematic review of the world literature to determine current success rates of Helicobacter pylori eradication treatment .

ABSTRACT Culture and susceptibility testing of Helicobacter pylori strains was performed in a large multinational , multicenter r and omized clinical trial . Culture was carried out on gastric biopsy sample s obtained from 516 patients at entry and had a sensitivity of 99 % when the [13C]urea breath test was used as a reference . Susceptibility testing was performed for clarithromycin and metronidazole on 485 strains by an agar dilution method and the epsilometer test ( Etest ) and for amoxicillin by an agar dilution method only . Resistance to clarithromycin ( > 1 μg/ml ) was found in 3 % of the H. pylori strains , with a perfect correlation between Etest and agar dilution methods . Resistance to metronidazole ( > 8 μl/ml ) was found in 27 % of the strains by agar dilution , but there were important discrepancies between it and the Etest method . No resistance to amoxicillin was found . The logarithms of the MICs of the three antibiotics against susceptible strains had a distribution close to normal . The impact of resistance was tested in the four arms of the trial . There were not enough clarithromycin-resistant strains to evaluate the impact of resistance on the cure rate of clarithromycin-based regimens . For metronidazole-resistant strains , the impact noted in the clarithromycin-metronidazole arm was partially overcome when omeprazole was added ( 76 % eradication for resistant strains versus 95 % for susceptible strains ) . Secondary resistance to clarithromycin occurred in strains from 12 of 105 patients ( 11.4 % ) after the failure of a clarithromycin-based regimen to effect eradication . The detection of point mutations in clarithromycin-resistant strains was performed by a combination of PCR and restriction fragment length polymorphism . Mutations ( A2142 G and 2143 G ) were found in all strains tested except one . This study stresses the importance of performing susceptibility tests in clinical trials in order to explain the results of different treatments BACKGROUND Helicobacter pylori eradication with omeprazole , amoxycillin , and metronidazole is both effective and inexpensive . However , eradication rates with different dosages and dosing vary , and data on the impact of resistance are sparse . In this study , three different dosages of omeprazole , amoxycillin , and metronidazole were compared , and the influence of metronidazole resistance on eradication was assessed . METHODS Patients ( n = 394 ) with a positive H. pylori screening test result and endoscopy-proven duodenal ulcer in the past were enrolled into a multicenter study performed in four European countries and Canada . After baseline endoscopy , patients were r and omly assigned to treatment for 1 week with either omeprazole , 20 mg twice daily , plus amoxycillin , 1,000 mg twice daily , plus metronidazole , 400 mg twice daily ( low M ) ; or omeprazole , 40 mg once daily , plus amoxycillin , 500 mg three times daily , plus metronidazole , 400 mg three times daily ( medium M ) ; or omeprazole , 20 mg twice daily , plus amoxycillin , 1,000 mg twice daily , plus metronidazole , 800 mg twice daily ( high M ) . H. pylori status at entry was assessed by a 13C urea breath test and a culture . Eradication was defined as two negative 13C-urea breath test results 4 and 8 weeks after therapy . Susceptibility testing using the agar dilution method was performed at entry and in patients with persistent infection after therapy . RESULTS The eradication rates , in terms of intention to treat ( ITT ) ( population n = 379 ) ( and 95 % confidence interval [ CI ] ) were as follows : low M 76 % ( 68 % , 84 % ) , medium M 76 % ( 68 % , 84 % ) , and high M 83 % ( 75 % , 89 % ) . By per- protocol analysis ( population n = 348 ) , the corresponding eradication rates were : low M 81 % , medium M 80 % , and high M 85 % . No H. pylori strains were found to be resistant to amoxycillin . Pre study resistance of H. pylori strains to metronidazole was found in 72 of 348 ( 21 % ) of the cultures at entry ( range , 10%-39 % in the five countries ) . The overall eradication rate in pre study metronidazole-susceptible strains was 232 of 266 ( 87 % ) and , for resistant strains , it was 41 of 70 ( 57 % ; p < .001 ) . Within each group , the results were as follows ( susceptible/resistant ) : low M , 85%/54 % ; medium M , 86%/50 % ; and high M , 90%/75 % . There were no statistically significant differences among the treatment groups . 23 strains susceptible to metronidazole before treatment were recultured after therapy failed ; 20 of these had now developed resistance . CONCLUSIONS H. pylori eradication rates were similar ( approximately 80 % ) with all three regimens . Metronidazole resistance reduced efficacy ; increasing the dose of metronidazole appeared not to overcome the problem or significantly improve the outcome . Treatment failure was generally associated with either pre study or acquired metronidazole resistance . These findings are of importance when attempting H. pylori eradication in communities with high levels of metronidazole resistance Objectives : Rabeprazole is a new fast acting proton pump inhibitor that has recently been proven to be effective in the treatment of peptic ulceration and reflux esophagitis . The aim of this study was to evaluate rabeprazole in combination with antibiotics for the eradication of Helicobacter pylori ( H. pylori ) in patients with chronic active gastritis with or without peptic ulcer disease . Methods : Seventy-five H. pylori-infected patients were r and omized in a double-blind fashion to receive a 7-day treatment regimen consisting of : RAC , RAM , RCM , or RC ( R = rabeprazole 20 mg b.d . , A = amoxycillin 1 g b.d . , C = clarithromycin 500 mg b.d . , M = metronidazole 400 mg b.d . ) . R and omized patients were H. pylori-positive by gastric biopsy urease test , histology and 13C urea breath test ( 13C-UBT ) . H. pylori eradication was assessed by 13C-UBT , 4 and 8 wk after finishing treatment . Endoscopy with histology and culture for antibiotic sensitivity testing was performed pretreatment and if treatment failed . Results : On an intention-to-treat analysis , treatment success was : RCM 100 % , RAC 95 % , RAM 90 % , and RC 63 % . The most common side effects were loose stools , headache , and taste disturbance , but there were no serious adverse events related to the study medication . The two patients failing RAM treatment had metronidazole-resistant strains before and after treatment . None of the pretreatment H. pylori isolates from six patients failing RC were clarithromycin resistant , but three of five successfully cultured posttreatment had developed clarithromycin resistance . Conclusion : Rabeprazole-based triple therapy with two antibiotics for 1 wk is safe and effective in eradicating H. pylori . Dual therapy with clarithromycin is less successful , and the majority of treatment failures develop clarithromycin resistance OBJECTIVES To treat previously untreated adult patients infected with Helicobacter pylori with one of two regimens in an ambulatory community setting to assess the efficacy and safety of these regimens . METHODS Sixty five adult patients with histologically confirmed H. pylori infection were r and omly assigned in this open cohort study to 2 wk , low dose , twice daily treatment with omeprazole 20 mg and clarithromycin 250 mg ( OC ) ( n = 31 ) or OC plus metronidazole 500 mg ( OCM ) ( n = 34 ) . At least 4 wk after treatment , H. pylori status was assessed by histology ( four gastric biopsies , two each from antrum and body ) . RESULTS Triple therapy with OCM was significantly better than dual therapy with OC in intent-to-treat ( 82.4 vs 58.1 % , p = 0.03 ) and per protocol analysis ( 93.3 vs 62.1 % , p = 0.004 ) . Although there were frequent side effects ( OC 19/31 61.3 % ; OCM 22/34 64.7 % with at least one side effect ) , these were generally mild , and patients were able to complete nearly all of their medications ( OC 97.2 % , OCM 96.7 % of pills taken ) . The only patient withdrawn due to medication side effects was in the OC arm . CONCLUSIONS Triple therapy with OCM in a community setting eradicates H. pylori more effectively than dual therapy with OC . OCM is tolerated with high compliance despite frequent minor side effects and appears safe without the development of serious adverse events OBJECTIVES Triple therapy and amoxycillin plus omeprazole are the two most widely recommended regimens for the eradication of Helicobacter pylori . However , no controlled studies with a large number of cases are available for the reliable comparison of these two regimens . The aim of this controlled , r and omized , prospect i ve study was to compare the effect of these two regimens and a further regimen for metronidazole-resistant patients on duodenal ulcer healing , H. pylori eradication , and prevention of ulcer relapse . METHODS Patients ( n = 144 ) with proven duodenal ulcer ( DU ) were r and omized to one of the three following regimens : group A , omeprazole ( 2 x 40 mg ) plus amoxycillin ( 4 x 500 mg ) for 2 wk ; group B , triple therapy : bismuth nitrate ( 4 x 375 mg ) plus metronidazole ( 4 x 250 mg ) and tetracycline ( 4 x 500 mg ) daily for 2 wk and ranitidine ( 150 mg ) for the first week and bismuth nitrate ( 4 x 375 mg ) alone for a further 2 wk ; group C , omeprazole ( 20 mg ) plus amoxycillin ( 4 x 500 mg ) and tinidazole ( 2 x 500 mg ) for 2 wk . RESULTS A total of 46 patients in group A , 39 in group B , and 43 in group C completed the study . One patient in group A and three in group B did not tolerate the regimens and dropped out of the study . Control endoscopy was performed 8 wk after the start of treatment and when symptoms appeared ( up to 1 yr after the start of treatment ) . In subjects who completed the study , both the healing rate of DU in group B ( 97 % compared with 74 and 73 % in A and C , respectively , p < 0.02 ) and the H. pylori eradication rate in group B ( 85 compared with 35 % , p < 0.0001 in A and 58 % , p < 0.02 , in C ) were significantly higher than in groups A and C. The symptomatic ulcer relapse during the 1-yr follow-up in patients with initially healed ulcers was similar in all groups ( 18 , 16 , and 19 % in A , B , and C , respectively ) . The predictor of healing using logistic regression analysis was night pain ( p < 0.05 ) . The predictor of H. pylori eradication was sex ( p < 0.05 ) . CONCLUSION The 2-wk triple therapy plus an additional 2-wk treatment with the bismuth derivative ( without a prolonged administration of acid suppressing drugs ) seems to be an effective and economic treatment not only for the eradication of H. pylori but also for the healing of acute DU . The higher incidence of side effects found after triple therapy compared with the other two regimens was tolerated by the patients : In Asian countries with limited re sources , clarithromycin‐based triple therapy may not be readily available . There are also few direct comparisons of different regimens in Asia OBJECTIVES Our objectives were to determine the effect of dual therapy with omeprazole and amoxicillin and of triple therapy with omeprazole , amoxicillin , and metronidazole in the eradication of Helicobacter pylori ( HP ) and to study the long-term results of eradication in these patients . METHODS A prospect i ve , r and omized , controlled trial was performed . Patients who were recruited had unequivocal evidence of HP infection based on culture , histology , rapid urease test , and Gram 's stain of a tissue smear . Eradication was defined as the absence of bacteria in all tests performed on both corpus and antral biopsies . RESULTS The infection was eradicated in 15 of 19 ( 78.9 % ) patients r and omized to receive dual therapy and in 19 of 22 ( 86.4 % ) patients who received triple therapy . We followed the course of 30 patients in whom HP had been eradicated for a prolonged term ( up to 12 months ) . All remained clear of HP . Twenty-five of 28 patients ( 89.3 % ) with duodenal ulcers in whom HP was successfully eradicated remained healed at 12 months . Fewer side effects were reported among patients who received the dual therapy . CONCLUSIONS Combination therapy with omeprazole and amoxicillin with or without metronidazole is effective in the eradication of HP . In particular , the dual therapy regimen with amoxicillin is not only effective but is also well tolerated by patients The aim of our study is to evaluate the efficacy and tolerability of four different therapeutic regimens for Helicobacter pylori eradication . One-hundred and thirty-two consecutive patients suffering from either peptic ulcer or non-ulcer dyspepsia , with Helicobacter pylori infection , were allocated to one of the following 4 groups with different therapeutic regimens : A ) omeprazole 20 mg bid for 14 days/amoxycillin 1000 mg bid for 14 days/tinidazole 500 mg bid for 14 days ( 30 patients , 13 with peptic ulcer ) ; B ) omeprazole 20 mg bid for 14 days/amoxycillin 1000 mg bid for 14 days ( 41 patients , 23 with peptic ulcer ) ; C ) omeprazole 20 mg bid for 14 days/azithromycin 500 mg/day for 3 days for 2 consecutive weeks ( 25 patients , 12 with peptic ulcer ) ; D ) omeprazole 20 mg/day for 7 days/clarithromycin 250 mg bid for 7 days/tinidazole 500 mg bid for 7 days/ ( 36 patients , 14 with peptic ulcer ) . The Helicobacter pylori status was evaluated by means of histology , culture and urease test , at entry and 8 weeks after treatment . 2 group A , B and D patients , 1 D patient did n't complete the treatment . In evaluable patients , the Helicobacter pylori eradication was obtained in 24 patients of group A ( 85.71 % ) , in 24 of group B ( 58.98 % ) , in 11 of group C ( 45.83 % ) and in 24 of group D ( 70.58 % ) . On intention-to-treat analysis , Helicobacter pylori eradication was 80 % in group A , 56.09 % in group B , 44 % in group D and 66.67 % in group D. Sideeffects occurred in 6 patients of group A ( 20.68 % ) , in 5 of group B ( 12.5 % ) , in 3 group D ( 8.82 % ) and none of group C. In conclusion , triple therapy with omeprazole/clarithro-mycin/tinidazole is better for cost/benefit ratio ; omeprazole/amoxycillin/tinidazole is more effective than others regimens in the Helicobacter pylori eradication , but causes more side effects ; double therapy with omeprazole/azithromycin is the most tolerable and the least efficacy for Helicobacter pylori eradication BACKGROUND A previous study showed that 14 days of qid bismuth-based triple therapy with tetracycline 500 mg , metronidazole 250 mg and colloidal bismuth subcitrate 120 mg result ed in excellent Helicobacter pylori eradication rates ( 89.5 % ) . The present study looked at a shorter treatment period by adding omeprazole and by reducing the dose of tetracycline . METHODS One hundred sixty-one patients with H pylori confirmed by histology and (13)carbon urea breath test were included in the study . They were treated for seven days with bismuth subcitrate 120 mg plus metronidazole 250 mg plus tetracycline 250 mg qid plus omeprazole 20 mg bid ( OBMT ) . Patients were 18 to 75 years of age and had dyspepsia with or without a history of peptic ulcer . Patients with irritable bowel syndrome , active ulcer or previous attempt at eradication , or those who had used antibiotics or antiulcer drugs in the previous 30 days were excluded . Eradication was determined by two (13)carbon urea breath tests done one and three months , respectively , after treatment . Strains with minimal inhibitory concentrations of 8 microg/mL or higher were considered to be resistant to metronidazole . RESULTS The overall per protocol eradication rate was 84%-89.5 % in metronidazole-sensitive and 70.8 % in metronidazole-resistant strains . Modified intent-to-treat analysis result ed in a 80 % eradication rate--82.5 % in metronidazole-sensitive and 66.7 % in metronidazole-resistant strains . Only one patient discontinued treatment because of adverse events . CONCLUSIONS The OBMT regimen used in this study is safe and effective against metronidazole-sensitive H pylori strains BACKGROUND & AIMS The role of omeprazole in triple therapy and the impact of Helicobacter pylori resistance on treatment outcome are not established . This study investigated the role of omeprazole and influence of primary H. pylori resistance on eradication and development of secondary resistance . METHODS Patients ( n = 539 ) with a history of duodenal ulcer and a positive H. pylori screening test result were r and omized into 4 groups . OAC group received 20 mg omeprazole , 1000 mg amoxicillin , and 500 mg clarithromycin ; OMC group received 20 mg omeprazole , 400 mg metronidazole , and 250 mg clarithromycin ; and AC ( amoxicillin , 1000 mg , and clarithromycin , 500 mg ) and MC ( metronidazole , 400 mg , and clarithromycin , 250 mg ) groups received no omeprazole . All doses were administered twice daily for 1 week . H. pylori status was assessed before and after therapy by 13C-urea breath test . Susceptibility testing was performed at entry and in patients with persistent infection after therapy . RESULTS Eradication ( intention to treat [ n = 514]/per protocol [ n = 449 ] ) was 94%/95 % for OAC , 26%/25 % for AC ( P < 0.001 ) , 87%/91 % for OMC , and 69%/72 % for MC ( P < 0.001 ) . Primary resistance was 27 % for metronidazole , 3 % for clarithromycin , and 0 % for amoxicillin . Eradication in primary metronidazole-susceptible/-resistant strains was 95%/76 % for OMC and 86%/43 % for MC . Secondary metronidazole and clarithromycin resistance each developed in 12 patients : 8 treated with omeprazole and 16 without omeprazole . CONCLUSIONS Addition of omeprazole achieves high eradication rates , reduces the impact of primary resistance , and may decrease the risk of secondary resistance compared with regimens containing only two antibiotics Studies assessing the efficacy of triple therapy containing clarithromycin and amoxicillin for the eradication of Helicobacter pylori infection and healing of duodenal ulcers in Asian and African countries are limited Sixty patients with Helicobacter Pylori positive non ulcer dyspepsia were r and omly allocated to one of the following treatment groups : Group I -- norfloxacin 400 mg bid for 10 days , Group II -- amoxycillin 500 mg bid plus tinidazole 500 mg bid for 15 days , Group III -- colloidal bismuth subcitrate ( CBS ) 240 mg bid for 4 weeks . H pylori elimination was achieved in 14 % , 81 % , and 62 % in Groups I , II and III respectively . Eradication of H pylori was not observed in Groups I and II , but was achieved in 25 % of patients in Group III . Antral gastritis improved in 69 % in Group II and 50 % in Group III . We conclude that norfloxacin is not effective in H pylori infection . A combination of amoxycillin and tinidazole is highly effective in H pylori elimination with improvement in associated gastritis , but H pylori eradication is not observed with this therapy . CBS is also effective in H pylori elimination though H pylori eradication is achieved in only 25 % A combination of amoxycillin and omeprazole is often used to treat Helicobacter pylori infection . A three-drug regimen comprising metronidazole , amoxycillin and omeprazole has been proposed as an alternative therapy . In a prospect i ve , r and omized , comparative study , we evaluated these two regimens with respect to safety and efficacy in patients with H. pylori infection . Sixty patients with peptic ulcer ( gastric , 32 patients ; duodenal , 28 patients ) who had a history of ulcer recurrence were r and omly assigned to dual therapy with amoxycillin ( 500 mg three times daily for 2 weeks ) and omeprazole ( 20 mg once daily for 8 weeks ) or to triple therapy with metronidazole ( 500 mg twice daily for 2 weeks ) plus amoxycillin and omeprazole , given in the same dosages as dual therapy . Forty-eight patients completed the protocol ; treatment was discontinued because of side effects in nine patients , and three patients dropped out of the study . On the basis of all patients treated , the rate of H. pylori eradication was significantly higher for triple therapy 20/23 cases , 87.0 % ; 95 % confidence interval ( CI ) , 0.664 - 0.972 ) than for dual therapy 13/25 , 52.0 % ; 0.313 - 0.722 ; P < 0.05 ) . On an intention-to-treat basis , the difference between the groups in the rate of H. pylori eradication was marginally significant ( P = 0.06 [ 0.028 - 0.512 ] ) . Side effects were reported by five patients receiving triple therapy ( skin rash , one ; nausea , two ; headache , one ; abdominal pain , one ) , and four patients receiving dual therapy ( skin rash , two ; abdominal pain , one ; diarrhoea , one ) . All side effects resolved spontaneously after termination of treatment . There was no significant difference in safety between the two regimens . Triple therapy with metronidazole , amoxycillin , and omeprazole was significantly more effective for the eradication of H. pylori than dual therapy with amoxycillin and omeprazole alone . The safety of these regimens was similar , and triple therapy was found to be clinical ly acceptable Background : Specific data on anti‐H. pylori treatments in elderly people are very scarce . The aim of the study was to evaluate in the elderly the efficacy of different anti‐H. pylori therapies and the behaviour of serum anti‐H. pylori antibodies , pepsinogen A and C , and PGA/PGC ratio induced by the anti‐H. pylori treatment

There is moderate evidence that ( 1 ) tailored ( customised to the patient to control lateral tilt , glide and spin ) and untailored patellar taping provides immediate pain reduction of large and small effect , respectively and ( 2 ) tailored patellar taping promotes earlier onset of vastus medialis oblique ( VMO ) contraction ( relative to vastus lateralis contraction ) . There is limited evidence that ( 1 ) tailored patellar taping combined with exercise provides superior pain reduction compared to exercise alone at 4 weeks , ( 2 ) untailored patellar taping added to exercise at 3 - 12 months has no benefit and ( 3 ) tailored patellar taping promotes increased internal knee extension moments . CONCLUSIONS Tailoring patellar taping application ( ie , to control lateral tilt , glide and spin ) to optimise pain reduction is important for efficacy . Possible mechanisms behind patellar taping efficacy include earlier VMO onset and improved knee function capacity ( ie , ability to tolerate greater internal knee extension moments )

OBJECTIVE Patellar taping is frequently used to treat patellofemoral pain ( PFP ) . This systematic review and meta- analysis ( 1 ) evaluates the efficacy of patellar taping for patients with PFP , ( 2 ) compares the efficacy of various taping techniques and ( 3 ) identifies potential biomechanical mechanisms of action .

OBJECTIVE To investigate the efficacy of patellar taping on pain control , patellar alignment , and neuromuscular control ( ie , vastus medialis oblique activation , knee extensor moment , etc ) in subjects with patellofemoral pain syndrome . DATA SOURCES We search ed MEDLINE , SPORT Discus , PEDro , and CINAHL through December 2004 , using the key words patellar taping , therapeutic taping , McConnell taping , taping , chronic injury , patellofemoral pain , and knee . STUDY SELECTION Criteria for inclusion criteria were studies that exclusively recruited patients diagnosed with patellofemoral pain syndrome or anterior knee pain and outcome measures specific to pain reduction , neuromuscular control , and patellar positioning . DATA EXTRACTION We identified and review ed 16 studies with an average PEDro score of 4.25/10 . Articles were divided into 3 categories based on primary outcome measures : 4 r and omized controlled trials on treatment methods and pain , 9 studies on neuromuscular control , and 3 on patellar positioning . DATA SYNTHESIS Although patellar taping seems to reduce pain and improve function in people with patellofemoral pain syndrome during activities of daily living and rehabilitation exercise , strong evidence to identify the underlying mechanisms is still not available BACKGROUND AND PURPOSE Quadriceps strengthening , quadriceps stretching and patellar taping are commonly prescribed together for patellofemoral pain patients . This study aim ed to examine the effectiveness of each of these techniques in isolation for one week and in combination for one week . METHODS A prospect i ve double-blind r and omized control study was design ed involving 41 subjects with 60 knees diagnosed with patellofemoral pain . The knees were r and omized in onto one of four groups ( n = 15 ) : infrapatellar taping , quadriceps strengthening , quadriceps stretching and control . The taping was worn continually for the week ; the strengthening group followed a programme of non-weight-bearing terminal range quadriceps exercises , the stretching group performed rectus femoris stretches . The control group did not receive treatment . All subjects received advice . Seven pre- and post-treatment measures included isokinetic quadriceps strength , quadriceps length , pain measured during four activities and maximum eccentric , posturally controlled , pain-free knee flexion angle during a step-down . Results showed significant changes over time ( p < 0.01 ) in two out of seven measures for the taping group , in five out of seven for the strengthening group and five out of seven for the stretching group and none in the control group . When the three modalities were combined for one week , ( n = 60 ) all seven measures improved significantly ( p < 0.01 ) . CONCLUSION In isolation , quadriceps stretching and quadriceps strengthening result ed in more improvements than taping . Combining these treatments is recommended as the initial approach to treating patellofemoral pain but further individualized more functional , global treatment is essential Abstract Although patellar taping has been shown to reduce pain in participants with patellofemoral pain syndrome , the mechanisms of pain reduction have not completely been established following its application . The purpose of this study was to evaluate EMG activity of vastus medialis and vastus lateralis following the application of patellar taping during a functional single leg squat . Both vastus medialis obliquus – vastus lateralis onset and vastus medialis obliquus/vastus lateralis amplitude of 18 participants with patellofemoral pain syndrome and 18 healthy participants as controls were measured using an EMG unit . This procedure was performed on the affected knee of participants with patellofemoral pain syndrome , before , during , and after patellar taping during unilateral squatting . The same procedure was also performed on the unaffected knees of both groups . The mean values of vastus medialis obliquus – vastus lateralis onset prior to taping ( 2.54 ms , s = 4.35 ) were decreased significantly following an immediate application of tape ( −3.22 ms , s = 3.45 ) and after a prolonged period of taping ( −6.00 ms , s = 3.40 s ) ( P < 0.05 ) . There was also a significant difference between the mean values of vastus medialis obliquus – vastus lateralis onset among controls ( −2.03 ms , s = 6.04 ) and participants with patellofemoral pain syndrome prior to taping ( P < 0.05 ) . However , there were no significant difference between the ranked values of vastus medialis obliquus/vastus lateralis amplitude of the affected and unaffected knees of participants with patellofemoral pain syndrome and controls during different conditions of taping ( P > 0.05 ) . Decreased values of vastus medialis obliquus – vastus lateralis onset may contribute to patellar realignment and explain the mechanism of pain reduction following patellar taping in participants with patellofemoral pain syndrome Background Since knee complaints are common among athletes and are frequently presented in general practice , it is of interest to investigate the type of knee complaints represented in general practice of athletes in comparison with those of non-athletes . Therefore , the aim of this study is to investigate the differences in type of knee complaints between sport participants , in this study defined as athletes , and non-sport participants , defined as non-athletes , presenting in general practice . Further , differences in the initial policy of the GP , medical consumption , and outcome at one-year follow-up were also investigated . Methods Patients consulting their GP for a new episode of knee complaints were invited to participate in this prospect i ve cohort study . From the total HONEUR knee cohort population ( n = 1068 ) we extracted patients who were athletes ( n = 421 ) or non-athletes ( n = 388 ) . Results The results showed that acute distortions of the knee were significantly more diagnosed in athletes than in non-athletes ( p = 0.04 ) . Further , more athletes were advised by their GP to ' go easy on the knee ' than the non-athletes ( p < 0.01 ) , but no differences were found in number of referrals and medication prescribed by the GP . The medical consumption was significantly higher among athletes ; however , no significant differences were found between the two groups for recovery at one-year follow-up . Conclusion There are no major differences in the diagnosis and prognosis of knee complaints between athletes and non-athletes presented to the GP . This implies that there are no indications for different treatment strategies applied in both groups . However , athletes are more often advised to ' go easy on the knee ' and to rest than non-athletes . Further , there is a trend towards increased medical consumption among athletes while functional disability and pain are lower than among the non-athletes OBJECTIVE The purpose of this prospect i ve , r and omized , controlled study was to determine the effects of kinesio taping in the treatment of patients with patellofemoral pain syndrome ( PFPS ) . METHODS Thirty-one women with PFPS ( mean age : 44.88 years ; range : 17 to 50 years ) were r and omly assigned to either a kinesio taping ( KT ) ( n=15 ) or control ( n=16 ) group . Both groups received the same muscle strengthening and soft tissue stretching exercises for six weeks and the KT group additionally received kinesio taping at four day intervals for six weeks . Visual analog scale was used to measure pain intensity . Tension of the iliotibial b and /tensor fascia lata and hamstring muscles and the mediolateral location of the patella were measured before the treatment and at the end of the third and sixth week . The Anterior Knee Pain Scale / Kujala Scale was used for the analysis of functional performance . RESULTS Comparing pretreatment and 6th week values , significant improvements were found in pain , soft tissue flexibility and functional performance of both groups ( p<0.05 ) . However , patellar shift was unchanged ( p>0.05 ) . The KT group had significantly better hamstring flexibility than the control group at the end of three weeks ( p<0.05 ) . CONCLUSION The addition of kinesio taping to the conventional exercise program does not improve the results in patients with PFPS , other than a faster improvement in hamstring muscle flexibility The aim of this study was to assess the effect of patellar taping of the proprioceptive status of patients with patellofemoral pain syndrome ( PFPS ) . A total of 32 subjects ( 18 males , 14 females of age 31.9 + /- 11.2 , body mass index 25.8 + /- 5.3 ) with PFPS were tested for Joint Position Sense ( JPS ) using a Biodex dynamometer . Outcomes of interest were the absolute error ( AE ) , the variable error ( VE ) and the relative error ( RE ) of the JPS values for both active ( AAR ) and passive ( PAR ) angle reproduction at an angular velocity of 2 degrees /s with a start angle at 90 degrees and target angles of 60 degrees and 20 degrees . Taping was applied in r and om order across the patella of each subject with each of the subjects acting as their own internal control . Results indicated initially that application of patellar tape did not enhance and in some cases worsened the JPS of the subjects ( P > 0.05 ) . However , when the subjects ' proprioceptive status was grade d according to their closeness to the target angles into ' good ' ( 5 degrees , N = 10 ) and ' poor ' ( > 5 degrees , N = 22 ) taping enhanced nearly all values of those with ' poor ' proprioception , with AE at 20 degrees to statistical significance ( P = 0.021 ) . In conclusion , this study has shown that patellar taping did not improve the AAR and PAR JPS tests of a whole sample of 32 PFPS patients . It also has shown that a subgroup of PFPS patients with poor proprioception may exist and be helped by patellar taping STUDY DESIGN A r and omized controlled trial . OBJECTIVES To investigate the effectiveness of daily patella taping and exercise on pain and function in individuals with patellofemoral pain syndrome . BACKGROUND Patella taping and muscle-strengthening programs are commonly used to treat patellofemoral pain syndrome . There is , however , little evidence for the effectiveness of these approaches . METHODS AND MEASURES Twenty-four men and 6 women aged 17 to 25 years ( mean + /- SD , 18.7 + /- 1.2 years ) participated in the study . Subjects were r and omly and exclusively assigned to 1 of 3 treatment groups : patella taping combined with a st and ardized exercise program , placebo patella taping and exercise program , or exercise program alone ( n = 10 in each group ) . Taping was applied and exercises performed on a daily basis for 4 weeks . Outcome measures were visual analog scales for pain and the functional index question naire , recorded at weekly intervals by a therapist who was blinded to group allocation . RESULTS Separate mixed-model ANOVAs , with repeated measures on time , indicated statistically significant improvements in pain and function over time for all groups ( P<.01 ) and also significant differences between groups for all measures ( P<.01 ) . Separate independent sample s t tests showed that the group receiving taping and exercises had better pain and function scores following treatment than the placebo taping- and -exercise group and the exercise-alone group . There were no significant differences between the placebo taping- and -exercise group and exercise-alone group at any time point . CONCLUSIONS These findings indicate that over a period of 4 weeks a combination of daily patella taping and exercises was successful in improving pain and function in individuals with patellofemoral pain syndrome . The combination of patella taping and exercise was superior to the use of exercise alone Objective : To examine the immediate effects of experimentally induced anterior knee pain ( AKP ) on involuntary and voluntary quadriceps strength and activation . Design : Crossover 3 × 3 r and omized controlled laboratory study with repeated measures . Setting : Human Performance Research Center , Brigham Young University . Participants : Thirteen neurologically sound volunteers ( age , 21.9 ± 3.2 years ) . Interventions : Subjects underwent 3 different conditions ( pain , sham , and control ) . To induce AKP and sham condition , 5 % sodium chloride and 0.9 % sodium chloride ( total volume of 1.0 mL for each condition ) , respectively , were injected into the infrapatellar fat pad on the dominant leg . No injection was performed for the control condition . Main Outcome Measures : The vastus medialis peak Hoffmann reflex normalized by the peak motor response ( H : M ratio ) was used to measure involuntary quadriceps activation . Quadriceps central activation ratio ( CAR ) using maximal isometric knee extension torque ( N·m ) was calculated to assess voluntary quadriceps activation . The visual analog scale was used to measure pain perception . Results : Our pain model increased perceived pain immediately after the 5 % hypertonic saline injection and pain lasted for 12 minutes on average ( F40,743 = 16.85 , P < 0.001 ) . During the pain condition , subjects showed a 12 % decrease in H : M ratio ( F2,59 = 8.64 , P < 0.001 ) , a 34 % decrease in maximal isometric knee extension torque ( F2,59 = 5.89 , P < 0.01 ) , and a 5 % decrease in CAR ( F2,59 = 3.83 , P = 0.03 ) . Conclusions : Our data showed that joint pain may be an independent factor to alter function of the muscles surrounding the painful joint . Both involuntary and voluntary inhibitory pathways may play a role in an immediate reduction of muscle activation STUDY DESIGN A multicenter , single-masked study of patients with patellofemoral pain syndrome ( PFPS ) using a repeated- measures design . OBJECTIVE To compare 3 different methods of patellar taping for individuals with PFPS . BACKGROUND Patellar taping is commonly used as a treatment for PFPS . It is commonly thought that taping works by medially realigning the patella . However , comparisons have been rarely made with other methods of taping which attempt to realign the patella in different directions . METHODS AND MEASURES Seventy-one patients with PFPS ( 39 men , 32 women ; average age + /- SD , 34 + /- 10 years ) from 3 different treatment centers were tested . Each patient performed 4 single step-downs from a st and ard 8-inch ( 20.3-cm ) platform , initially with the patella untaped and then with the patella taped in a medial , neutral , and lateral direction . Pain was recorded on a st and ard 11-point numerical pain rating scale . The sequence of taping was r and omly allocated and patients were masked to the method used . The methods of taping were compared using repeated- measures generalized linear model analysis . RESULTS All methods of taping significantly decreased pain when compared to the untaped condition ( P<.0001 ) . Neutral- and lateral-glide techniques produced a significantly greater degree of pain relief ( P<.0001 ) than the medial-glide technique . CONCLUSION In this study , patellar taping produced an immediate decrease in pain in patients with PFPS , irrespective of how taping was applied . These data raise questions as to the mechanism of action of patellar taping . Furthermore , these results suggest that it is unlikely that taping works by altering patellar position Background Patellar taping is widely used clinical ly to treat patients with patellofemoral pain syndrome ( PFPS ) . Although patellar taping has been demonstrated to reduce patellofemoral pain in patients with PFPS , the kinematic source for this pain reduction has not been identified . Objective The purpose of this study was to quantify the changes in the 6-degrees-of-freedom patellofemoral kinematics due to taping in patients with PFPS . Design A within-subject design and a sample of convenience were used . Participants Fourteen volunteers ( 19 knees ) who were diagnosed with patellofemoral pain that was present for a year or longer were included . Each knee had to meet at least 1 of the following inclusion criteria : Q-angle of ≥15 degrees , a positive apprehension test , patellar lateral hypermobility ( ≥10 mm ) , or a positive “ J sign . ” Methods Each knee underwent 2 r and omly ordered testing conditions ( untaped and taped ) . A full fast-phase contrast ( PC ) magnetic resonance image set was acquired for each condition while the participants volitionally extended and flexed their knee . Three-dimensional displacements and rotations were calculated through integration of the fast-PC velocity data . Statistical comparisons between baseline patellofemoral kinematics and the change in kinematics due to taping were performed using a 2-tailed paired Student t test . Correlations between baseline patellofemoral kinematics and the change in kinematics due to taping also were quantified . Results Patellar taping result ed in a significant patellofemoral inferior shift . The strongest correlation existed between the change in lateral-medial displacement with taping and baseline ( r=−.60 ) . Conclusions The inferior shift in patellar displacement with taping partially explains the previously documented decrease in pain due to increases in contact area . The lack of alteration in 5 of the 6 kinematic variables with taping may have been due to the fact that post-taping kinematic alterations are sensitive to the baseline kinematic values PURPOSE To investigate the effect of physical therapy treatment on the timing of electromyographic ( EMG ) activity of the vasti in individuals with patellofemoral pain syndrome ( PFPS ) . METHODS Sixty-five ( 42 female , 23 male ) participants aged 40 yr or less ( 29.2 + /- 7.8 yr ) diagnosed with PFPS . Participants were r and omly allocated into physical therapy treatment ( McConnell-based ) or placebo groups . Treatment programs were st and ardized and consisted of six-treatment sessions over 6 wk . Vastus medialis oblique ( VMO ) and vastus lateralis ( VL ) EMG activity was recorded with surface electrodes during a stair-stepping task and onsets of EMG activity were measured pre- and post-treatment . RESULTS Before treatment , the EMG onset of VL occurred before that of VMO in both participant groups . After physical therapy intervention , there was a reduction in symptoms , and this improvement was associated with a significant change in the time of onset of VMO EMG compared with that of VL in both phases of the stair-stepping task . After physical therapy treatment , the onset of VMO preceded VL in the eccentric phase and occurred at the same time in the concentric phase of the stair-stepping task . There was no change in time of EMG onset in the placebo group . CONCLUSION This study demonstrates that a " McConnell"-based physical therapy treatment regime for PFPS alters the motor control of VMO relative to VL in a functional task and this is associated with a positive clinical outcome Objectives : To investigate the effect of patellar taping on the amplitude of electromyographic activity ( EMG ) of vasti activation in subjects with and without patellofemoral pain ( PFP ) . Methods : Ten participants with PFP and 12 asymptomatic controls were recruited to the study . The study was design ed as a r and omised crossover trial . Participants completed a stair stepping task . Three experimental conditions were assessed : no tape , therapeutic medially directed tape , and placebo vertically directed tape . The main outcome measure was the EMG amplitude of the vastus medialis obliquus and vastus lateralis during the concentric phase of stair stepping . Results : The application of medially directed therapeutic tape significantly decreased pain in subjects with PFP . However , application of tape over the patella ( therapeutic or placebo ) did not alter the amplitude of vasti EMG when either the PFP or control participants completed the concentric stair stepping task . Conclusion : The results of this study indicate that the positive clinical effects of medially directed therapeutic tape are not due to changes in EMG amplitude of the vasti muscle . Thus other effects such as changes in timing of contraction of the vasti are more likely c and i date s for the mechanism of efficacy 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 . OBJECTIVE To determine the efficacy of the individual components of physiotherapy in subjects with anterior knee pain . METHODS An observer blind , prospect i ve , factorial design r and omised controlled trial . 81 young adults with anterior knee pain were r and omly allocated to one of four treatment groups : ( 1 ) exercise , taping , and education ; ( 2 ) exercise and education ; ( 3 ) taping and education ; and ( 4 ) education alone . Each group received six physiotherapist-led treatments over three months . Follow up took place at three months using the following outcome measures : patient satisfaction ( discharge/refer for further treatment ) ; a visual analogue pain score ; the WOMAC lower limb function score ; the Hospital Anxiety and Depression scale ( HAD ) ; and quadriceps strength . At 12 months the WOMAC and HAD were assessed by postal question naire . RESULTS All groups showed significant improvements in WOMAC , visual analogue , and HAD scores ; these improvements did not vary significantly between the four groups or between exercising/non-exercising and taped/non-taped patients at three and 12 months . However , patients who exercised were significantly more likely to be discharged at three months than non-exercising patients ( χ2 , p<0.001 ) . Taping was not significantly associated with discharge . Significantly greater improvements in WOMAC , visual analogue , and the anxiety score ( but not the depression score ) were seen in patients who were discharged than in those who were referred . CONCLUSIONS The proprioceptive muscle stretching and strengthening aspects of physiotherapy have a beneficial effect at three months sufficient to permit discharge from physiotherapy . These benefits are maintained at one year . Taping does not influence the outcome Background Although physical therapy forms the mainstay of nonoperative management for patellofemoral pain , its efficacy has not been established . Hypothesis Significantly more pain relief will be achieved from a 6-week regimen of physical therapy than from placebo treatment . Study Design Multicenter , r and omized , double-blinded , placebo-controlled trial . Methods Seventy-one subjects , 40 years of age or younger with patellofemoral pain of 1 month or longer , were r and omly allocated to a physical therapy or placebo group . A st and ardized treatment program consisted of six treatment sessions , once weekly . Physical therapy included quadriceps muscle retraining , patellofemoral joint mobilization , and patellar taping , and daily home exercises . The placebo treatment consisted of sham ultrasound , light application of a nontherapeutic gel , and placebo taping . Results Sixty-seven participants completed the trial . The physical therapy group ( N = 33 ) demonstrated significantly greater reduction in the scores for average pain , worst pain , and disability than did the placebo group ( N = 34 ) . Conclusions A six-treatment , 6-week physical therapy regimen is efficacious for alleviation of patellofemoral pain Background Delayed onset of vastus medialis obliquus activity has been described in patellofemoral pain patients . No prospect i ve study investigating the development of patellofemoral pain has tested the onset timing of electromyographic activity of the vastus medialis obliquus and vastus lateralis muscles during a functional task . Hypothesis Before the development of patellofemoral pain , subjects demonstrate an altered firing order of the vastus medialis obliquus and vastus lateralis muscles compared with healthy subjects during a functional task . Study Design Cohort study ; Level of evidence , 2 . Methods The onset of vastus medialis obliquus and vastus lateralis activity was measured with surface electromyography during a functional task ( rocking back on the heels ) in 79 healthy subjects subsequently su bmi tted to a 6-week strenuous basic military training . Afterward , these subjects were reassessed . Results Thirty-two percent of the recruits developed patellofemoral pain during training . Patellofemoral pain subjects demonstrated a significant delay of onset of vastus medialis obliquus electromyographic activity compared with the healthy controls ( P = .023 ) , even before basic military training . In healthy subjects , no significant differences in electromyographic activity onset of the vastus medialis obliquus compared with the vastus lateralis could be identified before and after basic military training . A significant ( P < .001 ) delay could be demonstrated in the patellofemoral pain group after basic military training . A binary logistic regression could be constructed wherein the onset of the electromyographic activity of the vastus medialis obliquus and vastus lateralis was withheld in the model . The most optimal cutoff value , which is based on the receiver operating characteristic curve , is a timing difference of −0.67 milliseconds ( vastus medialis obliquus – vastus lateralis ) . The area under the receiver operating characteristic curve is considered as fair ( 0.68 ) . Conclusion Delayed onset of electromyographic activity of the vastus medialis obliquus – vastus lateralis is one of the contributing risk factors to the development of patellofemoral pain Objective : To investigate the effects of patellar taping on the electromyographic onset of vastus medialis obliquus and vastus lateralis , and their magnitudes of reflex contraction before and after quadriceps muscle fatigue in subjects with patellofemoral pain . Methods : Sixteen adults ( 5 males ) diagnosed with patellofemoral pain were studied . The timing of surface electromyography onset and magnitude of vastus medialis obliquus and vastus lateralis contractions were measured during a postero-anterior knee perturbation test . The tests were conducted in r and om order under three conditions of real taping , placebo taping and no taping . Afterwards , the subjects performed knee extension exercises until fatigue and the above tests were repeated , so as to examine the effects of patellar taping in a muscle fatigued condition . Results : There was no significant difference in electromyographic onset timing of vastus medialis obliquus and vastus lateralis or in the amplitude of vastus lateralis contraction among the different testing conditions . For vastus medialis obliquus amplitude , however , it was significantly higher in the no taping than the real taping condition regardless of the state of fatigue ( P = 0.013 ) . Conclusions : The present study suggests that patellar taping might not enhance the temporal activation of vastus medialis obliquus in subjects with patellofemoral pain before and after muscle fatigue . Furthermore , vastus medialis obliquus contraction might be inhibited by patellar taping Objective To examine the effect of the application of tape over the patella on the onset of electromyographic ( EMG ) activity of vastus medialis obliquus ( VMO ) relative to vastus lateralis ( VL ) in participants with and without patellofemoral pain syndrome ( PFPS ) . Design R and omised within subject . Setting sUniversity laboratory . Participants Ten participants with PFPS and 12 asymptomatic controls . Interventions Three experimental taping conditions : no tape , therapeutic tape , and placebo tape . Main Outcome Measures Electromyographic onset of VMO and VL assessed during the concentric and eccentric phases of a stair stepping task . Results When participants with PFPS completed the stair stepping task , the application of therapeutic patellar tape was found to alter the temporal characteristics of VMO and VL activation , whereas placebo tape had no effect . In contrast , there was no change in the EMG onset of VMO and VL with the application of placebo or therapeutic tape to the knee in the asymptomatic participants . Conclusions These data support the use of patellar taping as an adjunct to rehabilitation in people with PFPS Objective : To examine the immediate effects of patellar taping on pain and relative activity of vastus medialis obliquus to vastus lateralis in subjects with patellofemoral pain and patellofemoral joint malalignment . Design : Pre- and post-treatment design , with order of testing determined r and omly . Setting : Outpatient physiotherapy department . Subjects : Fifteen subjects with patellofemoral joint pain and malalignment . Interventions : With and without patellar taping with a st and ard force of application . Main outcome measures : Pain and surface EMG activity ratio of vastus medialis obliquus to vastus lateralis during single-legged semi-squat with 20 % of extra body weight loading . Results : There was a significant decrease in anterior knee pain ( p < 0.001 ) and vastus medialis obliquus to vastus lateralis activity ratio ( p = 0.05 ) during single-legged st and ing after patellar taping . Conclusions : Patellar taping can reduce pain in people with patellofemoral pain syndrome and patellofemoral malalignment but it decreases the relative activity of vastus medialis obliquus to vastus lateralis . Such a decrease in relative activity of vastus medialis obliquus after taping implies that it may not be suitable to combine patellar taping with vastus medialis obliquus facilitative exercise training BACKGROUND Patellofemoral pain syndrome is one of the most common knee problems and may be related to abnormal patellar tracking . Our purpose was to compare , in vivo and noninvasively , the patellar tracking patterns in symptomatic patients with patellofemoral pain and those in healthy subjects during squatting . We tested the hypothesis that patients with patellofemoral pain exhibit characteristic patterns of patellar tracking that are different from those of healthy subjects . METHODS Three-dimensional patellar kinematics were recorded in vivo with use of a custom-molded patellar clamp and an optoelectronic motion capture system in ten healthy subjects and nine subjects with patellofemoral pain . The position of osseous knee l and marks was digitized while subjects stood upright , and then patellofemoral kinematics were recorded during squatting . The tracking technique was vali date d with use of both in vitro and in vivo method ologies , and the average absolute error was < 1.2 degrees and < 1.1 mm . RESULTS At 90 degrees of knee flexion , the patella showed lateral spin ( the distal pole of the patella rotated laterally ) in subjects with patellofemoral pain ( mean and st and ard deviation , -10.13 degrees + /- 2.24 degrees ) and medial spin in healthy subjects ( mean , 4.71 degrees + /- 1.17 degrees ) ( p < 0.001 ) . At 90 degrees of knee flexion , the patella demonstrated significantly more lateral translation in subjects with patellofemoral pain ( mean , 5.05 + /- 3.73 mm ) than in healthy subjects ( mean , -4.93 + /- 3.93 mm ) ( p < 0.001 ) . CONCLUSIONS Kinematic differences between healthy subjects and subjects with patellofemoral pain were demonstrated through a large , dynamic range of knee flexion angles . Increased lateral patellar translation and lateral patellar spin in subjects with patellofemoral pain suggest that the patella is not adequately balanced during functional activities in this group . Prospect i ve studies are needed to identify when patellofemoral pain-related changes begin to occur and to determine the risk for the development of patellofemoral pain in individuals with abnormal kinematics Background Patellar taping is a common treatment modality for physical therapists managing patellofemoral pain . However , the mechanisms of action remain unclear , with much debate as to whether its efficacy is due to a change in patellar alignment or an alteration in sensory input . Objective The purpose of this study was to investigate the sensory input hypothesis using functional magnetic resonance imaging when taping was applied to the knee joint during a proprioception task . Design This was an observational study with patellar taping intervention . Methods Eight male volunteers who were healthy and right-leg dominant participated in a motor block design study . Each participant performed 2 right knee extension repetitive movement tasks : one simple and one proprioceptive . These tasks were performed with and without patellar taping and were auditorally paced for 400 seconds at 72 beats/min ( 1.2 Hz ) . Results The proprioception task without patellar taping caused a positive blood oxygenation level – dependant ( BOLD ) response bilaterally in the medial supplementary motor area , the cingulate motor area , the basal ganglion , and the thalamus and medial primary sensory motor cortex . For the proprioception task with patellar taping , there was a decreased BOLD response in these regions . In the lateral primary sensory cortex , there was a negative BOLD response with less activity for the proprioception task with taping . Limitations This study may have been limited by the small sample size , a possible learning effect due to a nonr and om order of tasks , and use of a single-joint knee extension task . Conclusions This study demonstrated that patellar taping modulates brain activity in several areas of the brain during a proprioception knee movement task OBJECTIVE Musculoskeletal conditions of the knee involve changes in sensorimotor function , but it is unclear whether these changes are a cause or result of pain . Induction of experimental pain may help solve this issue . Although this is commonly achieved by injection of hypertonic saline into muscle , muscle is commonly not the source of pain . This study investigated whether pain induced by injection of saline into the infrapatellar fat pad changes motor control of the quadriceps muscles of the knee . METHODS Ten participants performed a st and ardized task involving ascending and descending a series of steps . Electromyographic activity ( EMG ) of vastus medialis obliquus ( VMO ) and vastus lateralis ( VL ) was recorded with surface electrodes . Trials were conducted without pain , with anterior knee pain induced by injection ( 0.25 ml ) of hypertonic saline ( 5 % ) into the infrapatellar fat pad , with anticipation of pain associated with unpredictable electrical shocks to the knee , and 20 minutes after pain cessation . EMG onset and amplitude were analyzed . RESULTS When participants ascended the steps with pain , the onset of VMO EMG was delayed relative to that of VL , in contrast to simultaneous or earlier activation of VMO EMG in the pre- and postpain trials . VL EMG amplitude was decreased significantly from the control condition . CONCLUSION These data show that alterations in coordination of knee muscle activity can be caused by pain , even when it is of nonmuscle origin . Treatment of pain is therefore important to facilitate performance of the quadriceps muscles , which are essential for locomotor and functional tasks as well as for knee stability

Compared to usual care , no negative effects on patient quality of life , knowledge and satisfaction were reported . Discussion Few rigorous studies evaluated the use of shared medical appointments for chronic illnesses . Overall , there appears to be no patient harms .

Objectives Shared medical appointments are group appointments , with an optional individual consultation , for patients diagnosed with chronic illnesses . Shared medical appointments improve diabetes management , but little is known about their use for other illnesses . The objective was to determine the effect that shared medical appointments have on patients with a physical chronic illness , healthcare providers , and the healthcare system .

Abstract Objective : To compare the effect of individual educational visits versus group visits using academic detailing to discuss prescribing of highly anticholinergic antidepressants in elderly people . Design : R and omised controlled trial with three arms ( individual visits , group visits , and a control arm ) . Setting : Southwest Netherl and s. Participants : 190 general practitioners and 37 pharmacists organised in 21 peer review groups were studied using a data base covering all prescriptions to people covered by national health insurance in the area ( about 240 000 ) . Intervention : All general practitioners and pharmacists in both intervention arms were offered two educational visits . For physicians in groups r and omised to the individual visit arm , 43 of 70 general practitioners participated ; in the group visit intervention arm , five of seven groups ( 41 of 52 general practitioners ) participated . Main outcome measures : Numbers of elderly people ( 60 years ) with new prescriptions of highly anticholinergic antidepressants and less anticholinergic antidepressants . Results : An intention to treat analysis found a 26 % reduction in the rate of starting highly anticholinergic antidepressants in elderly people ( 95 % confidence interval —4 % to 48 % ) in the individual intervention arm and 45 % ( 8 % to 67 % ) in the group intervention arm . The use of less anticholinergic antidepressants increased by 40 % ( 6 % to 83 % ) in the individual intervention arm and 29 % ( —7 % to 79 % ) in the group intervention arm . Conclusions : Both the individual and the group visits decreased the use of highly anticholinergic antidepressants and increased the use of less anticholinergic antidepressant in elderly people . These approaches are practical means to improve prescribing by continuing medical education Background —This trial tested the effects of multidisciplinary group clinic appointments on the primary outcome of time to first heart failure ( HF ) rehospitalization or death . Methods and Results —HF patients ( n=198 ) were r and omly assigned to st and ard care or st and ard care plus multidisciplinary group clinics . The group intervention consisted of 4 weekly clinic appointments and 1 booster clinic at month 6 , where multidisciplinary professionals engaged patients in HF self-management skills . Data were collected prospect ively for 12 months beginning after completion of the first 4 group clinic appointments ( 2 months post r and omization ) . The intervention was associated with greater adherence to recommended vasodilators ( P=0.04 ) . The primary outcome ( first HF-related hospitalization or death ) was experienced by 22 ( 24 % ) in the intervention group and 30 ( 28 % ) in st and ard care . The total HF-related hospitalizations , including repeat hospitalizations after the first time , were 28 in the intervention group and 45 among those receiving st and ard care . The effects of treatment on rehospitalization varied significantly over time . From 2 to 7 months post r and omization , there was a significantly longer hospitalization-free time in the intervention group ( Cox proportional hazard ratio=0.45 ( 95 % confidence interval , 0.21–0.98 ; P=0.04 ) . No significant difference between groups was found from month 8 to 12 ( hazard ratio=1.7 ; 95 % confidence interval , 0.7–4.1 ) . Conclusions —Multidisciplinary group clinic appointments were associated with greater adherence to selected HF medications and longer hospitalization-free survival during the time that the intervention was underway . Larger studies will be needed to confirm the benefits seen in this trial and identify methods to sustain these benefits . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00439842 Background : Over the past decade , group medical visits have become more prevalent . Group medical visits may have some advantages in treating chronic illnesses such as chronic pain as they can be more patient centered . The empowerment model is a novel approach used to provide support , education , and healthy activities guided by participants . Objective : To evaluate the early stages of a chronic pain group medical visit program based on the empowerment model . Methods : This prospect i ve cohort study recruited 60 female participants to participate between October 2004 and May 2005 . All enrolled participants completed the SF-36 question naire , which was administered at baseline and again after 6 months of participation . Data from chart review included age , race , weight , height , chronic illness , chronic pain diagnosis , and degree of participation . Chronic pain diagnoses included back pain , osteoarthritis , fibromyalgia , rheumatoid/inflammatory arthritis , and other/unknown . Results : Forty-two participants were enrolled in the program for 6 months . Their average Charleson Comorbidity Index score was 3.1 ( SD=1.5 ) . Statistically significant changes ( P<.05 ) were seen in the following SF-36 categories : Role-Physical , Bodily Pain , General Health , Social Function , and Mental Health . All factors trended toward improvement , with the largest improvements seen in Role-Physical and Role-Emotional . Conclusion : Participants in the chronic pain group medical visit program had a high degree of comorbidity and poor health related quality of life in regards to functioning . There was improvement in many domains of health-related quality of life Purpose Group medical consultations ( GMCs ) provide individual medical visits conducted within a group of four to eight peer patients . This study evaluated the feasibility and efficacy of GMCs in the follow-up of breast cancer . Methods In this r and omized controlled trial , 38 patients participated in a single GMC ( intervention group ) , while the control group ( n = 31 ) received individual outpatient visits . Feasibility is measured in terms of acceptability , dem and , practicability and costs , integration and implementation , and efficacy . Between-group differences on the efficacy outcomes distress ( SCL-90 ) and empowerment ( CEQ ) , 1 week and 3 months after the visit , were analyzed using ANCOVAs . Results GMCs scored high on most areas of feasibility . Patients in GMCs and individual visits were equally satisfied . Patients and professionals reported more discussed themes in GMCs , despite no between-group differences on information needs prior to the visit . Sixty-nine percent of GMC patients experienced peer support . Costs for GMCs were higher compared to individual visits . However , involving a clinical nurse specialist ( CNS ) instead of a medical specialist reduced costs to the level of individual CNS care . Efficacy outcomes ( distress and empowerment ) were equal in both groups . Conclusion GMCs in this study were feasible . Further optimization of GMCs in future (cost-)effectiveness trials is possible by increasing the frequency of GMCs , stating criteria for the type of professionals , number of patients involved , and time limits . Implication s for Cancer SurvivorsBCS may benefit from GMCs by receiving more information and additional peer support . GMCs cover all aspects of follow-up and may be a good alternative for individual follow-up Background : Group patient visits are medical appointments shared among patients with a common medical condition . This care delivery method has demonstrated benefits for individuals with chronic conditions but has not been evaluated for Parkinson disease ( PD ) . Methods : We conducted a 12-month , r and omized trial of group patient visits vs usual ( one-on-one ) care for patients with PD . Visits were led by one of 3 study physicians , included patients and caregivers , and lasted approximately 90 minutes . Those receiving group visits had 4 sessions over 12 months . The primary outcome measure was feasibility as measured by the ability to recruit participants and by the proportion of participants who completed the study . The primary efficacy outcome was quality of life as measured by the PD Question naire-39 . Results : Thirty patients and 27 caregivers enrolled in the study . Thirteen of the 15 patients r and omized to group patient visits and 14 of the 15 r and omized to usual care completed the study . Quality of life measured 12 months after baseline between the 2 groups was not different ( 25.9 points for group patient visits vs 26.0 points for usual care ; p = 0.99 ) . Conclusions : Group patient visits may be a feasible means of providing care to individuals with PD and may offer an alternative or complementary method of care delivery for some patients and physicians . Classification of evidence : This study provides Class II evidence that group patient visits did not improve quality of life for individuals with PD over a 1-year period CONTEXT Emergency department utilization by chronically ill older adults may be an important sentinel event signifying a breakdown in care coordination . A primary care group visit ( i.e. , several patients meeting together with the provider at the same time ) may reduce fragmentation of care and subsequent emergency department utilization . OBJECTIVE To determine whether primary care group visits reduce emergency department utilization in chronically ill older adults . DESIGN R and omized trial conducted over a 2-year period . SETTING Group-model HMO in Denver , Colorado . PATIENTS 295 older adults ( > or = 60 years of age ) with frequent utilization of outpatient services and one or more chronic illnesses . INTERVENTION Monthly group visits ( generally 8 to 12 patients ) with a primary care physician , nurse , and pharmacist held in 19 physician practice s. Visits emphasized self-management of chronic illness , peer support , and regular contact with the primary care team . MEASURES Emergency department visits , hospitalizations , and primary care visits . RESULTS On average , patients in the intervention group attended 10.6 group visits during the 2-year study period . These patients averaged fewer emergency department visits ( 0.65 vs. 1.08 visits ; P = 0.005 ) and were less likely to have any emergency department visits ( 34.9 % vs. 52.4 % ; P = 0.003 ) than controls . These differences remained statistically significant after controlling for demographic factors , comorbid conditions , functional status , and prior utilization . Adjusted mean difference in visits was -0.42 visits ( 95 % CI , -0.13 to -0.72 ) , and adjusted RR for any emergency department visit was 0.64 ( CI , 0.44 to 0.86 ) . CONCLUSION Monthly group visits reduce emergency department utilization for chronically ill older adults Background : Primary care providers ( PCPs ) in safety net setting s face barriers to optimizing care for patients with diabetes . We conducted this study to assess PCPs ' perspectives on the effectiveness of two language -concordant diabetes self-management support programs . Methods : One year postintervention , we surveyed PCPs whose patients with diabetes participated in a three-arm multiclinic r and omized controlled trial comparing usual care ( UC ) , weekly automated telephone self-management ( ATSM ) support with nurse care management , and monthly group medical visits ( GMVs ) . We compared PCP perspectives on patient activation to create and achieve goals , quality of care , and barriers to care using regression models accounting for within-PCP clustering . Results : Of 113 eligible PCPs caring for 330 enrolled patients , 87 PCPs ( 77 % ) responded to surveys about 245 ( 74 % ) enrolled patients . Intervention patients were more likely to be perceived by PCPs as activated to create and achieve goals for chronic care when compared with UC patients ( st and ardized effect size , ATSM vs UC , + 0.41 , p = 0.01 ; GMV vs UC , + 0.31 , p = 0.05 ) . Primary care providers rated quality of care as higher for patients exposed to ATSM compared to UC ( odds ratio 3.6 , p < 0.01 ) . Compared with GMV patients , ATSM patients were more likely to be perceived by PCPs as overcoming barriers related to limited English proficiency ( 82 % ATSM vs 44 % GMV , p = 0.01 ) and managing medications ( 80 % ATSM vs 53 % GMV , p = 0.01 ) . Conclusions : Primary care providers perceived that patients receiving ATSM support had overcome barriers , participated more actively , and received higher quality diabetes care . These views of clinician stakeholders lend additional evidence for the potential to upscale ATSM more broadly to support PCPs in their care of diverse , multi-linguistic population Objective : To assess whether shared medical appointments ( SMAs ) for neuromuscular patients represent a way of using clinicians ' time efficiently without compromising quality of care for patients . Methods : Patients with a chronic neuromuscular disease ( NMD ) ( n = 272 ) were r and omly allocated to either an SMA or a regular individual annual appointment and followed up for a period of 6 months . Data on re source utilization and quality of life ( EQ-5D ) were collected prospect ively , using a health care perspective . Incremental costs and changes in quality -adjusted life-years ( QALYs ) were computed using a probabilistic decision model . Factors critical to the incremental cost-effectiveness of SMAs were explored in sensitivity analyses . Results : No substantial differences between SMAs and individual visits in terms of costs per QALY were found ( incremental cost-effectiveness ratio € −960.00 ; 95 % confidence interval € −34,600.00 , € + 36,800.00 ) . Sensitivity analyses showed that the cost-effectiveness ratio was particularly sensitive to SMA group size and proportion of patients seeing their treating neurologist . Conclusions : Cost-effectiveness of SMAs did not show a significant difference vs that of individual appointments based on data from our r and omized controlled trial . On the other h and , we were able to show that a minimum of 6 patients per SMA and 75 % of patients attending their treating neurologist are specific conditions under which SMAs qualify as a cost-effective alternative . This implies that SMAs may be a means to increase productivity of the physician without compromising quality of care . Classification of evidence : This study provides Class III evidence that SMAs are not significantly more cost-effective than individual appointments for patients with NMDs . The study lacks the precision to exclude important differences in cost-effectiveness between SMAs and individual appointments Failed patient appointments in ambulatory care may result in decreased revenues . The purpose of this study was to determine if patient reminders would affect the “ no-show ” rate of a medical ambulatory care setting . Patients of 10 physicians participated in a 6-week study . Patients were r and omly assigned to one of three groups : 2 weeks of appointment reminder postcards , 2 weeks of appointment reminder phone calls , and 2 weeks of no intervention . Chi-square analysis revealed significant differences between the control group and the two groups receiving interventions . Patient reminders may be a mechanism to decrease the no-show rate in ambulatory care OBJECTIVES To compare the effectiveness of Cooperative Health Care Clinic ( ( CHCC ) group outpatient model for chronically ill , older health maintenance organization ( HMO ) patients ) with usual care . DESIGN Two-year , r and omized , controlled trial conducted with recruitment from February 1995 through July of 1996 . SETTING Nonprofit group model HMO . PARTICIPANTS Two hundred ninety-four adults ( 145 intervention and 149 usual care ) , aged 60 and older ( mean age 74.1 ) with 11 or more outpatient visits in the prior 18 months , one or more self-reported chronic conditions , and expressed interest in participating in a group clinic . INTERVENTION Monthly group meetings held by patients ' primary care physicians . MEASUREMENT Differences in clinic visits , inpatient admissions , emergency room visits , hospital outpatient services , professional services , home health , and skilled nursing facility admissions ; measures of patient satisfaction , quality of life , self-efficacy , and activities of daily living ( ADLs ) . RESULTS Outpatient , pharmacy services , home health , and skilled nursing facility use did not differ between groups , but CHCC patients had fewer hospital admissions ( P=.012 ) , emergency visits ( P=.008 ) , and professional services ( P=.005 ) . CHCC patients ' costs were $ 41.80 per member per month less than those of control patients . CHCC patients reported higher satisfaction with their primary care physician ( P=.022 ) , better quality of life ( P=.002 ) , and greater self-efficacy ( P=.03 ) . Health status and ADLs did not differ between groups . CONCLUSION The CHCC model result ed in fewer hospitalizations and emergency visits , increased patient satisfaction , and self-efficacy , but no effect on outpatient use , health , or functional status ABSTRACT Heart failure continues to be the leading cause of hospitalization among older adults . Noncompliance with medications , dietary indiscretion , failure to recognize symptoms , and failed social support systems contribute to increased morbidity . Multidisciplinary medical approaches have proven successful for heart failure . In 2004 , the Naval Medical Center San Diego started a multidisciplinary shared medical appointment for patients with complicated cases of heart failure . Patients enrolled in the heart failure clinic were monitored prospect ively for 6 months . Vali date d question naires concerning satisfaction with care , self-care management , depression , and quality -of-life measures were administered at baseline and 6 months after enrollment . Thirty-nine individuals were enrolled in the clinic , with 33 completing 6 months of follow-up monitoring to date . Hospital admissions for any cause decreased from 11 to eight , whereas congestive heart failure-related admissions decreased from four to two . There was a total of six deaths . During the 6 months of enrollment , use of angiotensin-converting enzyme inhibitors and beta-receptor blockers had absolute increases of 20 % and 19 % , respectively . Statistically significant improvements were seen in the Beck Depression Inventory and Self-Care Management Index results . A multidisciplinary approach to heart failure patients using the shared medical appointment model can improve patient satisfaction , enhance quality of life , and help reduce hospitalizations while improving provider efficiency Background BRCA mutation carriers have a 40 - 80 % life-time risk of developing breast cancer . They may opt for yearly breast cancer surveillance or for prophylactic mastectomy . Both options show increased survival rates . It is a complex choice to be made between these two options . As a result most women experience high levels of distress and high needs for information . To fulfill the needs for psychosocial support and information we have introduced group medical consultations ( GMCs ) . A GMC provides individual medical visits conducted within a group . This 90 minute group-visit with 8 - 12 patients gives patients the opportunity to spend more time with their clinician and a behavioral health professional and learn from other patients experiencing similar topics . However , it should be noted that group sessions may increase fear in some patients or influence their decision making . Methods / design In this r and omized controlled trial , 160 BRCA mutation carriers diagnosed maximally 2 years ago are recruited from the Radboud University Nijmegen Medical Centre . Participants are r and omized in a 1:1 ratio to either the GMC intervention group ( onetime participation in a GMC instead of a st and ard individual visit ) or to a usual care control group . Primary outcome measures are empowerment and psychological distress ( SCL 90 ) . Secondary outcome measures are fear of cancer , information needs before the consultation and the received information , self-examination of the breasts , patient satisfaction , quality of life and cost-effectiveness . Data are collected via self-reported question naires 1 week before the visit , and at 1 week and at 3 months follow-up . A pilot study was conducted to test all procedures and question naires . Discussion The possibility for interaction with other BRCA mutation carriers within a medical visit is unique . This study will assess the effectiveness of GMCs for BRCA mutation carriers to improve empowerment and decrease distress compared to individual visits . If GMCs prove to be effective and efficient , implementation of GMCs in regular care for BRCA mutation carriers will be recommended . Trial registration The study is registered at Clinical Trials.gov ( NCT01329068 Asthma education decreases the number of emergency visits in specific subgroups of patients with asthma . However , it remains unknown whether this improvement is related only to the use of an action plan alone or to other components of the educational intervention . A total of 126 patients consulting urgently for an acute asthma exacerbation were recruited ; 98 completed the study . The first 45 patients were assigned to Group C ( control ; usual treatment ) . Thereafter , patients were r and omized to either Group LE ( limited education ; teaching of the inhaler technique plus self- action plan given by the on call physician ) or Group SE ( same as group LE plus a structured educational program emphasizing self-capacity to manage asthma exacerbations ) . At baseline , there was no difference between groups in asthma morbidity , medication needs , or pulmonary function . After 12 mo , only Group SE showed a significant improvement in knowledge , willingness to adjust medications , quality of life scores , and peak expiratory flows . In the last 6 mo , the number of unscheduled medical visits for asthma was significantly lower in Group SE in comparison with groups C and LE ( p = 0.03 ) . The number ( % ) of patients with unscheduled medical visits also decreased significantly in Group SE compared with Groups C and LE ( p = 0.02 ) . We conclude that a structured educational intervention emphasizing self-management improves patient outcomes significantly more than a limited intervention or conventional treatment Summary To determine whether a process re design could improve detection and treatment of osteoporosis , at-risk women over the age of 65 were identified using an electronic medical record and proactively contacted by letter and phone call . This result ed in a significant increase in testing for osteoporosis by DXA scan . The high-risk patients were then offered a shared medical appointment , which result ed in improved treatment outcomes compared to usual care . Introduction Our objective was to determine if re design ing care through proactive contact with women 65 at-risk of osteoporosis increased BMD testing and to determine if a shared medical appointment ( SMA ) improved treatment for high-risk women . Methods Two primary care sites received the re design intervention and two other sites served as the usual care controls . At the intervention sites , all women 65 who had not had a DXA scan performed in the prior 2 years were contacted by mail and phone calls . High-risk patients were invited to attend a SMA or follow-up visit with their primary physician . Results A significantly higher proportion of women at the intervention sites had a DXA ( 39.6 % vs. 13.2 % , p < 0.0001 ) . Patients who attended the SMA were more likely to have calcium and vitamin D recommended , a vitamin D level checked , and receive a prescription medicine than those patients who had follow-up with their primary care physician . Conclusions The re design ed process was highly effective in improving BMD testing for women 65 . The SMA was shown to be a more effective method to make calcium and vitamin D recommendations , to evaluate secondary causes of low bone density , and to prescribe prescription medications , compared to usual care with the PCP OBJECTIVE Patients with heart failure need education and support to improve knowledge and self-care . Shared medical groups that provide education and support have been successful in other patient population s. This study compares an advanced practice nurse-led shared medical appointment intervention in the office setting with st and ard care relative to self-care and knowledge among community-living adults with heart failure . METHODS Participants were r and omized to shared appointment and st and ard care groups , and completed the Heart Failure Knowledge Test and Self-Care Heart Failure Index at baseline and 8 weeks . RESULTS From baseline to 8 weeks , Heart Failure Knowledge Test scores improved more for the intervention group than the control group ( F time X group = 4.90 , df = 1.21 ; P = .038 ) . There was no difference in groups ' rates of change on the total Self-Care Heart Failure Index . CONCLUSION The findings reveal improved knowledge when education and support are provided in a shared medical appointment setting . The shared medical visit model may be feasible as a way to provide patients with heart failure and their families with ongoing education and a supportive environment This two-group , repeated- measures experimental study assessed the efficacy of a nurse practitioner-facilitated chronic kidney disease ( CKD ) group visit ( GV ) model versus usual nephrology care for patients with Stage 4 CKD . The study enrolled patients from two sites of an outpatient nephrology practice ( n = 30 ) and r and omized subjects to usual care ( n = 14 ) or to the GV model ( n = 16 ) . Data regarding CKD knowledge , self-efficacy/disease self-management , and physiologic measures were collected at baseline , 6 months , and 9 months . Satisfaction was obtained at 6 months and 9 months . Usual nephrology office visit components were maintained during six monthly GVs , with group discussion s of CKD-related topies . Results indicated a statistical improvement in CKD knowledge for both groups ( F[1.498 , 34.446 ] = 6.363 , p = 0.008 ) . An upward trend in mean scores for self-management subscales and self-efficacy scores was demonstrated in the GV patients , with no improvement found in the usual care group . Twenty-six of 30 patients completed the study , with 92 % attendance in the GV group . GV satisfaction was high Background : The Self-management and Care of Heart Failure through Group Clinics Trial evaluated the effects of multidisciplinary group clinic appointments on self-care skills and rehospitalizations in high-risk heart failure ( HF ) patients . Objective : The purpose of this article is to ( 1 ) describe key Self-management and Care of Heart Failure through Group Clinics Trial group clinic interactive learning strategies , ( 2 ) describe re sources and material s used in the group clinic appointment , and ( 3 ) present results supporting this patient-centered group intervention . Methods : This clinical trial included 198 HF patients ( r and omized to either group clinical appointments or to st and ard care ) . Data were collected from 72 group clinic appointments via patients ’ ( 1 ) group clinic session evaluations , ( 2 ) HF self-care behaviors skills , ( 3 ) HF-related discouragement and quality of life scores , and ( 4 ) HF-related reshopitalizations during the 12-month follow-up . Also , the costs of delivery of the group clinical appointments were tabulated . Results : Overall , patients rated group appointments as 4.8 of 5 on the “ helpfulness ” in managing HF score . The statistical model showed a 33 % decrease in the rate of rehospitalizations ( incidence rate ratio , 0.67 ) associated with the intervention over the 12-month follow-up period when compared with control patients ( & khgr;21 = 3.9 , P = .04 ) . The total cost for implementing 5 group appointments was $ 243.58 per patient . Conclusion : The intervention was associated with improvements in HF self-care knowledge and home care behavior skills and managing their for HF care . In turn , better self-care was associated with reductions in HF-related hospitalizations OBJECTIVE Short postpartum stays are common . Current guidelines provide scant guidance on how routine follow-up of newly discharged mother-infant pairs should be performed . We aim ed to compare 2 short-term ( within 72 hours of discharge ) follow-up strategies for low-risk mother-infant pairs with postpartum length of stay ( LOS ) of < 48 hours : home visits by a nurse and hospital-based follow-up anchored in group visits . METHODS We used a r and omized clinical trial design with intention-to-treat analysis in an integrated managed care setting that serves a largely middle class population . Mother-infant pairs that met LOS and risk criteria were r and omized to the control arm ( hospital-based follow-up ) or to the intervention arm ( home nurse visit ) . Clinical utilization and costs were studied using computerized data bases and chart review . Breastfeeding continuation , maternal depressive symptoms , and maternal satisfaction were assessed by means of telephone interviews at 2 weeks postpartum . RESULTS During a 17-month period in 1998 to 1999 , we enrolled and r and omized 1014 mother-infant pairs ( 506 to the control group and 508 to the intervention group ) . There were no significant differences between the study groups with respect to maternal age , race , education , household income , parity , previous breastfeeding experience , early initiation of prenatal care , or postpartum LOS . There were no differences with respect to neonatal LOS or Apgar scores . In the control group , 264 mother-infant pairs had an individual visit only , 157 had a group visit only , 64 had both a group and an individual visit , 4 had a home health and a hospital-based follow-up , 13 had no follow-up within 72 hours , and 4 were lost to follow-up . With respect to outcomes within 2 weeks after discharge , there were no significant differences in newborn or maternal hospitalizations or urgent care visits , breastfeeding discontinuation , maternal depressive symptoms , or a combined clinical outcome measure indicating whether a mother-infant pair had any of the above outcomes . However , mothers in the home visit group were more likely than those in the control group to rate multiple aspects of their care as excellent or very good . These included the preventive advice delivered ( 76 % vs 59 % ) and the skills and abilities of the provider ( 84 % vs 73 % ) . Mothers in the home visit group also gave higher ratings on overall satisfaction with the newborn 's posthospital care ( 71 % vs 59 % ) , as well as with their own posthospital care ( 63 % vs 55 % ) . The estimated cost of a postpartum home visit to the mother and the newborn was $ 265 . In contrast , the cost of the hospital-based group visit was $ 22 per mother-infant pair ; the cost of an individual 15-minute visit with a registered nurse was $ 52 ; the cost of a 15-minute individual pediatrician visit was $ 92 ; and the cost of a 10-minute visit with an obstetrician was $ 92 . CONCLUSIONS For low-risk mothers and newborns in an integrated managed care organization , home visits compared with hospital-based follow-up and group visits were more costly but achieved comparable clinical outcomes and were associated with higher maternal satisfaction . Neither strategy is associated with significantly greater success at increasing continuation of breastfeeding . This study had limited power to identify group differences in rehospitalization and may not be generalizable to higher-risk population s without comparable access to integrated hospital and outpatient care Background The prevalence of diabetes mellitus is ubiquitous . Complications and costs of diabetes are rising and are depleting limited re sources . It is imperative for healthcare professionals and patients alike to confront this chronic condition by exploring new interventions . An innovative health care delivery model has emerged in the last 25 years in the form of the group medical visit . Group medical visits can range from of six to twenty patients scheduled together with time allotted for individual care as well as in the group setting . Objectives The review objective was to conduct a systematic review and meta‐ analysis to synthesize the best available evidence related to effectiveness of group medical visits on HbA1c , blood pressure and cholesterol measurements /levels for adult patients with type II diabetes in outpatient setting s. Search strategy A three‐step literature search for studies in English language from 1990 to 2010 was conducted utilising ( a ) a primary search of Medline , CINAHL , PsycINFO and Cochrane Central Register of Controlled Trials , ( b ) a secondary search of non‐indexed data bases , and ( c ) a search of the grey literature . In addition , a manual review of the reference lists of all identified reports and articles was performed to identify additional studies . Inclusion criteria All r and omised and quasi‐experimental studies of adult patients ( > 18 ) with type II diabetes mellitus seen in outpatient health setting s were considered if they met one or more of the following diagnostic outcome measurements : haemoglobin A1c , systolic and diastolic blood pressure , and low density lipoprotein cholesterol . Critical appraisal , data collection and analysis Each of the eligible articles was review ed by two independent review ers . Disagreements between the review ers were resolved through discussion , or with a third review er . Studies that met the inclusion criteria were assessed for method ological quality using the JBI st and ardized critical appraisal tools . Data extraction was undertaken using the st and ardised data extraction tool from JBI‐MAStARI . Main results The search strategy identified 2,040 articles in the published and unpublished literature . Of these , 11 r and omised controlled trials and 4 quasi‐experimental trials met the inclusion criteria and represented 2240 patients included in the final review . There are clear benefits of group medical visits for patients ' HbA1c levels which are consistent in the post‐intervention and change from baseline effect sizes . The most significant effect observed is with the change from baseline results . Some evidence suggests post‐intervention and change from baseline systolic blood pressure improvement at the nine to twelve month interval and change from baseline improvement at the 4 year timeframe . There is no evidence that group visits improve LDL cholesterol values of the group visit participants . Conclusions Group medical visits should be considered by clinicians as an effective non‐pharmacologic intervention that can have a positive impact on biologic markers such as haemoglobin A1c and systolic blood pressure . Implication s for practice The evidence suggests that the most powerful model of Group medical visits ( GMV ) is when a clinician prescriber is present during or immediately after GMV sessions for medication reconciliation or individual patient needs . Implication s for research Future research should include this GMV intervention in r and omised controlled trials across different health systems and socio‐economic and ethnic groups OBJECTIVE To compare the impact of group outpatient visits to traditional " physician-patient dyad " care among older chronically ill HMO members on health services utilization and cost , self-reported health status , and patient and physician satisfaction . DESIGN A 1-year r and omized trial . SETTING A group model HMO in the Denver Metropolitan area . PARTICIPANTS Three hundred twenty-one members aged 65 and older , r and omized to a group visit intervention ( n = 160 ) or to usual care ( n = 161 ) . INTERVENTION Patients with high health services utilization and one or more chronic conditions had monthly group visits with their primary care physician and nurse . Visits included health education , prevention measures , opportunities for socialization , mutual support , and for one-to-one consultations with their physician , where necessary . MEASUREMENTS Health services utilization and associated cost , health status , and patient and physician satisfaction . RESULTS Outcome measures obtained after a 1-year follow-up period showed that group participants had fewer emergency room visits ( P = .009 ) , visits to subspecialists ( P = .028 ) , and repeat hospital admissions per patient ( P = .051 ) . Group participants made more visits ( P = .021 ) and calls ( P = .038 ) to nurses than control group patients and fewer calls to physicians ( P = .019 ) . In addition , a greater percentage of group participants received influenza and pneumonia vaccinations ( P < .001 ) . Group participants had greater overall satisfaction with care ( P = .019 ) , and participating physicians reported higher levels of satisfaction with the groups than with individual care . No differences were observed between groups on self-reported health and functional status . Cost of care per member per month was $ 14.79 less for the group participants . CONCLUSIONS Group visits for chronically ill patients reduce repeat hospital admissions and emergency care use , reduce cost of care , deliver certain preventive services more effectively , and increase patient and physician satisfaction BACKGROUND We evaluated the effectiveness of a low-cost group visit intervention for changing the dietary intake and lipid levels of patients with known coronary artery disease ( CAD ) . METHODS We performed a controlled r and om group assignment trial in 4 community outpatient clinics . The Dietary Intervention and Evaluation Trial r and omized 97 patients with CAD to either a control group that followed the National Cholesterol Education Program 's Step II-III diet plan ( n=48 ) or an experimental group that received meal plans , recipes , and nutritional information during monthly group office sessions ( n=49 ) . Both groups received lipid-lowering medications and were followed-up over 12 months . We assessed dietary intake , fasting lipid profiles , hemoglobin A1C levels , and per member per month ( PMPM ) expense data . RESULTS Food frequency data showed that eating fruits and vegetables and cooking with monounsaturated fat increased significantly in the experimental group compared with the control group at 1 year ( P=.0072 ; P=.0001 ; P=.0004 ) . The total PMPM expenses decreased for both groups ( 38 % for the experimental group and 10 % for the control group ) , but the cost difference was statistically nonsignificant ( P=.2975 ) . Both groups noted low-density lipoprotein reductions , significant only in the experimental group ( P=.0035 ) . CONCLUSIONS Our study suggests that using group office visits for patients with CAD was an effective method for helping subjects make dietary changes and for improving lipid levels . Patients with known CAD and elevated lipid levels were willing to make significant lifestyle changes when offered a program that emphasizes healthy foods in a group visit format To determine the effect of a self-care communication-based health education program on ambulatory care utilization , a prospect i ve , r and omized , controlled trial was conducted with a Medicare population within a health maintenance organization . A statistically significant decrease of 15 % in total medical visits was found in the experimental group as compared with a control . Although not evident in the control , a statistically significant decrease in the ratio of follow-up visits from pre-entry to postentry was realized in the experimental group . Medical-visit decreases result ed in a savings of $ 36.65 per household in the experimental group for a benefit-cost ratio of 2.19 saved for every dollar spent on intervention . These results demonstrate that a health education program can reduce utilization while having no known negative impact on the quality of health PURPOSE The clinical effectiveness of a group-visit model versus individual point-of-care visits is compared by International Normalized Ratio ( INR ) monitoring in a pharmacist-managed anticoagulation clinic . METHODS This study was a prospect i ve , r and omized , repeated- measures , two-group , intention-to-treat comparison and survey at a pharmacist-managed anticoagulation clinic in a managed-care ambulatory care setting . Patients were eligible for this study if they were taking warfarin therapy for at least 30 days , had a goal INR range , and provided consent . At a routine point-of-care visit , eligible patients were r and omly invited to participate in group visits . The number of visits and INR values were documented prospect ively for both groups during the 16-week study period . RESULTS Of the 45 patients who consented and enrolled in group visits , 28 patients participated for the 16-week study period . The control group included 108 patients seen by a pharmacist for individual anticoagulation appointments . No significant difference in the percentage of INR values within the therapeutic range was detected between patients in the group-visit model versus patients receiving individual visits ( 59 % versus 56.6 % , respectively ; p = 0.536 ) . Seventy-three percent of INR values for patients who attended group visits were within + /- 0.2 of the desired INR range compared with 71.9 % of those in the control group ( p = 0.994 ) . In addition , 79 % of group-visit patients were within the therapeutic range at their last clinic visit compared with 67 % of patients who attended individual appointments ( p = 0.225 ) . Group visits were preferred by 51 % ( n = 38 ) of patients who completed the satisfaction survey . Of the 92 patients who declined group-visit participation , 36 % indicated that the time of day that group visits were offered was inconvenient . There were no thromboembolic or hemorrhagic events documented in either group during the study period . CONCLUSION Group visits in a pharmacist-managed anticoagulation clinic may provide a safe and effective alternative to individual appointments In a pair of r and omized controlled trials in the Kaiser Permanente delivery system in Colorado in the 1990s , group visits for older adults ( monthly non-disease-specific group medical appointments for a cohort of patients led by primary care teams ) were proven to reduce costs , decrease hospitalizations , and improve patient and provider satisfaction . As part of a translational effort , this group visit intervention was replicated in a delivery system in Seattle , Washington , and the log of total healthcare costs was measured in the first year of the intervention . Utilization and patient and physician satisfaction were secondary outcomes . For the cost and utilization analysis , a retrospective case-control design compared 221 case patients aged 65 and older with high outpatient usage in the previous 18 months with 1,015 control patients selected r and omly from clinics not participating in the intervention . Controls were matched to cases on the number of primary care visits in the prior 18 months . Total costs were not statistically different for intervention patients and controls ( $ 8,845 vs $ 10,288 , P=.11 ) , nor were there statistically significant differences in utilization , including hospital admissions and outpatient visits , but patient and provider satisfaction with the intervention was high . This translational effort did not demonstrate the cost savings of the original efficacy trials . Possible explanations for these divergent results may have to do with differences between those who participated and differences between the two delivery systems AIMS Current management guidelines propose pelvic floor muscle training ( PFMT ) as first line treatment for female stress urinary incontinence ( SUI ) . The aim of this study is to compare the efficacy of group PFMT under intensive supervision to that of individual home therapy in women with SUI . MATERIAL AND METHODS Thirty women with clinical and urodynamic diagnosis of SUI were r and omized in two equal-number groups . Following a common demonstration course , Group A women received a detailed schedule for home training , while Group B in addition attended a weekly hospital group visit . At 12 weeks both groups were assessed for changes in subjective and objective outcomes . RESULTS Twenty-two women , ( 10 Group A , 12 Group B ) with a mean age of 47.3 years completed the study . Although significant ( P<0.05 ) improvements were noted in both groups in quality of life scores , number of incontinence episodes/week , 24-hr frequency , and endurance , repetitions and fast contractions upon vaginal assessment of the PFMs , comparative analysis at the end of the study demonstrated significantly better results for women in Group B , who also improved in daily pad usage , underwear wetting , modified Oxford grading of the PFMs and hold with cough . Consequently , significantly more women in Group B reported improvement in their continence ( 100 % vs. 20 % in Group A ) . CONCLUSIONS Group PFMT under intensive supervision produced significantly better improvements in primary and secondary outcomes in the short-term compared to individual , unsupervised home application of PFMT Objective : To systematic ally study the effects of shared medical appointments ( SMAs ) compared with individual appointments for patients with a chronic neuromuscular disorder and their partners . Methods : In this r and omized controlled trial with a follow-up of 6 months , we included patients with a chronic neuromuscular disorder and their partners . Participants were r and omly allocated to an SMA or an individual outpatient appointment . The primary outcome measure was patients ' health-related quality of life ( QOL ) ( 36-Item Short Form Health Survey ) . Secondary outcome measures included self-efficacy , social support , patient and partner satisfaction with the appointment , and time available per patient . Results : Two hundred seventy-two patients and 149 partners were included . Health-related QOL showed greater improvement in patients who had attended an SMA ( mean difference 2.8 points , 95 % confidence interval 0.0–5.7 , p = 0.05 ) . Secondary outcomes showed small improvements in the control group for satisfaction with the appointment ( p = 0.01 ) . Neurologists spent less time per patient during the SMAs : mean 16 minutes ( range 11–30 ) vs 25 minutes ( range 20–30 ) for individual appointments . Conclusions : This study provides evidence that SMAs can improve aspects of QOL of patients with a chronic neuromuscular disorder . This could result in an alternative to individual appointments and improvements in both effectiveness and efficiency . Further research to optimize SMAs and to identify critical success factors seems warranted . These data extend evidence on SMAs for neurologic patients . Classification of evidence : This study provides Class III evidence that for patients with chronic neuromuscular disorders , SMAs improve QOL as compared with individual medical appointments

Effective preventive interventions exist primarily for behaviour and , to a lesser extent , emotional problems , and could be disseminated from research to mainstream in Australia , ensuring fidelity to original programmes .

In childhood , mental health problems primarily consist of behaviour and emotional problems . These affect one in every seven children ( i.e. 200 000 in Australia ) . Left untreated , up to 50 % of preschool problems continue through the childhood years . Because of their high prevalence , population -based approaches will be needed to reduce their associated burden . The aim of the present study was therefore to identify evidence -based preventive interventions for behavioural and emotional problems of children aged 0–8 years .

Objectives : 1 ) To investigate the comorbidity of verbal and nonverbal learning disability subtypes with several domains of behavior problems among 8-year-old children . 2 ) To determine whether receipt of an early intervention modified the association between childhood behavior problems and learning disabilities ( LD ) . Methods : This is a secondary data analysis of the Infant Health and Development Program ( IHDP ) , a r and omized clinical trial of an early intervention provided between ages 0 and 3 involving 985 children born low birthweight and premature . The findings are based on a prospect i ve follow-up of these children at 8 years of age . Results : Compared to children without verbal LD ( VLD ) , those with VLD were twice as likely to exhibit clinical levels of total behavior problems and 89 % more likely to exhibit externalizing behavior problems . Analysis of specific subscales of behavior revealed significant associations with anxious/depressed and withdrawn behaviors , as well as an increased likelihood of attention problems among children with VLD . No significant association was found between nonverbal LD ( NVLD ) and any type of behavior problem . Furthermore , there was a significant interaction between VLD and the intervention , in which the odds of internalizing behavior problems were greater among children with VLD . No interaction effect of the intervention occurred for any type of behavior problem among children with NVLD . Conclusions : These findings provide evidence that distinct differences exist for different learning disability subtypes with regards to behavioral outcomes and the effects of early intervention services among 8-year-old children A population -based , r and omized universal classroom intervention trial for the prevention of disruptive behavior ( i.e. , attention-deficit/hyperactivity problems , oppositional defiant problems , and conduct problems ) is described . Impact on developmental trajectories in young elementary schoolchildren was studied . Three trajectories were identified in children with high , intermediate , or low levels of problems on all 3 disruptive behaviors at baseline . The intervention had a positive impact on the development of all disruptive behavior problems in children with intermediate levels of these problems at baseline . Effect sizes of mean difference at outcome were medium or small . In children with the highest levels of disruptive behavior at baseline , a positive impact of the intervention was found for conduct problems A population -based r and omized intervention trial for the prevention of conduct problems ( i.e. , oppositional defiant disorder and conduct disorder ) is described . The LIFT ( Linking the Interests of Families and Teachers ) intervention was design ed for all first- and fifth- grade elementary school boys and girls and their families living in at-risk neighborhoods characterized by high rates of juvenile delinquency . The 10-week intervention strategy was carefully targeted at proximal and malleable antecedents in three social domains that were identified by a developmental model of conduct problems . From 12 elementary schools , 671 first and fifth grade rs and their families participated either in the theory-based universal preventive intervention or in a control condition . The intervention consisted of parent training , a classroom-based social skills program , a playground behavioral program , and systematic communication between teachers and parents . A multiple measure assessment strategy was used to evaluate participant satisfaction and participation , fidelity of implementation , and the immediate impacts of the program on targeted antecedents OBJECTIVE . To examine the extent to which the Early Start program of home visitation had beneficial consequences in the areas of maternal health , family functioning , family economic circumstances , and exposure to stress and adversity . METHODS . The study used a r and omized , controlled trial design in which 220 families receiving the Early Start program were contrasted with a control series of 223 families not receiving the program . Families were enrolled in the program after population screening conducted by community health nurses . Families were enrolled in the program for up to 36 months . Outcomes were assessed at 6 , 12 , 24 , and 36 months after trial entry . RESULTS . There was a consistent lack of association between maternal and family outcomes and group membership . There were no significant differences between the Early Start and control series in any comparisons . CONCLUSIONS . This evaluation suggested that the Early Start program failed to lead to parent- and family-related benefits . This absence of benefit for parent/family outcomes is contrasted with the benefits found previously for child-related outcomes , including child health , preschool education , child abuse and neglect , parenting , and behavioral adjustment . This comparison suggests that home visitation programs may provide benefits for child-related outcomes in the absence of parent- or family-related outcomes The outcomes of a r and omized clinical trial of a new behavioral family intervention , Stepping Stones Triple P , for preschoolers with developmental and behavior problems are presented . Forty-eight children with developmental disabilities participated , 27 r and omly allocated to an intervention group and 20 to a wait-list control group . Parents completed measures of parenting style and stress , and independent observers assessed parent-child interactions . The intervention was associated with fewer child behavior problems reported by mothers and independent observers , improved maternal and paternal parenting style , and decreased maternal stress . All effects were maintained at 6-month follow-up 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 report describes the 3 year outcomes of three different variants of the Triple P-Positive Parenting Program , a behavioural family intervention . Families were r and omly assigned to one of three intervention conditions or to a waitlist condition . At 1 year follow-up there were similar improvements on observational and self-report measures of preschooler disruptive behaviour for Enhanced , St and ard and Self Directed variants of Triple P. At 3 year follow-up ( completed by 139 families ) , each condition showed a similar level of maintenance of intervention effects . Approximately 2/3 of preschoolers who were clinical ly elevated on measures of disruptive behaviour at pre-intervention moved from the clinical to the non- clinical range . Across conditions , there was a comparable preventive effect for each intervention for these high risk children . The implication s of the findings for the development of brief , cost effective parenting interventions within a public health framework are discussed OBJECTIVE Despite recognition of the need for parenting interventions to prevent childhood behavioral problems , few community programs have been evaluated . This report describes the r and omized controlled evaluation of a four-session psychoeducational group for parents of preschoolers with behavior problems , delivered in community agencies . METHOD In 1998 , 222 primary caregivers , recruited through community ads , filled out question naires on parenting practice s and child behavior . Parents were r and omly assigned to immediate intervention or a wait-list control . The intervention comprised three weekly group sessions and a 1-month booster , the focus being to support effective discipline ( using the video 1 - 2 - 3 Magic ) and to reduce parent-child conflict . RESULTS Using an intent-to-treat analysis , repeated- measures analyses of variance indicated that the parents who received the intervention reported significantly greater improvement in parenting practice s and a significantly greater reduction in child problem behavior than the control group . The gains in positive parenting behaviors were maintained at 1-year follow-up in a subset of the experimental group . CONCLUSIONS This brief intervention program may be a useful first intervention for parents of young children with behavior problems , as it seems both acceptable and reasonably effective OBJECTIVE To determine if a home-based nurse intervention ( INT ) , focusing on parenting education/skills and caregiver emotional support , reduces child behavioral problems and parenting stress in caregivers of in utero drug-exposed children . DESIGN R and omized clinical trial of a home-based INT . SETTING S Two urban hospital newborn nurseries ; homes of infants ( the term infant is used interchangeably in this study with the term child to denote those from birth to the age of 36 months ) ; and a research clinic in Baltimore , Md. PARTICIPANTS In utero drug-exposed children and their caregivers ( N = 100 ) were examined when the child was between the ages of 2 and 3 years . Two groups were studied : st and ard care ( SC ) ( n = 51 ) and INT ( n = 49 ) . INTERVENTION A home nurse INT consisting of 16 home visits from birth to the age of 18 months to provide caregivers with emotional support and parenting education and to provide health monitoring for the infant . MAIN OUTCOME MEASURES Scores on the Child Behavior Checklist and the Parenting Stress Index . RESULTS Significantly more drug-exposed children in the SC group earned t scores indicative of significant emotional or behavioral problems than did children in the INT group on the Child Behavior Checklist Total ( 16 [ 31 % ] vs 7 [ 14 % ] ; P = .04 ) , Externalizing ( 19 [ 37 % ] vs 8 [ 16 % ] ; P = .02 ) , and Internalizing ( 14 [ 27 % ] vs. 6 [ 12 % ] ; P = .05 ) scales and on the anxiety-depression subscale ( 16 [ 31 % ] vs. 5 [ 10 % ] ; P = .009 ) . There was a trend ( P = .06 ) in more caregivers of children in the SC group reporting higher parenting distress than caregivers of children in the INT group . CONCLUSIONS In utero drug-exposed children receiving a home-based nurse INT had significantly fewer behavioral problems than did in utero drug-exposed children receiving SC ( P = .04 ) . Furthermore , those caregivers receiving the home-based INT reported a trend toward lower total parenting distress compared with caregivers of children who received SC with no home visits This article describes a 20-year program of research on the Nurse Home Visitation Program , a model in which nurses visit mothers beginning during pregnancy and continuing through their children 's second birthdays to improve pregnancy outcomes , to promote children 's health and development , and to strengthen families ' economic self-sufficiency . The results of two r and omized trials ( one in Elmira , New York , and the second in Memphis , Tennessee ) are summarized , and an ongoing trial in Denver , Colorado , is briefly described . Results of the Elmira and Memphis trials suggest the following : The program benefits the neediest families ( low-income unmarried women ) but provides little benefit for the broader population . Among low-income unmarried women , the program helps reduce rates of childhood injuries and ingestions that may be associated with child abuse and neglect , and helps mothers defer subsequent pregnancies and move into the workforce . Long-term follow-up of families in Elmira indicates that nurse-visited mothers were less likely to abuse or neglect their children or to have rapid successive pregnancies . Having fewer children enabled women to find work , become economically self-sufficient , and eventually avoid substance abuse and criminal behavior . Their children benefitted too . By the time the children were 15 years of age , they had had fewer arrests and convictions , smoked and drank less , and had had fewer sexual partners . The program produced few effects on children 's development or on birth outcomes , except for children born to women who smoked cigarettes when they registered during pregnancy . The positive effects of the program on child abuse and injuries to children were most pronounced among mothers who , at registration , had the lowest psychological re sources ( defined as high levels of mental health symptoms , limited intellectual functioning , and little belief in their control of their lives ) . Generally , effects in Elmira were of greater magnitude and covered a broader range of outcomes than in Memphis , perhaps because of differences between the population s studied , community context s , or a higher rate of turnover among home visitors in Memphis than in Elmira . The article concludes that the use of nurses as home visitors is key ; that services should be targeted to the neediest population s , rather than being offered on a universal basis ; that clinical ly tested methods of changing health and behavioral risks should be incorporated into program protocol s ; and that services must be implemented with fidelity to the model tested if program benefits found in scientifically controlled studies are to be reproduced as the program is replicated in new communities Aims : To test the effectiveness at one year of the Webster Stratton Parents and Children Series group parenting programme in a population sample of parents . Methods : In a multicentre block r and omised controlled trial , parents of children aged 2–8 years in 116 families who scored in the upper 50 % on a vali date d behaviour inventory , took part in Webster-Stratton ’s 10 week parenting programme led by trained and supervised health visitors . The following outcome measures were used : Eyberg Child Behaviour Inventory , Goodman Strengths and Difficulties Question naire , General Health Question naire , Parenting Stress Index , Rosenberg Self Esteem Scale . Results : The intervention significantly reduced child behaviour problems and improved mental health at immediate and 6 month follow ups . One year differences between control and intervention groups were not significant . Qualitative results suggest that these findings might be attributable in part to either Hawthorne effects or contamination of control group . At interview parents described ways in which the programme had improved their mental health . They reported gains in confidence and feeling less stressed . Some also reported beneficial changes in their own and their children ’s behaviour and improved relationships with their children . Some spoke of a need for further sessions to support the behaviour changes they had managed to make , and some the desire for attendance by both parents . Conclusions : Parenting programmes have the potential to promote mental health and reduce social inequalities , but further work is needed to improve long term effectiveness OBJECTIVE This study aim ed to : ( 1 ) Assess the community utility of a screening tool to identify families with child abuse or neglect risk factors in the immediate postnatal period ( 2 ) Determine the social validity and effectiveness of a home visiting program using community child health nurses and offering social work services for identified families , and ( 3 ) Identify factors in the immediate postnatal period associated with the child 's environment that predict poor adjustment to the parenting role . METHOD A r and omized controlled trial using a cohort of 181 families was undertaken to evaluate the impact of a home visiting program . Mothers were recruited in the immediate postnatal period and allocated either into the home visiting program or into a comparison group . The research design required self- identification into the study by providing positive responses to a range of risk factors . A repeated measures design was used to test parenting stress and maternal depression from the immediate postnatal period to 12-month follow-up and physical child abuse potential to 18-month follow-up . To test whether measures taken in the immediate postnatal period were predictive for poor adjustment to the parenting role , a linear regression model was used . RESULTS The screening procedure was shown to have utility in the context of recruitment to a research trial and mothers were willing to accept the home visiting program examined by this study from the immediate postnatal period . From as early as 6 weeks the program demonstrated ability to impact positively on maternal , infant , family , and home environment variables ( testing 90 r and omly allocated intervention vs. 91 comparison families ) . At follow-up , parental adjustment variables were not significantly different between groups ( testing the remaining 68 ( 75.5 % ) intervention vs. 70 ( 76.9 % ) comparison families ) and home environment assessment scores had converged . Predictive analysis of factors measured in the immediate postnatal period revealed an absence of any predictive value to demographic characteristics , which secondary prevention efforts typically target . CONCLUSIONS Follow-up evaluation did not demonstrate a positive impact on parenting stress , parenting competence , or quality of the home environment confirming the need to test early program success on longer term outcomes . Further , the study not only demonstrated that there was a relationship between maternal , family and environmental factors identified in the immediate postnatal period . and adjustment to the parenting role , but also challenged demographic targeting for child abuse and neglect risk . At the same time , the immediate postnatal period presented an exciting window of opportunity to access high-risk families who may otherwise have become marginalized from traditional services Objective . To evaluate the extent to which a program of home visitation ( Early Start ) , targeted at families who are facing stress and difficulty , had beneficial consequences for child health , preschool education , service utilization , parenting , child abuse and neglect , and behavioral adjustment . Methods . The study used a r and omized , controlled trial design in which 220 families who were participating in the Early Start program were contrasted with a control series of 223 families who were not participating in the program . Families were enrolled in the program after population screening that was conducted by community health nurses . Families were enrolled in the program for up to 36 months . Outcomes were assessed at 6 , 12 , 24 , and 36 months after trial entry . Results . Families in the Early Start series received a mean of 24 months of service . Comparisons between the Early Start and control series over the 36-month follow-up period revealed that families in the Early Start program showed significant benefits in the areas of improved utilization of child health services , reduced rates of hospital attendance for injury/poisoning , increased preschool education , increased positive and nonpunitive parenting , reduced rates of severe parent/child assaults , and reduced rates of early problem behaviors . Effect sizes ( Cohen 's “ d ” ) were found to be in the small to moderate range , with d ranging from .03 to .31 ( median : .22 ) . Conclusions . The Early Start program was associated with small to moderate benefits in a wide range of areas relating to child health , preschool education , parenting , child abuse , and early behavioral adjustment . Comparisons with other studies are made , and threats to validity are considered In a r and omized prevention trial , 238 recently separated mothers and their young sons were assigned to either Parent Management Training ( PMT ) or a comparison group . Families were intensively assessed at baseline and at each 6-month interval through 30 months . To underst and the effects of PMT , we first evaluated effect sizes among family variables over time . Second , because observed parenting was the target of PMT , we hypothesized a sequential pattern of structured changes within and between individuals . Using constructs with mismatched sources of data , we conducted a set of latent growth mediational analyses to test hypothesized mechanisms explaining change . Effect sizes indicated that parenting changed first within 12 months , followed by changes in boy behaviors and finally changes in maternal depression within 30 months . Unique follow-up findings indicated that intervention effects on reductions in maternal depression were mediated by reductions in boy externalizing ; intervention effects on externalizing were mediated by reductions in boy depression . As expected , increases in effective parenting predicted reductions in child behavior problems . PMT effects on internalizing were direct and indirect , partially mediated by parenting practice s. Results are discussed from a system 's perspective on PMT amplifiers BACKGROUND To test effectiveness of a parenting intervention , delivered in a community-based voluntary-sector organisation , for reducing conduct problems in clinical ly-referred children . METHODS R and omised controlled trial , follow-up at 6 , 18 months , assessors blind to treatment status . Participants --76 children referred for conduct problems , aged 2 - 9 , primarily low-income families , r and omised to treatment vs. 6-month wait-list group . Retention was 93 % at 6 months , 90 % at 18 months . Interventions --Webster-Stratton Incredible Years video-based 14-week group programme , teaches cognitive-behavioural principles for managing behaviour , using a collaborative , practical , problem-solving approach . Primary outcomes --child problem behaviour by parent-report ( Eyberg ) and home-based direct observation ; secondary outcomes --observed positive and negative parenting ; parent-reported parenting skill , confidence and depression . RESULTS Post-treatment improvements were found in child problem behaviour , by parent-report ( effect size ( ES ) .48 , p = .05 ) and direct observation ( ES .78 , p = .02 ) ; child independent play ( ES .77 , p = .003 ) ; observed negative ( ES .74 , p = .003 ) and positive ( ES .38 , p = .04 ) parenting ; parent-reported confidence ( ES .40 , p = .03 ) and skill ( ES .65 , p = .01 ) , using ANCOVA to control for baseline scores . Maternal depression did not change . Consumer satisfaction was high . At 18-month follow-up , although no r and omised comparison was possible , changes appeared to maintain , with no significant change toward baseline level on any measure . Change in observed positive parenting appeared to mediate change in child problem behaviour ( p < .025 ) . CONCLUSIONS Findings suggest that a group-based cognitive-behavioural parenting programme , delivered by well-trained and supervised staff , can be effective in a community voluntary-sector setting , for reducing conduct problems and enhancing parenting skills . Change in parenting skill appears to be a key mechanism for change in child behaviour . Findings have implication s for feasibility of translating evidence -based programmes , even for clinical ly-referred conduct problems , into less specialised community setting s , likely to have lower costs and be more accessible for families Objective To determine whether a parenting programme , offered universally in primary care , can prevent behavioural problems in children and improve parenting and maternal mental health . Design Cluster r and omised trial . Setting 40 primary care nursing centres ( clusters ) in Victoria , Australia . Participants 733 English speaking mothers of 8 month old children sequentially recruited from well child appointments ; 656 retained at 24 months . Intervention Structured three session programme at age 8 - 15 months , co-led by well child providers and a parenting expert . The programme covered normal development and behaviour , strategies to increase desired behaviour , and strategies to reduce unwanted behaviour . Main outcome measures Maternal report of child externalising behaviour ( child behavior checklist 1½-5 year old ) , parenting ( parent behavior checklist ) , and maternal mental health ( depression anxiety stress scales ) at 18 and 24 months . Results At 18 months , child behaviour and parenting scores were similar in the two groups . At 24 months , externalising scores in the intervention and control groups were similar ( mean 11.9 ( SD 7.2 ) v 12.9 ( 7.4 ) ) ; however , on the parent behavior checklist subscale scores , intervention group parents were less likely to report harsh/abusive parenting ( mean 38.9 ( SD 7.7 ) v 40.5 ( 8.8 ) ; adjusted mean difference −1.83 , 95 % confidence interval −3.12 to −0.55 ) and unreasonable expectations of child development ( 40.9 ( 9.9 ) v 42.7 ( 9.6 ) ; −2.18 , −3.74 to −0.62 ) . Mean scores for nurturing parenting and maternal mental health were similar in the two groups at both times . Conclusions A universal parenting programme result ed in modest improvement in parenting factors that predict behavioural problems in children but did not reduce externalising behavioural problems or affect maternal mental health at 2 years . Trial registration IS RCT N 77531789 We assessed the immediate effects of two universal , first- grade preventive interventions on the proximal targets of poor achievement , concentration problems , aggression , and shy behaviors , known early risk behaviors for later substance use/abuse , affective disorder , and conduct disorder . The classroom-centered ( CC ) intervention was design ed to reduce these early risk behaviors by enhancing teachers ' behavior management and instructional skills , whereas the family-school partnership ( FSP ) intervention was aim ed at improving parent-teacher communication and parental teaching and child behavior management strategies . Over the course of first and second grade s , the CC intervention yielded the greatest degree of impact on its proximal targets , whereas the FSP 's impact was somewhat less . The effects were influenced by gender and by preintervention levels of risk . Analyses of implementation measures demonstrated that greater fidelity to the intervention protocol s was associated with greater impact on behavior ratings and on achievement scores , thus providing some evidence of specificity in the effect of the interventions Fast Track is a multisite , multicomponent preventive intervention for young children at high risk for long-term antisocial behavior . Based on a comprehensive developmental model , intervention included a universal-level classroom program plus social skills training , academic tutoring , parent training , and home visiting to improve competencies and reduce problems in a high-risk group of children selected in kindergarten . At the end of Grade 1 , there were moderate positive effects on children 's social , emotional , and academic skills ; peer interactions and social status ; and conduct problems and special-education use . Parents reported less physical discipline and greater parenting satisfaction/ease of parenting and engaged in more appropriate/consistent discipline , warmth/positive involvement , and involvement with the school . Evidence of differential intervention effects across child gender , race , site , and cohort was minimal 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 OBJECTIVE To examine the effects of prenatal and infancy nurse home visitation on the surveillance of child abuse and neglect by examining differences in the health , living conditions , and maltreatment characteristics of nurse-visited and comparison children who had been identified as maltreated in the first 4 years of life . DESIGN R and omized controlled trial . SETTING Carried out in a semirural community in upstate , New York . Families dispersed throughout 14 other states during 2-year period after children 's second birthdays . PARTICIPANTS 400 primiparous women registered before 30th week of pregnancy , 85 % of whom were either teenaged ( < 18 years at registration ) , unmarried , or from Hollingshead social class IV or V. Maltreated sub sample consisted of 56 families in which children had a state-verified report of child abuse or neglect during the first 4 years of the children 's life . INTERVENTION Nurse home visitation from pregnancy through the second year of the child 's life . MAIN RESULTS During the two-year period after the program ended , nurse-visited maltreated children lived in homes with fewer observed safety hazards for children ; their homes contained more intellectually stimulating toys , games , and reading material s ; their mothers were less controlling ; and the children paid 87 % fewer visits to the physician for injuries or ingestions , and 38 % fewer visits to the emergency department . CONCLUSIONS Children who were identified as maltreated and who were visited by nurses during pregnancy and the first two years of life had less serious expressions of caregiving dysfunction . This is likely to be a reflection , in part , of earlier and more comprehensive detection of child maltreatment on the part of nurse-visited families Despite knowledge of early pathways to conduct problems , few preventive interventions are specifically design ed to modify disruptive behavior in toddlerhood . One potential prevention target is proactive and positive parenting , which is associated with reduced risk of conduct problems in preschoolers . This r and omized trial with 120 low-income 2-year-old boys examined whether a brief family-centered intervention that reduces disruptive behavior ( D. Shaw , T. Dishion , L. Supplee , F. Gardner , & K. Arnds , 2006 ) also leads to increases in proactive and positive parenting . It also explored whether change in parenting predicts change in disruptive behavior . In the intervention group , proactive and positive parenting skills increased among parents of 3-year-olds . Change in proactive and positive parenting of 2- to 3-year-old toddlers correlated with change in child disruptive behavior , although the mediation effect of positive parenting was of only borderline significance . Findings suggest that even within a brief and multifaceted preventive intervention , change in proactive parenting skills contributes modestly but significantly to change in child problem behavior The central question addressed was , how effective is parent training in reducing conduct problems in children in comparison to client-centered parent counseling ? A secondary question was the relative effectiveness of the two treatment groups in comparison to a wait control group that when untreated during the 8-week period of treatment provided the other groups . Families of 36 , 5- to 12-year-old conduct problem children were screened and assigned at r and om to treatment groups , but wait control group assignment depended upon therapist availability . Supervised graduate student therapists conducted 10 treatment sessions for each family . Parent reports and paper and pencil tests of child deviance and parent satisfaction showed a superior outcome for behavioral over the client-centered and wait control groups , and no differences between the latter two groups . At follow-up there was no maintenance of this superiority . Home observation data showed no advantage of behavioral over client-centered treatment , and these two groups did not improve significantly more than the wait control group . These results were discussed in the light of possible interactions between treatment and measurement , and method ological and sampling differences between this and other studies This paper reports a r and omized controlled trial of the effects of behavioral parenting skills training , social skills training , and supplemental reading instruction on the social behavior of early elementary school children ( K through 3 ) . We selected children based on teacher-rated aggressive behavior or reading-skill deficits , delivered the intervention over a 2-year period , and obtained follow-up data for two additional years . The intervention affected only two of eight measures of child functioning — parent daily reports of antisocial behavior and parent ratings of coercive behavior . There was evidence that parents of boys in the intervention condition displayed significantly greater declines in their rated use of coercive discipline than did parents of boys in the control condition AIM Parenting programmes have been shown to improve children 's adjustment and reduce problem behaviour ; however , little research has addressed outcomes for Indigenous families . The aim of this project was to assess the impact and cultural appropriateness of a parenting programme tailored for Indigenous families , an adaptation of the evidence -based Group Triple P - Positive Parenting Program . METHODS A repeated measures r and omised group design methodology was used , comparing the intervention with a waitlist control condition pre- and post-intervention , with a 6-month follow-up of the intervention group . RESULTS Parents attending Group Triple P reported a significant decrease in rates of problem child behaviour and less reliance on some dysfunctional parenting practice s following the intervention in comparison to waitlist families . The programme also led to greater movement from the clinical range to the non-clinic range for mean child behaviour scores on all measures . Effects were primarily maintained at 6-month follow-up . Qualitative data showed generally positive responses to the programme re sources , content and process . However , only a small number of waitlist families subsequently attended groups , signalling the importance of engaging families when they first make contact , helping families deal with competing dem and s , and offering flexible service delivery so families can resume contact when circumstances permit . CONCLUSIONS This study provides empirical support for the effectiveness and acceptability of a culturally tailored approach to Group Triple P conducted by Child Health and Indigenous Health workers in a community setting . The outcomes of this trial may be seen as a significant step in increasing appropriate service provision for Indigenous families and reducing barriers to accessing available services in the community CONTEXT A program of home visitation by nurses has been shown to affect the rates of maternal welfare dependence , criminality , problems due to use of substances , and child abuse and neglect . However , the long-term effects of this program on children 's antisocial behavior have not been examined . OBJECTIVE To examine the long-term effects of a program of prenatal and early childhood home visitation by nurses on children 's antisocial behavior . DESIGN Fifteen-year follow-up of a r and omized trial . Interviews were conducted with the adolescents and their biological mothers or custodial parents . SETTING Semirural community in New York . PARTICIPANTS Between April 1978 and September 1980 , 500 consecutive pregnant women with no previous live births were recruited , and 400 were enrolled . A total of 315 adolescent offspring participated in a follow-up study when they were 15 years old ; 280 ( 89 % ) were born to white mothers , 195 ( 62 % ) to unmarried mothers , 151 ( 48 % ) to mothers younger than 19 years , and 186 ( 59 % ) to mothers from households of low socioeconomic status at the time of registration during pregnancy . INTERVENTION Families in the groups that received home visits had an average of 9 ( range , 0 - 16 ) home visits during pregnancy and 23 ( range , 0 - 59 ) home visits from birth through the child 's second birthday . The control groups received st and ard prenatal and well-child care in a clinic . MAIN OUTCOME MEASURES Children 's self-reports of running away , arrests , convictions , being sentenced to youth corrections , initiation of sexual intercourse , number of sex partners , and use of illegal substances ; school records of suspensions ; teachers ' reports of children 's disruptive behavior in school ; and parents ' reports of the children 's arrests and behavioral problems related to the children 's use of alcohol and other drugs . RESULTS Adolescents born to women who received nurse visits during pregnancy and postnatally and who were unmarried and from households of low socioeconomic status ( risk factors for antisocial behavior ) , in contrast with those in the comparison groups , reported fewer instances ( incidence ) of running away ( 0.24 vs 0.60 ; P = .003 ) , fewer arrests ( 0.20 vs 0.45 ; P = .03 ) , fewer convictions and violations of probation ( 0.09 vs 0.47 ; P<.001 ) , fewer lifetime sex partners ( 0.92 vs 2.48 ; P= .003 ) , fewer cigarettes smoked per day ( 1.50 vs 2.50 ; P= .10 ) , and fewer days having consumed alcohol in the last 6 months ( 1.09 vs 2.49 ; P = .03 ) . Parents of nurse-visited children reported that their children had fewer behavioral problems related to use of alcohol and other drugs ( 0.15 vs 0.34 ; P = .08 ) . There were no program effects on other behavioral problems . CONCLUSIONS This program of prenatal and early childhood home visitation by nurses can reduce reported serious antisocial behavior and emergent use of substances on the part of adolescents born into high-risk families The effectiveness of the Incredible Years Parenting Program was evaluated in a low-income sample of Caucasian , African American , Hispanic , and Asian mothers whose children were enrolled in Head Start . Data from two prior intervention studies [ Webster-Stratton ( 1998 ) Journal of Consulting and Clinical Psychology , 66(5 ) , 715–730 ; Webster-Stratton et al. ( in press ) Journal of Clinical Child Psychology ] were combined , yielding a sample of 634 families ( 370 Caucasian , 120 African American , 73 Asian , 71 Hispanic ) across 23 Head Start centers . Centers were matched and assigned r and omly to either an experimental condition ( 8–12 weeks of weekly 2-hr parenting classes ) , or a control condition ( the regular Head Start Program without parenting groups ) . Families in both conditions were assessed using home observations of parent – child interactions and parent reports of parenting style and discipline strategies and child behavior problems in the fall ( baseline ) and spring ( postintervention ) of the children 's Head Start year . Families were reassessed 1 year later . Following treatment , intervention mothers were observed to be more positive , less critical , more consistent , and more competent in their parenting than were control mothers . Additionally , children of intervention parents were observed to exhibit fewer behavior problems than were control children . Differences in treatment response across ethnic groups were few , and did not exceed the number expected by chance . Parents from all groups reported high satisfaction levels following the parenting program . Results indicate that the Incredible Years Program is accepted by and effective with diverse population 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 Seven hundred thirty-one income-eligible families in 3 geographical regions who were enrolled in a national food supplement program were screened and r and omized to a brief family intervention . At child ages 2 and 3 , the intervention group caregivers were offered the Family Check-Up and linked parenting support services . Latent growth models on caregiver reports at child ages 2 , 3 , and 4 revealed decreased behavior problems when compared with the control group . Intervention effects occurred predominantly among families reporting high levels of problem behavior at child age 2 . Families in the intervention condition improved on direct observation measures of caregivers ' positive behavior support at child ages 2 and 3 ; improvements in positive behavior support mediated improvements in children 's early problem behavior The effectiveness of a parenting program with 394 Head Start mothers was examined . Nine Head Start centers were r and omly assigned to either an experimental condition in which parents , teachers , and family service workers participated in the intervention or a control condition in which the regular Head Start program was offered . Mothers in the intervention group were observed at home to have significantly fewer critical remarks and comm and s , to use less harsh discipline , and to be more positive and competent in their parenting when compared with control mothers . Teachers reported that intervention mothers were more involved in their children 's education and that their children were more socially competent . Intervention children were observed to exhibit significantly fewer conduct problems , less noncompliance , less negative affect , and more positive affect than control children . One year later most of the improvements were maintained This study provided a r and omized , experimental test of the efficacy of a parent training intervention on coercive discipline , positive parenting practice s , and child noncompliance in a sample of 238 divorcing mothers and their sons in Grade s 1 - 3 . Intervention effects were evaluated 5 times from baseline to 30 months . The intervention produced enduring benefits to coercive discipline , positive parenting , and boys ' noncompliance . These benefits followed a classic prevention effect : Mothers and sons in the experimental group maintained stable outcome trajectories , whereas those in the control group deteriorated . The intervention 's impact on boys ' noncompliance was mediated independently by its impact on coercive discipline and positive parenting . Change in positive parenting was more strongly associated with change in noncompliance than was change in coercive discipline , although each explained unique variance in change in noncompliance This article reports results from an early intervention program aim ed at preventing the development of anxiety in preschool children . Children were selected if they exhibited a high number of withdrawn/inhibited behaviors -- one of the best identified risk factors for later anxiety disorders-- and were r and omly allocated to either a 6-session parent-education program or no intervention . The education program was group based and especially brief to allow the potential for public health application . Children whose parents were allocated to the education condition showed a significantly greater decrease in anxiety diagnoses at 12 months relative to those whose parents received no intervention . However , there were no significant effects demonstrated on measures of inhibition/withdrawal . The results demonstrate the value of ( even brief ) very early intervention for anxiety disorders , although these effects do not appear to be mediated through alterations of temperament OBJECTIVE The current study evaluated the efficacy of early intervention for preschool-aged children selected on the basis of risk who also met diagnostic criteria for anxiety disorders . METHOD Seventy-one 3- to 4-year-old children were selected based on demonstrating high levels of inhibition and having a parent with a current anxiety disorder . They were r and omly allocated to an eight-session parent intervention or waitlist . RESULTS At baseline , all of the children met criteria for one or more anxiety disorders . At 6-month follow-up , the intervention group showed a significantly greater reduction in anxiety disorders and less interference from their anxiety than the waitlist . In addition , children in the intervention condition showed greater reductions in parent and laboratory observed measures of behavioral inhibition . CONCLUSIONS The results suggest that a brief early intervention delivered through parents can reduce current anxiety and associated risk and may have the potential to alter the developmental trajectory of anxiety in a high-risk group of young children

Low doses of corticosteroids are recommended in patients with septic shock . In the absence of vasopressor requirement , corticosteroids should not be used to treat sepsis . High-dose corticosteroids are not recommended in severe sepsis .

OBJECTIVE In 2003 , critical care and infectious disease experts representing 11 international organizations developed management guidelines for the use of corticosteroid therapy in patients with sepsis and septic shock that would be of practical use for the bedside clinician , under the auspices of the Surviving Sepsis Campaign , an international effort to increase awareness and improve outcome in severe sepsis .

Nuclear factor-kappaB ( NF-kappaB ) and glucocorticoid receptor-alpha ( GR-alpha ) have diametrically opposed functions in regulating inflammation . We investigated whether unresolving acute respiratory distress syndrome ( ARDS ) is associated with systemic inflammation- induced glucocorticoid resistance and whether prolonged methylprednisolone administration accelerates the suppression of systemic inflammatory indices and normalizes the sensitivity of the immune system to glucocorticoids . Patients enrolled into a r and omized trial evaluating prolonged methylprednisolone administration in unresolving ARDS had serial plasma sample s collected before and after r and omization . In the plasma , we measured the concentrations of tumor necrosis factor-alpha ( TNF-alpha ) , interleukins ( IL ) IL-1beta and IL-6 , adrenocorticotropic hormone ( ACTH ) , and cortisol . The ability of patient plasma to influence the NF-kappaB and GR-signal transduction systems of normal peripheral blood leukocytes ( PBL ) was examined . Patients treated with methylprednisolone had progressive and sustained reductions of TNF-alpha , IL-1beta , IL-6 , ACTH , and cortisol concentrations over time . Normal PBL exposed to plasma sample s collected during methylprednisolone exhibited significant progressive increases in all aspects of GR-mediated activity and significant reductions in NF-kappaB DNA-binding and transcription of TNF-alpha and IL-1beta . These findings provide support for the presence of endogenous glucocorticoid inadequacy in the control of inflammation and systemic inflammation-induced peripheral glucocorticoid resistance in ARDS . Prolonged methylprednisolone administration accelerated the resolution of both systemic inflammation and peripheral acquired glucocorticoid resistance in ARDS ACTH stimulation is the st and ard test for assessment of adrenal function . It was suggested that the low dose ( 1 microg ) would be more sensitive for detecting mild secondary adrenal insufficiency than the usual dose of 250 microg . The aim of this study was to find the optimal diagnostic criteria and to compare st and ard dose test ( SDT ) with the low dose test ( LDT ) . A group of patients treated with corticosteroids for the 6 months was considered to have hypothalamo-pituitary-adrenal impairment . Studies were performed in 14 corticosteroid-treated and 28 control subjects in r and om order on 2 consecutive days . Tests were analyzed using the receiver operating characteristic curve method . The best test was cortisol increment at 15 min of the LDT . It was significantly better than the cortisol concentration at 15 min of the SDT , the best test during the SDT ( receiver operating characteristic curve area and 95 % confidence interval : LDT , 0.997 and 0.956 - 0.999 ; SDT , 0.827 and 0.662 - 0.929 ; P = 0.0113 ) . For the cortisol increment at 15 min of the LDT at 100 % sensitivity , the diagnostic value was 100 mmol/L , and the specificity was 96 % . Therefore , the LDT is superior to the st and ard dose test in the assessment of secondary adrenal insufficiency BACKGROUND Exposure to intense physical and psychological stress during septic shock can result in posttraumatic stress disorder in survivors . Patients with chronic posttraumatic stress disorder often show sustained reductions in serum cortisol concentration . This investigation examines whether increasing serum cortisol levels with hydrocortisone treatment during septic shock reduces the incidence of posttraumatic stress disorder in survivors . METHODS Patients ( n = 20 ) were recruited from a prospect i ve , r and omized double-blind study on the hemodynamic effects of hydrocortisone during septic shock . Eleven patients had received placebo and nine stress doses of hydrocortisone . Posttraumatic stress disorder was diagnosed 31 months ( median ) after intensive care unit discharge using SCID-IV ( DSM-IV- criteria ) . Furthermore , the number of categories of traumatic memory from ICU treatment was determined in both groups at that time . RESULTS Only one of nine patients from the hydrocortisone group developed posttraumatic stress disorder , compared with seven of 11 patients in the placebo group ( p = .02 ) . There was no significant difference with regard to the number of categories of traumatic memory between the hydrocortisone and placebo groups . CONCLUSIONS The administration of hydrocortisone during septic shock in a dosage similar to the endogenous maximal production rate was associated with a lower incidence of posttraumatic stress disorder in long-term survivors , which seems to be independent of the number of categories of traumatic memory Abstract . Objective : To study the time course of corticosteroid binding-globulin ( CBG ) level and the free cortisol index ( FCI ) in comparison with total cortisol and ACTH concentrations during acute and prolonged critical illness . Design : Prospect i ve observational clinical study . Setting : Twenty-bed medical/surgical intensive care unit . Patients and participants : Thirty patients with septic shock , eight patients with multitrauma , and forty healthy control subjects . Measurements and results : During 14 days or until discharge/death , we serially measured serum concentrations of CBG , cortisol , TNF-α , IL-6 , plasma ACTH immunoreactivity , and the FCI ( = cortisol/CBG × 100 ) . We also recorded haemodynamic parameters , APACHE II , ISS , SOFA scores , shock duration , inotrope use , and ICU mortality . In both groups we found markedly decreased CBG levels in the early phase ( septic shock : 17.5±5.9 , and trauma : 16.1±2.3 mg/l ) in comparison with controls ( 37.3±5.3 mg/l ) . The FCI was high in this early phase ( septic shock : 7.2±2.7 ; trauma : 6.5±1.3 ; controls : 1.25±0.76 ) . During follow-up , CBG levels significantly increased , reaching normal levels from day 7 on . The FCI showed an opposite biphasic pattern , with near-normalising FCI values during the second phase . Regression analysis showed a negative correlation between CBG and IL-6 levels ( rs=–0.63 ; P<0.05 ) , but no relation between CBG concentrations and disease severity , shock duration or death was found . Conclusions : We found extremely low CBG levels in early stage septic shock and multitrauma . These dramatic changes are reflected in a concomitant higher FCI , indicating a higher free cortisol level . A second phase displays increasing and normalising CBG levels , independent from clinical parameters . We believe that CBG plays an active role in the glucocorticoid response to severe stress and in the regulation of cortisol availability to target tissues Objective To investigate , in patients with severe septic shock , the adrenocortical function assessed by daily plasma cortisol determinations during the first 72 h and by the short synthetic ACTH stimulation test performed within 24 h of the onset of shock . Design Prospect i ve clinical investigation . Setting Medical intensive care unit in a university teaching hospital . Patients 40 consecutive patients with documented septic shock requiring at least hemodynamic resuscitation and respiratory support . Interventions There were no intervention . Measurements and results Basal cortisol concentrations were increased with a mean value of 36.8 μg/dl ( range 7.9–113 ) . Of the overall cortisol determinations 92 % were above 15 μg/dl . No statistically significant differences in basal cortisol concentrations were found when survival , type of infection , and positive blood cultures were considered . Patients with hepatic disease had significantly higher cortisol ( 50.1(±6.2 ) μ/dl versus 35.9(±3.3 ) μg/dl , p=0.035 ) levels compared to other patients . No correlations were found between basal plasma cortisol concentrations and factors such as SAPS , OSF , hemodynamic measurements , duration of shock , and amount of vasopressor and /or inotropic agents . Cortisol concentrations had significant but weak correlation with ACTH levels in survivors ( r=0.4;p=0.03;n=28 ) but not in non-survivors ( r=0.03;p=0.85;n=52 ) . Cortisol levels in non-survivors increased significantly from enrollment time to the 72nd hour of the survey ( day 1 : 38.9(±3.8 ) μg/dl versus day 3 : 66.7(±17.1 ) μg/dl;p=0.046 ) and were significantly higher than those recorded in survivors . Responses to the short ACTH stimulation test were not significantly different between survivors and non-survivors . According to the different criteria used to interpret the response to the ACTH stimulation test , incidence of adrenocortical insufficiency was highly variable ranging from 6.25–75 % in patients with septic shock . Only one patient had absolute adrenocortical insufficiency ( basal cortisol level below 10 μg/dl ; response to the ACTH stimulation test below 18 μg/dl . Conclusion Our data suggest that in a selected population of patients with severe septic shock single plasma cortisol determination has no predictive value . The short ACTH stimulation test performed within the first 24 h of onset shock can neither predict outcome nor estimate impairment in adrenocortical function in patients with high basal cortisol level . Adrenal insufficiency is rare in septic shock and should be suspected when cortisol level is below 15 μg/dl and then confirmed by a peak cortisol level lower than 18 μg/dl during the short ACTH stimulation test CONTEXT The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress . The relationship between its activation and patient outcome is not known . OBJECTIVE To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock . DESIGN AND SETTING Prospect i ve inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France . PARTICIPANTS A total of 189 consecutive patients who met clinical criteria for septic shock . INTERVENTION A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin ; blood sample s were taken immediately before the test ( T0 ) and 30 ( T30 ) and 60 ( T60 ) minutes afterward . MAIN OUTCOME MEASURES Twenty-eight-day mortality as a function of variables collected at the onset of septic shock , including cortisol levels before the corticotropin test and the cortisol response to corticotropin ( delta max , defined as the difference between T0 and the highest value between T30 and T60 ) . RESULTS The 28-day mortality was 58 % ( 95 % confidence interval [ CI ] , 51%-65 % ) and median time to death was 17 days ( 95 % CI , 14 - 27 days ) . In multivariate analysis , independent predictors of death ( P < or = .001 for all ) were McCabe score greater than 0 , organ system failure score greater than 2 , arterial lactate level greater than 2.8 mmol/L , ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg , cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified : good ( cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL ; 28-day mortality rate , 26 % ) , intermediate ( cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL ; 28-day mortality rate , 67 % ) , and poor ( cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL ; 28-day mortality rate , 82 % ) . CONCLUSION Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death BACKGROUND Preliminary reports suggest that patients with the acquired immunodeficiency syndrome ( AIDS ) and Pneumocystis carinii pneumonia may benefit from the addition of corticosteroid treatment to antibiotic therapy . METHODS We conducted a double-blind , placebo-controlled trial to assess the efficacy of adjunctive corticosteroids in patients with AIDS and severe P. carinii pneumonia . Patients with marked abnormalities in gas exchange who had been treated with antibiotics for less than 72 hours were r and omly assigned to receive either methylprednisolone ( 40 mg ) or placebo every 6 hours for 7 days , in addition to treatment for 21 days with trimethoprim-sulfamethoxazole . The primary outcome measures were survival until hospital discharge and the development of respiratory failure . RESULTS Twenty-three patients were enrolled in the study ; there were no significant differences in base-line clinical or laboratory measures between the two treatment groups . Of 12 patients treated with corticosteroids , 9 ( 75 percent ) survived until hospital discharge , as compared with only 2 of 11 placebo recipients ( 18 percent ) ( P less than 0.008 ) . Respiratory failure developed in nine placebo recipients , as compared with only three patients treated with corticosteroids ( P less than 0.008 ) . No patient required the interruption or discontinuation of corticosteroid or antibiotic treatment because of toxicity or a complicating event . Because of the marked difference in survival , it was deemed unethical to continue the trial , and the study was terminated . CONCLUSIONS Early adjunctive corticosteroid therapy can improve survival and decrease the occurrence of respiratory failure in patients with AIDS and severe P. carinii pneumonia Within the last few years , increasing evidence of relative adrenal insufficiency in septic shock evoked a re assessment of hydrocortisone therapy . To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation , 40 patients with septic shock were r and omized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 ( n = 20 ) or placebo ( n = 20 ) , followed by the opposite medication until Day 6 . Hydrocortisone infusion induced an increase of mean arterial pressure , systemic vascular resistance , and a decline of heart rate , cardiac index , and norepinephrine requirement . A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support . The inflammatory response ( interleukin-6 and interleukin-8 ) , endothelial ( soluble E-selectin ) and neutrophil activation ( expression of CD11b , CD64 ) , and antiinflammatory response ( soluble tumor necrosis factor receptors I and II and interleukin-10 ) were attenuated . In peripheral blood monocytes , human leukocyte antigen-DR expression was only slightly depressed , whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased . Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects . In conclusion , hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression CONTEXT No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome ( ARDS ) and mortality remains greater than 50 % . OBJECTIVE To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Medical intensive care units of 4 medical centers . PARTICIPANTS Twenty-four patients with severe ARDS who had failed to improve lung injury score ( LIS ) by the seventh day of respiratory failure . INTERVENTIONS Sixteen patients received methylprednisolone and 8 received placebo . Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days . Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment . MAIN OUTCOME MEASURES Primary outcome measures were improvement in lung function and mortality . Secondary outcome measures were improvement in multiple organ dysfunction syndrome ( MODS ) and development of nosocomial infections . RESULTS Physiological characteristics at the onset of ARDS were similar in both groups . At study entry ( day 9 [ SD , 3 ] of ARDS ) , the 2 groups had similar LIS , ratios of PaO2 to fraction of inspired oxygen ( FIO2 ) , and MODS scores . Changes observed by study day 10 for methylprednisolone vs placebo were as follows : reduced LIS ( mean [ SEM ] , 1.7 [ 0.1 ] vs 3.0 [ 0.2 ] ; P<.001 ) ; improved ratio of PaO2 to FIO2 ( mean [ SEM ] , 262 [ 19 ] vs 148 [ 35 ] ; P<.001 ) ; decreased MODS score ( mean [ SEM ] , 0.7 [ 0.2 ] vs 1.8 [ 0.3 ] ; P<.001 ) ; and successful extubation ( 7 vs 0 ; P=.05 ) . For the treatment group vs the placebo group , mortality associated with the intensive care unit was 0 ( 0 % ) of 16 vs 5 ( 62 % ) of 8 ( P=.002 ) and hospital-associated mortality was 2 ( 12 % ) of 16 vs 5 ( 62 % ) of 8 ( P=.03 ) . The rate of infections per day of treatment was similar in both groups , and pneumonia was frequently detected in the absence of fever . CONCLUSIONS In this study , prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality Abstract . Objectives : To compare cortisol levels during " low-dose " hydrocortisone therapy to basal and ACTH-stimulated endogenous levels and to assess whether clinical course and the need for catecholamines depend on cortisol levels and /or pretreatment adrenocortical responsiveness . Design and setting : Prospect i ve observational study in a medical ICU of a university hospital . Patients : Twenty consecutive patients with septic shock and a cardiac index of 3.5 l/min or higher , started on " low-dose " hydrocortisone therapy ( 100 mg bolus , 10 mg/h for 7 days and subsequent tapering ) within 72 h of the onset of shock . Measurements and results : Basal total and free plasma cortisol levels ranged from 203 to 2169 and from 17 to 372 nmol/l . In 11 patients cortisol production was considered " inadequate " because there was neither a response to ACTH of at least 200 nmol/l nor a baseline level of at least 1000 nmol/l . Following the initiation of hydrocortisone therapy total and free cortisol levels increased 4.2- and 8.5-fold to median levels of 3587 ( interquartile range 2679–5220 ) and 1210 ( interquartile range 750–1846 ) nmol/l on day 1 , and thereafter declined to median levels of 1310 nmol/l and 345 nmol/l on day 7 . Patients with " inadequate " steroid production could be weaned from vasopressor therapy significantly faster , although their plasma free cortisol concentrations during the hydrocortisone treatment period did not differ . Conclusions : ( a ) During proposed regimens of " low-dose " hydrocortisone therapy , initially achieved plasma cortisol concentrations considerably exceed basal and ACTH stimulated levels . ( b ) Cortisol concentrations decline subsequently , despite continuous application of a constant dose . ( c ) " Inadequate " endogenous steroid production appears to sensitize patients to the hemodynamic effects of a " therapeutic rise " in plasma cortisol levels The effects of massive doses of steroids on septic shock were tested in 48 patients being treated for extensive cellulitis , wet gangrene , or severe peritonitis . From diagnosis until maximum weight gain ( average , 47 hours ) , they received an average of 17.7 L of crystalloid solution and 1.0 L of blood and voided 3.1 L of urine . Of the 48 patients , 23 were selected in r and om fashion to receive dexamethasone sodium phosphate ( 6 mg/kg ) over 48 hours . The average age ( 55 years ) , duration of shock ( 36 minutes ) , and insult were similar for both groups . Each group received similar volumes of fluid and blood . Steroid therapy was associated with a statistically significant rise in diastolic pressure ( 88 v 78 mm Hg ) , mean arterial pressure ( 105 v 95 mm Hg ) , and central venous pressure ( 16 v 10 cm H2O ) . Concomitant blood volume was lower in patients treated with steroids ( 5.2 v 6.1 L ) . All differences between the two groups disappeared after 48 hours when steroid therapy was discontinued . No differences were noted in morbidity and five patients in each group died The short ACTH stimulation test is an easy , reliable , and extensively used test in the assessment of the hypothalamo-pituitary-adrenal ( HPA ) axis . However , its use immediately after pituitary surgery is a matter of debate . The insulin tolerance test ( ITT ) is the gold st and ard in the evaluation of the HPA axis , but it is not always without side effects and may be unpleasant early after pituitary surgery . Our aim was to investigate the value of the 1-microg ACTH test in the assessment of the HPA axis early after pituitary surgery . We also aim ed to determine the value of the 1-microg and 250-microg ACTH tests and the ITT in the estimation of HPA axis status after 3 months postoperatively . Nineteen patients subjected to pituitary tumor surgery were included in the study , and the ITT and the 1-microg and 250-microg ACTH tests were performed between the 4th and 11th days of surgery . The tests were repeated at the first month in 3 patients with subnormal peak cortisol responses ( 454 , 125 , and 301 nmol/L ) and in 18 patients at the third month postoperatively . ACTH stimulation tests were performed by using 1 microg and 250 microg ACTH iv as a bolus injection , and blood sample s were drawn at 0 , 30 , and 60 min for measurement of serum cortisol levels . The ITT was performed by using iv regular insulin , and serum glucose and cortisol levels were measured . The 1-microg and 250-microg ACTH stimulation tests and the ITT were performed consecutively . At least 48 h were allowed between each test . A peak serum cortisol level of 550 nmol/L or greater was considered as a normal response for both the ITT and the ACTH tests . The serum cortisol level was measured by RIA using commercial kits . Serum glucose was determined by glucose oxidase method . There were correlations between the peak cortisol response to the ITT and the 1-microg ACTH test ( r = 0.39 , P < 0.05 ) in the early postoperative period . No correlation was found between the ITT and the 250-microg ACTH test responses . In the early postoperative period , two patients showed normal cortisol responses ( > or = 550 nmol/L ) to the 1-microg ACTH test and five patients showed normal cortisol responses to the 250-microg ACTH test among the six patients with subnormal cortisol responses to the ITT . Three patients with subnormal cortisol responses to ITT and baseline cortisol values less than 240 nmol/L showed normal HPA axis at the end of the first month . In the late postoperative period , at the third month , all the patients showed normal HPA axis . In the early postoperative period of pituitary surgery , the 1-microg ACTH test results are more concordant than the 250-microg ACTH test in comparison with the ITT . Our results also indicate that HPA axis dysfunction shown by ACTH stimulation tests and the ITT in early postoperative period may be normalized 1 - 3 months after surgery . For this reason , we think that dynamic tests including the ITT may not be useful early after pituitary surgery OBJECTIVE To determine whether oral corticosteroids can prevent early deterioration in patients with acquired immunodeficiency syndrome (AIDS)-related Pneumocystis carinii pneumonia . DESIGN Prospect i ve , double-blind , placebo-controlled , r and omized trial . METHODS Included patients were having their first P. carinii pneumonia episode , had no other known active pulmonary pathology , had no contraindications for corticosteroids , received no anti-P. carinii pneumonia medications for more than 48 hours , and had oxygen saturation by pulse oximetry of 85 % or more and less than 90 % at rest or a 5-percentage-point decrease in oxygen saturation with exercise while breathing room air . Consenting subjects were r and omly assigned to prednisone , 60 mg/d for 7 days , followed by a progressive tapering over 14 days or to an identical placebo . Early deterioration , the endpoint of the trial , was defined as a 10 % decrease in baseline oxygen saturation on day 3 or thereafter . The cases of patients developing early deterioration were considered to be failures of treatment ; the code was then broken , and the patient 's treatment was left to the judgment of the treating physician . Sequential analysis was done with the primary variable being development of early deterioration . RESULTS The trial was terminated 5 April 1989 on the basis of the sequential analysis when a total of nine episodes of early deterioration had occurred in the first 37 patients at an overall significance level of P = 0.0136 . A total of 8 of 19 placebo-treated patients ( 42.1 % ) developed early deterioration compared with only 1 of 18 patients ( 5.6 % ) treated with corticosteroids . Baseline characteristics were not statistically different between the two treatment groups . The adjusted odds ratio for the treatment effect was 5.87 ( 95 % CI , 1.27 to 27.4 ) . The adjusted point estimates for the probability of early deterioration in the placebo and corticosteroid groups were 43 % and 12 % , respectively . All 8 patients in the placebo group developing early deterioration recovered rapidly with addition of corticosteroid treatment . The single patient with early deterioration in the corticosteroid group died on day 6 from overwhelming P. carinii pneumonia , as documented at autopsy . The corticosteroid group had an increased exercise tolerance on day 7 that persisted at day 30 . CONCLUSION Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with moderately severe AIDS-related P. carinii pneumonia OBJECTIVE To evaluate the effects of high-dose methylprednisolone sodium succinate on biochemical markers of hepatic and renal function in patients with severe sepsis and septic shock . DESIGN Retrospective analysis of serial serum chemistries in 382 patients who were entered prospect ively into a r and omized , placebo-controlled , double-blind clinical trial of high-dose methylprednisolone or placebo in the sepsis syndrome . SETTING The original study was conducted at 19 academic centers . PATIENTS Adult patients in severe sepsis or septic shock who met the study entry criteria , which included a clinical ly defined source of infection and signs of systemic sepsis , were enrolled into the study . Three hundred eighty-two patients were evaluated . INTERVENTIONS Patients received either methylprednisolone ( 30 mg/kg ) or placebo by iv infusion every 6 hrs for four doses . Hemodynamic variables and serum concentrations of creatinine , urea nitrogen , bilirubin , and aspartate aminotransferase ( AST ) were recorded on entering the study , at 12 and 24 hrs , and at 3 , 7 , and 14 days after the first infusion of methylprednisolone or placebo . These data were analyzed retrospectively . MAIN OUTCOME MEASUREMENTS Hemodynamic and biochemical data were analyzed to determine whether or not hepatic and renal function in the sepsis syndrome had been influenced by methylprednisolone treatment . RESULTS Differences between methylprednisolone and placebo in hemodynamic variables , the occurrence rate of shock and recovery from shock , mortality rates and serum concentrations of creatinine and AST were not statistically significant . At 12 and 24 hrs , and at 3 and 7 days after the first drug infusion ( of methylprednisolone or placebo ) , blood urea nitrogen was increased from baseline values in a significantly ( p < .01 ) greater proportion of the methylprednisolone-treated patients compared with placebo-treated patients . The frequency of increased serum bilirubin concentrations was significantly ( p < .01 ) greater among methylprednisolone patients vs. the placebo group at 12 and 24 hrs . CONCLUSIONS The frequency of acutely increased blood urea nitrogen and bilirubin concentrations in severe sepsis was increased significantly with high-dose methylprednisolone therapy . Similar frequencies of circulatory shock in the study groups excluded differences in global perfusion as a cause of this phenomenon . Possible adverse effects of pharmacologic concentrations of methylprednisolone in critically ill patients should be considered in planning treatment We conducted a prospect i ve , r and omized , double-blind study to determine whether high-dose methylprednisolone could prevent parenchymal lung injury , including the adult respiratory distress syndrome ( ARDS ) , or improve mortality when administered early in septic shock . All patients already hospitalized in or newly admitted to the medical and surgical intensive care units at San Francisco General Hospital between September 1 , 1983 and August 29 , 1986 were eligible for admission to the study if they had either ( 1 ) an increase in temperature of 1.5 degrees C and a decrease in systolic blood pressure of 20 mm Hg or more from baseline values ( in already hospitalized patients ) , or ( 2 ) a temperature greater than 38.5 degrees C or less than 35.5 degrees C and a systolic blood pressure of less than 90 mm Hg ( in newly admitted patients ) . Patients meeting these criteria were excluded if they ( 1 ) had severe immunodeficiency , ( 2 ) were less than 18 or greater than 76 yr of age , ( 3 ) had multilobar roentgenographic infiltrates , or ( 4 ) were already receiving corticosteroids . Eighty-seven patients enrolled in the study received either methylprednisolone , 30 mg/kg per dose , or mannitol placebo for a total of 4 doses every 6 h , following the presumptive diagnosis of septic shock . Of these patients , 75 ultimately were determined on the basis of culture results to have actually had septic shock at the time of entry . Thirteen of the patients who received methylprednisolone developed ARDS , compared to 14 patients who received placebo . Lesser degrees of parenchymal lung injury did not differ between the 2 groups . ( ABSTRACT TRUNCATED AT 250 WORDS Objective To determine whether a baseline ( r and om ) cortisol concentration < 25 & mgr;g/dL in patients with septic shock was a better discriminator of adrenal insufficiency than the st and ard ( 250 & mgr;g ) and the low-dose ( 1 & mgr;g ) corticotropin stimulation tests as assessed by the hemodynamic response to steroid replacement . Setting Intensive care unit . Patients Fifty-nine patients with septic shock . Their mean age was 57 ± 16.7 yrs ; 29 were male . Interventions A baseline cortisol concentration was obtained . Patients then received an intravenous injection of 1 & mgr;g of corticotropin ( low-dose test ) followed 60 mins later by an injection of 249 & mgr;g of corticotropin ( high-dose test ) . Cortisol concentrations were obtained 30 and 60 mins after low- and high-dose corticotropin . All patients were administered hydrocortisone ( 100 mg every 8 hrs ) for the first 24 hrs while awaiting results of cortisol assessment . Patients were considered steroid responsive if the pressor agent could be discontinued within 24 hrs of the first dose of hydrocortisone . Measurements and Main Results Forty-seven percent of patients died . Twenty-two percent of patients met the diagnostic criteria of adrenal insufficiency by the low-dose test and 8 % by the high-dose test . However , 61 % of patients met the criteria of adrenal insufficiency when we used a baseline cortisol concentration of < 25 & mgr;g/dL. Twenty-two patients ( 37 % ) were steroid responsive ; the baseline serum cortisol was 14.1 ± 5.2 & mgr;g/dL in the steroid-responsive patients compared with 33.3 ± 18 & mgr;g/dL in the steroid-nonresponsive patients ( p < .0001 ) . Ninety-five percent of steroid-responsive patients had a baseline cortisol concentration < 25 & mgr;g/dL. Fifty-four percent of steroid responders had a diagnostic low-dose test and 22 % a diagnostic high-dose test . Receiver operating characteristic curve analysis revealed that a stress cortisol concentration of 23.7 & mgr;g/dL was the most accurate diagnostic threshold for determination of the hemodynamic response to glucocorticoid therapy . Conclusions Adrenal insufficiency is common in patients with septic shock , the incidence depending largely on the diagnostic test and criteria used to make the diagnosis . There is clearly no absolute serum cortisol concentration that distinguishes an adequate from an insufficient adrenal response . However , we believe that a r and om cortisol concentration of < 25 & mgr;g/dL in a highly stressed patient is a useful diagnostic threshold for the diagnosis of adrenal insufficiency OBJECTIVES Preliminary studies have suggested that low doses of corticosteroids might rapidly improve hemodynamics in late septic shock treated with catecholamines . We examined the effect of hydrocortisone on shock reversal , hemodynamics , and survival in this particular setting . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled study . SETTING Two intensive care units of a University hospital . PATIENTS Forty-one patients with septic shock requiring catecholamine for > 48 hrs . INTERVENTIONS Patients were r and omly assigned either hydrocortisone ( 100 mg i.v . three times daily for 5 days ) or matching placebo . MEASUREMENTS AND MAIN RESULTS Reversal of shock was defined by a stable systolic arterial pressure ( > 90 mm Hg ) for > or = 24 hrs without catecholamine or fluid infusion . Of the 22 hydrocortisone-treated patients and 19 placebo-treated patients , 15 ( 68 % ) and 4 ( 21 % ) achieved 7-day shock reversal , respectively , a difference of 47 % ( 95 % confidence interval 17 % to 77 % ; p = .007 ) . Serial invasive hemodynamic measurements for 5 days did not show significant differences between both groups . At 28-day follow-up , reversal of shock was higher in the hydrocortisone group ( p = .005 ) . Crude 28-day mortality was 7 ( 32 % ) of 22 treated patients and 12 ( 63 % ) of 19 placebo patients , a difference of 31 % ( 95 % confidence interval 1 % to 61 % ; p = .091 ) . Shock reversal within 7 days after the onset of corticosteroid therapy was a very strong predictor of survival . There were no significant differences in outcome in responders and nonresponders to a short corticotropin test . The respective rates of gastrointestinal bleeding and secondary infections did not differ between both groups . CONCLUSIONS Administration of modest doses of hydrocortisone in the setting of pressor-dependent septic shock for a mean of > 96 hrs result ed in a significant improvement in hemodynamics and a beneficial effect on survival . These beneficial effects do not appear related to adrenocortical insufficiency STEROIDS might be of benefit to the patient with a serious infection.1 In 1961 a Cooperative double-blind study of the effects of administering a dose of 300 mg of hydrocortisone to patients with s To determine whether corticosteroids are efficacious in severe septic shock , we conducted a prospect i ve study of 59 patients r and omly assigned to a methylprednisolone , dexamethasone , or control group . Patients were treated 17.5 + /- 5.4 hours ( mean + /- S.E.M. ) after the onset of shock , and 55 patients required vasopressor agents . Early in the hospital course , reversal of shock was more likely in patients who received corticosteroids than in those who did not . Four ( 19 per cent ) of 21 methylprednisolone-treated , 7 ( 32 per cent ) of 22 dexamethasone-treated , and none of 16 control patients had reversal of shock 24 hours after drug administration ( corticosteroid groups vs. control group , P less than 0.05 ) . Patients treated with corticosteroids within four hours after the onset of shock had a higher incidence of shock reversal ( P less than 0.05 ) . At 133 hours after drug administration , 17 ( 40 per cent ) of 43 corticosteroid-treated patients had died , and 11 ( 69 per cent ) of 16 control patients had died ( P less than 0.05 ) . However , these differences in reversal of shock and survival disappeared later in the course . Overall , 16 ( 76 per cent ) of 21 patients receiving methylprednisolone , 17 ( 77 per cent ) of 22 patients receiving dexamethasone , and 11 ( 69 per cent ) of 16 controls in the hospital died . We conclude that corticosteroids do not improve the overall survival of patients with severe , late septic shock but may be helpful early in the course and in certain subgroups of patients Abstract This study was design ed to determine the effect of steroid/antibiotic treatment on the survival of baboons subjected to LD100 Escherichia coli shock . Fourteen baboons ( Papio c. cynocephalus ) , r and omly divided into three groups , were anesthetized and administered 2-hr infusions of LD100 viable E. coli . Group A received E. coli alone ; Group B was administered E. coli followed by infusions of both gentamicin sulfate ( GS ) ( 18 mg/kg ) and methylprednisolone sodium succinate ( MPSS ) ( 75 mg/kg ) during a 12-hr period . Group C was given E. coli plus GS ( 18 mg/kg ) alone . Groups B and C baboons were also given GS intramuscularly , 4.5 mg/kg at 12 hr and twice daily for 3 days . Insensible fluid loss during the intial 12-hr period was replaced by minimal volumes of saline . Fully treated baboons ( Group B ) received steroid after 0.7 × 1010 organisms/kg body wt had been administered . All fully treated baboons survived ; however , all animals of Groups A and C died within 42 hr . Systemic hypotension observed in every baboon within 2 hr was reversed in Group B animals . Hypoglycemia , hypoinsulinemia , anuria , and extensive adrenal pathology were prevented by steroid/antibiotic treatment . Serum creatinine and blood urea nitrogen concentrations increased in all baboons but returned to normal in the fully treated group . Increased survival may have been due in part to augmented antibacterial activity elicited by ( a ) improved peripheral distribution of the antibiotic and ( b ) stimulation of the bone marrow by the steroid . Findings demonstrate that the lethal pathophysiology of E. coli-induced shock is effectively prevented by combined steroid and antibiotic therapy A prospect i ve ( Part I ) and a retrospective ( Part II ) study were used to determine the safety and efficacy of corticosteroids in the treatment of septic shock . In Part 1 , 172 consecutive patients in septic shock admitted over an 8-year period were treated with either steroid or saline : 43 received dexamethasone ( DMP ) , 43 received methylprednisolone ( MPS ) , and 86 received saline . The study was double-blind and r and omized , and the three groups were compared for age , severity of shock , presence of underlying disease , and year of study . In the 86 saline-treated patients , the mortality rate was 38.4 % ( 33/86 ) ; in the steroid-treated patients , it was 10.4 % ( 9/86 ) . With MPS the mortality rate was 11.6 % ( 5/43 ) , and with DMP it was 9.3 % ( 4/43 ) . Thus , overall mortality was significantly less in the steroid-treated group than in the control group . Further , there was no significant difference in mortality rate between the DMP- and the MPS-treated patients . In Part II , 328 patients were studied retrospectively . One-hundred sixty were treated without steroid , and 168 were treated with either DMP or MPS . Again , the two groups of patients were compared for severity of shock , underlying disease , age , and year of study . Mortality among patients treated without steroid was 42.5 % ( 68/160 ) and among patients treated with steroid was 14 % ( 24/168 ) ; there was no significant difference in mortality rate between DMP- and MPS-treated patients . In Parts I and II combined , complications occurred in 6 % of steroid-treated patients with no significant difference between DMP- and MPS-treated groups OBJECTIVE To determine the effect of moderate dose dexamethasone administered before antibiotics on the outcome of African children with sepsis . METHODS The design was a r and omized , double blinded , placebo-controlled trial of dexamethasone ( 0.2 mg/kg ) vs. placebo given intravenously before antibiotic therapy . Patients were recruited from the patient population s at two missionary hospitals . Primary outcome variables were determined before analysis of data . RESULTS Seventy-two children with sepsis were enrolled in the study . Treatment with dexamethasone was not associated with improved outcome for any of six outcome variables : survival to discharge ( 83 % , dexamethasone group ; 89 % , placebo group ) ; hemodynamic stability at 48 h ( 33 % , dexamethasone group ; 49 % , placebo group ) ; median length of hospital stay ( 11 days , dexamethasone group ; 11 days , placebo group ) ; normal at discharge ( 90 % , dexamethasone group ; 75 % , placebo group ) ; normal at follow-up ( 90 % , dexamethasone group ; 72 % , placebo group ) ; and afebrile at 48 to 72 h ( 61 % , dexamethasone group ; 44 % , placebo group ) . CONCLUSIONS These data indicate that a moderate dose of dexamethasone given before antibiotic therapy did not improve outcome in the pediatric patients with sepsis whom we studied OBJECTIVE To investigate the effects of stress doses of hydrocortisone on the duration of vasopressor therapy in human septic shock . DESIGN Prospect i ve , r and omized , double-blind , single-center study . SETTING Twenty-bed multidisciplinary intensive care unit in a 1400-bed university hospital . PATIENTS Forty consecutive patients who met the ACCP/SCCM criteria for septic shock . An additional criterion for inclusion in the study was vasopressor support and high-output circulatory failure with a cardiac index of > 4 L/min/m2 after fluid resuscitation ( pulmonary capillary wedge pressure : 12 - 15 mm Hg ) and without the use of positive inotropes such as dobutamine or dopexamine . The primary study end point was the time to cessation of vasopressor support ( norepinephrine or epinephrine in any dose , dopamine > or = 6 microg/kg/min ) . Secondary study end points were the evolution of hemodynamics and the multiple organ dysfunction syndrome ( MODS ) . The severity of illness at recruitment was grade d using the Acute Physiology and Chronic Health Evaluation II and the Simplified Acute Physiology Score II scoring systems . MODS was described by the Sepsis-related Organ Failure Assessment score . INTERVENTIONS All eligible patients were prospect ively r and omized to receive either stress doses of hydrocortisone or placebo . Hydrocortisone was started with a loading dose of 100 mg given within 30 mins and followed by a continuous infusion of 0.18 mg/ kg/hr . When septic shock had been reversed , the dose of hydrocortisone was reduced to 0.08 mg/kg/hr . This dose was kept constant for 6 days . As soon as the underlying infection had been treated successfully or sodium serum concentrations had increased to > 155 mmol/L , the hydrocortisone infusion was tapered in steps of 24 mg/day . Physiologic saline solution was the placebo . MEASUREMENTS AND MAIN RESULTS Hemodynamic and oxygen-derived variables were measured at previously defined time points over a study period of 5 days . Relevant clinical and laboratory measurements were registered for a study period of 14 days to assess the evolution of organ dysfunction . Baseline data at recruitment did not differ between the two groups . Shock reversal was achieved in 18 of the 20 patients treated with hydrocortisone vs. 16 of the 20 patients treated with placebo . Hydrocortisone significantly reduced the time to cessation of vasopressor support . The median time of vasopressor support was 2 days ( 1st and 3rd Quartiles , 1 and 6 days ) in the hydrocortisone-treated group and 7 days ( 1st and 3rd Quartiles , 3 and 19 days ) in the placebo group ( p = .005 Breslow test ) . There was a trend to earlier resolution of the organ dysfunction syndrome in the hydrocortisone group . CONCLUSIONS Infusion of stress doses of hydrocortisone reduced the time to cessation of vasopressor therapy in human septic shock . This was associated with a trend to earlier resolution of sepsis-induced organ dysfunctions . Overall shock reversal and mortality were not significantly different between the groups in this low-sized single-center study BACKGROUND In experimental models of meningitis and in children with meningitis , dexamethasone has been shown to reduce meningeal inflammation and to improve the outcome of disease . METHODS We conducted a placebo-controlled , double-blind trial of dexamethasone therapy in 101 infants and children admitted to the National Children 's Hospital , San José , Costa Rica , who had culture-proved bacterial meningitis or clinical signs of meningitis and findings characteristic of bacterial infection on examination of the cerebrospinal fluid . The patients were r and omly assigned to receive either dexamethasone and cefotaxime ( n = 52 ) or cefotaxime plus placebo ( n = 49 ) . Dexamethasone ( 0.15 mg per kilogram of body weight ) was given 15 to 20 minutes before the first dose of cefotaxime and was continued every 6 hours thereafter for four days . RESULTS The demographic , clinical , and laboratory profiles were similar for the patients in the two treatment groups . By 12 hours after the beginning of therapy , the mean opening cerebrospinal pressure and the estimated cerebral perfusion pressure had improved significantly in the dexamethasone-treated children but worsened in the children treated only with cefotaxime ( controls ) . At 12 hours meningeal inflammation and the concentrations of two cytokines ( tumor necrosis factor alpha and platelet-activating factor ) in the cerebrospinal fluid had decreased in the dexamethasone-treated children , whereas in the controls the inflammatory response in the cerebrospinal fluid had increased . At 24 hours the clinical condition and mean prognostic score were significantly better among those treated with dexamethasone than among the controls . At follow-up examination after a mean of 15 months , 7 of the surviving 51 dexamethasone-treated children ( 14 percent ) and 18 of 48 surviving controls ( 38 percent ) had one or more neurologic or audiologic sequelae ( P = 0.007 ) ; the relative risk of sequelae for a child receiving placebo as compared with a child receiving dexamethasone was 3.8 ( 95 percent confidence interval , 1.3 to 11.5 ) . CONCLUSIONS The results of this study , in which dexamethasone administration began before the initiation of cefotaxime therapy , provide additional evidence of a beneficial effect of dexamethasone therapy in infants and children with bacterial meningitis We compared high-dose dexamethasone ( initial dose , 3 mg per kilogram of body weight ) with placebo in a r and omized , double-blind trial involving 38 patients with culture-positive , specifically defined severe typhoid fever . The patients in the two treatment groups ranged in age from 5 to 54 and were comparable at the outset . All patients received chloramphenicol . The case-fatality rate of 10 per cent ( 2 of 20 patients ) in the dexamethasone group was significantly lower than the fatality rate of 55.6 per cent ( 10 of 18 ) in the placebo group ( P = 0.003 ) . There was no significant difference in the incidence of complications among the survivors in either group . Delirium , obtundation , and stupor were grave prognostic signs that were useful for predicting which patients were at high risk of dying before they became comatose or went into shock . Dexamethasone is unnecessary for most patients with typhoid but is recommended for all patients with suspected typhoid fever who are delirious , obtunded , stuporous , comatose , or in shock We enrolled 200 infants and older children with bacterial meningitis in two prospect i ve double-blind , placebo-controlled trials to evaluate the efficacy of dexamethasone therapy in addition to either cefuroxime ( Study 1 ) or ceftriaxone ( Study 2 ) . Altogether , 98 patients received placebo and 102 received dexamethasone ( 0.15 mg per kilogram of body weight every six hours for four days ) . At the beginning of therapy , the clinical and demographic characteristics of the patients in the treatment groups were comparable . The mean increase in the cerebrospinal fluid concentration of glucose and the decreases in lactate and protein levels after 24 hours of therapy were significantly greater in those who received dexamethasone than in those who received placebo ( glucose , 2.0 vs. 0.4 mmol per liter [ 36.0 vs. 6.9 mg per deciliter ] , P less than 0.001 ; lactate , 4.0 vs. 2.1 mmol per liter [ 38.3 vs. 19.8 mg per deciliter ] , P less than 0.001 ; and protein , 0.64 vs. 0.25 g per liter [ 64.0 vs. 25.3 mg per deciliter ] , P less than 0.05 ) . One patient in the placebo group in Study 1 died . As compared with those who received placebo , the patients who received dexamethasone became afebrile earlier ( 1.6 vs. 5.0 days ; P less than 0.001 ) and were less likely to acquire moderate or more severe bilateral sensorineural hearing loss ( 15.5 vs. 3.3 percent ; P less than 0.01 ) . Twelve patients in the two placebo groups ( 14 percent ) had severe or profound bilateral hearing loss requiring the use of a hearing aid , as compared with 1 ( 1 percent ) in the two dexamethasone groups ( P less than 0.001 ) . We conclude that dexamethasone is beneficial in the treatment of infants and children with bacterial meningitis , particularly in preventing deafness AIMS To investigate the relationship between adrenal gl and function and pressor response to noradrenaline in septic shock . METHODS Basal cortisol level , noradrenaline -- mean arterial pressure dose-response curve and cortisol response to intravenous corticotrophin bolus were obtained in nine patients fulfilling usual criteria for septic shock and in six normal volunteers . In patients with septic shock , dose-response curve to noradrenaline was determined a second time 60 min after a 50 mg intravenous hydrocortisone bolus . RESULTS As compared with controls , patients with septic shock had increased basal cortisol levels ( mean+/-s.d . : 1564+/-818 vs 378+/-104 nmol l(-1 ) , P=0.002 , 95 % confidence interval for difference in means : [ 452 , 1920 ] ) and a blunted cortisol response to corticotrophin ( 403+/-461 vs 1132+/-195 nmol l(-1 ) , P=0.008 , [ -1163 , -2951 ) . Five patients had impaired adrenal function reserve . As compared with controls , septic patients displayed a moderate and non significant decrease in pressor sensitivity to noradrenaline ( P=0.112 ) . As compared with patients with adequate adrenal response , patients with impaired adrenal function reserve showed a significant decrease in pressor sensitivity to noradrenaline ( P=0.038 ) . In septic patients , hydrocortisone improved pressor response to noradrenaline ( P=0.032 ) . This effect was more marked in patients with impaired adrenal function reserve so that , as compared with patients with adequate response , the difference was no longer significant ( P=0.123 ) . CONCLUSIONS In septic shock , impaired adrenal function reserve may partly be accounted for by the depressed pressor sensitivity to noradrenaline . The latter may be substantially improved by physiological doses of hydrocortisone The use of high-dose corticosteroids in the treatment of severe sepsis and septic shock remains controversial . Our study was design ed as a prospect i ve , r and omized , double-blind , placebo-controlled trial of high-dose methylprednisolone sodium succinate for severe sepsis and septic shock . Diagnosis was based on the clinical suspicion of infection plus the presence of fever or hypothermia ( rectal temperature greater than 38.3 degrees C [ 101 degrees F ] or less than 35.6 degrees C [ 96 degrees F ] ) , tachypnea ( greater than 20 breaths per minute ) , tachycardia ( greater than 90 beats per minute ) , and the presence of one of the following indications of organ dysfunction : a change in mental status , hypoxemia , elevated lactate levels , or oliguria . Three hundred eighty-two patients were enrolled . Treatment -- either methylprednisolone sodium succinate ( 30 mg per kilogram of body weight ) or placebo -- was given in four infusions , starting within two hours of diagnosis . No significant differences were found in the prevention of shock , the reversal of shock , or overall mortality . In the subgroup of patients with elevated serum creatinine levels ( greater than 2 mg per deciliter ) at enrollment , mortality at 14 days was significantly increased among those receiving methylprednisolone ( 46 of 78 [ 59 percent ] vs. 17 of 58 [ 29 percent ] among those receiving placebo ; P less than 0.01 ) . Among patients treated with methylprednisolone , significantly more deaths were related to secondary infection . We conclude that the use of high-dose corticosteroids provides no benefit in the treatment of severe sepsis and septic shock

In Africa and Asia , LSM is another policy option , alongside LLINs and IRS , for reducing malaria morbidity in both urban and rural areas where a sufficient proportion of larval habitats can be targeted .

BACKGROUND Malaria is an important cause of illness and death in people living in many parts of the world , especially sub-Saharan Africa . Long-lasting insecticide treated bed nets ( LLINs ) and indoor residual spraying ( IRS ) reduce malaria transmission by targeting the adult mosquito vector and are key components of malaria control programmes . However , mosquito numbers may also be reduced by larval source management ( LSM ) , which targets mosquito larvae as they mature in aquatic habitats . This is conducted by permanently or temporarily reducing the availability of larval habitats ( habitat modification and habitat manipulation ) , or by adding substances to st and ing water that either kill or inhibit the development of larvae ( larviciding ) . OBJECTIVES To evaluate the effectiveness of mosquito LSM for preventing malaria .

Background Malaria control in Africa is most tractable in urban settlements yet most research has focused on rural setting s. Elimination of malaria transmission from urban areas may require larval control strategies that complement adult mosquito control using insecticide-treated nets or houses , particularly where vectors feed outdoors . Methods and Findings Microbial larvicide ( Bacillus thuringiensis var . israelensis ( Bti ) ) was applied weekly through programmatic , non-r and omized community-based , but vertically managed , delivery systems in urban Dar es Salaam , Tanzania . Continuous , r and omized cluster sampling of malaria infection prevalence and non-r and om programmatic surveillance of entomological inoculation rate ( EIR ) respectively constituted the primary and secondary outcomes surveyed within a population of approximately 612,000 residents in 15 fully urban wards covering 55 km2 . Bti application for one year in 3 of those wards ( 17 km2 with 128,000 residents ) reduced crude annual transmission estimates ( Relative EIR [ 95 % Confidence Interval ] = 0.683 [ 0.491–0.952 ] , P = 0.024 ) but program effectiveness peaked between July and September ( Relative EIR [ CI ] = 0.354 [ 0.193 to 0.650 ] , P = 0.001 ) when 45 % ( 9/20 ) of directly observed transmission events occurred . Larviciding reduced malaria infection risk among children ≤5 years of age ( OR [ CI ] = 0.284 [ 0.101 to 0.801 ] , P = 0.017 ) and provided protection at least as good as personal use of an insecticide treated net ( OR [ CI ] = 0.764 [ 0.614–0.951 ] , P = 0.016 ) . Conclusions In this context , larviciding reduced malaria prevalence and complemented existing protection provided by insecticide-treated nets . Larviciding may represent a useful option for integrated vector management in Africa , particularly in its rapidly growing urban centres The study was conducted in eight adjacent villages in central Sri Lanka where there are many shallow pits dug by gem miners that fill with water . These become breeding places of the main malarial vector Anopheles culicifacies , and of the second most important vector Anopheles subpictus , but not of Anopheles varuna , the third most important vector . With the help of local volunteers , data on the adult population s of these three species was collected by various st and ard methods , and data on the incidence of malaria cases was collected by two clinics set up for the project and through the existing hospitals . Prevalence of malaria infection in symptom-less people was investigated by mass blood surveys . On the basis of a year 's pre-intervention data the villages were stratified into four with high levels of malaria transmission and four with lower transmission . Within each stratum two villages were r and omly assigned for mosquito control by treating all the gem pits , as well as river bed pools , with a granular formulation of the insect growth regulator pyriproxyfen at a target dose of 0.01 mg a.i./litre . The intervention caused significant reductions in the adult population s of An . culicifacies and An . subpictus . Similarly , incidence of malaria was reduced in the intervention villages to about 24 % ( 95 % c.l . 20 - 29 % ) of that in the controls . Prevalence of parasitaemia also declined significantly . It is concluded that in this situation where , with active community participation , the breeding sites of the main vectors could be located ; vector control by a highly active and persistent insect growth regulator can be a very effective means of malaria control The relationship between malaria transmission intensity and efficiency is important for malaria epidemiology , for the design of r and omized control trials that measure transmission or incidence as end points , and for measuring and modelling malaria transmission and control . Five kinds of studies published over the past century were assembled and reanalysed to quantify malaria transmission efficiency and describe its relation to transmission intensity , to underst and the causes of inefficient transmission and to identify functions suitable for modelling mosquito-borne disease transmission . In this study , we show that these studies trace a strongly nonlinear relationship between malaria transmission intensity and efficiency that is parsimoniously described by a model of heterogeneous biting . When many infectious bites are concentrated on a few people , infections and parasite population structure will be highly aggregated affecting the immunoepidemiology of malaria , the evolutionary ecology of parasite life history traits and the measurement and stratification of transmission for control using entomological and epidemiological data An evaluation of pyriproxyfen as a larval control agent with the aim of reducing malaria vector population s and incidence of malaria was conducted in 12 villages in an irrigated settlement scheme in the dry zone of central Sri Lanka . In these villages , there are many pools in the beds of rivers , streams , and irrigation ditches during the dry season of the year . These are the major breeding places of the malaria vectors Anopheles culicifacies and An . subpictus . Collection s of adult mosquitoes were carried out by using st and ard methods and parasitological data were collected by daily malaria clinics set up for the project and through the 2 government hospitals . All villages in the study area were under residual house spraying with lambdacyhalothrin water-dispersible powder . Using the 1st year 's baseline data collection , the villages were stratified into 6 villages with high malaria incidence and 6 villages with low incidence . Within each group , 3 villages were r and omly assigned for larval control by treating all the pools in the beds of rivers , streams , and irrigation ditches and agricultural wells with a granular formulation of the insect growth regulator pyriproxyfen at the rate of 0.01 mg active ingredient/liter . The field bioassays indicated that a single treatment of pyriproxyfen effectively inhibited the emergence of adult mosquitoes in the riverbed pools for a period of 190 days . The treatment caused significant reduction of the adult population s of An . culicifacies ( 78 % ) and An . subpictus ( 72 % ) . Similarly , incidence of malaria was reduced in the treatment villages by about 70 % ( 95 % confidence interval 58 - 78 % ) compared with the controls . The conclusion is made that pyriproxyfen can be a very effective means of malaria control if all possible vector breeding places in the area can be located

Conclusion EGDT is not superior to usual care for ED patients with septic shock but is associated with increased utilisation of ICU re sources

Purpose To determine whether early goal -directed therapy ( EGDT ) reduces mortality compared with other resuscitation strategies for patients presenting to the emergency department ( ED ) with septic shock .

OBJECTIVE To compare the efficacy of fluid resuscitation as guided by lactate clearance rate ( LCR ) and central venous oxygen saturation ( ScvO2 ) in patients with sepsis . METHODS A prospect i ve r and omized control study was conducted . Fifty patients diagnosed with severe sepsis or septic shock from January 2011 to February 2012 in department of critical care medicine of Fourth Hospital of Hebei Medical University were enrolled in the study . The patients were r and omly divided into two groups according to the sequence ( each n=25 ) : ScvO2 group and LCR group . After ICU admission , the patients were treated symptomatically timely , and fluid resuscitation was started as early as possible according to Surviving Sepsis Campaign guidance for management of severe sepsis and septic shock 2008 . Central venous pressure (CVP)≥8 mm Hg ( 1 mm Hg=0.133 kPa ) , mean arterial pressure (MAP)≥65 mm Hg and ScvO2≥0.70 served as goal values to accomplish the fluid resuscitation therapy in ScvO2 group , while CVP≥8 mm Hg , MAP≥65 mm Hg , LCR≥10 % served as goal value to accomplish the fluid resuscitation therapy in LCR group . The general condition and clinical characteristics on arrival in ICU , changes in CVP , MAP , ScvO2 , lactate level and /or LCR before ( 0 hour ) and 3 , 6 , 72 hours after the start of fluid resuscitation and the other related conditions during the therapy were recorded . RESULTS There was no significant difference in general data or clinical characteristics before the start of therapy , occurrence of organ dysfunction , or treatment measures during different time periods after start of fluid resuscitation . Compared with the condition immediately before fluid resuscitation , at 3 hours after start of fluid resuscitation , CVP were improved in LCR and ScvO2 groups ( 8.58±1.17 mm Hg vs. 6.33±1.21 mm Hg , 9.08±2.43 mm Hg vs. 5.33±0.98 mm Hg , both P<0.05 ) ; at 6 hours after start of fluid resuscitation , heart rate ( HR ) and respiratory rate ( RR ) were lowered in LCR and ScvO2 groups ( HR : 96±18 bpm vs. 127±13 bpm , 98±13 bpm vs. 116±19 bpm , RR : 23±3 times/min vs. 33±9 times/min , 24±5 times/min vs. 35±6 times/min , all P<0.05 ) , oxygenation index ( PaO2/FiO2 ) was increased in LCR and ScvO2 groups ( 179±41 mm Hg vs. 86±21 mm Hg , 202±33 mm Hg vs. 95±17 mm Hg , both P<0.05 ) , and there was no significant difference in MAP in both groups . There was no significant difference in all indexes between two groups . In LCR group , 3 hours after start of fluid resuscitation , lactate level was significantly decreased ( 2.81±0.18 mmol/L vs. 3.43±1.31 mmol/L , P<0.05 ) . Compared with the value 3 hours after start of fluid resuscitation , LCR was significantly improved at 6 hours and 72 hours after start of fluid resuscitation in LCR group [ (42.69±8.75)% , (48.87±9.69)% vs. (20.32±4.58)% , both P<0.05 ] . Compared with that immediately before fluid resuscitation , ScvO2 was significant improved in ScvO2 group at 3 hours after start of fluid resuscitation ( 0.65±0.04 vs. 0.53±0.06 , P<0.05 ) . There was no significant difference in success rate of fluid resuscitation comparing that of 6 hours and that of 72 hours [ 6 hours : 72 % ( 18/25 ) vs. 64 % ( 16/25 ) , χ(2)=0.368 , P=0.762 ; 72 hours : 88 % ( 22/25 ) vs. 88 % ( 22/25 ) , χ(2)=0.000 , P=1.000 ] , length of ICU stay ( 8±3 days vs. 10±4 days , t=0.533 , P=0.874 ) , length of hospital stay ( 29±11 days vs. 35±16 days , t=0.692 , P=0.531 ) , improvement rate [ 84 % ( 21/25 ) vs. 76%(19/25 ) , χ(2)=0.500 , P=0.480 ] or 28-day mortality [ 20 % ( 5/25 ) vs. 28 % ( 7/25 ) , χ(2)=0.439 , P=0.742 ] between LCR and ScvO2 groups . CONCLUSIONS Both LCR and ScvO2 can be taken as the index in confirming the endpoint of fluid resuscitation for patients with severe sepsis and septic shock . Fluid resuscitation therapy under the guidance of LCR is accurate and reliable in patients with severe sepsis and septic shock 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 . ) 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 . ) CONTEXT Goal -directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department . OBJECTIVE To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation ( ScvO2 ) as goals of early sepsis resuscitation . DESIGN , SETTING , AND PATIENTS Multicenter r and omized , noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals . INTERVENTIONS We r and omly assigned patients to 1 of 2 resuscitation protocol s. The ScvO2 group was resuscitated to normalize central venous pressure , mean arterial pressure , and ScvO2 of at least 70 % ; and the lactate clearance group was resuscitated to normalize central venous pressure , mean arterial pressure , and lactate clearance of at least 10 % . The study protocol was continued until all goals were achieved or for up to 6 hours . Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment . MAIN OUTCOME MEASURE The primary outcome was absolute in-hospital mortality rate ; the noninferiority threshold was set at Delta equal to -10 % . RESULTS Of the 300 patients enrolled , 150 were assigned to each group and patients were well matched by demographic , comorbidities , and physiological features . There were no differences in treatments administered during the initial 72 hours of hospitalization . Thirty-four patients ( 23 % ) in the ScvO2 group died while in the hospital ( 95 % confidence interval [ CI ] , 17%-30 % ) compared with 25 ( 17 % ; 95 % CI , 11%-24 % ) in the lactate clearance group . This observed difference between mortality rates did not reach the predefined -10 % threshold ( intent-to-treat analysis : 95 % CI for the 6 % difference , -3 % to 15 % ) . There were no differences in treatment-related adverse events between the groups . CONCLUSION Among patients with septic shock who were treated to normalize central venous and mean arterial pressure , additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00372502 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 . ) 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 The Protocol ized Care for Early Septic Shock study is a r and omised , multicentre , prospect i ve , three-arm , parallel-group trial of alternative resuscitation strategies for early septic shock . OBJECTIVE To state our analysis plan for trial data . METHODS Our plan is to guide data collection and analysis using pre-existing definitions and testing , with local consensus-based efforts where needed . We examine protocol ised care ( two experimental approaches ) and compare this to usual " wild type " care . RESULTS Our plan is to address three aims ( clinical efficacy , biology of illness and recovery , and costs and cost-effectiveness ) and four hypotheses , and we specify rules for h and ling data and determining outcomes . CONCLUSION By using measures to maintain study conduct and analysis rigour , we hope to improve underst and ing of early septic shock resuscitation and care of patients Introduction The ACCM/PALS guidelines address early correction of paediatric septic shock using conventional measures . In the evolution of these recommendations , indirect measures of the balance between systemic oxygen delivery and dem and s using central venous or superior vena cava oxygen saturation ( ScvO2 ≥ 70 % ) in a goal -directed approach have been added . However , while these additional goal -directed endpoints are based on evidence -based adult studies , the extrapolation to the paediatric patient remains unvali date d. Objective The purpose of this study was to compare treatment according to ACCM/PALS guidelines , performed with and without ScvO2 goal -directed therapy , on the morbidity and mortality rate of children with severe sepsis and septic shock . Design , participants and interventions Children and adolescents with severe sepsis or fluid-refractory septic shock were r and omly assigned to ACCM/PALS with or without ScvO2 goal -directed resuscitation . Measurements Twenty-eight-day mortality was the primary endpoint . Results Of the 102 enrolled patients , 51 received ACCM/PALS with ScvO2 goal -directed therapy and 51 received ACCM/PALS without ScvO2 goal -directed therapy . ScvO2 goal -directed therapy result ed in less mortality ( 28-day mortality 11.8 % vs. 39.2 % , p = 0.002 ) , and fewer new organ dysfunctions ( p = 0.03 ) . ScvO2 goal -directed therapy result ed in more crystalloid ( 28 ( 20–40 ) vs. 5 ( 0–20 ) ml/kg , p < 0.0001 ) , blood transfusion ( 45.1 % vs. 15.7 % , p = 0.002 ) and inotropic ( 29.4 % vs. 7.8 % , p = 0.01 ) support in the first 6 h. Conclusions This study supports the current ACCM/PALS guidelines . Goal -directed therapy using the endpoint of a ScvO2 ≥ 70 % has a significant and additive impact on the outcome of children and adolescents with septic shock AIM Determine current resuscitation practice s and outcomes in patients presenting to the emergency department ( ED ) with sepsis and hypoperfusion or septic shock in Australia and New Zeal and ( ANZ ) . METHODS Three-month prospect i ve , multi-centre , observational study of all adult patients with sepsis and hypoperfusion or septic shock in the ED of 32 ANZ tertiary-referral , metropolitan and rural hospitals . RESULTS 324 patients were enrolled ( mean [ SD ] age 63.4 [ 19.2 ] years , APACHE II score 19.0 [ 8.2 ] , 52.5 % male ) . Pneumonia ( n=138/324 , 42.6 % ) and urinary tract infection ( n=98/324 , 30.2 % ) were the commonest sources of sepsis . Between ED presentation and 6hours post-enrolment ( T6hrs ) , 44.4 % ( n=144/324 ) of patients received an intra-arterial catheter , 37 % ( n=120/324 ) a central venous catheter and 0 % ( n=0/324 ) a continuous central venous oxygen saturation ( ScvO(2 ) ) catheter . Between enrolment and T6hrs , 32.1 % ( n=104/324 ) received a vasopressor infusion , 7.4 % ( n=24/324 ) a red blood cell transfusion , 2.5 % ( n=8/324 ) a dobutamine infusion and 18.5 % ( n=60/324 ) invasive mechanical ventilation . Twenty patients ( 6.2 % ) were transferred from ED directly to the operating theatre , 36.4 % ( n=118/324 ) were admitted directly to ICU , 1.2 % ( n=4/324 ) died in the ED and 56.2 % ( n=182/324 ) were transferred to the hospital floor . Overall ICU admission rate was 52.4 % ( n=170/324 ) . ICU and overall in-hospital mortality were 18.8 % ( n=32/170 ) and 23.1 % ( n=75/324 ) respectively . In-hospital mortality was not different between patients admitted to ICU ( 24.7 % , n=42/170 ) and the hospital floor ( 21.4 % , n=33/154 ) . CONCLUSIONS Management of ANZ patients presenting to ED with sepsis does not routinely include protocol ised , ScvO(2)-directed resuscitation . In-hospital mortality compares favourably with reported mortality in international sepsis trials and nationwide surveys of resuscitation practice OBJECTIVE To determine the clinical effectiveness of implementing early goal -directed therapy ( EGDT ) as a routine protocol in the emergency department ( ED ) . METHODS Prospect i ve interventional study conducted over 2 years at an urban ED . Inclusion criteria included suspected infection , criteria for systemic inflammation , and either systolic BP < 90 mm Hg after a fluid bolus or lactate concentration > /= 4 mol/L. Exclusion criteria were age < 18 years , contraindication to a chest central venous catheter , and need for immediate surgery . We prospect ively recorded preintervention clinical and mortality data on consecutive , eligible patients for 1 year when treatment was at the discretion of board-certified emergency physicians . We then implemented an EGDT protocol ( the intervention ) and recorded clinical data and mortality rates for 1 year . Prior to the first year , we defined a 33 % relative reduction in mortality ( relative mortality reduction that was found in the original EGDT trial ) to indicate clinical effectiveness of the intervention . RESULTS We enrolled 79 patients in the preintervention year and 77 patients in the postintervention year . Compared with the preintervention year , patients in the postintervention year received significantly greater crystalloid volume ( 2.54 L vs 4.66 L , p < 0.001 ) and frequency of vasopressor infusion ( 34 % vs 69 % , p < 0.001 ) during the initial resuscitation . In-hospital mortality was 21 of 79 patients ( 27 % ) before intervention , compared with 14 of 77 patients ( 18 % ) after intervention ( absolute difference , - 9 % ; 95 % confidence interval , + 5 to - 21 % ) . CONCLUSIONS Implementation of EGDT in our ED was associated with a 9 % absolute ( 33 % relative ) mortality reduction . Our data provide external validation of the clinical effectiveness of EGDT to treat sepsis and septic shock in the ED BACKGROUND The Protocol ised Management in Sepsis ( ProMISe ) trial is an open , multicentre , r and omised controlled trial ( RCT ) of the clinical effectiveness and cost-effectiveness of early , goal directed , protocol ised resuscitation compared with usual resuscitation for patients presenting to emergency departments ( EDs ) in the United Kingdom with early signs of severe sepsis or septic shock . The rationale for the ProMISe trial derives from a single-centre United States RCT that reported a reduction in hospital mortality from 46.5 % to 30.5 % . OBJECTIVE To describe the proposed statistical analyses for the evaluation of clinical effectiveness for the ProMISe trial . It is important to complete this plan before inspecting the data , and before completion of two related international studies , so that post-hoc , data -derived decisions are avoided . METHODS The primary and secondary outcomes were defined precisely , and the approach to safety monitoring and data collection summarised , with a description of the planned statistical analyses including prespecified subgroup and secondary analyses . RESULTS The primary outcome is all-cause mortality at 90 days . The primary analysis will be reported as a relative risk and absolute risk reduction and tested with the Fisher exact test . Prespecified subgroup analyses will be based on age , baseline Medical Emergency Department Sepsis score , baseline Sequential Organ Failure Assessment score , and time from ED presentation to r and omisation . Secondary analyses include adjustment for baseline covariates , estimation of learning curve effects and adjustment for noncompliance . CONCLUSION In keeping with best practice , we have developed a statistical analysis plan for the ProMISe trial and place it in the public domain before inspecting data from the trial OBJECTIVE To observe the clinical effects of 10 % , 30 % lactate clearance rate and early goal -directed therapy ( EGDT ) as 6-hour resuscitation goals directing treatment in septic shock patients with severe pneumonia . METHODS In this r and omized , perspective study , septic shock patients with severe pneumonia were divided into control group and experimental group , which included 10 % lactate clearance rate group and 30 % lactate clearance rate group , adopting r and om number method . The control group was treated with 6-hour EGDT strategy , and the experimental groups were treated with 10 % lactate clearance rate protocol and 30 % lactate clearance rate protocol respectively , beside the EGDT . RESULTS There were 19 patients in control group , and 43 patients in experimental group , which included 22 patients in 10 % lactate clearance rate group and 21 patients in 30 % lactate clearance rate group . Patients were well matched by basic features . After 48 hours , the acute physiology and chronic health evaluation II ( APACHE II ) score of both 10 % lactate clearance rate group ( 13.76 ± 6.00 , P < 0.05 ) and 30 % lactate clearance rate group ( 13.60 ± 6.18 , P < 0.05 ) were lower than that of control group ( 18.15 ± 6.62 ) . There were no differences in time of mechanical ventilation ( hours ) between control group and experimental group ( 10 % group 136.90 ± 100.02 , 30 % group 97.00 ± 75.20 , control group 152.32 ± 96.51 , P > 0.05 ) . The length in intensive care unit ( ICU , days ) of 10 % and 30 % lactate clearance rate groups were significantly shorter than control group ( 10 % group 7.94 ± 6.00 , 30 % group 7.51 ± 3.99 , control group 11.31 ± 5.97 , both P < 0.05 ) . The three groups had no differences in 7-day mortality rate ( 10 % group 18.18 % , 30 % group 14.29 % , control group 21.05 % , all P > 0.05 ) , but the 28-day mortality of 10 % and 30 % lactate clearance rate groups were significantly lower than control group ( 10 % group 36.36 % , 30 % group 28.57 % , control group 63.16 % ) , especially in 30 % lactate clearance rate group ( P < 0.05 ) . CONCLUSION For the septic shock patients with severe pneumonia , prompt archiving EGDT strategy and 6-hour lactate clearance more than 30 % were associated with an optimal outcome OBJECTIVE To investigate the efficacy and effect on outcome of goal -directed therapy in patients with septic shock compared with conventional therapy . METHODS Sixteen patients with septic shock were r and omly assigned to receive goal -directed therapy , with central venous pressure ( CVP ) 8 - 12 mm Hg ( 1 mm Hg=0.133 kPa ) , mean arterial pressure ( MAP ) > or=65 mm Hg , venous oxygen saturation ( SvO(2))>0.70 ( superior vena cava saturation ) , and urine output > or=0.5 ml/min as therapeutic goals . Another 17 patients received conventional therapy as controls . The arterial oxygen saturation ( SaO(2 ) ) , SvO(2 ) , MAP , CVP , heart stroke volume cardiac index ( CI ) , serum lactate , volume of fluid , amount of vasopressors , the numbers of organ injured and patients who needed continuity blood purification ( CBP ) and /or ventilation were recorded serially for 6 - 48 hours , and they were compared between the two groups . The mortality of the patients in two groups on 7 days and 14 days were also recorded . RESULTS There were no significant differences between the groups with respect to base-line characteristics . During the interval from 24 to 48 hours , the patients assigned to goal -directed therapy had a significantly higher in SaO(2 ) , SvO(2 ) , MAP , CVP , CI ( P<0.05 or P<0.01 ) , a lower lactate concentration ( P<0.01 ) , significantly more fluid during 6 - 24 hours and less vasopressors ( both P<0.01 ) . Seven and 14 days in-hospital mortality were lower in goal -directed therapy group as compared with the control group(P<0.05 ) . CONCLUSION The efficacy of goal -directed therapy in patients with septic shock is significantly better than conventional therapy in ameliorating outcome of shock and can be easily used in intensive care unit ( ICU ) OBJECTIVE To investigate the effect of early goal -directed therapy ( EGDT ) on treatment of critical patients with severe sepsis/septic shock . METHODS A multi-center , prospect i ve , r and omized , controlled study was deployed . Totally 314 critical patients , from eight comprehensive hospitals in Zhejiang Province admitted during January , 2005 to January , 2008 , suffering from severe sepsis/septic shock were r and omized into conventional treatment group ( n=151 ) and EGDT group ( n=163 ) , the patients of the former underwent fluid resuscitation guided by central venous pressure ( CVP ) , systolic blood pressure ( SBP ) or mean artery pressure ( MAP ) and urinary output ( UO ) , and the latter guided by CVP , SBP or MAP and UO plus central venous oxygen saturation ( ScvO2 ) . The patients were treated with fluid , blood transfusions and cardiac stimulants in a period of 6 hours after enrollment to reach the goal . The difference of 28-day survival rate and intensive care unit ( ICU ) mortality ( primary end points ) , the length of ICU stay , the duration of mechanical ventilation , duration of antibiotics treatment , incidence of newly occurred infection , and severity scores ( secondary end points ) were compared between two groups . RESULTS Finally , a total of 303 patients were eligible to enter this study , with 157 patients in EGDT group and 146 patients in conventional treatment group . In comparison with conventional treatment group , the 28-day survival rate of EGDT group was increased by 17.7 % ( 75.2 % vs. 57.5 % , P=0.001 ) and the ICU mortality of EGDT group was decreased by 15.7 % ( 35.0 % vs. 50.7 % , P=0.035 ) , the acute physiology and chronic health evaluation II ( APACHEII ) score ( 14.4+/-8.5 vs. 18.0+/-7.1 , P=0.043 ) , multiple organ dysfunction syndrome ( MODS ) score ( 5.8+/-3.1 vs. 8.9+/-3.7 , P=0.014 ) and sepsis-related organ failure assessment ( SOFA ) score ( 5.6+/-2.9 vs. 10.4+/-3.7 , P=0.001 ) were significantly decreased in EGDT group . Meanwhile , a significant shortening of duration of using antibiotics was also found [ ( 13.4+/-10.0 ) days vs. ( 19.7+/-13.5 ) days , P=0.004 ] , with a lowering of incidence of occurrence of new infection ( 37.6 % vs. 53.4 % , P=0.014 ) . There were no differences in other parameters for secondary end points . CONCLUSION EGDT improves 28-day survival rate and clinical scores , and it shows beneficial effects on outcome of critical patients with severe sepsis/septic shock OBJECTIVE To explore the effect of early goal -directed therapy ( EGDT ) according to pulse indicated continuous cardiac output ( PiCCO ) on septic shock patients . METHODS Eighty-two septic shock patients in Subei People 's Hospital of Jiangsu Province from January 2009 to December 2012 were enrolled and r and omly divided into two groups using a r and om number table , st and ard surviving sepsis bundle group ( n=40 ) and modified surviving sepsis bundles group ( n=42 ) . The patients received the st and ard EGDT bundles in st and ard surviving sepsis bundle group . PiCCO catheter was placed in modified surviving sepsis bundles group . Fluid resuscitation was guided by intrathoracic blood volume index ( ITBVI ) with the aim of 850 - 1 000 mL/m(2 ) . Dobutamine was used to improve the heart function according to left ventricular contractile index ( dPmax ) and stroke volume index ( SVI ) . The mean arterial blood pressure ( MAP ) was maintained 65 mmHg ( 1 mmHg=0.133 kPa ) or above with norepinephrine . Extra-vascular lung water was monitored for the titration of liquid and diuretics . The acute physiology and chronic health evaluation II ( APACHEII ) score , sequential organ failure assessment ( SOFA ) score , the number of patients needed vasopressor , serum procalcitonin ( PCT ) , lactic acid and lactate extraction ratio , the amount of fluid resuscitation , duration of mechanical ventilation , duration of intensive care unit ( ICU ) stay , hospital mortality were recorded in both groups . RESULTS After treatment , the APACHEII score , SOFA score and the number of patients needed vasopressor were gradually reduced in both groups , and those in modified surviving sepsis bundle group were significantly lower than those of st and ard sepsis bundle group at 72 hours ( APACHEII score : 13.1±6.5 vs. 20.9±7.5 , SOFA score : 8.8±4.3 vs. 14.6±4.9 , the number of patients needed vasopressor : 8 vs. 17 , all P<0.05 ) . Arterial blood lactate clearance rate was gradually increased after treatment in both groups . Lactate clearance rate in modified surviving sepsis bundle group was significantly higher than that of st and ard surviving sepsis bundle group [ 6 hours : (18.2±8.3)% vs. (10.8±7.5)% , t=-6.036 , P=0.001 ; 12 hours : (22.6±7.3)% vs. (12.4±8.1)% , t=-4.536 , P=0.001 ; 24 hours : (27.8±5.6)% vs. (16.4±9.5)% , t=-5.882 , P=0.000 ] . The amount of fluid resuscitation within 6 hours in modified surviving sepsis bundle group increased significantly compared with st and ard surviving sepsis bundle group ( 3 608±715 mL vs. 2 809±795 mL , t=-3.865 , P=0.033 ) . The amount of fluid resuscitation within 24 , 48 and 72 hours in modified surviving sepsis bundle group was significantly less than that of st and ard modified surviving sepsis bundle group with the nadir at 72 hours ( 918±351 mL vs. 1 805±420 mL , t=5.907 , P=0.037 ) . Duration of mechanical ventilation ( 98.4±20.3 hours vs. 143.3±29.6 hours , t=9.766 , P=0.001 ) and ICU stay ( 7.1±3.1 days vs. 9.5±2.5 days , t=2.993 , P=0.004 ) were significantly reduced in modified surviving sepsis bundle group compared with st and ard surviving sepsis bundle group . The hospital mortality in modified surviving sepsis bundle group was slightly lower than that in st and ard surviving sepsis bundle group [ 16.7 % ( 7/42 ) vs. 17.5%(7/40 ) , χ (2)=0.010 , P=0.920 ] . CONCLUSIONS Modified surviving sepsis bundle treatment according PiCCO can reduce the severity of disease in patients with septic shock , can make more accurately guide fluid resuscitation , and can reduce lung water and duration of mechanical ventilation and ICU stay . It has great clinical significance

Bone disease , assessed by changes in PTH levels , is improved by all vitamin D preparations . However , no consistent differences between routes of administration , frequencies of dosing or vitamin D preparations were demonstrated . Although fewer episodes of high calcium levels occurred with the non-calcium-containing phosphate binder , sevelamer , compared with calcium-containing binders , there were no differences in serum phosphorus and calcium overall and phosphorus values were reduced to similar extents . All studies were small with few data available on patient-centred outcomes ( growth , bone deformities ) and limited data on biochemical parameters or bone histology result ing in considerable imprecision of results thus limiting the applicability to the care of children with CKD

BACKGROUND Bone disease is common in children with chronic kidney disease ( CKD ) and when untreated may result in bone deformities , bone pain , fractures and reduced growth rates . This is an up date of a review first published in 2010 . OBJECTIVES This review aim ed to examine the benefits ( improved growth rates , reduced risk of bone fractures and deformities , reduction in PTH levels ) and harms ( hypercalcaemia , blood vessel calcification , deterioration in kidney function ) of interventions ( including vitamin D preparations and phosphate binders ) for the prevention and treatment of metabolic bone disease in children with CKD .

BACKGROUND Intermittent oral or intravenous doses of calcitriol given two or three times per week are commonly used to treat secondary hyperparathyroidism ( secondary HPT ) . This study was undertaken to compare the biochemical and skeletal responses to thrice weekly intraperitoneal ( i.p . ) versus oral doses of calcitriol in children with secondary HPT undergoing peritoneal dialysis ( CCPD ) . METHODS Forty-six patients aged 12.5+/-4.8 years on CCPD for 22+/-25 months were r and omly assigned to treatment with oral ( p.o . ) or i.p . calcitriol for 12 months ; 17 subjects given p.o . calcitriol and 16 subjects given i.p . calcitriol completed the study . Bone biopsies were performed at the beginning and at the end of the study , while determinations of serum and total ionized calcium , phosphorus , alkaline phosphatase , parathyroid hormone ( PTH ) and calcitriol levels were done monthly . RESULTS Serum total and ionized calcium levels were higher in subjects treated with i.p . calcitriol , P < 0.0001 , whereas serum phosphorus levels were higher in those given p.o . calcitriol , P < 0.0001 . For the i.p . group , serum PTH levels decreased from pre-treatment values of 648+/-125 pg/ml to a nadir of 169+/-57 pg/ml after nine months . In contrast , serum PTH levels did not change from baseline values of 670+/-97 pg/ml in subjects given p.o . calcitriol , P < 0.0001 by multiple regression analysis . Serum alkaline phosphatase levels were also lower in patients treated with i.p . calcitriol , P < 0.0001 , but there was no difference between groups in the average dose of calcitriol given thrice weekly . The skeletal lesions of secondary HPT improved in both groups , 33 % of patients developed adynamic bone lesion . CONCLUSION Differences in the bioavailability of calcitriol and /or in phosphorus metabolism may account for the divergent biochemical response to p.o . and i.p . calcitriol Amino-terminally truncated parathyroid hormone ( PTH ) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays ( PTH-IMAs ) , and acute changes in serum calcium affect the proportion of these fragments in circulation . However , the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined . In this study , 60 pediatric dialysis patients , aged 13.9 ± 0.7 years , with secondary hyperparathyroidism were r and omized to 8 months of therapy with oral vitamin D combined with either calcium carbonate ( CaCO3 ) or sevelamer . Serum phosphorus levels did not differ between groups . Serum calcium levels rose from 9.3 ± 0.1 to 9.7 ± 0.1 mg/dl during CaCO3 therapy ( p < 0.01 from baseline ) but remained unchanged during sevelamer therapy . In the CaCO3 and sevelamer groups , baseline serum PTH levels ( 1st PTH-IMA ; Nichols Institute Diagnostics , San Clemente , CA ) were 964 ± 75 and 932 ± 89 pg/ml , and levels declined to 491 ± 55 and 543 ± 59 pg/ml , respectively ( nonsignificant between groups ) . Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO3 . The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs , despite differences in serum calcium levels BACKGROUND Oral and intravenous calcitriol bolus therapy are both recommended for the treatment of secondary hyperparathyroidism , but it has been cl aim ed that the latter is less likely to induce absorptive hypercalcemia . The present study was undertaken to verify whether intravenous calcitriol actually stimulates intestinal calcium absorption less than oral calcitriol and whether it is superior in suppressing parathyroid hormone ( PTH ) secretion . METHODS Twenty children ( 16 males , age range of 5.1 to 16.9 years , mean creatinine clearance 21.9 + /- 11.5 mL/min/1.73 m2 , range of 7.4 to 52.7 ) with chronic renal failure ( CRF ) and secondary hyperparathyroidism [ median intact PTH ( iPTH ) , 327 pg/mL ; range 143 to 1323 ] received two single calcitriol boli ( 1.5 mg/m2 body surface area ) orally and intravenously using a r and omized crossover design . iPTH and 1,25(OH)2D3 levels were measured over 72 hours , and intestinal calcium absorption was measured 24 hours after the calcitriol bolus using stable strontium ( Sr ) as a surrogate marker . Baseline control values for Sr absorption were obtained in a separate group of children with CRF of similar severity . RESULTS The peak serum level of 1,25(OH)2D3 and area under the curve baseline to 72 hours ( AUC0 - 72h ) were significantly higher after intravenous ( IV ) calcitriol ( AUC0 - 72h oral , 1399 + /- 979 pg/mL. hour vs. IV 2793 + /- 1102 pg/mL. hour , P < 0.01 ) , but the mean intestinal Sr absorption was not different [ SrAUC0 - 240min during the 4 hours after Sr administration 2867 + /- 1101 FAD% ( fraction of the absorbed dose ) vs. 3117 + /- 1581 FAD% with oral and IV calcitriol , respectively ] . The calcitriol-stimulated Sr absorption was more then 30 % higher compared with control values ( 2165 + /- 176 FAD% ) . A significant decrease in plasma iPTH was noted 12 hours after the administration of the calcitriol bolus , which was maintained for up to 72 hours without any differences regarding the two routes of administration . CONCLUSIONS These results demonstrate that under acute conditions , intravenous and oral calcitriol boli equally stimulate calcium absorption and had a similar efficacy in suppressing PTH secretion Secondary hyperparathyroidism was suppressed over a period of one year in 12 children with chronic renal failure by using a regimen of mild dietary phosphate restriction and high dose phosphate binders . The patients were r and omised to receive either aluminium hydroxide or calcium carbonate by mouth for six months and then crossed over to the other medication . Vitamin D ( dihydrotachysterol ) dosage was unchanged . Serum parathyroid hormone concentrations were reduced to within the normal range , urinary cyclic adenosine monophosphate values fell , plasma phosphate concentrations decreased , and the theoretical renal phosphate threshold increased significantly . Transiliac bone biopsy findings improved in four patients with adequate suppression of parathyroid hormone concentrations , deteriorated in two patients who were not compliant , and did not change in five patients in whom initial bone disease was mild . Growth velocity improved significantly . There was no difference in the clinical response , biochemical changes , or incidence of complications during treatment with the two agents . In view of the risk of aluminium toxicity the use of high dose calcium carbonate with dietary phosphate restriction and vitamin D supplementation is recommended in the control of secondary hyperparathyroidism in children with chronic renal failure T he renal bone diseases represent a spectrum of skeletal disorders ranging from the high-turnover lesions of secondary hyperparathyroidism to the lowturnover lesions of osteomalacia and adynamic bone . Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing regular dialysis ; in contrast , the adynamic lesion of renal osteodystrophy without aluminum has become pre dominant in adult patients treated with continuous ambulatory peritoneal dialysis ( CAPD ) ( 1 - 3 ) . Peritoneal dialysis , on the other h and , is the most common dialytic modality for children with end-stage renal disease , and persistent bone disease remains a major challenge in the clinical management of these patients . Treatment with daily doses of calcitriol or with 1,25dihydroxyvitamin D has been recommended for pediatric patients with chronic renal failure to improve linear growth and to prevent bone deformities . However , secondary hyperparathyroidism persists in a substantial proportion of patients treated with daily calcitriol therapy and receiving peritoneal dialysis ( 1,4 ) . More recently , large intermittent doses of calcitriol given two or three times per week have been used to treat secondary hyperparathyroidism in both children and adults ( 5 - 7 ) . Most studies have employed the oral or intravenous routes of calcitriol adminis tration , but there is little available information about the effect of intraperitoneal ( IP ) doses of calcitriol on bone and mineral metabolism in patients undergoing regular peritoneal dialysis . We have recently completed a prospect i ve r and omized clinical trial to evaluate the biochemical and his tological responses to intermittent calcitriol therapy using thrice weekly IP or oral ( PO ) doses in Background There are no robust guidelines on strategies to prevent the adverse skeletal effects of glucocorticoids in children . Objectives To evaluate the role of prophylactic calcium and vitamin D on bone health in children with new-onset nephrotic syndrome ( NS ) treated with short-term ( 12 weeks ) , high-dose glucocorticoids . Methods Prospect i ve , r and omized , controlled , single blind , interventional study conducted on 41 steroid-naïve pre-pubertal children ( 29 boys , 12 girls ) . All children received prednisolone for 12 weeks ( 60 mg/m2/day daily for 6 weeks , followed by 40 mg/m2/day alternate days for 6 weeks ) . Recruited children were r and omized into the intervention group ( IG ; vitamin D 1,000 IU/day and elemental calcium 500 mg/day ) and the control group ( CG ) . Bone mineral content ( BMC ) and bone mineral density ( BMD ) at the lumbar spine ( L1–L4 ) were estimated at baseline and at 12 weeks . Mean percentage changes in BMC and BMD in IG and CG were compared . Results Children in the IG showed an increase of 11.2 % in BMC versus the CG , who showed an 8.9 % fall ( p < 0.0001 ) . Net intervention-attributable difference in BMC was 20.1 % . BMD increased in both groups ( IG 2.8 % vs CG 0.74 % ) , but the difference was not statistically significant ( p = 0.27 ) . Conclusions Short-term , high-dose glucocorticoid therapy decreases the BMC of the lumbar spine in steroid-naïve children with NS . Vitamin D and calcium co-administration not only prevents this decline , but also enhances BMC of the lumbar spine Background The relative effectiveness and safety of sevelamer , a mineral-free phosphate binder , for treatment of hyperphosphatemia in children with chronic kidney disease is uncertain . Aim This study was design ed to compare the efficacy and acceptability of sevelamer hydrochloride to calcium acetate as a phosphate binder in pediatric patients with chronic kidney disease . Methods A 12-week open-label trial of sevelamer hydrochloride vs calcium acetate was initiated in 22 patients , aged 2–18 , with CKD stages 3 and 4 . After a 2-week washout of phosphate binders and vitamin D , patients were r and omized to receive sevelamer hydrochloride or calcium acetate . The effect of therapy was adjusted for baseline blood levels of calcium , phosphorus , calcium-phosphate product , alkaline phosphatase , PTH and GFR using ANOVA . The primary end point was the decrease in serum phosphorus levels after 12 weeks of treatment . Results Of the 22 patients enrolled , data of 19 patients were used for analysis . The adjusted mean serum phosphate levels at 12 weeks did not differ significantly between calcium acetate- ( 5.3 mg/dl ) and sevelamer-treated subjects ( 6.1 mg/dl ) ( P adjusted means = 0.6 ) . The adjusted blood level of calcium at 12 weeks was significantly lower in the sevelamer-treated patients ( 8.2 mg/dl ) compared to those treated with calcium acetate ( 9.1 mg/dl ) ( P adjusted means = 0.01 ) . In the sevelamer group , there was a non-significant decrease in serum bicarbonate , whereas the total and LDL cholesterol significantly decreased at 12 weeks ( P = 0.04 ) . Sevelamer hydrochloride was well tolerated and without adverse effects related to the drug . Conclusions Compared to calcium acetate , use of sevelamer in children with chronic kidney disease is associated with similar reduction in serum phosphate levels , lower risk of hypercalcemia , and marked decrease in serum lipid levels Recent studies in adults have suggested that parenteral 1,25-dihydroxyvitamin D3 ( 1,25[OH]2D3 ) may have advantages over oral therapy in the management of renal osteodystrophy . The purpose of this study was to determine whether there were clear differences between oral and IP 1,25(OH)2D3 treatments in children who did not pose a treatment problem . Seven children ( 5 males , 2 females , aged 1.8 to 16 years , median 4.8 years ) undergoing peritoneal dialysis were initially treated with oral 1,25(OH)2D3 for a one month equilibration period They were r and omly assigned to 3 months of either oral or intraperitoneal ( IP ) therapy with 1,25(OH)2D3 followed by 3-months-treatment using the alternative route . No significant differences in serum creatinine , phosphate , or parathyroid hormone concentrations were found between the different routes of administration in the patients . No significant differences in height st and ard deviation scores or renal osteodystrophy scores were found over the six-month study . Paired oral and IP pharmacokinetic studies were performed on these 7 patients and 2 other children who had been treated for at least 2 months using either oral or IP 1,25(OH)2D3 . Serum was taken prior to one of the usual 1,25(OH)2D3 doses and 0.5 , 1.5 , 3 , 6 , and 24 h afterward . The highest measured concentrations of 1,25(OH)2D3 were found at 1.5 h for both oral and IP treatments ( mean Cmax [ SD ] : oral 116 [ 23 ] pmol/l , IP 121 [ 24 ] pmol/l , p > 0.05 ) . The AUC 's for oral and IP therapy were similar ( 1701 [ 276 ] and 1645 [ 301 ] pmol/h/l , respectively ) . In the paired pharmacokinetic studies no significant differences were found between oral and IP treatments for the serum half life ( 27.4 [ 11.6 ] h and 19.2 [ 8.1 ] h , respectively ) and total body clearance ( 15.3 [ 2.1 ] h and 18.4 [ 3.3 ] h , respectively ) of 1,25(OH)2D3 . In children who respond appropriately to oral 1,25(OH)2D3 there is no biological advantage to the use of IP 1,25(OH)2D3 ABSTRACT . Ten children with end stage renal disease on chronic hemofiltration ( HF ) were studied for a 1-yr period to evaluate the efficacy of l,25-dihydroxyvitamin-D3 ( 1,25(OH)2D3 ) therapy on biohumoral parameters of renal osteodystrophy and bone mineral content . In six of these children an acute study was done of the direct effect of the HF procedure on calcium and phosphate balance during 12 HF sessions . During the first 6 months of the study all children were treated with 1,25(OH)2D3 ( 0.25 - 0.50 µg/day ) to maintain plasma calcium at 9.5 - 11.0 mg/dl . There was a significant increase in plasma calcium ( p<0.05 ) and a significant decrease in plasma phosphate ( p<0.01 ) and alkaline phosphatase concentrations ( p<0.05 ) . The circulating levels of NH2 immunoreactive parathyroid hormone did not change , remaining at the upper limits of reference values . Immunoreactive parathyroid hormone- COOH terminal fragment levels decreased significantly ( p<0.05 ) . Bone mineral content rose significantly ( p<0.01 ) . During the last 6 months of the study , to evaluate the possibility that HF alone might control secondary hyperparathyroidism , 1,25(OH)2D3 treatment was discontinued in five children ; plasma calcium and phosphate were well controlled whereas hyperparathyroidism worsened in all five , and one also developed intense pruritus and hypertension . The other five children remained on 1,25(OH)2D3 treatment ; two of these were transplanted , and the other three continued to show an improvement of mineral balance . The results of the acute study showed that calcium balance was positive with a mean Ca++ gain of 140 mg/HF session . The mean total phosphate removed per HF run was 574 mg . We conclude that even though a calcium gain and a high phosphate removal was obtained with our HF prescription , secondary hyperparathyroidism in children on chronic HF may be maintainued under control if 1,25(OH)2D3 supplementation is provided Ensuring the integrity of a study such as the GFRD Study requires close cooperation among all groups involved with the study and the patient . Many factors may influence the outcome and validity of a multicenter , double-masked , r and omized trial . Any dosage modifications that may need to be made rely totally on established communication between the centers , the DCC , and the Core Pharmacy . When the procedures outlined above are followed , masking is ensured and patient compliance can be measured Little is known about the impact of various phosphate binders on the skeletal lesions of secondary hyperparathyroidism ( 2 degrees HPT ) . The effects of calcium carbonate ( CaCO3 ) and sevelamer were compared in pediatric peritoneal dialysis patients with bone biopsy-proven 2 degrees HPT . Twenty-nine patients were r and omly assigned to CaCO3 ( n = 14 ) or sevelamer ( n = 15 ) , concomitant with either intermittent doses of oral calcitriol or doxercalciferol for 8 mo , when bone biopsies were repeated . Serum phosphorus , calcium , parathyroid hormone ( PTH ) , and alkaline phosphatase were measured monthly . The skeletal lesions of 2 degrees HPT improved with both binders , and bone formation rates reached the normal range in approximately 75 % of the patients . Overall , serum phosphorus levels were 5.5 + /- 0.1 and 5.6 + /- 0.3 mg/dl ( NS ) with CaCO3 and sevelamer , respectively . Serum calcium levels and the Ca x P ion product increased with CaCO3 ; in contrast , values remained unchanged with sevelamer ( 9.6 + /- 01 versus 8.9 + /- 0.2 mg/dl ; P < 0.001 , respectively ) . Hypercalcemic episodes ( > 10.2 mg/dl ) occurred more frequently with CaCO3 ( P < 0.01 ) . Baseline PTH levels were 980 + /- 112 and 975 + /- 174 pg/ml ( NS ) ; these values decreased to 369 + /- 92 ( P < 0.01 ) and 562 + /- 164 pg/ml ( P < 0.01 ) in the CaCO3 and the sevelamer groups , respectively ( NS between groups ) . Serum alkaline phosphatase levels also diminished in both groups ( P < 0.01 ) . Thus , treatment with either CaCO3 or sevelamer result ed in equivalent control of the biochemical and skeletal lesions of 2 degrees HPT . Sevelamer , however , maintained serum calcium concentrations closer to the lower end of the normal physiologic range , thereby increasing the safety of treatment with active vitamin D sterols BACKGROUND AND OBJECTIVES Vitamin D deficiency is an important contributor to the development of hyperparathyroidism and is independently associated with cardiovascular and bone disease . The hypothesis was that nutritional vitamin D ( ergocalciferol ) supplementation in children with CKD stages 2 - 4 delays the onset of secondary hyperparathyroidism . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS A r and omized , double-blinded , placebo-controlled study in children with CKD2 - 4 who had 25-hydroxyvitamin D [ 25(OH)D ] deficiency was conducted . Ergocalciferol ( or a matched placebo ) was given daily as per Kidney Disease Outcomes Quality Initiative guidelines . The primary endpoint was the time to development of hyperparathyroidism . RESULTS Seventy-two children were screened . Forty-seven children were 25(OH)D-deficient and r and omly assigned to receive ergocalciferol or placebo . Twenty children in each arm completed the study ; median follow-up was 12 months . Groups were well matched for age , race , estimated GFR , and season when recruited . Nine of 20 children on placebo and 3 of 20 children on ergocalciferol developed hyperparathyroidism ( odds ratio , 4.64 ; 95 % confidence interval , 1.02 - 21.00 ) . The time to development of hyperparathyroidism was significantly longer with ergocalciferol treatment compared with placebo ( hazard ratio , 0.30 ; 95 % confidence interval , 0.09 - 0.93 , P=0.05 ) . With ergocalciferol treatment , normal 25(OH)D levels were achieved in all 8 children with CKD2 , 8 of 11 children with CKD3 , but not in the single patient with CKD4 . There were no ergocalciferol-related adverse events . 25(OH)D levels > 100 nmol/L were required to achieve normal levels of 1,25-dihydroxyvitamin D. CONCLUSIONS Ergocalciferol is an effective treatment that delays the development of secondary hyperparathyroidism in children with CKD2 - 3 The efficacy of 1 alpha-hydroxycholecalciferol in the prevention of renal osteodystrophy in children commencing continuous ambulatory peritoneal dialysis was studied in 12 patients , 0.8 - 17 years of age , who were r and omly assigned to either group I receiving st and ard therapy or to group II receiving in addition 10 - 20 ng/kg body weight/day of 1 alpha-hydroxycholecalciferol . Calcium carbonate compounds were used to control hyperphosphataemia . Mean plasma calcium ( total and ionised ) and phosphate levels were not significantly different between the two groups . All group I patients continued to have elevated plasma immunoreactive parathyroid hormone levels at 6 months compared to only 1 patient in group II ( p less than 0.05 ) . Four patients in group I developed subperiosteal erosions on radiography compared to the healing of mild lesions in 2 patients in group II . Bone histomorphometry on iliac crest needle biopsy specimens revealed a significant reduction in osteoid index and seam width in group II . Serum aluminum levels decreased during the course of continuous ambulatory peritoneal dialysis , and the significant staining for bone aluminum in 6 patients at the beginning of the study was no longer present in 5 patients at 6 months . Our data demonstrate that 1 alpha-hydroxycholecalciferol is beneficial in the prevention and treatment of bone disease in children on continuous ambulatory peritoneal dialysis Quantitative histology was performed on serial iliac crest biopsies obtained from 14 children with terminal renal failure . A long-term study on the comparative effects of vitamin D2 and 25-hydroxycholecalciferol [ 25-(OH)D3 ] , in five patients with severe lesions of osteomalacia and /or osteitis fibrosa , demonstrated the efficiency of 25 to 200 mug/day of 25-(OH)D3 and the lack of therapeutic action of 345 to 685 mug/day of vitamin D2 . In nine subjects with normal roentgenograms or minimal skeletal alterations , the first biopsy taken at the beginning of intermittent hemodialysis showed evidence of defective mineralization and /or lesions of resorption . Four of these children were treated with 25-(OH)D3 ( 25 to 50 mug/day ) and calcium supplementation orally ( 0.5 to 1.5 g/day ) ; five children received calcium orally ( 0.5 to 0.75 g/day ) alone . Aggravation of bone lesions during intermittent hemodialysis was observed in patients treated with calcium supplements alone . In subjects who were given 25-(OH)D3 , mineralization improved and marrow fibrosis disappeared . However , as the two groups of patients were different in composition and in the manner in which they were treated , it is difficult to state whether the beneficial effects observed were solely attributable to 25-(OH)D3 administration . 25-(OH)D3 therapy induced severe intoxication in two patients . A rise in plasma calcium concentration to 11.0 to 11.5 mg/100 ml was observed in two other patients . It is concluded that : a ) pharmacologic doses of 25-(OH)D3 are highly effective in healing bone lesions of children with terminal renal failure ; b ) such treatment requires strict clinical surveillance as 25-(OH)D3 intoxication may occur even in anephric patients Background : Steroid-induced osteoporosis ( SIO ) is a serious complication of long-term steroid therapy and is of particular concern in growing children . Recently bisphosphonates have been applied in the treatment or prevention of SIO . We investigated the efficacy of pamidronate on SIO in childhood nephropathy patients receiving long-term corticosteroid therapy . Methods : Forty-four children receiving high doses of steroids were enrolled in the study . There was no history of bone , liver , or endocrine disease . Patients were r and omly classified into two groups , the control group and the study group . All patients received corticosteroids for 3 months . Control group took oral calcium supplements ( 500 mg/day ) only , and the study group oral calcium and pamidronate ( 125 mg ) for 3 months . Biochemical tests , long bone radiography , and bone mineral density ( BMD ) were performed in the first month and 3 months later in all patients . Results : The differences in the results of biochemical tests such as serum calcium , BUN , and cre atinine level obtained in the first month and three months later were not of statistical significance in both the control and the study groups . However , the mean BMD of the lumbar spine decreased from 0.654 ± 0.069 ( g/cm2 ) to 0.631 ± 0.070 ( g/cm2 ) in the control group ( p = 0.0017 ) , while it did not in the study group from 0.644 ± 0.189 ( g/cm2 ) to 0.647 ± 0.214 ( g/cm2 ) . Conclusions : Pamidronate appears to be effective in preventing SIO in children with nephropathy requiring long-term steroid therapy . Further long-term follow-up studies regarding the efficacy and side effects appear to be necessary to set a more solid basis for such pediatric uses of bisphosphonates such as pamidronate Successful renal transplantation corrects many of the metabolic abnormalities associated with the development of renal osteodystrophy , but despite a well-functioning graft osteopenia , growth failure , spontaneous fractures , and avascular necrosis remain prevalent in adult and pediatric kidney recipients . A paucity of information exists regarding the effects of different therapies to prevent and treat bone loss in the renal transplant recipients . We constructed a design to study the effect of different modalities of treatment on bone mass in our renal transplant children . Among 93 patients who underwent renal transplantation at the age of 17 yr or less and were subjected to dual-energy X-ray absorptiometry ( DEXA ) , we blindly r and omized 60 patients who had osteopenia or osteoporosis ( T-score = -1 by DEXA ) in a prospect i ve study . Their mean age at time of transplantation was 13.4 + /- 4.3 yr . The mean duration after transplantation was 48 + /- 34 months . The patients were classified r and omly into four groups . Each group consisted of 15 patients : group 1 was the control group , group 2 received oral alfacalcidol 0.25 microg daily , group 3 received oral alendronate 5 mg daily , and group 4 received 200 IU/day nasal spray calcitonin . Parameters of bone turnover , calcium metabolism , and DEXA were measured before and after 12 months of treatment duration . The characteristics of all groups were comparable at the beginning of the study . At the lumber spine , bone mass density decreased from -2.4 to -2.8 in group 1 , increased from -2.3 to -0.5 in group 2 , from -2.3 to -1.9 in group 3 , and from -2.3 to -1.0 in group 4 . The four groups had similar patient profiles , serum creatinine , intact parathyroid hormone , osteocalcin , and deoxypyridinoline . This study confirmed the value of alfacalcidol and antiresorptive agents in the treatment of osteopenia and osteoporosis in young renal transplant recipients . These therapies were safe , tolerable , simple to administer and potentially applicable to other renal transplant patients Metabolic effects of deflazacort vs. methylprednisone were studied in prepubertal patients after kidney transplantation . Thirty-one patients participated : 15 received deflazacort and 16 remained on methylprednisone . The study started at a mean of 2.1 years after transplantation , when patients were r and omized to either continue with methylprednisone or switch to deflazacort . Height velocity increased more in the deflazacort than in the methylprednisone group only during the first 2 years : 5.4 ± 0.5 vs. 3.5 ± 0.3 cm/year , and 4.2 ± 0.8 vs. 2.2 ± 0.4 cm/year p = 0.007 , [ by two-way analysis of variance ( ANOVA ) ] . After 2 and 3 years , the number of patients who were overweight increased in the methylprednisone group and decreased in the deflazacort group ; p < 0.01 . Lean body mass increased more in the deflazacort than in the methylprednisone group ( p = 0.003 ) . Fat body mass increased only in the methylprednisone group ( p < 0.01 ) . Total cholesterol and low-density-lipoprotein ( LDL ) cholesterol increased in the methylprednisone group ( p < 0.05 and p < 0.01 , respectively ) . Total and LDL cholesterol were reduced ( p < 0.01 and p < 0.001 , respectively ) , whereas high-density-lipoprotein ( HDL ) cholesterol increased ( p < 0.001 ) during deflazacort therapy . Lumbar spine bone mineral density ( BMD ) decreased in both groups , but total skeleton BMD decreased only in the methylprednisone group ( p < 0.001 ) . Finally , normal glucose/insulin ratio , defined as > 7 , was associated ( p < 0.05 ) with the deflazacort group . Our data suggest that deflazacort therapy might improve linear growth and lean body mass and prevent excessive bone loss and fat accumulation . It also leads to an improvement in lipoprotein profile without reduction in insulin sensitivity BACKGROUND A multicenter , r and omized , open-label , crossover study was performed to compare the efficacy and safety of sevelamer , a calcium-free phosphate binder , with calcium acetate in pediatric patients with chronic kidney disease ( CKD ) . METHODS Children ( age , 0.9 to 18 years ) with CKD undergoing hemodialysis or peritoneal dialysis or with a glomerular filtration rate of 20 or greater and less than 60 mL/min/1.73 m2 ( > or = 0.33 and < 1.00 mL/s/1.73 m2 ) were r and omly assigned to the following treatment scheme : 2 weeks of washout followed by 8 weeks of treatment with either sevelamer or calcium acetate in a crossover fashion . Phosphorus , calcium , and intact parathyroid hormone in serum were measured every 2 weeks , and phosphate binder dosages were adjusted , if needed . Serum lipid and vitamin concentrations were measured at the beginning and end of each treatment period . The primary end point was the decrease in serum phosphorus levels after 8 weeks of treatment . RESULTS Forty-four patients were screened . Altogether , data for 18 patients ( 5 girls ) aged 12.4 + /- 4.1 years were used for the crossover analysis . There was no significant difference in serum phosphorus levels at 8 weeks after the start of treatment in both groups . Total cholesterol ( -27 % ) and low-density lipoprotein cholesterol ( -34 % ) levels decreased significantly with sevelamer treatment ( P < 0.02 and P < 0.005 ) . An increased incidence of hypercalcemia ( P < 0.0005 ) was observed with calcium acetate treatment , whereas metabolic acidosis was more frequent with sevelamer treatment ( P < 0.005 ) . CONCLUSION Treatment of children with CKD with sevelamer and calcium acetate provides similar phosphorus level control . The marked decrease in lipid levels and lower rate of hypercalcemia may augment the long-term benefit of sevelamer Abstract Kidney function , growth velocity , weight/ height ratio , body composition , lipid profile , and bone mass were studied in a r and omized , multicenter trial of deflazacort versus methylprednisone in 27 prepubertal patients with kidney transplantation . Methylprednisone ( 0.20±0.03 ) was replaced by deflazacort ( 13 patients , 0.30±0.03 mg/kg per day ) . After 12 months , creatinine clearance decreased significantly only during methylprednisone therapy . Growth velocity increased only in patients treated with deflazacort from 3.3±0.6 to 5.6±0.5 cm/year . Serum levels of several components of the insulin-like growth factor axis did not change . Weight/height ratio was increased in methylprednisone-treated patients ( P<0.05 ) and decreased in deflazacort-treated patients ( P<0.005 ) . Lean body mass increased in both groups ( P<0.005 ) . Fat body mass and serum leptin increased only in methylprednisone-treated patients ( P<0.025 ) . Total cholesterol and low-density lipoprotein-cholesterol increased in methylprednisone-treated patients by 9.9 % ( P<0.05 ) and 12.5 % ( P<0.025 ) . High-density lipoprotein-cholesterol increased by 21 % ( P<0.005 ) and apolipoprotein B decreased by 11 % ( P<0.005 ) in deflazacort-treated patients . Total skeleton and lumbar spine bone mineral density decreased in both groups , but at 1 year methylprednisone-treated patients had lost 50 % more bone . Bone mineral content decreased only in methylprednisone-treated patients ( P<0.01 ) . Our data suggest that substituting deflazacort for maintenance methylprednisone might prevent height loss , excessive bone loss , and fat accumulation ; and leads to an improvement in the lipoproteins of these children Calcitriol ( C ) treatment strategies for secondary hyperparathyroidism remain controversial regarding efficacy and safety . In children , intermittent C administration has been suspected of impairing body growth . In a prospect i ve , r and omized multicenter study , we compared the effect of daily versus twice weekly C on plasma intact parathyroid hormone ( iPTH ) levels and growth in 24 prepubertal children with chronic renal insufficiency ( mean creatinine clearance 20±9 ml/min per 1.73 m2 ) . After a 3-week washout period , the patients were r and omly assigned to 10 ng/kg per day or 35 ng/kg twice a week oral C. The C dose was kept constant for 2 months and could then be adapted to maintain an iPTH target range of 140–280 pg/ml . Median ( range ) baseline iPTH levels were 567 ( 114–1209 ) pg/ml in the daily and 332 ( 93–614 ) pg/ml in the intermittent treatment group ( P = NS ) . After 12 months , iPTH had decreased to 255 ( 85–710 ) and 179 ( 51–443 ) pg/ml ( P<0.01 ) . The average weekly dose of C was 76±34 and 62±34 ng/kg ( P = NS ) . Five episodes of calcium phosphate product≥70 occurred in the daily group and four in the intermittent group . The change in height st and ard deviation score during the study period was not affected by either treatment modality ( −0.18±0.34 vs. −0.05±0.52 , P = NS ) . Daily and intermittent C do not differentially affect growth rate and are equally effective in controlling secondary hyperparathyroidism in children with chronic renal failure This double-blind , placebo-controlled study evaluated the safety and efficacy of intravenous ( IV ) calcitriol ( Calcijex ) for treatment of secondary hyperparathyroidism ( 2 ° HPT ) in pediatric end-stage renal disease ( ESRD ) patients on hemodialysis ( HD ) . After a 2 to 6-week washout period of all vitamin D compounds , patients with two consecutive PTH values > 400 pg mL−1 , calcium levels ≤10.5 mg dL−1 and calcium × phosphorus product values ≤70 mg2 dL−2 were eligible for the treatment phase . Patients received a bolus injection of calcitriol or placebo three times a week , immediately after dialysis for up to 12 weeks . Initial doses ( 0.5–1.5 μg ) were based on the severity of 2ºHPT . The dose was increased every two weeks by 0.25 μg until there was at least a 30 % decrease in PTH from baseline , or Ca>11.0 mg dL−1 , or Ca × P>75 mg2 dL−2 . Overall , 11/21 ( 52 % ) patients in the calcitriol group had two consecutive ≥30 % decreases from baseline in serum PTH compared with 5/26 ( 19 % ) patients in the placebo group ( P=0.03 ) . The mean total alkaline phosphatase decreased from 274 to 232 IU L−1 in the calcitriol group and increased from 547 to 669 IU L−1 in the placebo group ( P=0.002 ) . The mean bone-specific alkaline phosphatase decreased from 72.5 to 68 μg L−1 in the calcitriol group and increased from 105.3 to 148.5 μg L−1 in the placebo group ( P=0.03 ) . The incidence of two consecutive occurrences of elevated calcium × phosphorus ( Ca × P>75 mg2 dL−2 ) product was higher in the calcitriol group than in the placebo group ( P=0.01 ) . Two consecutive occurrences of phosphorus > 6.5 mg dL−1 occurred in 71 % of the calcitriol group and 46 % of the placebo group ( P=0.14 ) . Calcium levels > 10.5 mg dL−1 were more common in the calcitriol group than in the placebo group ( P=0.01 ) . There was a direct relationship between serum phosphorus concentration and the percentage change in PTH from baseline in both the calcitriol group ( r=0.46 ; P<0.0001 ) and the placebo group ( r=0.21 ; P=0.0005 ) . This study demonstrates that IV calcitriol , at initial doses of 0.5–1.5 μg , effectively reduces PTH levels in pediatric HD patients and that patients should be closely monitored for hyperphosphatemia and elevated Ca × P product Daily calcitriol therapy has been reported to improve linear growth in children with renal bone disease , and 1,25-dihydroxyvitamin D is a key regultor of chondrocyte proliferation and differentiation . Whereas large intermittent doses of calcitriol can lower serum parathyroid hormone ( PTH ) levels and reverse the skeletal changes of secondary hyperparathyroidism , the impact of intermittent calcitriol therapy on linear growth in children is not known . Thus , we studied 16 pre-pubertal patients with bone biopsy-proven secondary hyperparathyroidism who completed a 12-month prospect i ve clinical trial of intermittent calcitriol therapy . Biochemical results and growth data obtained during intermittent calcitriol therapy were compared to values determined during the preceding 12 months of daily calcitriol therapy in each study subject ; changes in bone histology were assessed after one year of intermittent calcitriol therapy . Z-scores for height did not change during 12 months of daily calcitriol therapy . Although the skeletal lesions of secondary hyperparathyroidism improved in most patients , Z-scores for height decreased from -1.8 + /- 0.32 to -2.0 + /- 0.33 , P < 0.01 , during intermittent calcitriol therapy . The largest reductions were seen in patients who developed adynamic bone lesions after 12 months of treatment . Delta Z-scores for height correlated with serum PTH , r = 0.71 , P < 0.01 , and alkaline phosphatase levels , r = 0.67 , P < 0.01 , during intermittent calcitriol therapy but not during daily calcitriol therapy . The data suggest that high dose intermittent calcitriol therapy adversely affects linear growth , particularly in patients with the adynamic lesion . The higher doses of calcitriol or the intermittent schedule of calcitriol administration may directly inhibit chondrocyte activity within growth plate cartilage of children with end-stage renal disease The Growth Failure in Children With Renal Diseases Study , a double-blind , multicenter clinical trial with 108 children entered into the control period over 4.3 years of patient enrollment ( December 1984 to April 1989 ) , is being extended for 3 years ( December 1988 to December 1991 ) to provide the time needed to accrue additional patients , aged between 1 1/2 and 10 years , with glomerular filtration rates of 20 to 75 ml/min/1.73 m2 . The study design of r and omization to two treatment arms ( 1,25-dihydroxyvitamin D vs dihydrotachysterol ) requires a total of 108 patients with a minimum of 6 months of treatment to test the long-term effectiveness and safety of 1,25-dihydroxyvitamin D , an essential part of the therapeutic regimen for children with chronic renal insufficiency . The frequent longitudinal assessment s of nutrition and growth in children with chronic renal insufficiency can better define the natural history of renal disease and its influence on growth . Similar data in the treatment period will define the impact of treatment with 1,25-dihydroxyvitamin D3 versus dihydrotachysterol on this natural history . Linear growth must be observed long enough ( 6 to 12 months minimum ) to permit valid quantitation and comparison of the two vitamin D treatment arms , the multiple confounding variables that affect growth ( e.g. , steroid therapy , diabetes mellitus , prior vitamin D treatment ) must be rigorously excluded or controlled , and the assignment of patients to the two groups must be r and om . These controls -- sufficient study duration , sufficient patient numbers , and r and omization -- should eliminate extraneous sources of variation , including seasonal periodicity . This carefully developed , double-blind clinical trial with multiple participating centers and an effective organizational structure is coming close to achieving the goals of the study . An explosion of data regarding the natural history of chronic renal insufficiency and its treatment with vitamin D metabolites will be forthcoming at the conclusion of the study Abstract Calcitriol oral pulse therapy has been suggested as the treatment of choice for secondary hyperparathyroidism , but its efficacy and safety are still under discussion . The present r and omized multicenter study compares the effect of an 8-week course of daily versus intermittent ( twice weekly ) calcitriol therapy on parathyroid hormone ( PTH ) suppression in 59 children ( mean age 8.4±4.7 years ) with chronic renal insufficiency ( mean Ccr 22.4±11.6 ml/min per 1.73 m2 ) and secondary hyperparathyroidism . After a 3-week washout period , the patients were r and omly assigned to treatment with daily oral calcitriol ( 10 ng/kg per day ) or intermittent oral calcitriol ( 35 ng/kg given twice a week ) . The calcitriol dose was not changed throughout the study period of 8 weeks . At start of the study , the median intact PTH ( iPTH ) level was 485 pg/ml ( range 83–2032 ) in the daily group ( n=29 ) and 315 pg/ml ( range 93–1638 ) in the intermittent group ( n=30 ) . After 8 weeks , the respective median iPTH concentrations were 232 pg/ml ( range 63–1614 ) and 218 pg/ml ( range 2–1785 ) ( ns ) . The mean iPTH decrease from baseline was 19.2±57.8 % and 13.7±46.7 % respectively ( not significant ) . Calcitriol reduced the iPTH concentration in 23/29 patients in the daily group and in 21/30 in the intermittent group . One episode of hypercalcemia ( > 11.5 mg/dl ) was observed in both groups and a single episode of hyperphosphatemia ( > 7.5 mg/dl ) was observed in the daily group . It is concluded that oral calcitriol pulse therapy does not control secondary hyperparathyroidism more effectively than the daily administration of calcitriol in children with chronic renal failure prior to dialysis Quality control procedures are critically important in a clinical trial in which dietitians in geographically separated units perform collaborative nutritional intervention and data collection during a period of several years . Typically , the quality control measures developed within the nutritional component of a clinical trial encompass the following areas of activity : 1 . Uniform collection and coding procedures for dietary intake records 2 . Collection of accurate and reliable anthropometric measurements 3 . Nutritional assessment , intervention , and counseling of patients 4 . Assessment of patient compliance with dietary intervention Accordingly , the functions of the core nutritional unit of a multicenter clinical trial are as follows : 1 . To ensure the collection of uniform , accurate nutrient and anthropometric data in participating centers using st and ardized procedures 2 . To provide consistent nutritional education to ensure st and ardized counseling of the patient , the primary caretaker , or both The major objective of the nutritional component of this clinical trial is to identify changes in nutriture and appetite as evidence d by food consumption records , appetite assessment , and anthropometric measurements , and to intervene as study guidelines permit . From December 1984 to June 1989 , the core During the training- and -orientation session held at the beginning of the GFRD Study , and repeated when new centers joined the study , the necessity of uniform sample collection was emphasized . To avoid trace mineral contamination , collectors used all-plastic syringes and containers to collect blood for measurement of serum creatinine , magnesium , zinc , aluminum , and osteocalcin concentrations . A 5 ml blood sample is drawn from a fasting patient into a Peel-A-Way regular blood sample r ( Peel-A-Way Scientific , South E1 Monte , Calif. ) or trace mineral-free Vacutainer tubes ( Becton Dickinson Vacutainer Systems , Rutherford , N.J. ) . The blood is allowed to clot at room temperature , and the clot is reamed with a disposable polyethylene fine-tip pipet . The tube is then centrifuged at 3000 rpm for 10 minutes and 0.5 ml of the serum is pipetted into each of five vials for the measurement of creatinine , zinc , magnesium , aluminum , and osteocalcin concentrations . The vials are frozen at 2 0 ~ C and mailed in dry ice by overnight courier to the GFRD Study Core Laboratory Serial measurements of 51Cr edetic acid clearance were made over a period of one year in two groups of 8 children , in a double blind trial of 1 alpha-hydroxycholecalciferol ( 10 ng/kg/day ) and calciferol ( 670 ng/kg/day ) . Glomerular filtration rate ( GFR ) at the beginning of the trial was 20 - 50 ml/min/1.73 m2 ; it rose in the children given 1 alpha-hydroxycholecalciferol ( group A ) after 6 months but was not appreciably different from the pretreatment value after 12 months . The GFR in the children given calciferol ( group B ) showed no significant difference at 6 or 12 months . Parathyroid hormone values fell markedly in group A after 6 months but not in group B. Quantitative bone histology improved considerably in group A but not in group B at 12 months . Low dose 1 alpha-hydroxycholecalciferol may be used effectively for renal osteodystrophy in children with moderate but stable renal failure without jeopardising renal function Nutritional data compiled during the Growth Failure in Children with Renal Diseases Clinical Trial were analyzed to determine the relationship between the dietary intake of divalent minerals and sodium , nutritional status , and serum calcium , phosphorus , and parathyroid hormone ( PTH ) concentrations and blood pressure in black versus white children . One hundred eighteen patients are included in this report ; 25 were black ( 21 % ) and 93 were white ( 79 % ) . Although more of the blacks were male , the age distribution , midarm circumference , midarm muscle circumference , blood pressure , and serum calcium , phosphorus , and PTH concentrations were comparable in the two groups . Phosphorus intake was within the recommended daily allowance in both groups ; in contrast , calcium intake was inadequate in all patients : 81 % of the recommended daily allowance in whites , and 74 % in blacks . Sixteen children were noted to be hypertensive during the observation period ; six patients were receiving a variety of antihypertensive medications , including diuretics in two children . Linear regression analysis revealed that systolic and diastolic blood pressures were directly related to calcium and phosphorus intake in black patients . In white children , only dietary phosphorus intake and diastolic blood pressure were directly related . There was no relationship between sodium intake or GFR and blood pressure in the white or black children . PTH levels were directly correlated with systolic and diastolic blood pressure in all children . The correlations between PTH and blood pressure were stronger in white versus black patients . ( ABSTRACT TRUNCATED AT 250 WORDS During the control period of the Growth Failure in Children With Renal Diseases Study , investigators at 23 centers were able to observe and characterize growth and to make anthropometric and nutritional measurements in 82 children with mild to moderate renal insufficiency . As a multicenter , controlled clinical trial design ed to study the relative efficacy of 1,25-dihydroxyvitamin D3 and dihydrotachysterol in the treatment of renal osteodystrophy , no prior vitamin D exposure and a creatinine clearance of 25 to 75 ml/min/1.73 m2 were criteria for entrance into the clinical trial . Ages ranged from 18 months to 11 years ( mean 5.6 + /- 3.1 years ) , and distribution by age category was as follows : 38 % , 1 to 3 years ; 28 % , 4 to 6 years ; and 34 % , 7 to 10 years . There was a 3:1 male/female ratio ; 72 % of the patients had congenital disease by the International Classification of Diseases ( ninth revision ) . Mean creatinine clearance was 49.5 + /- 20 ml/min/1.73 m2 . The C-terminal parathyroid hormone values ( 1121 + /- 1562 pg/ml ) were well above 2 SD of the mean of a normal growing population of similar age . Parathyroid hormone values correlated with degree of renal insufficiency ( r = -0.57 ) and with height by bone age but not with chronologic height or growth velocity . The bone age/height age ratio , a predictor of growth potential in normal children , was low for the entire series of patients ( 0.88 + /- 0.35 ) but failed to correlate with growth velocity and was negatively correlated with rising parathyroid hormone levels . Average values for height , weight , triceps skin fold , mid-arm muscle circumference , and body mass index were within 2 SD of the mean of the normal population , although measurements for the 1- to 3-year age group were significantly less than those of the older patients . Total energy intake averaged less than 86 % of the recommended dietary allowances ; total protein intake was more than 161 % of the allowance . Nitrogen balance in 23 patients was positive and correlated most significantly with increasing energy intake ( r = 0.6 ) . Growth velocity , calculated from the interval gain during the month control period , averaged + 0.3 SD , with the highest growth velocity z scores recorded for those with acquired disease . A growth velocity index , expressed as the slope of the regression between change in height SD and growth velocity z score , was used to describe the growth accomplished in the control period by age category . ( ABSTRACT TRUNCATED AT 400 WORDS The DDC of the GFRD Study works closely with the Administrative Core and with all participating clinical centers to ensure the timely collection of accurate , reliable , and complete data . The development and maintenance of a data -base management system , including continuous monitoring of all data , represent primary responsibilities of the DCC . Coordination and communication tasks in the multicenter study have been challenging but rewarding . Proper planning and positive attitudes have enhanced the effectiveness of the DCC throughout this clinical trial Masking — hiding identities of treatments from the patient , physician and /or statistician — is a critical element in clinical trials . Wherever possible , masking is implemented to eliminate observational bias or systematic error . In this paper , general concepts of masking in clinical trials are examined . Specific masking procedures used in the “ Growth Failure in Children with Renal Diseases ” ( GFRD ) Clinical Trial are described . A method to evaluate the “ success ” of this masking procedure for physicians is introduced . For each r and omized patient at each clinical center , the clinic director was asked to predict which treatment ( 1,25-dihydroxyvitamin D3 or dihydrotachysterol ) was assigned . Results showed that 72 % of responses initially indicated “ absolutely no idea ” of treatment . Additional analyses revealed that the number and percentage of “ correct ” guesses were essentially equal for the two treatment groups and that a patient 's time on treatment did not affect the mask . We conclude that the mask of physicians in the GFRD Clinical Trial was well maintained BACKGROUND AND OBJECTIVES Left ventricular hypertrophy ( LVH ) is an independent risk factor and an intermediate end point of dialysis-associated cardiovascular comorbidity . We utilized a global pediatric registry to assess the prevalence , incidence , and predictors of LVH as well as its evolution in the longitudinal follow-up in dialyzed children . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS Cross-sectional echocardiographic , clinical , and biochemical data were evaluated in 507 children on peritoneal dialysis ( PD ) , and longitudinal data were evaluated in 128 patients . The 95(th ) percentile of LV mass index relative to height age was used to define LVH . RESULTS The overall LVH prevalence was 48.1 % . In the prospect i ve analysis , the incidence of LVH developing de novo in patients with normal baseline LV mass was 29 % , and the incidence of regression from LVH to normal LV mass 40 % per year on PD . Transformation to and regression from concentric LV geometry occurred in 36 % and 28 % of the patients , respectively . Hypertension , high body mass index , use of continuous ambulatory peritoneal dialysis , renal disease other than hypo/dysplasia , and hyperparathyroidism were identified as independent predictors of LVH . The use of renin-angiotensin system ( RAS ) antagonists and high total fluid output ( sum of urine and ultrafiltration ) were protective from concentric geometry . The risk of LVH at 1 year was increased by higher systolic BP st and ard deviation score and reduced in children with renal hypo/dysplasia . CONCLUSIONS Using height-adjusted left ventricular mass index reference data , LVH is highly prevalent but less common than previously diagnosed in children on PD . Renal hypo/dysplasia is protective from LVH , likely because of lower BP and polyuria . Hypertension , fluid overload , and hyperparathyroidism are modifiable determinants of LVH We compared the effects of calcitriol and doxercalciferol , in combination with either calcium carbonate or sevelamer , on bone , mineral , and fibroblast growth factor-23 ( FGF-23 ) metabolism in patients with secondary hyperparathyroidism . A total of 60 pediatric patients treated with peritoneal dialysis were r and omized to 8 months of therapy with either oral calcitriol or doxercalciferol , combined with either calcium carbonate or sevelamer . Bone formation rates decreased during therapy and final values were within the normal range in 72 % of patients . A greater improvement in eroded surface was found in patients treated with doxercalciferol than in those given calcitriol . On initial bone biopsy , a mineralization defect was identified in the majority of patients which did not normalize with therapy . Serum phosphate concentrations were controlled equally well by both binders , but serum calcium levels increased during treatment with calcium carbonate , and serum parathyroid hormone levels were decreased by 35 % in all groups . Baseline plasma FGF-23 values were significantly elevated and rose over fourfold with calcitriol and doxercalciferol , irrespective of phosphate binder . Thus , doxercalciferol is as effective as calcitriol in controlling serum parathyroid hormone levels and suppressing the bone formation rate . Sevelamer allows the use of higher doses of vitamin D. Implication s of these changes on bone and cardiovascular biology remain to be established The Growth Failure in Children With Renal Diseases ( GFRD ) Study was funded by the National Institutes of Health ( NIH ) in mid-1983 to test the efficacy of treating early childhood renal osteodystrophy with either 1,25dihydroxyvitamin D 3 or dihydrotachysterol to determine which promotes the best linear growth and nutrient consumption and results in the least deterioration of renal function . In addition , the study was design ed to evaluate the anthropometric , biochemical , and nutritional status of children with moderate renal insufficiency

Despite the increase in the number of new studies identified , our overall finding is similar to that of the previous review . Tailored implementation can be effective , but the effect is variable and tends to be small to moderate . It is not yet clear how best to tailor interventions and therefore not clear what the effect of an optimally tailored intervention would be

BACKGROUND Tailored intervention strategies are frequently recommended among approaches to the implementation of improvement in health professional performance . Attempts to change the behaviour of health professionals may be impeded by a variety of different barriers , obstacles , or factors ( which we collectively refer to as determinants of practice ) . Change may be more likely if implementation strategies are specifically chosen to address these determinants . OBJECTIVES To determine whether tailored intervention strategies are effective in improving professional practice and healthcare outcomes . We compared interventions tailored to address the identified determinants of practice with either no intervention or interventions not tailored to the determinants .

Background The aim of the SPHERE study is to design , implement and evaluate tailored practice and personal care plans to improve the process of care and objective clinical outcomes for patients with established coronary heart disease ( CHD ) in general practice across two different health systems on the isl and of Irel and .CHD is a common cause of death and a significant cause of morbidity in Irel and . Secondary prevention has been recommended as a key strategy for reducing levels of CHD mortality and general practice has been highlighted as an ideal setting for secondary prevention initiatives . Current indications suggest that there is considerable room for improvement in the provision of secondary prevention for patients with established heart disease on the isl and of Irel and . The review literature recommends structured programmes with continued support and follow-up of patients ; the provision of training , tailored to practice needs of access to evidence of effectiveness of secondary prevention ; structured recall programmes that also take account of individual practice needs ; and patient-centred consultations accompanied by attention to disease management guidelines . Methods SPHERE is a cluster r and omised controlled trial , with practice -level r and omisation to intervention and control groups , recruiting 960 patients from 48 practice s in three study centres ( Belfast , Dublin and Galway ) . Primary outcomes are blood pressure , total cholesterol , physical and mental health status ( SF-12 ) and hospital re-admissions . The intervention takes place over two years and data is collected at baseline , one-year and two-year follow-up . Data is obtained from medical charts , consultations with practitioners , and patient postal question naires . The SPHERE intervention involves the implementation of a structured systematic programme of care for patients with CHD attending general practice . It is a multi-faceted intervention that has been developed to respond to barriers and solutions to optimal secondary prevention identified in preliminary qualitative research with practitioners and patients . General practitioners and practice nurses attend training sessions in facilitating behaviour change and medication prescribing guidelines for secondary prevention of CHD . Patients are invited to attend regular four-monthly consultations over two years , during which targets and goals for secondary prevention are set and review ed . The analysis will be strengthened by economic , policy and qualitative components BACKGROUND The decreased use of electronic fetal monitoring ( EFM ) for healthy women in labour and the increased provision of professional support to all women in labour is recommended by experts . We evaluated the effectiveness of a community-wide approach to transferring research results to practice using a regional committee , newsletter articles and annual conference presentations compared with an additional tailored hospital intervention involving workshops to enhance self-efficacy for nurses , policy review , multidisciplinary meetings , rounds and unit discussion s. METHODS We compared the proportion of women at low risk who received EFM and the proportion of nurses ' time spent providing labour support before and after the intervention within each of 4 hospitals ( 2 tertiary and 2 secondary ) . One hospital of either type was r and omly selected to receive the tailored intervention . R and omly selected charts ( n = 200 ) were review ed for the use of EFM at each hospital before ( 1995 ) and after ( 1996 ) the intervention . Trained observers at r and omly selected times recorded the nurses ' activities , including time spent providing labour support before and after the intervention . RESULTS At the intervention secondary hospital , there was a large decrease in the use of EFM , from 90.1 % before to 41.0 % after the intervention ( p < 0.001 ) , but no change in nurses ' time spent providing labour support . At the intervention tertiary hospital there was no change in EFM rates , but there was a small , statistically significant increase in time spent providing labour support ( 23.5 % to 29.8 % , p < 0.001 ) . A negative effect on time spent providing labour support was found at the control secondary hospital ( decrease from 19.6 % to 12.8 % , p < 0.001 ) , with no change in the EFM rate . At the control tertiary hospital there was a small decrease in the use of EFM , from 99.5 % to 91.4 % ( p < 0.001 ) , but no change in time spent providing labour support . INTERPRETATION The results are mixed , and the tailored intervention thus appeared to have limited effects . No association was found between the reduction in the use of EFM and an increase in nurses ' time spent providing labour support Background Apart from direct protection and reduced productivity loss during epidemics , the main reason to immunize healthcare workers ( HCWs ) against influenza is to provide indirect protection of frail patients through reduced transmission in healthcare setting s. Because the vaccine uptake among HCWs remains far below the health objectives , systematic programs are needed to take full advantage of such vaccination . In an earlier report , we showed a mean 9 % increase of vaccine uptake among HCWs in nursing homes that implemented a systematic program compared with control homes , with higher rates in those homes that implemented more program elements . Here , we report in detail the process of the development of the implementation program to enable research ers and practitioners to develop intervention programs tailored to their setting . Methods We applied the intervention mapping ( IM ) method to develop a theory- and evidence -based intervention program to change vaccination behaviour among HCWs in nursing homes . Results After a comprehensive needs assessment , we were able to specify proximal program objectives and selected methods and strategies for inducing behavioural change . By consensus , we decided on planning of three main program components , i.e. , an outreach visit to all nursing homes , plenary information meetings , and the appointment of a program coordinator -- preferably a physician -- in each home . Finally , we planned program adoption , implementation , and evaluation . Conclusion The IM methodology result ed in a systematic , comprehensive , and transparent procedure of program development . A potentially effective intervention program to change influenza vaccination behaviour among HCWs was developed , and its impact was assessed in a clustered r and omised controlled trial UNLABELLED INTRODUCTION AND OBJECTIVES . Clinical practice in unstable angina is not always based on best evidence . Guidelines have the potential to improve quality of health care . There are no r and omised trials assessing implementation strategies in the public healthcare system of Spain yet . OBJECTIVE to compare the effectiveness of a multifaceted strategy ( interactive educational meetings , local consensus process ) for guideline implementation in unstable angina , with a passive dissemination strategy . Patients and method . SETTING 10 wards from 3 university hospitals in Sevilla . PARTICIPANTS 153 specialists ( cardiologists , internists ) and their patients admitted for an unstable angina episode . DESIGN a pragmatic , before and after cluster r and omized controlled trial . Intervention was delivered from January to April 1998 . Retrospective data collection took place in July 1999 , of those pre and post-intervention episodes attended from January to October 1997 and from September 1998 to June 1999 , respectively . OUTCOMES compliance with the guideline recommendations for coronary angiography and stress testing , and ejection fraction assessment . RESULTS The multifaceted strategy compared with the passive one , was associated with an absolute improvement in the appropriateness of use of coronary angiography and stress testing of 11 % ( 95 % CI , 0.85 - 21.1 ) , P=.03 . There was no association for the assessment of the ejection fraction : absolute improvement of 1.1 % ( 95 % CI , --15.9 to 18.1 ) , P=.88 . CONCLUSIONS Our results show that a combination of interactive educational meetings and local consensus process delivered to wards of physicians may improve the appropriateness of use of coronary angiography and stress testing Abstract Objective : To compare the effect of individual educational visits versus group visits using academic detailing to discuss prescribing of highly anticholinergic antidepressants in elderly people . Design : R and omised controlled trial with three arms ( individual visits , group visits , and a control arm ) . Setting : Southwest Netherl and s. Participants : 190 general practitioners and 37 pharmacists organised in 21 peer review groups were studied using a data base covering all prescriptions to people covered by national health insurance in the area ( about 240 000 ) . Intervention : All general practitioners and pharmacists in both intervention arms were offered two educational visits . For physicians in groups r and omised to the individual visit arm , 43 of 70 general practitioners participated ; in the group visit intervention arm , five of seven groups ( 41 of 52 general practitioners ) participated . Main outcome measures : Numbers of elderly people ( 60 years ) with new prescriptions of highly anticholinergic antidepressants and less anticholinergic antidepressants . Results : An intention to treat analysis found a 26 % reduction in the rate of starting highly anticholinergic antidepressants in elderly people ( 95 % confidence interval —4 % to 48 % ) in the individual intervention arm and 45 % ( 8 % to 67 % ) in the group intervention arm . The use of less anticholinergic antidepressants increased by 40 % ( 6 % to 83 % ) in the individual intervention arm and 29 % ( —7 % to 79 % ) in the group intervention arm . Conclusions : Both the individual and the group visits decreased the use of highly anticholinergic antidepressants and increased the use of less anticholinergic antidepressant in elderly people . These approaches are practical means to improve prescribing by continuing medical education Astract Background Evidence implementation continues to challenge health professionals most especially those from developing countries . Filipino physiotherapists represent a group of health professionals in a developing country who by tradition and historical practice , take direction from a doctor , on treatment options . Lack of autonomy in decision-making challenges their capacity to deliver evidence -based care . However , this scenario should not limit them from updating and up-skilling themselves on evidence - based practice ( EBP ) . EBP training tailored to their needs and practice was developed to address this gap . This study will be conducted to assess the effectiveness of a tailored EBP-training program for Filipino physiotherapists , in improving knowledge , skills , attitudes and behaviour to EBP . Participation in this program aims to improve capacity to EBP and engage with referring doctors to determine the most effective treatments for their patients . Methods / Design A double blind r and omised controlled trial , assessing the effectiveness of the EBP training intervention , compared with a waitlist control , will be conducted . An adequately powered sample of 54 physiotherapists from the Philippines will be recruited and r and omly allocated to EBP intervention or waitlist control . Intervention : The EBP program for Filipino physiotherapists is a one-day program on EBP principles and techniques , delivered using effective adult education strategies . It consists of lectures and practical workshops . A novel component in this program is the specially-developed recommendation form , which participants can use after completing their training , to assist them to negotiate with referring doctors regarding evidence -based treatment choices for their patients .Pre and post measures of EBP knowledge , skills and attitudes will be assessed in both groups using the Adapted Fresno Test and the Questions to EBP attitudes . Behaviour to EBP will be measured using activity diaries for a period of three months . Discussion Should the EBP-training program be found to be effective in improving EBP-uptake in Filipino physiotherapists , it will form the basis of a much needed national intervention which is context ually appropriate to Filipino physiotherapists . It will therefore form the genesis for a model for building EBP capacity of other health professionals in the Philippines as well as physiotherapists in developing countries . Trial Registration Current Controlled Trials : IS RCT BACKGROUND The number of people residing in nursing homes has increased . General practitioners ( GPs ) receive an increased capitation fee for elderly patients in recognition of their higher consultation rate . However , there is no distinction between elderly patients residing in nursing homes and those in the community . AIM To determine whether nursing home residents receive greater general practice input than people residing in the community . METHOD Prospect i ve comparative study of all 345 residents of eight nursing homes in Glasgow and a 2:1 age , sex , and GP matched comparison group residing in the community . A comparison of contacts with primary care over three months in terms of frequency , nature , length , and outcome was carried out . RESULTS Nursing home residents received more total contacts with primary care staff ( P < 0.0001 ) and more face-to-face consultations with GPs ( P < 0.0001 ) . They were more likely to be seen as an emergency ( P < 0.01 ) but were no more likely to be referred to hospital , and were less likely to be followed-up by their GP ( P < 0.0001 ) . Although individual consultations with nursing home residents were shorter than those with the community group ( P < 0.0001 ) , the overall time spent consulting with them was longer ( P < 0.001 ) . This equated to an additional 28 minutes of time per patient per annum . Some of this time would have been offset by less time spent travelling , since 61 % of nursing home consultations were done during the same visit as other consultations , compared with only 3 % of community consultations ( P < 0.0001 ) . CONCLUSION Our study suggests that nursing home residents do require a greater input from general practice than people of the same age and sex who are residing in the community . While consideration may be given to greater financial reimbursement of GPs who provide medical care to nursing home residents , consideration should also be given to restructuring the medical cover for nursing home residents . This would result in a greater scope for proactive and preventive interventions and for consulting with several patients during one visit BACKGROUND We assessed patient outcomes 90 days after hospital admission for stroke following a multidisciplinary intervention targeting evidence -based management of fever , hyperglycaemia , and swallowing dysfunction in acute stroke units ( ASUs ) . METHODS In the Quality in Acute Stroke Care ( QASC ) study , a single-blind cluster r and omised controlled trial , we r and omised ASUs ( clusters ) in New South Wales , Australia , with immediate access to CT and on-site high dependency units , to intervention or control group . Patients were eligible if they spoke English , were aged 18 years or older , had had an ischaemic stroke or intracerebral haemorrhage , and presented within 48 h of onset of symptoms . Intervention ASUs received treatment protocol s to manage fever , hyperglycaemia , and swallowing dysfunction with multidisciplinary team building workshops to address implementation barriers . Control ASUs received only an abridged version of existing guidelines . We recruited pre-intervention and post-intervention patient cohorts to compare 90-day death or dependency ( modified Rankin scale [ mRS ] ≥2 ) , functional dependency ( Barthel index ) , and SF-36 physical and mental component summary scores . Research assistants , the statistician , and patients were masked to trial groups . All analyses were done by intention to treat . This trial is registered at the Australia New Zeal and Clinical Trial Registry ( ANZCTR ) , number ACTRN12608000563369 . FINDINGS 19 ASUs were r and omly assigned to intervention ( n=10 ) or control ( n=9 ) . Of 6564 assessed for eligibility , 1696 patients ' data were obtained ( 687 pre-intervention ; 1009 post-intervention ) . Results showed that , irrespective of stroke severity , intervention ASU patients were significantly less likely to be dead or dependent ( mRS ≥2 ) at 90 days than control ASU patients ( 236 [ 42 % ] of 558 patients in the intervention group vs 259 [ 58 % ] of 449 in the control group , p=0·002 ; number needed to treat 6·4 ; adjusted absolute difference 15·7 % [ 95 % CI 5·8 - 25·4 ] ) . They also had a better SF-36 mean physical component summary score ( 45·6 [ SD 10·2 ] in the intervention group vs 42·5 [ 10·5 ] in the control group , p=0·002 ; adjusted absolute difference 3·4 [ 95 % CI 1·2 - 5·5 ] ) but no improvement was recorded in mortality ( 21 [ 4 % ] of 558 in intervention group and 24 [ 5 % ] of 451 in the control group , p=0·36 ) , SF-36 mean mental component summary score ( 49·5 [ 10·9 ] in the intervention group vs 49·4 [ 10·6 ] in the control group , p=0·69 ) or functional dependency ( Barthel Index ≥60 : 487 [ 92 % ] of 532 patients vs 380 [ 90 % ] of 423 patients ; p=0·44 ) . INTERPRETATION Implementation of multidisciplinary supported evidence -based protocol s initiated by nurses for the management of fever , hyperglycaemia , and swallowing dysfunction delivers better patient outcomes after discharge from stroke units . Our findings show the possibility to augment stroke unit care . FUNDING National Health & Medical Research Council ID 353803 , St Vincent 's Clinic Foundation , the Curran Foundation , Australian Diabetes Society-Servier , the College of Nursing , and Australian Catholic University BACKGROUND Antibiotic misuse is common and costly and may promote antibiotic resistance . We tested the efficacy of a targeted one-on-one educational program ( " academic detailing " ) design ed to improve the appropriateness of broad-spectrum antibiotic use . METHODS A r and omized controlled trial was conducted in a large US teaching hospital . During an 18-week study period , 17 general medical , oncology , and cardiology services either received academic detailing or did not . The intervention was prompted by an order for either levofloxacin or ceftazidime that led to a computer-based review of data for that patient . Orders for the 2 target antibiotics deemed unnecessary by a priori criteria were included in the study . The primary outcome examined was the number of days that unnecessary levofloxacin or ceftazidime was administered in intervention and control groups . RESULTS Before the trial , intervention and control services had similar prescribing patterns for the target antibiotics ; the drugs were used for similar indications throughout the study period . During the intervention , there was a reduction of 37 % in days of unnecessary levofloxacin or ceftazidime use per 2-week interval on services r and omized to the educational intervention vs control services ( P < .001 ) . In multivariable analyses controlling for baseline prescribing and study interval , the rate of unnecessary use of the 2 target antibiotics was reduced by 41 % on the intervention services compared with controls ( 95 % confidence interval , 44%-78 % ; P < .001 ) . Length of stay , intensive care unit transfers , readmission rates , and in-hospital death rates were similar in both groups ( P > or = .10 for all ) . CONCLUSION Targeted one-on-one education is a practical , effective , and safe method for reducing excessive broad-spectrum antibiotic use OBJECTIVE To assess the effects of a facilitator enhanced multifaceted intervention to implement a locally adapted guideline on the shared care for people with type 2 diabetes . METHODS During 1 year a cluster-r and omized trial was performed in 30 general practice s. In the intervention group , nurse facilitators enhanced guideline implementation by analysing barriers to change , introducing structured care , training practice staff and giving performance feedback . Targets for HbA1c% , systolic blood pressure as well as indications for angiotensin converting enzyme/angiotensin receptor blocking agent prescription differed from the national guidelines . In the control group , GPs were asked to continue the care for people with diabetes as usually . Generalized estimating equations were used to control for the clustered design of the study . RESULTS In the intervention group , more people were seen on a 3-monthly basis ( 88 % versus 69 % , P < 0.001 ) and more blood pressure and bodyweight measurements were performed every 3 months ( blood pressure 83 % versus 66 % , P < 0.001 and bodyweight 78.9 % versus 48.5 % , P < 0.001 ) . Apart from a marginal difference in mean cholesterol , differences in HbA1c% , blood pressure , body mass index and treatment satisfaction were not significant . CONCLUSION Multifaceted implementation of locally adapted shared care guidelines did improve the process of diabetes care but hardly changed intermediate outcomes . In the short term , local adaptation of shared care guidelines does not improve the cardiovascular risks of people with type 2 diabetes BACKGROUND Most clinicians have no training about domestic violence , fail to identify patients experiencing abuse , and are uncertain about management after disclosure . We tested the effectiveness of a programme of training and support in primary health-care practice s to increase identification of women experiencing domestic violence and their referral to specialist advocacy services . METHODS In this cluster r and omised controlled trial , we selected general practice s in two urban primary care trusts , Hackney ( London ) and Bristol , UK . Practice s in which investigators from this trial were employed or those who did not use electronic records were excluded . Practice s were stratified by proportion of female doctors , postgraduate training status , number of patients registered , and percentage of practice population on low incomes . Within every primary care trust area , we r and omised practice s with a computer-minimisation programme with a r and om component to intervention or control groups . The intervention programme included practice -based training sessions , a prompt within the medical record to ask about abuse , and a referral pathway to a named domestic violence advocate , who also delivered the training and further consultancy . The primary outcome was recorded referral of patients to domestic violence advocacy services . The prespecified secondary outcome was recorded identification of domestic violence in the electronic medical records of the general practice . Poisson regression analyses accounting for clustering were done for all practice s receiving the intervention . Practice staff and research associates were not masked and patients were not aware they were part of a study . This study is registered at Current Controlled Trials , IS RCT N74012786 . FINDINGS We r and omised 51 ( 61 % ) of 84 eligible general practice s in Hackney and Bristol . Of these , 24 received a training and support programme , 24 did not receive the programme , and three dropped out before the trial started . 1 year after the second training session , the 24 intervention practice s recorded 223 referrals of patients to advocacy and the 24 control practice s recorded 12 referrals ( adjusted intervention rate ratio 22·1 [ 95 % CI 11·5 - 42·4 ] ) . Intervention practice s recorded 641 disclosures of domestic violence and control practice s recorded 236 ( adjusted intervention rate ratio 3·1 [ 95 % CI 2·2 - 4·3 ) . No adverse events were recorded . INTERPRETATION A training and support programme targeted at primary care clinicians and administrative staff improved referral to specialist domestic violence agencies and recorded identification of women experiencing domestic violence . Our findings reduce the uncertainty about the benefit of training and support interventions in primary care setting s for domestic violence and show that screening of women patients for domestic violence is not a necessary condition for improved identification and referral to advocacy services . FUNDING Health Foundation Objective To determine if a structured complex intervention increases opportunistic chlamydia screening testing of patients aged 15–24 years attending English general practitioner ( GP ) practice s. Methods A prospect i ve , Cluster R and omised Controlled Trial with a modified Zelen design involving 160 practice s in South West Engl and in 2010 . The intervention was based on the Theory of Planned Behaviour ( TPB ) . It comprised of practice -based education with up to two additional contacts to increase the importance of screening to GP staff and their confidence to offer tests through skill development ( including videos ) . Practical re sources ( targets , posters , invitation cards , computer reminders , newsletters including feedback ) aim ed to actively influence social cognitions of staff , increasing their testing intention . Results Data from 76 intervention and 81 control practice s were analysed . In intervention practice s , chlamydia screening test rates were 2.43/100 15–24-year-olds registered preintervention , 4.34 during intervention and 3.46 postintervention ; controls testing rates were 2.61/100 registered patients prior intervention , 3.0 during intervention and 2.82 postintervention . During the intervention period , testing in intervention practice s was 1.76 times as great ( CI 1.24 to 2.48 ) as controls ; this persisted for 9 months postintervention ( 1.57 times as great , CI 1.27 to 2.30 ) . Chlamydia infections detected increased in intervention practice s from 2.1/1000 registered 15–24-year-olds prior intervention to 2.5 during the intervention compared with 2.0 and 2.3/1000 in controls ( Estimated Rate Ratio intervention versus controls 1.4 ( CI 1.01 to 1.93 ) . Conclusions This complex intervention doubled chlamydia screening tests in fully engaged practice s. The modified Zelen design gave realistic measures of practice full engagement ( 63 % ) and efficacy of this educational intervention in general practice ; it should be used more often . Trial registration The trial was registered on the UK Clinical Research Network Study Portfolio data base . UKCRN number 9722 BACKGROUND In the future , primary care groups ( PCGs ) will have to consider how best to apply audit and education to fulfil their commitment to clinical governance and to facilitate the implementation of research findings . AIM To establish whether an exploration of ' barriers to change ' can enhance the effectiveness of an educational intervention design ed to improve the management of hypertension in the elderly . METHOD A parallel-arm , r and omized , single-blind , controlled trial of practice -based educational visits in 18 practice s. These practice s had previously taken part in a multi practice audit of the management of hypertension in the elderly . Both groups received outreach visits in their own practice , during which they received the results of the previous audit . The nine ' intervention ' practice s were encouraged to explore barriers that would prevent them from implementing pertinent research findings . The control group was not encouraged to do this . The main outcome measure of the trial was determined in advance as ' the stated management of systolic hypertension in patients aged 70 to 79 ' . A secondary endpoint was the stated management of a specific patient scenario . The endpoints were tested by question naire before and after the educational intervention . RESULTS For the primary endpoint , there was a statistically significant difference in the stated threshold for treating systolic hypertension between intervention and control groups after the visits ( 161.8 mmHg versus 167.2 mmHg ; P = 0.007 ) . For the secondary endpoint , there was also a statistically significant difference between the two groups , after the visits , in their willingness to treat a 70-year-old male with mild hypertension ( 89 % of doctors would treat in the intervention group versus 57 % in the control group ; P = 0.047 ) . CONCLUSION The effectiveness of an educational intervention is significantly improved by addressing the barriers preventing practitioners from implementing the findings of research Background Anxiety and depressive disorders are highly prevalent disorders and are mostly treated in primary care . The management of these disorders by general practitioners is not always consistent with prevailing guidelines because of a variety of factors . Design ing implementation strategies tailored to prospect ively identified barriers could lead to more guideline -recommended care . Although tailoring of implementation strategies is promoted in practice , little is known about the effect on improving the quality of care for the early recognition , diagnosis , and stepped care treatment allocation in patients with anxiety or depressive disorders in general practice . This study examines whether the tailored strategy supplemented with training and feedback is more effective than providing training and feedback alone . Methods In this cluster r and omised controlled trial , a total of 22 general practice s will be assigned to one of two conditions : ( 1 ) training , feedback , and tailored interventions and ( 2 ) training and feedback . The primary outcome measure is the proportion of patients who have been recognised to have anxiety and /or depressive disorder . The secondary outcome measures in patients are severity of anxiety and depressive symptoms , level of functioning , expectation towards and experience with care , quality of life , and economic costs . Measures are taken after the start of the intervention at baseline and at three- and six-month follow-ups . Secondary outcome measures in general practitioners are adherence to guideline -recommended care in care that has been delivered , the proportion of antidepressant prescriptions , and number of referrals to specialised mental healthcare facilities . Data will be gathered from the electronic medical patient records from the patients included in the study . In a process evaluation , the identification of barriers to change and the relations between prospect ively identified barriers and improvement interventions selected for use will be described , as well as the factors that influence the provision of guideline -recommended care . Discussion It is hypothesised that the adherence to guideline recommendations will be improved by design ing implementation interventions that are tailored to prospect ively identified barriers in the local context of general practitioners . Currently , there is insufficient evidence on the most effective and efficient approaches to tailoring , including how barriers should be identified and how interventions should be selected to address the barriers . Trial registration Background This study evaluated the effectiveness of the context ualized EBP training program for Filipino physical therapists in terms of knowledge , skills , attitudes and behavior . Methods A r and omized controlled trial was design ed to assess the effectiveness of the EBP training program . Fifty four physical therapists were r and omly allocated to the EBP group ( intervention ) and waitlist ( control ) group . The EBP group had a one day face-to-face training with an online support , whilst the control was waitlisted . There were three measurement points which were pre , post , and three months post intervention for knowledge , skills and attitudes . Activity diaries were used to measure behavior . The diaries were collected after three months . Data analysis was by intention to treat in EBP domains of knowledge , skills and attitudes . Results Fifty-four physical therapists were included in the study . Fifty two ( 52 ) completed the post training assessment and 26 completed the 3 months post training assessment for EBP knowledge , skills and attitudes . There were significant improvements in these domains in the EBP group from pre to post training and over a period of three months ( p < 0.05 ) compared with the waitlist control group . Thirty seven ( 37 ) physical therapists completed their activity diaries over three months . Behavior significantly improved in the EBP group in terms of EBP behaviors ( formulating PICO , search ing , appraising and applying the evidence ) when faced with both new/unique and usual case scenarios ( p < 0.05 ) . More physical therapists in the waitlist control group significantly performed non-EBP behaviors ( asking doctors and reading textbooks ) when faced with new/unique cases compared with the EBP group ( p < 0.05 ) . No differences were noted between groups regarding non-EBP behaviors ( asking colleagues and doctors and reading textbooks ) particularly when faced with usual cases . Conclusion The context ually design ed EBP training program for Filipino physical therapists was effective in improving knowledge , skills and attitudes to EBP from pre to post training . Improvements were also observed at three months post training in knowledge , skills , attitudes and behavior to EBP . This model of training can be modified as needed based on the needs of the local context . Findings need to be interpreted with caution due to study limitations .Current controlled trialsIS RCT N74485061 ( Registration date : February 9 , 2011 ) OBJECTIVE To apply the UK Medical Research Council ( MRC ) framework for development and evaluation of trials of complex interventions to a primary healthcare intervention to promote secondary prevention of coronary heart disease . STUDY DESIGN Case report of intervention development . METHODS First , literature relating to secondary prevention and lifestyle change was review ed . Second , a preliminary intervention was modeled , based on literature findings and focus group interviews with patients ( n = 23 ) and staff ( n = 29 ) from 4 general practice s. Participants ' experiences of and attitudes toward key intervention components were explored . Third , the preliminary intervention was pilot-tested in 4 general practice s. After delivery of the pilot intervention , practitioners evaluated the training sessions , and qualitative data relating to experiences of the intervention were collected using semistructured interviews with staff ( n = 10 ) and patient focus groups ( n = 17 ) . RESULTS Literature review identified 3 intervention components : a structured recall system , practitioner training , and patient information . Initial qualitative data identified variations in recall system design , training requirements ( medication prescribing , facilitating behavior change ) , and information appropriate to the prospect i ve study participants . Identifying detailed structures within intervention components clarified how the intervention could be tailored to individual practice , practitioner , and patient needs while preserving the theoretical functions of the components . Findings from the pilot phase informed further modeling of the intervention , reducing administrative time , increasing practical content of training , and omitting unhelpful patient information . CONCLUSION Application of the MRC framework helped to determine the feasibility and development of a complex intervention for primary care research Background Patients in hospitals and nursing homes are at risk of the development of , often preventable , adverse events ( AEs ) , which threaten patient safety . Guidelines for prevention of many types of AEs are available , however , compliance with these guidelines appears to be lacking . Besides general barriers that inhibit implementation , this non-compliance is associated with the large number of guidelines competing for attention . As implementation of a guideline is time-consuming , it is difficult for organisations to implement all available guidelines . Another problem is lack of feedback about performance using quality indicators of guideline based care and lack of a recognisable , unambiguous system for implementation . A program that allows organisations to implement multiple guidelines simultaneously may facilitate guideline use and thus improve patient safety . The aim of this study is to develop and test such an integral patient safety program that addresses several AEs simultaneously in hospitals and nursing homes . This paper reports the design of this study . Methods and design The patient safety program addresses three AEs : pressure ulcers , falls and urinary tract infections . It consists of bundles and outcome and process indicators based on the existing evidence based guidelines . In addition it includes a multifaceted tailored implementation strategy : education , patient involvement , and a computerized registration and feedback system . The patient safety program was tested in a cluster r and omised trial on ten hospital wards and ten nursing home wards . The baseline period was three months followed by the implementation of the patient safety program for fourteen months . Subsequently the follow-up period was nine months . Primary outcome measure was the incidence of AEs on every ward . Secondary outcome measures were the utilization of preventive interventions and the knowledge of nurses regarding the three topics . R and omisation took place on ward level . The results will be analysed separately for hospitals and nursing homes . Discussion Major challenges were the development of the patient safety program including a digital registration and feedback system and the implementation of the patient safety program . Trial registration Trial registration : Clinical Trials.gov ID [ NCT00365430 Background Only 1 - 3 % of ischemic stroke patients receive thrombolytic therapy . Provider barriers to adhering with guidelines recommending tPA delivery in acute stroke are not well known . The main objective of this study was to describe barriers to thrombolytic use in acute stroke care . Methods Twenty-four hospitals were r and omly selected and matched into 12 pairs . Barrier assessment occurred at intervention sites only , and utilized focus groups and structured interviews . A pre-specified taxonomy was employed to characterize barriers . Two investigators independently assigned themes to transcribed responses . Seven facilitators ( three emergency physicians , two nurses , and two study coordinators ) conducted focus groups and interviews of emergency physicians ( 65 ) , nurses ( 62 ) , neurologists ( 15 ) , radiologists ( 12 ) , hospital administrators ( 12 ) , and three others ( hospitalists and pharmacist ) . Results The following themes represented the most important external barriers : environmental and patient factors . Important barriers internal to the clinician included familiarity with and motivation to adhere to the guidelines , lack of self-efficacy and outcome expectancy . The following themes were not substantial barriers : lack of awareness of the existence of acute stroke guidelines , presence of conflicting guidelines , and lack of agreement with the guidelines . Conclusions Healthcare providers perceive environmental and patient-related factors as the primary barriers to adherence with acute stroke treatment guidelines . Interventions focused on increasing physician familiarity with and motivation to follow guidelines may be of highest yield in improving adherence . Improving self-efficacy in performing guideline concordant care may also be useful . Trial Registration Clinical Trials.gov identifier : BACKGROUND A cluster r and omized trial of tailored interventions to support the implementation of guidelines for sore throat and urinary tract infection found little or no change in the main outcomes , which were antibiotic prescriptions , use of laboratory tests and use of telephone consultations . There was great variation between the practice s in the change in these outcomes . OBJECTIVES Our aim was to evaluate how the interventions were received and to underst and why practice s did or did not change . METHODS The trial was conducted in general practice s in Norway . Data for this process evaluation were collected from the 120 practice s that completed the trial . Multiple methods were used : observations , semi-structured telephone interviews , a postal survey and data extracted from electronic medical records . We investigated factors that might explain a lack of change , including : agreement with the guidelines ; communication within each practice ; degree of participation in the project ; taking time to discuss the guidelines and their implementation ; use of the components of the interventions ; and routines for telephone consultations . Possible explanatory factors were explored in relation to variation in change and the overall extent of change in rates of use of antibiotics , laboratory tests and telephone consultations . RESULTS Sixty-three per cent of practice s agreed with the guidelines . Only 35 % reported having regular meetings , and 33 % discussed the project before its start , although 75 % reported agreement about participating within the practice . Only 33 % reported meeting to discuss the guidelines . Use of the components of the interventions ranged from 11 % for the increased fee for telephone consultations to 48 % for the computerized decision support . Forty-four per cent reported problems with telephone routines . No single factor explained the observed variation in the extent of change across practice s. CONCLUSIONS Inadequate time , re sources and support were the most salient factors that might explain a lack of change . Problems with internal communication and telephone routines were important contributing factors in many practice This study tests whether a managed behavioral health care organization can influence adherence to practice guidelines for the treatment of major depression in a r and omized trial of guideline dissemination . Guidelines were disseminated to mental health clinicians ( N=443 ) under one of three conditions : ( 1 ) a general mailing of guidelines to clinicians , ( 2 ) a mailing in which guidelines were targeted to a patient starting treatment with the clinician , and ( 3 ) no mailing of guidelines . The results showed no effects of guideline dissemination as measured by self-report of patients and clinicians and through episode characteristics derived from cl aims data , despite sentinel effects . Results also showed high rates of clinician-reported guideline adherence that were not detected in the cl aims data , indicating significant undertreatment of depression . Results suggest that mental health systems must look to other dissemination strategies to improve adherence to st and ards of care and raise the performance of independent practicing The objective of this research was to identify determinants of the magnitude of intracluster correlation coefficients ( ICCs ) in cluster r and omized trials from the field of implementation research . A survey of experts was conducted to generate a priori hypotheses of factors that might affect ICC size . Hypotheses were tested on empirical estimates of ICCs calculated from 21 implementation research data sets , mainly from the UK . Effects of setting ( primary or secondary care ) , type of variable ( process or outcome ) , type of measurement ( objective or subjective ) , prevalence of outcome and size of cluster were tested . In total , 220 ICCs were available ( range 0 to 0.415 ) . Significant differences in ICC magnitude were found . The ICCs were significantly higher for process than for outcome variables , and for secondary care outcomes compared with primary care outcomes . The effects of prevalence and size were less clear cut . There was no evidence to suggest that type of measurement affected ICC size . In conclusion , accurate estimates of ICCs are essential for sample size calculations for cluster r and omized trials of professional behaviour change interventions . This study demonstrates that ICCs are sensitive to a number of trial factors , particularly setting and outcome type . These factors must be considered when planning such cluster r and omized trials Background Multimorbid patients frequently receive complex medication regimens and are at higher risk for adverse drug reactions and hospitalisations . Managing patients with polypharmacy is dem and ing , because it requires coordination of multiple prescribers and intensive monitoring . Three evidence -based recommendations addressing polypharmacy in primary care are structured medication counselling , use of medication lists and medication review s to avoid potentially inappropriate medication ( PIM ) . Although promising to improve patient outcomes , these recommendations are not well implemented in German routine care . Implementation of guidelines is often hindered by specific “ determinants of change ” . “ Tailored ” interventions are design ed to specifically address previously identified determinants . This study examines a tailored intervention tto implement the aforementioned recommendations into German primary care practice s. This study is part of the European Tailored Interventions for Chronic Diseases project , which aims at contributing knowledge about the methods used for tailoring . Methods / Design The study is design ed as a cluster r and omized controlled trial with primary care practice s of general practitioners ( GPs ) who are organized in quality circles . Quality circles will be the unit of r and omization with a 1:1 ratio . Follow-up time is 6 months . GPs and healthcare assistants in the intervention group will receive training on medication management . Each GP will create a tailored concept of how to implement the three recommendations into his/her practice . Evidence -based checklists for medication counselling and medication review s will be provided for physicians . A tablet PC with an interactive educational tool and information leaflets will be provided for use by patients to inform about the necessity of continuous medication management . Control practice s will not receive special training and will provide care as usual . Primary outcome is the degree of implementation of the three recommendations , which will be measured using a prespecified set of indicators . Additionally , the PIM prescription rate , patient activation , patients ’ beliefs about medicine , medication adherence and patients ’ social support will be measured . Discussion This study will contribute knowledge about the feasibility of implementing recommendations for managing patients with polypharmacy in primary care practice s. Additionally , this study will contribute knowledge about methods for tailoring of implementation interventions .Trial registration Clinical trials.govIS RCT Summary Background Robust evidence of the effectiveness of task shifting of antiretroviral therapy ( ART ) from doctors to other health workers is scarce . We aim ed to assess the effects on mortality , viral suppression , and other health outcomes and quality indicators of the Streamlining Tasks and Roles to Exp and Treatment and Care for HIV ( STRETCH ) programme , which provides educational outreach training of nurses to initiate and represcribe ART , and to de central ise care . Methods We undertook a pragmatic , parallel , cluster-r and omised trial in South Africa between Jan 28 , 2008 , and June 30 , 2010 . We r and omly assigned 31 primary -care ART clinics to implement the STRETCH programme ( intervention group ) or to continue with st and ard care ( control group ) . The ratio of r and omisation depended on how many clinics were in each of nine strata . Two cohorts were enrolled : eligible patients in cohort 1 were adults ( aged ≥16 years ) with CD4 counts of 350 cells per μL or less who were not receiving ART ; those in cohort 2 were adults who had already received ART for at least 6 months and were being treated at enrolment . The primary outcome in cohort 1 was time to death ( superiority analysis ) . The primary outcome in cohort 2 was the proportion with undetectable viral loads ( < 400 copies per mL ) 12 months after enrolment ( equivalence analysis , prespecified difference < 6 % ) . Patients and clinicians could not be masked to group assignment . The interim analysis was blind , but data analysts were not masked after the data base was locked for final analysis . Analyses were done by intention to treat . This trial is registered , number IS RCT N46836853 . Findings 5390 patients in cohort 1 and 3029 in cohort 2 were in the intervention group , and 3862 in cohort 1 and 3202 in cohort 2 were in the control group . Median follow-up was 16·3 months ( IQR 12·2–18·0 ) in cohort 1 and 18·0 months ( 18·0–18·0 ) in cohort 2 . In cohort 1 , 997 ( 20 % ) of 4943 patients analysed in the intervention group and 747 ( 19 % ) of 3862 in the control group with known vital status at the end of the trial had died . Time to death did not differ ( hazard ratio [ HR ] 0·94 , 95 % CI 0·76–1·15 ) . In a preplanned subgroup analysis of patients with baseline CD4 counts of 201–350 cells per μL , mortality was slightly lower in the intervention group than in the control group ( 0·73 , 0·54–1.00 ; p=0·052 ) , but it did not differ between groups in patients with baseline CD4 of 200 cells per μL or less ( 0·94 , 0·76–1·15 ; p=0·577 ) . In cohort 2 , viral load suppression 12 months after enrolment was equivalent in intervention ( 2156 [ 71 % ] of 3029 patients ) and control groups ( 2230 [ 70 % ] of 3202 ; risk difference 1·1 % , 95 % CI −2·4 to 4·6 ) . Interpretation Expansion of primary -care nurses ' roles to include ART initiation and represcription can be done safely , and improve health outcomes and quality of care , but might not reduce time to ART or mortality . Funding UK Medical Research Council , Development Cooperation Irel and , and Canadian International Development Agency Objective : To compare baseline cardiovascular risk management between people from two different healthcare systems recruited to a research trial of an intervention to optimise secondary prevention . Design : Cross-sectional study . Setting : 16 r and omly selected general practice s in Northern Irel and ( NI ) ( UK NHS , strong infrastructure , pay-for-performance ) and 32 in the Republic of Irel and ( RoI ) ( mixed healthcare economy , less infrastructure , no pay-for-performance ) . Patients : 903 ( mean age 67.5 years ; 69.9 % male ) r and omly selected patients with known coronary heart disease . Main outcome measures : Blood pressure ( BP ) , cholesterol , medications ; vali date d question naires for diet ( DINE ) , exercise ( Godin ) and quality of life ( SF-12 ) ; healthcare usage . Results : More RoI than NI participants had systolic BP > 140 mm Hg ( 37 % vs 28 % , p = 0.01 ) and cholesterol > 5 mmol/l ( 24 % vs 17 % , p = 0.02 ) . RoI mean systolic BP was higher ( 139 vs 132 mm Hg ) . More RoI participants reported a high fibre intake ( 35 % vs 23 % ) , higher levels of physical activity ( 62 % vs 44 % ) and better physical and mental health ( SF-12 ) ; they also had more GP ( 5.6 vs 4.4 ) and fewer nurse visits ( 1.6 vs 2.1 ) in the previous year . Fewer participants in the RoI ( 55 % vs 70 % ) were prescribed β blockers . ACE inhibitor prescribing was similar for both groups ( 41 % ; 48 % ) ; high proportions were prescribed statins ( 84 % ; 85 % ) and aspirin ( 83 % ; 77 % ) . Conclusions : BP and cholesterol are better controlled among patients in a primary healthcare system with a strong infrastructure supporting computerisation and rewarding measured performance , but this is not associated with healthier lifestyle or better quality of life . Further exploration of differences in professionals ’ and patients ’ engagement in secondary prevention in different healthcare systems is needed Abstract Objective To test the effectiveness of educational interventions in improving detection rates and management of dementia in primary care . Design Unblinded , cluster r and omised , before and after controlled study . Setting General practice s in the United Kingdom ( central Scotl and and London ) between 1999 and 2002 . Interventions Three educational interventions : an electronic tutorial carried on a CD Rom ; decision support software built into the electronic medical record ; and practice based workshops . Participants 36 practice s participated in the study . Eight practice s were r and omly assigned to the electronic tutorial ; eight to decision support software ; 10 to practice based workshops ; and 10 to control . Electronic and manual search es yielded 450 valid and usable medical records . Main outcome measures Rates of detection of dementia and the extent to which medical records showed evidence of improved concordance with guidelines regarding diagnosis and management . Results Decision support software ( P = 0.01 ) and practice based workshops ( P = 0.01 ) both significantly improved rates of detection compared with control . There were no significant differences by intervention in the measures of concordance with guidelines . Conclusions Decision support systems and practice based workshops are effective educational approaches in improving detection rates in dementia Background Childhood asthma is common in Cape Town , a province of South Africa , but is underdiagnosed by general practitioners . Medications are often prescribed inappropriately , and care is episodic . The objective of this study is to assess the impact of educational outreach to general practitioners on asthma symptoms of children in their practice . Methods This is a cluster r and omised trial with general practice s as the unit of intervention , r and omisation , and analysis . The setting is Mitchells Plain ( population 300,000 ) , a dormitory town near Cape Town . Solo general practitioners , without nurse support , operate from storefront practice s. Caregiver-reported symptom data were collected for 318 eligible children ( 2 to 17 years ) with moderate to severe asthma , who were attending general practitioners in Mitchells Plain . One year post-intervention follow-up data were collected for 271 ( 85 % ) of these children in all 43 practice s. Practice s r and omised to intervention ( 21 ) received two 30-minute educational outreach visits by a trained pharmacist who left material s describing key interventions to improve asthma care . Intervention and control practice s received the national childhood asthma guideline . Asthma severity was measured in a parent-completed survey administered through schools using a symptom frequency and severity scale . We compared intervention and control group children on the change in score from pre-to one-year post-intervention . Results Symptom scores declined an additional 0.84 points in the intervention vs. control group ( on a nine-point scale . p = 0.03 ) . For every 12 children with asthma exposed to a doctor allocated to the intervention , one extra child will have substantially reduced symptoms . Conclusion Educational outreach was accepted by general practitioners and was effective . It could be applied to other health care quality problems in this setting ABSTRACT Cancer pain management can be improved by overcoming patients ’ attitudinal barriers to reporting pain and using analgesics . A simple cost‐effective barriers intervention design ed to reach a large number of persons with cancer has not yet been tested . Such an intervention should be tested against barriers ’ assessment ‐alone , as well as no‐treatment control . The purpose of this study was to test the efficacy and the cost effectiveness of a tailored barriers intervention ( TBI ) , an educational intervention tailored to participants ’ attitudinal barriers toward reporting pain and using analgesics . This was a r and omized three‐group ( TBI , assessment ‐alone , or control ) trial with measures at baseline and 28 days later conducted at the North Central and Heartl and offices of the Cancer Information Service ( CIS ) , an NCI program that provides information to persons seeking answers to cancer‐related questions . Participants ( 1256 adult CIS callers diagnosed with cancer with moderate to severe pain in the past week ) joined the study and were r and omized . Of these participants , 970 ( 77.23 % ) provided follow‐up data . The TBI consisted of educational messages tailored to each participant ’s attitudinal barriers , delivered orally over the telephone , followed by a printed mailed copy . The outcome measures were attitudinal barriers to pain management , as well as pain outcomes ( duration , severity , and interference with life activities ) . At follow‐up the TBI group had significantly lower attitudinal barriers scores compared to assessment ‐alone and control , but the groups did not differ on the pain outcome variables . TBI and assessment ‐alone had similar cost effectiveness . The TBI needs to be strengthened to achieve reductions in pain severity Community clinics provide inadequate breast cancer screening services to low-income , racially- and ethnically-diverse communities . This study develops and evaluates the effectiveness of multifaceted organizational system interventions —operational assessment s , tracking systems , reminder calls , tailored education , physician prompts and a tailored counseling call — on mammography rescreening rates within three community clinics . We used the Chronic Care Model and Put Prevention Into Practice framework to re design breast screening delivery services within the California Cancer Detection Programs : Every Woman Counts(CDP : EWC ) , community clinic setting s. We used a quasi-experimental design with a r and om selection of 400 patients at pre-intervention . To establish a post-intervention clinic ’s rescreening rate a new comparable cross-sectional r and om sample of 347 women was drawn . Measures A chart abstract ion instrument was used to establish clinics ’ rescreening rates . Subjects Participants at pre and post-intervention were low-income women 50 years of age and older who had received normal mammography results and had not been diagnosed with breast cancer in the last five years . General linear mixed model analysis revealed significant improvements for the organizational system re design condition [ pre-intervention rescreening rate : 32.1 percent v. post-intervention rescreening rate 50.2 percent , ( p < .001 ) ] . For the organizational system re design plus tailored counseling call condition , there was maintenance in the rescreening rate following the intervention [ pre-intervention : 44.4 percent v. post-intervention : 45.1 percent , ( p > 0.05 ) ] . Multilevel interventions directed at re design ing community clinics primary care breast cancer screening services , can improve mammography rescreening rates Background The prevalence of depression is high and the elderly have an increased risk of developing chronic course . International data suggest that depression in the elderly is under-recognised , the latency before clinicians provide a treatment plan is longer and elderly patients with depression are not offered psychotherapy to the same degree as younger patients . Although recommendations for the treatment of elderly patients with depression exist , health-care professionals adhere to these recommendations to a limited degree only . We conducted a systematic review to identify recommendations for managing depression in the elderly and prioritised six recommendations . We identified and prioritised the determinants of practice related to the implementation of these recommendations in primary care , and subsequently discussed and prioritised interventions to address the identified determinants . The objective of this study is to evaluate the effectiveness of these tailored interventions for the six recommendations for the management of elderly patients with depression in primary care . Methods / design We will conduct a pragmatic cluster r and omised trial comparing the implementation of the six recommendations using tailored interventions with usual care . We will r and omise 80 municipalities into one of two groups : an intervention group , to which we will deliver tailored interventions to implement the six recommendations , and a control group , to which we will not deliver any intervention . We will r and omise municipalities rather than patients , individual clinicians or practice s , because we will deliver the intervention for the first three recommendations at the municipal level and we want to minimise the risk of contamination across GP practice s for the other three recommendations . The primary outcome is the proportion of actions taken by GPs that are consistent with the recommendations . Discussion This trial will investigate whether a tailored implementation approach is an effective strategy for improving collaborative care in the municipalities and health-care professionals ’ practice towards elderly patients with depression in primary care . The effectiveness evaluation described in this protocol will be accompanied with a process evaluation exploring why and how the interventions were effective or ineffective . Trial registration Clinical Trials.gov : Summary Background Medication errors are common in primary care and are associated with considerable risk of patient harm . We tested whether a pharmacist-led , information technology-based intervention was more effective than simple feedback in reducing the number of patients at risk of measures related to hazardous prescribing and inadequate blood-test monitoring of medicines 6 months after the intervention . Methods In this pragmatic , cluster r and omised trial general practice s in the UK were stratified by research site and list size , and r and omly assigned by a web-based r and omisation service in block sizes of two or four to one of two groups . The practice s were allocated to either computer-generated simple feedback for at-risk patients ( control ) or a pharmacist-led information technology intervention ( PINCER ) , composed of feedback , educational outreach , and dedicated support . The allocation was masked to general practice s , patients , pharmacists , research ers , and statisticians . Primary outcomes were the proportions of patients at 6 months after the intervention who had had any of three clinical ly important errors : non-selective non-steroidal anti-inflammatory drugs ( NSAIDs ) prescribed to those with a history of peptic ulcer without co-prescription of a proton-pump inhibitor ; β blockers prescribed to those with a history of asthma ; long-term prescription of angiotensin converting enzyme ( ACE ) inhibitor or loop diuretics to those 75 years or older without assessment of urea and electrolytes in the preceding 15 months . The cost per error avoided was estimated by incremental cost-effectiveness analysis . This study is registered with Controlled-Trials.com , number IS RCT N21785299 . Findings 72 general practice s with a combined list size of 480 942 patients were r and omised . At 6 months ' follow-up , patients in the PINCER group were significantly less likely to have been prescribed a non-selective NSAID if they had a history of peptic ulcer without gastroprotection ( OR 0·58 , 95 % CI 0·38–0·89 ) ; a β blocker if they had asthma ( 0·73 , 0·58–0·91 ) ; or an ACE inhibitor or loop diuretic without appropriate monitoring ( 0·51 , 0·34–0·78 ) . PINCER has a 95 % probability of being cost effective if the decision-maker 's ceiling willingness to pay reaches £ 75 per error avoided at 6 months . Interpretation The PINCER intervention is an effective method for reducing a range of medication errors in general practice s with computerised clinical records . Funding Patient Safety Research Portfolio , Department of Health , Engl and Background Despite accurate diagnostic tests and effective therapies , the management of osteoporosis has been observed to be suboptimal in many setting s. We tested the effectiveness of an intervention to improve care in patients at-risk of osteoporosis . Design R and omized controlled trial . Participants Primary care physicians and their patients at-risk of osteoporosis , including women 65 years and over , men and women 45 and over with a prior fracture , and men and women 45 and over who recently used ≥90 days of oral glucocorticoids . InterventionA multifaceted program of education and reminders delivered to primary care physicians as well as mailings and automated telephone calls to patients . Outcome : Either undergoing a bone mineral density ( BMD ) testing or filling a prescription for a bone-active medication during the 10 months of follow-up . Results After the intervention , 144 ( 14 % ) patients in the intervention group and 97 ( 10 % ) patients in the control group received either a BMD test or filled a prescription for an osteoporosis medication . This represents a 4 % absolute increase and a 45 % relative increase ( 95 % confidence interval 9–93 % , p = 0.01 ) in osteoporosis management between the intervention and control groups . No differences between groups were observed in the incidence of fracture . Conclusion An intervention targeting primary care physicians and their at-risk patients increased the frequency of BMD testing and /or filling prescriptions for osteoporosis medications . However , the absolute percentage of at-risk patients receiving osteoporosis management remained low Background A major barrier to accessing free government-provided antiretroviral treatment ( ART ) in South Africa is the shortage of suitably skilled health professionals . Current South African guidelines recommend that only doctors should prescribe ART , even though most primary care is provided by nurses . We have developed an effective method of educational outreach to primary care nurses in South Africa . Evidence is needed as to whether primary care nurses , with suitable training and managerial support , can initiate and continue to prescribe and monitor ART in the majority of ART-eligible adults . Methods / design This is a protocol for a pragmatic cluster r and omised trial to evaluate the effectiveness of a complex intervention based on and supporting nurse-led antiretroviral treatment ( ART ) for South African patients with HIV/AIDS , compared to current practice in which doctors are responsible for initiating ART and continuing prescribing . We will r and omly allocate 31 primary care clinics in the Free State province to nurse-led or doctor-led ART . Two groups of patients aged 16 years and over will be included : a ) 7400 registering with the programme with CD4 counts of ≤ 350 cells/mL ( mainly to evaluate treatment initiation ) and b ) 4900 already receiving ART ( to evaluate ongoing treatment and monitoring ) . The primary outcomes will be time to death ( in the first group ) and viral suppression ( in the second group ) . Patients ' survival , viral load and health status indicators will be measured at least 6-monthly for at least one year and up to 2 years , using an existing province-wide clinical data base linked to the national death register . Trial registration Controlled Clinical Trials IS RCT Background The Normalization Process Model is a theoretical model that assists in explaining the processes by which complex interventions become routinely embedded in health care practice . It offers a framework for process evaluation and also for comparative studies of complex interventions . It focuses on the factors that promote or inhibit the routine embedding of complex interventions in health care practice . Methods A formal theory structure is used to define the model , and its internal causal relations and mechanisms . The model is broken down to show that it is consistent and adequate in generating accurate description , systematic explanation , and the production of rational knowledge cl aims about the workability and integration of complex interventions . Results The model explains the normalization of complex interventions by reference to four factors demonstrated to promote or inhibit the operationalization and embedding of complex interventions ( interactional workability , relational integration , skill-set workability , and context ual integration ) . Conclusion The model is consistent and adequate . Repeated calls for theoretically sound process evaluations in r and omized controlled trials of complex interventions , and policy-makers who call for a proper underst and ing of implementation processes , emphasize the value of conceptual tools like the Normalization Process Model OBJECTIVES We examined the effects of a manualized care management protocol specifically design ed for care managers working with caregivers , the Tailored Caregiver Assessment and Referral ® ( TCARE ® ) protocol , on caregiver identity discrepancy , burden , and depressive symptoms . METHODS Preliminary data from a longitudinal , r and omized , controlled intervention study with 266 family caregivers served by 52 care managers in 4 states were analyzed using repeated measures r and om effects regression procedures . Caregivers in the intervention and control groups were repeatedly assessed for up to 9 months on caregiver identity discrepancy , 3 areas of caregiving burden- objective , relationship , and stress burdens ; depression ; and intention for nursing home placement . RESULTS We found significant group by time interaction effects for caregiver identity discrepancy , relationship burden , stress burden , depression , and intention for nursing home placement . Caregivers in the intervention group experienced significant improvement on these measures , whereas caregivers in the control group worsened on these measures over time . DISCUSSION The preliminary findings provide strong support for effectiveness of the TCARE ® protocol on improving caregiver well-being and mental health outcomes OBJECTIVES To develop and evaluate a new model of continuing medical education ( CME ) for general practitioners ( GPs ) . The study is part of the joint European Drug Education Project ( DEP ) . This paper presents the Swedish part regarding the design of the evaluation study , the educational methodology , and the participants ' evaluation . METHODS An educational model was developed . Two peer group discussion s ( facilitated by a GP/pharmacist team ) , including individual feedback on the GPs ' judgments of written simulated cases and prescribing , were main components . The model was tested in a parallel r and omized controlled study including 36 GP groups , allocated to education on asthma or urinary tract infections . Background and outcome data were knowledge and attitudes ( K/A ) assessed by a question naire and prescribing practice s for actual and written simulated cases . The GPs ' evaluation of the model was captured through a question naire . RESULTS All 36 groups completed the program . The mean participation rate in the group discussion s was 75 % . The response rates were 82 - 98 % regarding outcome data K/A question naire and written cases ) , and 80 % regarding the evaluation question naire . Prescribing data were captured for 99 % of the GPs . Both group discussion s were considered important by 84 - 89 % . Eighty-seven percent wished to take part in similar CME activities for other conditions . About 80 % reported that their purpose in participating had been fulfilled . CONCLUSIONS It was feasible to evaluate the developed educational model by using a two-armed parallel study design . The model was well received by the participants BACKGROUND Tuberculosis is re-emerging as an important health problem in industrialised countries . Uncertainty surrounds the effect of public-health control options . We therefore aim ed to assess a programme to promote screening for tuberculosis in a UK primary health care district . METHODS In a cluster r and omised controlled trial , we r and omised 50 of 52 ( 96 % ) eligible general practice s in Hackney , London , UK , to receive an outreach programme that promoted screening for tuberculosis in people registering in primary care , or to continue with usual care . Screening was verbal , and proceeded to tuberculin skin testing , if appropriate . The primary outcome was the proportion of new cases of active tuberculosis identified in primary care . Analyses were done on an intention-to-treat basis . This study was registered at clinical trials.gov , number NCT00214708 . FINDINGS Between June 1 , 2002 , and Oct 1 , 2004 , 44,986 and 48,984 patients registered with intervention and control practice s , respectively . In intervention practice s 57 % ( 13,478 of 23,573 ) of people attending a registration health check were screened for tuberculosis compared with 0.4 % ( 84 of 23 051 ) in control practice s. Intervention practice s showed increases in the diagnosis of active tuberculosis cases in primary care compared with control practice s ( 66/141 [ 47 % ] vs 54/157 [ 34 % ] , odds ratio ( OR ) 1.68 , 95 % CI 1.05 - 2.68 , p=0.03 ) . Intervention practice s also had increases in diagnosis of latent tuberculosis ( 11/59 [ 19 % ] vs 5/68 [ 9 % ] , OR 3.00 , 0.98 - 9.20 , p=0.055 ) and BCG coverage ( mean BCG rate 26.8/1000 vs 3.8/1000 , intervention rate ratio 9.52 , 4.0 - 22.7 , p<0.001 ) . INTERPRETATION Our educational intervention for promotion of screening for tuberculosis in primary care improved identification of active and latent tuberculosis , and increased BCG coverage . Yield from screening was low , but was augmented by improved case-finding . Screening programmes in primary care should be considered as part of tuberculosis control initiatives in industrialised countries BACKGROUND We have little systematic information about the extent to which st and ard processes involved in health care -- a key element of quality --are delivered in the United States . METHODS We telephoned a r and om sample of adults living in 12 metropolitan areas in the United States and asked them about selected health care experiences . We also received written consent to copy their medical records for the most recent two-year period and used this information to evaluate performance on 439 indicators of quality of care for 30 acute and chronic conditions as well as preventive care . We then constructed aggregate scores . RESULTS Participants received 54.9 percent ( 95 percent confidence interval , 54.3 to 55.5 ) of recommended care . We found little difference among the proportion of recommended preventive care provided ( 54.9 percent ) , the proportion of recommended acute care provided ( 53.5 percent ) , and the proportion of recommended care provided for chronic conditions ( 56.1 percent ) . Among different medical functions , adherence to the processes involved in care ranged from 52.2 percent for screening to 58.5 percent for follow-up care . Quality varied substantially according to the particular medical condition , ranging from 78.7 percent of recommended care ( 95 percent confidence interval , 73.3 to 84.2 ) for senile cataract to 10.5 percent of recommended care ( 95 percent confidence interval , 6.8 to 14.6 ) for alcohol dependence . CONCLUSIONS The deficits we have identified in adherence to recommended processes for basic care pose serious threats to the health of the American public . Strategies to reduce these deficits in care are warranted Background Task shifting and the integration of human immunodeficiency virus ( HIV ) care into primary care services have been identified as possible strategies for improving access to antiretroviral treatment ( ART ) . This paper describes the development and content of an intervention involving these two strategies , as part of the Streamlining Tasks and Roles to Exp and Treatment and Care for HIV ( STRETCH ) pragmatic r and omised controlled trial . Methods : Developing the interventionThe intervention was developed following discussion s with senior management , clinicians , and clinic staff . These discussion s revealed that the establishment of separate antiretroviral treatment services for HIV had result ed in problems in accessing care due to the large number of patients at ART clinics . The intervention developed therefore combined the shifting from doctors to nurses of prescriptions of antiretrovirals ( ARVs ) for uncomplicated patients and the stepwise integration of HIV care into primary care services . Results : Components of the interventionThe intervention consisted of regulatory changes , training , and guidelines to support nurse ART prescription , local management teams , an implementation toolkit , and a flexible , phased introduction . Nurse supervisors were equipped to train intervention clinic nurses in ART prescription using outreach education and an integrated primary care guideline . Management teams were set up and a STRETCH coordinator was appointed to oversee the implementation process . Discussion Three important processes were used in developing and implementing this intervention : active participation of clinic staff and local and provincial management , educational outreach to train nurses in intervention sites , and an external facilitator to support all stages of the intervention rollout . The STRETCH trial is registered with Current Control Trials IS RCT N46836853 STUDY OBJECTIVE To measure the effectiveness of a multifaceted educational intervention to improve ambulatory hypertension control . DESIGN Cluster-r and omized trial . SETTING Academic health system using an ambulatory electronic medical record . SUBJECTS A total of 10,696 patients with a diagnosis of hypertension cared for by 93 primary care providers . INTERVENTION Academic detailing , provision of provider-specific data about hypertension control , provision of educational material s to the provider , and provision of educational and motivational material s to patients . MEASUREMENTS AND MAIN RESULTS The primary outcome was blood pressure control , defined as a blood pressure measurement below 140/90 mm Hg , and was ascertained from electronic medical records over 6 months of follow-up . We determined the adjusted odds ratio for the association between the intervention and the achievement of controlled blood pressure . When we accounted for clustering by provider , this adjusted odds ratio was 1.13 ( 95 % confidence interval 0.87 - 1.47 ) . Adjusted odds ratios were 1.03 ( 95 % confidence interval 0.78 - 1.36 ) in patients whose blood pressure was controlled at baseline and 1.25 ( 95 % confidence interval 0.94 - 1.65 ) in those whose blood pressure was not . These odds ratios were not significantly different ( p=0.11 ) . CONCLUSIONS These results were consistent with no effect or , at best , a relatively modest effect of the intervention among patients with hypertension . Had we not included a concurrent control group , the data would have provided an unduly optimistic view of the effectiveness of the program . The effectiveness of future interventions may be improved by focusing on patients whose blood pressure is uncontrolled at baseline Background Despite evidence that erythropoietin and intra- and postoperative blood salvage are expensive techniques considered to be non-cost-effective in primary elective total hip and knee arthroplasties in the Netherl and s , Dutch medical professionals use them frequently to prevent the need for allogeneic transfusion . To actually change physicians ’ practice , a tailored strategy aim ed at barriers that hinder physicians in ab and oning the use of erythropoietin and perioperative blood salvage was systematic ally developed . The study aims to examine the effectiveness , feasibility and costs of this tailored de-implementation strategy compared to a control strategy . Methods / Design A cluster r and omized controlled trial including an effect , process and economic evaluation will be conducted in a minimum of 20 Dutch hospitals . R and omisation takes place at hospital level . The hospitals in the intervention group will receive a tailored de-implementation strategy that consists of four components : interactive education , feedback in educational outreach visits , electronically sent reports on hospital performance ( all aim ed at orthopedic surgeons and anesthesiologists ) , and information letters or emails aim ed at other involved professionals within the intervention hospital ( transfusion committee , OR-personnel , pharmacists ) . The hospitals in the control group will receive a control strategy ( i.e. , passive dissemination of available evidence ) . Outcomes will be measured at patient level , using retrospective medical record review . This will be done in all hospitals at baseline and after completion of the intervention period . The primary outcome of the effect evaluation is the percentage of patients undergoing primary elective total hip or knee arthroplasty in which erythropoietin or perioperative blood salvage is applied . The actual exposure to the tailored strategy and users ’ experiences will be assessed in the process evaluation . In the economic evaluation , the costs of the tailored strategy and the control strategy in relation to the difference in their effectiveness will be compared . Discussion This study will show whether a systematic ally developed tailored strategy is more effective for de-implementation of non-cost-effective blood saving measures than the control strategy . This knowledge can be used in national and international initiatives to make healthcare more efficient . It also provides more generalized knowledge regarding de-implementation strategies . Trial registration This trial is registered at the Dutch Trial Register NTR4044 Abstract Background Cardiovascular disease ( CVD ) is an important worldwide cause of mortality . In The Netherl and s , CVD is the leading cause of death for women and the second cause of death for men . Recommendations for diagnosis and treatment of CVD are not well implemented in primary care . In this study , we aim to examine the effectiveness of a tailored implementation program targeted at practice nurses to improve healthcare for patients with ( high risk for ) CVD . Methods / design A two-arm cluster r and omized trial is planned . We offer practice nurses a tailored program to improve adherence to six specific recommendations related to blood pressure and cholesterol target values , risk profiling and lifestyle advice . Practice nurses are offered training and feedback on their motivational interviewing technique and an e-learning program on cardiovascular risk management ( CVRM ) . They are also advised to screen for the presence and severity of depressive symptoms in patients . We also advise practice nurses to use selected E-health options ( selected websites and Twitter-consult ) in patients without symptoms of depression . Patients with mild depressive symptoms are referred to a physical exercise group . We recommend referring patients with major depressive symptoms for assessment and treatment of depressive symptoms if appropriate before starting CVRM . Data from 900 patients at high risk of CVD or with established CVD will be collected in 30 general practice s in several geographical areas in The Netherl and s. The primary outcome measure is performance of practice nurses in CVRM and reflects application of recommendations for personalized counselling and education of CVRM patients . Patients ’ health-related lifestyles ( physical exercise , diet and smoking status ) will be measured with vali date d question naires and medical record audit will be performed to document estimated CVD risk . Additionally , we will survey and interview participating healthcare professionals for exploration of processes of change . The control practice s will provide usual care . Discussion Tailored interventions can improve healthcare . An underst and ing of the methods to reach the improved healthcare can be improved . This research contributes a share of it . Identification of the determinants of practice and developing implementation interventions were two steps which were completed . The subsequent step was implementation of the tailored intervention program . Trial registration Name trial register : Nederl and s trial registerWeb address of trial register : http://www.trialregister.nl Data of registration : 11 July 2013Number of registration : Background The underlying reasons for differences between clinical practice and systematic ally developed guidelines vary from one clinical problem to another . It is therefore logical to tailor strategies to support the implementation of guidelines to address identified barriers to change . The objective of this trial is to evaluate the effects of a tailored intervention to support the implementation of systematic ally developed guidelines for the use of antihypertensive and cholesterol-lowering drugs for the primary prevention of cardiovascular disease . Methods / Design Unblinded , cluster-r and omised trial . 150 general practice s will be recruited from two geographical areas in Norway , and r and omised to the intervention or control group ( passive dissemination of guidelines ) . Outcomes will be measured for all eligible patients seen in the participating practice s during one year after the intervention . A multifaceted intervention has been tailored to address identified barriers to change . Key components are an educational outreach visit with audit and feedback , and computerised reminders . Pharmacists will conduct the visits . During the outreach visit the main recommendations will be presented and software will be installed that links to the electronic medical record systems used in the participating practice s. The software will perform an audit that will be fed back during the visit , present pop-up reminders for patients with high blood pressure or cholesterol , and provide a cardiovascular risk calculator and patient education material . The main outcomes are the proportions of 1 ) first time prescriptions for hypertension where thiazides are not prescribed , 2 ) patients not assessed for cardiovascular risk before prescribing antihypertensive or cholesterol-lowering drugs , and 3 ) patients treated for hypertension or high cholesterol for three months or more who have not achieved recommended treatment goals OBJECTIVE To determine whether augmenting st and ard feedback on resident performance with a multi source feedback intervention improved pediatric resident communication skills and professionalism . DESIGN R and omized controlled trial . SETTING Children 's Hospital Medical Center , Cincinnati , Ohio , from June 21 , 2004 , to July 7 , 2005 . PARTICIPANTS Thirty-six first-year pediatric residents . INTERVENTIONS Residents assigned to the multi source feedback group ( n = 18 ) completed a self- assessment , received a feedback report about baseline parent and nurse evaluations , and participated in a tailored coaching session in addition to receiving st and ard feedback . Residents in the control group ( n = 18 ) received st and ard feedback only . The control group and their residency directors were blinded to parent and nurse evaluations until the end of the study . MAIN OUTCOME MEASURES Residents ' specific communication skills and professional behaviors were rated by parents and nurses of pediatric patients . Both groups were evaluated at baseline and after 5 months . Scores were calculated on each item as percentage in the highest response category . RESULTS Both groups had comparable baseline characteristics and ratings . Parent ratings increased for both groups . While parent ratings increased more for the multi source feedback group , differences between groups were not statistically significant . In contrast , nurse ratings increased for the multi source feedback group and decreased for the control group . The difference in change between groups was statistically significant for communicating effectively with the patient and family ( 35 % ; 95 % confidence interval , 11.0%-58.0 % ) , timeliness of completing tasks ( 30 % ; 95 % confidence interval , 7.9%-53.0 % ) , and demonstrating responsibility and accountability ( 26 % ; 95 % confidence interval , 2.9%-49.0 % ) . CONCLUSION A multi source feedback intervention positively affected communication skills and professional behavior among pediatric residents OBJECTIVES The aim of this study was to test the effectiveness of a theory of planned behaviour intervention to increase adherence of community mental health professionals to a national suicide prevention guideline . DESIGN Routinely collected audit adherence data from an intervention and control site were collected and analysed using time series analysis to test whether the intervention significantly increased adherence . The effects of a local and national event on adherence were also examined . METHOD A Theory of Planned Behaviour ( TPB ) question naire , developed from interview findings , was administered to the health professionals . Subjective norms were found to be the most significant predictor of intention to adhere to the guideline , and were targeted with an interactive educational intervention . Time series analysis applied to routinely collected audit adherence data was used to test intervention effectiveness . RESULTS The TPB accounted for 58 % of the variance in intention to adhere , with subjective norms the only significant predictor . The intervention did not significantly increase adherence ; however , the national and local events were found to have significantly increased adherence . CONCLUSIONS The TPB was a useful framework for exploring barriers to adherence ; however , this did not translate into an effective intervention . Future research should seek collaboration with local experts , and use this information in combination with the TPB , to develop interventions . Collaborative research with experts in pedagogy may also help to develop more effective interventions , particularly education-based interventions that require adult learning Objective The primary care visit represents an important venue for intervening with a large population of smokers . However , physician adherence to the Smoking Cessation Clinical Guideline ( 5As ) remains low . We evaluated the effectiveness of a computer-tailored intervention design ed to increase smoking cessation counseling by primary care physicians . Methods Physicians and their patients were r and omized to either intervention or control conditions . In addition to brief smoking cessation training , intervention physicians and patients received a one-page report that characterized the patients ’ smoking habit and history and offered tailored recommendations . Physician performance of the 5As was assessed via patient exit interviews . Quit rates and smoking behaviors were assessed 6 months postintervention via patient phone interviews . Intervention effects were tested in a sample of 70 physicians and 518 of their patients . Results were analyzed via generalized and mixed linear modeling controlling for clustering . Measurements and Main Results Intervention physicians exceeded controls on “ Assess ” ( OR 5.06 ; 95 % CI 3.22 , 7.95 ) , “ Advise ” ( OR 2.79 ; 95 % CI 1.70 , 4.59 ) , “ Assist – set goals ” ( OR 4.31 ; 95 % CI 2.59 , 7.16 ) , “ Assist – provide written material s ” ( OR 5.14 ; 95 % CI 2.60 , 10.14 ) , “ Assist – provide referral ” ( OR 6.48 ; 95 % CI 3.11 , 13.49 ) , “ Assist – discuss medication ” ( OR 4.72;95 % CI 2.90 , 7.68 ) , and “ Arrange ” ( OR 8.14 ; 95 % CI 3.98 , 16.68 ) , all p values being < 0.0001 . Intervention patients were 1.77 ( CI 0.94 , 3.34,p = 0.078 ) times more likely than controls to be abstinent ( 12 versus 8 % ) , a difference that approached , but did not reach statistical significance , and surpassed controls on number of days quit ( 18.4 versus 12.2 , p < .05 ) but not on number of quit attempts . Conclusions The use of a brief computer-tailored report improved physicians ’ implementation of the 5As and had a modest effect on patients ’ smoking behaviors 6 months postintervention Background There is increasing evidence that clinical guidelines can lead to improvements in clinical care . However , they are not self-implementing . While educational outreach visits may improve prescribing behaviour , the effectiveness of routine delivery of these visits by existing pharmaceutical advisers is unknown . Methods Within a pragmatic r and omized controlled trial , involving all general practice s in two primary care trusts ( PCTs ) , routine methods were used to distribute guidelines for the choice of antidepressants for the management of depression . Intervention practice s were offered two visits ( most accepted only one ) by their PCT pharmaceutical adviser who had been trained in the techniques of outreach visiting . Intervention practice s were visited regardless of whether they had prior problems with prescribing ( ' untargeted ' visits ) . The intervention was evaluated using level three prescribing analysis and cost ( PACT ) data for antidepressant drugs for the six months during which the intervention was delivered and the subsequent twelve months . Results Across the 72 study practice s there was no significant impact of the intervention on usage of any group of antidepressant drugs . Conclusion The routine use of untargeted educational outreach visiting delivered by existing pharmaceutical advisers may not be a worthwhile strategy .Trial registration Clinical Trials.gov Background More than half of all antibiotic prescriptions in general practice are issued for respiratory tract infections ( RTIs ) , despite convincing evidence that many of these infections are caused by viruses . Frequent misuse of antimicrobial agents is of great global health concern , as we face an emerging worldwide threat of bacterial antibiotic resistance . There is an increasing need to identify determinants and patterns of antibiotic prescribing , in order to identify where clinical practice can be improved . Methods / Design Approximately 80 peer continuing medical education ( CME ) groups in southern Norway will be recruited to a cluster r and omized trial . Participating groups will be r and omized either to an intervention- or a control group . A multifaceted intervention has been tailored , where key components are educational outreach visits to the CME-groups , work-shops , audit and feedback . Prescription Peer Academic Detailers ( Rx-PADs ) , who are trained GPs , will conduct the educational outreach visits . During these visits , evidence -based recommendations of antibiotic prescriptions for RTIs will be presented and software will be h and ed out for installation in participants PCs , enabling collection of prescription data . These data will subsequently be linked to corresponding data from the Norwegian Prescription Data base ( NorPD ) . Individual feedback reports will be sent all participating GPs during and one year after the intervention . Main outcomes are baseline proportion of inappropriate antibiotic prescriptions for RTIs and change in prescription patterns compared to baseline one year after the initiation of the tailored pedagogic intervention . Discussion Improvement of prescription patterns in medical practice is a challenging task . A thorough evaluation of guidelines for antibiotic treatment in RTIs may impose important benefits , whereas inappropriate prescribing entails substantial costs , as well as undesirable consequences like development of antibiotic resistance . Our hypothesis is that an educational intervention program will be effective in improving prescription patterns by reducing the total number of antibiotic prescriptions , as well as reducing the amount of broad-spectrum antibiotics , with special emphasis on macrolides Background Age-related alterations in metabolism and excretion of medications increase the risk of adverse drug events in the elderly . Inappropriate polypharmacy and prescription practice entails increased burdens of impaired quality of life and drug related morbidity and mortality . The main objective of this trial is to evaluate effects of a tailored educational intervention towards general practitioners ( GPs ) aim ed at supporting the implementation of a safer drug prescribing practice for elderly patients ≥ 70 years . Methods / design Approximately 80 peer continuing medical education ( CME ) groups ( about 600 GPs ) in southern Norway will be recruited to a cluster r and omized trial . Participating groups will be r and omized either to an intervention- or a control group . The control group will not receive any intervention towards prescription patterns in elderly , but will be the target of an educational intervention for prescription of antibiotics for respiratory tract infections . A multifaceted intervention has been tailored , where key components are educational outreach visits to the CME-groups , work-shops , audit and feedback . Prescription Peer Academic Detailers ( Rx-PADs ) , who are trained GPs , will conduct the educational outreach visits . During these visits , a set of quality indicators ( QIs ) , i.e. explicit recommendations for safer prescribing for elderly patients , will be presented and discussed . Software will be h and ed out for installation in participants ' practice computers to enable extraction of pre-defined prescription data . These data will subsequently be linked to corresponding data from the Norwegian Prescription Data base ( NorPD ) . Individual feedback reports will be sent all participating GPs during and one year after the intervention . Feedback reports will include QI-scores on individual- and group levels , before and after the intervention . The main outcome of this trial is the change in proportions of inappropriate prescriptions ( QIs ) for elderly patients ≥ 70 years following intervention , compared to baseline levels . Discussion Improvement of prescription patterns in medical practice is a challenging task . Evidence suggests that a thorough evaluation of diagnostic indications for drug treatment in the elderly and /or a reduction of potentially inappropriate drugs may impose significant clinical benefits . Our hypothesis is that an educational intervention program will be effective in improving prescribing patterns for elderly patients in GP setting CONTEXT Mortality rates among US hemodialysis patients are the highest in the industrialized world at 23 % per year . Measures of dialysis dose ( Kt/V ) correspond strongly with survival and are inadequate in one sixth of patients . Inadequate dialysis is also associated with increased hospitalizations and high inpatient costs . Our previous work identified 3 barriers to adequate hemodialysis : dialysis underprescription , catheter use , and shortened treatment time . OBJECTIVE To determine the effect of a tailored intervention on adequacy of hemodialysis . DESIGN AND SETTING Community-based r and omized controlled trial with recruitment from April 1999 to June 2000 at 29 hemodialysis facilities in northeast Ohio . PARTICIPANTS Forty-four nephrologists and their 169 r and omly selected adult patients receiving inadequate hemodialysis . INTERVENTION Nephrologists were r and omly assigned to an intervention ( n = 21 ) or control ( n = 23 ) group . For patients in the intervention group ( n = 85 ) , depending on the barrier(s ) present , a study coordinator gave nephrologists recommendations about optimizing dialysis prescriptions , expedited conversion of catheters to surgically created grafts or fistulas , and educated patients about the importance of compliance with treatment time . Patients in the control group ( n = 84 ) continued to receive usual care . MAIN OUTCOME MEASURES Changes in Kt/V and specific barriers after 6 months . RESULTS At baseline , intervention and control patients had similar Kt/V measurements , specific barriers , and demographic and medical characteristics . After 6 months , intervention patients had 2-fold larger increases in Kt/V compared with control patients ( + 0.20 vs + 0.10 ; P<.001 ) and were more likely to achieve their facility Kt/V goal ( 62 % vs 42 % ; P = .01 ) . Intervention patients also had nearly 3-fold larger increases in dialysis prescription ( + 0.16 vs + 0.06 ; P<.001 ) and were 4 times more likely to change from use of catheters to use of fistulas/grafts ( 28 % vs 7 % ; P = .04 ) . CONCLUSIONS An intervention tailored to patient-specific barriers result ed in increased hemodialysis dose . Extending this approach to the 33 000 persons in the United States receiving inadequate hemodialysis may substantially enhance patient survival , diminish hospitalizations , and decrease inpatient expenditures PURPOSE / OBJECTIVES To demonstrate the effects of a program , directed at homecare nurses , of structured educational interventions on the management of pain and opioid-related side effects in homecare patients with cancer . DESIGN A longitudinal multilevel , r and omized , controlled clinical trial . SETTING Midwestern region in the United States . SAMPLE 202 nurses caring for patients with cancer recruited from homecare agencies . METHODS The two-tiered educational program focused on basic and advanced pain management strategies , particularly in the area of pharmacologic options and assertive communication skills . Instruments used were the Nurses ' Knowledge and Attitudes Survey Regarding Pain , the barriers question naire , perception of control over pain , and a demographic question naire . MAIN RESEARCH VARIABLES Knowledge and attitudes about pain management , barriers to pain management , and perception of control over pain . FINDINGS Nurses in the intervention group had a significant increase in their knowledge , a more positive attitude about pain management , fewer perceived barriers to pain management , and an increase in perceived control over pain compared to the nurses who did not receive the intervention . CONCLUSIONS The educational program Power Over Pain has beneficial effects for homecare nurses caring for patients with cancer pain . IMPLICATION S FOR NURSING A need exists for homecare nurses to gain more insight into pain management strategies and enhance their advocacy skills to improve pain management for patients with cancer treated in the home CONTEXT Antenatal corticosteroids for fetal maturation have been underused , despite evidence for their benefits in cases of preterm birth . OBJECTIVE To evaluate dissemination strategies aim ed at increasing appropriate use of this therapy . DESIGN AND SETTING Twenty-seven tertiary care institutions were r and omly assigned to either usual dissemination of practice recommendations ( n = 14 ) or usual dissemination plus an active , focused dissemination effort ( n = 13 ) . SUBJECTS Obstetricians and their preterm delivery cases at participating hospitals . INTERVENTION Recommendations by a National Institutes of Health ( NIH ) Consensus Conference held in late February-early March 1994 were disseminated in early May 1994 . Usual dissemination was publication of the recommendations and endorsement by the American College of Obstetricians and Gynecologists . Active dissemination was a year-long educational effort led by an influential physician and a nurse coordinator at each facility , consisting of gr and rounds , a chart reminder system , group discussion of case scenarios , monitoring , and feedback . MAIN OUTCOME MEASURE Use or nonuse of antenatal corticosteroids was abstract ed from medical records of eligible women delivering at the participating hospitals in the 12 months immediately prior to release of the NIH recommendations ( average number of records abstract ed , 130 ) and in the 12 months following their release ( average number of records abstract ed , 122 ) . RESULTS Active dissemination significantly increased the odds of corticosteroid use after the conference . Use increased from 33.0 % of eligible patients receiving corticosteroids to 57.6 % , or by 75 % over baseline , in usual dissemination hospitals . Use increased from 32.9 % to 68.3 % , oran 108 % increase , in active dissemination hospitals . Gestational age and maternal diagnosis affected use of the therapy in complex ways . CONCLUSION An active , focused dissemination effort increased the effectiveness of usual dissemination methods when combined with key principles to change physician practice BACKGROUND Antibiotics are a medication class for which inappropriate prescribing is frequently described . We sought to assess the effectiveness of a mailed intervention combining confidential prescribing feedback with targeted educational bulletins in increasing the use of less expensive , first-line antibiotics by practising physicians . METHODS The participants were 251 r and omly selected primary care physicians from southern Ontario who consented to participate ( 135 in the feedback group and 116 in the control group ) . Prescribing data were obtained from the cl aims data base of the Ontario Drug Benefit program , which covers all Ontarians over age 65 years for drugs selected from a minimally restrictive formulary . Confidentially prepared profiles of antibiotic prescriptions coupled with guidelines -based educational bulletins were mailed to the intervention group every 2 months for 6 months . The control group received no intervention until after completion of the study . The main outcome measures were change from baseline in physician 's median antibiotic cost and proportion of episodes of care in which a prespecified first-line antibiotic was used first . RESULTS The median prescription cost of about $ 11 remained constant in the feedback group but rose in the control group ( change of $ 0.05 v. $ 3.37 , p < 0.002 ) . First-line drug use increased in the feedback group but decreased in the control group ( change of 2.6 % v. -1.7 % , p < 0.01 ) . In a mailed survey of 100 feedback recipients ( response rate 76 % ) , 82 % indicated that they would participate readily in another , similar program . INTERPRETATION A simple program of confidential feedback and educational material s blunted cost increases , increased the use of first-line antibiotics and was highly acceptable to Ontario primary care physicians Background Antenatal care ( ANC ) reduces maternal and perinatal morbidity and mortality directly through the detection and treatment of pregnancy-related illnesses , and indirectly through the detection of women at increased risk of delivery complications . The potential benefits of quality antenatal care services are most significant in low-re source countries where morbidity and mortality levels among women of reproductive age and neonates are higher . WHO developed an ANC model that recommended the delivery of services scientifically proven to improve maternal , perinatal and neonatal outcomes . The aim of this study is to determine the effect of an intervention design ed to increase the use of the package of evidence -based services included in the WHO ANC model in Mozambique . The primary hypothesis is that the intervention will increase the use of evidence -based practice s during ANC visits in comparison to the st and ard dissemination channels currently used in the country . Methods This is a demonstration project to be developed through a facility-based cluster r and omized controlled trial with a stepped wedge design . The intervention was tailored , based on formative research findings , to be readily applicable to local prenatal care services and acceptable to local pregnant women and health providers . The intervention includes four components : the provision of kits with all necessary medicines and laboratory supplies for ANC ( medical and non-medical equipment ) , a storage system , a tracking system , and training sessions for health care providers . Ten clinics were selected and will start receiving the intervention in a r and om order . Outcomes will be computed at each time point when a new clinic starts the intervention . The primary outcomes are the delivery of selected health care practice s to women attending the first ANC visit , and secondary outcomes are the delivery of selected health care practice s to women attending second and higher ANC visits as well as the attitude of midwives in relation to adopting the practice s. This demonstration project is pragmatic in orientation and will be conducted under routine conditions . Discussion There is an urgent need for effective and sustainable scaling-up approaches of health interventions in low-re source countries . This can only be accomplished by the engagement of the country ’s health stakeholders at all levels . This project aims to achieve improvement in the quality of antenatal care in Mozambique through the implementation of a multifaceted intervention on three levels : policy , organizational and health care delivery levels . The implementation of the trial will probably require a change in accountability and behaviour of health care providers and we expect this change in ‘ habits ’ will contribute to obtaining reliable health indicators , not only related to research issues , but also to health care outcomes derived from the new health care model . At policy level , the results of this study may suggest a need for revision of the supply chain management system . Given that supply chain management is a major challenge for many low-re source countries , we envisage that important lessons on how to improve the supply chain in Mozambique and other similar setting s , will be drawn from this study .Trial registration Pan African Clinical Trial Registry data base . Identification number : PACTR201306000550192 Abstract Objectives To assess the effectiveness of a multiple intervention aim ed at reducing antibiotic prescription rates for symptoms of the respiratory tract in primary care . Design R and omised controlled trial . Subjects Twelve peer review groups including 100 general practitioners with their collaborating pharmacists in the region of Utrecht , Netherl and s. Intervention The intervention consisted of group education meetings , with a consensus procedure on indication for and type of antibiotics and with training in communication skills ; monitoring and feedback on prescribing behaviour ; group education for assistants of general practitioners and pharmacists ; and educational material for patients . The control group did not receive any of these elements . Main outcome measures Antibiotic prescription rates for acute symptoms of the respiratory tract and patients ' satisfaction . Results 89 general practitioners completed the study ( 89 % ) . At baseline , prescription rates for antibiotics for respiratory tract symptoms did not differ between intervention and control group ( 27 % v 29 % , respectively ) . After nine months , the prescription rates in the intervention group fell to 23 % , whereas the control group 's rose to 37 % ( mean difference in change −12 % , 95 % confidence interval −18.9 % to −4.0 % ) . Multilevel analysis confirmed the results of the unadjusted analysis ( intervention effect −10.7 % , −20.3 % to −1.0 % ) . Patients ' satisfaction was high and did not differ in the two groups at baseline or after the intervention . Conclusions A multiple intervention reduced prescribing rates of antibiotics for respiratory tract symptoms while maintaining a high degree of satisfaction among patients . Further research should focus on the sustainability and cost effectiveness of this intervention Theory-based intervention programmes to support health-related behaviour change aim to increase health impact and improve underst and ing of mechanisms of behaviour change . However , the science of intervention development remains at an early stage . We present a causal modelling approach to developing complex interventions for evaluation in r and omized trials . In this approach a generic model links behavioural determinants , causally through behaviour , to physiological and biochemical variables , and health outcomes . It is tailored to context , target population , behaviours and health outcomes . The development of a specific causal model based on theory and evidence is illustrated by the ProActive programme , supporting increased physical activity among individuals at risk of Type 2 diabetes . The model provides a rational guide to appropriate measures , intervention points and intervention techniques , and can be tested quantitatively . Causal modelling is critically compared to other approaches to intervention development and evaluation , and research directions are indicated OBJECTIVES Assessing the efficacy of an educational intervention that aim ed to reduce unnecessary antibiotic prescriptions in primary care by motivating GPs to change their attitudes to communication and by empowering patients . METHODS One hundred and four GPs in North-Rhine/Westphalia-Lippe , Germany were cluster-r and omized into intervention and control . GPs r and omized to receive the intervention were visited by peers . The intervention strategy was focused on the communication within the encounter , not on sharing knowledge about antibiotic prescribing . Leaflets and posters were provided that aim ed at patient empowerment , thus enabling patients to raise the topic of antibiotic prescriptions themselves . RESULTS Eighty-six GPs ( 83 % ) remained in the study at 6 weeks and 61 GPs ( 59 % ) at 12 months . Antibiotic prescription rates within the control group were 54.7 % at baseline and 36.4 % within the intervention group at baseline . Generalized estimating equation models were applied . Baseline imbalances and confounding variables were controlled by adjustment . After the intervention , the ORs for the prescription of an antibiotic dropped to 0.58 [ 95 % CI : ( 0.43;0.78 ) , P < 0.001 ] after 6 weeks and were 0.72 [ 95 % CI : ( 0.54;0.97 ) , P = 0.028 ] after 12 months in the intervention group . In the control group , the ORs rose to 1.52 [ 95 % CI : ( 1.19;1.95 ) , P = 0.001 ] after 6 weeks and were 1.31 [ 95 % CI : ( 1.01;1.71 ) , P = 0.044 ] after 12 months ; these ORs correspond to an approximately 60 % relative reduction in antibiotic prescription rates at 6 weeks and a persistent 40 % relative reduction at 12 months . CONCLUSIONS An interventional strategy that focused on doctor-patient communication and patient empowerment is an effective concept to reduce antibiotic prescriptions in primary care Abstract Objective : To assess the effectiveness of tailored interventions to implement guidelines for urinary tract infections in women and sore throat Design : Unblinded , cluster r and omised pretest-post-test trial Setting : 142 general practice s in Norway Participants : 72 practice s received interventions to implement guidelines for urinary tract infection and 70 practice s received interventions to implement guidelines for sore throat , serving as controls for each other . 59 practice s in the urinary tract infection group and 61 practice s in the sore throat group completed the study . Outcomes were measured in 16 939 consultations for sore throat and 9887 consultations for urinary tract infection . Interventions : Interventions were developed to overcome identified barriers to implementing the guidelines . The main components of the tailored interventions were patient educational material , computer based decision support and reminders , an increase in the fee for telephone consultations , and interactive courses for general practitioners and practice assistants Main outcome measures : Changes in rates of use of antibiotics , laboratory tests , and telephone consultations Results : Patients in the sore throat group were 3 % less likely to receive antibiotics after the intervention . Women with symptoms of urinary tract infection in the intervention group were 5.1 % less likely to have a laboratory test ordered . No significant differences were found between the groups for the other outcomes . Large variation was found across the included practice sin the rates of antibiotic prescription , use of laboratory tests and telephone consultations , and in the extent of change for all three outcome measures Conclusions : Passively delivered , complex interventions targeted at identified barriers to change had little effect in changing Background We describe a simple approach we used to identify barriers and tailor an intervention to improve pharmacological management of hypertension and hypercholesterolaemia . We also report the results of a post hoc exercise and survey we carried out to evaluate our approach for identifying barriers and tailoring interventions . Methods We used structured reflection , search ed for other relevant trials , surveyed general practitioners and talked with physicians during pilot testing of the intervention . The post hoc exercise was carried out as focus groups of international research ers in the field of quality improvement in health care . The post hoc survey was done by telephone interviews with physicians allocated to the experimental group of a r and omised trial of our multifaceted intervention . Results A wide range of barriers was identified and several interventions were suggested through structured reflection . The survey led to some adjustments . Study ing other trials and pilot testing did not lead to changes in the design of the intervention . Neither the post hoc focus groups nor the post hoc survey revealed important barriers or interventions that we had not considered or included in our tailored intervention . Conclusions A simple approach to identifying barriers to change appears to have been adequate and efficient . However , we do not know for certain what we would have gained by using more comprehensive methods and we do not know whether the result ing intervention would have been more effective if we had used other methods . The effectiveness of our multifaceted intervention is under evaluation in a r and omised controlled trial Background To describe and evaluate the effectiveness of tailored intervention on village doctor ’s use of electronic health records ( EHR ) in rural community health services in less developed areas . Methods Ten townships were selected . In each township , two similar health service station ( CHSS ) were chosen . One was r and omly as allocated to the intervention group , the other to the control group . Over six monthly visits , a structured on-site intervention including education , supervision and technical support was provided to village doctors in the intervention group tailored to their needs . The Control group received no visits . A sample of 20 families from each CHSS was r and omly chosen . An online evaluation of each family ’s EHR was conducted by the investigators at baseline and at the end of the 6 month intervention . Results In the intervention group , the proportion of households with complete records increased : basic personal information from 2.6 % to 32.5 % , ( Z = -15.099 , P = 0.000 ) and health education records from 0.3 % to 1.6 % ( Z = -4.459 , P = 0.000 ) . Similarly at baseline none of the 80 elders had her records . This increased in the intervention group to 16.4 % recorded in part and 37.0 % in full ( Z = -7.480 , P = 0.000 ) . The proportion of complete health management records for children aged 1 to 2 years and 3 to 6 years increased from 28.6 % and 33.3 % to 66.7 % and 74.2 % respectively ( the difference of children group 3 to 6 years of age was statistically significant , Z = -3.860 , p = 0.000 ) . The proportion of complete basic clinic records in the intervention group increased from 7.6 % to 13.9 % ( Z = -3.252 , P = 0.001 ) . There were no significant differences in the control group . Conclusions The pilot study showed that a on-site education , supervision and technical support tailored to their needs was associated with improvements in village doctors use of EHR . This model is worthy of implementation in other rural areas Background A gap exists between evidence and practice regarding the management of cardiovascular risk factors . This gap could be narrowed if systematic ally developed clinical practice guidelines were effectively implemented in clinical practice . We evaluated the effects of a tailored intervention to support the implementation of systematic ally developed guidelines for the use of antihypertensive and cholesterol-lowering drugs for the primary prevention of cardiovascular disease . Methods and Findings We conducted a cluster-r and omized trial comparing a tailored intervention to passive dissemination of guidelines in 146 general practice s in two geographical areas in Norway . Each practice was r and omized to either the tailored intervention ( 70 practice s ; 257 physicians ) or control group ( 69 practice s ; 244 physicians ) . Patients started on medication for hypertension or hypercholesterolemia during the study period and all patients already on treatment that consulted their physician during the trial were included . A multifaceted intervention was tailored to address identified barriers to change . Key components were an educational outreach visit with audit and feedback , and computerized reminders linked to the medical record system . Pharmacists conducted the visits . Outcomes were measured for all eligible patients seen in the participating practice s during 1 y before and after the intervention . The main outcomes were the proportions of ( 1 ) first-time prescriptions for hypertension where thiazides were prescribed , ( 2 ) patients assessed for cardiovascular risk before prescribing antihypertensive or cholesterol-lowering drugs , and ( 3 ) patients treated for hypertension or hypercholesterolemia for 3 mo or more who had achieved recommended treatment goals . The intervention led to an increase in adherence to guideline recommendations on choice of antihypertensive drug . Thiazides were prescribed to 17 % of patients in the intervention group versus 11 % in the control group ( relative risk 1.94 ; 95 % confidence interval 1.49–2.49 , adjusted for baseline differences and clustering effect ) . Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals . Conclusions Our tailored intervention had a significant impact on prescribing of antihypertensive drugs , but was ineffective in improving the quality of other aspects of managing hypertension and hypercholesterolemia in primary care The purpose of this study was to determine the efficacy of providing ( i ) tailored injury prevention information ( T-IPI ) to parents and ( ii ) concurrent T-IPI to parents and providers to promote parent adoption of safety practice s. During well-child visits , parents of children ages 4 and younger completed a computer assessment and were r and omized to receive generic injury prevention information , T-IPI or T-IPI supplemented with a tailored summary for providers . Follow-up assessment s were completed by telephone 1 month later . Parents receiving T-IPI alone or with supplementary provider information were more likely to report adopting a new injury prevention behavior than those receiving generic information ( 49 and 45 % , respectively , compared with 32 % ; odds ratio=2.0 and 1.9 , respectively ) , and these effects were greatest among the least educated parents . In addition , more complicated behavior changes were reported by those receiving tailored information . Provider receipt of feedback did not result in significantly different provider-parent communication or change in parents ' safety practice s. Providing parents with individually tailored pediatric injury prevention information may be an effective method for delivering injury prevention anticipatory guidance . Tailoring may have particular utility for more complicated behaviors and for communication with less educated parents Background In the UK around 22 % of men and 24 % of women are obese , and there are varying but worrying levels in other European countries . Obesity is a chronic condition that carries an important health risk . National guidelines , for use in Engl and , on the management of people who are overweight or obese have been published by the National Institute for Health and Clinical Excellence ( NICE , 2006 ) . NICE recommendations for primary care teams are : determine the degree of overweight and obesity ; assess lifestyle , comorbidities and willingness to change ; offer multicomponent management of overweight and obesity ; referral to external services when appropriate . This study investigates a tailored intervention to improve the implementation of these recommendations by primary care teams . Methods / Design The study is a cluster r and omised controlled trial . Primary care teams will be recruited from the East Midl and s of Engl and , and r and omised into two study arms : 1 ) the study group , in which primary care teams are offered a set of tailored interventions to help implement the NICE guidelines for overweight and obesity ; or 2 ) the control group in which primary care teams continue to practice usual care . The primary outcome is the proportion of overweight or obese patients for whom the primary care team adheres to the NICE guidelines . Secondary outcomes include the proportion of patients with a record of lifestyle assessment , referral to external weight loss services , the proportion of obese patients who lose weight during the intervention period , and the mean weight change over the same period . Discussion Although often recommended , the methods of tailoring implementation interventions to account for the determinants of practice are not well developed . This study is part of a programme of studies seeking to develop the methods of tailored implementation . Trial registration Current Controlled Trials IS RCT N07457585 . Registered 09/08/2013 . R and omisation commenced 30/08/2013 Background Chronic obstructive pulmonary disease ( COPD ) remains a major health problem , strongly related to smoking . Despite the publication of practice guidelines on prevention and treatment , not all patients with the disease receive the recommended healthcare , particularly with regard to smoking cessation advice where applicable . We have developed a tailored implementation strategy for enhancing general practitioners ’ adherence to the disease management guidelines . The primary aim of the study is to evaluate the effects of this tailored implementation intervention on general practitioners ’ adherence to guidelines . Methods / Design A pragmatic two-arm cluster r and omized trial has been planned to compare care following the implementation of tailored interventions of four recommendations in COPD patients against usual care . The study will involve 18 general practice s ( 9 in the intervention group and 9 in the control group ) in Pol and , each with at least 80 identified ( at the baseline ) patients with diagnosed COPD . The nine control practice s will provide usual care without any interventions . Tailored interventions to implement four recommendations will be delivered in the remaining nine practice s. At follow-up after nine months , data will be collected for all 18 general practice s. The primary outcome measure is physicians ’ adherence to all four recommendations : brief anti-smoking advice , dyspnea assessment , care checklist utilization and demonstration to patients of correct inhaler use . This measurement will be based on data extracted from identified patients ’ records . Additionally , we will survey and interview patients with chronic obstructive pulmonary disease about the process of care . Discussion The results of this trial will be directly applicable to primary care in Pol and and add to the growing body of evidence on interventions to improve chronic illness care . Trial registration This trial has been registered with Clinical Trials Protocol Registration System . Trial number : NCT01893476 Background Mild head injuries commonly present to emergency departments . The challenges facing clinicians in emergency departments include identifying which patients have traumatic brain injury , and which patients can safely be sent home . Traumatic brain injuries may exist with subtle symptoms or signs , but can still lead to adverse outcomes . Despite the existence of several high quality clinical practice guidelines , internationally and in Australia , research shows inconsistent implementation of these recommendations . The aim of this trial is to test the effectiveness of a targeted , theory- and evidence -informed implementation intervention to increase the uptake of three key clinical recommendations regarding the emergency department management of adult patients ( 18 years of age or older ) who present following mild head injuries ( concussion ) , compared with passive dissemination of these recommendations . The primary objective is to establish whether the intervention is effective in increasing the percentage of patients for which appropriate post-traumatic amnesia screening is performed . Methods / design The design of this study is a cluster r and omised trial . We aim to include 34 Australian 24-hour emergency departments , which will be r and omised to an intervention or control group . Control group departments will receive a copy of the most recent Australian evidence -based clinical practice guideline on the acute management of patients with mild head injuries . The intervention group will receive an implementation intervention based on an analysis of influencing factors , which include local stakeholder meetings , identification of nursing and medical opinion leaders in each site , a train-the-trainer day and st and ardised education and interactive workshops delivered by the opinion leaders during a 3 month period of time . Clinical practice outcomes will be collected retrospectively from medical records by independent chart auditors over the 2 month period following intervention delivery ( patient level outcomes ) . In consenting hospitals , eligible patients will be recruited for a follow-up telephone interview conducted by trained research ers . A cost-effectiveness analysis and process evaluation using mixed- methods will be conducted . Sample size calculations are based on including 30 patients on average per department . Outcome assessors will be blinded to group allocation . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12612001286831 ( date registered 12 December 2012 ) BACKGROUND The potential of primary care practice setting s to prevent disease and morbidity through health habit counseling , screening for asymptomatic disease , and immunizations has been incompletely met . This study was design ed to test a practice -tailored approach to increasing preventive service delivery with particular emphasis on health habit counseling . DESIGN Group r and omized clinical trial and multi method process assessment . SETTING / PARTICIPANTS Seventy-seven community family practice s in northeast Ohio . INTERVENTION After a 1-day practice assessment , a nurse facilitator met with practice clinicians and staff and assisted them with choosing and implementing individualized tools and approaches aim ed at increasing preventive service delivery . MAIN OUTCOME MEASURE Summary scores of the health habit counseling , screening and immunization services recommended by the U.S. Preventive Services Task Force up to date for consecutive patients during r and omly selected chart review days . RESULTS A significant increase ( p=0.015 ) in global preventive service delivery rates at the 1-year follow-up was found in the intervention group ( 31 % to 42 % ) compared to the control group ( 35 % to 37 % ) . Rates specifically for health habit counseling ( p=0.007 ) and screening services ( p=0.048 ) were increased , but not for immunizations . CONCLUSIONS An approach to increasing preventive service delivery that is individualized to meet particular practice needs can increase global preventive service delivery rates Abstract Background : Adverse drug reaction ( ADR ) reporting systems are the basic component for comprehensive postmarketing surveillance of the risk of drug-induced adverse effects . The aim of this study was to evaluate the effectiveness of educational outreach visits aim ed at improving ADR reporting by pharmacists . Methods : The study population comprised all pharmacists working in a catchment area covered by Portugal ’s Northern Regional Health Authority . Using unequal r and omization , four spatial-clusters were assigned to the intervention group ( n = 342 ) and eleven to the control group ( n = 1091 ) . The intervention took the form of 1-hour long educational outreach visits tailored to training needs detected in a previous study , with a 13- to 16-month follow-up period ( March – June 2004 through June 2005 ) . This study is registered as an international st and ard r and omized controlled trial , number IS RCT N45 894687 . Results : At baseline , ADR reporting rates ( per 1000 pharmacist-years ) did not differ significantly between the intervention and control groups ( 32.28 vs 29.16 ) . The adjusted increase in ADR reporting attributable to the intervention was 275.63 per 1000 pharmacist-years ( 95 % CI 162.15 , 389.12 ; relative risk RR ] = 5.87 , 95 % CI 1.98 , 17.39 ) . The intervention succeeded in multiplying the reporting rate of : serious ADRs , 10-fold ( RR = 9.79 ; 95 % CI 2.24 , 42.66 ) ; unexpected ADRs , 4-fold ( RR = 4.41 ; 95 % CI 1.11 , 17.53 ) ; high-causality ADRs , 9-fold ( RR = 8.67 ; 95 % CI 2.12 , 35.42 ) ; and new drug-related ADRs , 9-fold ( RR = 9.33 ; 95 % CI 2.53 , 34.40 ) . While the greatest effect was registered during the first 4 months post-intervention , differences remained statistically significant for 8 months . Conclusions : Educational outreach visits improve ADR reporting by pharmacists in terms of quantity and relevance BACKGROUND Although psychoactive medications have substantial side effects in the elderly , these drugs are used frequently in nursing homes . Few interventions have succeeded in changing this situation , and little is known about the clinical effects of such interventions . METHODS We studied six matched pairs of nursing homes ; at one r and omly selected nursing home in each pair , physicians , nurses , and aides participated in an educational program in geriatric psychopharmacology . At base line we determined the type and quantity of drugs received by all residents ( n = 823 ) , and a blinded observer performed st and ardized clinical assessment s of the residents who were taking psychoactive medications . After the five-month program , drug use and patient status were reassessed . RESULTS Scores on an index of psychoactive-drug use , measuring both the magnitude and the probable inappropriateness of medication use , declined significantly more in the nursing homes in which the program was carried out ( experimental nursing homes ) than in the control nursing homes ( decrease , 27 percent vs. 8 percent ; P = 0.02 ) . The use of antipsychotic drugs was discontinued in more residents in the experimental nursing homes than in the control nursing homes ( 32 percent vs. 14 percent ) ; the comparable figures for the discontinuation of long-acting benzodiazepines were 20 percent vs. 9 percent , and for antihistamine hypnotics , 45 percent vs. 21 percent . In the experimental nursing homes residents who were initially taking antipsychotic drugs showed less deterioration on several measures of cognitive function than similar residents in the control facilities , but they were more likely to report depression . Those who were initially taking benzodiazepines or antihistamine hypnotic agents reported less anxiety than controls but had more loss of memory . Most other measures of clinical status remained unchanged in both groups . CONCLUSIONS An educational program targeted to physicians , nurses , and aides can reduce the use of psychoactive drugs in nursing homes without adversely affecting the overall behavior and level of functioning of the residents BACKGROUND The Prochaska model of readiness to change has been proposed to be used in educational interventions to improve medical care . OBJECTIVE To evaluate the impact on readiness to change of an educational intervention on management of depressive disorders based on a modified version of the Prochaska model in comparison with a st and ard programme of continuing medical education ( CME ) . METHODS This is a r and omized controlled trial within primary care practice s in southern Tehran , Iran . The participants included 192 general physicians working in primary care ( GPs ) were recruited after r and om selection and r and omized to intervention ( 96 ) and control ( 96 ) . Intervention consisted of interactive , learner-centred educational methods in large and small group setting s depending on the GPs ' stages of readiness to change . Change in stage of readiness to change measured by the modified version of the Prochaska question naire was the MAIN OUTCOME MEASURE RESULTS The final number of participants was 78 ( 81 % ) in the intervention arm and 81 ( 84 % ) in the control arm . Significantly ( P < 0.01 ) , more GPs ( 57/96 = 59 % versus 12/96 = 12 % ) in the intervention group changed to higher stages of readiness to change . The intervention effect was 46 % points ( P < 0.001 ) and 50 % points ( P < 0.001 ) in the large and small group setting , respectively . CONCLUSIONS Educational formats that suit different stages of learning can support primary care doctors to reach higher stages of behavioural change in the topic of depressive disorders . Our findings have practical implication s for conducting CME programmes in Iran and are possibly also applicable in other parts of the world BACKGROUND Limited data exist on the most effective approach to increase the quality of antibiotic use for lower respiratory tract infections at hospitals . METHODS One thous and nine hundred six patients with community-acquired pneumonia or an exacerbation of chronic obstructive pulmonary disease ( acute exacerbation of chronic bronchitis ) were included in a cluster-r and omized , controlled trial at 6 medium-to-large Dutch hospitals . A multifaceted guideline -implementation strategy that was tailored to baseline performance and considered the barriers in the target group was used . Principal outcome measures were ( 1 ) guideline -adherent antibiotic prescription , ( 2 ) adaptation of dose and dose interval of antibiotics according to renal function , ( 3 ) switches in therapy , ( 4 ) streamlining of therapy , and ( 5 ) Gram staining and culture of sputum sample s. Secondary process outcomes were applicable to community-acquired pneumonia ( e.g. , timely administration of antibiotics ) or acute exacerbation of chronic bronchitis ( e.g. , not prescribing macrolides ) . RESULTS The rate of guideline -adherent antibiotic prescription increased from 50.3 % to 64.3 % in the intervention hospitals ( odds ratio [ OR ] , 2.63 ; 95 % confidence interval [ CI ] , 1.57 - 4.42 ; P=.0008 ) . The rate of adaptation of antibiotic dose according to renal function increased from 79.4 % to 95.1 % in the intervention hospitals ( OR , 7.32 ; 95 % CI , 2.09 - 25.7 ; P=.02 ) . The switch from intravenous to oral therapy improved more in the control hospitals ( from 53.3 % to 71.9 % ) than in the intervention hospitals ( from 74 % to 83.6 % ) . The change from broad-spectrum empirical therapy to pathogen-directed therapy improved by 5.7 % in the intervention hospitals ( P = not significant ) . Fewer sputum sample s were obtained from both the intervention group ( rate of sputum sample s obtained decreased from 55.8 % to 53.1 % ) and the control group ( rate of sputum sample s obtained decreased from 49.6 % to 42.7 % ) . Timely administration of antibiotics for community-acquired pneumonia increased significantly in the intervention group ( from 55.2 % to 62.9 % ; OR , 2.49 ; 95 % CI , 1.11 - 5.57 ; P=.026 ) . CONCLUSIONS With regard to some important aspects , tailoring interventions to change antibiotic use improved the quality of treatment for patients hospitalized with lower respiratory tract infection Objective To investigate whether PALSA PLUS , an on-site educational outreach programme of non-didactic , case based , iterative clinical education of staff , led by a trainer , can increase access to and comprehensiveness of care for patients with HIV/AIDS . Design Cluster r and omised trial . Setting Public primary care clinics offering HIV/AIDS care , antiretroviral treatment ( ART ) , tuberculosis care , and ambulatory primary care in Free State province , South Africa . Participants Fifteen clinics all implementing de central isation and task shifting were r and omised . The clinics cared for 400 000 general primary care patients and 10 136 patients in an HIV/AIDS/ART programme . There were 150 nurses . Intervention On-site outreach education in eight clinics ; no such education in seven ( control ) . Main outcome measures Provision of co-trimoxazole prophylaxis among patients referred to the HIV/AIDS/ART programme , and detection of cases of tuberculosis among those in the programme . Proportion of patients in the programme enrolled through general primary care consultations . Results Patients referred to the HIV/AIDS programme through general primary care at intervention clinics were more likely than those at control clinics to receive co-trimoxazole prophylaxis ( 41 % , ( 2253/5523 ) v 32 % ( 1340/4210 ) ; odds ratio 1.95 , 95 % confidence interval 1.11 to 3.40 ) , and tuberculosis was more likely to be diagnosed among patients with HIV/AIDS/ART ( 7 % ( 417/5793 ) v 6 % ( 245/4343 ) ; 1.25 , 1.01 to 1.55 ) . Enrolment in the HIV/AIDS and ART programme through HIV testing in general primary care was not significantly increased ( 53 % v 50 % ; 1.19 , 0.51 to 2.77 ) . Secondary outcomes were similar , except for weight gain , which was higher in the intervention group ( 2.3 kg v 1.9 kg , P<0.001 ) . Conclusion Though outreach education is an effective and feasible strategy for improving comprehensiveness of care and wellbeing of patients with HIV/AIDS , there is no evidence that it increases access to the ART programme . It is now being widely implemented in South Africa . Trial registration Current Controlled Trials IS RCT N 24820584 Introduction : It was hypothesized that after a continuing medical education ( CME ) event , practice enablers and reinforcers addressing main clinical barriers to preventive care would be more effective in improving general practitioners ' ( GPs ) adherence to cardiovascular guidelines than a CME event only . Methods : A cluster‐r and omized trial was conducted on a convenience sample of 122 GPs who were r and omly assigned to either CME only ( control group ) or CME with practice enablers and reinforcers ( PER group ) . In the PER group , nurses visited GPs ' offices once a month to implement the clinical intervention on patients ≥ 55 years old with a scheduled visit in the month following the nurse visit : ( 1 ) screening medical records for potentially undermanaged high‐risk patients ; ( 2 ) prompting physicians to reassess preventive care in these patients ; ( 3 ) enclosing a checklist reporting most recent information relevant to guidelines ' implementation ; and ( 4 ) enclosing a summary of experts ' recommendations in the form of a follow‐up and treatment algorithm . Results : A retrospective chart audit of 2344 consenting patients , potentially undermanaged at baseline , demonstrated that the PER intervention following CME significantly improved adherence to guidelines compared to CME alone ( OR : 1.78 , 95 % CI : 1.32–2.41 ) . Discussion : The intervention was design ed for self‐implementation in primary care practice s that have their own nursing staff . PER GPs were highly satisfied with the intervention ; the majority said that they would implement it in their practice if someone trained their nurse , thus suggesting support for development of a multiprofessional CME program to disseminate this clinical approach to primary care practice groups PURPOSE To compare group versus individual academic detailing to increase diuretic or beta-blocker use in hypertension . METHODS We conducted a cluster-r and omized controlled trial in a large health maintenance organization . Subjects ( N=9820 ) were patients with newly treated hypertension in the year preceding the intervention ( N=3692 ) , the 9 months following the intervention ( N=3556 ) , and the second year following intervention ( N=2572 ) . We r and omly allocated 3 practice sites to group detailing ( N=227 prescribers ) , 3 to individual detailing ( N=235 prescribers ) , and 3 to usual care ( N=319 prescribers ) . Individual detailing entailed a physician-educator meeting individually with clinicians to address barriers to prescribing guideline -recommended medications . The group detailing intervention incorporated the same social marketing principles in small groups of clinicians . RESULTS In the first year following the intervention , the rates of diuretic or beta-blocker use increased by 13.2 % in the group detailing practice s , 12.5 % in the individual detailing practice s , and 6.2 % in the usual care practice s. As compared with usual care practice s , diuretic or beta-blocker use was more likely in group detailing practice s ( adjusted odds ratio ( OR ) , 1.40 ; 95 % confidence interval ( CI ) , 1.11 - 1.76 ) and individual detailing practice s ( adjusted OR , 1.30 ; 95 % CI , 0.95 - 1.79 ) . Neither intervention affected blood pressure control . Two years following this single-visit intervention , there was still a trend suggesting a persistent effect of individual ( OR , 1.22 ; 95 % CI , 0.92 - 1.62 ) , but not group , detailing ( OR , 1.06 ; 95 % CI , 0.80 - 1.39 ) , as compared with usual care . CONCLUSION Both group and individual academic detailing improved antihypertensive prescribing over and above usual care but may require reinforcement to sustain improvements Background Falls are a common hospital occurrence complicating the care of patients . From an economic perspective , the impact of in-hospital falls and related injuries is substantial . However , few studies have examined the economic implication s of falls prevention interventions in an acute care setting . The 6-PACK programme is a targeted nurse delivered falls prevention programme design ed specifically for acute hospital wards . It includes a risk assessment tool and six simple strategies that nurses apply to patients classified as high-risk by the tool . Objective To examine the incremental cost-effectiveness of the 6-PACK programme for the prevention of falls and fall-related injuries , compared with usual care practice , from an acute hospital perspective . Methods and design The 6-PACK project is a multicentre cluster r and omised controlled trial ( RCT ) that includes 24 acute medical and surgical wards from six hospitals in Australia to investigate the efficacy of the 6-PACK programme . This economic evaluation will be conducted alongside the 6-PACK cluster RCT . Outcome and hospitalisation cost data will be prospect ively collected on approximately 16 000 patients admitted to the participating wards during the 12-month trial period . The results of the economic evaluation will be expressed as ‘ cost or saving per fall prevented ’ and ‘ cost or saving per fall-related injury prevented ’ calculated from differences in mean costs and effects in the intervention and control groups , to generate an incremental cost-effectiveness ratio ( ICER ) . Discussion This economic evaluation will provide an opportunity to explore the cost-effectiveness of a targeted nurse delivered falls prevention programme for reducing in-hospital falls and fall-related injuries . This protocol provides a detailed statement of a planned economic evaluation conducted alongside a cluster RCT to investigate the efficacy of the 6-PACK programme to prevent falls and fall-related injuries . Trial registration number The protocol for the cluster RCT is registered with the Australian New Zeal and Clinical Trials Registry ( ACTRN12611000332921 ) OBJECTIVES To evaluate the effects of integrated home care and discharge practice ( IHCaD- practice ) on the use of services and cost-effectiveness . METHODS A cluster r and omised trial with Finnish municipalities ( n=22 ) as the units of r and omisation . At baseline the sample included 668 home care patients aged 65 years or over . Data consisted of interviews ( discharge , 3-week , 6-month ) and care registers . The intervention was a generic prototype of care/case management- practice that was tailored to each municipality 's needs . The effects were evaluated in terms of the use and cost of health and social care services . Unit costs of services were calculated . Cost-effectiveness was calculated for changes in health-related quality of life using the Nottingham Health Profile ( NHP ) and the EQ-5D instruments . All analyses were based on intention-to-treat . RESULTS At 6-month follow-ups , the patients in the trail group used less home care , doctor and laboratory services than patients in the non-trial group . Similar differences between groups were found regarding costs . According to the NHP instrument , the IHCaD- practice showed higher cost-effectiveness compared to the old practice . No evidence for cost-effectiveness was found with the EQ-5D instrument . CONCLUSIONS The study suggests that the IHCaD- practice may be a cost-effective alternative to usual care In an attempt to evaluate the efficacy of different methods of interventions to improve the appropriate use of drugs for acute diarrhoea , a controlled study has been carried out in 6 districts in Yogyakarta and Central Java provinces , Indonesia . This study was design ed to investigate the impacts of two different methods of educational intervention , i.e. a small group face-to-face intervention and a formal seminar for prescribers , on prescribing practice in acute diarrhoea . The districts were r and omly assigned into 3 groups and 15 health centers were selected from each district . Prescribers in Group 1 underwent a small group face-to-face intervention conducted in the respective health center . Those in Group 2 attended a formal seminar conducted at the district level . Prescribers in Group 3 served as the control group . Both interventions were given on a single occasion without follow-up supervision or monitoring . Written information material s on the appropriate management of acute diarrhoea were developed and were provided to all prescribers in the intervention groups . Focus group discussion s ( FGDs ) involving prescribers and consumers in the 6 districts were carried out to identify various underlying motivations of drug use in acute diarrhoea . The findings of the FGDs were used as part of the intervention material s. To evaluate the impacts of these interventions on prescribing practice , a prescribing survey for patients under five years old with acute diarrhoea was carried out in health centers covering 3-month periods before and after the intervention . The results showed that both interventions were equally effective in improving the levels of knowledge of prescribers about the appropriate management of acute diarrhoea . They were also partially effective in improving the appropriate use of drugs , reducing the use of non-rehydration medications . There was a highly significant reduction of antimicrobial usage either after small-group face-to-face intervention ( 77.4 + /- 2.7 % to 60.4 + /- 2.9 % ; P < 0.001 ) or formal seminar ( 82.3 + /- 3.0 % to 72.3 + /- 3.6 % ; P < 0.001 ) , and the former caused significantly ( P < 0.001 ) greater reduction than the latter . There was also a significant ( P < 0.01 ) reduction in the usage of antidiarrhoeals after both interventions , i.e. from 20.3 + /- 3.7 % to 12.5 + /- 3.3 % ( P < 0.01 ) after face-to-face intervention and from 48.5 + /- 4.1 % to 27.0 + /- 4.3 % ( P < 0.01 ) after seminar . However , the formal seminar had a significantly ( P < 0.01 ) greater impact than the small group face-to-face intervention . There was also a trend toward increased oral rehydration solution ( ORS ) usage after both interventions , but this did not achieve the level of statistical significance ( P > 0.05 ) . No changes were observed in the control group . Although the small group face-to-face intervention did not appear to offer greater impacts over large seminars in improving the appropriate use of drugs in acute diarrhoea , since the unit cost of training is far less costly than the seminar , it might be feasibly implemented in the existing supervisory structure of the health system Objective To test the effectiveness of a complex intervention design ed , within a theoretical framework , to improve outcomes for patients with coronary heart disease . Design Cluster r and omised controlled multicentre trial . Setting General practice s in Northern Irel and and the Republic of Irel and , regions with different healthcare systems . Participants 903 patients with established coronary heart disease registered with one of 48 practice s. Intervention Tailored care plans for practice s ( practice based training in prescribing and behaviour change , administrative support , quarterly newsletter ) , and tailored care plans for patients ( motivational interviewing , goal identification , and target setting for lifestyle change ) with review s every four months at the practice s. Control practice s provided usual care . Main outcome measures The proportion of patients at 18 month follow-up above target levels for blood pressure and total cholesterol concentration , and those admitted to hospital , and changes in physical and mental health status ( SF-12 ) . Results At baseline the numbers ( proportions ) of patients above the recommended limits were : systolic blood pressure greater than 140 mm Hg ( 305/899 ; 33.9 % , 95 % confidence interval 30.8 % to 33.9 % ) , diastolic blood pressure greater than 90 mm Hg ( 111/901 ; 12.3 % , 10.2 % to 14.5 % ) , and total cholesterol concentration greater than 5 mmol/l ( 188/860 ; 20.8 % , 19.1 % to 24.6 % ) . At the 18 month follow-up there were no significant differences between intervention and control groups in the numbers ( proportions ) of patients above the recommended limits : systolic blood pressure , intervention 98/360 ( 27.2 % ) v control , 133/405 ( 32.8 % ) , odds ratio 1.51 ( 95 % confidence interval 0.99 to 2.30 ; P=0.06 ) ; diastolic blood pressure , intervention 32/360 ( 8.9 % ) v control , 40/405 ( 9.9 % ) , 1.40 ( 0.75 to 2.64 ; P=0.29 ) ; and total cholesterol concentration , intervention 52/342 ( 15.2 % ) v control , 64/391 ( 16.4 % ) , 1.13 ( 0.63 to 2.03 ; P=0.65 ) . The number of patients admitted to hospital over the 18 month study period significantly decreased in the intervention group compared with the control group : 107/415 ( 25.8 % ) v 148/435 ( 34.0 % ) , 1.56 ( 1.53 to 2.60 ; P=0.03 ) . Conclusions Admissions to hospital were significantly reduced after an intensive 18 month intervention to improve outcomes for patients with coronary heart disease , but no other clinical benefits were shown , possibly because of a ceiling effect related to improved management of the disease . Trial registration Current Controlled Trials IS RCT N24081411 BACKGROUND Educational outreach visits , particularly when combined with social marketing , appear to be a promising approach to modifying health professional behaviour , especially prescribing . Results from previous studies have shown a varying effect . OBJECTIVE The purpose of the study is to examine the effect of academic detailing as a method of implementing a clinical guideline in general practice . METHODS A cluster r and omized , controlled , blinded study was carried out of the effect of an academic detail visit compared with postal distribution of a guideline for prescribing asthma medication . Half the practice s in a Danish county with 100 practice s were visited once . The outcome measure was routinely collected data from all Danish pharmacies on the sales of asthma medication . Data were collected monthly for 2 years before to 1 year after the intervention . RESULTS There was no effect on the pattern of prescription of asthma medicines following the visit , neither immediately nor long term . CONCLUSION We found no effect of academic detailing as a single intervention Purpose : To determine whether group academic detailing with performance feedback increases recommended laboratory monitoring among out patients dispensed medications . Methods : Thirty-eight primary care practice s in 3 states were r and omized to group academic detailing with physician-level performance feedback ( intervention ) or a control group . Adjusted differences in creatinine and potassium testing between intervention and control group patients with a new or continuing dispensing for angiotensin-converting enzyme ( ACE ) inhibitors/angiotensin receptor blockers ( ARBs ) , diuretics , or digoxin were evaluated using generalized estimating equation approaches . Results : Monitoring among patients with an initial ACE/ARB and diuretic dispensing significantly improved with the intervention [ odds ratio ( OR ) = 1.22 , 95 % confidence interval ( CI ) : 1.08–1.38 ; and OR = 1.25 , 95 % CI : 1.08–1.44 , respectively ) . The intervention also significantly improved monitoring among patients with a continuing dispensing for an ACE/ARB ( OR = 1.39 , 95 % CI : 1.11–1.74 ) or a diuretic ( OR = 1.28 , 95 % CI : 1.02–1.60 ) . Adjusted differences in testing rates between study arms were modest ( ranging from 2.5 % to 4.9 % ) . No significant differences in monitoring by study arm were detected among patients dispensed digoxin . Conclusions : The impact of a group academic detailing program with feedback on recommended laboratory monitoring among medication users was modest . Yet , given the numbers of out patients dispensed medications for which laboratory monitoring is recommended , group academic detailing may offer 1 method by which outpatient medication safety can be significantly improved BACKGROUND The long-term effect of most interventions has not been studied . Changes due to interventions to improve patient care may revert to baseline after the intervention stimulus ends . This analysis reports the 24-month follow-up of a practice -tailored intervention to increase preventive service delivery rates . DESIGN Group r and omized clinical trial with 24-month follow-up of intervention sites . SETTING / PARTICIPANTS Seventy-seven community family practice s in northeast Ohio . INTERVENTION Practice -individualized facilitation of implementation of tools and approaches . MAIN OUTCOME MEASURES Summary scores of health habit counseling , screening , and immunization services recommended by the U.S. Preventive Services Task Force that were up to date for consecutive patients during r and omly selected chart review days . RESULTS Previously reported increases in global preventive service delivery rates , health habit counseling , and screening rates at 12 months were sustained after 24 months . CONCLUSIONS A practice -individualized approach can result in sustainable increases in rates of preventive service delivery , even 1 year after the outside intervention stimulus ends . Tailoring of approaches to the unique characteristics of each practice may result in institutionalization of changes BACKGROUND Previous research has not shown any significant health gain for patients as a result of providing education about depression for GPs . Reasons for this , however , are unclear . AIMS To explore relationships between process and outcome in the setting of a r and omised controlled trial of a complex educational intervention design ed to provide GPs with training in the assessment and management of depression . DESIGN OF STUDY Qualitative study utilising semi-structured interviews . SETTING General practice in the northwest of Engl and . METHOD Semi-structured interviews with 30 GPs in Liverpool and Manchester who participated in a r and omised controlled trial . RESULTS Three major barriers to the effectiveness of the intervention were identified : the lack of the GP 's belief that he/she could have an impact on the outcome of depression , the appropriateness of the training , and the organisational context in which doctors had to implement what they had learned . CONCLUSION Attitudes toward treating depression may need addressing at a much earlier point in medical education . If students are introduced to a biosocial model of depression at an early stage , they may feel more hopeful about their ability to intervene when faced with patients who exhibit significant degrees of functional disability in the context of apparently socially determined disorders . Postgraduate interventions should be tailored to the treatment of depression as a common chronic condition and be focused at the level of the organisation , not the individual practitioner Background : International guidelines for the management of nonvariceal upper gastrointestinal bleeding have not been widely adopted in clinical practice . We sought to determine whether a national , multifaceted intervention could improve adherence to guidelines , especially for patients at high risk of nonvariceal upper gastrointestinal bleeding . Methods : In this r and omized trial , we stratified hospitals by region and size and allocated sites to either the control or experimental group . Health care workers in the experimental group were given published guidelines , generic algorithms , stratification scoring systems and written reminders and attended multidisciplinary guideline education groups and case-based workshops . These interventions were implemented over a 12-month period after r and omization , with performance feedback and benchmarking . The primary outcome of adherence rates to key guidelines in endoscopic and pharmacologic management , determined by chart review , was adjusted according to site characteristics and possible within-site dependencies . We also report the rates of adherence to other recommendations . Results : Forty-three sites were r and omized to the experimental ( n = 21 ) or control ( n = 22 ) groups . In our primary analysis , we compared patients before ( experimental group : n = 402 patients ; control group : n = 424 patients ) and after ( experimental group : n = 361 patients ; control group : n = 389 patients ) intervention . Patient-level analysis revealed no significant difference in adherence rates to the guidelines after the intervention ( experimental group : 9.8 % ; control group : 4.8 % ; p = 0.99 ) after adjustment for the rate of adherence before the intervention ( experimental group : 13.2 % ; control group : 7.1 % ) . The adherence rates to other guidelines were similar and decreased over time , varying between 5 % and 93 % . Interpretation : This national knowledge translation – based trial suggests poor adherence to guidelines on nonvariceal upper gastrointestinal bleeding . Adherence was not improved by an educational intervention , which highlights both the complexity and poor predictability of attempting to alter the behaviour of health care providers ( Trial registration : Clinical Trials.gov , no. MCT-88113 ) Background The World Wide Web has led to the rapid growth of medical information and continuing medical educational offerings . Ease of access and availability at any time are advantages of the World Wide Web . Existing physician-education sites have often been design ed and developed without systematic application of evidence and cognitive-educational theories ; little rigorous evaluation has been conducted to determine which design factors are most effective in facilitating improvements in physician performance and patient-health outcomes that might occur as a result of physician participation in Web-based education . Theory and evidence -based Web design principles include the use of : needs assessment , multimodal strategies , interactivity , clinical cases , tailoring , credible evidence -based content , audit and feedback , and patient-education material s. Ease of use and design to support the lowest common technology denominator are also important . Objective Using these principles , design and develop a Web site including multimodal strategies for improving chlamydial-screening rates among primary care physicians . Methods We used office- practice data in needs assessment and as an audit/feedback tool . In the intervention introduced in 4 phases over 11 months , we provided a series of interactive , tailored , case vignettes with feedback on peer answers . We included a quality -improvement toolbox including clinical practice guidelines and printable patient education material s. Results In the formative evaluation of the first 2 chlamydia modules , data regarding the recruitment , enrollment , participation , and reminders have been examined . Preliminary evaluation data from a r and omized , controlled trial has tested the effectiveness of this intervention in improving chlamydia screening rates with a significant increase in intervention physicians ' chlamydia knowledge , attitude , and skills compared to those of a control group . Conclusions The application of theory in the development and evaluation of a Web-based continuing medical education intervention offers valuable insight into World Wide Web technology 's influence on physician performance and the quality of medical care BACKGROUND Patients in hospitals and nursing homes are at risk for the development of often preventable adverse events . Guidelines for the prevention of many types of adverse events are available , however compliance with these guidelines appears to be lacking . As a result many patients do not receive appropriate care . We developed a patient safety program that allows organisations to implement multiple guidelines simultaneously and therefore facilitates guideline use to improve patient safety . This program was developed for three frequently occurring nursing care related adverse events : pressure ulcers , urinary tract infections and falls . For the implementation of this program we developed educational activities for nurses as a main implementation strategy . OBJECTIVES The aim of this study is to describe the effect of interactive and tailored education on the knowledge levels of nurses . DESIGN A cluster r and omised trial was conducted between September 2006 and July 2008 . SETTING S Ten hospital wards and ten nursing home wards participated in this study . Prior to baseline , r and omisation of the wards to an intervention or control group was stratified for centre and type of ward . PARTICIPANTS All nurses from participating wards . METHODS A knowledge test measured nurses ' knowledge on the prevention of pressure ulcers , urinary tract infections and falls , during baseline en follow-up . The results were analysed for hospitals and nursing homes separately . RESULTS After correction for baseline , the mean difference between the intervention and the control group on hospital nurses ' knowledge on the prevention of the three adverse events was 0.19 points on a zero to ten scale ( 95 % CI : -0.03 to 0.42 ) , in favour of the intervention group . There was a statistically significant effect on knowledge of pressure ulcers , with an improved mean mark of 0.45 points ( 95 % CI : 0.10 - 0.81 ) . For the other two topics there was no statistically significant effect . Nursing home nurses ' knowledge did neither improve ( 0 points , CI : -0.35 to 0.35 ) overall , nor for the separate subjects . CONCLUSION The educational intervention improved hospital nurses ' knowledge on the prevention of pressure ulcers only . More research on long term improvement of knowledge is needed OBJECTIVE To test the primary study hypothesis that a physician-delivered coronary heart disease risk evaluation and communication program can lower patients ' predicted 10-year risk of myocardial infa rct ion or death due to coronary heart disease by 10 % within 6 months compared to usual care . DESIGN Prospect i ve , parallel group , open-label , controlled , cluster-r and omized multinational trial ; the study site is the unit of r and omization . SETTING Patients were recruited from 106 general practice s located in nine European countries . PATIENTS Men and women aged 45 to 64 ( N=1500 ) with a documented history of hypertension ( treated or untreated ) , systolic blood pressure > or = 140 mmHg ( or > or = 130 mmHg in the presence of renal or kidney disease ) , no history of cardiovascular disease , and a predicted 10-year risk of myocardial infa rct ion or death due to coronary heart disease > or = 10 % . INTERVENTION Sites were r and omized to deliver a physician-directed coronary heart disease risk communication and education program or usual care . The intervention program included informing patients of their 10-year risk of myocardial infa rct ion or death due to coronary heart disease , educating patients about modifiable risk factors and their control , and three follow-up phone calls by a physician or study nurse . MAIN OUTCOME MEASURE Predicted 10-year risk of myocardial infa rct ion or death due to coronary heart disease at 6 months . CONCLUSIONS REACH OUT will evaluate a novel , patient-focused , physician-implemented application of coronary heart disease risk equations . Results of the study will be of practical relevance to physicians , health care organizations , and those who issue clinical guidelines for the reduction of cardiovascular risk Background : We implemented a comprehensive intervention program targeting general practice staff , that proved successful in optimizing practice organization and clinical decision-making . In this paper , health-related quality of life ( HRQL ) is investigated as a clinical outcome . Objective : To evaluate the effect of the implementation of an intervention program on the HRQL in patients at high cardiovascular risk . Research design : R and omized controlled trial . Intervention practice s ( n = 62 ) received a comprehensive intervention program ( by means of outreach visitors ) lasting 21 months . HRQL of patients at high cardiovascular risk was assessed by the MOS 36-Item Short-Form Health Survey ( SF-36 ) , at baseline and after intervention . Three patient categories were distinguished : diabetes mellitus , cardiovascular disease and hypertension . Results : HRQL deteriorated in all respondents , but more pronounced in the control group . In diabetes patients the differences between intervention and control group were significant for the Vitality and Mental Health scales , with mean difference in change of 3.93 ( 95 % CI : 1.08–6.78 ) and 3.71 ( 95 % CI : 0.73–6.68 ) , respectively . Patients with cardiovascular disease had significantly different changes on three scales : physical functioning ( 3.57 , 95 % CI : 0.71–6.43 ) , vitality ( 3.01 , 95 % CI : 0.72–5.30 ) and social functioning ( 3.96 , 95 % CI : 0.50–7.42 ) . In patients with hypertension , there were no differences between the intervention and control group . Conclusion : Our comprehensive intervention program result ed in changes in HRQL on several domains , particularly in patients with diabetes and cardiovascular disease AIMS To evaluate efficacy of a pathway-based quality improvement intervention on appropriate prescribing of the low molecular weight heparin , enoxaparin , in patients with varying risk categories of acute coronary syndrome ( ACS ) . METHODS Rates of enoxaparin use retrospectively evaluated before and after pathway implementation at an intervention hospital were compared to concurrent control patients at a control hospital ; both were community hospitals in south-east Queensl and . The study population was a group of r and omly selected patients ( n = 439 ) admitted to study hospitals with a discharge diagnosis of chest pain , angina , or myocardial infa rct ion , and stratified into high , intermediate , low-risk ACS or non-cardiac chest pain : 146 intervention patients ( September-November 2003 ) , 147 historical controls ( August-December 2001 ) at the intervention hospital ; 146 concurrent controls ( September-November 2003 ) at the control hospital . Interventions were active implementation of a user-modified clinical pathway coupled with an iterative education programme to medical staff versus passive distribution of a similar pathway without user modification or targeted education . Outcome measures were rates of appropriate enoxaparin use in high-risk ACS patients and rates of inappropriate use in intermediate and low-risk patients . RESULTS Appropriate use of enoxaparin in high-risk ACS patients was above 90 % in all patient groups . Inappropriate use of enoxaparin was significantly reduced as a result of pathway use in intermediate risk ( 9 % intervention patients vs 75 % historical controls vs 45 % concurrent controls ) and low-risk patients ( 9 % vs 62 % vs 41 % ; P < 0.001 for all comparisons ) . Pathway use was associated with a 3.5-fold ( 95 % CI : 1.3 - 9.1 ; P = 0.012 ) increase in appropriate use of enoxaparin across all patient groups . CONCLUSION Active implementation of an acute chest pain pathway combined with continuous education reduced inappropriate use of enoxaparin in patients presenting with intermediate or low-risk ACS RATIONAL AND OBJECTIVES To assess the effects of a tailored and activating educational intervention , based on a three-stage modified Prochaska model of readiness-to-change , on the performance of general physicians in primary care ( GPs ) regarding management of depressive disorders . METHODS Parallel group , r and omized control trial . Primary hypothesis was that performance would improve by 20 percentage units in the intervention arm . The setting was primary care in southern Tehran . The participants were 192 GPs stratified on stage of readiness-to-change , sex , age and work experience . The intervention was a 2-day interactive workshop for a small group of GPs ' at a higher stage of readiness-to-change ( ' intention ' ) and a 2-day interactive large group meeting for those with lower propensity to change ( ' attitude ' ) at the pre- assessment . GPs in the control arm participated in a st and ard educational programme on the same topic . The main outcome measures were vali date d tools to assess GPs ' performance by unannounced st and ardized patients , regarding diagnosis and treatment of depressive disorders . The assessment s were made 2 months before and 2 months after the intervention . RESULTS GPs in the intervention arm significantly improved their overall mean scores for performance regarding both diagnosis , with an intervention effect of 14 percentage units ( P = 0.007 ) , and treatment and referral , with an intervention effect of 20 percentage units ( P < 0.0001 ) . The largest improvement after the intervention appeared in the small group : 30 percentage units for diagnosis ( P = 0.027 ) and 29 percentage units for treatment and referral ( P < 0.0001 ) . CONCLUSIONS Activating learning methods , tailored according to the participants ' readiness to change , improved clinical performance of GPs in continuing medical education and can be recommended for continuing professional development OBJECTIVES To assess the effect of a tailored professional intervention , including academic detailing , on antibiotic prescribing for acute cough . METHODS In a cluster-r and omized controlled before and after study 85 Flemish GPs included adult patients with acute cough consulting in the periods February-April 2000 and 2001 . The intervention consisted of a clinical practice guideline for acute cough , an educational outreach visit and a postal reminder to support its implementation in January 2001 . Antibiotic prescribing rates and patients ' symptom resolution were the main outcome measures . RESULTS Thirty-six of 42 GPs received the intervention and 35 of 43 GPs served as controls ; 1503 patients were eligible for analysis . Only in the intervention group were patients less likely to receive antibiotics after the intervention [ OR(adj ) ( 95 % CI)=0.56 ( 0.36 - 0.87 ) ] . Prescribed antibiotics were also more in line with the guideline in the intervention group [ 1.90 ( 0.96 - 3.75 ) ] and less expensive from the perspective of the National Sickness and Invalidity Insurance Institute [ MD(adj ) ( 95 % CI)= Euro -6.89 [ -11.77-(-2.02 ) ] ] . No significant differences were found between the groups for the time to symptom resolution . CONCLUSIONS An (inter)actively delivered tailored intervention implementing a guideline for acute cough is successful in optimizing antibiotic prescribing without affecting patients ' symptom resolution . Further research efforts should be devoted to cost-effectiveness studies of such interventions BACKGROUND We undertook a project to promote evidence -based medicine ( EBM ) within a network of GPs ( the Monash Division of General Practice ) in Melbourne , Australia . A principal promotional strategy was to conduct practice visits ( ' academic detailing ' ) . OBJECTIVES The aim of this study was to measure the impact of academic detailing on GP attitudes and knowledge of EBM . METHODS All 132 GP members of the division were invited by mail to accept a practice visit about EBM . The GPs had been r and omized to one of two groups : to receive academic detailing during the study period or to be visited at a later date . The practice visit consisted of a 30- 45 minute discussion about EBM and the barriers to its practice . Pre- and post-intervention question naires were used to measure change in knowledge of and attitudes to EBM over a 3-month period in both groups . RESULTS AND CONCLUSIONS Academic detailing led to a significant improvement in knowledge scores and self-perceived underst and ing of EBM , but had little influence on GP attitudes toward it . It is not known whether this would lead to change in clinical behaviour among GPs BACKGROUND Frail older people admitted to nursing homes are at risk of a range of adverse outcomes , including pressure ulcers . Clinical decision support systems are believed to have the potential to improve care and to change the behaviour of healthcare professionals . OBJECTIVES To determine whether a multi-faceted tailored strategy to implement an electronic clinical decision support system for pressure ulcer prevention improves adherence to recommendations for pressure ulcer prevention in nursing homes . DESIGN Two-armed r and omized controlled trial in a nursing home setting in Belgium . The trial consisted of a 16-week implementation intervention between February and June 2010 , including one baseline , four intermediate , and one post-testing measurement . Primary outcome was the adherence to guideline -based care recommendations ( in terms of allocating adequate pressure ulcer prevention in residents at risk ) . Secondary outcomes were the change in resident outcomes ( pressure ulcer prevalence ) and intermediate outcomes ( knowledge and attitudes of healthcare professionals ) . SETTING R and om sample of 11 wards ( 6 experimental ; 5 control ) in a convenience sample of 4 nursing homes in Belgium . PARTICIPANTS In total , 464 nursing home residents and 118 healthcare professionals participated . METHODS The experimental arm was involved in a multi-faceted tailored implementation intervention of a clinical decision support system , including interactive education , reminders , monitoring , feedback and leadership . The control arm received a hard-copy of the pressure ulcer prevention protocol , supported by st and ardized 30 min group lecture . RESULTS Patients in the intervention arm were significantly more likely to receive fully adequate pressure ulcer prevention when seated in a chair ( F=16.4 , P=0.003 ) . No significant improvement was observed on pressure ulcer prevalence and knowledge of the professionals . While baseline attitude scores were comparable between both groups [ exp . 74.3 % vs. contr . 74.5 % ( P=0.92 ) ] , the mean score after the intervention was 83.5 % in the experimental group vs. 72.1 % in the control group ( F=15.12 , P<0.001 ) . CONCLUSION The intervention was only partially successful to improve the primary outcome . Attitudes improved significantly while the knowledge of the healthcare workers remained unsatisfactorily low . Further research should focus on the underlying reasons for these findings Study Design . Cluster r and omized controlled trial for a multifaceted implementation strategy . Objectives . To assess the effectiveness of tailored interventions ( multifaceted implementation strategy ) to implement the Dutch low back pain guideline for general practitioners with regard to adherence to guideline recommendations . Summary of Background Data . Guidelines for the management of low back pain in primary care have been developed in various countries , but little is known about the optimal implementation strategy . A multifaceted implementation strategy was developed to overcome identified barriers to the implementation of the Dutch low back pain guideline for general practitioners . Methods . General practitioners were r and omized to an intervention or a control group . The general practitioners in the intervention group ( n = 21 ) received tailored interventions consisting of the Dutch low back pain guideline for general practitioners , a 2-hour educational and clinical practice workshop ; two scientific articles on low back pain management ; the guideline for occupational physicians ; a tool for patient education ; and a tool for reaching agreement on low back care with physical , exercise , and manual therapists . The control group ( n = 20 ) received no intervention . The participating general practitioners were asked to recruit consecutive patients with a new episode of low back pain as the main reason for consultation . General practitioners completed registration forms of each individual consultation with regard to the main outcome measures : advice and information , referral to other health-care providers , and prescription of medication . Results . Forty-one of the 67 r and omized general practitioners reported on a total of 616 consultations for 531 patients with nonspecific low back pain . The advice and explanation provided by the general practitioners , the prescription of paracetamol or nonsteroidal anti-inflammatory drugs , and prescription of pain medication on atime contingent or a pain contingent basis showed no statistically significant differences between the intervention and control groups . There were also no differences in overall referral rate . However , in follow-up consultations fewer patients were referred to a physical or exercise therapist by the general practitioners in the intervention group than in the control group . Conclusions . The multifaceted intervention strategy modestly improved implementation ( for parts of the recommendations in ) the Dutch low back pain guideline by general practitioners and produced small concomitant changes in patient management . The implementation strategy produced fewer referrals to therapists during follow-up consultations BACKGROUND Low Chlamydia trachomatis screening rates create an opportunity to test innovative continuing medical education ( CME ) programs . Few studies of Internet-based physician learning have been evaluated with objective data on practice patterns . DESIGN This r and omized controlled trial tested a multicomponent Internet CME ( mCME ) intervention for increasing chlamydia screening of at-risk women aged 16 to 26 years . SETTING Eligible physician offices had > or = 20 patients at risk for chlamydia as defined by the Health Plan Employer Data and Information Set ( HEDIS ) , had at least one primary care physician ( internal medicine , family medicine/general practice , pediatrics ) with Internet access , and participated in the study managed care organization . The 191 r and omized primary care offices represented 20 states . INTERVENTION The intervention , available from February to December 2001 , consisted of four case-based learning modules , was tailored in real time to each physician based on theory of behavior change , and included office-level feedback of chlamydia screening rates . MAIN OUTCOME MEASURE HEDIS chlamydia screening rates for the pre-intervention ( 2000 ) and post-intervention ( 2002 ) periods . RESULTS Pre-intervention screening rates for the intervention and comparison offices were 18.9 % and 16.2 % ( p = 0.135 ) . Post-intervention screening rates for the intervention and comparison offices were 15.5 % and 12.4 % , respectively ( p = 0.044 , adjusting for baseline performance ) . CONCLUSIONS The substantial decline in chlamydia screening rates observed in the comparison offices was significantly attenuated for the intervention offices . The mCME favorably influenced chlamydia screening by primary care physicians The purpose of this study was to evaluate the potential for online continuing medical education ( CME ) seminars to improve quality of care . Primary care physicians ( 113 ) participated in a r and omized controlled trial to evaluate an online CME series . Physicians were r and omized to view either a seminar about type 2 diabetes or a seminar about systolic heart failure . Following the seminar , physicians were presented with 4 clinical vignettes and asked to describe what tests , treatments , counseling , or referrals they would recommend . Physicians who viewed the seminars were significantly more likely to recommend guideline -consistent care to patients in the vignettes . For example , physicians who viewed the diabetes seminar were significantly more likely to order an eye exam for diabetes patients ( 63 % ) compared with physicians in the control group ( 27 % ) . For some guidelines there were no group differences . These results provide early evidence of the effectiveness of online CME programs to improve physician clinical practice . ( Am J Med Qual 2008;23:475 - 483 BACKGROUND Sub-optimal management of cardiovascular disease ( CVD ) patients is widespread in primary and secondary care , with risk factors frequently unrecorded or untreated . AIM To investigate the effectiveness of educational interventions developed in primary care , on recording , prescribing and control of risk factors among all patients recorded by their general practitioner as having CVD . DESIGN OF STUDY Factorial , duster-r and omised controlled trial . SETTING Primary care teams representing the range of practice development in a geographically defined area in inner London . METHOD Participating practice s were r and omly allocated to one of the four intervention groups : information , evidence , both or neither . Interventions were tailored to suit individual practice needs . At a mean of 19 months after baseline , and three months after the end of intervention , practice s carried out the follow-up assessment of recording , treatment , and control of risk factors in the same CVD patients . RESULTS Adequate recording of all three risk factors , found inapproximately a third of patients at baseline , increased non-significantly by 10.5 % ( 95 % confidence interval [ CI ] = 3.9 to 24.9 ) in the information ( versus not information ) group and by 6.6 % ( 95 % [ CI ] = 8.9 to 22.0 ) in the evidence ( versus not evidence ) group . Factorial improvements in prescribing and control of risk factors tended not to be significant . Adequate recording of an three risk factors showed the greatest improvement in the information plus evidence group ( 19.9 % increase , P for heterogeneity across the four groups < or = 0.001 ) . Mean change from baseline to follow-up within the four intervention groups suggested improvements in the combined information plus evidence group in cholesterol recording ( 22.5 % increase ) , prescribing of lipid lowering drugs ( 4.4 % increase ) and mean cholesterol ( 0.7 mmol/l decrease ) . CONCLUSIONS Adequate risk factor recording did not differ between the information ( versus not information ) or the evidence ( versus not evidence ) intervention groups . Combined training in information systems and evidence -based medicine should be considered in the design of future interventions , to improve secondary prevention of CVD Objective : To evaluate the effect on antibiotic prescribing of an intervention in existing local quality circles promoting an evidence -based guideline for acute rhinosinusitis . Design : A pragmatic cluster-r and omised controlled trial comparing st and ard dissemination of the guideline by mail with an additional strategy using quality circles . Setting : General practice in Fl and ers , Belgium . Participants : General practitioners ( GPs ) in 18 local quality circles were r and omly allocated to two study arms . All GPs received the guideline by mail . GPs in the nine quality circles allocated to the intervention arm received an additional group intervention , which consisted of one self-led meeting using material introduced to the group moderator by a member of the research team . Main outcome measures : Adherence to the guideline was measured as differences in the proportion of antibiotic prescriptions , including the choice of antibiotic , between the two study arms after the intervention period . GPs registered their encounters with patients presenting with signs and symptoms of acute rhinosinusitis in a booklet design ed for the study . Results : A total of 75 doctors ( 29 % of GPs in the participating quality circles ) registered 408 consultations . In the intervention group , 56.9 % of patients received an antibiotic compared with 58.3 % in the control group . First-choice antibiotics were issued in 34.5 % of antibiotic prescriptions in the intervention group compared with 29.4 % in the control group . After adjusting for patient and GP characteristics , the ORadj for antibiotics prescribed in the intervention arm compared with the control arm was 0.63 ( 95 % CI 0.29 to 1.37 ) . There was no effect on the choice of antibiotic ( ORadj 1.07 , 95 % CI 0.34 to 3.37 ) . Conclusion : A single intervention in quality circles of GPs integrated in the group ’s normal working procedure did not have a significant effect on the quality of antibiotic prescribing . More attention to the context and structure of primary care practice , and insight into the process of self-reflective learning may provide clues to optimise the effectiveness of quality circles BACKGROUND Statins reduce the risk of vascular events , however statin prescribing is often sub optimal and better evidence is needed to inform quality improvements . The Statin Outreach Support ( SOS ) trial was design ed to test the efficacy of pharmacist led educational outreach directed at General Practice s , aim ing to improve statin prescribing for community dwelling patients with vascular disease . This paper describes the study rationale , design , methods and baseline characteristics of participants . DESIGN The SOS trial was design ed to investigate whether practice s receiving SOS improve their statin prescribing and patients achieve reduced cholesterol levels . It was a prospect i ve , single blind , cluster r and omised controlled trial with a follow-up period of 5months minimum post SOS intervention delivery . RESULTS Thirty one practice s were recruited from the UK 's largest Health Board area . At r and omisation , 16 practice s were allocated to SOS and 15 to usual care with 4040 patients included at baseline . Participating practice s showed few differences compared with non-participating practice s ; practice s and patients r and omised to each arm of the study had similar distributions with respect to age , complications , cholesterol levels and statin prescribing . Baseline data compared favourably with l and mark , placebo-controlled statin trials . CONCLUSIONS Compared with existing implementation research , SOS trial has more participants , a detailed description of baseline characteristics and over 90 % power ( at 5 % significance ) to detect a difference of 12 % in the proportion of patients with controlled cholesterol after SOS BACKGROUND Patient care guidelines are usually implemented one at a time , yet patients are at risk for multiple , often preventable , adverse events simultaneously . OBJECTIVE The SAFE or SORRY ? programme targeted three adverse events ( pressure ulcers , urinary tract infections and falls ) and was successful in reducing the incidence of these events . This article explores the process of change and describes the effect on the preventive care given . DESIGN Separate data on preventive care were collected along the cluster r and omised trial , which was conducted between September 2006 and November 2008 . SETTING S Ten hospital wards and ten nursing home wards . PARTICIPANTS We monitored nursing care given to adult patients with an expected length of stay of at least five days . METHODS The SAFE or SORRY ? programme consisted of the essential recommendations of guidelines for pressure ulcers , urinary tract infections and falls . A multifaceted implementation strategy was used to implement this multiple guidelines programme . Data on preventive care given to patients were collected in line with these guidelines and the difference between the intervention and the usual care group at follow-up was analysed . RESULTS The study showed no overall difference in preventive pressure ulcer measures between the intervention and the usual care group in hospitals ( estimate=6 % , CI : -7 - 19 ) and nursing homes ( estimate=4 % , CI : -5 - 13 ) . For urinary tract infections , even statistically significantly fewer hospital patients at risk received preventive care ( estimate=19 % , CI : 17 - 21 ) . For falls in hospitals and nursing homes , no more patients at risk received preventive care . CONCLUSION Though the SAFE OR SORRY ? programme effectively reduced the number of adverse events , an increase in preventive care given to patients at risk was not demonstrated . These results seem to emphasise the difficulties in measuring the compliance to guidelines . More research is needed to explore the possibilities for measuring the implementation of multiple guidelines using process indicators This study compared different methods for assigning confidence intervals to the analysis of variance estimator of the intraclass correlation coefficient ( rho ) . The context of the comparison was the use of rho to estimate the variance inflation factor when planning cluster r and omized trials . The methods were compared using Monte Carlo simulations of unbalanced clustered data and data from a cluster r and omized trial of an intervention to improve the management of asthma in a general practice setting . The coverage and precision of the intervals were compared for data with different numbers of clusters , mean numbers of subjects per cluster and underlying values of rho . The performance of the methods was also compared for data with Normal and non-Normally distributed cluster specific effects . Results of the simulations showed that methods based upon the variance ratio statistic provided greater coverage levels than those based upon large sample approximations to the st and ard error of rho . Searle 's method provided close to nominal coverage for data with Normally distributed r and om effects . Adjusted versions of Searle 's method to allow for lack of balance in the data generally did not improve upon it either in terms of coverage or precision . Analyses of the trial data , however , showed that limits provided by Thomas and Hultquist 's method may differ from those of the other variance ratio statistic methods when the arithmetic mean differs markedly from the harmonic mean cluster size . The simulation results demonstrated that marked non-Normality in the cluster level r and om effects compromised the performance of all methods . Confidence intervals for the methods were generally wide relative to the underlying size of rho suggesting that there may be great uncertainty associated with sample size calculations for cluster trials where large clusters are r and omized . Data from cluster based studies with sample sizes much larger than those typical of cluster r and omized trials are required to estimate rho with a reasonable degree of precision BACKGROUND Use of alteplase improves outcome in some patients with stroke . Several types of barrier frequently prevent its use . We assessed whether a st and ardised , barrier- assessment , multicomponent intervention could increase alteplase use in community hospitals in Michigan , USA . METHODS In a cluster-r and omised controlled trial , we selected adult , non-specialty , acute-care community hospitals in the Lower Peninsula of Michigan , USA . Eligible hospitals discharged at least 100 patients who had had a stroke per year , had less than 100 000 visits to the emergency department per year , and were not academic comprehensive stroke centres . Using a computer-generated r and omisation sequence , we selected 12 matched pairs of eligible hospitals . Within pairs , the hospitals were allocated to intervention or control groups with restricted r and omisation in January , 2007 . Between January , 2007 , and December , 2007 , intervention hospitals implemented a multicomponent intervention that included qualitative and quantitative assessment of barriers to alteplase use and ways to address the findings , and provided additional support . The primary outcome was change in alteplase use in patients with stroke in emergency departments between the pre-intervention period ( January , 2005 , to December , 2006 ) and the post-intervention period ( January , 2008 , to January , 2010 ) . Physicians in participating hospitals and the coordinating centre could not be masked to group assignment , but were masked to progress made in paired control hospitals . External medical review ers who were masked to group assignment assessed outcomes . We did intention-to-treat ( ITT ) and target- population ( without one pair that was excluded after r and omisation ) analyses . This trial is registered at Clinical Trials.gov , number NCT00349479 . FINDINGS All 24 hospitals completed the study . Overall , 745 of 40 823 patients with stroke received intravenous alteplase treatment . In the ITT analysis , the proportion of patients with stroke who were admitted and treated with alteplase increased between the pre-intervention and post-intervention periods in intervention hospitals ( 89 [ 1·25 % ] of 7119 patients to 235 [ 2·79 % ] of 8419 ) to a greater extent than in control hospitals ( 99 [ 1·25 % ] of 7946 to 194 [ 2·10 % ] of 9222 ) , but the difference between groups was not significant ( relative risk [ RR ] 1·37 , 95 % CI 0·96 - 1·93 ; p=0·08 ) . In the target- population analysis , the increase in alteplase use in intervention hospitals ( 59 [ 1·00 % ] of 5882 to 191 [ 2·62 % ] of 7288 ) was significantly greater than in control hospitals ( 65 [ 1·09 % ] of 5957 to 120 [ 1·72 % ] of 6989 ; RR 1·68 , 95 % CI 1·09 - 2·57 ; p=0·02 ) , but was still clinical ly modest . INTERPRETATION The intervention did not significantly increase alteplase use in patients with ischaemic stroke . The increase in use of alteplase in the target population was significant , but smaller than the effect to which the study was powered . Additional strategies to increase acute stroke treatment are needed . FUNDING National Institutes of Health National Institute of Neurological Disorders and Stroke Few empirical studies are available to guide best practice s for transferring evidence d-based treatments to community substance abuse providers . To maximize the learning and maintenance of new clinical skills , this study tested a context -tailored training ( CTT ) model , which used st and ardized patient actors in role-plays tailored to agency clinical context , repetitive cycles of practice and feedback , and enhanced organizational support . This study reports the results of a r and omized pilot evaluation of CTT for motivational interviewing ( MI ) . Investigators r and omly assigned community substance abuse treatment agencies to receive either CTT or a st and ard 2-day MI workshop . The study also evaluated the effects of counselor-level and organizational-level variables on the learning of MI . No between-condition differences were observed on the acquisition and maintenance of MI skills despite reported higher satisfaction with the more costly context -tailored model . Analyses revealed that those counselors with more formal education and less endorsement of a disease model of addiction made the greatest gains in MI skills , irrespective of training condition . Similarly , agencies whose individual counselors viewed their organization as being more open to change and less supportive of autonomy showed greater average staff gains in MI skills , again , irrespective of training method . Posttraining activities within agencies that supported the ongoing learning and implementation of MI mediated the effects of organizational openness to change . This pilot study suggests that tailored training methods may not produce better outcomes than traditional workshops for the acquisition of evidence -based practice , and that efforts to enhance skill acquisition can be focused on characteristics of learners and ongoing organizational support of learning Background and aims In-hospital fall-related injuries are a source of personal harm , preventable hospitalisation costs , and access block through increased length of stay . Despite increased fall prevention awareness and activity over the last decade , rates of reported fall-related fractures in hospitals appear not to have decreased . This cluster r and omised controlled trial ( RCT ) aims to determine the efficacy of the 6-PACK programme for preventing fall-related injuries , and its generalisability to other acute hospitals . Methods 24 acute medical and surgical wards from six to eight hospitals throughout Australia will be recruited for the study . Wards will be matched by type and fall-related injury rates , then r and omly allocated to the 6-PACK intervention ( 12 wards ) or usual care control group ( 12 wards ) . The 6-PACK programme includes a nine-item fall risk assessment and six nursing interventions : ‘ falls alert ’ sign ; supervision of patients in the bathroom ; ensuring patient 's walking aids are within reach ; establishment of a toileting regime ; use of a low-low bed ; and use of bed/chair alarm . Intervention wards will be supported by a structured implementation strategy . The primary outcomes are fall and fall-related injury rates 12 months following 6-PACK implementation . Discussion This study will involve approximately 16 000 patients , and as such is planned to be the largest hospital fall prevention RCT to be undertaken and the first to be powered for the important outcome of fall-related injuries . If effective , there is potential to implement the programme widely as part of daily patient care in acute hospital wards where fall-related injuries are a problem . Trial registration The protocol for this study is registered with the Australian New Zeal and Clinical Trials Registry ( ACTRN12611000332921 ) Mortality rates among American hemodialysis patients are the highest in the industrialized world . Measures of delivered dialysis ( Kt/V ) correspond strongly with survival and are estimated to be inadequate in one third of patients . We sought to determine the importance of potential barriers to adequate dialysis , including patient-related and technical factors . Using a cross-sectional study design , we abstract ed the charts of 721 r and omly selected patients from all 22 chronic hemodialysis units in northeast Ohio . For each of 1,836 treatments provided to these patients , we assessed delivered dialysis ( Kt/V ) and patient-related factors ( ie , hypotension , intradialytic symptoms , and treatment time missed due to noncompliance or transportation problems ) and technical factors ( ie , dialysis prescription , type of vascular access , clotting , and dialyzer reuse ) . We used hierarchical regression analysis to determine which potential barriers were independently related to delivered dialysis after adjustment for patient demographic and medical characteristics . Barriers independently related to dialysis delivery ( all P values < 0.001 ) included patient noncompliance , present in 3 % of treatments ; low dialysis prescription , 14 % ; use of a catheter for vascular access , 11 % ; and clotting , 1 % . The prevalence of identified barriers varied dramatically across facilities ( eg , the prevalence of low dialysis prescription ranged from 0 % to 37 % , while the prevalence of catheter use ranged from 3 % to 28 % ) . In conclusion , patient noncompliance , low dialysis prescription , catheter use , and clotting are the most important barriers to dialysis delivery . Further work is needed to develop interventions to overcome these barriers and to determine the effect of such interventions on dialysis adequacy and patient survival OBJECTIVE To develop an intervention program to improve health outcomes among patients with allergic rhinitis in a managed care environment . STUDY DESIGN The Episodes of Care ( EOC ) team at Lovelace Health Systems selected allergic rhinitis for an intervention program because it was identified as one of the top 10 reasons for visits to primary care clinics . The intervention program was based on a multidisciplinary team process design ed to create a customized provider and patient education program to alter inconsistence or deficiencies in the treatment of allergic rhinitis . PATIENTS AND METHODS The EOC team research ed literature and current practice s and then identified inconsistencies in diagnostic and treatment patterns . Based on this research , the team developed guidelines and a provider education program . Intervention strategies were structured around decision points in a treatment protocol . More than 500 patients were monitored throughout the allergy season by using written and telephone surveys , symptom diaries , and encounter data . Measurable outcomes were established for provider and patient behavior . Patient outcomes were derived from a preventive behavior index and administrative data reporting usage of 5 classes of medication . RESULTS Approximately 50 % of providers altered their practice patterns as a result of the intervention program . Patient outcomes showed a decrease in the use of rescue medications , particularly antibiotics , and an increase in preventive measures in the treatment group compared with the control group . CONCLUSION The EOC model result ed in positive changes in provider and patient behavior . The multidisciplinary approach result ed in broad provider participation Background : Current underst and ing of implementation methods is limited , and research has focused on changing doctors ’ behaviors . Aim : Our aim was to evaluate the impact of audit and feedback and educational outreach in improving nursing practice and patient outcomes . Methods : Using a factorial design , cluster r and omized controlled trial , we evaluated 194 community nurses in 157 family practice s and 1078 patients with diagnosis of urinary incontinence ( UI ) for nurses compliance with evidence -linked review criteria for the assessment and management of UI and impact on psychologic and social well-being and symptoms . In the outreach arms , nurses ’ self-reported barriers informed development of tailored strategies . Results : In comparison with educational material s alone , the implementation methods tested did not improve care at 6 months follow-up . Moderate rates of improvement ( 10–17 % of patients ) in performance for the assessment of UI and greater rates of improvement ( 20–30 % of patients ) for the management of care were found but effects were similar across arms . Improvement in patient outcomes was more consistently positive for educational outreach than for audit and feedback but differences were not significant . Adjustment for caseload size , severity or duration of UI and patients ’ age did not alter results . Conclusions : Printed educational material s alone may be as effective as audit and feedback and educational outreach in improving nurses ’ performance and outcomes of care for people with UI . Greater underst and ing of the underlying processes in improving performance within multidisciplinary teams through further , theory-driven studies with “ no intervention ” control groups and longer follow-up are needed BACKGROUND Implementation of evidence -based obstetrical practice s remains a significant challenge . Effective strategies to disseminate and implement such practice s are needed . METHODS We r and omly assigned 19 hospitals in Argentina and Uruguay to receive a multifaceted behavioral intervention ( including selection of opinion leaders , interactive workshops , training of manual skills , one-on-one academic detailing visits with hospital birth attendants , reminders , and feedback ) to develop and implement guidelines for the use of episiotomy and management of the third stage of labor or to receive no intervention . The primary outcomes were the rates of prophylactic use of oxytocin during the third stage of labor and of episiotomy . The main secondary outcomes were postpartum hemorrhage and birth attendants ' readiness to change their behavior with regard to episiotomies and management of the third stage of labor . The outcomes were measured at baseline , at the end of the 18-month intervention , and 12 months after the end of the intervention . RESULTS The rate of use of prophylactic oxytocin increased from 2.1 % at baseline to 83.6 % after the end of the intervention at hospitals that received the intervention and from 2.6 % to 12.3 % at control hospitals ( P=0.01 for the difference in changes ) . The rate of use of episiotomy decreased from 41.1 % to 29.9 % at hospitals receiving the intervention but remained stable at control hospitals , with preintervention and postintervention values of 43.5 % and 44.5 % , respectively ( P<0.001 for the difference in changes ) . The intervention was also associated with reductions in the rate of postpartum hemorrhage of 500 ml or more ( relative rate reduction , 45 % ; 95 % confidence interval [ CI ] , 9 to 71 ) and of 1000 ml or more ( relative rate reduction , 70 % ; 95 % CI , 16 to 78 ) . Birth attendants ' readiness to change also increased in the hospitals receiving the intervention . The effects on the use of episiotomy and prophylactic oxytocin were sustained 12 months after the end of the intervention . CONCLUSIONS A multifaceted behavioral intervention increased the prophylactic use of oxytocin during the third stage of labor and reduced the use of episiotomy . ( Clinical Trials.gov number , NCT00070720 [ Clinical Trials.gov ] ; Current Controlled Trials number , IS RCT N82417627 [ controlled-trials.com ] . ) R and omized trials have indicated that well-managed anticoagulation with warfarin could prevent more than half of the strokes related to atrial fibrillation . However , many patients with atrial fibrillation who are eligible for this therapy either do not receive it or are not maintained within an optimal prothrombin time-international normalized ratio ( INR ) range . We sought to determine whether an anticoagulation service within a managed care organization would be a feasible alternative for providing anticoagulation care . We performed a multi-site r and omized trial in six large managed care organizations in the United States . Subjects were aged 65 years or older and had nonvalvular atrial fibrillation . At each site , physician practice s were divided into two geographically defined practice clusters ; each site was r and omly assigned to have one intervention and one control cluster . The intervention cluster received an anticoagulation service that satisfied specifications for high- quality anticoagulation care and was coordinated through the managed care organization . Control clusters continued with their usual provider-based care . We measured the proportion of time that warfarin-treated patients in each of the clusters ( intervention and control ) were in the target range for the INR at baseline , and again during a follow-up period . Five of the six selected sites succeeded at developing an anticoagulation service . Patients in the intervention and control clusters had similar demographic characteristics , contraindications to warfarin , and risk factors for stroke . Among patients ( n = 144 in the intervention clusters ; n = 118 in the control clusters ) for whom data were available during the baseline and follow-up periods , the changes in percentages of time in the target range were similar for those in the intervention clusters ( baseline : 47.7 % ; follow-up : 55.6 % ) and in the control clusters ( baseline : 49.1 % ; follow-up : 52.3 % ; intervention effect : 5 % ; 95 % confidence interval : -5 % to 14 % ; P = 0.32 ) . Although it was feasible in a managed care organization to implement anticoagulation services that were tailored to local circumstances , provision of this service did not improve anticoagulation care compared with usual care . The effect of the anticoagulation service was limited by the utilization of the service , the degree to which the referring physician supports strict adherence to recommended target ranges for the INR , and the ability of the anticoagulation service to identify and to respond to out-of-range values promptly Private pharmacies are an important source of health care in developing countries . A number of studies have documented deficiencies in treatment , but little has been done to improve practice s. We conducted two controlled trials to determine the efficacy of face-to-face educational outreach in improving communication and product sales for cases of diarrhoea in children in 194 private pharmacies in two developing countries . A training guide was developed to enable a national diarrhoea control programme to identify problems and their causes in pharmacies , using quantitative and qualitative research methods . The guide also facilitates the design , implementation , and evaluation of an educational intervention , which includes brief one-on-one meetings between diarrhoea programme educators and pharmacists/owners , followed by one small group training session with all counter attendants working in the pharmacies . We evaluated the short-term impact of this intervention using a before- and -after comparison group design in Kenya , and a r and omized controlled design in Indonesia , with the pharmacy as unit of analysis in both countries ( n = 107 pharmacies in Kenya ; n = 87 in Indonesia ) . Using trained surrogate patients posing as mothers of a child under five with diarrhoea , we measured sales of oral rehydration salts ( ORS ) ; sales of antidiarrhoeal agents ; and history-taking and advice to continue fluids and food . We also measured knowledge about dehydration and drugs to treat diarrhoea among Kenyan pharmacy employees after training . Major discrepancies were found at baseline between reported and observed behaviour . For example , 66 % of pharmacy attendants in Kenya , and 53 % in Indonesia , reported selling ORS for the previous case of child diarrhoea , but in only 33 % and 5 % of surrogate patient visits was ORS actually sold for such cases . After training , there was a significant increase in knowledge about diarrhoea and its treatment among counter attendants in Kenya , where these changes were measured . Sales of ORS in intervention pharmacies increased by an average of 30 % in Kenya ( almost a two-fold increase ) and 21 % in Indonesia compared to controls ( p < 0.05 ) ; antidiarrhoeal sales declined by an average of 15 % in Kenya and 20 % in Indonesia compared to controls ( p < 0.05 ) . There was a trend toward increased communication in both countries , and in Kenya we observed significant increases in discussion of dehydration during pharmacy visits ( p < 0.05 ) . We conclude that face-to-face training of pharmacy attendants which targets deficits in knowledge and specific problem behaviours can result in significant short-term improvements in product sales and communication with customers . The positive effects and cost-effectiveness of such programmes need to be tested over a longer period for other health problems and in other countries Objective : We evaluated the effect of performance feedback on acute ischemic stroke care quality in Minnesota hospitals . Methods : A cluster-r and omized controlled trial design with hospital as the unit of r and omization was used . Care quality was defined as adherence to 10 performance measures grouped into acute , in-hospital , and discharge care . Following preintervention data collection , all hospitals received a report on baseline care quality . Additionally , in experimental hospitals , clinical opinion leaders delivered customized feedback to care providers and study personnel worked with hospital administrators to implement changes targeting identified barriers to stroke care . Multilevel models examined experimental vs control , preintervention and postintervention performance changes and secular trends in performance . Results : Nineteen hospitals were r and omized with a total of 1,211 acute ischemic stroke cases preintervention and 1,094 cases postintervention . Secular trends were significant with improvement in both experimental and control hospitals for acute ( odds ratio = 2.7 , p = 0.007 ) and in-hospital ( odds ratio = 1.5 , p < 0.0001 ) care but not discharge care . There was no significant intervention effect for acute , in-hospital , or discharge care . Conclusion : There was no definite intervention effect : both experimental and control hospitals showed significant secular trends with performance improvement . Our results illustrate the potential fallacy of using historical controls for evaluating quality improvement interventions . Classification of evidence : This study provides Class II evidence that informing hospital leaders of compliance with ischemic stroke quality indicators followed by a structured quality improvement intervention did not significantly improve compliance more than informing hospital leaders of compliance with stroke quality indicators without a quality improvement intervention Despite the recommendation of the Dutch association of nursing home physicians ( NVVA ) to be immunized against influenza , vaccine uptake among HCWs in nursing homes remains unacceptably low . Therefore we conducted a cluster r and omised controlled trial among 33 Dutch nursing homes to assess the effects of a systematic ally developed multi-faceted intervention program on influenza vaccine uptake among HCWs . The intervention program result ed in a significantly higher , though moderate , influenza vaccine uptake among HCWs in nursing homes . To take full advantage of this measure , either the program should be adjusted and implemented over a longer time period or m and atory influenza vaccination should be considered This study aims to compare h and search ing to a basic MEDLINE search for the identification of reports of r and omized trials in specialized health care journals . Twenty-two specialized health care journals , published in the U.K. , were h and search ed for all reports of controlled trials ( as defined by the Cochrane Collaboration ) . The reports of trials , which were judged to be definitely r and omized , were identified from a r and om sample of three years per journal and form one element of this study . A MEDLINE search using the publication type terms ' r and omized controlled trial ' and ' controlled clinical trial ' was also performed for the same journal years . The reports of trials retrieved by h and search ing were then compared against those retrieved from the MEDLINE search , to identify differences in retrieval between the two techniques . Reports of r and omized trials identified by the MEDLINE search but not found by h and search ing were individually assessed to see if they met the Cochrane eligibility criteria for a report of a r and omized trial . A total of 714 reports of r and omized trials were found by using a combination of both h and search ing and MEDLINE search ing . Of these , 369 ( 52 per cent ) were identified only by h and search ing and 32 ( 4 per cent ) were identified only by MEDLINE search ing . Of the reports identified only by h and search ing , 252 had no MEDLINE record , of which 232 ( 92 per cent ) were meeting abstract s or published in supplements ; 117 ( 25 per cent ) of the 462 reports of r and omized trials which had a MEDLINE record were missed by the electronic search because they did not have either of the publication type terms ' r and omized controlled trial ' or ' controlled clinical trial ' . This proportion varied depending on when the reports of r and omized trials were published ( that is , before or after the introduction of the MEDLINE publication type terms above ) . The highest additional yield from h and search ing compared to MEDLINE search ing was for reports of r and omized trials published prior to 1991 and from h and search ing the non- MEDLINE indexed parts of a journal . The results of this study suggest that a combination of MEDLINE and h and search ing is required to identify adequately reports of r and omized trials BACKGROUND Various methods are available for implementing change in the clinical behaviour of general practitioners ( GPs ) . Although passive dissemination of information is generally ineffective , other methods can be variably effective . Few studies have investigated the impact of tailored methods . AIM To determine whether methods tailored to overcome obstacles to change using psychological theories are more effective than dissemination alone in the implementation of guidelines for depression among GPs . DESIGN OF STUDY R and omised controlled trial . SETTING Sixty general practice s in Engl and ; 30 GPs in the control group , 34 in the intervention group . METHOD Practitioners identified patients presenting with depression before and after the implementation of guidelines ( control group n = 192 in the first data collection , n = 181 in the second ; intervention group n = 210 in the first data collection and n = 197 in the second ) . The main outcome measures were : record of adherence to guideline recommendations in clinical records ; proportion of patients with Beck Depression Inventory ( BDI ) score less than 11 at 16 weeks after diagnosis . RESULTS In comparison with the control group , in the group of GPs receiving tailored implementation , there were increases in the proportions of patients assessed for suicide risk . In the intervention group , the proportion of patients with BDI scores of less than 11 at 16 weeks increased . CONCLUSION Obstacles to implementation can be identified and strategies tailored to address them . The findings indicate a new approach for research to underst and and develop methods of implementation AIM To develop a feasible/theoretically based training programme in patient-centred consulting , for evaluation in a r and omised controlled trial of diabetes care from diagnosis . METHODS The programme was developed with four primary care teams and their patients in an action research framework , with observation of diabetes review consultations before and after training , and evaluated by question naire after each training session , among 23 general practitioners and 32 practice nurses from 21 practice s in the trial . RESULTS The observation study identified opportunities and obstacles to introducing a patient-centred approach into daily practice , especially in relation to time management and skill needs . The modified training programme was rated highly by participating general practitioners and nurses . CONCLUSIONS Developing training programmes with the help of participating primary care teams ensures relevance and feasibility . Patient-centred consulting dem and s a shift from habitual consulting patterns . Practitioners are implementing the approach in practice , and the impact on patients is now under evaluation in the r and omised controlled trial Study Design . This study used a prospect i ve cohort design . Objective To examine factors associated with favorable self-reported patient outcomes 1 year after elective surgery for degenerative back problems . Summary of Background Data . Many previous studies addressing the results of low back surgery have been conducted in academic institutions or by single surgeons . As part of a quality improvement effort , surgeons in private practice led a community-based outcomes management project in Washington State . Methods . Patients ages 18 and older with the following diagnoses were eligible for the study : degenerative changes , herniated disc , instability , and spinal stenosis . Nine orthopedists and neurosurgeons enrolled a total of 281 patients . Participants were asked to complete baseline and 1-year follow-up surveys . Data concerning diagnoses , clinical signs , and operative procedures were provided by the surgeons . The research ers examined sociodemographic characteristics , self-reported symptoms before surgery , preoperative clinical signs , diagnoses , and operative procedures associated with three primary outcomes : better functioning , improved quality of life , and overall treatment satisfaction . Results . Follow-up surveys were completed by 236 ( 84 % ) of the enrolled patients . Approximately two thirds of the study participants reported much better functioning ( 65 % ) , a great quality of life improvement ( 64 % ) , and a very positive perspective about their treatment outcome ( 68 % ) . The following variables were associated with worse patient outcomes : older age , previous low back surgery , workers ’ compensation coverage , and consultation with an attorney before surgery . Patients undergoing a fusion procedure were more likely to report good outcomes . Conclusions . The authors ’ experience indicates that community-based outcomes data collection efforts are feasible and can be incorporated into usual clinical practice . The study results indicate that compensation payments and litigation are two important predictors of poor outcomes after low back surgery in community practice .Because of small numbers , varied diagnoses , and possible selection bias , the findings with respect to fusion should be interpreted cautiously Background : Following surgery for rectal cancer , two unfortunate outcomes for patients are permanent colostomy and local recurrence of cancer . We tested whether a quality -improvement strategy to change surgical practice would improve these outcomes . Methods : Sixteen hospitals were cluster-r and omized to the intervention ( Quality Initiative in Rectal Cancer strategy ) or control ( normal practice ) arm . Consecutive patients with primary rectal cancer were accrued from May 2002 to December 2004 . Surgeons at hospitals in the intervention arm could voluntarily participate by attending workshops , using opinion leaders , inviting a study team surgeon to demonstrate optimal techniques of total mesorectal excision , completing postoperative question naires , and receiving audits and feedback . Main outcome measures were hospital rates of permanent colostomy and local recurrence of cancer . Results : A total of 56 surgeons ( n = 558 patients ) participated in the intervention arm and 49 surgeons ( n = 457 patients ) in the control arm . The median follow-up of patients was 3.6 years . In the intervention arm , 70 % of surgeons participated in workshops , 70 % in intraoperative demonstrations and 71 % in postoperative question naires . Surgeons who had an intraoperative demonstration provided care to 86 % of the patients in the intervention arm . The rates of permanent colostomy were 39 % in the intervention arm and 41 % in the control arm ( odds ratio [ OR ] 0.97 , 95 % confidence interval [ CI ] 0.63–1.48 ) . The rates of local recurrence were 7 % in the intervention arm and 6 % in the control arm ( OR 1.06 , 95 % CI 0.68–1.64 ) . Interpretation : Despite good participation by surgeons , the re source -intense quality -improvement strategy did not reduce hospital rates of permanent colostomy or local recurrence compared with usual practice . ( Clinical Trials.gov trial register no. NCT00182130 . BACKGROUND Interventions to promote prescribing of preventive therapies in patients with cardiovascular disease ( CVD ) or diabetes have reported variable success . OBJECTIVE ( i ) To evaluate the effect of prescribing feedback on GP practice using academic detailing compared to postal bulletin on prescribing of CVD preventive therapies in patients with CVD or diabetes at 3 and 6 months post intervention and ( ii ) to evaluate the intervention from a GP 's perspective . METHODS Volunteer GP practice s ( n = 98 ) were r and omized to receive individualized prescribing feedback via academic detailing ( postal bulletin plus outreach visit ) ( n = 48 ) or postal bulletin ( n = 50 ) . The proportion of CVD or diabetic patients on statins and antiplatelet agents/warfarin pre- and post-intervention was calculated for each GP practice . Multivariate regression with a r and om effects model was used to compare differences between the groups adjusting for GP clustering and confounding factors . beta-Coefficients and 95 % confidence intervals ( CIs ) are presented . RESULTS There was a 3 % increase in statin prescribing in CVD patients at 6 months post-intervention for both r and omized groups , but there was no statistical difference between the groups ( beta = 0.004 ; 95 % CI = -0.01 to 0.02 ) . Statin and antiplatelet/warfarin prescribing also increased in the diabetic population ; there was no significant differences between the groups . GPs participating in the project expressed a high level of satisfaction with both interventions . CONCLUSION Prescribing of preventive therapies increased in both r and omized groups over the study period . But academic detailing did not have an additional effect on changing prescribing over the postal bulletin alone An accurate algorithm for screening for chlamydial infections is available in general practice , but GPs experience numerous barriers to sexually transmitted infections ( STI ) counselling . In this study we assessed if a short educational package , under the form of a commented video footage on communication skills , was helpful in implementing the screening strategy . A cluster r and omised controlled trial was carried out in 36 general practitioners in Antwerp , Belgium . Main outcome measures were : number of patients included in the risk assessment , number of patients tested , and proportion of appropriately tested patients . The results show that GPs in the intervention group did not include more patients overall , but that the quality of the screening process was significantly better ( 81.6 % versus 56.2 % appropriate tests , P = 0.02 ) . Conclusively , GPs who participated in a short educational package on communication skills , selected eligible c and i date s for screening more accurately and decreased the risk of overscreening BACKGROUND A dissemination intervention to facilitate adoption of a preventive practice guideline ( influenza vaccination for older adults ) in group practice s was developed and evaluated . The intervention , small-group consensus process , started with a physician expert presenting the guideline and followed with the group participating in a structured discussion of ways to implement the guideline that culminated in a public commitment ( ie , " buy in " ) to adopt the guideline . METHODS Thirteen group practice s and their primary care physicians ( mean size , 5 ) were assigned r and omly to intervention or control arms . In each group practice , physicians in the intervention arm met for 1 hour . Control physicians participated in an unrelated discussion ( non-steroidal drug use ) . Guideline adoption was determined by changes in physicians ' vaccination rates that were obtained through prechart and postchart review s of 51 physicians . Pre question naires and post question naires measured influenza knowledge and prevention attitudes . RESULTS Using analysis of covariance , the small-group consensus process was found to increase physician vaccination rates by 34 % compared with the control arm ( F ( 1,48 ) = 19.49 ) . All intervention arm physicians increased vaccination rates from before to after compared with 54 % of control arm physicians . Attitudes and knowledge did not change and were unrelated to increased vaccination rates . CONCLUSIONS A case is made for the small-group consensus process as an effective utilization-focused dissemination method . Interventions based on group dynamics and sensitive to local practice context s can be useful in facilitating adoption of guidelines by physicians in group practice CONTEXT The effectiveness of recruiting local medical opinion leaders to improve quality of care is poorly understood . OBJECTIVE To evaluate a guideline -implementation intervention of clinician education by local opinion leaders and performance feedback to ( 1 ) increase use of lifesaving drugs ( aspirin and thrombolytics in eligible elderly patients , beta-blockers in all eligible patients ) for acute myocardial infa rct ion ( AMI ) , and ( 2 ) decrease use of a potentially harmful therapy ( prophylactic lidocaine ) . DESIGN R and omized controlled trial with hospital as the unit of r and omization , intervention , and analysis . SETTING Thirty-seven community hospitals in Minnesota . PATIENTS All patients with AMI admitted to study hospitals over 10 months before ( 1992 - 1993 , N=2409 ) or after ( 1995 - 1996 , N=2938 ) the intervention . INTERVENTION Using a vali date d survey , we identified opinion leaders at 20 experimental hospitals who influenced peers through small and large group discussion s , informal consultations , and revisions of protocol s and clinical pathways . They focused on ( 1 ) evidence ( drug efficacy ) , ( 2 ) comparative performance , and ( 3 ) barriers to change . Control hospitals received mailed performance feedback . MAIN OUTCOME MEASURES Hospital-specific changes before and after the intervention in the proportion of eligible patients receiving each study drug . RESULTS Among experimental hospitals , the median change in the proportion of eligible elderly patients receiving aspirin was + 0.13 ( 17 % increase from 0.77 at baseline ) , compared with a change of -0.03 at control hospitals ( P=.04 ) . For beta-blockers , the respective changes were + 0.31 ( 63 % increase from 0.49 at baseline ) vs + 0.18 ( 30 % increase from baseline ) for controls ( P=.02 ) . Lidocaine use declined by about 50 % in both groups . The intervention did not increase thrombolysis in the elderly ( from 0.73 at baseline ) , but nearly two thirds of eligible nonrecipients were older than 85 years , had severe comorbidities , or presented after at least 6 hours . CONCLUSIONS Working with opinion leaders and providing performance feedback can accelerate adoption of some beneficial AMI therapies ( eg , aspirin , beta-blockers ) . Secular changes in knowledge and hospital protocol s may extinguish out date d practice s ( eg , prophylactic lidocaine ) . However , it is more difficult to increase use of effective but riskier treatments ( eg , thrombolysis ) for frail elderly patients BACKGROUND Only 31 % of Americans with hypertension have their blood pressure ( BP ) under effective control . We describe a study that tests 3 different interventions in a r and omized controlled trial using home BP telemedicine monitoring . METHODS A sample of hypertensive patients with poor BP control at baseline ( N = 600 ) are r and omized to 1 of 4 arms : ( 1 ) control group -- a group of hypertensive patients who receive usual care ; ( 2 ) nurse-administered tailored behavioral intervention ; ( 3 ) nurse-administered medication management according to a hypertension decision support system ; ( 4 ) combination of the 2 interventions . The interventions are triggered based on home BP values transmitted via telemonitoring devices over st and ard telephone lines . The tailored behavioral intervention involves promoting adherence with medication and health behaviors . Patients r and omized to the medication management or the combined arm have their hypertension regimen changed by the study team using a vali date d hypertension decision support system based on evidence -based hypertension treatment guidelines and individualized to patients ' comorbid illnesses . The primary outcome is BP control : < or = 140/90 mm Hg ( nondiabetic ) and < or = 130/80 mm Hg ( diabetics ) measured at 6-month intervals over 18 months ( 4 total measurements ) . CONCLUSIONS Given the increasing prevalence of hypertension and our inability to achieve adequate BP control using traditional models of care , testing novel interventions in patients ' homes may improve access , quality , and outcomes Background : The relationship between patient adherence and treatment outcomes has been documented across chronic health conditions , but the evidence base for effective adherence interventions in human immunodeficiency virus ( HIV ) and acquired immune deficiency syndrome ( AIDS ) requires more rigorous research and reporting . Objectives : The aims of this study were to determine whether a tailored , nurse-delivered adherence intervention program-Client Adherence Profiling and Intervention Tailoring (CAP-IT)-improved adherence to HIV medications , compared with st and ard care , and to identify the relationship among adherence measures . Methods : A r and omized controlled trial ( RCT ) with repeated measures was used to test the efficacy of CAP-IT over a 6-month period . A convenience sample of 240 participants was recruited from a freest and ing public HIV/AIDS clinic in Houston , TX , that provides medical , psychological , and pharmaceutical services for over 5,000 clients . Study instruments and measures included demographics ; chart audit to capture CD4 count , viral load , and prescribed medications ; health literacy ; and five measures of adherence ( AIDS Clinical Trial Group-Revised Reasons for Missing Medications , Morisky Self-Report of Medication Non-Adherence , Pill Count , Medication Event Monitoring System [ MEMS ] caps , and Pharmacy Refill ) . Results : A logistic regression using generalized estimating equations method showed no significant differences over time on the five medication-adherence measures between the experimental and control groups . Little correlation was documented among the five different adherence measures , and there was minimal correlation with clinical markers . Discussion : It is unclear why the tailored adherence intervention was not efficacious in improving medication adherence . The findings suggest that these measures of medication adherence did not perform as expected and that , perhaps , they are not adequate measures of adherence . Effective and efficient adherence interventions are needed to address the barriers to medication adherence in HIV/AIDS CONTEXT Data on the adverse effects of newly marketed drugs are limited . Voluntary reporting is an important part of postmarketing surveillance but is underused by physicians . OBJECTIVE To evaluate the effectiveness of educational outreach visits for improving adverse drug reaction ( ADR ) reporting by physicians . DESIGN , SETTING , AND PARTICIPANTS A cluster-r and omized controlled trial covering all National Health System physicians in the north of Portugal , with intervention in March 2004 through July 2004 , and 13 to 16 months of follow-up . A total of 1388 physicians were assigned in 4 spatial clusters to the intervention group , and 5063 were assigned in 11 clusters to the control group . INTERVENTION One-hour educational outreach visits tailored to training needs identified in a previous study . MAIN OUTCOME MEASURES Change in total number of reported ADRs and number of serious , high-causality , unexpected , and new-drug-related ADRs , using generalized linear mixed models adjusted for baseline ADR reporting , age , specialty , and work setting . RESULTS At baseline , ADR reporting rates ( per 1000 physician-years ) did not differ significantly between the intervention groups and the control groups in reporting ADRs overall ( 7.6 vs 11.3 ) , nor did they differ significantly by category : serious , 4.3 vs 6.0 ; high-causality , 5.4 vs 7.6 ; unexpected , 1.6 vs 3.5 ; and new-drug-related ADRs , 3.7 vs 3.8 . ( P>.05 for all comparisons ) . The control group had no significant increase in ADR reports during follow-up . The adjusted increase in ADR reporting rates attributable to intervention was 90.19 for total ADRs ( 95 % confidence interval [ CI ] , 54.51 - 125.87 ; relative risk [ RR ] , 10.23 ; 95 % CI , 3.81 - 27.51 ) , 30.16 for serious ADRs ( 95 % CI , 18.84 - 41.47 ; RR , 6.32 ; 95 % CI , 2.09 - 19.16 ) , 64.90 for high-causality ADRs ( 95 % CI , 38.38 - 91.42 ; RR , 8.75 ; 95 % CI , 3.05 - 25.07 ) , 28.04 for unexpected ADRs ( 95 % CI , 16.25 - 39.83 ; RR , 30.21 ; 95 % CI , 4.54 - 200.84 ) , and 42.17 for new-drug-related ADRs ( 95 % CI , 21.58 - 62.76 ; RR , 8.05 ; 95 % CI , 2.10 -30.83 ) . The greatest difference occurred during the first 4 months after intervention , but differences remained statistically significant for 12 months . CONCLUSION A targeted outreach program may improve high- quality reporting of ADRs among physicians Objective : To evaluate the effectiveness of a tailored and multifaceted approach to the implementation of nationally recommended and evidence -based guidelines in primary care within existing systems and re sources . Methods : A non-r and omised Latin square to compare guideline implementation in two neighbouring health districts covering 180 general practice s. Evidence -based guidelines for the treatment of patients with asthma and angina were implemented actively in one district and passively disseminated in the other district . Outcome measures for asthma were smoking status and inhaler technique . For angina the outcome measures were : smoking status ; blood pressure ; aspirin prescribed , contraindicated or self-medicated ; beta-blocker prescribed or contraindicated ; routine hospital admission ; prescribed drugs ; self-reported change . Results : There were improvements in all outcome criteria between baseline and follow-up audits , regardless of whether the guideline was actively implemented or passively disseminated . The estimated increase in the proportion of records complying with guidelines was 4 % [ 95 % confidence intervals ( CI ) : 0 , 8 ] and was higher in intervention than in control practice s. Using only records not compliant at baseline , the corresponding difference was 15 % ( 95 % CI : 7 , 24 ) . The only significant improvement associated with active implementation was smoking status in angina patients . Both prescribing and hospital admission monthly totals changed during the period of the trial , but there was no significant difference between the pattern of changes in intervention and control districts . A significantly greater proportion of health professionals saw the intervention guideline compared with the control ( 75 % versus 25 % ) . There was a significant correlation between self-reported change and interventions steps ( P < 0.05 ) . Conclusions : Increases in quality markers occurred irrespective of the multifaceted implementation efforts . Some of this increase was due to the method of data collection . Nevertheless , national initiatives may have more influence than local implementation initiatives OBJECTIVE To determine if written feedback improves the chart documentation and knowledge of physicians doing evaluations for child sexual abuse and to learn what other factors are associated with better documentation and knowledge . DESIGN R and omized , controlled trial . SETTING A statewide network of physicians performing child abuse evaluations . PARTICIPANTS All physicians who performed evaluations for sexual abuse during 1991 to 1992 . One hundred forty-seven physicians were r and omized to control ( n = 75 ) and intervention ( n = 72 ) groups , 122 ( 83 % ) remained at follow-up , and 87 of the 122 ( 71 % ) had done evaluations for child sexual abuse . INTERVENTIONS Tailored written feedback based on chart review s and relevant articles were sent to a r and omly selected one-half of the physicians during a 3-month period . MAIN OUTCOME MEASURES The quality of documentation and physician knowledge before and after the intervention . RESULTS Documentation by chart review of up to five r and omly chosen records per physician ( preintervention , n = 552 ; postintervention , n = 259 ) by review ers blinded to intervention status and physician knowledge was assessed by survey ( 78 % completion ) . Change in documentation and knowledge for physicians in the intervention group was not statistically significant compared with the control group . The risk ratio for a mean overall history rating of excellent/good was 0.89 ( 0.63 , 1.25 ) and for a mean overall physical examination rating of excellent/good was 1.03 ( 0.73 , 1.45 ) . Both groups improved significantly during the time period . The largest improvements in the time period were in documenting the history of where abuse occurred , in the physical examination position , hymenal description , penile findings , and knowing that chlamydia infection should be assessed by culture . A structured medical record , female physicians , and credits in continuing medical education were associated with better documentation . CONCLUSIONS Tailored feedback to the physician with directed educational material s did not seem to improve most aspects of documentation and knowledge of child sexual abuse , although notable improvement was seen during the time period studied . This study suggests that chart audits may not be the best use of re sources for trying to improve physician behavior ; credits in continuing medical education and use of structured records may be more likely to be beneficial Objective To evaluate the effectiveness and efficiency of a tailored multifaceted strategy , delivered by a national clinical effectiveness programme , to implement a guideline on induced abortion OBJECTIVE To determine the effectiveness of specialist nurse delivered education in primary care to improve control of hypertension and hyperlipidaemia in patients with diabetes . DESIGN AND SETTING Practice -level r and omized controlled trial , Salford , Engl and . SUBJECTS From 44 practice s , 10 303 subjects presenting in general practice with raised blood pressure (= 140/80 mmHg ) , raised total cholesterol (= 5.0 mmol/l ) or both . INTERVENTIONS Practice s were r and omized to receive either the intervention for hyperlipidaemia or for hypertension ; practice s acted as control for the intervention not received . Specialist nurses arranged a schedule of visits with general practitioners and general practice nurses , reminding them of diabetes protocol s and clinical targets . They provided educational material s and protocol s used in secondary care for nurse and doctor interventions including stepping up pharmacotherapy when necessary . Practice s received a list of patients in their practice who were poorly controlled at their last annual review ; new and recalled patients were targeted . OUTCOME MEASURES At subsequent annual review , blood pressure and total cholesterol values were obtained from the Salford electronic diabetes register for patients from participating practice s. RESULTS Overall , specialist nurse-led educational outreach to primary care was associated with no improvement in patients achieving target after 1 year-odds ratio ( OR ) : 1.03 ( 95 % CI 0.95 - 1.11 ; P = 0.52 ) . Similar results were achieved with hyperlipidaemia OR : 1.04 ( 95 % CI 0.88 - 1.23 ; P = 0.62 ) and hypertension OR : 1.01 ( 95 % CI 0.80 - 1.27 ; P = 0.93 ) . CONCLUSION This study provides evidence that the use of specialist nurses to perform educational outreach to improve target adherence to patients with diabetes in primary care is not effective We describe the design of the Managing Anti-coagulation Services Trial ( MAST ) , a practice -improvement trial testing whether anticoagulation services are a preferred method of managing anticoagulation for stroke prevention among patients with atrial fibrillation . Most r and omized trials within the health care environment are design ed as efficacy studies to determine what works under ideal conditions or ideal clinical practice . In contrast , effectiveness trials seek to generalize the results of efficacy studies by determining what works under more typical practice conditions . Practice -improvement trials are effectiveness trials that examine the management of a clinical problem in the context in which care is usually given . Noteworthy features of the MAST include defining the intervention in functional terms and collaboration with managed care organizations BACKGROUND Urinary tract infection is the most frequent health care-associated complication . We hypothesized that the implementation of a multifaceted prevention strategy could decrease its incidence after surgery . METHODS In a controlled , prospect i ve , before-after intervention trial with 1328 adult patients scheduled for orthopedic or abdominal surgery , nosocomial infection surveillance was conducted until hospital discharge . A multifaceted intervention including specifically tailored , locally developed guidelines for the prevention of urinary tract infection was implemented for orthopedic surgery patients , and abdominal surgery patients served as control subjects . Infectious and noninfectious complications , adherence to guidelines , and antibiotic use were monitored before and after the intervention and again 2 years later . RESULTS The incidence of urinary tract infection decreased from 10.4 to 3.9 episodes per 100 patients in the intervention group ( incidence-density ratio , 0.41 ; 95 % CI , 0.20 - 0.79 ; P=.004 ) . Adherence to guidelines was 82.2 % . Both the frequency and the duration of urinary catheterization decreased following the intervention . Recourse to antibiotic therapy after surgery dropped in the intervention group from 17.9 to 15.6 defined daily doses per 100 patient-days ( P<.005 ) because of a reduced need for the treatment of urinary tract infection ( P<.001 ) . Follow-up after 2 years revealed a sustained impact of the strategy and a subsequent low use of antibiotics , consistent with stable adherence to guidelines ( 80.8 % ) . CONCLUSIONS A multifaceted prevention strategy can dramatically decrease postoperative urinary tract infection and contribute to the reduction of the overall use of antibiotics after surgery OBJECTIVE Facilitate primary care physicians ' compliance with recommended st and ards of care for late life depression by reducing barriers to recognition and treatment . DESIGN R and omized controlled clinical trial of physician-targeted interventions . SETTING Academic primary care group practice caring for an urban , medically indigent patient population . PATIENTS / PARTICIPANTS Patients aged 60 and older who exceeded the threshold on the Centers for Epidemiologic Studies Depression Scale ( CES-D ) and the Hamilton Depression Rating Scale ( HAM-D ) and their primary care physicians . INTERVENTION Physicians of intervention patients were provided with patient-specific treatment recommendations during 3 special visits scheduled specifically to address the patient 's symptoms of depression . In general , physicians were encouraged to establish a diagnosis of depression and educate their patient about the diagnosis , discontinue medications that can cause or exacerbate depressive symptoms , initiate antidepressants when appropriate , and consider referral to psychiatry . Guidelines for prescribing antidepressants were provided . Control physicians received no intervention , and control patients received usual care . MAIN OUTCOME MEASURES Frequency of recording a depression diagnosis , stopping medications associated with depression , initiating antidepressant medication , and psychiatry referral ; mean changes in HAM-D and Sickness Impact Profile ( SIP ) scores . RESULTS One hundred three physicians and 175 patients were involved in the clinical trial . Physicians of intervention patients were more likely to diagnose depression and prescribe antidepressants ( P < 0.01 ) . There were no differences between the groups in the frequency of stopping medications associated with depression or referrals to psychiatry . Medications with the strongest cause and effect relationship to depression were infrequently used in this cohort of patients . Although both groups showed improvement in HAM-D and SIP scores , we were unable to demonstrate significant differences in HAM-D or SIP scores between the 2 groups . CONCLUSIONS Intensive screening and feedback of patient-specific treatment recommendations increased the recognition and treatment of late life depression by primary care physicians . However , we were unable to demonstrate significant improvement in depression or disability severity among intervention patients despite the informational support provided to their physicians . Efforts to improve the functional status of these patients may require more integrated interventions and more aggressive attempts to target psychosocial stressors traditionally outside the purview of primary care BACKGROUND Although guidelines for the management of low back pain have been published in the past decade , there is potential for further improvement in back pain care . AIM To document the management of non-specific low back pain by general practitioners ( GPs ) in the Netherl and s , to determine how this management of care is related to patient and physician factors , and to explore possible reasons for not adhering to the guidelines . METHOD A prospect i ve study was set up in which 57 GPs in 30 general practice s completed a computerised question naire after each consultation for low back pain during a four-month period . RESULTS Of 1640 back pain contacts , 1180 referred to non-specific low back pain . Diagnostic tests were ordered in 2 % of first consultations and in 7 % of follow-up consultations within one episode . The advice to stay active despite pain was given in 76 % and 69 % of these cases respectively . Patients were prescribed an analgesic in 53 % and 41 % of cases respectively ( mainly NSAIDs [ 80 % ] ) . Patients were referred to a physiotherapist in 22 % of first and in 50 % of follow-up consultations . Older patients were physically examined less often , prescribed analgesics more often , and were told less often that staying active could benefit them . The advice to remain active was omitted more often when symptoms lasted longer . Only a small part of the variance in management was accounted for by patient characteristics or by differences between practice s. CONCLUSION The management of low back pain met the guidelines to a large extent . Management decisions were often related to characteristics in which the guidelines lack differentiation . Important reasons for non-adherence were perceived patients ' preferences . Further implementation of guidelines will be difficult unless doctors ' and patients ' views are more explicitly known OBJECTIVE This study describes physicians ' satisfaction with care for patients with depression before and after the implementation of a primary care-based collaborative care program . METHOD Project Improving Mood , Promoting Access to Collaborative Treatment for late-life depression ( IMPACT ) is a multisite , r and omized controlled trial comparing a primary care-based collaborative disease management program for late-life depression with care as usual . A total of 450 primary care physicians at 18 participating clinics participated in a satisfaction survey before and 12 months after IMPACT initiation . The preintervention survey focused on physicians ' satisfaction with current mental health re sources and ability to provide depression care . The postintervention survey repeated these and added questions about physician 's experience with the IMPACT collaborative care model . RESULTS Before intervention , about half ( 54 % ) of the participating physicians were satisfied with re sources to treat patients with depression . After intervention , more than 90 % reported the intervention as helpful in treating patients with depression and 82 % felt that the intervention improved patients ' clinical outcomes . Participating physicians identified proactive patient follow-up and patient education as the most helpful components of the IMPACT model . CONCLUSIONS Physicians perceived a substantial need for improving depression treatment in primary care . They were very satisfied with the IMPACT collaborative care model for treating depressed older adults and felt that similar care management models would also be helpful for treating other chronic medical illnesses Objectives .The objective of the study was to evaluate the effectiveness of 2 educational strategies aim ed at improving prescribing st and ards in primary care . Methods .A pragmatic controlled trial was design ed ; the study population included general and family practitioners in Galicia ( northwestern Spain ) divided into 3 study groups : a one-to-one education group ( n = 98 ) , a by-group education group ( n = 92 ) , and a control group ( n = 405 ) . The educational intervention included explicit recommendations for selecting nonsteroidal anti-inflammatory drugs ( NSAIDs ) for inflammation signs . Some of the subjects were given reminders . Mixed-effect linear models were applied to data analysis . Analyses were done by intention-to-treat . The dependent variable is a rate with a numerator that is the number of prescribed units of the NSAIDs recommended during intervention ; the denominator is the total number of prescribed units of the NSAID total . Results .One-to-one education obtained an average prescribing behavior improvement of 6.5 % ( P < 0.001 ) in the 9 months after intervention . In the education group , the average improvement was 2.4 % ( P < 0.05 ) for the same period . Statistically significant differences were observed between the group intervention and one-to-one groups . The reminder increased significantly the effectiveness of the one-to-one intervention . Conclusions .A single , short educational session to primary care doctors can improve their prescribing st and ards during long periods of ≥9 months . Of the 2 strategies followed in the trial , one-to-one education has shown to be the most effective . Results also show that the effectiveness of these interventions increases when presented together with written material This study tests whether an outreach educational program tailored to institutional specific patient care practice s would improve the quality of care delivered to mechanically ventilated intensive care unit ( ICU ) patients in rural hospitals . The study was conducted as a r and omized control trial using 20 rural Iowa hospitals as the unit of analysis . Twelve r and omly selected hospitals received an outreach educational program . After review of the medical records of eligible patients , a multidisciplinary team of intensive care unit specialists from an academic medical center delivered an educational program with content specific to the findings and capacity of the hospital . The outcome measures included patient care processes , patient morbidity and mortality outcomes , and re source use . Results indicated that the outreach program significantly improved many patient care processes ( lab work , nursing , dietary management , ventilator management , ventilator weaning ) . The program marginally reduced hospital ventilator days . Both total length of stay and ICU length of stay fell markedly in the intervention group ( by an average of 3.2 and 2.1 d , respectively ) , while the control group fell only 0.6 and 0.3 d , respectively . However , these effects did not reach statistical significance . Unfortunately , the program had no detectable effects on the clinical outcomes of mortality or nosocomial events . We conclude that an outreach program of this type can effectively improve processes of care in rural ICUs . However , improving processes of care may not always translate into improvement of specific outcomes OBJECTIVE To determine the effectiveness of different types of interventions in improving health professional performance and health outcomes . DATA SOURCES MEDLINE , SCI SEARCH , CINAHL and the Research and Development Re source Base in CME were search ed for trials of educational interventions in the health care professions published between 1970 and 1993 inclusive . STUDY SELECTION Studies were selected if they provided objective measurements of health professional performance or health outcomes and employed r and om or quasi-r and om allocation methods in their study design s to assign individual subjects or groups . Interventions included such activities as conferences , outreach visits , the use of local opinion leaders , audit and feedback , and reminder systems . DATA EXTRACTION Details extracted from the studies included the study design ; the unit of allocation ( e.g. , patient , provider , practice , hospital ) ; the characteristics of the targeted health care professionals , educational interventions and patients ( when appropriate ) ; and the main outcome measure . DATA SYNTHESIS The inclusion criteria were met by 102 trials . Areas of behaviour change included general patient management , preventive services , prescribing practice s , treatment of specific conditions such as hypertension or diabetes , and diagnostic service or hospital utilization . Dissemination-only strategies , such as conferences or the mailing of unsolicited material s , demonstrated little or no changes in health professional behaviour or health outcome when used alone . More complex interventions , such as the use of outreach visits or local opinion leaders , ranged from ineffective to highly effective but were most often moderately effective ( result ing in reductions of 20 % to 50 % in the incidence of inappropriate performance ) . CONCLUSION There are no " magic bullets " for improving the quality of health care , but there are a wide range of interventions available that , if used appropriately , could lead to important improvements in professional practice and patient outcomes OBJECTIVE Recent studies have shown that lack of continuing primary care for asthma is associated with increased levels of morbidity in low-income minority children . Although effective preventive therapy is available , many African-American and Latino children receive episodic treatment for asthma that does not follow current guidelines for care . To see if access , continuity , and quality of care could be improved in pediatric clinics serving low-income children in New York City , we trained staff in New York City Bureau of Child Health clinics to provide continuing , preventive care for asthma . METHODS We evaluated the impact of the intervention over a 2-year period in a controlled study of 22 clinics . Training for intervention clinic staff was based on National Asthma Education and Prevention Program guidelines for the diagnosis and management of asthma , and included screening to identify new cases and health education to improve family management . The intervention included strong administrative support by the Bureau of Child Health to promote staff behavior change . We hypothesized that after the intervention , clinics that received the intervention would , compared with control clinics , have increased numbers of children with asthma receiving continuing care in the clinics and increased staff use of new pharmacologic and educational treatment methods . RESULTS In both the first and second follow-up years , the intervention clinics had greater positive changes than control clinics on measures of access , continuity , and quality of care . For second year follow-up data these include : for access , greater rate of new asthma patients ( 40/1000 vs 16/1000 ; P < .01 ) ; for continuity , greater percentage of asthma patients returning for treatment 2 years in a row ( 42 % vs 12 % ; P < .001 ) and greater annual frequency of scheduled visits for asthma per patient ( 1.85 vs .88 ; P < .001 ) ; and for quality , greater percentage of patients receiving inhaled beta agonists ( 52 % vs 15 % ; P < .001 ) and inhaled antiinflammatory drugs ( 25 % vs 2 % ; P < .001 ) , and greater percentages of parents who reported receiving patient education on 12 topics from Bureau of Child Health physicians ( 71 % vs 58 % ; P < .01 ) and nurses ( 61 % vs 44 % ; P < .05 ) . CONCLUSION We conclude that the intervention substantially increased the Bureau of Child Health staff 's ability to identify children with asthma , involve them in continuing care , and provide them with state-of-the-art care for asthma BACKGROUND Effective new strategies that complement primary care are needed to reduce disability risks and improve self-management of chronic illness in frail older people living in the community . OBJECTIVE To evaluate the impact of a 1-year , senior center-based chronic illness self-management and disability prevention program on health , functioning , and healthcare utilization in frail older adults . DESIGN A r and omized controlled trial . SETTING A large senior center located in a northeast Seattle suburb . The trial was conducted in collaboration with primary care providers of two large managed care organizations . PARTICIPANTS A total of 201 chronically ill older adults seniors aged 70 and older recruited through medical practice s. INTERVENTION A targeted , multi-component disability prevention and disease self-management program led by a geriatric nurse practitioner ( GNP ) . MEASUREMENTS Self-reported Physical function , physical performance tests , health care utilization , and health behaviors . RESULTS Each of 101 intervention participants met with the GNP from 1 to 8 times ( median = 3 ) during the study year . The intervention group showed less decline in function , as measured by disability days and lower scores on the Health Assessment Question naire . Other measures of function , including the SF-36 and a battery of physical performance tests , did not change with the intervention . The number of hospitalized participants increased by 69 % among the controls and decreased by 38 % in the intervention group ( P = .083 ) . The total number of inpatient hospital days during the study year was significantly less in the intervention group compared with controls ( total days = 33 vs 116 , P = .049 ) . The intervention led to significantly higher levels of physical activity and senior center participation and significant reductions in the use of psychoactive medications . CONCLUSIONS This project provides evidence that a community-based collaboration with primary care providers can improve function and reduce inpatient utilization in chronically ill older adults . Linking organized medical care with complementary community-based interventions may be a promising direction for research and practice Abstract Objectives : Voluntary adverse drug reaction ( ADR ) reporting is fundamental to medical drug safety surveillance ; however , substantial under-reporting exists and is the main limitation of the system . This study sought to identify the knowledge- and attitude-related factors associated with ADR reporting by physicians in Northern Portugal . Methods : Case-control study covering a population of National Health Service medical practitioners . The 88 cases comprised physicians who had reported at least one ADR to the drug surveillance unit from the year 2000 to the date of enrolment in the study . The 771 controls were r and omly selected from among the remaining physicians . All interviews were conducted using a self-administered question naire . Knowledge and attitudes regarding spontaneous ADR reporting were based on Inman ’s ‘ seven deadly sins ’ . Agreement with the questions included in the question naire was measured using a horizontal , continuous visual analogue scale , which was unnumbered . Recorded answers were read in a range from zero ( total disagreement ) to ten ( total agreement ) . We used logistic regression to determine the ADR reporting adjusted odds ratio ( ORadj ) for a change in exposure corresponding to the interquartile range for each attitude . Results : A total of 397 question naires were received from 731 eligible practitioners ( 54.3 % ) . Physicians who worked in primary versus hospital care ( ORadj 7.74 [ 95 % CI 1.85 , 32.30 ] ) and in general medicine ( ORadj 1.05 [ 95 % CI 0.30 , 3.69 ] ) versus medical specialities were more likely to report ADRs . In contrast , physicians working in the medical-surgical/surgical fields were significantly less likely to report ADRs compared with medical specialists ( ORadj 0.10 [ 95 % CI 0.02 , 0.46 ] ) . Attitudes to ADRs were strongly associated with reporting probability . Hence , an interquartile decrease in any of the following attitudes increased the probability of reporting by : ( i ) 87 % ( p < 0.05 ) for complacency ( the belief that really serious ADRs are well documented by the time a drug is marketed ) ; ( ii ) 109 % ( p < 0.01 ) for insecurity ( the belief that it is nearly impossible to determine whether a drug is responsible for a particular adverse reaction ) ; ( iii ) 143 % ( p < 0.001 ) for diffidence ( the belief that one would only report an ADR if one were sure that it was related to the use of a particular drug ) ; ( iv ) 220 % ( p < 0.001 ) for indifference ( the belief that the one case an individual doctor might see could not contribute to medical knowledge ) ; and ( v ) 71 % ( p < 0.05 ) for ignorance ( the belief that it is only necessary to report serious or unexpected ADRs ) . Conclusion : This study shows that there are attitudes strongly associated with under-reporting . The implementation of purpose - design ed educational interventions based on the attitudes identified in this study may serve to improve reporting substantially Background The effectiveness of dementia-care mapping ( DCM ) for institutionalised people with dementia has been demonstrated in an explanatory cluster-r and omised controlled trial ( c RCT ) with two DCM research ers carrying out the DCM intervention . In order to be able to inform daily practice , we studied DCM effectiveness in a pragmatic c RCT involving a wide range of care homes with trained nursing staff carrying out the intervention . Methods Dementia special care units were r and omly assigned to DCM or usual care . Nurses from the intervention care homes received DCM training and conducted the 4-months DCM-intervention twice during the study . The primary outcome was agitation , measured with the Cohen-Mansfield agitation inventory ( CMAI ) . The secondary outcomes included residents ’ neuropsychiatric symptoms ( NPSs ) and quality of life , and staff stress and job satisfaction . The nursing staff made all measurements at baseline and two follow-ups at 4-month intervals . We used linear mixed-effect models to test treatment and time effects . Results 34 units from 11 care homes , including 434 residents and 382 nursing staff members , were r and omly assigned . Ten nurses from the intervention units completed the basic and advanced DCM training . Intention-to-treat analysis showed no statistically significant effect on the CMAI ( mean difference between groups 2·4 , 95 % CI −2·7 to 7·6 ; p = 0·34 ) . More NPSs were reported in the intervention group than in usual care ( p = 0·02 ) . Intervention staff reported fewer negative and more positive emotional reactions during work ( p = 0·02 ) . There were no other significant effects . Conclusions Our pragmatic findings did not confirm the effect on the primary outcome of agitation in the explanatory study . Perhaps the variability of the extent of implementation of DCM may explain the lack of effect . Trial Registration Dutch Trials Registry NTR2314 BACKGROUND Patient care guidelines are usually implemented one at a time , yet patients are at risk for multiple , often preventable , adverse events simultaneously . OBJECTIVE This study aim ed to test the effect of the SAFE or SORRY ? programme on the incidence of three adverse events ( pressure ulcers , urinary tract infections and falls ) . This paper describes Part I of the study : the effect on the incidence of adverse events . DESIGN A cluster r and omised trial was conducted between September 2006 and November 2008 . After a three-month baseline period the intervention was implemented followed by a nine-month follow-up period . SETTING S Ten wards from four hospitals and ten wards from six nursing homes were stratified for institute and ward type and then r and omised to intervention or usual care group . PARTICIPANTS During baseline and follow-up , patients ( ≥18 years ) with an expected length of stay of at least five days , were asked to participate . METHODS The SAFE or SORRY ? programme consisted of the essential recommendations of guidelines for the three adverse events . A multifaceted implementation strategy was used for the implementation : education , patient involvement and feedback on process and outcome indicators . The usual care group continued care as usual . Data were collected on the incidence of adverse events and a Poisson regression model was used to estimate the rate ratio of the adverse events between the intervention and the usual care group at follow-up . RESULTS At follow-up , 2201 hospital patients with 3358 patient weeks and 392 nursing home patients with 5799 patient weeks were observed . Poisson regression analyses showed a rate ratio for the development of an adverse event in favour of the intervention group of 0.57 ( 95 % CI : 0.34 - 0.95 ) and 0.67 ( 95 % CI : 0.48 - 0.99 ) for hospital patients and nursing home patients respectively . CONCLUSION This study showed that implementing multiple guidelines simultaneously is possible , which is promising . Patients in the intervention groups developed 43 % and 33 % fewer adverse events compared to the usual care groups in hospitals and nursing homes respectively . Even so , more research is necessary to underline these results . TRIAL REGISTRATION clinical trials.gov , number NCT00365430 RATIONALE AND AIMS Clinical practice guidelines ( CPG ) reflect the evidence of effective pharmacotherapy of chronic ( systolic ) heart failure ( CHF ) which needs to be implemented . This study aim ed to evaluate the effect of a new , multifaceted intervention ( educational train-the-trainer course plus pharmacotherapy feedback = TTT ) compared with st and ard education on guideline adherence ( GA ) in general practice . METHOD Thirty-seven participating general practitioners ( GPs ) were r and omized ( 18 vs. 19 ) and included 168 patients with ascertained symptomatic CHF [ New York Heart Association ( NYHA ) II-IV ] . Groups received CPG , the TTT intervention consisted of four interactive educational meetings and a pharmacotherapy feedback , while the control group received a usual lecture ( St and ard ) . Outcome measure was GA assessed by prescription rates and target dosing of angiotensin converting enzyme ( ACE ) inhibitors ( ACE-I ) or angiotensin receptor blockers ( ARB ) , beta-blockers ( BB ) and aldosterone antagonists ( AA ) at baseline and 7-month follow-up . Group comparisons at follow-up were adjusted to GA , sex , age and NYHA stage at baseline . RESULTS Prescription rates at baseline ( n = 168 ) were high ( ACE-I/ARB 90 , BB 79 and AA 29 % ) in both groups . At follow up ( n = 146 ) , TTT improved compared with St and ard regarding AA ( 43 % vs. 23 % , P = 0.04 ) and the rates of reached target doses of ACE-I/ARB ( 28 % vs. 15 % , P = 0.04 ) . TTT group achieved significantly higher mean percentages of daily target dose ( 52 % vs. 42 % , mean difference 10.3 % , 95 % CI 0.84 - 19.8 , P = 0.03 ) . CONCLUSION Despite of pre-existing high GA in both groups and an active control group , the multifaceted intervention was effective in quality of care measured by GA . Further research is needed on the choice of interventions in different provider population Although the American Heart Association recommends a prehospital electrocardiogram ( ECG ) be recorded for all patients who access the emergency medical system with symptoms of acute coronary syndrome ( ACS ) , widespread use of prehospital ECG has not been achieved in the United States . A 5-year prospect i ve r and omized clinical trial was conducted in a predominately rural county in northern California to test a simple strategy for acquiring and transmitting prehospital ECGs that involved minimal paramedic training and decision making . A 12-lead ECG was synthesized from 5 electrodes and continuous ST-segment monitoring was performed with ST-event ECGs automatically transmitted to the destination hospital emergency department . Patients r and omized to the experimental group had their ECGs printed out in the emergency department with an audible voice alarm , whereas control patients had an ECG after hospital arrival , as was the st and ard of care in the county . The result was that nearly 3/4 ( 74 % ) of 4,219 patients with symptoms of ACS over the 4-year study enrollment period had a prehospital ECG . Mean time from 911 call to first ECG was 20 minutes in those with a prehospital ECG versus 79 minutes in those without a prehospital ECG ( p < 0.0001 ) . Mean paramedic scene time in patients with a prehospital ECG was just 2 minutes longer than in those without a prehospital ECG ( 95 % confidence interval 1.2 to 3.6 , p < 0.001 ) . Patients with non-ST-elevation myocardial infa rct ion or unstable angina pectoris had a faster time to first intravenous drug and there was a suggested trend for a faster door-to-balloon time and lower risk of mortality in patients with ST-elevation myocardial infa rct ion . In conclusion , increased paramedic use of prehospital ECGs and decreased hospital treatment times for ACS are feasible with a simple approach tailored to characteristics of a local geographic region

RCTs with low risk of bias suggested increased melanoma risk . Results for most outcomes were similar when we included all RCTs in the meta- analysis , regardless of risk of bias . Summary RRs for site-specific cancers showed limited changes compared with estimates from high- quality studies alone , except for liver cancer , for which results were reversed . No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies .Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types , but null and direct relations have also been reported , and no systematic pattern suggesting dose-response relations has emerged . Overall , there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans .

BACKGROUND This review is the third up date of the Cochrane review " Selenium for preventing cancer " . Selenium is a naturally occurring element with both nutritional and toxicological properties . Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer . OBJECTIVES To gather and present evidence needed to address two research questions :1 . What is the aetiological relationship between selenium exposure and cancer risk in humans?2 . Describe the efficacy of selenium supplementation for cancer prevention in humans .

In many observational studies , a higher intake of individual antioxidants is inversely associated with lung cancer risk . Data from in vitro and animal experiments suggest that there are biochemical interactions among antioxidant nutrients ; therefore , consideration of multiple antioxidants simultaneously may be important in terms of risk estimation . The authors constructed a dietary antioxidant index and evaluated its ability to predict lung cancer risk within the Alpha-Tocopherol , Beta-Carotene Cancer Prevention Study cohort . At baseline ( 1985 - 1988 ) , 27,111 Finnish male smokers aged 50 - 69 years completed a dietary question naire that assessed usual frequency of consumption and portion sizes for the previous 12 months . A total of 1,787 incident cases of lung cancer were identified during a follow-up period of up to 14.4 years ( 1985 - 1999 ) . Principal components analyses were individually applied to the carotenoid , flavonoid , and vitamin E nutrient groups , and summation of retained principal component scores , plus selenium and vitamin C , yielded the composite antioxidant index . In multivariate proportional hazards models , the relative risks for lung cancer according to increasing quintiles of the antioxidant index were 1.00 ( referent ) , 1.00 ( 95 % confidence interval ( CI ) : 0.87 , 1.14 ) , 0.91 ( 95 % CI : 0.79 , 1.05 ) , 0.79 ( 95 % CI : 0.68 , 0.92 ) , and 0.84 ( 95 % CI : 0.72 , 0.98 ) ( p for trend = 0.002 ) . These findings support the hypothesis that a combination of dietary antioxidants reduces lung cancer risk in male smokers Oxidative stress may enhance prostatic carcinogenesis . A polymorphism [ valine ( V ) -- > alanine ( A ) ] of manganese superoxide dismutase ( MnSOD ) , the primary antioxidant enzyme in mitochondria , has been recently associated with prostate cancer . We examined the relationship between prostate cancer and the MnSOD polymorphism and its interactions with baseline plasma antioxidant levels ( selenium , lycopene , and alpha-tocopherol ) and beta-carotene treatment among 567 cases and 764 controls nested in the prospect i ve Physicians ' Health Study . We found little overall association between MnSOD polymorphism and prostate cancer risk ; however , this polymorphism significantly modified risk of prostate cancer associated with prediagnostic plasma antioxidants ( P(interaction ) > or = 0.05 ) . Among men with the AA genotype , high selenium level ( 4th versus 1st quartile ) was associated with a relative risk ( RR ) of 0.3 [ 95 % confidence interval ( CI ) , 0.2 - 0.7 ] for total prostate cancer ; for clinical ly aggressive prostate cancer , the RR was 0.2 ( 95 % CI , 0.1 - 0.5 ) . In contrast , among men with the VV/VA genotype , the RRs were 0.6 ( 0.4 - 1.0 ) and 0.7 ( 0.4 - 1.2 ) for total and clinical ly aggressive prostate cancer . These patterns were similar for lycopene and alpha-tocopherol and were particularly strong when these antioxidants and selenium were combined ; men with the AA genotype had a 10-fold gradient in risk for aggressive prostate cancer across quartiles of antioxidant status . Men with AA genotype who were r and omly assigned to beta-carotene treatment ( versus placebo ) had a RR of 0.6 ( 95 % CI , 0.2 - 0.9 ; P(interaction ) = 0.03 ) for fatal prostate cancer , but no significant association was observed in men with the VV/VA genotype . Both endogenous and exogenous antioxidants play an important and interdependent role in preventing clinical ly significant prostate cancer BACKGROUND Multivitamin supplements are used by millions of Americans because of their potential health benefits , but the relationship between multivitamin use and prostate cancer is unclear . METHODS We prospect ively investigated the association between multivitamin use and risk of prostate cancer ( localized , advanced , and fatal ) in 295,344 men enrolled in the National Institutes of Health (NIH)-AARP Diet and Health Study who were cancer free at enrollment in 1995 and 1996 . During 5 years of follow-up , 10,241 participants were diagnosed with incident prostate cancer , including 8765 localized and 1476 advanced cancers . In a separate mortality analysis with 6 years of follow-up , 179 cases of fatal prostate cancer were ascertained . Multivitamin use was assessed at baseline as part of a self-administered , mailed food-frequency question naire . Relative risks ( RRs ) and 95 % confidence intervals ( CIs ) were calculated by use of Cox proportional hazards regression , adjusted for established or suspected prostate cancer risk factors . RESULTS No association was observed between multivitamin use and risk of localized prostate cancer . However , we found an increased risk of advanced and fatal prostate cancers ( RR = 1.32 , 95 % CI = 1.04 to 1.67 and RR = 1.98 , 95 % CI = 1.07 to 3.66 , respectively ) among men reporting excessive use of multivitamins ( more than seven times per week ) when compared with never users . The incidence rates per 100,000 person-years for advanced and fatal prostate cancers for those who took a multivitamin more than seven times per week were 143.8 and 18.9 , respectively , compared with 113.4 and 11.4 in never users . The positive associations with excessive multivitamin use were strongest in men with a family history of prostate cancer or who took individual micronutrient supplements , including selenium , beta-carotene , or zinc . CONCLUSION These results suggest that regular multivitamin use is not associated with the risk of early or localized prostate cancer . The possibility that men taking high levels of multivitamins along with other supplements have increased risk of advanced and fatal prostate cancers is of concern and merits further evaluation Interest in the chemopreventive effects of the trace element selenium has spanned the past three decades . Of > 100 studies that have investigated the effects of selenium in carcinogen-exposed animals , two-thirds have observed a reduction in tumor incidence and /or preneoplastic endpoints ( G. F. Combs and S. B. Combs , The Role of Selenium in Nutrition Chapter 10 , pp . 413 - 462 . San Diego , CA : Academic Press , 1986 , and B. H. Patterson and O. A. Lev and er , Cancer Epidemiol . Biomark . Prev . , 6 : 63 - 69 , 1997 ) . The Nutritional Prevention of Cancer Trial , a r and omized clinical trial reported by Clark et al. ( L. C. Clark et al. , JAMA , 276 : 1957 - 1963 , 1996 ) , showed as a secondary end point , a statistically significant decrease in lung cancer incidence with selenium supplementation . The adjusted hazard ratio ( HR ) was 0.56 [ 95 % confidence interval ( CI ) , 0.31 - 1.01 ; P = 0.05 ] . These results were based on active follow-up of 1312 participants . This re analysis used an extended Nutritional Prevention of Cancer Trial participant follow-up through the end of the blinded clinical trial on February 1 , 1996 . The additional 3 years added 8 cases to the selenium-treated group and 4 cases to the placebo group , and increased follow-up to 7.9 years . The relative risk of 0.70 ( 95 % CI , 0.40 - 1.21 ; P = 0.18 ) is not statistically significant . Whereas the overall adjusted HR is not significant ( HR = 0.74 ; 95 % CI , 0.44 - 1.24 ; P = 0.26 ) , and the HR for current and former smokers was not significant , the trend is toward a reduction in risk of incident lung cancer with selenium supplementation . In a subgroup analysis there was a nominally significant HR among subjects with baseline plasma selenium in the lowest tertile ( HR = 0.42 ; 95 % CI , 0.18 - 0.96 ; P = 0.04 ) . The analysis for the middle and highest tertiles of baseline showed HRs of 0.91 and 1.25 . The current re analysis indicates that selenium supplementation did not significantly decrease lung cancer incidence in the full population , but a significant decrease among individuals with low baseline selenium concentrations was observed BACKGROUND Selenium is a potential chemopreventive agent against prostate cancer , whose chemoprotective effects are possibly mediated through the antioxidative properties of selenoenzymes . Interrelations with other antioxidative agents and oxidative stressors , such as smoking , are poorly understood . OBJECTIVES The aims were to investigate the association between serum selenium and prostate cancer risk and to examine interactions with other antioxidants and tobacco use . DESIGN A nested case-control study was performed within the screening arm of the Prostate , Lung , Colorectal , and Ovarian Cancer Screening Trial . Serum selenium in prospect ively collected sample s was compared between 724 incident prostate cancer case subjects and 879 control subjects , frequency-matched for age , time since initial screen , and year of blood draw . The men were followed for up to 8 y. RESULTS Overall , serum selenium was not associated with prostate cancer risk ( P for trend = 0.70 ) ; however , higher serum selenium was associated with lower risks in men reporting a high ( more than the median : 28.0 IU/d ) vitamin E intake [ odds ratio ( OR ) for the highest compared with the lowest quartile of selenium : 0.58 ; 95 % CI : 0.37 , 0.91 ; P for trend = 0.05 ; P for interaction = 0.01 ] and in multivitamin users ( OR for highest compared with the lowest quartile of selenium : 0.61 ; 95 % CI : 0.36 , 1.04 ; P for trend = 0.06 ; P for interaction = 0.05 ) . Furthermore , among smokers , high serum selenium concentrations were related to reduced prostate cancer risk ( OR for the highest compared with the lowest quartile of selenium : 0.65 ; 95 % CI : 0.44 , 0.97 ; P for trend = 0.09 ; P for interaction = 0.007 ) . CONCLUSION Greater prediagnostic serum selenium concentrations were not associated with prostate cancer risk in this large cohort , although greater concentrations were associated with reduced prostate cancer risks in men who reported a high intake of vitamin E , in multivitamin users , and in smokers The association between prostate cancer and baseline vitamin E and selenium was evaluated in the trial-based cohort of the Alpha-Tocopherol , Beta-Carotene Cancer Prevention Study ( n = 29,133 ) . During up to 9 years of follow-up , 317 men developed incident prostate cancer . Multivariate Cox proportional hazards models that adjusted for intervention group , benign prostatic hyperplasia , age , smoking , and urban residence were used to evaluate associations between prostate cancer and exposures of interest . There were no significant associations between baseline serum alpha-tocopherol , dietary vitamin E , or selenium and prostate cancer overall . The associations between prostate cancer and vitamin E and some of the baseline dietary tocopherols differed significantly by alpha-tocopherol intervention status , with the suggestion of a protective effect for total vitamin E among those who received the alpha-tocopherol intervention ( relative risk was 1.00 , 0.68 , 0.80 , and 0.52 for increasing quartiles ; P = 0.07 ) Nonexperimental studies suggest that individuals with higher selenium ( Se ) status are at decreased risk of cancer . The Nutritional Prevention of Cancer ( NPC ) study r and omized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo ; selenium supplementation decreased the risk of lung , colon , prostate , and total cancers but increased the risk of nonmelanoma skin cancer . In this article , we report on a small sub study in Macon , GA , which began in 1989 and r and omized 424 patients to 400-mcg/day of Se or to matched placebo . The subjects from both arms had similar baseline Se levels to those treated by 200 mcg , and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg . The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25 % ; however , 400-mcg/day of Se had no effect on total cancer incidence Linxian , China has some of the highest rates of esophageal/gastric cardia cancer in the world , and epidemiological evidence suggests that chronically low intake of micronutrients may contribute to these high cancer rates . To examine whether supplementation with multiple vitamins and minerals can affect the occurrence of esophageal/gastric cardia cancer in this population , a two-arm r and omized nutrition intervention trial was conducted among 3318 Linxian residents with cytological evidence of esophageal dysplasia . During the 6-year intervention , esophageal/gastric cardia cancer mortality was 8 % lower among those receiving the active supplements . After 30 and 72 months of intervention , endoscopic surveys were carried out to see if the nutritional supplements had affected the prevalence of clinical ly silent precancerous lesions and early invasive cancers of the esophagus and stomach . In the first survey , in 1987 , 833 subjects were endoscoped ; in the second survey , in 1991 , 396 subjects were examined . The histological diagnoses from each survey were compared by treatment group . Cancer or dysplasia was diagnosed in 28 % of the subjects endoscoped in 1987 and 24 % of those examined in 1991 . The odds ratio for subjects in the treatment group ( versus those in the placebo group ) having esophageal or gastric dysplasia or cancer was 0.84 ( 95 % confidence interval , 0.61 - 1.15 ) in 1987 and 0.86 ( 0.54 - 1.38 ) in 1991 . Although modest protective effects on worst overall diagnosis were seen in the supplemented group in both surveys , none of the results was statistically significant , and the findings must be considered inconclusive . ( ABSTRACT TRUNCATED AT 250 WORDS Using a prospect i ve case-control study design , baseline levels of plasma selenium , retinol , and retinol-binding protein , and baseline blood uric acid levels were compared in 136 case patients who subsequently died from cancer and 238 matched control subjects . Subjects were followed for an average of 8 1/2 years . In matched analyses , selenium levels were lower in case patients with gastrointestinal or prostate cancer ; retinol levels , lower in those with gastrointestinal or breast cancer ; retinol-binding protein levels , lower in case patients with gastrointestinal cancer ; and uric acid levels , lower in a group with " other " cancers . However , only the uric acid association with " other " cancers and the retinol-binding protein association with gastrointestinal cancer were statistically significant ( P < or = .02 ) in conditional logistic regression analyses controlling for multiple potential covariates . Relationships for each of the substances varied by cancer site , and although some relationships were suggestive , our results point to the need for larger studies with adequate numbers for site-specific analyses The hypothesis that a dietary supplement of selenium ( Se ) may reduce cancer risk was tested experimentally in humans . Patients with histories of basal/squamous cell carcinomas of the skin were assigned r and omly in double-blind fashion to daily oral supplements of either Se-enriched yeast ( 200 micrograms Se/day ) , or a low-Se yeast placebo . A total of 1312 patients recruited in 1983 - 1990 were followed with regular dermatologic examinations through 1993 for a total of 8269 person-years of observation . Skin cancer diagnoses were confirmed histologically . Plasma Se concentration was determined at 6 - 12 months intervals . All deaths and patient-reported illnesses were recorded ; reported cancers were confirmed and documented by consultation with the patient medical care providers . The results indicate that Se did not significantly affect the primary endpoints : incidences of recurrent basal/squamous cell carcinomas of the skin . However , Se-treatment was associated with reductions in several secondary endpoints : total mortality , mortality from all cancers combined , as well as the incidence of all cancers combined , lung cancer , colorectal cancer and prostate cancer . The consistencies of these associations over time , between study clinics and for the leading cancer sites strongly suggests benefits of Se-supplementation for this cohort of patients , supporting the hypothesis that supplemental Se can reduce cancer risk . Although Se did not shown protective effects against non-melanoma skin cancers , the suggested reductions in risks to other frequent cancers dem and further evaluation in well controlled clinical intervention trials BACKGROUND Epidemiologic studies suggest that low selenium levels are associated with an increased incidence of prostate cancer , although results are conflicting . We examined the association between pre-diagnostic plasma selenium levels and risk of prostate cancer in men enrolled in the Physicians ' Health Study . METHODS Using plasma sample s obtained in 1982 from healthy men enrolled in the study , we conducted a nested case-control study among 586 men diagnosed with prostate cancer during 13 years of follow-up and 577 control subjects . Odds ratios ( ORs ) and 95 % confidence intervals ( CIs ) for the risk of prostate cancer in pre- ( before October 1990 ) and post- ( after October 1990 ) prostate-specific antigen ( PSA ) screening eras were calculated using multivariable logistic regression . RESULTS Pre-diagnostic plasma selenium levels were inversely associated with risk of advanced prostate cancer ( 5th versus 1st quintile OR = 0.52 , 95 % CI = 0.28 to 0.98 ; P(trend ) = .05 ) , even among men diagnosed after 1990 ( 5th versus 1st quintile OR = 0.39 , 95 % CI = 0.16 to 0.97 ) . The inverse association with prostate cancer risk was observed only for case subjects with elevated baseline PSA levels ( PSA > 4 ng/mL , 5th versus 1st quintile OR = 0.49 , 95 % CI = 0.28 to 0.86 ; P(trend ) = .002 ) . These inverse associations were observed in both pre- and post-PSA eras . CONCLUSIONS The inverse association between baseline plasma selenium levels and risk of advanced prostate cancer , even among men diagnosed during the post-PSA era , suggests that higher levels of selenium may slow prostate cancer tumor progression . Ongoing r and omized trials of selenium supplements may help to further evaluate this issue BACKGROUND Antioxidant micronutrients , such as alpha-tocopherol ( vitamin E ) , the carotenoids , and selenium , may protect against the development of cancer by preventing free radical damage at the cellular level . PURPOSE A nested case -- control study was conducted among donors to a serum bank to examine the association between levels of serum micronutrients and /or cholesterol and the development of ovarian cancer . METHODS In 1974 , sera were collected from 20,305 residents of Washington County , MD , over a 4-month period and stored at -70 degrees C. Serum micronutrient concentrations of women who developed ovarian cancer ( case subjects , n = 35 ) were compared with those of women who remained free of cancer and who were matched to case subjects on age and menopausal status ( control subjects , n = 67 ) . Serum levels of retinol ( vitamin A ) , alpha- and beta-carotene ( the major provitamin A ) , lycopene ( a carotenoid ) , and alpha- and gamma-tocopherol were measured using high-performance liquid chromatography . Serum selenium was measured by neutron activation analysis . Cholesterol was measured by enzymatic assay . The data were categorized into thirds and conditional logistic regression analyses were performed to determine the association between prediagnostic serum cholesterol and micronutrient levels and the development of ovarian cancer ; matched odds ratios ( ORs ) were determined from these regression analyses . P values for trend and for interaction were calculated with the use of two-sided likelihood ratio tests . RESULTS Higher serum alpha-tocopherol levels were associated with an increased risk of ovarian cancer ( P for trend = .04 ) ; however , this association diminished after adjustment for cholesterol . Women with higher serum cholesterol levels had an increased risk of ovarian cancer compared with women in the lowest third of cholesterol levels ( OR = 3.2 ; 95 % confidence interval = 0.9 - 11.3 ) . The association between serum cholesterol levels and the risk of ovarian cancer was examined , stratifying by micronutrient level . The general pattern observed was an increased risk of ovarian cancer associated with cholesterol levels greater than 200 mg/dL , regardless of the micronutrient level . Serum selenium was associated with a decreased risk of ovarian cancer only among case participants diagnosed 4 or more years after blood collection s ( P for trend = .02 ) . Concentrations of carotenoids and retinol were not associated with the development of ovarian cancer . CONCLUSIONS Selenium may have a protective role against the development of ovarian cancer . Higher serum cholesterol levels were associated with an increased risk of developing ovarian cancer ; an association that persisted regardless of serum micronutrient level . IMPLICATION S Given the small size of this study and the inconsistency of results among the few prospect i ve studies of ovarian cancer conducted to test these associations , replications of these findings are highly desirable The independent and joint associations of serum selenium and vitamin A ( retinol ) and E ( alpha tocopherol ) concentrations with the risk of death from cancer were studied in 51 case-control pairs -- that is , 51 patients with cancer , each paired with a control matched for age , sex , and smoking . Case-control pairs came from a r and om sample of some 12000 people aged 30 - 64 years resident in two provinces of eastern Finl and who were followed up for four years . Patients who died of cancer during the follow up period had a 12 % lower mean serum selenium concentration ( p = 0.015 ) than the controls . The difference persisted when deaths from cancer in the first follow up year were excluded . The adjusted risk of fatal cancer was 5.8-fold ( 95 % confidence interval 1.2 - 29.0 ) among subjects in the lowest tertile of selenium concentrations compared with those with higher values . Subjects with both low selenium and low alpha tocopherol concentrations in serum had an 11.4-fold adjusted risk . Among smoking men with cancer serum retinol concentrations were 26 % lower than in smoking controls ( p = 0.002 ) . These data suggest that dietary selenium deficiency is associated with an increased risk of fatal cancer , that low vitamin E intake may enhance this effect , and that decreased vitamin or provitamin A intake contributes to the risk of lung cancer among smoking men with a low selenium intake Epidemiological studies have suggested that low levels of selenium are associated with a higher incidence of both lung and prostate cancer . We analyzed the selenium serum concentration in 356 Carotene and Retinol Efficacy Trial ( CARET ) participants who later developed lung cancer and 356 matched controls and in 235 prostate cancer cases and 456 matched controls . Serum sample s were obtained a mean of 4.7 years before diagnosis for both tumor types . Controls were matched to cases by year of r and omization , age , smoking status , treatment arm , exposure population ( asbestos workers or cigarette smokers ) , and year of blood draw . In the control population ( n = 820 ) , significant predictors of low serum selenium concentration were current smoking status and East Coast locations of the study center . Overall , there was no significant difference in mean serum selenium in lung cancer cases versus controls ( 11.91 microg/dl versus 11.77 microg/dl ) or prostate cancer cases versus controls ( 11.48 microg/dl versus 11.43 microg/dl ) . No statistically significant trend in odds ratio was seen across quartiles of serum selenium for lung cancer ( P = 0.49 ) or prostate cancer ( P = 0.69 ) . In a sub population of 174 prostate cancer patients who had clinical and pathological staging material review ed , there was no association between serum selenium and Gleason score or clinical or pathological stage . In the CARET population of current and former smokers consuming an ad libitum diet , the serum concentration of selenium was not a risk factor for either lung cancer or prostate cancer Prostate cancer is the commonest non-skin malignancy in the United States and has a substantial mortality rate despite the use of PSA-based screening . Furthermore , therapy for prostate cancer by surgery , radiotherapy or hormonal manipulation carries a significant risk of treatment-related morbidity . Recent analysis of secondary endpoints of several large-scale r and omized prospect i ve clinical trials for other malignancies has suggested that selenium or vitamin E may result in a decreased incidence and mortality from prostate cancer . In vitro and pre clinical studies of these antioxidants support this hypothesis . This review outlines the rationale and design of SELECT , the Selenium and Vitamin E Cancer Prevention Trial , design ed to test the hypothesis that selenium or vitamin E alone or in combination can reduce the clinical incidence of prostate cancer in a population -based cohort of men at risk . SELECT is a phase III , r and omized , double-blinded , prospect i ve , 2 × 2 factorial clinical trial which will r and omize 32,400 healthy men with normal DRE and serum PSA to one of four study arms : selenium alone , vitamin E alone , selenium+vitamin E , or placebo . Study agents will be taken orally for a minimum of 7 and maximum of 12 y with assessment s of general health , incident prostate cancer and toxicity performed at 12 month intervals . Under the assumptions described , the detectable risk reduction is 25 % for an effective single agent relative to placebo , with an additional 25 % reduction for the combination relative to an effective single agent . The estimated power for the comparison of a single agent vs placebo is 96 % and the power for the comparison of an effective single agent vs combination is 89 % . Secondary endpoints will include prostate cancer-free survival , all-cause mortality , and the incidence and mortality of other cancers and diseases potentially impacted by the chronic use of selenium and vitamin E. Other trial objectives will include periodic quality of life assessment s , assessment of serum micronutrient levels and prostate cancer risk , and studies of the evaluation of biological and genetic markers with the risk of prostate cancer A r and omized nutrition intervention trial was conducted among 29,584 adult residents of Linxian , China , to examine the effects of vitamin/mineral supplementation on the occurrence of esophageal/gastric cardia cancer in this high-risk population . A fractional factorial study design allowed evaluations of four different combinations of nutrients : ( A ) retinol and zinc ; ( B ) riboflavin and niacin ; ( C ) vitamin C and molybdenum ; and ( D ) beta-carotene , vitamin E , and selenium . During the 5.25-year intervention , significant reductions in total mortality , total cancer mortality , and stomach cancer mortality occurred among those receiving beta-carotene , vitamin E , and selenium . At the end of intervention , an endoscopic survey was carried out in a sample of subjects to see if the nutritional supplements had affected the prevalence of clinical ly silent precancerous lesions and early invasive cancers of the esophagus or stomach . Endoscopy was performed on 391 individuals from two study villages . The prevalences of esophageal and gastric dysplasia and cancer were compared by nutrient factor . Cancer or dysplasia was diagnosed in 15 % of the participants . No statistically significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen for any of the four vitamin/mineral combinations . The greatest reduction in risk ( odds ratio , 0.38 ; P = 0.09 ) was seen for the effect of retinol and zinc on the prevalence of gastric cancer . Although no significant protective effects were seen in this endoscopic survey , there was a suggestion that supplementation with retinol and zinc may protect against the development of gastric neoplasia in this high-risk population . Additional studies with larger numbers of endpoints will be needed to further evaluate this possibility BACKGROUND People have more and more concerned about allitridum as studies have shown that taking more raw garlic associated with a lower risk for cancers of the alimentary system . In the present study , we tried to examine whether a large dose of allitridum and a microdose of selenium prevent gastric cancer . METHODS A double-blind intervention study was performed on the participants aged ( 35 - 74 ) years , who had matched at least one of the following criteria : ( 1 ) a medical history of stomach disorder , ( 2 ) a family history of tumour , or ( 3 ) smoking and /or alcohol consumption . A total of 2,526 and 2,507 persons were r and omly enrolled into intervention group and control group respectively from 288 natural villages of seven communities in Qixia County , Sh and ong Province , China . Each person of the intervention group orally took 200 mg synthetic allitridum every day and 100 microg selenium every other day for one month of each year during November 1989 to December 1991 . At the same time , people in control group were given 2 placebo capsules containing corn oid with the identical appearance to that in the intervention group . RESULTS For all subjects the large dose of allitridum was accepted and no harmful side effects were found during the study . In the first follow-up five years ( 1992 - 1997 ) after stopping the intervention , the morbidity rates of malignant tumours in the intervention group declined by 22 % , in contrast to the control group , declined by 47.3 % . After adjusting for age , gender , and other potential confounders , relative risks ( RRs ) for all tumours and gastric cancer of the whole population were 0.67 ( 95 % CL : 0.43 - 1.03 ) and 0.48 ( 95 % CL : 0.21 - 1.06 ) , respectively , and for male group they were 0.51 ( 95 % CL : 0.30 - 0.85 ) and 0.36 ( 95 % CL : 0.14 - 0.92 ) , respectively . No signigicantly protective effect was found for the female subgroup . CONCLUSION The present study proves that large doses of allitridum and microdorse of selenium may effectively prevent gastric cancer , especially in men Objective To investigate the relationship between basal cell carcinoma ( BCC ) and antioxidant nutrients , specifically carotenoids , vitamin E and selenium . Methods The Nambour Skin Cancer Study is an ongoing , community-based study of r and omly selected adult residents of a township in sub-tropical Queensl and , Australia . Using a nested case – control design , incident cases of BCC ( n=90 ) were compared with age and sex matched controls ( n=90 ) . Dietary exposure was measured using food frequency question naire estimates of intake as well as serum biomarkers . Other determinants of skin cancer including sun exposure were also considered . Dietary intakes were adjusted for energy intake , and serum carotenoids and vitamin E were adjusted for serum cholesterol . Odds ratios were calculated across quartiles of dietary intake and serum biomarkers and linear trends were assessed using logistic regression , adjusting for age , sex and supplement use . Results and conclusions In this prospect i ve study no significant associations were found between BCC and carotenoids , vitamin E or selenium , as measured by serum biomarkers or dietary intake , although there was a suggestion of a positive association with lutein intake The association of serum selenium with the subsequent risk of death from cancer was investigated in a case-control study that was nested in a prospect i ve nine-year follow-up study in the Netherl and s. In 1975 - 1978 , 10,532 persons in the Dutch town of Zoetermeer who were aged five years or more participated in a medical survey . Serum sample s were collected and stored at -20 C. For the 82 persons who died of cancer since the baseline examination , 164 cohort members still alive by the end of 1983 were selected as controls and matched for age , sex , and smoking . Cancer deaths that occurred in the first year of follow-up were excluded , leaving 69 cases for statistical analyses . The mean serum selenium level of 116.7 + /- 4.0 micrograms/liter among male cancer deaths ( n = 40 ) was significantly different ( p = 0.04 ) from that in the control subjects ( 126.4 + /- 3.1 micrograms/liter ) . In females , selenium levels were similar among cases and controls . The adjusted risk of death from cancer for men in the lowest quintile of serum selenium ( below 100.8 micrograms/liter ) was more than twice that of subjects with higher levels ( relative risk = 2.7,90 % confidence interval = 1.2 - 6.2 ) . These data support recent findings of an increased cancer risk associated with low serum selenium levels in men but not in women Prostate cancer continues to be a major health threat , especially among African American men . The Selenium and Vitamin E Cancer Prevention Trial ( SELECT ) , which opened on July 25 , 2001 , was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States , including Puerto Rico , and Canada . SELECT is a phase III r and omized , placebo-controlled trial of selenium ( 200 microg/day from L-selenomethionine ) and /or vitamin E ( 400 IU/day of all rac alpha-tocopheryl acetate ) supplementation for a minimum of 7 years ( maximum of 12 years ) in non-African American men at least 55 years of age and African American men at least 50 years of age . SELECT is a large , simple trial that conforms as closely as possible with community st and ards of care . This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial , including the role of prostate cancer screening , the best forms and doses of the study agents , and estimation of the event ( prostate cancer ) rate of men on the placebo arm To present the results ( to January 1996 , the end of blinded treatment ) of the Nutritional Prevention of Cancer ( NPC ) Trial , a r and omized trial of selenium ( 200 µg daily ) design ed to test the hypothesis that selenium supplementation ( SS ) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA To investigate the associations between intake of antioxidant nutrients and risk of basal cell ( BCC ) and squamous cell carcinomas ( SCC ) of the skin , we carried out a prospect i ve study among 1001 r and omly selected adults living in an Australian community . Intake of antioxidants was estimated in 1996 . Incident , histologically-confirmed BCC and SCC were recorded between 1996 and 2004 . High dietary intake of lutein and zeaxanthin was associated with a reduced incidence of SCC in persons who had a history of skin cancer at baseline ( highest versus lowest tertile , multivariable adjusted relative risk (RR)=0.47 , 95 % confidence interval ( CI ) : 0.25 - 0.89 ; P for trend=0.02 ) . In persons without a history of skin cancer at baseline , development of BCC was positively associated with intake of vitamins C and E from foods plus supplements ( RR=3.1 , 95 % CI : 1.1 - 8.6 ; P for trend=0.03 and RR=2.6 , 95 % CI : 1.1 - 6.3 ; P for trend=0.02 , respectively ) . In those with a skin cancer history at baseline , dietary intake in the second tertile for beta-carotene ( multivariable adjusted RR=2.2 , 95 % CI : 1.2 - 4.1 ) and for vitamin E ( multivariable adjusted RR=2.1 , 95 % CI : 1.1 - 3.9 ) was associated with increased BCC risk , with no trend , and similar results were seen in those with a specific history of BCC . These data suggest quite different associations between antioxidant intake and SCC compared with BCC , consistent with other evidence of their different causal pathways We conducted a nested case-control study of squamous cell skin cancer ( SCC ) to determine whether risk was related to plasma concentrations of selenium , alpha-tocopherol , beta-carotene , and retinol . We derived the study sample from participants in our Skin Cancer Prevention Study , all of whom had at least one basal cell or squamous cell skin cancer before study entry . Those who developed a new squamous cell skin cancer during the 3 - 5-year follow-up period were selected as cases ( n = 132 ) . Controls ( n = 264 ) were chosen at r and om , with matching by age , sex , and study center , from among those who did not develop SCC but were being followed actively at the time the SCC case was diagnosed . Prediagnostic plasma sample s were analyzed for alpha-tocopherol , beta-carotene , and retinol using high-performance liquid chromatography . Selenium determinations were made using instrumental neutron activation analysis . Odds ratios were computed using conditional logistic regression for matched sample s. We found no consistent pattern of SCC risk associated with any of the nutrients examined . The odds ratios ( 95 % confidence intervals ) for the highest versus the lowest quartiles of beta-carotene , retinol , alpha-tocopherol , and selenium were 0.73 ( 0.38 - 1.41 ) , 1.43 ( 0.77 - 2.64 ) , 0.89 ( 0.43 - 1.85 ) , and 0.86 ( 0.47 - 1.58 ) , respectively . Thus , our data add to the growing body of evidence that these nutrients , at the concentrations we evaluated , are not related strongly to SCC risk Abstract Objective : To evaluate the association of prediagnostic serum antioxidants and lung cancer risk we conducted a case – control study nested in an occupational cohort of tin miners . Methods : Male workers free of cancer enrolled in the cohort . During up to 6 years of follow-up , 339 lung cancer cases were diagnosed and , among these cases , those who donated blood prospect ively ( n = 108 ) were eligible for this study . For each case , two controls alive and free of cancer at the time of case diagnosis were matched on age and date of blood collection . Results : Overall , we observed no association between serum alpha-tocopherol , gamma-tocopherol or selenium levels and lung cancer risk . However , a significant gradient of decreasing lung cancer risk with increasing serum alpha-tocopherol was apparent for men less than 60years old ( odds ratio by tertile : 1.0 , 0.9 , 0.2 ; trend p = 0.002 ) . Alpha-tocopherol was also protective in men who reported no alcohol drinking ( OR by tertile : 1.0 , 0.6 , 0.3 ; trend p = 0.008 ) . Conclusion : Although there were no significant overall associations between prospect ively collected serum alpha-tocopherol , gamma-tocopherol or selenium and incidence of lung cancer , results from this study suggest that higher alpha-tocopherol levels may be protective in men less than 60 years old and in those who do not drink alcohol PURPOSE Epidemiological studies and a r and omized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake . We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer . MATERIAL S AND METHODS A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry , including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease . Plasma selenium was measured at an average time plus or minus st and ard deviation of 3.83 + /- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry . Adjusted odds ratio and 95 % confidence interval were computed with logistic regression . RESULTS After correcting for years before diagnosis , body mass index , and smoking and alcohol use history , higher selenium was associated with a lower risk of prostate cancer . Compared with the lowest quartile of selenium ( range 8.2 to 10.7 microg./dl . ) , the odds ratios of the second ( 10.8 to 11.8 ) , third ( 11.9 to 13.2 ) and fourth ( 13.3 to 18.2 ) quartiles were 0.15 ( 95 % confidence interval 0.05 to 0.50 ) , 0.21 ( 0.07 to 0.68 ) and 0.24 ( 0.08 to 0.77 , respectively , p = 0.01 ) . Furthermore , plasma selenium decreased significantly with patient age ( p < 0.001 ) . CONCLUSIONS Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer . These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer . Because plasma selenium decreases with patient age , supplementation may be particularly beneficial to older men Antioxidant nutrients found in fruits , vegetables and other foods are thought to inhibit carcinogenesis and to influence immune status . We evaluated the association of these factors with risk of non-Hodgkin 's lymphoma ( NHL ) overall and for diffuse large B-cell lymphoma ( DLBCL ) and follicular lymphoma specifically in a prospect i ve cohort of 35,159 Iowa women aged 55 - 69 years when enrolled at baseline in 1986 . Diet was ascertained using a vali date d semiquantitative food frequency question naire . Through 2005 , 415 cases of NHL ( including 184 DLBCL and 90 follicular ) were identified . Relative risks ( RRs ) and 95 % confidence intervals ( CIs ) were estimated using Cox regression , adjusting for age and total energy . The strongest associations of antioxidants with risk of NHL ( RR for highest versus lowest quartile ; p for trend ) were observed for dietary vitamin C ( RR = 0.78 ; p = 0.044 ) , alpha-carotene ( RR = 0.71 ; p = 0.015 ) , proanthocyanidins ( RR = 0.70 ; p = 0.0024 ) and dietary manganese ( RR = 0.62 ; p = 0.010 ) . There were no associations with multivitamin use or supplemental intake of vitamins C , E , selenium , zinc , copper or manganese . From a food perspective , greater intake of total fruits and vegetables ( RR = 0.69 ; p = 0.011 ) , yellow/orange ( RR = 0.72 ; p = 0.015 ) and cruciferous ( RR = 0.82 ; p = 0.017 ) vegetables , broccoli ( RR = 0.72 ; p = 0.018 ) and apple juice/cider ( RR = 0.65 ; p = 0.026 ) were associated with lower NHL risk ; there were no strong associations for other antioxidant-rich foods , including whole grains , chocolate , tea or nuts . Overall , these associations were mainly observed for follicular lymphoma and were weaker or not apparent for DLBCL . In conclusion , these results support a role for vegetables , and perhaps fruits and associated antioxidants from food sources , as protective factors against the development of NHL and follicular lymphoma in particular Objective Vitamin E and selenium are promising nutrients for the prevention of prostate cancer , and both are currently being tested in a large r and omized trial for prostate cancer . However , results are not expected for at least 6 years . We aim ed to investigate the association of vitamin E and selenium supplementation with prostate cancer in the VITamins And Lifestyle ( VITAL ) study , a cohort study specifically design ed to examine supplement use and future cancer risk . Methods In a prospect i ve design , 35,242 men recruited between 2000 and 2002 from western Washington State completed a question naire , including detailed questions about vitamin E and selenium supplement intake during the past 10 years from br and -specific multivitamins and single supplements . Using linkage to the western Washington SEER cancer registry , we documented 830 new cases of prostate cancer from baseline through December 2004 . Results A 10-year average intake of supplemental vitamin E was not associated with a reduced prostate cancer risk overall [ hazard ratio ( HR ) 0.86 , 95 % confidence interval ( CI ) 0.65–1.1 for ≥400 IU/day vs. non-use , p for trend 0.36 ] ; however , risk for advanced prostate cancer ( regionally invasive or distant metastatic , n = 123 ) decreased significantly with greater intake of supplemental vitamin E ( HR 0.43 , 95 % CI 0.19–1.0 for 10-year average intake ≥400 IU/day vs. non-use , p for trend 0.03 ) . There was no association between selenium supplementation and prostate cancer risk ( HR 0.90 , 95 % CI 0.62–1.3 for 10-year average intake > 50 μg/day vs. non-use , p for trend 0.97 ) . Conclusions In this prospect i ve cohort , long-term supplemental intake of vitamin E and selenium were not associated with prostate cancer risk overall ; however , risk of clinical ly relevant advanced disease was reduced with greater long-term vitamin E supplementation We examined the effect of supplementation with four different combinations of vitamins and minerals in the prevention of lung cancer mortality among 29,584 healthy adults from Linxian , China . In accord with a partial factorial design , the participants were r and omly assigned to take either a vitamin/mineral combination or a placebo for 5.25 years . The combinations tested in this trial were as follows : factor A , retinol and zinc ; factor B , riboflavin and niacin ; factor C , ascorbic acid and molybdenum ; factor D , β-carotene , α-tocopherol , and selenium . Lung cancer deaths ( n = 147 ) identified during the trial period ( 1986 - 1991 ) and 10 years after the trial ended ( 1991 - 2001 ) were the study outcome . No significant differences in lung cancer death rates were found for any of the four combinations of supplements tested in this study , using log-rank tests ( all P values are > 0.20 ) or Cox proportional hazards models adjusted for age , sex , commune , and other treatments . No significant interactions were seen for age , sex , or smoking status . Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian , China . ( Cancer Epidemiol Biomarkers Prev 2006;15(8):1562–4 Objective : To study the predictive power of serum selenium with regard to cancer mortality in a large sample of the Belgian population given the lack of coherence in the results of observational epidemiological studies in this domain . Design : A prospect i ve case – control study within a stratified sample of the Belgian male and female population .Subjects : A total of 201 cases r and omly selected from all cancer deaths ( N=343 ) during a 10-y mortality follow-up of a large age- and sex-stratified sample of the total Belgian population aged 25–74 y were matched for age and gender with 603 controls . Statistics : Conditional logistic regression for both univariate and multivariate analyses using tertile distribution of serum selenium in controls . Odds ratios ( ORs ) are adjusted for 10 baseline characteristics . Results : Unadjusted ORs of cancer deaths taking the highest tertile of serum selenium as a reference : in male subjects T1/T3 is 2.2 ( CI 1.3–3.7 ) ( P for trend 0.011 ) , whereas in female subjects a nonsignificant OR of 0.8 is observed . In multivariate analyses , no significant modifications of the ORs are observed for the predictive relation of serum selenium with cancer mortality . Besides serum selenium , beta-carotene intake and smoking are independent predictors in male subjects . Conclusions : In this nested case – control study of a stratified sample from the Belgian population , serum selenium is an independent predictor of cancer mortality in male subjects only , in a country with rather high serum selenium levels with respect to most other European countries OBJECTIVE To study the preventive effects of selenium on primary liver cancer . METHODS After screening of blood sample s in 18,000 males from 20 to 65 years-old in Qidong , Jiangsu province ( a high risk area for liver cancer ) , 2,065 cases of HBsAg positive , AFP negative and normal liver function ( normal ALT values ) were found . The subjects were r and omly divided into two groups , based on their residence areas ; 1,112 subjects ( experimental group ) received one tablet of sodium selenite ( 0.5 mg Se ) every day and 953 subjects ( control group ) received one placebo tablet every day . RESULTS During three years of intervention and follow up , the blood selenium concentration and glutathione peroxidase activity of the subjects in the experimental group were increased and had significant difference as compared with those of the control group ( P < 0.01 ) . At the same time , the prevalence rate of micronucleus cells in peripheral blood lymphocytes in the experimental group was significantly lower than that of the control group ( P < 0.01 ) , and the incidence of new liver cancer in the experimental group ( 3 057.55/10(6 ) , 34 cases out of 1,112 subjects ) was significantly lower than the control group ( 5 981.11/10(6 ) ; 57 cases out of 953 subjects ) ( P < 0.01 ) . CONCLUSION The results confirms that selenium supplementation in general population s lived in high risk is effective in the prevention of liver cancer and the using of selenium tablets is simple and feasible Epidemiological and clinical studies suggesting a significant inverse relationship between intake of dietary selenium and overall cancer risk have led to initiation of a r and omized , placebo-controlled , phase III clinical trial testing the safety and efficacy of selenized yeast as a chemopreventive agent for prostate cancer . Participants eligible for the ' Negative Biopsy Study ' , which was initiated in August 1999 , are men considered to be at high risk for prostate cancer because of at least one negative sextant prostate biopsy , which was clinical ly indicated within 1 year of enrollment to the study . After a 30-day run-in period to ensure protocol compliance , participants are r and omized to receive either 200 or 400 microg selenized yeast or matched placebo once daily . Primary study endpoints include development of prostate cancer and prostate-specific antigen ( PSA ) velocity . Secondary biochemical endpoints include change in chromagranin A and alkaline phosphatase . As of 1 June 2003 , 514 eligible participants had been enrolled . R and omization schema was effective for selected parameters including age , body mass index , smoking status , baseline PSA and baseline plasma selenium level . Various data , including medical history , family history , and urological symptoms and specimens ( including blood and subsequent prostate biopsy sample s ) had been collected at baseline , and throughout both the intervention and follow-up stages of the protocol . The goal for accrual is 700 evaluable participants To evaluate relationships of serum carotenoids , α-tocopherol , selenium , and retinol with breast cancer prospect ively , we conducted a case-control study nested in a cohort from the Breast Cancer Serum Bank in Columbia , Missouri ( United States ) . Women free of cancer donated blood to this bank in 1977 - 87 . During up to 9.5 years of follow-up ( median = 2.7 years ) , 105 cases of histologically confirmed breast cancer were diagnosed . For each case , two women alive and free of cancer at the age of the case 's diagnosis and matched on age and date of blood collection were selected as controls . A nonsignificant gradient of decreasing risk of breast cancer with increasing serum β-cryptoxanthin was apparent for all women . Serum lycopene also was associated inversely with risk , and among women who donated blood at least two years before diagnosis , a significant gradient of decreasing breast cancer risk with increasing lycopene concentration was evident . Amarginally significant gradient of decreasing risk with increasing serum lutein/zeaxanthin also was apparent among these women . We did not observe any evidence for protective effects of α- and β-carotene , α-tocopherol , retinol , or selenium for breast cancer . Results of this study suggest that the carotenoids β-cryptoxanthin , lycopene , and lutein/zeaxanthin may protect against breast cancer From 1971 to 1975 , serum specimens were obtained from 6,860 men of Japanese ancestry in Hawaii . Since then , the following numbers of newly diagnosed cases with epithelial cancer have been identified : 82 colon , 71 lung , 66 stomach , 32 rectum , and 29 urinary bladder . The stored sera of the 280 cases and of 293 r and omly selected controls were tested to determine their levels of selenium . There was no association of serum selenium with lung , stomach , or rectal cancer . An increase in relative risk ( RR ) was noted only for subjects in the lowest quintile of selenium values , as compared to the RR for subjects in the highest quintile , for colon ( RR = 1.8 ) and urinary bladder cancer ( RR = 3.1 ) , but neither of these RR estimates was statistically significant ( P = .09 and P = .07 , respectively ) . Further work is needed to determine whether the antioxidant properties of selenium protect against specific types of cancer Geographic variations in bladder cancer risk , observed in the United States and other countries , have been ecologically related to soil selenium levels . Evidence from clinical trials , observational , and animal studies suggests that selenium is anticarcinogenic and can affect the risk of The incidence of esophageal adenocarcinoma ( EA ) and its precursor condition , Barrett 's esophagus , has risen rapidly in the United States for reasons that are not fully understood . Therefore , we evaluated the association between use of supplemental vitamins and minerals and risk of neoplastic progression of Barrett 's esophagus and EA . The Seattle Barrett 's Esophagus Program is a prospect i ve study based on 339 men and women with histologically confirmed Barrett 's esophagus . Participants underwent baseline and periodic follow-up exams , which included endoscopy and self-administered question naires on diet , supplement use , and lifestyle characteristics . Use of multivitamins and 4 individual supplements was calculated using time-weighted averages of reported use over the observational period . Cox proportional-hazards models were used to calculate hazard ratios ( HR ) for each endpoint : EA , tetraploidy , and aneuploidy . During a mean follow-up of 5 yr , there were 37 cases of EA , 42 cases of tetraploidy , and 34 cases of aneuploidy . After controlling for multiple covariates including diet , nonsteroidal anti-inflammatory drug use , obesity , and smoking , participants who took 1 or more multivitamin pills/day had a significantly decreased risk of tetraploidy [ HR = 0.19 ; 95 % confidence interval ( CI ) = 0.08–0.47 ) and EA ( HR = 0.38 ; 95 % CI = 0.15–0.99 ] compared to those not taking multivitamins . Significant inverse associations were also observed between risk of EA and supplemental vitamin C ( ≥ 250 mg vs. none : HR = 0.25 ; 95 % CI = 0.11–0.58 ) and vitamin E ( ≥ 180 mg vs. none : HR = 0.25 ; 95 % CI = 0.10–0.60 ) . In this cohort study , use of multivitamins and single antioxidant supplements was associated with a significantly reduced risk of EA and markers of neoplastic progression among individuals with Barrett 's esophagus BACKGROUND Epidemiologic evidence indicates that diets high in fruits and vegetables are associated with a reduced risk of several cancers , including cancers of the esophagus and stomach . Vitamins and minerals in these foods may contribute to the reduced cancer risk . The people of Linxian County , China , have one of the world 's highest rates of esophageal/gastric cardia cancer and a persistently low intake of several micronutrients . PURPOSE We sought to determine if dietary supplementation with specific vitamins and minerals can lower mortality from or incidence of cancer as well as mortality from other diseases in Linxian . METHODS Individuals of ages 40 - 69 were recruited in 1985 from four Linxian communes . Mortality and cancer incidence during March 1986-May 1991 were ascertained for 29,584 adults who received daily vitamin and mineral supplementation throughout this period . The subjects were r and omly assigned to intervention groups according to a one-half replicate of a 2(4 ) factorial experimental design . This design enabled testing for the effects of four combinations of nutrients : ( A ) retinol and zinc ; ( B ) riboflavin and niacin ; ( C ) vitamin C and molybdenum ; and ( D ) beta carotene , vitamin E , and selenium . Doses ranged from one to two times U.S. Recommended Daily Allowances . RESULTS A total of 2127 deaths occurred among trial participants during the intervention period . Cancer was the leading cause of death , with 32 % of all deaths due to esophageal or stomach cancer , followed by cerebrovascular disease ( 25 % ) . Significantly ( P = .03 ) lower total mortality ( relative risk [ RR ] = 0.91 ; 95 % confidence interval [ CI ] = 0.84 - 0.99 ) occurred among those receiving supplementation with beta carotene , vitamin E , and selenium . The reduction was mainly due to lower cancer rates ( RR = 0.87 ; 95 % CI = 0.75 - 1.00 ) , especially stomach cancer ( RR = 0.79 ; 95 % CI = 0.64 - 0.99 ) , with the reduced risk beginning to arise about 1 - 2 years after the start of supplementation with these vitamins and minerals . No significant effects on mortality rates from all causes were found for supplementation with retinol and zinc , riboflavin and niacin , or vitamin C and molybdenum . Patterns of cancer incidence , on the basis of 1298 cases , generally resembled those for cancer mortality . CONCLUSIONS The findings indicate that vitamin and mineral supplementation of the diet of Linxian adults , particularly with the combination of beta carotene , vitamin E , and selenium , may effect a reduction in cancer risk in this population . IMPLICATION S The results on their own are not definitive , but the promising findings should stimulate further research to clarify the potential benefits of micronutrient supplements

Discussion The planned systematic review and meta- analysis will provide reliable estimates of the risk for major bleeding events during extended anticoagulation .

Background The optimal duration of anticoagulation after a first unprovoked venous thromboembolism ( VTE ) remains controversial . Deciding to stop or continue anticoagulant therapy indefinitely after completing 3 to 6 months of initial treatment requires balancing the long-term risk of recurrent VTE if anticoagulation is stopped against the long-term risk of major bleeding if anticoagulation is continued . However , knowledge of the long-term risk for major bleeding events during extended anticoagulation in this patient population is limited . We plan to conduct a systematic review and meta- analysis to quantify the risk for major bleeding events during extended oral anticoagulation in patients with first unprovoked VTE .

Background Therapeutic decisions in atrial fibrillation ( AF ) are often influenced by assessment of bleeding risk . However , existing bleeding risk scores have limitations . Objectives We sought to develop and vali date a novel bleeding risk score using routinely available clinical information to predict major bleeding in a large , community-based AF population . Methods We analysed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation ( ORBIT-AF ) , a prospect i ve registry that enrolled incident and prevalent AF patients at 176 US sites . Using Cox proportional hazards regression , we identified factors independently associated with major bleeding among patients taking oral anticoagulation ( OAC ) over a median follow-up of 2 years ( interquartile range = 1.6–2.5 ) . We also created a numerical bedside risk score that included the five most predictive risk factors weighted according to their strength of association with major bleeding . The predictive performance of the full model , the simple five-item score , and two existing risk scores ( hypertension , abnormal renal/liver function , stroke , bleeding history or predisposition , labile INR , elderly , drugs/alcohol concomitantly , HAS-BLED , and anticoagulation and risk factors in atrial fibrillation , ATRIA ) were then assessed in both the ORBIT-AF cohort and a separate clinical trial population , Rivaroxaban Once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation ( ROCKET-AF ) . Results Among 7411 ORBIT-AF patients taking OAC , the rate of major bleeding was 4.0/100 person-years . The full continuous model ( 12 variables ) and five-factor ORBIT risk score ( older age [ 75 + years ] , reduced haemoglobin/haematocrit/history of anaemia , bleeding history , insufficient kidney function , and treatment with antiplatelet ) both had good ability to identify those who bled vs. not ( C-index 0.69 and 0.67 , respectively ) . These scores both had similar discrimination , but markedly better calibration when compared with the HAS-BLED and ATRIA scores in an external validation population from the ROCKET-AF trial . Conclusions The five-element ORBIT bleeding risk score had better ability to predict major bleeding in AF patients when compared with HAS-BLED and ATRIA risk scores . The ORBIT risk score can provide a simple , easily remembered tool to support clinical decision making Better underst and ing of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism ( VTE ) may help physicians when deciding on intensity and duration of treatment . The primary aim of this study was to identify risk factors for major and clinical ly relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE . We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study . Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model . We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation . Major bleeding occurred in 56/4118 ( 1.4 % ) patients given edoxaban and in 66/4122 ( 1.6 % ) patients given warfarin . Clinical ly relevant bleeding occurred in 349 ( 8.5 % ) and 423 ( 10.3 % ) , respectively . Significant risk factors for major bleeding during edoxaban treatment were female sex , concomitant antiplatelet therapy , haemoglobin ≤10 g/dl , history of arterial hypertension , and systolic blood pressure > 160 mmHg . The discrimination of the model was high ( C-statistic : 0.71 ) for major bleeding , lower for clinical ly relevant bleeding ( C-statistic : 0.62 ) and when the model was applied to patients receiving warfarin ( C-statistic 0.60 ) . In conclusion , we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE . A risk model based on these factors predicted an increased risk of bleeding with good discrimination Attempts at identifying patients with an elevated risk of bleeding while on anticoagulation following acute venous thromboembolism ( VTE ) have largely been unsuccessful thus far . We sought to develop a clinical prediction score for bleeding during stable anticoagulation treatment after acute VTE . We performed a post hoc analysis of the pooled RE-COVER studies , two double-blind r and omised “ sister ” trials evaluating dabigatran versus st and ard treatment in 5107 VTE patients . A score was derived from patients r and omised to dabigatran using logistic regression analysis covering the complete follow-up period . The final model , named VTE-BLEED , included six variables and yielded a c-statistic of 0.72 ( 95 % CI 0.67–0.76 ) . Patients from the derivation cohort in the low-risk group ( < 2 points ; 74 % of the derivation population ) had a bleeding incidence of 2.8 % compared to 12.6 % in the elevated-risk group ( OR 5.0 ; 95 % CI 3.5–7.1 ) . The score proved accurate for our primary end-point , i.e. prediction of major bleeding after day 30 ( “ stable ” anticoagulation ) , both in patients on dabigatran ( c-statistic 0.75 , 95 % CI 0.61–0.89 ) and those on warfarin ( 0.78 , 95 % CI 0.68–0.86 ; p=0.77 for difference ) . The new VTE-BLEED score accurately predicted major bleeding events in VTE patients on stable anticoagulation with both dabigatran and warfarin . The new VTE-BLEED score predicted major bleeding events in VTE patients on stable anticoagulation treatment Existing clinical scores do not perform well in predicting bleeding in elderly patients with acute venous thromboembolism ( VTE ) . We sought to derive an easy-to-use clinical score to help physicians identify elderly patients with VTE who are at high-risk of bleeding during extended anticoagulation ( > 3 months ) . Our derivation sample included 743 patients aged ≥65 years with VTE who were enrolled in a prospect i ve multicenter cohort study . All patients received extended anticoagulation with vitamin K antagonists . We derived our score using competing risk regression , with the time to a first major bleeding up to 36 months of extended anticoagulation as the outcome , and 17 c and i date variables as predictors . We used bootstrapping methods for internal validation . Sixty-six ( 9 % ) patients suffered major bleeding . The clinical score is based on seven clinical factors ( previous bleeding , active cancer , low physical activity , anemia , thrombocytopenia , antiplatelet drugs/NSAIDs , and poor INR control ) . Overall , 48 % of patients were classified as low-risk , 37 % as moderate-risk , and 15 % as high-risk of bleeding . The rate of major bleeding was 1.4 events in low-risk , 5.0 events in moderate-risk , and 12.2 events per 100 patient-years in high-risk patients . The c-statistic was 0.78 at 3 months and 0.71 at 36 months of extended anticoagulation . Model calibration was excellent ( p=0.93 ) . Internal validation showed similar results . This simple clinical score accurately identified elderly patients with VTE who are at high risk of major bleeding and who may not benefit from extended anticoagulation . Further validation of the score is important before its implementation into practice . The study is registered to https:// clinical trials.gov as NCT00973596 PURPOSE To determine the incidence of major bleeding in out patients treated with warfarin and to identify predictive factors known at the start of therapy . PATIENTS AND METHODS The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were review ed . Follow-up information was obtained for 562 patients ( 99.5 % ) . Bleeding was classified as major or minor using explicit criteria . The cumulative incidence of bleeding was estimated by means of survival analysis . Independent risk factors for major bleeding were identified using Cox regression analysis in 375 r and omly chosen patients ; they were tested in the remaining 187 patients . RESULTS Major bleeding occurred in 65 patients ( 12 % ) and was fatal in 10 patients ( 2 % ) . The cumulative incidences of major bleeding at one , 12 , and 48 months were 3 % , 11 % , and 22 % , respectively . The monthly risk of major bleeding decreased over time , from 3 % during the first month of outpatient therapy to 0.3 % per month after the first year of therapy . Five independent risk factors for major bleeding -- age 65 years or greater , history of stroke , history of gastrointestinal bleeding , a serious comorbid condition ( recent myocardial infa rct ion , renal insufficiency , or severe anemia ) , atrial fibrillation -- predicted major bleeding in the testing group ; the cumulative incidence of major bleeding at 48 months was 2 % in 57 low-risk patients , 17 % in 110 middle-risk patients , and 63 % in 20 high-risk patients . CONCLUSION These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin . Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined PURPOSE To evaluate the accuracy and clinical utility of the Outpatient Bleeding Risk Index for estimating the probability of major bleeding in out patients treated with warfarin . The index was previously derived in a retrospective cohort of 556 patients from a different hospital ( derivation cohort ) . SUBJECTS AND METHODS We enrolled 264 out patients starting warfarin ( validation cohort ) to vali date the index prospect ively . All patients were identified upon hospital discharge , and physician estimates of the probability of major bleeding were obtained before discharge in the validation cohort . RESULTS Major bleeding occurred in 87 of 820 out patients ( 6.5%/yr ) . The index included four independent risk factors for major bleeding : age 65 years or greater ; history of gastrointestinal bleeding ; history of stroke ; and one or more of four specific comorbid conditions . In the validation cohort , the index predicted major bleeding : the cumulative incidence at 48 months was 3 % in 80 low-risk patients , 12 % in 166 intermediate-risk patients , and 53 % in 18 high-risk patients ( c index , 0.78 ) . The index performed better than physicians , who estimated the probability of major bleeding no better than expected by chance . Of the 18 episodes of major bleeding that occurred in high-risk patients , 17 were potentially preventable . CONCLUSIONS The Outpatient Bleeding Risk Index prospect ively classified patients according to risk of major bleeding and performed better than physicians . Major bleeding may be preventable in many high-risk patients by avoidance of over-anticoagulation and nonsteroidal anti-inflammatory agents BACKGROUND St and ard therapy to prevent recurrent venous thromboembolism includes 3 to 12 months of treatment with full-dose warfarin with a target international normalized ratio ( INR ) between 2.0 and 3.0 . However , for long-term management , no therapeutic agent has shown an acceptable benefit-to-risk ratio . METHODS Patients with idiopathic venous thromboembolism who had received full-dose anticoagulation therapy for a median of 6.5 months were r and omly assigned to placebo or low-intensity warfarin ( target INR , 1.5 to 2.0 ) . Participants were followed for recurrent venous thromboembolism , major hemorrhage , and death . RESULTS The trial was terminated early after 508 patients had undergone r and omization and had been followed for up to 4.3 years ( mean , 2.1 ) . Of 253 patients assigned to placebo , 37 had recurrent venous thromboembolism ( 7.2 per 100 person-years ) , as compared with 14 of 255 patients assigned to low-intensity warfarin ( 2.6 per 100 person-years ) , a risk reduction of 64 percent ( hazard ratio , 0.36 [ 95 percent confidence interval , 0.19 to 0.67 ] ; P<0.001 ) . Risk reductions were similar for all subgroups , including those with and those without inherited thrombophilia . Major hemorrhage occurred in two patients assigned to placebo and five assigned to low-intensity warfarin ( P=0.25 ) . Eight patients in the placebo group and four in the group assigned to low-intensity warfarin died ( P=0.26 ) . Low-intensity warfarin was thus associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism , major hemorrhage , or death . According to per- protocol and as-treated analyses , the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent . CONCLUSIONS Long-term , low-intensity warfarin therapy is a highly effective method of preventing recurrent venous thromboembolism A score that can accurately determine the risk of major bleeding during anticoagulant therapy may help to make decisions on anticoagulant use . RIETE is an ongoing registry of consecutive patients with acute venous thromboembolism ( VTE ) . We composed a score to predict the risk for major bleeding within three months of anticoagulant therapy . Of 19,274 patients enrolled , 13,057 ( 67 % ) were r and omly assigned to the derivation sample , 6,572 to the validation sample . In the derivation sample 314 ( 2.4 % ) patients bled ( fatal bleeding , 105 ) . On multivariate analysis , age > 75 years , recent bleeding , cancer , creatinine levels > 1.2 mg/dl , anemia , or pulmonary embolism at baseline were independently associated with an increased risk for major bleeding . A score was composed assigning 2 points to recent bleeding , 1.5 to abnormal creatinine levels or anemia , 1 point to the remaining variables . In the derivation sample 2,654 ( 20 % ) patients scored 0 points ( low risk ) ; 9,645 ( 74 % ) 1 - 4 points ( intermediate ) ; 758 ( 5.8 % ) > 4 points ( high risk ) . The incidences of major bleeding were : 0.3 % ( 95 % confidence interval [ CI ] : 0.1 - 0.6 ) , 2.6 % ( 95 % CI : 2.3 - 2.9 ) , and 7.3 % ( 95 % CI : 5.6 - 9.3 ) , respectively . The likelihood ratio test was : 0.14 ( 95 % CI : 0.07 - 0.27 ) for patients at low risk;2.96 ( 95 % CI : 2.18 - 4.02 ) for those at high risk . In the validation sample the incidence of major bleeding was : 0.1 % , 2.8 % , and 6.2 % , respectively . In conclusion , a risk score based on six variables documented at entry can identify VTE patients at low , intermediate , or high risk for major bleeding during the first three months of therapy The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists ( VKAs ) for the treatment of acute symptomatic venous thromboembolism . We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies . Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model . Three time windows were considered , i.e. the initial three weeks , after the third week onwards , and the entire duration of the anticoagulant treatment . Model discrimination was estimated using the C-statistic and vali date d internally by bootstrap techniques . Major bleeding occurred in 40 ( 1.0 % ) of 4130 patients receiving rivaroxaban and in 72 ( 1.7 % ) of 4116 receiving enoxaparin/VKAs , with 44 % of the major bleeding events occurring in the first three weeks of treatment . Significant risk factors for major bleeding were older age , black race , low haemoglobin concentrations , active cancer , and antiplatelet or non-steroidal anti-inflammatory drug therapy . The discrimination of the model for major bleeding was high for the first three weeks ( C-statistic 0.73 ) , from the fourth week onwards ( C-statistic 0.68 ) , and the entire period of anticoagulant treatment ( C-statistic 0.74 ) . This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism . The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation

Adverse events were nonsignificantly more frequent and serious with carvedilol . CONCLUSIONS Carvedilol reduces portal hypertension significantly more than propranolol . However , available data do not allow a satisfactory comparison of adverse events .

BACKGROUND Propranolol is recommended for prophylaxis of variceal bleeding in cirrhosis . Carvedilol is a nonselective beta-blocker with a mild anti-alfa-1-adrenergic activity . Several studies have compared carvedilol and propranolol , yielding inconsistent results . AIM To perform a systematic review and meta- analysis of the r and omised clinical trials comparing carvedilol with propranolol for hepatic vein pressure gradient reduction .

BACKGROUND / AIMS A total of 213 patients with compensated cirrhosis , portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices . Predictors of the development of hepatocellular carcinoma ( HCC ) , including hepatic venous pressure gradient ( HVPG ) were analyzed . METHODS Baseline laboratory tests , ultrasound and HVPG measurements were performed . Patients were followed prospect ively every three months until development of varices or variceal bleeding or end of the study in 09/02 . The endpoint was HCC development according to st and ard diagnostic criteria . Univariate and multivariate Cox regression models were developed to identify predictors of HCC . RESULTS In a median follow-up of 58 months 26/213 ( 12.2 % ) patients developed HCC . Eight patients were transplanted and 28 patients died without HCC . Twenty-one ( 84 % ) HCC developed in patients with HCV . On multivariate analysis HVPG ( HR 1.18 ; 95%CI 1.08 - 1.29 ) , albumin ( HR 0.34 ; 95%CI 0.14 - 0.83 ) and viral etiology ( HR 4.59 ; 95%CI 1.51 - 13.92 ) were independent predictors of HCC development . ROC curves identified 10 mmHg of HVPG as the best cut-off ; those who had an HVPG above this value had a 6-fold increase in the HCC incidence . CONCLUSIONS Portal hypertension is an independent predictor of HCC development . An HVPG > 10 mmHg is associated with a 6-fold increase of HCC risk Objective Non-selective β-blockers or endoscopic b and ligation ( EBL ) are recommended for primary prophylaxis of variceal bleeding in patients with oesophageal varices . Additional α-adrenergic blockade ( as by carvedilol ) may increase the number of patients with haemodynamic response ( reduction in hepatic venous pressure gradient ( HVPG ) of ≥20 % or to values < 12 mm Hg ) . Design Patients with oesophageal varices undergoing measurement of HVPG before and under propranolol treatment ( 80–160 mg/day ) were included . HVPG responders were kept on propranolol ( PROP group ) , while non-responders were placed on carvedilol ( 6.25–50 mg/day ) . Carvedilol responders continued treatment ( CARV group ) , while non-responders to carvedilol underwent EBL . The primary aim was to assess haemodynamic response rates to carvedilol in propranolol non-responders . Results 36 % ( 37/104 ) of patients showed a HVPG response to propranolol . Among the propranolol non-responders 56 % ( 38/67 ) eventually achieved a haemodynamic response with carvedilol , while 44 % ( 29/67 ) patients were finally treated with EBL . The decrease in HVPG was significantly greater with carvedilol ( median 12.5 mg/day ) than with propranolol ( median 100 mg/day ) : −19±10 % versus −12±11 % ( p<0.001 ) . During a 2 year follow-up bleeding rates for PROP were 11 % versus CARV 5 % versus EBL 25 % ( p=0.0429 ) . Fewer episodes of hepatic decompensation ( PROP 38%/CARV 26 % vs EBL 55 % ; p=0.0789 ) and significantly lower mortality ( PROP 14%/CARV 11 % vs EBL 31 % ; p=0.0455 ) were observed in haemodynamic responders compared to the EBL group . Conclusions Carvedilol leads to a significantly greater decrease in HVPG than propranolol . Using carvedilol for primary prophylaxis a substantial proportion of non-responders to propranolol can achieve a haemodynamic response , which is associated with improved outcome with regard to prevention of variceal bleeding , hepatic decompensation and death UNLABELLED Current therapy for preventing the first variceal bleed includes beta-blocker and variceal b and ligation ( VBL ) . VBL has lower bleeding rates , with no differences in survival , whereas beta-blocker therapy can be limited by side effects . Carvedilol , a non-cardioselective vasodilating beta-blocker , is more effective in reducing portal pressure than propranolol ; however , there have been no clinical studies assessing the efficacy of carvedilol in primary prophylaxis . The goal of this study was to compare carvedilol and VBL for the prevention of the first variceal bleed in a r and omized controlled multicenter trial . One hundred fifty-two cirrhotic patients from five different centers with grade II or larger esophageal varices were r and omized to either carvedilol 12.5 mg once daily or VBL performed every 2 weeks until eradication using a multib and er device . Seventy-seven patients were r and omized to carvedilol and 75 to VBL . Baseline characteristics did not differ between the groups ( alcoholic liver disease , 73 % ; median Child-Pugh score , 8 ; median age , 54 years ; median follow-up , 20 months ) . On intention-to-treat analysis , carvedilol had lower rates of the first variceal bleed ( 10 % versus 23 % ; relative hazard 0.41 ; 95 % confidence interval 0.19 - 0.96 [ P = 0.04 ] ) , with no significant differences in overall mortality ( 35 % versus 37 % , P = 0.71 ) , and bleeding-related mortality ( 3 % versus 1 % , P = 0.26 ) . Six patients in the VBL group bled as a result of b and ing ulcers . Per- protocol analysis revealed no significant differences in the outcomes . CONCLUSION Carvedilol is effective in preventing the first variceal bleed . Carvedilol is an option for primary prophylaxis in patients with high-risk esophageal varices BACKGROUND AND AIMS Newer studies suggest that carvedilol , a beta-blocker with a moderate anti-alpha-1 activity , is superior to propranolol in reducing the portal pressure and risk of variceal bleeding . The effect on arterial blood pressure is a matter of concern especially in decompensated patients . AIMS to assess potential differential effects of beta-blockers and beta-blockers with moderate anti-alpha-1 activity on selected haemodynamic , humoral , and respiratory characteristics in cirrhosis . METHODS Patients with cirrhosis and portal hypertension were r and omised to receive carvedilol ( n=16 ) or propranolol ( n=13 ) . Cardiac , systemic and splanchnic parameters along with oxygen saturation and plasma renin were measured at inclusion and after 3 months . RESULTS Arterial blood pressure , heart rate , and cardiac output decreased equally , central circulation time and systemic vascular resistance increased significantly but similarly . Central blood volume , plasma volume and arterial compliance were unaltered . The QTc interval and renin levels decreased in the carvedilol group , however not significantly different from the propranolol group . Arterial oxygen saturation and alveolar arterial oxygen gradient remained constant in both groups . Hepatic venous pressure gradient decreased equally in the carvedilol and propranolol groups ( -17 % and -20 % , non significant ) . CONCLUSIONS Systemic haemodynamics and pulmonary effects of carvedilol and propranolol are modest and this study could not demonstrate any significant difference between the two treatments OBJECTIVE : Propranolol is known to decrease portal pressure in cirrhotic patients with portal hypertension ; however , a substantial number of patients do not respond to propranolol administration . The addition of isosorbide-5-mononitrate may enhance portal pressure reduction in patients receiving propranolol . Carvedilol is a nonselective β-blocker with α1-adrenergic blocking activity . It has been shown to decrease portal pressure in cirrhotic patients . Additionally , carvedilol has a greater portal hypotensive effect than propranolol alone in patients with cirrhosis . The current study is aim ed at comparing the acute hemodynamic effects of carvedilol with the effects of propranolol plus isosorbide-5-mononitrate in patients with viral cirrhosis . METHODS : Patients with viral cirrhosis were r and omly assigned to receive an oral administration of carvedilol of 25 mg ( n = 11 ) or an oral administration of propranolol 40 mg plus isosorbide-5-mononitrate 20 mg ( n = 11 ) . Hemodynamic values were measured at basal and 90 min after drugs administration . RESULTS : Both carvedilol and propranolol plus isosorbide-5-mononitrate significantly decreased cardiac index , heart rate , and HVPG . The magnitude of changes in HVPG observed between the basal and after drugs administration was greater in patients receiving carvedilol than in those receiving propranolol plus isosorbide-5-mononitrate ( −18.6 ± 3.6 % vs−10.1 ± 3.6 % , p < 0.05 ) . Hepatic blood flow increased following carvedilol administration but remained unchanged in patients receiving propranolol plus isosorbide-5-mononitrate . The magnitude of decrease in mean arterial pressure ( MAP ) did not differ between the two groups of patients . CONCLUSION : In our patients with viral cirrhosis , carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of HVPG . Carvedilol administration causes an increase in hepatic blood flow , but its systemic effects were similar to those of propranolol plus isosorbide-5-mononitrate BACKGROUND Carvedilol , a non-selective beta- and alpha-1 blocking agent , has portal hypotensive action . This study evaluates the acute and 7-day response to carvedilol , and compares it to that of propranolol . METHODS Thirty-six cirrhotics were r and omized into two groups of 18 each , and treated with carvedilol or propranolol . Hepatic venous pressure gradient ( HVPG ) was measured before and 90 min after either 25 mg carvedilol or 80 mg propranolol was administered orally , and again 7 days after 12.5 mg carvedilol daily or 80 mg propranolol daily , respectively . ' Responders ' were defined as those with HVPG reduction of > or = 20 % . RESULTS With carvedilol , 11/18(61.1 % ) and 11/17(64.7 % ) patients responded acutely and after 7 days , respectively , while 9/18(50 % ) and 10/16(62.5 % ) did so to propranolol . However , HVPG reduction ( percent ) by carvedilol was not superior to that by propranolol either acutely ( 27.67 + /- 31.49 compared to 22.98 + /- 27.40 , P = 0.6 ) or after 7 days ( 28.2 + /- 29.05 compared to 23.25 + /- 20.15 , P = 0.6 ) . With carvedilol , the acute HVPG response ( P < 0.001 ) and responder status ( P = 0.018 ) were good predictors of the response after 7 days , but were weak predictors in the case of propranolol ( 0.1 > P > 0.05 and P = 0.059 , respectively ) . On carvedilol , only one patient ( with ascites ) developed symptomatic systemic hypotension with oliguria . CONCLUSION Carvedilol is a relatively safe , effective portal hypotensive agent , both acutely and over 7 days , but not superior to propranolol , at least in Indians . The acute hemodynamic response seems promising in predicting long-term response BACKGROUND AND AIMS Our aim was to identify predictors of clinical decompensation ( defined as the development of ascites , variceal hemorrhage [ VH ] , or hepatic encephalopathy [ HE ] ) in patients with compensated cirrhosis and with portal hypertension as determined by the hepatic venous pressure gradient ( HVPG ) . METHODS We analyzed 213 patients with compensated cirrhosis and portal hypertension but without varices included in a trial evaluating the use of beta-blockers in preventing varices . All had baseline laboratory tests and HVPG . Patients were followed prospect ively every 3 months until development of varices or VH or end of study . To have complete information , until study termination , about clinical decompensation , medical record review was done . Patients who underwent liver transplantation without decompensation were censored at transplantation . Cox regression models were developed to identify predictors of clinical decompensation . Receiver operating characteristic ( ROC ) curves were constructed to evaluate diagnostic capacity of HVPG . RESULTS Median follow-up time of 51.1 months . Sixty-two ( 29 % ) of 213 patients developed decompensation : 46 ( 21.6 % ) ascites , 6 ( 3 % ) VH , 17 ( 8 % ) HE . Ten patients received a transplant and 12 died without clinical decompensation . Median HVPG at baseline was 11 mm Hg ( range , 6 - 25 mm Hg ) . On multivariate analysis , 3 predictors of decompensation were identified : HVPG ( hazard ratio [ HR ] , 1.11 ; 95 % confidence interval [ CI ] , 1.05 - 1.17 ) , model of end-stage liver disease ( MELD ) ( HR , 1.15 ; 95 % CI , 1.03 - 1.29 ) , and albumin ( HR , 0.37 ; 95 % CI , 0.22 - 0.62 ) . Diagnostic capacity of HVPG was greater than for MELD or Child-Pugh score . CONCLUSIONS HVPG , MELD , and albumin independently predict clinical decompensation in patients with compensated cirrhosis . Patients with an HVPG < 10 mm Hg have a 90 % probability of not developing clinical decompensation in a median follow-up of 4 years BACKGROUND & AIMS The association of prazosin to propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention . The aim of this study was to compare the portal pressure reduction and safety of the combination of propranolol plus prazosin with that of propranolol plus isosorbide-5-mononitrate ( ISMN ) . METHODS Fifty-six portal-hypertensive cirrhotics received r and omly propranolol plus prazosin ( n = 28 ) or propranolol plus ISMN ( n = 28 ) orally for 3 months . Hemodynamics and liver and renal function were assessed at baseline and after 3 months . RESULTS Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient ( HVPG ) than propranolol plus ISMN ( -24.2 % + /- 11 % vs. -16.1 % + /- 11 % ; P < 0.01 ) . A reduction in HVPG of > 20 % was significantly more frequent in the propranolol plus prazosin group than in the propranolol plus ISMN group ( 85 % vs. 53 % ; P < 0.05 ) . Neither treatment modified hepatic blood flow , quantitative liver function test results , glomerular filtration rate , plasma renin activity , or plasma aldosterone level . Side effects occurred in 13 patients receiving propranolol plus prazosin compared with 7 receiving propranolol plus ISMN ( P = 0.16 ) . CONCLUSIONS Propranolol plus prazosin has a greater portal pressure-lowering effect than propranolol plus ISMN . Both therapies were safe for liver and renal function . However , the combination of propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than propranolol plus ISMN BACKGROUND AND AIM Carvedilol has been shown to be more effective than propranolol in decreasing portal pressure . Sufficient data from controlled trials remains limited . This trial compared the relative safety and efficacy between carvedilol and nadolol plus isosorbide mononitrate in preventing variceal rebleeding . METHODS After successful control of acute esophageal variceal bleeding , eligible patients were r and omized to the carvedilol group , 61 patients , using carvedilol 6.25 - 12.5 mg daily or the N + I group , 60 patients , using nadolol 40 - 80 mg plus isorsorbide-5-mononitrate 20 mg daily . The end points were rebleeding from varices , adverse events or death . RESULTS After a median follow up of 30 months , recurrent upper gastrointestinal bleeding developed in 37 patients ( 61 % ) in the carvedilol group and 37 patients ( 62 % ) in the N + I group ( P = 0.90 ) . Recurrent bleeding from esophageal varices occurred in 31 patients ( 51 % ) in the carvedilol group and in 26 patients ( 43 % ) in the N + I group ( P = 0.46 ) . Recurrent bleeding from gastric varices occurred in two patients ( 3 % ) in the carvedilol group and in eight patients ( 13 % ) in the N + I group ( P = 0.05 ) . Severe adverse events occurred in one patient in the carvedilol group and 17 patients in the N + I group ( P < 0.0001 ) . Fifteen patients of the carvedilol group and 17 patients in the N + I group died ( P = 0.83 ) . Two patients in the carvedilol group and three patients in the N + I group died of variceal bleeding . CONCLUSIONS Carvedilol was as effective as nadolol plus isorsorbide-5 -mononitrate mononitrate in the prevention of gastroesophageal variceal rebleeding with fewer severe adverse events and similar survival Abstract Objectives . Carvedilol is a non-selective β-blocker with intrinsic anti-α1-adrenergic activity , potentially more effective than propranolol in reducing hepatic venous pressure gradient ( HVPG ) . We compared the long-term effect of carvedilol and propranolol on HVPG and assessed whether the acute response to oral propranolol predicted the long-term HVPG response on either drug . Material and methods . HVPG was measured in 38 patients with cirrhosis and HVPG ≥ 12 mm Hg at baseline and then again 90 min after an oral dose of 80 mg propranolol . Patients were double-blinded r and omized to either carvedilol ( 21 patients ) or propranolol ( 17 patients ) and after 90 days of treatment HVPG measurements were repeated . Results . HVPG decreased by 19.3 ± 16.1 % ( p < 0.01 ) and by 12.5 ± 16.7 % ( p < 0.01 ) in the carvedilol and propranolol groups , respectively , with no significant difference between treatment regimens ( p = 0.21 ) . Although insignificant , an acute decrease in HVPG of ≥12 % was the best cut-off value to predict long-term HVPG response to propranolol when using ROC curve analysis . Conclusions . This r and omized study showed that carvedilol is at least as effective as propranolol on HVPG after long-term administration . Furthermore , a predictive value of an acute propranolol test on HVPG could not be confirmed Short‐term carvedilol administration is more powerful than propranolol in decreasing hepatic venous pressure gradient ( HVPG ) in cirrhotic patients , but induces arterial hypotension that may prevent its long‐term use in portal hypertensive patients . This study compared the HVPG reduction and safety of long‐term carvedilol and propranolol . Fifty‐one cirrhotic patients were r and omly assigned to receive carvedilol ( n = 26 ) and propranolol ( n = 25 ) . Hemodynamic measurements and renal function were assessed at baseline and after 11.1 ± 4.1 weeks . Carvedilol caused a greater decrease in HVPG than popranolol ( − 19 ± 2 % vs. − 12 ± 2 % ; P < 0.001 ) . The proportion of patients achieving an HVPG reduction ⩾20 % or ⩽ 20 mm Hg was greater after carvedilol ( 54 % vs. 23 % ; P < 0.05 ) . Carvedilol , but not propranolol caused a significant decrease in mean arterial pressure ( MAP ) ( – 11 ± 1 % vs. – 5 ± 3 % ; P = 0.05 ) and a significant increase in plasma volume ( PV ) and body weight ( 11 ± 5 % and 2 ± 1 % , respectively ; P < 0.05 ) . Glomerular filtration rate ( GFR ) was unchanged with either drug , but the dose of diuretics was increased more frequently after carvedilol ( 27 % vs. 8 % P = 0.07 ) . Adverse events requiring discontinuation of treatment occurred in 2 patients receiving carvedilol and in 3 receiving propranolol . In conclusion , carvedilol has a greater portal hypotensive effect than propranolol in patients with cirrhosis . However , its clinical applicability may be limited by its systemic hypotensive effects . Further trials are needed to confirm the therapeutic potential of carvedilol . ( HEPATOLOGY2002;36:1367–1373 ) In patients with variceal bleeding as a complication of hepatic cirrhosis , propranolol therapy reduces the risk of recurrent variceal haemorrhage . However , the relation between portal pressure response to pharmacological treatment and clinical events has not been well defined . This relation was prospect ively investigated in 69 cirrhotic patients receiving continued propranolol therapy after an episode of variceal bleeding . Hepatic venous pressure gradient ( HVPG ) was measured before and at 3 months of continued drug therapy . At 3 months HVPG had fallen by 20 % or more in 25 patients . During follow-up of 28 ( SD 17 ) months rebleeding occurred in 2 of these 25 patients compared with 23 of 44 who had lesser reductions in HVPG . Cumulative probability of rebleeding at 1 , 2 , and 3 years was 4 % , 9 % , and 9 % in patients with a decrease in HVPG > or = 20 % , and 28 % , 39 % , and 66 % in patients with a decrease in HVPG < 20 % ( p < 0.001 , log-rank test ) . On multivariate analysis , a decrease in HVPG > or = 20 % was the only independent predictor of rebleeding ( relative risk 0.09 , 95 % CI 0.02 - 0.41 . Of the 8 patients in whom the HVPG fell to 12 mm Hg or less , none rebled . This study suggests that measurement of the HVPG response to pharmacotherapy will provide useful prognostic information on the long-term risk of variceal rebleeding In an attempt to identify variables predicting prognosis , 100 consecutive patients with compensated cirrhosis of the liver were followed for a mean of 4.9 ( SD 0.7 ) yr . Fifty-one patients belonged to Child-Pugh class A , 49 to class B. At entry , five laboratory parameters were considered , together with sex , the grade of esophageal varices , and seven variables measured by ultrasonography ( liver and spleen volume and the calibers of the splanchnic vessels ) . In a subgroup of 56 patients , the galactose elimination capacity also was determined . Forty-six patients were alive at the end of follow-up . Survival was analyzed according to Cox 's model . Six parameters were able to predict survival ( albumin , bilirubin , liver volume , prothrombin activity , cholesterol , varices ) . However , step-wise Cox regression analysis identified only four variables that independently correlated with survival : albumin , bilirubin , cholesterol , and liver volume . Galactose elimination failed to add any significance to routine liver function tests . This prospect i ve study confirms the ability of routine liver function tests in predicting survival in compensated cirrhosis . The measurement of liver volume , easily obtained by ultrasonography , is also significant for prognosis , and may be introduced into clinical practice The gradient between wedged and free hepatic venous pressures was measured in patients with alcoholic cirrhosis before and 1 , 3 , and 9 months after continuous oral administration of propranolol at doses reducing the heart rate by 25 % or after administration of a placebo . The gradient between wedged and free hepatic venous pressures decreased throughout the duration of propranolol administration , and it did not significantly change in the patients receiving placebo . Since the gradient between wedged and free hepatic venous pressures closely reflects portal venous pressure in alcoholic cirrhosis , it is concluded that continuous oral administration of propranolol produced sustained reduction in portal venous pressure in these patients

The literature used has shown that the population of kidney transplant patients is exposed to a high risk of psychiatric disorders with repercussions on the quality of life and the risk of rejection .

Kidney transplantation is a serious event that involves profound psychological , relational and social changes both for the patient and his family context . Assessment of personality profile , awareness of disease , family and social support of the patient c and i date for kidney transplantation are necessary because factors not adequately considered , can influence the success of the transplant and alter the psychological stability of the patient . The present study aims to provide a systematic review of the literature of the last twelve years ( 2006–2018 ) , focusing in particular on patient ’s readiness level and illness management and on possible psychopathology .

Background Little research has explored pre-transplantation psychological factors as predictors of outcome after liver or kidney transplantation . Our objective is to determine whether report of depressive symptoms on waiting list predicts outcome of liver and kidney transplantation . Methods Patients on waiting list for liver or kidney transplantation were classified for report or non-report of depressive symptoms on waiting list . 339 were transplanted 6 months later on average , and followed prospect ively . The main outcome measures were graft failure and mortality 18 months post-transplantation . Results Among the 339 patients , 51.6 % reported depressive symptoms on waiting list , 16.5 % had a graft failure and 7.4 % died post-transplantation . Report of depressive symptoms on waiting list predicted a 3 to 4-fold decreased risk of graft failure and mortality 18-months post-transplantation , independently from age , gender , current cigarette smoking , anxiety symptoms , main primary diagnosis , UNOS score , number of comorbid diagnoses and history of transplantation . Data were consistent for liver and kidney transplantations . Other baseline predictive factors were : for graft failure , the main primary diagnosis and a shorter length since this diagnosis , and for mortality , older age , male gender and the main primary diagnosis . Conclusion Further studies are needed to underst and the underlying mechanisms of the association between report of depressive symptoms on waiting list and decreased risk of graft failure and mortality after transplantation Background Little is known how health related quality of life ( HRQOL ) change in the transition from dialysis to renal transplantation ( RTX ) . Longitudinal data addressing the patient-related outcomes are scarce , and particularly data regarding kidney-specific HRQOL are lacking . Thus , the aim of the current study was to assess HRQOL in patients followed from dialysis to RTX . Furthermore , to compare HRQOL in RTX patients and the general population . Methods In a prospect i ve study , HRQOL was measured in a cohort of 110 patients ( median age 53.5 ( IQR 39–62 ) years , GFR 54 ( 45–72 ) ml/min/1.73 m2 ) in dialysis and after RTX using the self-administered Kidney Disease and Quality of Life Short Form version 1.3 ( KDQOL-SF ) . Generic HRQOL in the RTX patients was compared to that of the general population ( n = 5903 ) using the SF-36 . Clinical important change after RTX was defined as difference in HRQOL of SD/2 . Results Follow-up time was 55 ( IQR 50–59 ) months , and time after RTX was 41 ( 34–51 ) months . Four of nine domains in kidney-specific HRQOL improved after RTX , i.e. burden of kidney disease , effect of kidney disease , symptoms and work status . In SF-36 , general health , vitality , social function and role physical improved after RTX , but none of the domains improved sufficiently to be regarded as clinical ly relevant change . There were highly significant differences in HRQOL between RTX patients and the general population after adjustment for age and gender for all items of SF-36 except for bodily pain and mental health . Conclusions HRQOL improved in the transition from dialysis to transplantation , but clinical relevant change was only obtained in the kidney specific domains . HRQOL was perceived considerably poorer in RTX patients than in the general population . Our observations point to the need of improving HRQOL even after RTX , and should encourage further longitudinal research and clinical attention during treatment shift Background The high frequency of outpatient visits after kidney transplantation is burdensome to both the recovering patient and health care capacity . Self-monitoring kidney function offers a promising strategy to reduce the number of these outpatient visits . Objective The objective of this study was to investigate whether it is safe to rely on patients ’ self- measurements of creatinine and blood pressure , using data from a self-management r and omized controlled trial . Methods For self-monitoring creatinine , each participant received a StatSensor Xpress-i Creatinine Meter and related test material . For self-monitoring blood pressure , each participant received a Microlife WatchBP Home , an oscillometric device for blood pressure self-measurement on the upper arm . Both devices had a memory function and the option to download stored values to a computer . During the first year post transplantation , 54 patients registered their self-measured creatinine values in a Web-based Self-Management Support System ( SMSS ) which provided automatic feedback on the registered values ( eg , seek contact with hospital ) . Values registered in the SMSS were compared with those logged automatically in the creatinine device to study reliability of registered data . Adherence to measurement frequency was determined by comparing the number of requested with the number of performed measurements . To study adherence to provided feedback , SMSS-logged feedback and information from the electronic hospital files were analyzed . Results Level of adherence was highest during months 2 - 4 post transplantation with over 90 % ( 42/47 ) of patients performing at least 75 % of the requested measurements . Overall , 87.00 % ( 3448/3963 ) of all registered creatinine values were entered correctly , although values were often registered several days later . If ( the number of ) measured and registered values deviated , the mean of registered creatinine values was significantly lower than what was measured , suggesting active selection of lower creatinine values . Adherence to SMSS feedback ranged from 53 % ( 14/24 ) to 85 % ( 33/39 ) , depending on the specific feedback . Conclusions Patients ’ tendency to postpone registration and to select lower creatinine values for registration and the suboptimal adherence to the feedback provided by the SMSS might challenge safety . This should be well considered when design ing self-monitoring care systems , for example by ensuring that self-measured data are transferred automatically to an SMSS ABSTRACT We assessed salivary melatonin levels in renal transplant ( RTx ) recipients who participated in a r and omised , multicentre wait-list controlled trial on the effect of bright light therapy on their sleep and circadian rhythms . A large proportion of RTx recipients in our cohort had unexpectedly low melatonin values , which precluded calculation of the dim-light melatonin onset ( DLMO ) as a circadian marker . Thus , the aim of this post hoc analysis was to describe the melatonin profile of home-dwelling RTx recipients diagnosed with sleep – wake disturbances ( SWDs ) . The participants were characterised by means of sleep question naires , vali date d psychometric instruments [ Pittsburgh sleep quality Index ( PSQI ) , Epworth sleepiness scale ( ESS ) , Morningness-Eveningness Question naire ( MEQ ) and Depression , Anxiety and Stress Scale ( DASS ) ] in addition to melatonin assay in saliva . Data were analysed with descriptive statistics and group comparisons made with appropriate post hoc tests . RTx recipients [ n = 29 ( aged 54.83 ± 13.73 , transplanted 10.62 ± 6.84 years ago ) ] were retrospectively grouped into two groups : RTx recipients whose dim light melatonin onset ( DLMO ) could be calculated ( n = 11 ) and those whose DLMO could not be calculated ( n = 18 ) . RTx recipients having a measurable DLMO had a number of differences from those without DLMO : they were younger [ 46.4 ± 14.9 compared to 60.0 ± 10.3 ( p = .007 ) ] , had higher haemoglobin values [ 135.36 ± 12.01 versus 122.82 ± 11.56 ( p = .01 ) ] , less anxiety [ 4 ( 0;8 ) versus 12 ( 6.5;14 ) ( p = .021 ) ] and a better overall sense of coherence [ SOC Score : 71.09 ± 12.78 versus 56.28 ± 15.48 ( p = 0.013 ) ] . These results suggest that RTx recipients whose DLMO could be calculated have less health impairments , underlying the relevance of a stable circadian system This study assessed the effect and feasibility of morning bright light therapy ( BLT ) on sleep , circadian rhythms , subjective feelings , depressive symptomatology and cognition in renal transplant recipients ( RTx ) diagnosed with sleep-wake disturbances ( SWD ) . This pilot r and omized multicentre wait-list controlled trial included 30 home-dwelling RTx r and omly assigned 1:1 to either 3 weeks of BLT or a wait-list control group . Morning BLT ( 10 000 lux ) was individually scheduled for 30 min daily for 3 weeks . Wrist actimetry ( measuring sleep and circadian rhythms ) , vali date d instruments ( subjective feelings and cognition ) and melatonin assay ( circadian timing ) were used . Data were analysed via a r and om-intercept regression model . Of 30 RTx recipients ( aged 58 ± 15 , transplanted 15 ± 6 years ago ) , 26 completed the study . While BLT had no significant effect on circadian and sleep measures , sleep timing improved significantly . The intervention group showed a significant get-up time phase advance from baseline to intervention ( + 24 min ) [ ( st and ardized estimates ( SE ) : -0.23 ( -0.42 ; -0.03 ) ] and a small ( + 14 min ) but significant bedtime phase advance from intervention to follow-up ( SE : -0.25 ( -0.41 ; -0.09 ) . Improvement in subjective feelings and depressive symptomatology was observed but was not statistically significant . Bright light therapy showed preliminary indications of a beneficial effect in RTx with sleep-wake disturbances . ( Clinical Trials.gov number : NCT01256983 ) End-stage renal disease ( ESRD ) is a serious public health problem . The study of the impact of renal replacement therapy ( RRT ) in quality of life ( QoL ) has become increasingly important . The aim of this study was to evaluate the QoL of patients on RRT and associated factors . 3036 patients on RRT in Brazil were interviewed in relation to socioeconomic , demographic , clinical and QoL aspects . Patients were r and omly selected after a cluster sampling process on two levels : health services and patients . QoL was measured by Eq5D . The instrument allows the indirect measurement of QoL and utility calculation , in addition to the direct measurement of QoL by a visual analog scale ( VAS ) . It was observed that transplant patients have better QoL and that the most prejudicial aspects are pain/discomfort and anxiety/depression . The main factors associated with QOL are age , female gender , variables associated with the clinical condition of the patient such as the need for hospitalization and the presence of comorbidities , social class and variables associated with the health service use . The correlation between VAS and utility calculated was moderate and the 5 Eq5D questions explain 43 % of the variability of VAS . The calculated utility can be used in cost-utility analysis Non‐adherence with immunosuppressive regimen is a major risk factor for poor outcome after kidney transplantation . Identifying patients at risk for non‐adherence requires underst and ing the risk factors for non‐adherence . This prospect i ve study included a convenience sample of 249 adult kidney transplant patients > 1 year post‐transplant . Non‐adherence was monitored electronically using MEMS ® . Selected socio‐economic , therapy‐ , patient‐ , condition‐ and healthcare team‐related risk factors for non‐adherence were assessed . Period prevalences were expressed as the percent of prescribed doses taken ( taking adherence ) , the percent of correctly dosed days ( dosing adherence ) , the percentage of inter‐dose intervals not exceeding 25 % of the prescribed interval ( timing adherence ) , and the number of drug holidays per 100 days ( no intake for > 48 h if once daily or for > 24 h if twice daily intake ) . Testing occurred by simple mixed logistic regression analysis . Factors significant after correction for multiple testing were entered into a multiple logistic regression model . Mean taking , dosing , timing adherence , and drug holidays were 98 % , 96 % , 93 % , and 1.1 days , respectively . Non‐adherence was associated with lower self‐efficacy , higher self‐reported non‐adherence , no pillbox usage , and male gender . Adherence declined between Monday and Sunday . This study provides a framework for identifying patients at risk for non‐adherence and for developing adherence‐enhancing interventions INTRODUCTION The aim of this study was to compare the effect of continuous care model with routine care on the quality of life among patients who receive a kidney transplant . MATERIAL S AND METHODS In a r and omized clinical trial , 90 kidney transplant patients were selected from 4 hospitals in Tehran , Iran , and were r and omly assigned to 2 group . In the experimental group , continuous care model was applied for 3 months and the control group received routine care . The scale scores of the Kidney Transplant Question naire concerning quality of life were monthly compared between the two groups . RESULTS Of 90 patients , 4 in the experimental and 8 in the control group were excluded from the study . Final analysis was performed on 41 in the experimental and 37 in the control groups . No significant difference was found between the two groups in terms of demographic variables . Although the quality of life scores increased in both groups , the mean scores of the experimental group were significantly higher than those in the control group at 1 , 2 , and 3 months . CONCLUSIONS Continuous care model may improve the kidney transplant patients ' quality of life 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 Background Health-related quality of life ( HRQOL ) reflects a patient ’s disease burden , treatment effectiveness , and health status and is summarized by physical , mental , and kidney disease-specific scales among end-stage renal disease patients . Although on average HRQOL improves postkidney transplant ( KT ) , the degree of change depends on the ability of the patient to withst and the stressor of dialysis versus the ability to tolerate the intense physiologic changes of KT . Frail KT recipients may be extra vulnerable to either of these stressors , thus affecting change in HRQOL after KT . Methods We ascertained frailty , as well as physical , mental , and kidney disease-specific HRQOL in a multicenter prospect i ve cohort of 443 KT recipients ( May 2014 to May 2017 ) using Kidney Disease Quality of Life Instrument Short Form . We quantified the short-term ( 3 months ) rate of post-KT HRQOL change by frailty status using adjusted mixed-effects linear regression models . Results Mean HRQOL scores at KT were 43.3 ( SD , 9.6 ) for physical , 52.8 ( SD , 8.9 ) for mental , and 72.6 ( SD , 12.8 ) for kidney disease-specific HRQOL ; frail recipients had worse physical ( P < 0.001 ) and kidney disease-specific HRQOL ( P = 0.001 ) , but similar mental HRQOL ( P = 0.43 ) . Frail recipients experienced significantly greater rates of improvement in physical HRQOL ( frail , 1.35 points/month ; 95 % confidence interval [ CI ] , 0.65 - 2.05 ; nonfrail , 0.34 points/month ; 95 % CI , −0.17 - 0.85 ; P = 0.02 ) and kidney disease-specific HRQOL ( frail , 3.75 points/month ; 95 % CI , 2.89 - 4.60 ; nonfrail , 2.41 points/month ; 95 % CI , 1.78 - 3.04 ; P = 0.01 ) , but no difference in mental HRQOL ( frail , 0.54 points/month ; 95 % CI , −0.17 - 1.25 ; nonfrail , 0.46 points/month ; 95 % CI , −0.06 - 0.98 ; P = 0.85 ) post-KT . Conclusions Despite decreased physiologic reserve , frail recipients experience improvement in post-KT physical and kidney disease-specific HRQOL better than nonfrail recipients Under the auspices of the United Network for Organ Sharing , the American Society of Transplant Surgeons and the American Society of Transplantation , a meeting was convened on May 25 , 2006 , in Washington , DC , to develop guidelines for the psychosocial evaluation of prospect i ve living kidney donors who have neither a biologic nor longst and ing emotional relationship with the transplant c and i date . These ‘ unrelated ’ donors are increasingly often identified by transplant c and i date s via the Internet , print media and other public appeals . The expansion of living donor kidney transplantation to include significant numbers of donors with little to no preexisting relationship to the c and i date has caused concern in the medical community regarding such psychosocial factors as donor psychological status , motivation , knowledge about donation and the potential for undue pressure to donate under some circumstances . Therefore , experts in mental health ; psychosocial , behavioral and transplant medicine ; and medical ethics met to specify ( a ) characteristics of unrelated donors that increase their risk for , or serve as protective factors against , poor donor psychosocial outcomes , ( b ) basic principles underlying informed consent and evaluation processes pertinent to these donors and ( c ) the process and content of the donor psychosocial evaluation . The meeting deliberations result ed in the recommendations made in this report CONTEXT Patients who have received solid organ transplants continue to experience a myriad of complex symptoms related to their underlying disease and to chronic immunosuppression that reduce the quality of life . Beneficial nonpharmacologic therapies to address these symptoms have not been established in the transplant population . OBJECTIVE Assess the efficacy of mindfulness-based stress reduction ( MBSR ) in reducing symptoms of anxiety , depression , and poor sleep in transplant patients . DESIGN , SETTING , AND PATIENTS Controlled trial with a two-staged r and omization . Recipients of kidney , kidney/pancreas , liver , heart , or lung transplants were r and omized to MBSR ( n=72 ) or health education ( n=66 ) initially or after serving in a waitlist . Mean age was 54 years ( range 21 - 75 ) ; 55 % were men , and 91 % were white . INTERVENTIONS MBSR , a mindfulness meditation training program consisting of eight weekly 2.5-hour classes ; health education , a peer-led active control . PRIMARY OUTCOME MEASURES Anxiety ( State-Trait Anxiety Inventory ) , depression ( Center for Epidemiologic Studies Depression Scale ) , and sleep quality ( Pittsburgh Sleep Quality Index ) scales assessed by self-report at baseline , 8 weeks , 6 months , and 1 year . RESULTS Benefits of MBSR were above and beyond those afforded by the active control . MBSR reduced anxiety and sleep symptoms ( P < .02 ) , with medium treatment effects ( .51 and .56 ) at 1 year compared to health education in intention-to-treat analyses . Within the MBSR group , anxiety , depression , and sleep symptoms decreased and quality -of-life measures improved by 8 weeks ( P < .01 , all ) , and benefits were retained at 1 year ( P < .05 , all ) . Initial symptom reductions in the health education group were smaller and not sustained . Comparisons to the waitlist confirmed the impact of MBSR on both symptoms and quality of life , whereas health education improvements were limited to quality -of-life ratings . CONCLUSIONS MBSR reduced distressing symptoms of anxiety , depression , and poor sleep and improved quality of life . Benefits were sustained over 1 year . A health education program provided fewer benefits , and effects were not as durable . MBSR is a relatively inexpensive , safe , and effective community-based intervention Context Dialysis patients ' lifestyles are associated with low levels of physical activity , increasing the chances of being removed from kidney waiting lists or dying while awaiting transplant because of increased cardiovascular risk factors and deteriorating health conditions . Personalized mobile health ( mHealth ) delivered programs may support their engagement in healthier lifestyles , maintain transplant eligibility , and reduce premature mortality . Objective To explore barriers and perceptions of physical activity behaviors and gauge interest in using mHealth in a physical activity wellness program for dialysis patients on the kidney transplant waiting list . Participants and Design In-depth key informant interviews were conducted with 22 r and omly selected dialysis patients during dialysis treatment in an urban Southeastern coastal city . A theory-guided community-based participatory research approach was used to develop the interview content . Constructivist grounded theory guided the data analysis using NVIVO 10 ( QSR Int ) . The 32-item checklist from the Consoli date d Criteria for Reporting Qualitative Studies was used in the qualitative reporting . Results Dialysis patients had a mean age of 46 ( SD , 10.7 ) years , 45 % were female , and 82 % were African American . Their mean duration on transplant waiting lists was 6.7 ( SD 4.3 ) years , and 73 % owned smartphones . After saturation was reached , predominant themes included ( 1 ) physical activity was perceived as optional , ( 2 ) social support both encouraged and limited physical activity , ( 3 ) chronic stress and coping influenced physical activity , ( 4 ) spirituality provided strength to engage in physical activity , ( 5 ) self-care management practice s varied considerably , and ( 6 ) high interest ( 95 % ) for using mHealth to promote physical activity was found . Patients preferred their home and neighborhood environments to intradialytic setting s for engaging in physical activity BACKGROUND While medical criteria have been well established for each end-organ system , psychosocial listing criteria are less st and ardized . To address this limitation , we developed and tested a new assessment tool : the Stanford Integrated Psychosocial Assessment for Transplantation ( SIPAT ) . METHODS The SIPAT was developed from a comprehensive review of the literature on the psychosocial factors that impact transplant outcomes . Five examiners blindly applied the SIPAT to 102 r and omly selected transplant cases , including liver , heart , and lung patients . After all subject 's files had been rated by the examiners , the respective transplant teams provided the research team with the patient 's outcome data . RESULTS Univariate logistic regression models were fit in order to predict the transplant psychosocial outcome ( positive or negative ) using each rater 's SIPAT scores . These results show that SIPAT scores are highly predictive of the transplant psychosocial outcome ( P < 0.0001 ) . The instrument has excellent inter-rater reliability ( Pearson 's correlation coefficient = 0.853 ) , even among novice raters . CONCLUSIONS The SIPAT is a comprehensive screening tool to assist in the psychosocial assessment of organ transplant c and i date s. Its strengths includes the st and ardization of the evaluation process and its ability to identify subjects who are at risk for negative outcomes after the transplant , in order to allow for the development of interventions directed at improving the patient 's c and idacy . Our goal is that the SIPAT , in addition to a set of agreed upon minimal psychosocial listing criteria , would be used in combination with organ-specific medical listing criteria in order to establish st and ardized criteria for the selection of transplant recipients

Conclusions Tai Chi may represent an appropriate alternative or complement to st and ard rehabilitation programs .

Background Tai Chi is a systematic whole body movement developed in ancient China . It plays an increasingly important role in the field of pulmonary rehabilitation for patients with chronic obstructive pulmonary disease ( COPD ) . Our review aim ed to explore the impact of Tai Chi on the physical and mental health of patients with COPD .

Background In COPD , functional status is improved by pulmonary rehabilitation ( PR ) but requires specific facilities . Tai Chi , which combines psychological treatment and physical exercise and requires no special equipment , is widely practice d in China and is becoming increasingly popular in the rest of the world . We hypothesized that Tai Chi is equivalent ( ie , difference less than ±4 St. George ’s Respiratory Question naire [ SGRQ ] points ) to PR . Methods A total of 120 patients ( mean FEV1 , 1.11 ± 0.42 L ; 43.6 % predicted ) bronchodilator‐naive patients were studied . Two weeks after starting indacaterol 150 & mgr;g once daily , they r and omly received either st and ard PR thrice weekly or group Tai Chi five times weekly , for 12 weeks . The primary end point was change in SGRQ prior to and following the exercise intervention ; measurements were also made 12 weeks after the end of the intervention . Results The between‐group difference for SGRQ at the end of the exercise interventions was –0.48 ( 95 % CI PR vs Tai Chi , –3.6 to 2.6 ; P = .76 ) , excluding a difference exceeding the minimal clinical ly important difference . Twelve weeks later , the between‐group difference for SGRQ was 4.5 ( 95 % CI , 1.9 to 7.0 ; P < .001 ) , favoring Tai Chi . Similar trends were observed for 6‐min walk distance ; no change in FEV1 was observed . Conclusions Tai Chi is equivalent to PR for improving SGRQ in COPD . Twelve weeks after exercise cessation , a clinical ly significant difference in SGRQ emerged favoring Tai Chi . Tai Chi is an appropriate substitute for PR . Trial Registry Clinical Trials.gov ; No. : NCT02665130 ; URL : www . clinical trials.gov BACKGROUND Although the benefits of exercise on the health of patients with chronic obstructive pulmonary disease ( COPD ) have been widely reported , the effect of Tai Chi as an alternative exercise has not been thoroughly evaluated in patients with COPD . This study reported a r and omised controlled trial , which investigated the effects of Tai Chi on lung function , exercise capacity , and diaphragm strength in patients with COPD . TRIAL DESIGN Single blind r and omised controlled study . SETTING Department of Respiratory Medicine , Xiangya Hospital , Central South University . METHODS Forty patients with COPD were r and omised into either a control group or Tai Chi intervention group . Participants in the control group received only routine care , while participants in the Tai Chi group received routine care and completed a six-month Tai Chi exercise program . OUTCOMES Lung function parameters , blood gas parameters , 6-min walking distance ( 6MWD ) , and diaphragm strength parameters . RESULTS Lung function parameters ( FEV1 : 1.43 ± 0.08 and FEV1 ( % ) predicted : 47.6 ± 4.76 ) , 6MWD ( 476 ± 15 ) and diaphragm strength parameters ( TwPes : 1.17 ± 0.07 , TwPga : -1.12 ± 0.06 , and TwPdi : 1.81 ± 0.09 ) were found to be significantly increased in participants who successfully completed the six-month Tai Chi program compared to participants in the control group who only received routine care ( p<0.05 ) . These parameters were also found to be significantly increased in participants who completed the Tai Chi exercise program compared to the baseline ( p<0.05 ) . In contrast , no significant differences in PaO2 and PaCO2 were observed in participants before or after completing a Tai Chi program or between Tai Chi group and control group ( p>0.05 ) . CONCLUSIONS Tai Chi enhances lung function , exercise capacity , and diaphragm strength . However , this is only preliminary research data and a larger trial is needed for more detailed results OBJECTIVE To determine the feasibility of a r and omized controlled trial of the effect of a tai chi program on quality of life and exercise capacity in patients with COPD . METHODS We r and omized 10 patients with moderate to severe COPD to 12 weeks of tai chi plus usual care ( n = 5 ) or usual care alone ( n = 5 ) . The tai chi training consisted of a 1-hour class , twice weekly , that emphasized gentle movement , relaxation , meditation , and breathing techniques . Exploratory outcomes included disease-specific symptoms and quality -of-life , exercise capacity , pulmonary function tests , mood , and self-efficacy . We also conducted qualitative interviews to capture patient narratives regarding their experience with tai chi . RESULTS The patients were willing to be r and omized . Among 4 of the 5 patients in the intervention group , adherence to the study protocol was excellent . The cohort 's baseline mean ± SD age , percent-of-predicted FEV₁ , and ratio of FEV₁ to forced vital capacity were 66 ± 6 y , 50 ± 12 % , and 0.63 ± 0.14 , respectively . At 12 weeks there was significant improvement in Chronic Respiratory Question naire score among the tai chi participants ( 1.4 ± 1.1 ) , compared to the usual-care group ( -0.1 ± 0.4 ) ( P = .03 ) . There were nonsignificant trends toward improvement in 6-min walk distance ( 55 ± 47 vs -13 ± 64 m , P = .09 ) , Center for Epidemiologic Studies Depression Scale ( -9.0 ± 9.1 vs -2.8 ± 4.3 , P = .20 ) , and University of California , San Diego Shortness of Breath score ( -7.8 ± 3.5 vs -1.2 ± 11 , P = .40 ) . There were no significant changes in either group 's peak oxygen uptake . CONCLUSIONS A r and omized controlled trial of tai chi is feasible in patients with moderate to severe COPD . Tai chi exercise as an adjunct to st and ard care warrants further investigation BACKGROUND Persons with chronic obstructive pulmonary disease ( COPD ) have reduced exercise capacity and levels of physical activity . Supervised , facility-based pulmonary rehabilitation programs improve exercise capacity and reduce dyspnea , but novel long-term strategies are needed to maintain the benefits gained . Mind-body modalities such as Tai Chi which combine aerobic activity , coordination of breathing , and cognitive techniques that alleviate the physical inactivity , dyspnea , and anxiety and depression that are the hallmarks of COPD are promising strategies . METHODS / DESIGN We have design ed a r and omized controlled study to examine whether Tai Chi will maintain exercise capacity in persons with COPD who have recently completed a supervised pulmonary rehabilitation program , compared to st and ard care . The primary outcome is 6-min walk test distance at 6 months . Secondary outcomes include health-related quality of life , dyspnea , mood , occurrence of acute exacerbations , engagement in physical activity , exercise self-efficacy , and exercise adherence . Simultaneously , we are conducting a pilot study of group walking . We will enroll 90 persons who will be r and omized to one of three arms in a 2:2:1 ratio : Tai Chi , st and ard care , or group-based walking . DISCUSSION The Long-term Exercise After Pulmonary Rehabilitation ( LEAP ) study is a novel and clinical ly relevant trial . We will enroll a well-characterized cohort of persons with COPD and will comprehensively assess physiological and psychosocial outcomes . Results of this study will provide the evidence base for persons with COPD to engage in Tai Chi as a low-cost , long-term modality to sustain physical activity in persons who have completed a st and ard short-term pulmonary rehabilitation program . TRIAL REGISTRATION This trial is registered in Clinical Trials.gov , with the ID number of NCT01998724 Objectives . To evaluate the sustaining effects of Tai Chi Qigong ( TCQ ) in improving the psychosocial health in chronic obstructive pulmonary disease ( COPD ) patients in the sixth month . Background . COPD affects both physical and emotional aspects of life . Measures to minimize patients ' suffering need to be implemented . Methods . 206 COPD patients were r and omly assigned into three groups : TCQ group , exercise group , and control group . The TCQ group completed a three-month TCQ program , the exercise group practice d breathing and walking exercise , and the control group received usual care . Results . Significant group-by-time interactions in quality of life ( QOL ) using St. George 's respiratory question naire ( P = 0.002 ) and the perceived social support from friends using multidimensional scale of perceived social support ( P = 0.04 ) were noted . Improvements were observed in the TCQ group only . Conclusions . TCQ has sustaining effects in improving psychosocial health ; it is also a useful and appropriate exercise for COPD patients The aims of the study were to determine the effect of short-form Sun-style t’ai chi ( SSTC ) ( part A ) and investigate exercise intensity of SSTC ( part B ) in people with chronic obstructive pulmonary disease ( COPD ) . Part A : after confirmation of eligibility , participants were r and omly allocated to either the t’ai chi group or control group ( usual medical care ) . Participants in the t’ai chi group trained twice weekly for 12 weeks . Part B : participants who had completed training in the t’ai chi group performed a peak exercise test ( incremental shuttle walk test ) and SSTC while oxygen consumption ( VO2 ) was measured . Exercise intensity of SSTC was determined by the per cent of VO2 reserve . Of 42 participants ( mean±sd forced expiratory volume in 1 s 59±16 % predicted ) , 38 completed part A and 15 completed part B. Compared to control , SSTC significantly increased endurance shuttle walk time ( mean difference 384 s , 95 % CI 186–510 ) ; reduced medial-lateral body sway in semi-t and em st and ( mean difference -12.4 mm , 95 % CI -21– -3 ) ; and increased total score on the chronic respiratory disease question naire ( mean difference 11 points , 95 % CI 4–18 ) . The exercise intensity of SSTC was 53±18 % of VO2 reserve . SSTC was an effective training modality in people with COPD achieving a moderate exercise intensity which meets the training recommendations Introduction Although pulmonary rehabilitation ( PR ) is associated with significant clinical benefits in chronic obstructive pulmonary disease ( COPD ) and has been recommended by guidelines , PR with conventional exercise training has not been widely applied in the clinic because of its inherent limitations . Alternative exercise such as Tai Chi has been investigated and the results are promising . However , the strengths and weaknesses of the exercise modality of Tai Chi , conventional PR and a combination of Tai Chi and conventional PR and the possible mechanisms underlying Tai Chi exercise remain unclear . This study aims to address the above research gaps in a well- design ed clinical trial . Methods and analysis This study is a single-blind , r and omised controlled trial . Participants with stable COPD will be recruited and r and omly assigned to one of four groups receiving Tai Chi exercise , conventional PR using a total body recumbent stepper ( TBRS ) , combined Tai Chi and TBRS , or usual care ( control ) in a 1:1:1:1 ratio . Participants will perform 30 min of supervised exercise three times a week for 8 weeks ; they will receive sequential follow-ups until 12 months after recruitment . The primary outcome will be health-related quality of life as measured by the St George 's Respiratory Question naire . Secondary outcomes will include 6 min walking distance , pulmonary function , the modified Medical Research Council Dyspnoea Scale , the COPD Assessment Test , the Hospital Anxiety and Depression Scale , the Berg Balance Scale , exacerbation frequency during the study period , and systemic inflammatory and immune markers . Ethics and dissemination Ethics approval has been granted by the Clinical Trial and Biomedical Ethics Committee of West China Hospital of Sichuan University ( No TCM-2015 - 82 ) . Written informed consent will be obtained from each participant before any procedures are performed . The study findings will be published in peer- review ed journals and presented at national and international conferences . Trial registration number ChiCTR-IOR-15006874 ; Pre- results OBJECTIVES To evaluate the sustaining effects of Tai chi Qigong in improving the physiological health for COPD patients at sixth month . DESIGN A r and omized controlled trial . Subjects were in three r and omly assigned groups : Tai chi Qigong group , exercise group , and control group . SETTING The 206 subjects were recruited from five general outpatient clinics . INTERVENTIONS Tai chi Qigong group completed a 3-month Tai chi Qigong program . Exercise group practice d breathing and walking as an exercise . Control group received usual care . MAIN OUTCOME MEASURES Primary outcomes included six-minute walking distance and lung functions . Secondary outcomes were dyspnea and fatigue levels , number of exacerbations and hospital admissions . RESULTS Tai chi Qigong group showed a steady improvement in exercise capacity ( P<.001 ) from baseline to the sixth month . The mean walking distance increased from 298 to 349 meters ( + 17 % ) . No significant changes were noted in the other two groups . Tai chi Qigong group also showed improvement in lung functions ( P<.001 ) . Mean forced expiratory volume in 1s increased from .89 to .99l ( + 11 % ) . No significant change was noted in the exercise group . Deterioration was found in the control group , with mean volume decreased from .89 to .84l ( -5.67 % ) . Significant decreased in the number of exacerbations was observed in the Tai chi Qigong group . No changes in dyspnea and fatigue levels were noted among the three groups . CONCLUSIONS Tai chi Qigong has sustaining effects in improving the physiological health and is a useful and appropriate exercise for COPD patients OBJECTIVE To evaluate the effects of shadow boxing training on the exercise endurance and quality of life of Chinese patients with COPD ( chronic obstructive pulmonary disease ) . METHODS From May 2010 to March 2011 , a total of 70 COPD patients in stable phases were recruited from Liwan , Yuexiu and Haizhu districts of Guangzhou . There were 35 patients in the shadow boxing exercise group and 35 patients in the control group . And they were matched by gender and age . The patients in the shadow boxing group exercised for 3 months while those in the control group received the conventional out-hospital management only . Their demographic , medical history , smoking status , medicinal use , spirometric data , clinical COPD question naire ( CCQ ) scores , 6-minute walking distance and Borg scores were collected before and after trial . RESULTS A total of 63 COPD patients ( 33 in shadow boxing group vs. 30 in control group ) completed the study . There was an average dropout rate of 5.7 % ( 2/35 ) in shadow boxing group and 14.3 % ( 5/35 ) in control group . No differences existed between two groups in age ( 67 ± 8 vs 69 ± 9 yr ) , male proportion ( 84.8 % vs 86.7 % ) , body mass index ( 22.8 ± 2.6 vs 22.7 ± 3.0 ) , usage proportion of medicine ( 42.4 % vs 33.3 % ) , duration of disease ( 4.0 ± 7.5 vs 5.5 ± 7.3 ) , percentage of smokers ( 78.8 % vs 80.0 % ) , 6-minute walking distance ( 447 ± 94 vs 414 ± 100 ) , CCQ total score ( 15.0 ± 9.4 vs 14.1 ± 8.8 ) , CCQ symptom score ( 9.2 ± 5.6 vs 8.3 ± 5.0 ) and activity score ( 5.8 ± 4.5 vs 5.8 ± 4.4 ) at baseline ( all P > 0.05 ) . At the end of study , the 6-minute walking distance of patients had statistical differences between two groups ( P < 0.01 ) . The shadow boxing group increased by ( 51 ± 55 ) m while the control dropped by ( 19 ± 58 ) m. The total score , symptom score and activity score of clinical COPD question naire had statistical differences between two groups . They decreased significantly in the shadow boxing group as compared with the baseline data while there was no significant change in the control group . No statistical differences existed between two groups in the changes of forced vital capacity ( FVC ) , forced expiratory volume in one second ( FEV(1 ) ) , FEV(1)% pred , Borg score and dyspnea scales . CONCLUSION Capable of improving the exercise endurance and life quality of COPD patients , shadow boxing exercise may become one of effective rehabilitation programs for COPD patients in stable phases in communities OBJECTIVE To evaluate the effectiveness of a Tai chi Qigong ( TCQ ) program in enhancing respiratory functions and activity tolerance in clients with chronic obstructive pulmonary disease ( COPD ) . DESIGN A single-blind , r and omized controlled trial . SETTING Five general outpatient clinics in Hong Kong . INTERVENTION In total , 206 COPD clients were r and omly assigned into one of the three groups , namely , TCQ , exercise , and control group . Subjects in the TCQ group received a TCQ program consisting of two 60-min sessions each week for three months . Subjects in the exercise group were taught to practice breathing techniques combined with walking as an exercise . Subjects in the control group were instructed to maintain their usual activities . Data collection was performed at baseline and at the 6-week and 3-month marks . OUTCOMES Lung functions , 6-min walk test , and COPD exacerbation rate . RESULTS Results of repeated measures of analysis of covariance demonstrated that there were significant interaction effects between time and group in forced vital capacity ( p=.002 , η(2)=.06 ) , forced expiratory volume in 1s ( p<.001 , η(2)=.02 ) , walking distance ( p<.001 ) , and exacerbation rate ( p=.006 , η(2)=.06 ) at 3 months . Improvements were noted in the TCQ group . No changes were observed in the exercise group , while a decline in lung functions was noticed in the control group . CONCLUSION Tai chi Qigong was able to improve respiratory functions and activity tolerance level in COPD clients . The breathing and walking exercise helped maintain lung functions and slow down disease progression BACKGROUND AND OBJECTIVE 24-form Tai Chi is a traditional exercise popular among old people in China , but it has some complex movements beyond of capabilities of patients with COPD . This study was to modify and simplify 24-form Tai Chi and evaluate effects of the modified Tai Chi on lung function , exercise capacity , dyspnea symptom and health status in patients with COPD . METHODS A two-step procedure was applied : an initial qualitative research module consisting of focus group discussion , expert consultation and patient interviews was conducted to simplified and modified 24-form Tai Chi for patients with COPD . Then , a r and omized controlled trial consisting of 60 patients with II to IV COPD was conducted to evaluate effects of the modified Tai Chi on lung function ( FEV1 % ) , exercise capacity ( Six minutes walking distance,6MWD ) , dyspnea symptom ( Modified Medical Research Council Scale , mMRC ) and health status ( COPD Assessment Test , CAT ) . All measures were obtained at baseline , 3-month follow-up and 9-month follow-up . RESULTS A new simpler 6-form Tai Chi that combining characteristics of COPD , the experts ' wisdom and patients ' needs was developed . Patients with COPD can grasp it in about 3 h and participants showed 86.0 % adherence to the Tai Chi training and no negative accidents occurred . Generalized estimating equations ( GEE ) showed that there were significant differences in FEV1 % , 6MWD and CAT scores between modified Tai Chi ( MTC ) group and the control group over time ( model group × time interaction χ2 = 13.68 , P < 0.001 ; χ2 = 192.39 , P < 0.001;χ2 = 6.05 , P = 0.014 , respectively ) , however , no statistical significance in mMRC scores was found between the 2 groups over time ( model group × time interaction χ2 = 3.54 , P = 0.06 ) . The baseline of FEV1%,6MWD , mMRC scores and CAT scores are significant covariates for lung function , exercise capacity , dyspnea symptom and health status , respectively ( χ2 = 149.43 , P < 0.001 ; χ2 = 5.78 , P = 0.016 ; χ2 = 66.71 , P < 0.001 ; χ2 = 81.83 , P < 0.001 , respectively ) . CONCLUSIONS This modified 6-form Tai Chi routine is easy to grasp , easy to adhere to , safe to practice and effective to improve lung function , exercise capacity , health status and to prevent dyspnea symptom from getting worse for patients with COPD and it can be recommended as a suitable exercise therapy for them

Conclusions Increases in vagal-related indices of resting and post-exercise HRV , post-exercise HRR , and HR acceleration are evident when positive adaptation to training has occurred , allowing for increases in performance . However , increases in post-exercise HRV and HRR also occur in response to overreaching , demonstrating that additional measures of training tolerance may be required to determine whether training-induced changes in these parameters are related to positive or negative adaptations . Resting HRV is largely unaffected by overreaching , although this may be the result of method ological issues that warrant further investigation . HR acceleration appears to decrease in response to overreaching training , and thus may be a potential indicator of training-induced fatigue

Background Autonomic regulation of heart rate ( HR ) as an indicator of the body ’s ability to adapt to an exercise stimulus has been evaluated in many studies through HR variability ( HRV ) and post-exercise HR recovery ( HRR ) . Recently , HR acceleration has also been investigated . Objective The aim of this systematic literature review and meta- analysis was to evaluate the effect of negative adaptations to endurance training ( i.e. , a period of overreaching leading to attenuated performance ) and positive adaptations ( i.e. , training leading to improved performance ) on autonomic HR regulation in endurance-trained athletes .

BACKGROUND It is unclear from prior reports whether the relationships between self-ratings of anxiety or emotional stress and parasympathetic nervous system components of heart rate variability are independent of personality and cardiorespiratory fitness . We examined those relationships in a clinical setting prior to a st and ardized exercise test . METHODS AND RESULTS Heart rate variability ( HRV ) was measured during 5 min of supine rest among 92 healthy men ( N=52 ) and women ( N=40 ) who had above-average cardiorespiratory fitness as indicated by peak oxygen uptake measured during grade -incremented treadmill exercise . HRV data sets were decomposed into low-frequency ( LF ; 0.05 - 0.15 Hz ) and high-frequency ( HF ; 0.15 - 0.5 Hz ) components using spectral analysis . Self-ratings of trait anxiety and perceived emotional stress during the past week were also assessed . CONCLUSIONS There was an inverse relationship between perceived emotional stress during the past week and the normalized HF component of HRV ( P=0.038 ) . This indicates a lower cardiac vagal component of HRV among men and women who perceived more stress . That relationship was independent of age , gender , trait anxiety , and cardiorespiratory fitness . It was also independent of heart rate ; mean arterial blood pressure ; and respiration rate , factors which can influence HRV and might be elevated among people reporting anxiety and perceived stress . We conclude that vagal modulation of heart period appears to be sensitive to the recent experience of persistent emotional stress , regardless of a person 's level of physical fitness and disposition toward experiencing anxiety PURPOSE We analyzed HR variability ( HRV ) to detect alterations in autonomic function that may be associated with functional overreaching ( F-OR ) in endurance athletes . METHODS Twenty-one trained male triathletes were r and omly assigned to either intensified training ( n = 13 ) or normal training ( n = 8) groups during 5 wk . HRV measures were taken daily during a 1-wk moderate training ( baseline ) , a 3-wk overload training , and a 1-wk taper . RESULTS All the subjects of the intensified training group demonstrated a decrease in maximal incremental running test performance at the end of the overload period ( -9.0 % ± 2.1 % of baseline value ) followed by a performance supercompensation after the taper and were therefore diagnosed as F-OR . According to a qualitative statistical analysis method , a likely to very likely negative effect of F-OR on HR was observed at rest in supine and st and ing positions , using isolated seventh-day values and weekly average values , respectively . When considering the values obtained once per week , no clear effect of F-OR on HRV parameters was found . In contrast , the weekly mean of each HRV parameter showed a larger change in indices of parasympathetic tone in the F-OR group than the control group in supine position ( with a 96%/4%/0 % chance to demonstrate a positive/trivial/negative effect on Ln RMSSD after the overload period ; 77%/22%/1 % on LnHF ) and st and ing position [ 98%/1%/1 % on Ln RMSSD ; 99%/0%/1 % on LnHF ; 95%/1%/4 % on Ln(LF + HF ) ] . During the taper , theses responses were reversed . CONCLUSIONS Using daily HRV recordings averaged over each week , this study detected a progressive increase in the parasympathetic modulation of HR in endurance athletes led to F-OR . It also revealed that due to a wide day-to-day variability , isolated , once per week HRV recordings may not detect training-induced autonomic modulations in F-OR athletes Purpose of this study was to test utility of heart rate variability ( HRV ) in daily endurance exercise prescriptions . Twenty-six healthy , moderately fit males were r and omized into predefined training group ( TRA , n = 8) , HRV-guided training group ( HRV , n = 9 ) , and control group ( n = 9 ) . Four-week training period consisted of running sessions lasting 40 min each at either low- or high-intensity level . TRA group trained on 6 days a week , with two sessions at low and four at high intensity . Individual training program for HRV group was based on individual changes in high-frequency R – R interval oscillations measured every morning . Increase or no change in HRV result ed in high-intensity training on that day . If there was significant decrease in HRV ( below reference value [ 10-day mean-SD ] or decreasing trend for 2 days ) , low-intensity training or rest was prescribed . Peak oxygen consumption ( VO2peak ) and maximal running velocity ( Loadmax ) were measured in maximal treadmill test before and after the training . In TRA group , Loadmax increased from 15.1 ± 1.3 to 15.7 ± 1.2 km h−1 ( P = 0.004 ) , whereas VO2peak did not change significantly ( 54 ± 4 pre and 55 ± 3 ml kg−1 min−1 post , P = 0.224 ) . In HRV group , significant increases were observed in both Loadmax ( from 15.5 ± 1.0 to 16.4 ± 1.0 km h−1 , P < 0.001 ) and VO2peak ( from 56 ± 4 to 60 ± 5 ml kg−1 min−1 , P = 0.002 ) . The change in Loadmax was significantly greater in HRV group compared to TRA group ( 0.5 ± 0.4 vs. 0.9 ± 0.2 km h−1 , P = 0.048 , adjusted for baseline values ) . No significant differences were observed in the changes of VO2peak between the groups . We concluded that cardiorespiratory fitness can be improved effectively by using HRV for daily training prescription Daily aerobic training results in autonomic control of the heart toward vagal dominance . The constancy of vagal dominance after controlled training followed by a home-based training program in accordance with contemporary guidelines is not known . We set out here to study whether the vagal dominance induced by 8 weeks of controlled aerobic training is preserved after a 10-month home-based training program . For the controlled study , healthy men were r and omized as training ( n=18 ) and control subjects ( n=6 ) . The training was started by a supervised 8-week period with six training sessions a week [ 45 ( 15 ) min each ] at an intensity of 70–80 % of maximum heart rate , followed by a home-based training program for 10 months in accordance with the American College of Sports Medicine recommendations . Cardiovascular autonomic function was assessed by analyzing HR variability over a 24-h period and separately during the night hours ( midnight–6 a.m. ) . Maximal running performance improved during the controlled training 16 (7)% ( range 4–31 % , P<0.001 ) and remained 8 (8)% ( range −3 to 23 % , P<0.001 ) above the baseline level after the home-based training program . At night , the vagally mediated high-frequency ( HF ) power of R-R intervals increased during the controlled training from 6.7 ( 1.3 ) to 7.3 ( 1.1 ) ln ms2 ( P<0.001 ) and remained higher than the baseline after the home-based training [ 7.0 ( 1.3 ) ln ms2 , P<0.05 ] . The changes in running performance correlated with the changes in HF power at night ( r=0.41 , P<0.05 ) and over 24 h ( r=0.44 , P<0.05 ) after the home-based training program . Similarly , the changes in body mass index correlated with the changes in HF power over 24 h ( r=−0.44 , P<0.05 ) after the home-based training program . The high vagal outflow to the heart after the home-based training is associated with good physical performance and body mass control OBJECTIVES Heart rate kinetics are faster in well-trained athletes at exercise onset , indicating sensitivity to training status , but whether they track performance changes due to changes in training load is unknown . DESIGN R and omised , counterbalanced , cross-over . METHODS 17 cyclists completed two weeks of light and two weeks of heavy training . The day after each training period heart rate was recorded during 5 min cycling at 100 W to determine the maximal rate of heart rate increase . Participants then performed a 5 min cycle time-trial after which heart rate recovery was determined . RESULTS Work during 5 min cycle time-trial decreased 3.5 % ( P<0.04 ) in participants ( n=8 ) who increased training load ( completed light training then heavy training ) and , although maximal rate of heart rate increase did not change ( P=0.27 ) , within-individual changes in work were correlated with changes in maximal rate of heart rate increase ( r=0.87 , P=0.005 ) . Work during 5 min cycle time-trial increased 6.5 % ( P<0.001 ) in 9 participants who decreased training load ( completed heavy training then light training ) and maximal rate of heart rate increase increased 28 % ( P=0.002 ) but the changes in maximal work were not related to changes in rate of heart rate increase ( r=0.32 , P=0.40 ) . Heart rate recovery tended to track changes in 5 min cycle time-trial work following increases and decreases in training load ( r=0.65 - 0.75 , P=0.03 - 0.08 ) . CONCLUSIONS Maximal rate of heart rate increases during cycling at 100 W tracks reductions in exercise performance when training load is increased , but not performance improvements when training loads are reduced . Maximal rate of heart rate increase may be a useful adjunct to heart rate recovery for tracking changes in exercise performance 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 The effects of intensified training in combination with a reduced training volume on muscle ion kinetics , transporters , and work capacity were examined . Eight well-trained cyclists replaced their regular training with speed-endurance training ( 12 × 30 s sprints ) 2 - 3 times per week and aerobic high-intensity training ( 4 - 5 × 3 - 4 min at 90 - 100 % of maximal heart rate ) 1 - 2 times per week for 7 wk and reduced training volume by 70 % ( intervention period ; IP ) . The duration of an intense exhaustive cycling bout ( EX2 ; 368 ± 6 W ) , performed 2.5 min after a 2-min intense cycle bout ( EX1 ) , was longer ( P < 0.05 ) after than before IP ( 4:16 ± 0:34 vs. 3:37 ± 0:28 min : s ) , and mean and peak power during a repeated sprint test improved ( P < 0.05 ) by 4 % and 3 % , respectively . Femoral venous K(+ ) concentration in recovery from EX1 and EX2 was lowered ( P < 0.05 ) after compared with before IP , whereas muscle interstitial K(+ ) concentration and net muscle K(+ ) release during exercise was unaltered . No changes in muscle lactate and H(+ ) release during and after EX1 and EX2 were observed , but the in vivo buffer capacity was higher ( P < 0.05 ) after IP . Expression of the ATP-sensitive K(+ ) ( KATP ) channel ( Kir6.2 ) decreased by IP , with no change in the strong inward rectifying K(+ ) channel ( Kir2.1 ) , muscle Na(+)-K(+ ) pump subunits , monocarboxylate transporters 1 and 4 ( MCT1 and MCT4 ) , and Na(+)/H(+ ) exchanger 1 ( NHE1 ) . In conclusion , 7 wk of intensified training with a reduced training volume improved performance during repeated intense exercise , which was associated with a greater muscle reuptake of K(+ ) and muscle buffer capacity but not with the amount of muscle ion transporters Numerous symptoms have been associated with the overtraining syndrome ( OT ) , including changes in autonomic function . Heart rate variability ( HRV ) provides non‐invasive data about the autonomic regulation of heart rate in real‐life conditions . The aims of the study were to : ( i ) characterize the HRV profile of seven athletes ( OA ) diagnosed as suffering of OT , compared with eight healthy sedentary ( C ) and eight trained ( T ) subjects during supine rest and 60 ° upright , and ( ii ) compare the traditional time‐ and frequency‐domain analysis assessment of HRV with the non‐linear Poincaré plot analysis . In the latter each R‐R interval is plotted as a function of the previous one , and the st and ard deviations of the instantaneous ( SD1 ) and long‐term R‐R interval variability are calculated . Total power was higher in T than in C and OA both in supine ( 1158 ± 1137 , 6092 ± 3554 and 2970 ± 2947 ms2 for C , T and OA , respectively ) and in upright ( 640 ± 499 , 1814 ± 806 and 1092 ± 712 ms2 for C , T and OA , respectively ; P<0·05 ) positions . In supine position , indicators of parasympathetic activity to the sinus node were higher in T compared with C and OA ( high‐frequency power : 419·1 ± 381·2 , 1105·3 ± 781·4 and 463·7 ± 715·8 ms2 for C , T and OA , respectively ; P<0·05 ; SD1 : 29·5 ± 18·5 , 75·2 ± 17·2 and 37·6 ± 27·5 for C , T and OA , respectively ; P<0·05 ) . OA had a marked predominance of sympathetic activity regardless of the position ( LF/HF were 0·47 ± 0·35 , 0·47 ± 0·50 and 3·96 ± 5·71 in supine position for C , T and OA , respectively , and 2·09 ± 2·17 , 7·22 ± 6·82 and 12·04 ± 10·36 in upright position for C , T and OA , respectively ) . The changes in HRV indexes induced by the upright posture were greater in T than in OA . The shape of the Poincaré plots allowed the distinction between the three groups , with wide and narrow shapes in T and OA , respectively , compared with C. As Poincaré plot parameters are easy to compute and associated with the ‘ width ’ of the scatter gram , they corroborate the traditional time‐ and frequency‐domain analysis . We suggest that they could be used to indicate fatigue and /or prevent OT Heart rate variability ( HRV ) was assessed during the short- ( within 1 h ) and long- ( within 48 h ) term recovery following a single bout of either constant ( CST ) or interval training ( SWEET ) exercise performed at the same total physical work [ 9.4 ( 0.3 ) kJ kg−1 ] . R-R intervals , systolic ( SAP ) and diastolic ( DAP ) arterial pressures were recorded in supine and upright positions before and 1 , 24 and 48 h after the termination of the exercises in ten male subjects [ mean ( SEM ) , age 24.6 ( 0.6 ) years , height 177.2 ( 1.1 ) cm and body mass 68.5 ( 0.9 ) kg ] . The parameters were also recorded in the supine position during the first 20 min following the end of the exercise . Spectral analysis parameters of HRV [ total ( TP ) , low- ( LF ) , and high- ( HF ) frequency power , and LF/TP , HF/TP and LF/HF ratios ] were determined over 5 min during each phase . Except for higher HF values in both supine and upright positions during the first hour following CST compared with SWEET , cardiovascular and HRV analysis responses were of the same magnitude after their termination . R-R intervals , TP , and HF/TP were significantly decreased while LF/TP and LF/HF were significantly increased during the early recovery , when compared with control values . This could be a response to the significant decrease in SAP and DAP at this time . Twenty-four and 48 h after the end of the exercise , HRV parameters were at the same levels as before exercises in the supine posture , but a persistent tachycardia continued to be observed in the upright posture , together with reduced TP values , showing that cardiovascular functions were still disturbed . The short-term HRV recovery seemed dependent on the type of exercise , contrary to the long-term recovery PURPOSE This research investigated the age and gender differences in cardiovascular adaptation to a st and ardized/quantified endurance-training program that included two taper periods . METHODS The latter was analyzed from spectral analysis of electrocardiogram records of heart rate variability ( HRV ) at rest in groups of young ( 19 - 21 yr ) and middle aged ( 40 - 45 yr ) , mixed gender groups ( 6 males and 6 females ) , pre- and postst and ardized training . All subjects were recreational runners who completed the same 12-wk running program . Before , and subsequent to training , HRV was measured during supine rest and submaximal cycling . RESULTS There was a significant decrease in heart rate both at rest ( 2.7 + /- 0.45 beats x min-1 ) and during submaximal exercise ( 8.1 + /- 0.67 beats x min-1 ) in both age groups after training . After training , total spectral power increased ( 560.7 + /- 308.9 ms2 ) , as well as high-frequency power ( 362.3 + /- 405.5 ms2 ) , in both age groups at rest . The young group showed a greater increase in total power ( 849.0 + /- 308.7 ms2 ) after the training program . CONCLUSION It is concluded that a well- design ed 12-wk endurance-training program will decrease resting and submaximal heart rate in both younger and older adults . The significant increase in HRV , total power , and high-frequency power in all groups after endurance training indicates that HRV measurement appears to provide an effective , noninvasive assessment of cardiovascular adaptation to aerobic training Objective The effect of 12 weeks of high-intensity intermittent exercise ( HIIE ) on cardiac , vascular , and autonomic function of young males was examined . Methods Thirty-eight young men with a BMI of 28.7 ± 3.1 kg m−2 and age 24.9 ± 4.3 years were r and omly assigned to either an HIIE or control group . The exercise group underwent HIIE three times per week , 20 min per session , for 12 weeks . Aerobic power and a range of cardiac , vascular , and autonomic measures were recorded before and after the exercise intervention . Results The exercise , compared to the control group , recorded a significant reduction in heart rate accompanied by an increase in stroke volume . For the exercise group forearm vasodilatory capacity was significantly enhanced , P < 0.05 . Arterial stiffness , determined by pulse wave velocity and augmentation index , was also significantly improved , after the 12-week intervention . For the exercise group , heart period variability ( low- and high-frequency power ) and baroreceptor sensitivity were significantly increased . Conclusion High-intensity intermittent exercise induced significant cardiac , vascular , and autonomic improvements after 12 weeks of training OBJECTIVES Reductions in maximal rate of heart rate increase ( rHRI ) correlate with performance reductions when training load is increased . This study evaluated whether rHRI tracked performance changes across a range of training states . DESIGN Prospect i ve intervention . METHODS rHRI was assessed during five min of cycling at 100W ( rHRIcyc ) and running at 8 km/h ( rHRIrun ) in 13 male triathletes following two weeks of light-training ( LT ) , two weeks of heavy-training ( HT ) and a two-day recovery period ( RP ) . A five min cycling time-trial assessed performance and peak oxygen consumption ( V˙O2peak ) . RESULTS Performance likely decreased following HT ( Effect size±90 % confidence interval=-0.18±0.09 ) , then very likely increased following RP ( 0.32±0.14 ) . rHRIcyc very likely decreased ( -0.48±0.24 ) , and rHRIrun possibly decreased ( -0.33±0.48 ) , following HT . Changes in both measures were unclear following RP . Steady-state HR was almost certainly lower ( -0.81±0.31 ) during rHRIcyc than rHRIrun . A large correlation was found between reductions in performance and rHRIrun ( r±90 % ; CI=0.65±0.34 ) from LT to HT , but was unclear for rHRIcyc . Trivial within-subject correlations were found between rHRI and performance , but the strength of relationship between rHRIrun and performance was largely associated with V˙O2peak following LT ( r=-0.58±0.38 ) . CONCLUSIONS Performance reductions were most sensitively tracked by rHRIrun following HT . This may be due to rHRIrun being assessed at a higher intensity than rHRIcyc , inferred from a higher steady-state HR and supported by a stronger within-subject relationship between rHRIrun and performance in individuals with a lower V˙O2peak , in whom the same exercise intensity would represent a greater physiological stress . rHRI assessed at relatively high exercise intensities may better track performance changes PURPOSE To analyze performance and fatigue effects of small-sided games ( SSG ) vs high-intensity interval training ( HIIT ) performed during a 4-wk in-season period in high-level youth football . METHODS Nineteen players from 4 youth teams ( 16.5 [ SD 0.8 ] y , 1.79 [ 0.06 ] m , 70.7 [ 5.6 ] kg ) of the 2 highest German divisions completed the study . Teams were r and omly assigned to 1 of 2 training sequences ( 2 endurance sessions per wk ) : One training group started with SSG , whereas the other group conducted HIIT during the first half of the competitive season . After the winter break , training programs were changed between groups . Before and after the training periods the following tests were completed : the Recovery-Stress Question naire for Athletes , creatine kinase and urea concentrations , vertical-jump height ( countermovement jump [ CMJ ] , drop jump ) , straight sprint , agility , and an incremental field test to determine individual anaerobic threshold ( IAT ) . RESULTS Significant time effects were observed for IAT ( + 1.3 % , η(p)(2 ) = .31 ) , peak heart rate ( -1.8 % , η(p)(2 ) = .45 ) , and CMJ ( -2.3 % , η(p)(2 ) = .27 ) , with no significant interaction between groups ( P > .30 ) . Players with low baseline IAT values ( + 4.3 % ) showed greater improvements than those with high initial values ( ± 0.0 % ) . A significant decrease was found for total recovery ( -5.0 % , η(p)(2 ) = .29 ) , and an increase was found for urea concentration ( + 9.2 % , η(p)(2 ) = .44 ) . CONCLUSION Four weeks of in-season endurance training can lead to relevant improvements in endurance capacity . The decreases in CMJ height and total-recovery score together with the increase in urea concentration might be interpreted as early signs of fatigue . Thus , the danger of overtaxing players should be considered Abstract The overall purpose of this two-part study was to examine factors that influenced fatigue status in university level swimmers . Participants were 25 swimmers ( 14 male , 11 female ) from one university swim team . A mixed methods approach was used . Quantitative data were collected using an orthostatic heart rate test and self-report question naire at multiple time points throughout a competitive season . Qualitative data were collected via focus groups conducted at the end of the season . Analysis of the quantitative data indicated high levels of accumulated physiological and psychological fatigue that improved with increased recovery . Specifically , heart rate indices , form , feeling , and energy level improved during taper periods and worsened during and immediately after intensive training blocks . Analysis of the qualitative data revealed that one factor ( flexible structure of training programme ) had a positive influence on athletes ’ fatigue while two factors ( teammate expectations and balancing school , work , and sleep ) had a negative influence on athletes ’ fatigue

Conclusion Our results suggest that MRI is superior for the diagnosis of obstructive CAD compared with ECHO and SPECT . ECHO and SPECT demonstrated similar diagnostic performance . Key Points• MRI can assess myocardial perfusion.• MR perfusion diagnoses coronary artery disease better than echocardiography or SPECT.• Echocardiography and SPECT have similar diagnostic performance.• MRI can save coronary artery disease patients from more invasive tests.• MRI and SPECT show evidence of publication bias , implying possible overestimation

Objectives To determine and compare the diagnostic performance of stress myocardial perfusion imaging ( MPI ) for the diagnosis of obstructive coronary artery disease ( CAD ) , using conventional coronary angiography ( CCA ) as the reference st and ard .

Background —With MRI , an index of myocardial perfusion reserve ( MPRI ) can be determined . We assessed the value of this technique for the noninvasive detection of coronary artery disease ( CAD ) in patients with suspected CAD . Methods and Results —Eighty-four patients referred for a primary diagnostic coronary angiography were examined with a 1.5 T MRI tomograph ( Philips-ACS ) . For each heartbeat , 5 slices were acquired during the first pass of 0.025 mmol gadolinium-diethylenetriamine pentaacetic acid/kg body weight before and during adenosine vasodilation by using a turbo-gradient echo/echo-planar imaging-hybrid sequence . MPRI was determined from the alteration of the upslope of the myocardial signal intensity curves for 6 equiangular segments per slice . Receiver operating characteristics were performed for different criteria to differentiate ischemic and nonischemic segments . Prevalence of CAD was 51 % . Best results were achieved when only the 3 inner slices were assessed and a threshold value of 1.1 was used for the second smallest value as a marker for significant CAD . This approach yielded a sensitivity of 88 % , specificity of 90 % , and accuracy of 89 % . Conclusion —The determination of MPRI with MRI yields a high diagnostic accuracy in patients with suspected CAD Summary Background Real world cardiology is faced with a low diagnostic yield of coronary angiography ( CXA ) in patients presenting with ACC/AHA class II CXA indication . Our aim was to analyze the clinical implication of a Cardiac MR ( CMR ) protocol including adenosine stress perfusion in this patient population . We examined whether CMR could enhance appropriate CXA indication and thus reduce the rate of pure diagnostic CXA . In addition , we compared the relative impact of CMR exam components ( perfusion , function and viability assessment ) in achieving this target . Methods 176 patients were referred for CXA with class II indication . 171 underwent complete additional CMR exam in a 1.5-T whole body CMR-scanner for myocardial function , ischemia and viability prior to CXA . The routine protocol for assessment of CAD consisted of functional imaging ( long and short axes ) , adenosine stress- and rest-perfusion in short axis orientation and “ late enhancement ” imaging in long and short axes . Images were analyzed by two independent and blinded investigators . Interobserver differences were resolved by a third reader . Results There was a high association between CMR results and subsequent invasive findings ( chi square for CMR perfusion deficit and stenosis > 70 % in CXA : 113.7 , p<0.0001 ) . 109 ( 63.7 % ) of our patients had relevant perfusion deficits as seen by CMR and matching coronary artery stenosis > 70 % . Four ( 2.3 % ) patients had false negative CMR findings . In 58 patients ( 33.9 % ) no relevant coronary artery stenosis could be observed , correctly predicted by CMR in 48 cases ; in 10 ( 5.8 % ) patients CMR provided false positive results . Sensitivity of CMR to detect relevant CAD ( > 70 % luminal narrowing ) was 0.96 , specificity 0.83 , positive predictive value 0.92 and negative predictive value 0.92 . Of the CMR components , perfusion deficit was the strongest independent predictor ( odds ratio 132.3 , p < 0.0001 ) . Conclusion In a great number of patients being referred to cath lab with ACC/AHA class II indication for CXA , CMR provides a high accuracy for decision making regarding appropriateness of the invasive exam . CMR prior to CXA could substantially reduce pure diagnostic coronary angiographies in patients with intermediate probability for CAD , in our patient-cohort from approximately 34 % to 6 % . Further studies are warranted to identify rare false negative CMR results BACKGROUND Qualitative interpretation of myocardial contrast echocardiography ( MCE ) improves the accuracy of wall-motion analysis for assessment of coronary artery disease ( CAD ) . We examined the feasibility and accuracy of quantitative MCE for diagnosis of CAD . METHODS Dipyridamole/exercise stress MCE ( destruction-replenishment protocol with real-time imaging ) was performed in 90 patients undergoing quantitative coronary angiography , 48 of whom had significant ( > 50 % ) stenoses . MCE was repeated with exercise alone in 18 patients . Myocardial blood flow ( A*beta ) was obtained from blood volume ( A ) and time to refill ( beta ) . RESULTS Quantification of flow reserve was feasible in 88 % . The mean A*beta reserve in the anterior wall was significantly impaired for patients with left anterior descending coronary artery disease ( n = 28 ) compared with those with no disease ( 1.6 + /- 1.2 vs 4.0 + /- 2.5 , P < or = .001 ) . This reflected impaired beta reserve , with no difference in the A reserve . Applying a receiver operating characteristic curve derived cutoff of 2.0 for A*beta reserve , quantitative MCE was 76 % sensitive and 71 % specific for the diagnosis of significant left anterior descending coronary artery stenosis . Posterior circulation results were similar , with 78 % sensitivity and 59 % specificity for detection of posterior CAD . Overall , quantitative MCE was similarly sensitive to qualitative approach for diagnosis of CAD ( 88 % vs 93 % ) , but with lower specificity ( 52 % vs 65 % , P = .07 ) . In 18 patients restudied with pure exercise stress , the mean myocardial blood flow reserve was less than after combined stress ( 2.1 + /- 1.6 vs 3.7 + /- 1.9 , P = .01 ) . CONCLUSION Quantitative MCE is feasible for the diagnosis of CAD with dipyridamole/exercise stress . Dipyridamole prolongs postexercise hyperemia , augmenting the degree of hyperemia at the time of imaging To investigate prospect ively , in patients with suspicion of coronary artery disease ( CAD ) , the added value of coronary calcium scoring ( CS ) as adjunct to cardiac magnetic resonance ( CMR ) for the diagnosis of morphological coronary stenosis in comparison to catheter angiography ( CA ) . Sixty consecutive patients ( 8 women ; 64 ± 10 years ) referred to CA underwent CMR ( 1.5 T ) including perfusion and late gadolinium-enhancement imaging as well as CS with computed tomography . Diagnostic performance was evaluated for CMR and CS separately , and for both methods combined , with CA as reference st and ard . Best CS threshold combined with a specificity > 90 % to predict significant stenosis in patients without abnormalities on CMR was determined from receiver operator characteristics ( ROC ) analysis . Abnormal CMR results were considered to indicate significant stenosis regardless of CS ; CS above threshold reclassified patients to have CAD regardless of CMR . CA identified 104/960 ( 11 % ) coronary segments with coronary artery stenosis > 50 % in 36/60 ( 60 % ) patients . ROC revealed an area-under-the-curve of 0.83 ( 95%CI : 0.68 - 0.99 ) with the best CS threshold of 495 Agatston score ( sensitivity 50 % ) . CMR depicted 128/960 ( 13 % ) myocardial segments with abnormalities in 31/60 ( 52 % ) patients . Sensitivity , specificity , negative ( NPV ) and positive predictive value ( PPV ) of CMR were 78 , 88 , 72 and 90 % . When adding CS to CMR , sensitivity and NPV increased to 89 and 83 % , while specificity and PPV slightly decreased to 83 and 89 % . Accuracy of the combined approach ( 87 % ) was significantly ( P < 0.05 ) higher than that of CMR ( 82 % ) alone . Adding CS to CMR improves the accuracy for the detection of morphological CAD UNLABELLED The purpose of this study was to prospect ively evaluate the diagnostic accuracy of a cardiovascular magnetic resonance ( MR ) k-space and time ( k-t ) broad-use linear acquisition speed-up technique ( BLAST ) accelerated perfusion sequence for depicting clinical ly relevant coronary artery disease ( CAD ) , with use of coronary angiography as the reference st and ard . The local ethics committee approved this study , and informed consent was obtained from 40 patients ( 28 men , 12 women ; mean age , 61 years + /- 8 [ st and ard deviation ] ) scheduled for coronary catheterization . A balanced steady-state free precession pulse sequence ( 2.6 x 2.6 x 10 mm ) with a net k-t acceleration factor of 3.8 ( repetition time msec/echo time msec , 3.2/1.6 ; flip angle , 50 degrees ) was applied . Visual analysis of perfusion images and quantitative analysis of signal-time curves obtained in the myocardium were performed by using segmental myocardial upslope , peak enhancement , and their respective ratios . Visual analysis revealed sensitivity , specificity , and diagnostic accuracy of 86 % , 78 % , and 83 % , respectively , in the detection of coronary stenoses with at least 50 % luminal narrowing . Significant ( P < .05 ) changes between ischemic and remote segments could be shown for all perfusion indexes applied . Use of myocardial perfusion imaging with k-t BLAST for accelerated data acquisition is feasible in the identification of patients with substantial CAD ( coronary stenosis > or= 50 % ) . SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/245/3/863/DC1 The coronary artery calcium ( CAC ) score is a readily and widely available tool for the noninvasive diagnosis of atherosclerotic coronary artery disease ( CAD ) . The aim of this study was to investigate the added value of the CAC score as an adjunct to gated SPECT for the assessment of CAD in an intermediate-risk population . Methods : Seventy-seven prospect ively recruited patients with intermediate risk ( as determined by the Framingham Heart Study 10-y CAD risk score ) and referred for coronary angiography because of suspected CAD underwent stress 99mTc-tetrofosmin SPECT myocardial perfusion imaging ( MPI ) and CT CAC scoring within 2 wk before coronary angiography . The sensitivity and specificity of SPECT alone and of the combination of the 2 methods ( SPECT plus CAC score ) in demonstrating significant CAD ( ≥50 % stenosis on coronary angiography ) were compared . Results : Forty-two ( 55 % ) of the 77 patients had CAD on coronary angiography , and 35 ( 45 % ) had abnormal SPECT results . The CAC score was significantly higher in subjects with perfusion abnormalities than in those who had normal SPECT results ( 889 ± 836 [ mean ± SD ] vs. 286 ± 335 ; P < 0.0001 ) . Similarly , with rising CAC scores , a larger percentage of patients had CAD . Receiver-operating-characteristic analysis showed that a CAC score of greater than or equal to 709 was the optimal cutoff for detecting CAD missed by SPECT . SPECT alone had a sensitivity and a specificity for the detection of significant CAD of 76 % and 91 % , respectively . Combining SPECT with the CAC score ( at a cutoff of 709 ) improved the sensitivity of SPECT ( from 76 % to 86 % ) for the detection of CAD , in association with a nonsignificant decrease in specificity ( from 91 % to 86 % ) . Conclusion : The CAC score may offer incremental diagnostic information over SPECT data for identifying patients with significant CAD and negative MPI results Myocardial flow reserve ( MFR ) is not routinely assessed in myocardial perfusion imaging ( MPI ) studies but has been hypothesized to affect test accuracy when assessing disease severity by coronary vessel lumenography . Magnetic resonance imaging ( MRI ) is an emerging diagnostic technique that can both perform MPI and assess MFR . We studied women ( n = 184 ) enrolled in the Women 's Ischemia Syndrome Evaluation ( WISE ) study with symptoms suggesting ischemic heart disease . Tests performed were coronary angiography and MPI by both MR and gated radionuclide single photon emission computed tomography ( gated-SPECT ) . The MFR index was calculated using the MR data acquired at baseline and under vasodilation ( dipyridamole ) conditions . The study was structured with a pilot and an implementation phase . During the pilot phase ( n = 46 ) data were unmasked and an MFR threshold was defined to divide patients into those with an adequate ( AMFRI ) or inadequate ( IMFRI ) MFR index . During the implementation phase , the MFR index threshold was prospect ively applied to patients ( n = 138 ) . In the implementation phase , MPI ischemia detection accuracy compared to severe ( > or = 70 % ) coronary artery diameter narrowing by angiography was higher in the AMFRI vs. the IMFRI group for MRI ( 86 % vs. 70 % , p < 0.05 ) and gated-SPECT ( 89 % vs. 67 % , p < 0.01 ) . The IMFRI group ( n = 55 , 30 % of study population ) had a higher resting rate-pressure product compared with the AMFRI group ( 10,599 + /- 2871 vs. 9378 + /- 2447 bpm mm Hg , p < 0.01 ) , consistent with higher resting myocardial flow . When compared with each other , MRI and gated-SPECT MPI showed no difference in accuracy among MFR groups . Myocardial perfusion patterns in the IMFRI group may have result ed in atypical perfusion patterns , which either masked or mimicked epicardial coronary artery disease OBJECTIVES We tested a pre-defined visual interpretation algorithm that combines cardiovascular magnetic resonance ( CMR ) data from perfusion and infa rct ion imaging for the diagnosis of coronary artery disease ( CAD ) . BACKGROUND Cardiovascular magnetic resonance can assess both myocardial perfusion and infa rct ion with independent techniques in a single session . METHODS We prospect ively enrolled 100 consecutive patients with suspected CAD scheduled for X-ray coronary angiography . Patients had comprehensive clinical evaluation , including Rose angina question naire , 12-lead electrocardiography , C-reactive protein , and calculation of Framingham risk . Cardiovascular magnetic resonance included cine , adenosine-stress and rest perfusion-CMR , and delayed enhancement-CMR ( DE-CMR ) for infa rct ion imaging . Matched stress-rest perfusion defects in the absence of infa rct ion by DE-CMR were considered artifactual . All patients underwent X-ray angiography within 24 h of CMR . RESULTS Ninety-two patients had complete CMR examinations . Significant CAD ( > or = 70 % stenosis ) was found in 37 patients ( 40 % ) . The combination of perfusion and DE-CMR had a sensitivity , specificity , and accuracy of 89 % , 87 % , and 88 % , respectively , for CAD diagnosis , compared with 84 % , 58 % , and 68 % , respectively , for perfusion-CMR alone . The combination had higher specificity and accuracy ( p < 0.0001 ) , owing to incorporating the exceptionally high specificity ( 98 % ) of DE-CMR . Receiver operating characteristic curve analysis demonstrated the combination provided better performance than cine , perfusion , or DE-CMR alone . The accuracy was high in single-vessel and multivessel disease and independent of CAD location . Multivariable analysis including st and ard clinical parameters demonstrated the combination was the strongest independent CAD predictor . CONCLUSIONS A combined perfusion and infa rct ion CMR examination with a visual interpretation algorithm can accurately diagnose CAD in the clinical setting . The combination is superior to perfusion-CMR alone PURPOSE To evaluate the technical performance of sensitivity encoding (SENSE)-accelerated myocardial perfusion magnetic resonance ( MR ) imaging and prospect ively assess the diagnostic accuracy of this examination for depiction of significant coronary artery disease ( CAD ) . MATERIAL S AND METHODS All 102 subjects provided written informed consent , and the local ethics committee approved the study . A saturation-recovery segmented k-space gradient-echo pulse sequence was combined with SENSE to allow dynamic acquisition of myocardial perfusion data on four parallel short-axis MR image sections at every heartbeat . This technique was evaluated in 10 healthy volunteers and in 92 patients scheduled to undergo conventional coronary angiography . Gadopentetate dimeglumine was peripherally injected at rest and during adenosine-induced stress . The maximal upslope of the signal intensity-time profiles was plotted for 16 myocardial segments defined on three MR image sections , and a myocardial perfusion reserve index ( MPRI ) between stress and rest , normalized to the input function from the blood pool of the most basal section , was calculated . Areas under receiver operating characteristic curves ( AUCs ) were used to assess the diagnostic performance of cardiac MR imaging for depiction of greater than 70 % CAD seen at coronary angiography , the reference st and ard . RESULTS In volunteers , the mean myocardial enhancement was 2.1 + /- 1.2 ( st and ard deviation ) , with homogeneous signal intensity distribution across the segments . The diagnostic accuracy of MPRI measurements was high ( AUC , 0.908 ; sensitivity , 88 % [ 52 of 59 patients ] ; specificity , 82 % [ 27 of 33 patients ] ) . Diagnostic performance was similar among separate analyses of the three coronary territories and among separate analyses of data in the patients with diabetes mellitus , left ventricular hypertrophy , or myocardial infa rct ion . CONCLUSION Multisection myocardial perfusion MR imaging with SENSE is feasible and has high diagnostic accuracy in the detection of CAD AIMS To determine in a multicentre , multivendor trial the diagnostic performance for perfusion-cardiac magnetic resonance ( perfusion-CMR ) in comparison with coronary X-ray angiography ( CXA ) and single-photon emission computed tomography ( SPECT ) . METHODS AND RESULTS Of 241 eligible patients from 18 centres , 234 were r and omly dosed with 0.01 , 0.025 , 0.05 , 0.075 , or 0.1 mmol/kg Gd-DTPA-BMA ( Omniscantrade mark , GE-Healthcare ) per stress ( 0.42 mg/kg adenosine ) and rest perfusion study . Coronary artery disease ( CAD ) was defined as diameter stenosis > or = 50 % on quantitative CXA . Five CMR and eight SPECT studies ( of 225 complete studies ) were excluded from analyses due to inadequate quality ( three blinded readers scored per modality ) . The comparison of CMR vs. SPECT was based on receiver operating characteristic ( ROC ) analysis . Perfusion-CMR at the optimal CM dose ( 0.1 mmol/kg ) had similar performance as SPECT , if only the SPECT studies of the 42 patients with this dose were considered [ area under ROC curve ( AUC ) : 0.86 + /- 0.06 vs. 0.75 + /- 0.09 for SPECT , P = 0.12 ] ; however , diagnostic performance of perfusion-CMR was better vs. the entire SPECT population ( AUC : 0.67 + /- 0.05 , n = 212 , P = 0.013 ) . CONCLUSIONS In this multicentre , multivendor trial , ROC analyses suggest perfusion-CMR as a valuable alternative to SPECT for CAD detection showing equal performance in the head-to-head comparison . Comparing perfusion-CMR with the entire SPECT population suggests CMR superiority over SPECT , which warrants further evaluation in larger trials To implement a high-resolution first-pass myocardial perfusion imaging protocol ( HRPI ) at 3 T , and to evaluate the feasibility , image quality and accuracy of this approach prospect ively in patients with suspected CAD . We hypothesized that utilizing the gain in SNR at 3 T to increase spatial resolution would reduce partial volume effects and subendocardial dark rim artifacts in comparison to 1.5 T. HRPI studies were performed on 60 patients using a segmented k-space gradient echo sequence ( in plane resolution 1.97 × 1.94 mm2 ) . Semiquantitative assessment of dark rim artifacts was performed for the stress studies on a slice-by-slice basis . Qualitative visual analysis was compared to quantitative coronary angiography ( QCA ) results ; hemodynamically significant CAD was defined as stenosis ≥70 % at QCA . Dark rim artifacts appeared in 108 of 180 slices ( average extent 1.3 ± 1.2 mm representing 11.8 ± 10.8 % of the transmural myocardial thickness ) . Sensitivity , specifity , and test accuracy for the detection of significant CAD were 89%,79 % , and 85 % . HRPI studies at 3 T are feasible in a clinical setting , providing good image quality and high accuracy for detection of significant CAD . The presence of dark rim artifacts does not appear to represent a diagnostic problem when using a HRPI approach RATIONALE AND OBJECTIVES Endowed with sufficient diagnostic accuracy , electron beam computed tomography angiography ( CTA ) is being increasingly used to evaluate coronary arteries . However , data on direct comparisons with nuclear myocardial perfusion studies are limited . In this study , we sought to compare the accuracies of CTA and myocardial perfusion imaging ( MPI ) for identifying symptomatic patients with hemodynamically significant obstructive coronary artery disease ( CAD ) . MATERIAL S AND METHODS In a single-center study , symptomatic out patients who were scheduled for cardiac catheterization were prospect ively enrolled . Only patients with exertional angina or dyspnea were included . After fulfilling the inclusion criteria , 30 patients were enrolled in the study ( mean age 54 + /- 9 years and 70 % males ) . Patients underwent MPI , CTA including coronary artery calcification ( CAC ) measure , and invasive coronary angiography for evaluation of obstructive coronary artery disease . Significant CAD was defined as > 50 % left main artery stenosis or > 70 % stenosis of any other epicardial vessel by invasive angiography . The sensitivities , specificities and predictive values of MPI , CAC , and CTA were analyzed per patient RESULTS CTA demonstrated significant higher sensitivity than MPI ( 95 % vs. 81 % , P < .05 ) . CTA demonstrated significantly higher specificity than both MPI ( 89 % versus 78 % , P = .04 ) and CAC ( 56 % , P = .002 ) . CTA also performed better in a per-vessel analysis ( sensitivity 94 % , specificity 96 % ) than both nuclear and CAC . There were no significant differences between the sensitivities and specificities of MPI and CAC . CONCLUSION CTA accurately detects obstructive CAD in symptomatic patients and may be more accurate than MPI or CAC assessment . Larger studies in a more diverse population are needed BACKGROUND Although dipyridamole and adenosine have been used as vasodilator agents , we believe they are inadequate for vasodilator perfusion magnetic resonance imaging , due to adverse effects ( flushing , warmth , headaches , and arrhythmia ) . Nicor and il , a potassium channel opener , has been reported to increase coronary blood flow and it was associated with fewer adverse effects than adenosine or dipiridamole . We set out to investigate whether the coronary artery stenosis could be assessed by nicor and il stress perfusion magnetic resonance imaging . METHODS First-pass contrast-enhanced magnetic resonance images of the left ventricle acquired from 50 patients at rest and during intravenous administration of nicor and il using multi-slice turbo field echo with multi shot echo-planar-imaging . Coronary angiography was performed within 1 week . RESULTS There was no adverse effects during nicor and il stress in any patients . The overall sensitivity and specificity of magnetic resonance imaging in identifying patients with significant stenosis of at least one coronary artery were 93.9 % ( 31 of 33 patients ) and 94.1 % ( 16 of 17 patients ) , respectively . The sensitivity of magnetic resonance imaging for detecting significant stenosis in the left anterior descending artery was 87.5 % ; the sensitivity in the left circumflex artery was 80 % ; the sensitivity in the right coronary artery was 92.3 % . Similar sensitivities were observed for all 3 vascular regions , indicating that all myocardial segments were visualized with similar image quality . CONCLUSIONS The present study shows that nicor and il stress perfusion magnetic resonance imaging is a safe , feasible technique for assessing coronary artery stenosis severity in a totally-noninvasive manner Background Most previous studies on the accuracy of myocardial perfusion imaging ( MPI ) are hampered by post-test referral bias , in that referral for coronary angiography was influenced by the MPI result . In this way , patients with a normal MPI result less frequently underwent catheterization , a tendency supposed to cause an underestimation of test specificity and an overestimation of test sensitivity . Methods and Results MPI by use of a gated dual-isotope protocol was undertaken before angiography in 357 patients referred for angiography for suspected stable angina pectoris . The MPI reports were kept secret to prevent post-test referral bias . The MPI study was normal in 215 patients ( 60 % ) and showed reversible perfusion abnormalities in 118 ( 33 % ) and fixed defects in 24 ( 7 % ) . Angiography was normal in 231 patients ( 65 % ) and revealed 1 or more significant stenoses in 126 ( 35 % ) . With angiography as the reference , the sensitivity and specificity of MPI for detecting significant coronary artery stenosis were 75 % and 79 % , respectively . Conclusions In this prospect i ve study without post-test referral bias , we found a lower sensitivity and slightly higher specificity than in studies with post-test referral bias . The imperfect accuracy may reflect differences between anatomic and physiologic imaging . ( J Nucl Cardiol 2005;12:530 - 7 . Objective : To evaluate the diagnostic impact of magnetic resonance imaging ( MRI ) first-pass perfusion using steady-state , free-precession ( SSFP ) sequences with parallel imaging ( SENSE ) for detection of coronary stenoses . Design : Prospect i ve observational study . Setting : University hospital , cardiac MRI and catheterisation laboratories . Patients and methods : 228 patients were examined with coronary angiography and MRI ( 1.5 T Intera CV ) . A three-slice , short-axis SSFP perfusion scan with a saturation prepulse was performed during infusion of adenosine and at rest followed by myocardial scar ( late enhancement ) imaging . Gadolinium-DTPA was given at 0.1 mmol/kg body weight . Perfusion images were visually assessed . Analysis for myocardial hypoperfusion was done according to patient group and according to vessel . Results : Sensitivity , specificity and accuracy of MRI first-pass perfusion for detection of a coronary artery stenosis ( > 50 % luminal narrowing ) in the total patient group were 93.0 % , 85.7 % , 91.2 % and for a significant lesion ( > 70 % luminal narrowing ) 96.1 % , 72.0 % , 88.2 % , respectively . Based on 536 coronary artery territories without myocardial scar , the sensitivity of MRI perfusion analysis for detection of a significant lesion was for the left anterior descending artery 91.4 % , for the circumflex artery 81.6 % and for the right coronary artery 65.1 % ( p<0.001 ) . Conclusions : MRI first-pass perfusion analysis using an SSFP sequence with three myocardial slices was a highly accurate diagnostic method for detection of coronary artery stenoses . This MRI technique can be included in daily practice and has the potential to guide the indication for invasive coronary angiography PURPOSE To prospect ively evaluate the feasibility and diagnostic accuracy of high spatial resolution myocardial perfusion imaging during high dose dobutamine/atropine stress magnetic resonance ( DSMR ) for the detection of coronary artery disease ( CAD ) . METHODS AND RESULTS DSMR-wall motion was combined with perfusion imaging ( DSMR-perfusion ) in 78 patients prior to clinical ly indicated invasive coronary angiography . For DSMR-perfusion an in-plane spatial resolution of 1.5 × 1.5mm(2 ) was attained by using 8 × k-space and time sensitivity encoding ( k-t SENSE ) . Image quality and extent of artifacts during perfusion imaging were evaluated . Wall motion and perfusion data were interpreted sequentially . Significant CAD ( stenosis ≥ 70 % ) was present in 52 patients and involved 86 coronary territories . One patient did not reach target heart rate despite maximum infusion of dobutamine/atropine . Two studies ( 3 % ) were non-diagnostic due k-t SENSE related artifacts result ing from insufficient breathhold capability . Overall image quality was good . Dark-rim artifacts were limited to the endocardial border at a mean width of 1.8 mm . The addition of DSMR-perfusion to DSMR-wall motion data improved sensitivity for the detection of CAD ( 92 % vs. 81 % , P=0.03 ) and accurate determination of disease extent ( 85 % vs. 66 % of territories , P<0.001 ) . There were no significant differences between DSMR-perfusion and DSRM-wall motion regarding overall specificity ( 83 % vs. 87 % , P=1 ) and accuracy ( 89 % vs. 83 % , P=0.13 ) . CONCLUSION High spatial resolution DSMR-perfusion imaging at maximum stress level was feasible , improved sensitivity over DSMR-wall motion for the detection of CAD and allowed an accurate determination of disease extent . Specificity of DSMR-perfusion with k-t SENSE improved compared to prior studies using lower spatial resolution PURPOSE To prospect ively determine the diagnostic performance of myocardial perfusion magnetic resonance ( MR ) imaging at 3 T for helping depict clinical ly relevant coronary artery stenosis ( > or = 50 % diameter ) in patients with suspected or known coronary artery disease ( CAD ) , with coronary angiography as the reference st and ard . MATERIAL S AND METHODS The study was approved by the local ethics committee ; written informed consent was obtained . Vasodilator stress perfusion imaging by using a turbo field-echo sequence was obtained in 101 patients ( 71 men , 30 women ; mean age , 62 years + /- 7.7 [ st and ard deviation ] ) scheduled for coronary angiography . Myocardial ischemia was defined as stress-inducible perfusion deficit in arterial territories without delayed enhancement ( DE ) or additional stress-inducible perfusion deficit in territories with nontransmural DE . Images were evaluated in consensus by two blinded readers . Diagnostic performance was determined on per-patient and per-coronary artery territory bases . The number of dark rim artifacts in patients without DE was determined in a second read . Interobserver variability was assessed in 40 r and omly selected patients . RESULTS One hundred one patients underwent MR examinations . Coronary angiography depicted relevant stenosis in 70 ( 69 % ) patients . Patient-based sensitivity and specificity were 90 % and 71 % , respectively . Sensitivity , specificity , and diagnostic accuracy for the detection of coronary stenosis in a specific territory were 76 % , 89 % , and 86 % , respectively . In 24 % of patients without DE , dark rim artifacts were detected , mostly in the left anterior descending artery territory ( 56 % ) . In 40 r and omly selected patients , there was agreement in the determination of myocardial perfusion deficits in 37 ( 93 % , kappa = 0.79 ) patients . CONCLUSION Myocardial perfusion MR imaging by using saturation-recovery spoiled gradient-echo imaging at 3 T has an accuracy of 84 % for depicting hemodynamically relevant coronary artery stenosis in patients with suspected and known CAD Background —Dobutamine stress MR ( DSMR ) is highly accurate for the detection of inducible wall motion abnormalities ( IWMAs ) . Adenosine has a more favorable safety profile and is well established for the assessment of myocardial perfusion . We evaluated the diagnostic value of IWMAs during dobutamine and adenosine stress MR and adenosine MR perfusion compared with invasive coronary angiography . Methods and Results —Seventy-nine consecutive patients ( suspected or known coronary disease , no history of prior myocardial infa rct ion ) scheduled for cardiac catheterization underwent cardiac MR ( 1.5 T ) . After 4 minutes of adenosine infusion ( 140 & mgr;g · kg−1 · min−1 for 6 minutes ) , wall motion was assessed ( steady-state free precession ) , and subsequently perfusion scans ( 3-slice turbo field echo-echo planar imaging ; 0.05 mmol/kg Gd-BOPTA ) were performed . After a 15-minute break , rest perfusion was imaged , followed by st and ard DSMR/atropine stress MR . Wall motion was classified as pathological if ≥1 segment showed IWMAs . The transmural extent of inducible perfusion deficits ( < 25 % , 25 % to 50 % , 51 % to 75 % , and > 75 % ) was used to grade segmental perfusion . Quantitative coronary angiography was performed with significant stenosis defined as > 50 % diameter stenosis . Fifty-three patients ( 67 % ) had coronary artery stenoses > 50 % ; sensitivity and specificity for detection by dobutamine and adenosine stress and adenosine perfusion were 89 % and 80 % , 40 % and 96 % , and 91 % and 62 % , respectively . Adenosine IWMAs were seen only in segments with > 75 % transmural perfusion deficit . Conclusions —DSMR is superior to adenosine stress for the induction of IWMAs in patients with significant coronary artery disease . Visual assessment of adenosine stress perfusion is sensitive with a low specificity , whereas adenosine stress MR wall motion is highly specific because it identifies only patients with high- grade perfusion deficits . Thus , DSMR is the method of choice for current state-of-the-art treatment regimens to detect ischemia in patients with suspected or known coronary artery disease but no history of prior myocardial infa rct ion The aim of this study was to compare the clinical value of 99Tcm-MIBI single photon emission tomography ( SPET ) and electron beam computed tomography ( EBCT ) in the assessment of coronary artery disease ( CAD ) in different age groups . 99Tcm-MIBI SPET ( stress-rest ) , EBCT and coronary angiography studies were performed in 64 consecutive patients with suspected CAD . The patients were classified into two groups : Group A = 40 patients > 45 years of age and Group B = 24 patients ⩽45 years of age . There were 31 and 14 patients with coronary stenosis ⩾50 % as determined by coronary angiography in Groups A and B , respectively . All patients ( 30 cases ) with abnormal 99Tcm-MIBI myocardial SPET and coronary calcification detected by EBCT had significant coronary artery disease , and 93.3 % of the patients with normal 99Tcm-MIBI SPET and normal EBCT had normal coronary angiography or < 50 % lumen narrowing of the coronary arteries . In Group B , the sensitivity of SPET for detecting CAD was significantly higher than that of EBCT ( 92.9 vs 42.9 % , P<0.01 ) ; the specificity of SPET was comparable to that of EBCT . In Group A , there was no significant difference between SPET and EBCT in terms of sensitivity ( 93.6 vs 90.3 % ) or specificity ( 88.9 vs 55.6 % ) . However , in the detection of individual coronary artery disease , the specificity of SPET was significantly higher than that of EBCT in Group A ( 94.1 vs 66.7 % , P<0.001 ) . The sensitivity of SPET was again significantly higher than that of EBCT ( 85.7 vs 38.1 % , P<0.005 ) in Group B. The accuracy of SPET was higher than that of EBCT in both groups ( 82.5 vs 67.5 % , P<0.01 in Group A ; 93.1 vs 76.4 % , P<0.01 in Group B , respectively ) . We conclude that 99Tcm-MIBI myocardial perfusion SPET has a higher sensitivity than EBCT in the detection of CAD in patients ⩽45 years old and a higher specificity in patients > 45 years of age . A combination of SPET and EBCT may assess CAD more accurately OBJECTIVE The aims of this prospect i ve study were to compare the diagnostic value of accelerated vasodilator stress real-time myocardial contrast echocardiography ( MCE ) and single photon emission computed tomography ( SPECT ) against coronary angiography and to evaluate whether the addition of MCE perfusion data improves the diagnostic accuracy of stress echocardiography . METHODS A total of 103 patients with suspected or known stable coronary artery disease ( CAD ) underwent SPECT and accelerated high-dose dipyridamole ( 0.84 mg/kg intravenously for 4 minutes ) atropine ( up to 1 mg intravenously ) stress real-time qualitative MCE . The presence of CAD was detected by coronary angiography . RESULTS CAD defined as > or= 70 % stenosis was detected in 77 % of patients , whereas 86 % of patients had CAD defined as > or= 50 % stenosis . In a territory-by-territory analysis , the concordance between MCE and SPECT in detecting perfusion defects varied from 72.8 % ( kappa = 0.386 ) to 89.3 % ( kappa = 0.642 ) . There were no significant differences between MCE and SPECT in sensitivity , specificity , and diagnostic accuracy for identifying patients with CAD . Combining MCE and wall motion abnormality analysis significantly improved the sensitivity of the test compared with wall motion abnormality analysis alone . CONCLUSIONS Accelerated vasodilator stress real-time MCE yields a good concordance with SPECT in detection of perfusion defects and a similar diagnostic value for the detection of CAD . The addition of MCE perfusion data improves the diagnostic value of stress echocardiography You are back where we put you in the previous article1 on diagnostic tests in this series on how to use the medical literature : in the library study ing an article that will guide you in interpreting ventilation-perfusion ( V/Q ) lung scans . Using the criteria in Table 1 , you have decided that the Prospect i ve Investigation of Pulmonary Diagnosis ( PIOPED ) study 2 will provide you with valid information . Just then , another PURPOSE To prospect ively determine the accuracy of a combined magnetic resonance ( MR ) imaging approach ( stress first-pass perfusion imaging followed by delayed-enhancement imaging ) for depicting clinical ly significant coronary artery stenosis ( > or = 70 % stenosis ) in patients suspected of having or known to have coronary artery disease ( CAD ) , with coronary angiography serving as the reference st and ard . MATERIAL S AND METHODS The committee on human research approved the study protocol , and all participants gave written informed consent . This study was HIPAA compliant . Forty-seven patients ( 38 men and nine women ; mean age , 63 years + /- 5.3 [ st and ard deviation ] ) scheduled for coronary angiography were prospect ively enrolled : 33 were suspected of having CAD ( group A ) and 14 had experienced a previous myocardial infa rct ion and were suspected of having new lesions ( group B ) . The MR imaging protocol included cine function , gadolinium-enhanced stress and rest first-pass perfusion MR imaging , and delayed-enhancement MR imaging . Myocardial ischemia was defined as a segment with perfusion deficit at stress first-pass perfusion MR imaging and no hyperenhancement at delayed-enhancement imaging . Myocardial infa rct ion was defined as an area with hyperenhancement at delayed-enhancement imaging . RESULTS One patient was excluded from analysis because of poor- quality MR images . Coronary angiography depicted significant stenosis in 30 of 46 patients ( 65 % ) . In a per-vessel analysis ( n = 138 ) , stress first-pass perfusion MR imaging and delayed-enhancement imaging yielded sensitivity of 0.87 , specificity of 0.89 , and accuracy of 0.88 , when compared with coronary angiography . The diagnostic accuracy of stress first-pass perfusion MR imaging and delayed-enhancement imaging was slightly better than that of stress and rest first-pass perfusion MR imaging in the entire population ( 0.88 vs 0.85 ) , in group A ( 0.86 vs 0.82 ) , and in group B ( 0.93 vs 0.90 ) . CONCLUSION Stress first-pass perfusion MR imaging followed by delayed-enhancement imaging is an accurate method to depict significant coronary stenosis in patients suspected of having or known to have CAD BACKGROUND No previous studies have compared myocardial contrast echocardiography ( MCE ) and single-photon emission computerized tomography ( SPECT ) for the detection of coronary artery disease ( CAD ) in patients with a medium likelihood of CAD . This study was developed to test the hypothesis that MCE is superior to SPECT for the detection of CAD . METHODS Fifty-five patients with a medium probability of CAD and no previous myocardial infa rct ion were recruited . Results of MCE and SPECT were compared to quantitative coronary arteriography , where CAD was defined as > 50 % stenosis . Each patient was examined for the anterior and posterior circulations . RESULTS On a coronary circulation basis ( n = 110 ) , the sensitivity of MCE was significantly greater than that of SPECT for the detection of CAD ( 86 % vs 43 % , P < .0001 ) . However , the specificities were similar ( 88 % and 93 % , P = .52 ) . Both techniques were marginally more accurate in the anterior compared to the posterior circulation ( 88 % vs 76 % , P = .07 for MCE and 79 % vs 63 % , P = .19 , for SPECT ) . On a patient basis ( n = 55 ) , MCE had a higher sensitivity than SPECT for the detection of CAD ( 83 % vs 49 % , P < .05 ) . Although specificity tended to be higher for SPECT than MCE ( 92 % vs 58 % ) , it was not significant ( P = .33 ) . When CAD was defined as > 40 % coronary stenosis , the specificity of MCE increased to 83 % without any change in sensitivity . CONCLUSION In this preliminary study , MCE was found to be superior to SPECT during dipyridamole stress for the diagnosis of CAD in patients with a medium pretest probability of CAD . Larger studies are required to confirm these findings OBJECTIVE The purpose of our study was to prospect ively evaluate the accuracy of a comprehensive assessment of coronary artery disease ( CAD ) with prospect ively ECG-gated coronary CT angiography ( CTA ) and perfusion-cardiac MRI for the detection of hemodynamically relevant coronary stenoses . SUBJECTS AND METHODS Forty-seven consecutive patients underwent k-space and time broad-use linear acquisition speed-up technique accelerated perfusion-cardiac MRI at 1.5 T and dual- source coronary CTA . Catheter coronary angiography ( CA ) , coronary CTA , and perfusion-cardiac MRI were all performed within a median time interval of 7.5 days . Detection of hemodynamically relevant stenoses by the combination of coronary CTA plus perfusion-cardiac MRI was compared with the combination of CA plus perfusion-cardiac MRI , the latter serving as the st and ard of reference . RESULTS CA identified stenoses in 75 of 141 coronary arteries ( 53.2 % ) in 33 of 47 patients ( 70.2 % ) . Cardiac MRI revealed perfusion defects in 30 of 47 patients ( 63.8 % ) . Image quality of coronary CTA was diagnostic in 635 of 638 segments ( 99.5 % ) . Coronary CTA revealed stenoses greater than 50 % in 76 of 141 coronary arteries ( 53.9 % ) of 33 of 47 patients ( 70.2 % ) . Sensitivity , specificity , negative and positive predictive value , and accuracy of coronary CTA and perfusion-cardiac MRI versus CA and perfusion-cardiac MRI for the detection of hemodynamically relevant stenoses were 96.7 % , 100 % , 94.4 % , 100 % , and 97.9 % , respectively . CONCLUSION The combination of coronary CTA and perfusion-cardiac MRI shows diagnostic performance comparable to that of CA and perfusion-cardiac MRI . Preliminary data suggest that coronary CTA may replace CA in the diagnosis of hemodynamically relevant CAD

We identified that XRCC1-rs25489 polymorphism was associated with an increased risk of urological neoplasms in heterozygote and dominant models . Moreover , in the subgroup analysis by cancer type , we found that XRCC1-rs25489 polymorphism was associated with an increased risk of bladder cancer ( BC ) in heterozygote model . Although overall analyses suggested a null result for XRCC1-rs25487 polymorphism , in the stratified analysis by ethnicity , an increased risk of urological neoplasms for Asians in allelic and homozygote models was identified . While for other polymorphisms in XRCC genes , no significant association was uncovered . To sum up , our results indicated that XRCC1-rs25489 polymorphism is a risk factor for urological neoplasms , particularly for BC .

Polymorphisms in X-ray repair cross-complementing ( XRCC ) genes have been implicated in altering the risk of various urological cancers . However , the results of reported studies are controversial . To ascertain whether polymorphisms in XRCC genes are associated with the risk of urological neoplasms , we conducted present up date d meta- analysis and systematic review .

We propose a hypothesis that differences in base excision repair capacity modulate the effect of dietary antioxidant intake on prostate cancer risk . As a preliminary test of this hypothesis , we conducted a pilot case-control study to evaluate prostate cancer risk in men with polymorphisms in the XRCC1 gene , a key player in base excision repair , across different strata of antioxidant intake . Seventy-seven prostate cancer patients and 183 community controls , for whom we have detailed dietary information , were frequency matched on age and race . We found a somewhat lower prostate cancer risk for men with one or two copies of the variant alleles at the XRCC1 codons 194 and 399 than for those who were homozygous for the common allele [ codon 194 : odds ratio ( OR ) = 0.8 ; 95 % confidence interval ( CI ) , 0.4 - 1.8 and codon 399 : OR = 0.8 ; 95 % CI , 0.5 - 1.3 ] . The variant at codon 280 was associated with a slightly increased prostate cancer risk ( OR = 1.5 ; 95 % CI , 0.7 - 3.6 ) . Only the codon 399 polymorphism occurred frequently enough to investigate its joint effect with antioxidant intake . Prostate cancer risk was highest among men who were homozygous for the common allele at codon 399 and had low dietary intake of vitamin E ( OR = 2.4 ; 95 % CI , 1.0 - 5.6 ) or lycopene ( OR = 2.0 ; 95 % CI , 0.8 - 4.9 ) , whereas low intake of these antioxidants in men without this genotype hardly increased prostate cancer risk . The polymorphism did not modulate risk associated with low intake of vitamin C , A , or beta-carotene . The data give some support for our hypothesis but should be regarded as preliminary , because it is limited by small sample size . We discuss what kind of data and what kind of studies are needed for future evaluation of this hypothesis As part of a population -based case-control study in Shanghai , China , we investigated whether variants in several DNA repair genes , either alone or in conjunction with other risk factors , are associated with prostate cancer risk . Genomic DNA from 162 patients newly diagnosed with prostate cancer and 251 healthy men r and omly selected from the population were typed for five nonsynonymous DNA repair markers . We found that the XRCC1-Arg399Gln AA and the MGMT-Leu84Phe CT+TT genotypes were associated with an increased risk of prostate cancer [ odds ratio ( OR ) , 2.18 ; 95 % confidence interval ( CI ) , 0.99 - 4.81 and OR , 1.99 ; 95 % CI , 1.19 - 3.34 , respectively ] . In contrast , XRCC3-Thr241Met , XPD-Lys751Gln , and MGMT-Ile143Val markers showed no significant associations with risk , although due to the much lower frequency of their variant alleles in this population we can not rule out small to modest effects . There was a significant interaction between the MGMT-84 marker and insulin resistance ( Pinteraction = 0.046 ) . Relative to men with the MGMT-84 CC genotype and a low insulin resistance ( < 0.097 ) , those having the CT-TT genotype and a greater insulin resistance had a 5.4-fold risk ( OR , 5.39 ; 95 % CI , 2.46 - 11.82 ) . In addition , for the XRCC3 - 241 marker , relative to men with the CC genotype and a low intake of preserved foods ( < 12.7 g/d ) , those harboring the CT+TT genotype and having a higher intake of preserved foods ( > 12.7 g/d ) , which contain nitrosamines and nitrosamine precursors , had a significantly increased risk of prostate cancer risk ( OR , 2.62 ; 95 % CI , 1.13 - 6.06 ) . In contrast , men with the CT+TT genotype and a low intake of preserved foods had a 69 % reduction in risk ( OR , 0.31 ; 95 % CI , 0.10 - 0.96 ; Pinteraction = 0.005 ) . These results suggest that genetic variants in the DNA repair pathways may be involved in prostate cancer etiology and that other risk factors , including preserved foods and insulin resistance , may modulate prostate cancer risk in combination with genetic susceptibility in these repair pathways . Replication in larger studies is necessary to preclude chance findings , particularly those among subgroups , and clarify the mechanisms involved DNA repair gene alterations have been shown to cause a reduction in DNA repair capacity and may influence an individual 's susceptibility to carcinogenesis . Single nucleotide polymorphisms ( SNPs ) of DNA repair genes have been shown to cause a reduction in repair activity . We hypothesized that SNPs of DNA repair genes may be a risk factor for renal cell carcinoma ( RCC ) . To test this hypothesis , DNA sample s from 112 cases of renal cell cancer and healthy controls ( n=180 ) were analyzed by PCR-RFLP to determine the genotypic frequency of six different polymorphic loci on five DNA repair genes ( XRCC1 , XPC , ERCC1 , XRCC3 , and XRCC7 ) . The chi(2 ) test was applied to compare the genotype frequency between patients and controls . We found that the frequency of 399Gln variant at XRCC1 Arg399Gln was significantly higher in RCC cases than in controls ( OR=2.83 , 95%CI=1.24 - 6.49 , P=0.01 ) . The frequency of T-A haplotype of XRCC1 194 Trp and XRCC1 399Gln was significantly higher in RCC than controls . No differences in genotypes were observed at the other sites . This is the first report on SNPs of DNA repair genes in renal cell carcinoma that suggests XRCC1 399Gln polymorphism may be a risk factor for RCC . Our present data suggest that the XRCC1 399Gln allele may be linked to susceptibility for RCC Environmental carcinogens contained in air pollution , such as polycyclic aromatic hydrocarbons , aromatic amines or N-nitroso compounds , predominantly form DNA adducts but can also generate interstr and cross-links and reactive oxygen species . If unrepaired , such lesions increase the risk of somatic mutations and cancer . Our study investigated the relationships between 22 polymorphisms ( and their haplotypes ) in 16 DNA repair genes belonging to different repair pathways in 1094 controls and 567 cancer cases ( bladder cancer , 131 ; lung cancer , 134 ; oral-pharyngeal cancer , 41 ; laryngeal cancer , 47 ; leukaemia , 179 ; death from emphysema and chronic obstructive pulmonary disease , 84 ) . The design was a case-control study nested within a prospect i ve investigation . Among the many comparisons , few polymorphisms were associated with the diseases at the univariate analysis : XRCC1 - 399 Gln/Gln variant homozygotes [ odds ratios ( OR ) = 2.20 , 95 % confidence intervals ( CI ) = 1.16 - 4.17 ] and XRCC3 - 241 Met/Met homozygotes ( OR = 0.51 , 95 % CI = 0.27 - 0.96 ) and leukaemia . The recessive model in the stepwise multivariate analysis revealed a possible protective effect of XRCC1 - 399Gln/Gln in lung cancer ( OR = 0.22 , 95 % CI = 0.05 - 0.98 ) , and confirmed an opposite effect ( OR = 2.47 , 95 % CI = 1.02 - 6.02 ) in the leukaemia group . Our results also suggest that the XPD/ERCC1-GAT haplotype may modulate leukaemia ( OR = 1.28 , 95 % CI = 1.02 - 1.61 ) , bladder cancer ( OR = 1.38 , 95 % CI = 1.06 - 1.79 ) and possibly other cancer risks . Further investigations of the combined effects of polymorphisms within these DNA repair genes , smoking and other risk factors may help to clarify the influence of genetic variation in the carcinogenic process

Prescribing replacement thyroxine , either with the anti-thyroid drug treatment , or after this was completed , had no significant effect on relapse . Limited evidence suggested 12 - 18 months of anti-thyroid drug treatment should be used . The titration regimen appeared as effective as the Block-Replace regimen , and was associated with fewer adverse effects . However , relapse rates over 50 % and high participant drop-out rates in trials mean that the results should be interpreted with caution , and may suggest that other strategies for the management of Graves ' disease , such as radioiodine , should be considered more frequently as first-line therapy .

We assessed the effects of dose , regimen and duration of anti-thyroid drug therapy for Graves ' thyrotoxicosis on recurrence of hyperthyroidism , course of ophthalmopathy , adverse effects , health-related quality of life and economic outcomes .

BACKGROUND Antithyroid drugs are effective in patients with hyperthyroidism due to Graves ' disease , but the rate of recurrence after treatment is high . In a recent Japanese study , adjunctive treatment with thyroxine ( T4 ) was associated with a recurrence rate 20 times lower than that among patients who received only an antithyroid drug . If these results are confirmed , combined therapy with an antithyroid drug and T4 might become the treatment of choice for all patients with Graves ' hyperthyroidism . METHODS We treated 111 patients ( 89 women and 22 men ) who had Graves ' hyperthyroidism . All patients initially received 40 mg of carbimazole daily for one month . Then one group received carbimazole alone for 17 months ( 52 patients ) , and the other group received carbimazole plus T4 for 17 months and T4 alone for 18 months ( 59 patients ) . In the carbimazole group , the dose was adjusted after one month to maintain a normal serum thyrotropin concentration . In the carbimazole-T4 group , the dose of carbimazole was not changed , but 100 micrograms of T4 per day was added to the regimen and the dose was adjusted to maintain an undetectable serum thyrotropin concentration ( < 0.04 microU per milliliter ) . RESULTS At the time of our analysis , 53 of the 111 patients had completed at least 3 months of follow-up ( median , 12 months ) after carbimazole was withdrawn . Hyperthyroidism recurred in eight patients in each group after a mean ( + /- SD ) of 6 + /- 4 months in the carbimazole group and 7 + /- 4 months in the carbimazole-T4 group . There was no difference between the recurrence rates in the two groups , despite the fact that serum thyrotropin concentrations were undetectable in 73 percent of patients in the carbimazole-T4 group on at least 75 percent of their visits . CONCLUSIONS The administration of T4 to patients with Graves ' disease during carbimazole treatment and after its withdrawal neither delays nor prevents the recurrence of hyperthyroidism BACKGROUND Antibodies to thyroid-stimulating hormone ( TSH ) receptors that stimulate the thyroid gl and cause hyperthyroidism in patients with Graves ' disease , and their production during antithyroid drug treatment is an important determinant of the course of the disease . One factor that might contribute to the persistent production of antibodies to TSH receptors is stimulation of the release of thyroid antigens by TSH during antithyroid drug therapy . We therefore studied the effect of the suppression of TSH secretion by thyroxine on the levels of antibodies to TSH receptors after thyroid hormone secretion had been normalized by methimazole . METHODS AND RESULTS The levels of antibodies to TSH receptors were measured during treatment with methimazole , either alone or in combination with thyroxine , in 109 patients with hyperthyroidism due to Graves ' disease . The patients first received 30 mg of methimazole daily for six months . All were euthyroid after six months , and their mean ( + /- SD ) level of antibodies to TSH receptors decreased from 64 + /- 9 percent to 25 + /- 15 percent ( P less than 0.01 ; normal , 2.9 + /- 1.4 percent ) . Sixty patients then received 100 micrograms of thyroxine and 10 mg of methimazole and 49 received placebo and 10 mg of methimazole daily for one year . In the thyroxine-treated group , the mean serum thyroxine concentration increased from 108 + /- 16 nmol per liter to 145 + /- 11 nmol per liter ( P less than 0.01 ) , and the level of antibodies to TSH receptors decreased from 28 + /- 10 percent to 10 + /- 3 percent after one month of combination therapy . In the patients who received placebo and methimazole , the mean serum thyroxine concentration decreased and the level of antibodies to TSH receptors did not change . Methimazole , but not thyroxine or placebo , was discontinued in each group 1 1/2 years after the beginning of treatment . The level of antibodies to TSH receptors further decreased ( from 6.6 + /- 3.2 percent at the time methimazole was discontinued to 2.1 + /- 1.2 percent one year later ) in the patients who continued to receive thyroxine , but it increased ( from 9.1 + /- 4.8 percent to 17.3 + /- 5.8 percent during the same period ) in the patients who received placebo . One patient in the thyroxine-treated group ( 1.7 percent ) and 17 patients in the placebo group ( 34.7 percent ) had recurrences of hyperthyroidism within three years after the discontinuation of methimazole . CONCLUSIONS The administration of thyroxine during antithyroid drug treatment decreases both the production of antibodies to TSH receptors and the frequency of recurrence of hyperthyroidism Antithyroid drugs are effective in restoring euthyroidism in Graves ' disease , but many patients experience relapse after withdrawal . Prevention of recurrence would therefore be a desirable goal . In a prospect i ve study , patients with successful outcome of 12 to 15 months antithyroid drug therapy were stratified for risk factors and r and omly assigned to receive levothyroxine in a variable thyrotropin (TSH)-suppressive dose for 2 years or no treatment . The levothyroxine group was r and omized to continue or discontinue levothyroxine after 1 year . End points included relapse of overt hyperthyroidism . Of 346 patients with Graves ' disease enrolled 225 were euthyroid 4 weeks after antithyroid drug withdrawal and were r and omly assigned to receive levothyroxine ( 114 patients ) or no treatment ( controls , 111 patients ) . Of those not r and omized , 39 patients showed early relapse within 4 weeks , 61 endogenous TSH suppression , 7 TSH elevation , and 14 had to be excluded . Dropout rate during the study were 13.3 % . Kaplan-Meier analyses showed relapse rates to be similar in the levothyroxine group ( 20 % after 1 year , 32 % after 2 years ) and the r and omized controls ( 18 % , 24 % ) , whereas relapses were significantly more frequent in the follow-up group of patients with endogenously suppressed TSH ( 33 % , 49 % ) . Levothyroxine therapy did not influence TSH-receptor antibody , nor did it reduce goiter size . The best prognostic marker available was basal TSH determined 4 weeks after withdrawal of antithyroid drugs ( posttreatment TSH ) . The study demonstrates that levothyroxine does not prevent relapse of hyperthyroidism after successful restoration of euthyroid function by antithyroid drugs and characterizes posttreatment TSH as a main prognostic marker Although antithyroid drugs ( ATD ) are widely used in the treatment of Graves ' disease , management protocol s , especially treatment duration , remain a subject of debate . The rate of relapse after short‐term regimens of less than 6 months with ATD at decreasing doses is higher than after longer treatments from 12 to 24 months . As no prospect i ve study has provided data on even longer protocol s exceeding 2 years , we conducted a prospect i ve trial to determine potential benefits of a 42‐month treatment compared with an 18‐month treatment Medical treatment of Graves ' disease involves antithyroid drugs with or without the addition of exogenous T4 . There have been conflicting reports as to whether the addition of T4 improves remission rates or delays relapse . To evaluate this issue in a North American population , 199 patients were treated with methimazole until they were euthyroid . They were then r and omized to either methimazole alone in a dose sufficient to normalize TSH ( group 1 ) , or to 30 mg methimazole daily plus sufficient T4 to maintain TSH in the upper normal range ( group 2 ) , or to 30 mg methimazole daily plus sufficient T4 to suppress TSH below 0.6 mIU/L ( group 3 ) . After 18 months , methimazole was stopped , and T4 was continued in groups 2 and 3 . Because not all patients in groups 2 and 3 achieved their target TSH concentration , they were reassigned to group A ( TSH > or = 1.0 ) or group B ( TSH < 1.0 ) , based on the mean TSH achieved during methimazole treatment . One hundred forty-nine patients have been followed for at least 6 months after stopping methimazole ( mean 27 months ) . Fifty-eight percent of patients have relapsed . There were no significant differences in relapse rates after stopping methimazole . Among those patients who did relapse , however , there was a significant difference in the months to relapse after stopping methimazole between groups B and 1 ( group 1 : 3.3 + /- 0.7 , group A : 5.6 + /- 0.8 , group B : 7.4 + /- 1.7 ; P = 0.01 for the comparison between groups B and 1 ) . We conclude that the addition of T4 to methimazole does not improve long-term remission rates in Graves ' disease A prospect i ve r and omized study was performed in patients with hyperthyroid Graves ' disease ( GD ) in order to compare long ( 18 months ) and short term ( 6 months ) antithyroid drug treatment on the remission rate . A therapeutic protocol was offered to all GD patients who had not been treated for this disease previously . All patients studied who followed the protocol were rechecked 2 yr after treatment was withdrawn , or earlier in the case of relapse . Of the patients having undergone long term treatment , 61.8 % still were in remission 2 yr after treatment withdrawal , whereas only 41.7 % of the patients treated for 6 months were in remission ( P less than 0.05 ) . Such findings clearly establish that treatment duration has a direct beneficial incidence on the remission rate . These results were confirmed by the fact that treatment for 18 months result ed in remission in 7 of 15 patients who had previously relapsed after a 6-month course of therapy . This improvement in relation to treatment duration might be due to the immunosuppressive action of carbimazole . No significant difference was observed between relapse and remission groups , regardless of treatment duration , for HLA ABDr , serum T3 and T4 , and T3/T4 ratio determined before treatment . Only the thyroid-stimulating antibody levels determined at the time of diagnosis and at the end of treatment were higher in the relapse group , a difference that was relevant only globally , due to value scattering . Furthermore , thyroid-stimulating antibody levels at the end of treatment may indicate remission or , conversely , continuance of the pathological process . ( ABSTRACT TRUNCATED AT 250 WORDS Sixty patients with Graves ' disease ( GD ) hyperthyroidism were distributed in two r and omized groups . Patients in group A ( n = 30 ) received carbimazole by a titration regimen , and patients in group B ( n = 30 ) were treated with higher doses of carbimazole plus T4 . Clinical and analytical evaluations were done at baseline , during treatment ( 18.4 + /- 2.6 months ) , and after , until the relapse of hyperthyroidism , or for 4.98 + /- 1.6 yr in patients who did not relapse . There were no differences in clinical parameters , thyroid hormones , or TSH binding inhibitory immunoglobulins ( TBII ) levels between the two groups , either at baseline or at the end of treatment . Serum TSH persisted undetectable in 16 out of 60 patients ( group A : 9 ; group B : 7 ) , after treatment . Relapse occurred in 38 patients ( 63.3 % ) , ( group A : 18 ( 60 % ) vs. group B : 20 ( 66.7 % ) ) . Patients who relapsed had bigger goiters at baseline ( P = 0.02 ) and at the end of treatment ( P = 0.03 ) . Eighty-seven percent ( 14/16 ) of patients with undetectable TSH after therapy relapsed , vs. 54.5 % ( 24/44 ) of those with normal TSH ( P = 0.01 ) . Undetectable TSH at the end of treatment was the only independent variable in the logistic analysis to predict relapse . Treatment modality did not influence the relapse rate . This study has found that , in Spanish patients , the use of high doses of carbimazole with T4 offers no advantages in the treatment of GD hyperthyroidism Antithyroid drugs are commonly used as first-line treatment for Graves ' disease , but the optimum regimen for inducing remission remains unclear . We gave the block-replace regimen of carbimazole plus thyroxine to 100 patients for 6 or 12 months , to determine whether prolonged treatment is associated with fewer relapses . The remission rate one year after cessation of treatment was 59 % with the 6 month course and 65 % with 12 months ; this was not significantly different . We also analysed HLA markers identified by restriction fragment length polymorphisms and could not confirm the recently reported associations of outcome with HLA-DR4 or with an HLA-DQA2 allele . These results show that six months treatment with a block-replace regimen of antithyroid drugs is probably sufficient , in the UK , to achieve maximum remission of Graves ' disease and that there are no HLA markers which clearly predict outcome OBJECTIVES To compare the relapse rates in Graves ' disease the first 2 years after methimazole 60 mg day-1 combined with thyroxine versus a titration regimen with methimazole alone , and to look for possible prognostic factors . DESIGN A r and omized , open , prospect i ve study . Methimazole was given for 6 months in both groups , and thyroid status evaluated every 3rd month during the first year , and every 6th month during the second year . SETTING The study was performed at our outpatient clinic with patients referred from primary care . SUBJECTS Fifty-six patients were included . One became pregnant and one dropped out during the treatment period . Furthermore , nine patients in the high-dose and four in the low-dose group stopped the treatment because of side-effects . Thus , 19 patients in the high- and 22 in the low-dose group completed 6 months with methimazole . RESULTS In those tolerating the treatment , the relapse rates in the high- and low-dose groups were 26.3 vs. 59.1 % ( P < 0.05 ) , 42.1 vs. 77.3 % ( P < 0.02 ) ; and 57.9 vs. 77.3 % ( NS ) after 3 , 12 and 24 months , respectively . The corresponding relapse rates calculated on an ' intention to treat ' basis were : 51.7 vs. 66.7 % ; 62.1 vs. 81.5 % : 72.4 vs. 81.5 % ( NS ) . The thyroid volume was significantly ( P < 0.05 ) larger in those that relapsed ( 17.8 + /- 2.9 vs. 11.6 + /- 1.2 mL ; mean + /- SEM ) . CONCLUSIONS In those tolerating the treatment , methimazole significantly reduced the relapse rate the 1st year when given in a high dose . However , the relapse rates in both groups , and the number of side-effects in the high-dose group , were unacceptably high TSH has been incriminated in Graves ’ disease for increasing the production of antibodies against TSH receptor ( TRAb ) . It has been , therefore , suggested that T4 administration after successful antithyroid drug ( ATD ) treatment may indirectly decrease the production of TRAb and , therefore , the frequency of recurrence of hyperthyroidism . To study the role of T4 and T3 on the recurrence rate of Graves ’ disease 108 patients with Graves ’ disease ( 22 males , age : 49.8±14.3 yr , mean±SD , and 86 females , age : 41.7±12 yr ) were followed-up for 24 months after successful treatment with ATD ( carbimazole ) . During the follow-up period , patients daily received either 100 μg T4 or 25 μg T3 or placebo after r and om and double-blinded assignment into three groups . They were evaluated trimonthly up to 12 months and at 24 months . Plasma TRAb levels were measured at the beginning and at 12 months . At 12 months of the follow-up period , 14 out of 33 ( 42.4 % ) , 6 out of 38 ( 15.8 % ) , and 9 out of 37 ( 24.3 % ) patients receiving T4 , T3 and placebo , respectively , recurred . Recurrence rate of T4-treated patients was statistically higher than that of the T3-treated patients or controls ( p<0.05 ) . At the beginning of the follow-up period patients who were going to recur had significantly higher TRAb levels and goiter weight than patients who were not ( p<0.05 ) . At 24 months of the follow-up period , from the patients who did not drop out of the study , none out of 11 ( 0 % ) , 2 out of 19 ( 10.5 % ) and 1 out of 12 ( 8.3 % ) receiving T4 , T3 and placebo , respectively , recurred . We conclude that T4 administration after successful ATD treatment of Graves ’ disease is associated with increased recurrence of hyperthyroidism as compared to the T3 or placebo administration . High TRAb levels and goiter weight at the end of ATD treatment may hint at recurrence Objective : To investigate the significance of treatment with antithyroid drugs longer than 12 months on lasting remission in Graves ’ hyperthyroid patients , and to study clinical and laboratory parameters of prognostic value . Patients : Fifty-two untreated Graves ’ hyperthyroid patients were assigned at r and om to two therapeutic groups . They were treated with Carbimazole during 12 and 24 months in Group I ( n= 28 ) and Group II ( n= 24 ) , respectively . Measurements : Serum levels of FT4 , T3 , sTSH and TSH receptor antibody ( TRAb ) were measured before starting treatment and at regular intervals during treatment and follow-up after drug withdrawal . We compared the relapse rate in both groups of patients , at short ( 2-yr ) and long-term ( 5-yr ) periods after drug withdrawal . Also , we compared clinical and biochemical parameters between patients who stayed in remission and who had relapse . Results : At the end of the short-term period , relapse had occurred in 13 ( 46.4 % ) Group I patients and in 13 ( 54.1 % ) Group II patients , p=0.36 . At the end of the long-term period , relapse had occurred in 24 ( 85.7 % ) Group I and 20 ( 83.3 % ) Group II patients , p=0.78 . No difference could be observed between patients who had stayed in remission and who had suffered relapse , within the 5-yr follow-up period regarding to goiter size , frequency of ophthalmopathy , TSH and TRAb levels . Conclusions : The high relapse rate observed could be due to high iodine intake in our country . In this study and in a review of the available data , we have been unable to find any rational basis for courses of antithyroid drugs longer than twelve months for the treatment of Graves ’ hyperthyroidism . Nor is a reliable prognosis for an individual patient possible by TRAb determination at any given time during therapy , owing to the low sensitivity and specificity of this variable Based on findings that thyroxine may have a beneficial effect on the recurrence of Graves ' hyperthyroidism , we prospect ively studied the effects of a TSH suppressive treatment with thyroxine on the course of Graves ' disease in fifty patients with recent onset of hyperthyroidism . After the normalization of serum tri-iodothyronine ( T3 ) and thyroxine ( T4 ) concentrations , one group of patients was r and omly assigned to a combined treatment with carbimazole and a TSH suppressive dose of T4 for 12 months , followed by another 12 months of TSH suppressive therapy alone . The other group of patients also received carbimazole for one year , but T4 was only added as indicated to normalize elevated TSH serum concentrations , and patients received no therapy during the second year . By the end of the second year , a relapse of hyperthyroidism had occurred in 43 % of the patients with and in 45 % of the patients without suppressive T4 treatment . In those patients without a relapse of hyperthyroidism , initial thyroid size significantly ( P = 0.01 ) decreased with time in both treatment groups . However , patients on suppressive T4 treatment tended to have a greater reduction in thyroid volume than patients with normal TSH serum concentrations ( P = 0.05 ) . In conclusion , we were unable to detect a preventive effect of exogenous TSH suppression on the recurrence of hyperthyroidism . However , our data suggest that TSH suppressive treatment may have a beneficial effect on thyroid enlargement in Graves ' disease In a prospect i ve , r and omized study of 135 newly diagnosed patients with hyperthyroidism due to Graves ' disease we compared the effect on remission rates of additional triiodothyronine ( T3 ) with conventional antithyroid drug therapy . To this end 114 patients were followed for at least 12 months ( 15.7+/-4.9 , mean+/-s.d . ) after the discontinuation of any therapy . After return of thyroid function to normal ( 8.5+/-7.4 weeks , mean+/-s.d . ) patients were maintained on antithyroid medication for 9.0+/-2.5 months . They were then r and omly assigned to one of three groups : group 1 ( n=44 ) stopped methimazole , groups 2 ( n=39 ) and 3 ( n=31 ) continued with exogenous T3 ( not exceeding 75 microgram/day in any patient ) for a further 6 months either with ( group 2 ) or without ( group 3 ) a fixed dose of 10 mg methimazole daily . The T3 dose was kept variable to keep TSH suppressed ( < 0 . 1mU/l ) , which could be achieved in 82 % of patients on 100 % of their monthly visits . No serious side-effect requiring the discontinuation of the study occurred in any patient . Total T3 , TSH-receptor antibodies and some previously suggested potential predictors of relapse including thyroid size by ultrasound , 24h urinary iodine excretion , history of cigarette smoking and ophthalmopathy were determined at the outset of the study and subsequently every 6 months ( and total T3 every 4 weeks ) . No significant difference ( P>0.05 , Chi square ) was seen in relapse of hyperthyroidism after a mean follow-up of 16 months ( range : 12 - 31 months ; groups 1:52 % , 2:44 % and 3:42 % ) in an area of low-to-moderate iodine intake ( prevalence of 24h urinary iodine excretion < 100 microgram/24h : 17 and 25 % at two different measurements respectively ) . Concomitantly , no predictor of recurrence of disease could be identified , irrespective of treatment modality The optimal treatment regimen with thionamide drugs remains a matter for debate . We have investigated whether high doses of carbimazole , when compared with low doses , reduce relapse rates of Graves ' disease The optimal antithyroid drug regimen for Graves ' disease remains a matter of controversy . The European Multicentre Trial Group has investigated the effects of methimazole drug dose on the long‐term outcome of Graves ' disease A comparative study of high-dose ( HD , carbimazole 60 mg plus thyroxine 100 - 150 micrograms daily ) and titration-dose ( TD ) regimens of carbimazole was carried out in 70 patients with Graves ' disease , the patients being assigned r and omly to one or other regimen . The treatment was given for 1 year and follow-up was for 2 years after stopping treatment . In both groups , recurrence of hyperthyroidism occurred , most commonly during the first 6 months ( 35 % of HD and 44 % of TD ) . By 2 years after stopping treatment , recurrence had occurred in 50 % of the HD and 66 % of the TD group . The differences were not significant . Thyroid antibodies , serum thyroglobulin and pertechnetate uptake fell similarly in both groups during treatment . Cigarette smoking was similar in both the groups and did not influence the frequency of relapse . In both HD and TD groups , when relapsing patients were examined according to whether they relapsed early ( within 6 months or less ) or late it was found that those who relapsed late were , in respect of goitre size , pertechnetate uptake and presence of detectable plasma TSH , similar to the patients who did not relapse at all . In conclusion , the changes in the measured variables and the progress of the patients was similar whether treated by the HD or TD regimen

A trend towards studies reporting greater numbers of VKA control measures over time was observed over our review time horizon , particularly , with AF and observational studies

Objective To aid trialists , systematic review ers and others , we evaluated the degree of st and ardisation of control measure reporting that has occurred in atrial fibrillation ( AF ) and venous thromboembolism ( VTE ) studies since 2000 ; and attempted to determine whether the prior recommendation of reporting ≥2 measures per study has been employed .

Background and Purpose Secondary prevention trials do not distinguish outcomes according to stroke cause . The purpose of the study was to determine whether trial efficacy of anticoagulation for secondary prevention could be replicated in clinical practice in strokes of different etiology . Methods A 2-year observation study was undertaken in 288 stroke patients with atrial fibrillation ( mean age 76 years ; 55 % women ) who were receiving anticoagulation therapy to maintain an international normalized ratio of 2.0 to 3.0 . Comparisons were made of ( 1 ) patient characteristics , anticoagulation control , and annual stroke/hemorrhage rates with those of the European Atrial Fibrillation Trial and ( 2 ) cause of recurrent stroke by initial stroke subtype . Results Subjects were 5 years older ( 95 % CI 3 to 7 years ) , and more patients had small-vessel stroke ( 26 % versus 14 % ; 95 % CI 3 % to 17 % ) compared with corresponding trial data . The duration spent in the target anticoagulation range ( 55 % versus 59 % ) , recurrent stroke rate ( 5.1 % versus 3.6 % per year ) , and major ( 2.3 % versus 2.2 % per year ) or minor ( 9.5 % versus 11.8 % per year ) hemorrhage rates were comparable with those in patients receiving warfarin in the r and omized study . Ten of 14 ( 71 % ) of embolic recurrences occurred in patients with a previous cardioembolic episode , and 8 of 11 ( 73 % ) lacunar recurrences occurred in patients with previous lacunar stroke as the qualifying event for anticoagulation ( P = 0.025 ) . Only 3 of 14 cardioembolic compared with 8 of 11 lacunar recurrences occurred during adequate anticoagulation . Conclusions Anticoagulation for secondary stroke prevention in clinical practice achieves outcomes comparable with those of r and omized trials . Nearly 26 % of qualifying strokes and 40 % of recurrences were nonembolic ; stroke subtype should be considered when making treatment decisions Abstract Background : This retrospective study was performed to develop a model to predict the maintenance dosage of the vitamin K antagonist acenocoumarol , based upon the first INR after a st and ard initial dosage regimen . Material and Methods : Out patients with atrial fibrillation ( n = 284 ) and initial regimens of 6 - 4 or 6 - 4 - 2 mg acenocoumarol on day 1 , 2 and 3 , respectively , were included . The maintenance dosage of the period 3–6 months after the instalment was related to the first INR after those st and ard initial dosage regimens , because in that period the INR was 76 % of the time within the therapeutic range and therefore considered suitable to perform the analysis . Results : A clear relation was found between the first INR , the maintenance dosage and the age . A model that predicts the maintenance dosage immediately after the st and ard initial dosage and based on the first INR and adjusted for age , has been developed , according to the formula : required dosage = 5.03 - 1.65 * ln ( first INR ) − 0.01 * age . Conclusion : We have developed a formula to predict the maintenance dosage of acenocoumarol . With this formula it is possible to install this maintenance dosage and thus achieve oral anticoagulant therapy within the therapeutic range at an earlier stage . This will have to be shown in a prospect i ve study Extremely elderly patients are being treated with anticoagulant therapy with increasing frequency . We sought to assess the rates of bleeding in such patients and to carefully examine risk factors that might predict this bleeding . This was a prospect i ve cohort study conducted from 1 January 2007 to 29 February 2008 at an anticoagulation clinic in Modena , Italy . Ninety patients , 90 years or older , among 1635 patients with nonvalvular atrial fibrillation were studied ; 69 ( 77 % ) were women with a median age of 91.71 years ( range 90–98 ) . During the enrolment period , all the patients were interviewed during an ambulatory visit and were followed in the outpatient setting . Hemorrhagic , thromboembolic and fatal events over 1 year of follow-up were monitored . Six ( 7 % ) patients discontinued vitamin K antagonists ( three due to bleeding , two due to noncompliance , two due to physician recommendation ) . Twenty-one ( 23 % ) patients died , and 35 ( 39 % ) were admitted to hospital . One patient had an intracranial hemorrhage [ 1 % , 95 % confidence interval ( CI ) 0.27–6.0 ] , two patients had a major extracranial hemorrhage ( 2 % , 95 % CI 0.7–8.0 ) . One patient had an ischemic stroke ( 1 % , 95 % CI 0.27–6.0 ) , two patients had embolic arterial ischemia ( 2 % , 95 % CI 0.7–8.0 ) . All the events occurred when the international normalized ratio was outside the target range , or after oral anticoagulation had been stopped . In our study of extremely elderly anticoagulated patients , we found low rates of bleeding and thromboembolism . These findings support the use of oral anticoagulants in such patients Background — Tecarfarin ( ATI-5923 ) is a novel oral vitamin K antagonist . Unlike warfarin , it is metabolized by esterases , escaping metabolism by the cytochrome P450 system and thereby avoiding cytochrome P450–mediated drug-drug or drug-food interactions as well as genetic variations found in the cytochrome P450 system . Both tecarfarin and warfarin can be monitored with the international normalized ratio . We hypothesized that the time in therapeutic range for tecarfarin will exceed values usually experienced with warfarin . Methods and Results — This was a 6- to 12-week open-label , multicenter , phase IIA study of 66 atrial fibrillation patients with a mild to moderate risk of stroke to determine the safety and tolerability of tecarfarin and to ascertain an optimal tecarfarin dosing regimen . Sixty-four subjects ( 97 % ) were taking warfarin at enrollment and were switched to tecarfarin . After the initial 3 weeks of tecarfarin treatment , the mean interpolated time in therapeutic range was 71.4 % . Only 10.9 % of patients had time in therapeutic range of < 45 % . Times in extreme international normalized ratio ranges of < 1.5 and > 4.0 were 1.2 % and 1.2 % , respectively . The median daily dose ( for an individual patient ) to maintain an international normalized ratio between 2 and 3 was 15.6 mg ( range , 6 to 29 mg ) . Conclusions — This is the first study of tecarfarin in patients with atrial fibrillation . It appears that tecarfarin may possess advantages over the currently available st and ard of care , warfarin , by improving time in therapeutic range . Adequately powered prospect i ve trials are warranted to definitively compare tecarfarin with warfarin in clinical setting s for which warfarin is indicated The purpose of this study was to establish the safety and efficacy of sodium warfarin in the secondary prophylaxis of venous thrombosis in patients with cancer . This was an inception cohort study of patients enrolled in an anticoagulation clinic between July 1991 and October 1996 . The rates of bleeding and recurrent thrombosis were evaluated in all the patients , and the results in patients with cancer ( n = 104 ) were compared with those without cancer ( n = 208 ) . The rate of major hemorrhage was 0.4 % and 0.3 % per treatment month in the patients with cancer and those without cancer , respectively . The rates of recurrent thrombosis were 1.2 % and 0.2 % per treatment month in the patients with cancer compared with those without cancer , respectively . We conclude that warfarin is safe when used for the secondary prophylaxis of patients with cancer who have had a venous or arterial thrombosis , and the risk of major hemorrhage is not significantly different when compared with the risk in patients without cancer . The rate of recurrent thrombosis is approximately sixfold higher in patients with cancer being treated with warfarin for secondary prophylaxis of thrombosis compared with patients without cancer . Nonetheless , the rate of recurrent thrombosis is not overly excessive , and warfarin can be viewed as a relatively effective form of therapy for these patients Background — Oral anticoagulation ( OAC ) therapy is effective in atrial fibrillation but requires vigilance to maintain the international normalized ratio in the therapeutic range . This report examines how differences in time in therapeutic range ( TTR ) between centers and between countries affect the outcomes of OAC therapy . Methods and Results — In a posthoc analysis , the TTRs of patients on OAC in a r and omized trial of OAC versus clopidogrel plus aspirin ( Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ ACTIVE W ] ) were used to calculate the mean TTR for each of 526 centers and 15 countries . Proportional-hazards analysis , with and without adjustment for baseline variables , was performed , with patients stratified by TTR quartile and country . A wide variation in TTRs was found between centers , with mean TTRs for centers in the 4 quartiles of 44 % , 60 % , 69 % , and 78 % . For patients at centers below the median TTR ( 65 % ) , no treatment benefit was demonstrated as measured by relative risk for vascular events of clopidogrel plus aspirin versus OAC ( relative risk , 0.93 ; 95 % confidence interval , 0.70 to 1.24 ; P=0.61 ) . However , for patients at centers with a TTR above the study median , OAC had a marked benefit , reducing vascular events by > 2-fold ( relative risk , 2.14 ; 95 % confidence interval , 1.61 to 2.85 ; P<0.0001 ) . Mean TTR also varied between countries from 46 % to 78 % ; relative risk ( clopidogrel plus aspirin versus OAC ) varied from 0.6 to 3.6 ( a 5-fold difference ) . A population -average model predicted that a TTR of 58 % would be needed to be confident that patients would benefit from being on OAC . Conclusions — A wide variation exists in international normalized ratio control , as measured by TTR , between clinical centers and between countries , which has a major impact on the treatment benefit of OAC therapy . For centers and countries , a target threshold TTR exists ( estimated between 58 % and 65 % ) below which there appears to be little benefit of OAC over antiplatelet therapy BACKGROUND Apixaban , an oral factor Xa inhibitor administered in fixed doses , may simplify the treatment of venous thromboembolism . METHODS In this r and omized , double-blind study , we compared apixaban ( at a dose of 10 mg twice daily for 7 days , followed by 5 mg twice daily for 6 months ) with conventional therapy ( subcutaneous enoxaparin , followed by warfarin ) in 5395 patients with acute venous thromboembolism . The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism . The principal safety outcomes were major bleeding alone and major bleeding plus clinical ly relevant nonmajor bleeding . RESULTS The primary efficacy outcome occurred in 59 of 2609 patients ( 2.3 % ) in the apixaban group , as compared with 71 of 2635 ( 2.7 % ) in the conventional-therapy group ( relative risk , 0.84 ; 95 % confidence interval [ CI ] , 0.60 to 1.18 ; difference in risk [ apixaban minus conventional therapy ] , -0.4 percentage points ; 95 % CI , -1.3 to 0.4 ) . Apixaban was noninferior to conventional therapy ( P<0.001 ) for predefined upper limits of the 95 % confidence intervals for both relative risk ( < 1.80 ) and difference in risk ( < 3.5 percentage points ) . Major bleeding occurred in 0.6 % of patients who received apixaban and in 1.8 % of those who received conventional therapy ( relative risk , 0.31 ; 95 % CI , 0.17 to 0.55 ; P<0.001 for superiority ) . The composite outcome of major bleeding and clinical ly relevant nonmajor bleeding occurred in 4.3 % of the patients in the apixaban group , as compared with 9.7 % of those in the conventional-therapy group ( relative risk , 0.44 ; 95 % CI , 0.36 to 0.55 ; P<0.001 ) . Rates of other adverse events were similar in the two groups . CONCLUSIONS A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding ( Funded by Pfizer and Bristol-Myers Squibb ; Clinical Trials.gov number , NCT00643201 ) CONTEXT When unfractionated heparin is used to treat acute venous thromboembolism , it is usually administered by intravenous infusion with coagulation monitoring , which requires hospitalization . However , subcutaneous administration of fixed-dose , weight-adjusted , unfractionated heparin may be suitable for inpatient and outpatient treatment of venous thromboembolism . OBJECTIVE To determine if fixed-dose , weight-adjusted , subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin for treatment of venous thromboembolism . DESIGN , SETTING , AND PATIENTS R and omized , open-label , adjudicator-blinded , noninferiority trial of 708 patients aged 18 years or older with acute venous thromboembolism from 6 university-affiliated clinical centers in Canada and New Zeal and conducted from September 1998 through February 2004 . Of the r and omized patients , 11 were subsequently excluded from the analysis of efficacy and 8 from the analysis of safety . INTERVENTIONS Unfractionated heparin was administered subcutaneously as an initial dose of 333 U/kg , followed by a fixed dose of 250 U/kg every 12 hours ( n = 345 ) . Low-molecular-weight heparin ( dalteparin or enoxaparin ) was administered subcutaneously at a dose of 100 IU/kg every 12 hours ( n = 352 ) . Both treatments could be administered out of hospital and both were overlapped with 3 months of warfarin therapy . MAIN OUTCOME MEASURES Recurrent venous thromboembolism within 3 months and major bleeding within 10 days of r and omization . RESULTS Recurrent venous thromboembolism occurred in 13 patients in the unfractionated heparin group ( 3.8 % ) compared with 12 patients in the low-molecular-weight heparin group ( 3.4 % ; absolute difference , 0.4 % ; 95 % confidence interval , -2.6 % to 3.3 % ) . Major bleeding during the first 10 days of treatment occurred in 4 patients in the unfractionated heparin group ( 1.1 % ) compared with 5 patients in the low-molecular-weight heparin group ( 1.4 % ; absolute difference , -0.3 % ; 95 % confidence interval , -2.3 % to 1.7 % ) . Treatment was administered entirely out of hospital in 72 % of the unfractionated heparin group and 68 % of the low-molecular-weight heparin group . CONCLUSION Fixed-dose subcutaneous unfractionated heparin is as effective and safe as low-molecular-weight heparin in patients with acute venous thromboembolism and is suitable for outpatient treatment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00182403 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 There is increased pressure on primary care physicians to monitor oral anticoagulation . OBJECTIVE To test the null hypothesis that oral anticoagulation care can be provided at least as well in primary care through a nurse-led clinic , involving near-patient testing and computerized decision support software , compared with routine hospital management based on a variety of clinical outcome measures . METHODS A r and omized , controlled trial in 12 primary care practice s in Birmingham , Engl and ( 9 intervention and 3 control ) . Two control population s were used : patients individually r and omly allocated as controls in the intervention practice s ( intra practice controls ) and all patients in control practice s ( inter practice controls ) . Intervention practice s ' patients were r and omized to the intervention ( practice -based anticoagulation clinic ) or control ( hospital clinic ) group . The main outcome measure was therapeutic control of the international normalized ratio . RESULTS Three hundred sixty-seven patients were recruited ( 122 intervention patients , 102 intra practice control patients , and 143 inter practice control patients ) . St and ard measures of control of the international normalized ratio ( point prevalence ) showed no significant difference between the intervention and control groups . Data on proportion of time spent in the international normalized ratio range showed significant improvement for patients in the intervention group ( paired t test , P = .008 ) . CONCLUSIONS Nurse-led anticoagulation clinics can be implemented in novice primary care setting s by means of computerized decision support software and near-patient testing . Care given by this model is at least as good as routine hospital follow-up . The model is generalizable to primary health care centers operating in developed health care systems OBJECTIVES This trial evaluated the efficacy and safety of the combination of antiplatelet and moderate-intensity anticoagulation therapy in patients with atrial fibrillation associated with recognized risk factors or mitral stenosis . BACKGROUND Warfarin was more effective than aspirin in preventing stroke in these patients ; combined therapy with low anticoagulant intensity was ineffective . Mitral stenosis patients were not investigated . METHODS We performed a multicenter r and omized trial in 1,209 patients at risk . The intermediate-risk group included patients with risk factors or age > 60 years : 242 received the cyclooxygenase inhibitor triflusal , 237 received acenocumarol , and 235 received a combination of both . The high-risk group included patients with prior embolism or mitral stenosis : 259 received anticoagulants and 236 received the combined therapy . Median follow-up was 2.76 years . Primary outcome was a composite of vascular death and nonfatal stroke or systemic embolism . RESULTS Primary outcome was lower in the combined therapy than in the anticoagulant arm in both the intermediate- ( hazard ratio [ HR ] 0.33 [ 95 % confidence interval (CI)0.12 to 0.91 ] ; p = 0.02 ) and the high-risk group ( HR 0.51 [ 95 % CI 0.27 to 0.96 ] ; p = 0.03 ) . Primary outcome plus severe bleeding was lower with combined therapy in the intermediate-risk group . Nonvalvular and mitral stenosis patients had similar embolic event rates during anticoagulant therapy . CONCLUSIONS The combined antiplatelet plus moderate-intensity anticoagulation therapy significantly decreased the vascular events compared with anticoagulation alone and proved to be safe in atrial fibrillation patients The primary objective of this study was to compare the safety of four fixed-dose regimens of edoxaban with warfarin in patients with non-valvular atrial fibrillation ( AF ) . In this 12-week , parallel-group , multicentre , multinational study , 1,146 patients with AF and risk of stroke were r and omised to edoxaban 30 mg qd , 30 mg bid , 60 mg qd , or 60 mg bid or warfarin dose-adjusted to a target international normalised ratio of 2.0 - 3.0 . The study was double-blind to edoxaban dose , but open-label to warfarin . Primary outcomes were occurrence of major and /or clinical ly relevant non-major bleeding and elevated hepatic enzymes and /or bilirubin . Mean age was 65 + /- 8.7 years and 64.4 % were warfarin-naïve . Whereas major plus clinical ly relevant non-major bleeding occurred in 3.2 % of patients r and omised to warfarin , the incidence of bleeding was significantly higher with the edoxaban 60 mg bid ( 10.6 % ; p=0.002 ) and 30 mg bid regimens ( 7.8 % ; p=0.029 ) , but not with the edoxaban 60 mg qd ( 3.8 % ) or 30 mg qd regimens ( 3.0 % ) . For the same total daily dose of 60 mg , both bleeding frequency and trough edoxaban concentrations were higher in the 30-mg bid group than in the 60-mg qd group . There were no significant differences in hepatic enzyme elevations or bilirubin values among the groups . The safety profiles of edoxaban 30 and 60 mg qd in patients with AF were similar to warfarin . In contrast , the edoxaban bid regimens were associated with more bleeding than warfarin . These results suggest that in this three-month study , edoxaban 30 or 60 mg qd are safe and well-tolerated Edoxaban is an oral , reversible , direct factor Xa inhibitor in phase III clinical development for the prevention of stroke in atrial fibrillation ( AF ) . A phase II study was undertaken to evaluate the safety and efficacy of edoxaban in Asian patients with non-valvular AF with CHADS2 score ≥1 . In a multicentre , active-controlled , double-blind edoxaban and open-label warfarin , parallel-group study , a total of 235 patients from four Asian countries were r and omly assigned to edoxaban 30 mg qd , 60 mg qd or warfarin dose adjusted to international normalised ratio of 2 - 3 for three months . The primary endpoint was the incidence of central ly adjudicated all bleeding events ( major , clinical ly relevant non-major and minor ) . Secondary endpoints included thromboembolic events , biomarkers of thrombus formation and all adverse events ( AEs ) . The incidence of all bleeding events ( 95 % CI ) was 20.3 % ( 12.9 , 30.4 ) for edoxaban 30 mg , 23.8 % ( 15.8 , 34.1 ) for edoxaban 60 mg , and 29.3 % ( 20.2 , 40.4 ) for warfarin . A subgroup analysis suggested low body weight ( ≤60 kg ) may affect the incidence of bleeding events with edoxaban . The incidence of study drug-related AEs was 22 % for edoxaban 30 mg , 29 % for edoxaban 60 mg and 33 % for warfarin . No thromboembolic events occurred in any treatment group . In conclusion , this phase II study found a trend for a reduction in the incidence of all bleeding events in Asian AF patients with edoxaban 30 mg and 60 mg compared with warfarin . Adverse events were similar between the edoxaban 60-mg and warfarin groups and were lower with the edoxaban 30-mg group Abstract Objective : To determine whether trial efficacy of prophylaxis with warfarin for patients with atrial fibrillation at high risk of stroke translates into effectiveness in clinical practice . Design : Two year prospect i ve cohort study . Setting : District general hospital . Participants : 167 patients with atrial fibrillation and at high stroke risk who were eligible for anticoagulation Interventions : Long term anticoagulation with warfarin at adjusted doses to maintain an international normalised ratio of 2.0 - 3.0 Main outcome measures : Comparison of patient characteristics , comorbidity , anticoagulation control , stroke rate , and haemorrhagic complications with pooled data from five r and omised controlled trials . Results : Patients in the study group were seven years older ( 95 % confidence interval 4 to 10 ) and comprised 33 % more women than patients in the pooled trials . The international normalised ratio was in the target range for 61 % of the time ( range 37%-85 % ) , below for 26 % of the time ( range 8%-32 % ) , and above for 13 % of the time ( range 6%-26 % ) . The time that patients in the study group spent in the target range was significantly less than in the pooled analysis . The incidence of stroke in the study group ( 2.0 % per year , 0.7 % to 4.4 % ) was comparable to that of patients receiving warfarin in pooled studies ( 1.4 % , 0.8 % to 2.3 % ) . Per year the incidence of major ( 1.7 % v 1.6 % ) and minor ( 5.4 % v 9.2 % ) bleeding complications was also similar . Conclusion : Rates of stroke and major haemorrhage after anticoagulation in clinical practice were comparable to those obtained from pooled data from r and omised controlled studies for patients with atrial fibrillation at high risk of BACKGROUND AND PURPOSE The optimal intensity of warfarin therapy for secondary prevention of stroke in nonvalvular atrial fibrillation ( NVAF ) remains unclear . We studied the efficacy and safety of conventional- and low-intensity warfarin therapy in a prospect i ve , r and omized , multicenter trial . METHODS The study population consisted of patients with NVAF ( < 80 years old ) who had a stroke or transient ischemic attack . The patients were r and omly allocated into a conventional-intensity group ( international normalized ratio [ INR ] 2.2 to 3.5 ) and a low-intensity group ( INR 1.5 to 2.1 ) . They were carefully monitored , and the annual rate of recurrent ischemic stroke and major hemorrhagic complications were compared between the groups . RESULTS We enrolled 115 patients ( mean age 66.7+/-6.5 years ) into the study . Fifty-five and 60 patients were allocated into the conventional- and low-intensity groups , respectively . The trial was stopped after a follow-up of 658+/-423 days , when major hemorrhagic complications occurred in 6 patients of the conventional-intensity group and the frequency ( 6.6 % per year ) was significantly higher than that in the low-intensity group ( 0 % per year , P=0.01 , Fisher 's exact test ) . All of the 6 patients with major bleeding were elderly ( mean age 74 years ) , and their mean INR before the major hemorrhage was 2.8 . The annual rate of ischemic stroke was low in both groups ( 1.1 % per year in the conventional-intensity group and 1.7 % per year in the low-intensity groups ) and did not differ significantly . CONCLUSIONS For secondary prevention of stroke in persons with NVAF , especially in old patients , the low-intensity warfarin ( INR 1.5 to 2 . 1 ) treatment seems to be safer than the conventional-intensity ( INR 2.2 to 3.5 ) treatment OBJECTIVES To determine whether atrial fibrillation ( AF ) patients with mental health conditions ( MHCs ) were less likely than AF patients without MHCs to be prescribed warfarin and , if receiving warfarin , to maintain an International Normalized Ratio ( INR ) within the therapeutic range . STUDY DESIGN Detailed chart review of AF patients using a Veterans Health Administration ( VHA ) facility in 2003 . METHODS For a r and om sample of 296 AF patients , records identified clinician-diagnosed MHCs ( independent variable ) and AF-related care in 2003 ( dependent variables ) , receipt of warfarin , INR values below/above key thresholds , and time spent within the therapeutic range ( 2.0 - 3.0 ) or highly out of range . Differences between the MHC and comparison groups were examined using X2 tests and logistic regression controlling for age and comorbidity . RESULTS Among warfarin-eligible AF patients ( n = 246 ) , 48.5 % of those with MHCs versus 28.9 % of those without MHCs were not treated with warfarin ( P = .004 ) . Among those receiving warfarin and monitored in VHA , highly supratherapeutic INRs were more common in the MHC group ; for example , 27.3 % versus 1.6 % had any INR > 5.0 ( P < .001 ) . Differences persisted after adjusting for age and comorbidity . CONCLUSIONS MHC patients with AF were less likely than those without MHC to have adequate management of their AF care . Interventions directed at AF patients with MHC may help to optimize their outcomes BACKGROUND The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism . METHODS In a r and omized , double-blind , noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days ( interquartile range , 8 to 11 ) , we compared oral dabigatran , administered at a dose of 150 mg twice daily , with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0 . The primary outcome was the 6-month incidence of recurrent symptomatic , objective ly confirmed venous thromboembolism and related deaths . Safety end points included bleeding events , acute coronary syndromes , other adverse events , and results of liver-function tests . RESULTS A total of 30 of the 1274 patients r and omly assigned to receive dabigatran ( 2.4 % ) , as compared with 27 of the 1265 patients r and omly assigned to warfarin ( 2.1 % ) , had recurrent venous thromboembolism ; the difference in risk was 0.4 percentage points ( 95 % confidence interval [ CI ] , -0.8 to 1.5 ; P<0.001 for the prespecified noninferiority margin ) . The hazard ratio with dabigatran was 1.10 ( 95 % CI , 0.65 to 1.84 ) . Major bleeding episodes occurred in 20 patients assigned to dabigatran ( 1.6 % ) and in 24 patients assigned to warfarin ( 1.9 % ) ( hazard ratio with dabigatran , 0.82 ; 95 % CI , 0.45 to 1.48 ) , and episodes of any bleeding were observed in 205 patients assigned to dabigatran ( 16.1 % ) and 277 patients assigned to warfarin ( 21.9 % ; hazard ratio with dabigatran , 0.71 ; 95 % CI , 0.59 to 0.85 ) . The numbers of deaths , acute coronary syndromes , and abnormal liver-function tests were similar in the two groups . Adverse events leading to discontinuation of the study drug occurred in 9.0 % of patients assigned to dabigatran and in 6.8 % of patients assigned to warfarin ( P=0.05 ) . CONCLUSIONS For the treatment of acute venous thromboembolism , a fixed dose of dabigatran is as effective as warfarin , has a safety profile that is similar to that of warfarin , and does not require laboratory monitoring . ( Clinical Trials.gov number , NCT00291330 . The efficacy of anticoagulation in reducing the risk of cardiogenic embolism has been demonstrated in patients with atrial fibrillation ( AF ) , but there are few prospect i ve studies assessing the influence of anticoagulation stability on ischemic stroke in such patients . Accordingly , the present study investigated prospect ively whether an instability of the anticoagulation intensity would affect the efficacy of the therapy in a total of 156 patients with non-rheumatic AF ( NRAF ) who received oral anticoagulation with warfarin . During a 2-year follow-up period , the annual event rate of ischemic stroke was 2.1 % . In patients without a history of prior stroke , no ischemic stroke occurred at a higher international normalized ratio ( INR > or = 2.0 ) . In contrast , patients who had had a prior stroke had no INR-dependent reduction of incidence . The coefficient of variation ( CV ) of measured INRs was significantly greater in patients with ischemic stroke than in those without . By multivariate analysis , only greater CV ( > or = 0.3 ) of INRs was an independent risk for ischemic stroke , although New York Heart Association functional class > or = II and treatment with diuretics were of borderline significance by univariate analysis . The present results suggest that stability of anticoagulation intensity is important to protect thromboembolic events in patients with NRAF BACKGROUND Warfarin is very effective in preventing recurrent venous thromboembolism but is also associated with a substantial risk of bleeding . After three months of conventional warfarin therapy , a lower dose of anticoagulant medication may result in less bleeding and still prevent recurrent venous thromboembolism . METHODS We conducted a r and omized , double-blind study , in which 738 patients who had completed three or more months of warfarin therapy for unprovoked venous thromboembolism were r and omly assigned to continue warfarin therapy with a target international normalized ratio ( INR ) of 2.0 to 3.0 ( conventional intensity ) or a target INR of 1.5 to 1.9 ( low intensity ) . Patients were followed for an average of 2.4 years . RESULTS Of 369 patients assigned to low-intensity therapy , 16 had recurrent venous thromboembolism ( 1.9 per 100 person-years ) , as compared with 6 of 369 assigned to conventional-intensity therapy ( 0.7 per 100 person-years ; hazard ratio , 2.8 ; 95 percent confidence interval , 1.1 to 7.0 ) . A major bleeding episode occurred in nine patients assigned to low-intensity therapy ( 1.1 events per 100 person-years ) and eight patients assigned to conventional-intensity therapy ( 0.9 event per 100 person-years ; hazard ratio , 1.2 ; 95 percent confidence interval , 0.4 to 3.0 ) . There was no significant difference in the frequency of overall bleeding between the two groups ( hazard ratio , 1.3 ; 95 percent confidence interval , 0.8 to 2.1 ) . CONCLUSIONS Conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long-term prevention of recurrent venous thromboembolism . The low-intensity warfarin regimen does not reduce the risk of clinical ly important bleeding Low-intensity warfarin ( INR 1.5 to 2.5 ) was started in 63 patients with atrial fibrillation ( AF ) and they were prospect ively followed for 2.3 + /- 1.4 years to determine the efficacy and safety of anticoagulation for stroke prevention in actual clinical practice . Although the patients in this practice were older ( 76 + /- 7 years ) , consisted of more women ( 52 % ) , and had more risk factors for stroke compared with those in clinical trials , the annual event rates of stroke and systemic embolism in this practice were comparable to those of patients receiving warfarin in clinical trials ( 2.0 % vs. 1.4 % and 0.7 % vs. 0.3 % ) . The rate of major bleeding did not significantly differ between this practice and clinical trials ( 0.7 % vs. 1.3 % ) . The rate of minor bleeding was significantly lower in this practice than in clinical trials ( 3.4 % vs. 7.9 % ) . The data suggest that low-intensity anticoagulation is effective and safe for stroke prevention in elderly patients with AF at stroke risk in actual clinical practice BACKGROUND Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects . The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known . METHODS We conducted a r and omized , double-blind , double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation ( median follow-up , 2.8 years ) . The primary efficacy end point was stroke or systemic embolism . Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period . The principal safety end point was major bleeding . RESULTS The annualized rate of the primary end point during treatment was 1.50 % with warfarin ( median time in the therapeutic range , 68.4 % ) , as compared with 1.18 % with high-dose edoxaban ( hazard ratio , 0.79 ; 97.5 % confidence interval [ CI ] , 0.63 to 0.99 ; P<0.001 for noninferiority ) and 1.61 % with low-dose edoxaban ( hazard ratio , 1.07 ; 97.5 % CI , 0.87 to 1.31 ; P=0.005 for noninferiority ) . In the intention-to-treat analysis , there was a trend favoring high-dose edoxaban versus warfarin ( hazard ratio , 0.87 ; 97.5 % CI , 0.73 to 1.04 ; P=0.08 ) and an unfavorable trend with low-dose edoxaban versus warfarin ( hazard ratio , 1.13 ; 97.5 % CI , 0.96 to 1.34 ; P=0.10 ) . The annualized rate of major bleeding was 3.43 % with warfarin versus 2.75 % with high-dose edoxaban ( hazard ratio , 0.80 ; 95 % CI , 0.71 to 0.91 ; P<0.001 ) and 1.61 % with low-dose edoxaban ( hazard ratio , 0.47 ; 95 % CI , 0.41 to 0.55 ; P<0.001 ) . The corresponding annualized rates of death from cardiovascular causes were 3.17 % versus 2.74 % ( hazard ratio , 0.86 ; 95 % CI , 0.77 to 0.97 ; P=0.01 ) , and 2.71 % ( hazard ratio , 0.85 ; 95 % CI , 0.76 to 0.96 ; P=0.008 ) , and the corresponding rates of the key secondary end point ( a composite of stroke , systemic embolism , or death from cardiovascular causes ) were 4.43 % versus 3.85 % ( hazard ratio , 0.87 ; 95 % CI , 0.78 to 0.96 ; P=0.005 ) , and 4.23 % ( hazard ratio , 0.95 ; 95 % CI , 0.86 to 1.05 ; P=0.32 ) . CONCLUSIONS Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes . ( Funded by Daiichi Sankyo Pharma Development ; ENGAGE AF-TIMI 48 Clinical Trials.gov number , NCT00781391 . ) Background and Purpose — Warfarin prevents stroke in atrial fibrillation ( AF ) ; however , concerns regarding international normalized ratio control and hemorrhage limit its use in the elderly . The oral direct thrombin inhibitors ( DTIs ) are potential alternatives to warfarin , offering fixed dosing without drug and dietary interactions and the need for international normalized ratio monitoring . Although ximelagatran , a DTI studied in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation trials , has been withdrawn , development of other DTIs continues . We report our experience in elderly high-risk AF patients on ximelagatran compared with warfarin therapy . Methods — Data from patients with AF and stroke risk factors r and omized in Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation III and V trials to ximelagatran or warfarin were analyzed for stroke/systemic emboli , bleeding , and raised alanine aminotransferase levels in those ≥75 ( n=2804 ) and < 75 ( n=4525 ) years . Results — Ximelagatran was as effective as warfarin in reducing stroke/systemic emboli in the elderly ( 2.23%/y with ximelagatran vs 2.27%/y with warfarin ) as in younger patients ( 1.25%/y vs 1.28%/y ) . Total bleeds were significantly lower with ximelagatran compared with warfarin in elderly ( 40 % vs 45 % , P=0.01 ) and younger ( 27 % vs 35 % , P<0.001 ) patients . Raised alanine aminotransferase values ( > 3-fold elevation ) among ximelagatran patients were more common in older ( 7.5 % old vs 5.3 % young ) patients , particularly women ( 9.5 % elderly women vs 6.1 % elderly men ) . Conclusions — In high-risk elderly AF patients , ximelagatran is as effective as warfarin with less bleeding , but alanine aminotransferase elevations are common , particularly in elderly women . Oral DTIs for stroke prevention show promise in elderly patients AIMS The r and omized NASPEAF study included non-valvular with prior embolism and mitral stenosis patients in the same group . This is a sub- study to specially focus on the antithrombotic therapy in mitral stenosis . METHODS AND RESULTS We analysed 311 patients with mitral stenosis , compared with 175 non-valvular atrial fibrillation patients with prior embolism , stratified by a history of previous embolism and assigned to anticoagulant therapy [ target international normalized ratio ( INR ) = 2.0 - 3.0 ] or combined antiplatelet plus moderate intensity anticoagulant therapy . Median follow-up was 2.9 years . Outcomes were fatal and non-fatal embolism , stroke and myocardial infa rct ion , sudden death , and death from bleeding . Combined therapy in mitral stenosis patients , compared with anticoagulant alone therapy , reduced the risk of vascular events by 58.3 % . During equal therapy , the outcome annual rates were essentially the same in non-valvular and valvular patients [ hazard ratio 0.90 ( 95 % confidence interval 0.37 - 2.16 ) , P = 0.81 ] . During anticoagulant alone therapy , the annual event rate in mitral stenosis patients without prior embolism was low ( 2.5 % ) and it was very high in patients with prior embolism ( 6.6 % ) . CONCLUSION Combined therapy was effective in mitral stenosis patients . Prior embolism patients are not efficiently protected with anticoagulant alone therapy for an INR of 2.0 - 3.0 BACKGROUND Knowledge of the net benefit of warfarin therapy in routine care is needed to define realistic management recommendations , but lack of r and omized controls precludes conventional risk-benefit analysis . OBJECTIVE Assess risk and benefit of routine warfarin therapy in an anticoagulation clinic . DESIGN Retrospective observational analysis . PATIENTS A total of 1435 out patients on warfarin for a total of 1613 patient years , treated to prevent the target events recurrent venous thromboembolism ( VTE ) or myocardial infa rct ion ( MI ) , and stroke in patients with atrial fibrillation ( AF ) or mechanical heart valves . MEASUREMENTS Major bleeding and thromboembolic ( TE ) events and all deaths . CALCULATIONS Expected annual target event rates without warfarin were from published data . Differences between combined major events observed with warfarin , and expected without warfarin were calculated . RESULTS In the total material , annual rates were 3.0 % major TE events , 1.1 % major bleeding events , 0.12 % fatal bleeding , and a benefit/risk ratio of 3.8 . The net gain , expressed in reduced combined bleeding and target TE annual event rate , was 9.9 % in secondary prophylaxis in AF , 4.4 % in VTE patients , 2.7 % in post-MI patients , 2.4 % in primary prophylaxis in AF and 0.6 in patients with mechanical heart valves . The apparent benefit/risk ratio was 3.9 in VTE patients , 5.8 in AF patients and 1.1 in patients with mechanical heart valves . CONCLUSION Net effects of prolonged warfarin therapy in patients with VTE and AF performed in an anticoagulation clinic have an acceptable risk/benefit ratio , comparable with what has been obtained in elective clinical trials BACKGROUND Venous thromboembolism is treated with unfractionated heparin or low-molecular-weight heparin , followed by a vitamin K antagonist . We investigated the potential use of idraparinux , a long-acting inhibitor of activated factor X , as a substitute for st and ard therapy . METHODS We conducted two r and omized , open-label noninferiority trials involving 2904 patients with deep-vein thrombosis and 2215 patients with pulmonary embolism to compare the efficacy and safety of idraparinux versus st and ard therapy . Patients received either subcutaneous idraparinux ( 2.5 mg once weekly ) or a heparin followed by an adjusted-dose vitamin K antagonist for either 3 or 6 months . The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolism ( nonfatal or fatal ) . RESULTS In the study of patients with deep venous thrombosis , the incidence of recurrence at day 92 was 2.9 % in the idraparinux group as compared with 3.0 % in the st and ard-therapy group ( odds ratio , 0.98 ; 95 % confidence interval [ CI ] , 0.63 to 1.50 ) , a result that satisfied the prespecified noninferiority requirement . At 6 months , the hazard ratio for idraparinux was 1.01 . The rates of clinical ly relevant bleeding at day 92 were 4.5 % in the idraparinux group and 7.0 % in the st and ard-therapy group ( P=0.004 ) . At 6 months , bleeding rates were similar . In the study of patients with pulmonary embolism , the incidence of recurrence at day 92 was 3.4 % in the idraparinux group and 1.6 % in the st and ard-therapy group ( odds ratio , 2.14 ; 95 % CI , 1.21 to 3.78 ) , a finding that did not meet the noninferiority requirement . CONCLUSIONS In patients with deep venous thrombosis , once-weekly subcutaneous idraparinux for 3 or 6 months had an efficacy similar to that of heparin plus a vitamin K antagonist . However , in patients with pulmonary embolism , idraparinux was less efficacious than st and ard therapy . ( Clinical Trials.gov numbers , NCT00067093 [ Clinical Trials.gov ] and NCT00062803 [ Clinical Trials.gov ] . ) BACKGROUND Although practice guidelines recommend outpatient care for selected , haemodynamically stable patients with pulmonary embolism , most treatment is presently inpatient based . We aim ed to assess non-inferiority of outpatient care compared with inpatient care . METHODS We undertook an open-label , r and omised non-inferiority trial at 19 emergency departments in Switzerl and , France , Belgium , and the USA . We r and omly assigned patients with acute , symptomatic pulmonary embolism and a low risk of death ( pulmonary embolism severity index risk classes I or II ) with a computer-generated r and omisation sequence ( blocks of 2 - 4 ) in a 1:1 ratio to initial outpatient ( ie , discharged from hospital ≤24 h after r and omisation ) or inpatient treatment with subcutaneous enoxaparin ( ≥5 days ) followed by oral anticoagulation ( ≥90 days ) . The primary outcome was symptomatic , recurrent venous thromboembolism within 90 days ; safety outcomes included major bleeding within 14 or 90 days and mortality within 90 days . We used a non-inferiority margin of 4 % for a difference between inpatient and outpatient groups . We included all enrolled patients in the primary analysis , excluding those lost to follow-up . This trial is registered with Clinical Trials.gov , number NCT00425542 . FINDINGS Between February , 2007 , and June , 2010 , we enrolled 344 eligible patients . In the primary analysis , one ( 0·6 % ) of 171 out patients developed recurrent venous thromboembolism within 90 days compared with none of 168 in patients ( 95 % upper confidence limit [ UCL ] 2·7 % ; p=0·011 ) . Only one ( 0·6 % ) patient in each treatment group died within 90 days ( 95 % UCL 2·1 % ; p=0·005 ) , and two ( 1·2 % ) of 171 out patients and no in patients had major bleeding within 14 days ( 95 % UCL 3·6 % ; p=0·031 ) . By 90 days , three ( 1·8 % ) out patients but no in patients had developed major bleeding ( 95 % UCL 4·5 % ; p=0·086 ) . Mean length of stay was 0·5 days ( SD 1·0 ) for out patients and 3·9 days ( SD 3·1 ) for in patients . INTERPRETATION In selected low-risk patients with pulmonary embolism , outpatient care can safely and effectively be used in place of inpatient care . FUNDING Swiss National Science Foundation , Programme Hospitalier de Recherche Clinique , and the US National Heart , Lung , and Blood Institute . Sanofi-Aventis provided free drug supply in the participating European centres Background — An effective and safe oral anticoagulant that needs no monitoring for dose adjustment is urgently needed for the treatment of diseases that require long-term anticoagulation . Rivaroxaban ( BAY 59 - 7939 ) is an oral direct factor Xa inhibitor currently under clinical development . Methods and Results — This r and omized , parallel-group phase II trial in patients with proximal deep-vein thrombosis explored the efficacy and safety of rivaroxaban 10 , 20 , or 30 mg BID or 40 mg once daily compared with enoxaparin 1 mg/kg BID followed by vitamin K antagonist . Each treatment was administered for 12 weeks . The primary efficacy end point was an improvement in thrombotic burden at day 21 ( assessed by quantitative compression ultrasonography ; ≥4-point improvement in thrombus score ) without recurrent symptomatic venous thromboembolism or venous thromboembolism – related death . The primary safety end point was major bleeding during 12 weeks of treatment . Outcomes were adjudicated central ly without knowledge of treatment allocation . The primary efficacy end point was achieved in 53 ( 53.0 % ) of 100 , 58 ( 59.2 % ) of 98 , 62 ( 56.9 % ) of 109 , and 49 ( 43.8 % ) of 112 patients receiving rivaroxaban 10 , 20 , or 30 mg BID or 40 mg once daily , respectively , compared with 50 ( 45.9 % ) of 109 patients treated with enoxaparin/vitamin K antagonist . There was no significant trend in the dose – response relationship between rivaroxaban BID and the primary efficacy end point ( P=0.67 ) . Major bleeding was observed in 1.7 % , 1.7 % , 3.3 % , and 1.7 % of patients receiving rivaroxaban 10 , 20 , or 30 mg BID or 40 mg once daily , respectively . There were no major bleeding events with enoxaparin/vitamin K antagonist . Conclusions — Results of this proof-of-concept and dose-finding study support phase III evaluation of the orally active direct factor Xa inhibitor rivaroxaban , because efficacy and safety were apparent in the treatment of proximal deep-vein thrombosis across a 3-fold range of fixed daily dosing BACKGROUND : Warfarin is recommended for prevention of stroke in patients with atrial fibrillation who are at moderate or high risk , but requires intensive management to achieve safe and optimal anticoagulation control . Anticoagulation clinics are often used to administer warfarin therapy more effectively . OBJECTIVE : To collect data from multiple sites and assess the quality and costs associated with anticoagulation clinic services . METHODS : A r and om sample of 600 adults with chronic nonvalvular atrial fibrillation ( CNVAF ) receiving warfarin was selected from anticoagulation clinics affiliated with 3 health plans . Patients were identified between 1996 and 1998 and followed for up to one year . We assessed the proportion of time that international normalized ratio ( INR ) values were within the recommended range ( 2.0–3.0 ) and the costs of anticoagulation clinic care . RESULTS : Patients had an average of 18 clinic contacts over a mean duration of follow-up of 10.5 months . On average , patients were within the recommended INR range 62 % of this time , with 25 % of days below range and 13 % above range . The mean per-patient cost of warfarin monitoring over the follow-up period averaged $ 261 at site A , $ 305 at site B , and $ 205 at site C ( in 2003 US$ ) . Mean costs for patients treated for one full year were $ 288 , $ 339 , and $ 216 , respectively . CONCLUSIONS : In 3 geographically diverse health plans , anticoagulation clinics provided a generally higher quality of control than previously reported in other observational studies . This study highlights the costs of obtaining this level of control BACKGROUND Increased dem and for oral anticoagulants is overwhelming facilities worldwide , result ing in increasing use of computer assistance . A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer-assisted dosage with dosage by experienced medical staff at the same centers . METHODS A r and omized study of dosage of two commercial computer-assisted dosage programs ( PARMA 5 and DAWN AC ) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries . The aim was to recruit a minimum of 16,000 patient-years r and omized to medical staff or computer-assisted dosage . In total , 13,219 patients participated , 6503 patients being r and omized to medical staff and 6716 to computer-assisted dosage . The safety and effectiveness of computer-assisted dosage were compared with those of medical staff dosage . RESULTS In total , 13,052 patients were recruited ( 18,617 patient-years ) . International Normalized Ratio ( INR ) tests numbered 193 890 with manual dosage and 193,424 with computer-assisted dosage . The number of clinical events with computer-assisted dosage was lower ( P = 0.1 ) , but in the 3209 patients with deep vein thrombosis/pulmonary embolism , they were reduced by 37 ( 24 % , P = 0.001 ) . Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers ( P < 0.001 ) . CONCLUSIONS The safety and effectiveness of computer-assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation . Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed . The reliability and safety of other marketed computer-assisted dosage programs need to be established BACKGROUND Few reports have addressed the value of unfractionated heparin ( UFH ) or low-molecular-weight heparin in treating the full spectrum of patients with venous thromboembolism ( VTE ) , including recurrent VTE and pulmonary embolism . METHODS In an open , multicenter clinical trial , 720 consecutive patients with acute symptomatic VTE , including 119 noncritically ill patients ( 16.5 % ) with pulmonary embolism and 102 ( 14.2 % ) with recurrent VTE , were r and omly assigned to treatment with subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm ( preceded by an intravenous loading dose ) , or fixed-dose ( adjusted only to body weight ) subcutaneous nadroparin calcium . Oral anticoagulant therapy was started concomitantly and continued for at least 3 months . We recorded the incidence of major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of follow-up . RESULTS Fifteen ( 4.2 % ) of the 360 patients assigned to UFH had recurrent thromboembolic events , as compared with 14 ( 3.9 % ) of the 360 patients assigned to nadroparin ( absolute difference between rates , 0.3 % ; 95 % confidence interval , -2.5 % to 3.1 % ) . Four patients assigned to UFH ( 1.1 % ) and 3 patients assigned to nadroparin ( 0.8 % ) had episodes of major bleeding ( absolute difference between rates , 0.3 % ; 95 % confidence interval , -1.2 % to 1.7 % ) . Overall mortality was 3.3 % in each group . CONCLUSIONS Subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm is as effective and safe as fixed-dose nadroparin for the initial treatment of patients with VTE , including those with pulmonary embolism and recurrent VTE BACKGROUND In ROCKET AF , rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation ( AF ) . We aim ed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack ( TIA ) . METHODS In ROCKET AF , patients with AF who were at increased risk of stroke were r and omly assigned ( 1:1 ) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin ( international normalised ratio 2·0 - 3·0 ) . Patients and investigators were masked to treatment allocation . Between Dec 18 , 2006 , and June 17 , 2009 , 14 264 patients from 1178 centres in 45 countries were r and omly assigned . The primary endpoint was the composite of stroke or non-CNS systemic embolism . In this sub study we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA . Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population . ROCKET AF is registered with Clinical Trials.gov , number NCT00403767 . FINDINGS 7468 ( 52 % ) patients had a previous stroke ( n=4907 ) or TIA ( n=2561 ) and 6796 ( 48 % ) had no previous stroke or TIA . The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA ( 2·79 % rivaroxaban vs 2·96 % warfarin ; hazard ratio [ HR ] 0·94 , 95 % CI 0·77 - 1·16 ) and those without ( 1·44%vs 1·88 % ; 0·77 , 0·58 - 1·01 ; interaction p=0·23 ) . The number of major and non-major clinical ly relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA ( 13·31 % rivaroxaban vs 13·87 % warfarin ; HR 0·96 , 95 % CI 0·87 - 1·07 ) and those without ( 16·69%vs 15·19 % ; 1·10 , 0·99 - 1·21 ; interaction p=0·08 ) . INTERPRETATION There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA . These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF . FUNDING Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare AIMS Atrial fibrillation patients with prior embolism have a high risk of vascular events in spite of anticoagulant therapy and elderly patients carry an additional risk . We analysed and compared vascular events-rate between older and younger than 75 years atrial fibrillation patients r and omized to anticoagulant-alone or combined antiplatelet plus moderate-level anticoagulant therapy . METHODS AND RESULTS A total of 967 patients stratified by age and the history of prior embolism were r and omized to therapeutic doses of anticoagulant-alone or combined antithrombotic therapy . Primary events were fatal and non-fatal ischaemic or haemorrhagic stroke/transient ischaemic attack , systemic embolism and myocardial infa rct ion , sudden death and death from bleeding . The elderly , compared with the younger patients , had higher event-rate [ hazard ratio 2.31 ( 95 % confidence interval 1.37 - 3.90 ) , P < 0.003 ] . The elderly suffered higher severe bleeding event-rate during anticoagulant therapy . The combined , compared with the anticoagulant therapy , reduced the vascular events-rate in the elderly ( P = 0.012 ) and caused less intracranial haemorrhages and less bleeding mortality , although more non-fatal gastric bleeding . CONCLUSION The elderly with AF had a higher event-rate than the younger patients . A higher severe bleeding event-rate was also registered in elderly patients receiving anticoagulant therapy . Combined , compared with anticoagulant therapy , significantly reduced vascular events and bleeding mortality in elderly patients AIMS The risk of stroke is greater among women with atrial fibrillation ( AF ) than men . Warfarin protects against stroke , but treatment-related bleeding occurs more often in women than in men . METHODS AND RESULTS SPORTIF III ( open label , n=3410 ) and V ( double-blind , n=3922 ) included 2257 women with AF and one or more stroke risk factors r and omized to warfarin [ target international normalized ratio ( INR ) 2.0 - 3.0 ] or ximelagatran ( 36 mg twice daily ) . Primary outcomes were all stroke ( ischaemic/haemorrhagic ) and systemic embolic event . Women were older , on average , than men , 73.4+/-8.0 vs. 69.8+/-9.0 years ( P<0.0001 ) . More women were > 75-years old and women had more risk factors than men had ( P<0.0001 ) . The INR on warfarin ( mean 2.5+/-0.7 ) was within target range for 67 % of follow-up regardless of gender . Women more often developed primary events [ 2.08%/year , 95 % confidence interval ( CI ) 1.60 - 2.56%/year vs. 1.44%/year , 95 % CI 1.18 - 1.71%/year in men ; P=0.016 ) . Major bleeding rates were similar ( P=0.766 ) but women experienced more overall ( major/minor ) bleeding ( P<0.001 ) . Warfarin was associated with more overall bleeding in both genders and more major bleeding in women than in men ( P=0.001 ) . CONCLUSION When compared with men with AF , women in these studies were older and had more stroke risk factors . Women were more prone to anticoagulant-related bleeding ; the higher rate of thrombo-embolism among women was related to more frequent interruption of anticoagulant therapy Patients receiving warfarin who have unstable control of anticoagulation have a significantly lower intake of dietary vitamin K compared with their stable counterparts . We hypothesized that supplementation with oral vitamin K would improve stability in patients with previously unstable control of anticoagulation . Seventy warfarin-treated patients with unstable anticoagulation control were r and omly assigned in a double-blinded fashion to receive a daily amount of 150 mug oral vitamin K or placebo orally for 6 months . Measures of stability of anticoagulation control in the 6-month study period were compared with those in the 6 months immediately prior to it . Vitamin K supplementation result ed in a significantly greater decrease in st and ard deviation of international normalized ratio ( INR ) compared with placebo ( -0.24 + /- 0.14 vs -0.11 + /- 0.18 ; P < .001 ) and a significantly greater increase in percentage time within target INR range ( 28 % + /- 20 % vs 15 % + /- 20 % ; P < .01 ) . Anticoagulation control improved in 33 of 35 patients receiving vitamin K supplementation ; of these , 19 fulfilled our criteria for having stable control of anticoagulation . However , only 24 of 33 patients receiving placebo demonstrated some degree of improvement , with only 7 patients fulfilling the criteria for having stable control . Concomitant supplementation of vitamin K , perhaps through reducing the relative day-to-day variability in dietary vitamin K intake , can significantly improve anticoagulation control in patients with unexplained instability of response to warfarin Objective To determine the optimum duration of oral anticoagulant therapy after an episode of deep vein thrombosis or pulmonary embolism , or both . Design Multicentre , prospect i ve , r and omised study with follow-up for one year . Setting 46 hospitals in United Kingdom . Participants Patients aged ≥18 with deep vein thrombosis or pulmonary embolism , or both . Interventions Three ( n=369 ) or six months ( n=380 ) of anticoagulation with heparin for five days accompanied and followed by warfarin , with a target international normalised ratio of 2.0 - 3.5 . Main outcome measures Death from deep vein thrombosis or pulmonary embolism ; failure to resolve , extension , recurrence of during treatment ; recurrence after treatment ; and major haemorrhage during treatment . Results In the patients allocated to three months ' treatment two died from deep vein thrombosis or pulmonary embolism during or after treatment , compared with three in the six month group . During treatment deep vein thrombosis or pulmonary embolism failed to resolve , extended , or recurred in six patients in the three month group without fatal consequences , compared with 10 in the six month group . After treatment there were 23 non-fatal recurrences in the three month group and 16 in the six month group . Fatal and non-fatal deep vein thrombosis or pulmonary embolism during treatment , and after treatment thus occurred in 31(8 % ) of those who had received three months ' anticoagulation compared with 29 ( 8 % ) of those who had received six months ' ( P=0.80 , 95 % confidence interval for difference −3.1 % to 4.7 % ) . There were no fatal haemorrhages during treatment but there were eight major haemorrhages in those treated for six months and none in those treated for three months ( P=0.008 , −3.5 % to −0.7 % ) . Thus 31 ( 8 % ) of the patients receiving three months ' anticoagulation experienced adverse outcomes as a result of deep vein thrombosis or pulmonary embolism or its treatment compared with 35 ( 9 % ) of those receiving six months ' ( P=0.79 , −4.9 % to 3.2 % ) . Conclusion For patients in the UK with deep vein thrombosis or pulmonary embolism and no known risk factors for recurrence , there seems to be little , if any , advantage in increasing the duration of anticoagulation from three to six months . Any possible advantage would be small and would need to be judged against the increased risk of haemorrhage associated with the longer duration of treatment with warfarin . Trial registration Clinical Trials NCT00365950 OBJECTIVES Evaluation of the effectiveness and safety of the low molecular weight heparin ( LMWH ) tinzaparin versus unfractionated heparin ( UFH ) followed by acenocoumarol in proximal deep venous thrombosis ( DVT ) . DESIGN Prospect i ve , r and omized clinical trial . MATERIAL AND METHODS Consecutive patients ( n=108 ) with acute leg DVT , confirmed by duplex , were r and omized to either tinzaparin alone or UFH and acenocoumarol for 6 months . Patients were evaluated ultrasonographically at entry , 1 , 3 , 6 and 12 months . Thrombus regression , reflux distribution and the incidence of complications were studied . A cost- analysis , comparing the two treatments , was performed . RESULTS The overall incidence of major events ( mortality , DVT recurrence , pulmonary embolism , major bleeding , heparin-induced thrombocytopenia ) was significantly different ( p=0.035 ) in favor of tinzaparin ( 7 versus 17 events ) . The ultrasonographic clot volume score ( an index of recanalization ) decreased significantly in both treatment groups . However , tinzaparin produced significantly more extended overall recanalization from 3 months onwards ( p<0.02 ) . Thrombus regression was equivalent or in favor of tinzaparin in the different DVT subgroups and venous segments , but the statistical significance varied . Reflux showed non-significant differences overall or in subgroups . A cost- analysis result ed in favor of LMWH . CONCLUSIONS A fixed daily dose of tinzaparin for 6 months was at least as effective and safe as UFH and acenocoumarol . Regarding major events and recanalization , there was a significant benefit in favor of tinzaparin . Long-term DVT treatment with tinzaparin could represent an alternative to conventional treatment AZD0837 is an investigational oral anticoagulant which is converted to the active form , AR-H067637 , a selective direct thrombin inhibitor . The present study , a multicentre , r and omised , parallel-group , dose-guiding study , assessed the safety and tolerability of an immediate-release formulation of AZD0837 compared with dose-adjusted warfarin in the prevention of stroke and systemic embolic events in atrial fibrillation ( AF ) patients . Two hundred fifty AF patients with at least one additional risk factor for stroke were r and omised to receive either immediate-release AZD0837 ( 150 mg twice daily [ bid ] or 350 mg bid , blinded treatment ) or dose-adjusted warfarin ( international normalised ratio 2.0 - 3.0 , open treatment ) for three months . The safety and tolerability of 150 mg bid AZD0837 appeared to be as good as that of warfarin . Total bleeding events were six with 150 mg bid AZD0837 , 15 with 350 mg bid AZD0837 and eight with warfarin . Alanine aminotransferase elevations ( > 3xupper limit of normal ) were infrequent , without apparent differences between treatment groups . A numerically higher incidence of serious adverse events was observed with 350 mg bid AZD0837 compared with 150 mg bid , with six of 13 being cardiac related , all with different diagnoses . An increase in mean serum creatinine of approximately 10 % was observed in both AZD0837 groups , which returned to baseline after completion of therapy . There were no strokes , transient ischaemic attacks or cerebral haemorrhages with any of the treatments . In conclusion , the safety and tolerability of 150 mg bid immediate-release AZD0837 appeared to be as good as that of dose-adjusted warfarin . However , larger studies will be needed to define the safety profile of AZD0837 BACKGROUND The global ROCKET AF study evaluated once-daily rivaroxaban vs. warfarin for stroke and systemic embolism prevention in patients with atrial fibrillation ( AF ) . A separate trial , J-ROCKET AF , compared the safety of a Japan-specific rivaroxaban dose with warfarin administered according to Japanese guidelines in Japanese patients with AF . METHODS AND RESULTS J-ROCKET AF was a prospect i ve , r and omized , double-blind , phase III trial . Patients ( n=1,280 ) with non-valvular AF at increased risk for stroke were r and omized to receive 15 mg once-daily rivaroxaban or warfarin dose-adjusted according to Japanese guidelines . The primary objective was to determine non-inferiority of rivaroxaban against warfarin for the principal safety outcome of major and non-major clinical ly relevant bleeding , in the on-treatment safety population . The primary efficacy endpoint was the composite of stroke and systemic embolism . Non-inferiority of rivaroxaban to warfarin was confirmed ; the rate of the principal safety outcome was 18.04 % per year in rivaroxaban-treated patients and 16.42 % per year in warfarin-treated patients ( hazard ratio [ HR ] 1.11 ; 95 % confidence interval 0.87 - 1.42 ; P<0.001 [ non-inferiority ] ) . Intracranial hemorrhage rates were 0.8 % with rivaroxaban and 1.6 % with warfarin . There was a strong trend for a reduction in the rate of stroke/systemic embolism with rivaroxaban vs. warfarin ( HR , 0.49 ; P=0.050 ) . CONCLUSIONS J-ROCKET AF demonstrated the safety of a Japan-specific rivaroxaban dose and supports bridging the global ROCKET AF results into Japanese clinical practice BACKGROUND St and ard therapy to prevent recurrent venous thromboembolism includes 3 to 12 months of treatment with full-dose warfarin with a target international normalized ratio ( INR ) between 2.0 and 3.0 . However , for long-term management , no therapeutic agent has shown an acceptable benefit-to-risk ratio . METHODS Patients with idiopathic venous thromboembolism who had received full-dose anticoagulation therapy for a median of 6.5 months were r and omly assigned to placebo or low-intensity warfarin ( target INR , 1.5 to 2.0 ) . Participants were followed for recurrent venous thromboembolism , major hemorrhage , and death . RESULTS The trial was terminated early after 508 patients had undergone r and omization and had been followed for up to 4.3 years ( mean , 2.1 ) . Of 253 patients assigned to placebo , 37 had recurrent venous thromboembolism ( 7.2 per 100 person-years ) , as compared with 14 of 255 patients assigned to low-intensity warfarin ( 2.6 per 100 person-years ) , a risk reduction of 64 percent ( hazard ratio , 0.36 [ 95 percent confidence interval , 0.19 to 0.67 ] ; P<0.001 ) . Risk reductions were similar for all subgroups , including those with and those without inherited thrombophilia . Major hemorrhage occurred in two patients assigned to placebo and five assigned to low-intensity warfarin ( P=0.25 ) . Eight patients in the placebo group and four in the group assigned to low-intensity warfarin died ( P=0.26 ) . Low-intensity warfarin was thus associated with a 48 percent reduction in the composite end point of recurrent venous thromboembolism , major hemorrhage , or death . According to per- protocol and as-treated analyses , the reduction in the risk of recurrent venous thromboembolism was between 76 and 81 percent . CONCLUSIONS Long-term , low-intensity warfarin therapy is a highly effective method of preventing recurrent venous thromboembolism Aims Oral anticoagulation with vitamin K antagonists ( VKAs ) for stroke prevention in atrial fibrillation ( AF ) is effective but has significant limitations . AZD0837 , a new oral anticoagulant , is a prodrug converted to a selective and reversible direct thrombin inhibitor ( AR-H067637 ) . We report from a Phase II r and omized , dose-guiding study ( NCT00684307 ) to assess safety , tolerability , pharmacokinetics , and pharmacodynamics of extended-release AZD0837 in patients with AF . Methods and results Atrial fibrillation patients ( n = 955 ) with ≥1 additional risk factor for stroke were r and omized to receive AZD0837 ( 150 , 300 , or 450 mg once daily or 200 mg twice daily ) or VKA ( international normalized ratio 2–3 , target 2.5 ) for 3–9 months . Approximately 30 % of patients were naïve to VKA treatment . Total bleeding events were similar or lower in all AZD0837 groups ( 5.3–14.7 % , mean exposure 138–145 days ) vs. VKA ( 14.5 % , mean exposure 161 days ) , with fewer clinical ly relevant bleeding events on AZD0837 150 and 300 mg once daily . Adverse events were similar between treatment groups ; with AZD0837 , the most common were gastrointestinal disorders ( e.g. diarrhoea , flatulence , or nausea ) . d-Dimer , used as a biomarker of thrombogenesis , decreased in all groups in VKA-naïve subjects with treatment , whereas in VKA pre-treated patients , d-dimer levels started low and remained low in all groups . As expected , only a few strokes or systemic embolic events occurred . In the AZD0837 groups , mean S-creatinine increased by ∼10 % from baseline and returned to baseline following treatment cessation . The frequency of serum alanine aminotransferase ≥3 × upper limit of normal was similar for AZD0837 and VKA . Conclusion AZD0837 was generally well tolerated at all doses tested . AZD0837 treatment at an exposure corresponding to the 300 mg od dose in this study provides similar suppression of thrombogenesis at a potentially lower bleeding risk compared with dose-adjusted VKA . This study is registered with Clinical Trials.gov , number NCT00684307 BACKGROUND The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment . Rivaroxaban , an oral factor Xa inhibitor , may provide more consistent and predictable anticoagulation than warfarin . METHODS In a double-blind trial , we r and omly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban ( at a daily dose of 20 mg ) or dose-adjusted warfarin . The per- protocol , as-treated primary analysis was design ed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism . RESULTS In the primary analysis , the primary end point occurred in 188 patients in the rivaroxaban group ( 1.7 % per year ) and in 241 in the warfarin group ( 2.2 % per year ) ( hazard ratio in the rivaroxaban group , 0.79 ; 95 % confidence interval [ CI ] , 0.66 to 0.96 ; P<0.001 for noninferiority ) . In the intention-to-treat analysis , the primary end point occurred in 269 patients in the rivaroxaban group ( 2.1 % per year ) and in 306 patients in the warfarin group ( 2.4 % per year ) ( hazard ratio , 0.88 ; 95 % CI , 0.74 to 1.03 ; P<0.001 for noninferiority ; P=0.12 for superiority ) . Major and nonmajor clinical ly relevant bleeding occurred in 1475 patients in the rivaroxaban group ( 14.9 % per year ) and in 1449 in the warfarin group ( 14.5 % per year ) ( hazard ratio , 1.03 ; 95 % CI , 0.96 to 1.11 ; P=0.44 ) , with significant reductions in intracranial hemorrhage ( 0.5 % vs. 0.7 % , P=0.02 ) and fatal bleeding ( 0.2 % vs. 0.5 % , P=0.003 ) in the rivaroxaban group . CONCLUSIONS In patients with atrial fibrillation , rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism . There was no significant between-group difference in the risk of major bleeding , although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group . ( Funded by Johnson & Johnson and Bayer ; ROCKET AF Clinical Trials.gov number , NCT00403767 . ) Abstract Background : R and omized control trials and observational studies show high- quality warfarin therapy leads to safe and effective stroke prophylaxis . In usual community practice , patient , physician and health care system factors are barriers to optimal anticoagulation . We examined the predictive relationship between inpatient and outpatient INR values in chronic non-valvular atrial fibrillation ( AF ) patients hospitalized for ischemic stroke ( S ) , bleed ( B ) and control events ( C ) in usual community practice . Methods : This nested case-control analysis identified AF patients hospitalized for S , B and C using medical and pharmacy cl aims spanning 4.5 years ( ‘ 98–‘03 ) and validating diagnosis with chart abstract ion . AF was defined as 2 medical cl aims for AF ≥ 42 days apart with a related prescription cl aim for warfarin . INRs from both outpatient and inpatient setting s were used to yield a continuous history of coagulation status . Time-in-therapeutic-range ( TTR ) was calculated by Rosendaal ’s linear interpolation method . Correlation of inpatient and prognostic utility of last outpatient INRs was tested with S or B hospitalizations using univariate and multivariate logistic regression . Results : Overall , 614 hospitalizations ( means : age 73.9 , CHADS2 = 3.24 ; 52 % male ) included S ( n = 98 ) , B ( n = 101 ) and C ( n = 415 ) events . Average TTR was 28.6 % ( 49.4 % at INR < 2.0 , 21.9 % at INR > 3.0 ) . First INR on admission ( INR < 2.0 or > 3.0 ) was associated with S and B hospitalizations ( OR-adjusted [ 95%CI ] , 1.68 [ 1.04–2.73 ] and 1.72 [ 1.02–2.90 ] ) , respectively . Last outpatient INR < 2.0 was not associated with S ( OR-adjusted [ 95%CI ] , 1.12 [ 0.77–1.81 ] ) , and INR > 3.0 was not associated with B ( OR-adjusted [ 95%CI ] , 1.25 [ 0.67–2.32 ] ) . Last outpatient INR measurement occurred at 28 , 22 and 24 days ( median ; S , B & C , respectively ) before hospitalization . Conclusion : Patients were observed within therapeutic range less than 30 % of their time on warfarin . While inpatient INRs were clearly associated with both ischemic stroke and bleed events , last outpatient INR before event was not predictive BACKGROUND In the ARISTOTLE trial , the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation ( AF ) . Patients with AF and previous stroke or transient ischaemic attack ( TIA ) have a high risk of stroke . We therefore aim ed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA . METHODS Between Dec 19 , 2006 , and April 2 , 2010 , patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries . 18,201 patients with AF or atrial flutter were r and omly assigned to receive apixaban 5 mg twice daily or warfarin ( target international normalised ratio 2·0 - 3·0 ) . The median duration of follow-up was 1·8 years ( IQR 1·4 - 2·3 ) . The primary efficacy outcome was stroke or systemic embolism , analysed by intention to treat . The primary safety outcome was major bleeding in the on-treatment population . All participants , investigators , and sponsors were masked to treatment assignments . In this subgroup analysis , we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA . The ARISTOTLE trial is registered with Clinical Trials.gov , number NTC00412984 . FINDINGS Of the trial population , 3436 ( 19 % ) had a previous stroke or TIA . In the subgroup of patients with previous stroke or TIA , the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group ( hazard ratio [ HR ] 0·76 , 95 % CI 0·56 to 1·03 ) ; in the subgroup of patients without previous stroke or TIA , the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin ( HR 0·82 , 95 % CI 0·65 to 1·03 ; p for interaction=0·71 ) . The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up ( 95 % CI -0·08 to 1·63 ) in patients with and 0·22 ( -0·03 to 0·47 ) in those without previous stroke or TIA . The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years ( 95 % CI 0·09 - 2·04 ) in patients with and 0·93 ( 0·54 - 1·32 ) in those without previous stroke or TIA . INTERPRETATION The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA . Owing to the higher risk of these outcomes in patients with previous stroke or TIA , the absolute benefits of apixaban might be greater in this population . FUNDING Bristol-Myers Squibb and Pfizer It has been observed that elderly patients with nonvalvular atrial fibrillation ( NVAF ) benefit from st and ard [ an international normalised ratio ( INR ) goal of 2.0 - 3.0 ] oral anticoagulant treatment ( OAT ) . The hypothesis that lower-intensity anticoagulation therapy can offset the higher bleeding risk in this population has never been tested in an ' ad hoc ' clinical trial . Patients over 75 years of age with NVAF were r and omised to receive warfarin to maintain the INR at 1.8 ( range 1.5 - 2.0 ) or at a st and ard target of 2.5 ( range 2.0 - 3.0 ) . There were 135 patients in the low-intensity and 132 in the st and ard-intensity groups . During a mean follow-up lasting 5.1 years , 59 primary outcome events ( thromboembolism and major haemorrhage ) were recorded , 24 ( 3.5 per 100 patient-years ) in the low-intensity group and 35 ( 5.0 per 100 patient-years ) in the st and ard-intensity group ( HR=0.7 , 95 % CI 0.4 - 1.1 , p=0.1 ) . The reduction in the primary endpoint was mainly due to a diminution in major bleedings ( 1.9 vs. 3.0 per 100 patient-years ; HR=0.6 , 95 % CI 0.3 - 1.2 , p=0.1 ) . The median achieved INR value was 1.86 in the low-intensity and 2.24 in the st and ard-intensity group ( p<0.001 ) . The frequency of INR testing was 26.1 + /- 13.5 vs. 24.3 + /- 11.6 days , p<0.0001 ) . In this exploratory study we observed a low rate of stroke and major bleeding in elderly patients ( > 75 ) being managed in an anticoagulation clinic for primary stroke prevention with low-intensity anticoagulation ( INR 1.5 - 2.0 ) . However , further trials are needed to confirm the hypothesis generated by the present study OBJECTIVE The objectives of this study were to observe a commercially insured sample diagnosed with a venous thromboembolism ( VTE ) event and treated postevent with warfarin and to detail the thromboembolic and bleeding outcomes in the time periods during warfarin therapy and after discontinuation of such therapy . METHODS This retrospective , observational cohort study used medical , pharmacy , and eligibility data from 2 US health plans . Study inclusion required an inpatient diagnosis of deep venous thrombosis ( DVT ) or pulmonary embolism ( PE ) between January 1 , 1998 , and December 31 , 2000 ; warfarin , heparin , or low-molecular-weight heparin within 30 days after diagnosis ; no VTE diagnosis ; and no anticoagulant use for 3 months preceding diagnosis . A r and om sample of medical charts was abstract ed to vali date VTE events and collect prothrombin time/international normalized ratio ( INR ) result data . Recurrent VTE events , bleeding events , and proportion of time within INR range were captured in the postindex VTE event time period . Univariate and multivariate statistical techniques were used to assess outcomes . RESULTS A total of 2,090 patients were identified with a newly diagnosed VTE event ( DVT only , 1450 ; PE with or without DVT , 640 ) . Mean ( SD ) age was 61.7 ( 16 ) years ; mean ( SD ) follow-up time after the index diagnosis was 21.3 ( 10 ) months . Overall mean ( SD ) length of warfarin therapy was 6.6 ( 6 ) months . During the follow-up period , 224 patients ( 10.7 % ) experienced a recurrent VTE event and 122 patients ( 5.8 % ) experienced a bleeding event requiring hospitalization . The cumulative incidence of recurrent VTE events over 3 and 6 months was 9.0 % and 10.9 % , respectively . Using the chart abstract ion subset , patients were within the appropriate INR range 37.7 % of the time while receiving warfarin . CONCLUSIONS Negative outcomes associated with warfarin therapy-recurrent VTE events and bleeding requiring hospitalization-were experienced by 10.7 % and 5.8 % of patients , respectively . These data suggest that negative outcomes may be more prevalent in usual community medical practice compared with rates observed in the controlled environment of the clinical trial or specialized anticoagulation clinic BACKGROUND The prevalence of atrial fibrillation increases with age , affecting approximately 5 % of people aged > 65 years and almost 10 % of people aged > 80 years . OBJECTIVE The goal of this study was to identify risk factors for bleeding during warfarin treatment of nonvalvular atrial fibrillation ( NNVAF ) in older patients ( those aged > or=75 years ) compared with younger patients ( those aged < 75 years ) in clinical practice . METHODS All patients with NVAF newly started on warfarin at an anticoagulation clinic in a large university hospital were included in this prospect i ve observational study . Patient details were recorded at their first visit ; details of any bleeding events were recorded via telephone interview every 4 to 6 weeks for a minimum of 10 months . Patients were divided into 2 groups ( ie , those > or=75 years old and those < 75 years old ) . Logistic regression analysis was used to identify risk factors for bleeding . RESULTS A total of 402 patients were included in the study . Group I comprised 203 patients < 75 years old ( mean [ SD ] age , 64.33 [ 8.33 ] years ) and group II comprised 199 patients > or=75 years old ( mean [ SD ] age , 80.44 [ 3.99 ] years ) . Follow-up ranged from 1 to 31 months ( mean [ SD ] , 19 [ 8.11 ] months ) . For major bleeding , number of medications was a significant risk factor in older patients ( odds ratio [ OR ] , 3.0 ; 95 % CI , 1.2 - 7.8 [ P = 0.02 ] ) and range of the international normalized ratio ( INR ) was a significant risk factor in both groups . For every unit increase in the range of INR , the odds of major bleeding increased by 0.6 ( OR , 1.6 ; 95 % CI , 1.2 - 2.4 [ P = 0.03 ] ) in younger patients and by 0.4 ( OR , 1.4 ; 95 % CI , 1.07 - 1.99 [ P = 0.04 ] ) in older patients . For minor bleeding , history of hypertension was the only significant risk factor in older patients ( OR , 3.3 ; 95 % CI , 1.3 - 8.1 [ P = 0.01 ] ) , while history of ischemic heart disease was the only risk factor in younger patients ( OR , 1.9 ; 95 % CI , 1.1 - 5.4 [ P = 0.04 ] ) . CONCLUSIONS Bleeding pattern was similar in both age groups regarding severity , onset , anatomic site of bleeding , and INR values during the bleeding event . Risk factors for episodes of major bleeding , which are more of a clinical concern , are potentially modifiable . They include quality of anticoagulation control in both groups and number of medications in the older age group Abstract Background / objectives Expert oral anticoagulation management is the key to good outcomes and is performed variably in different health care systems throughout the world . We set out to assess the quality of anticoagulation management in five countries in patients receiving vitamin K antagonists ( VKAs ) for stroke prophylaxis in chronic non-valvular atrial fibrillation ( NVAF ) , and to compare the anticoagulation management practice s in these countries . Methods and results This was a retrospective , multi-centre cohort study in the United States , Canada , France , Italy , and Spain . About 1,511 patients were r and omly recruited from representative practice s ( routine medical care ( RMC ) in the US , Canada , and France ; anticoagulation clinics in Italy and Spain ) and data pertaining to their oral anticoagulation care were abstract ed from their medical records . The predominant anticoagulant in use was warfarin in the US , Canada , and Italy ; acenocoumarol in Spain ; and fluindione in France . Documentation of care was poor in the US , Canada , and France , countries where RMC was studied . Percent INRs or time-in-therapeutic range was greater in the two anticoagulation clinic sample s compared with the RMC sample s. Conclusion Oral anticoagulation care varies considerably from country to country . Findings suggest that anticoagulation clinic care ( ACC ) may provide better outcomes as assessed by international normalized ratio ( INR ) time-in-range . Physicians tend to under treat more than over treat . Finally , documentation of care is often inadequate . Condensed Abstract Oral anticoagulation management ( routine medical care or anticoagulation clinic care ) was retrospectively assessed in 5 countries using a uniform , structured assessment tool . Major management differences were detected , especially between anticoagulation clinic care and routine care . Documentation was often a problem in the latter setting . Less time in therapeutic INR range was noted in routine medical care . Findings suggest that anticoagulation clinic care may provide better outcomes as assessed by international normalized ratio ( INR ) time-in-range . Physicians tend to under treat more than over treat . Finally , documentation of care is often inadequate BACKGROUND In atrial fibrillation ( AF ) patients stroke is nearly twice as likely to be fatal as non-AF patients and functional deficits are more likely to be severe among survivors . The incidence of stroke among AF patients is greatly reduced by oral anticoagulant treatment ( OAT ) . However , fluctuation of anticoagulation levels is intrinsically related to OAT and often international normalized ratio ( INR ) is out of the therapeutic range . METHODS Since the " anticoagulation history " is an ongoing process , we performed this prospect i ve study in 578 AF patients to investigate the role of the whole quality of OAT and of INR levels at the occurrence of transient ischemic attack ( TIA ) or stroke on the severity of cerebral ischemia . RESULTS During follow-up 13 patients had TIA and 18 had stroke ( rate 1.67 x 100 pt/years ) . In relation to the quality of anticoagulant treatment , no significant differences were found in the time spent below and within the intended therapeutic range , between patients with and without TIA/stroke . Patients with TIA/stroke spent a longer time above the intended therapeutic range with respect to other patients , even if this difference was not confirmed at multivariate analysis . Forty-six percent of patients with TIA and 66 % of patients with stroke had INR > or=2 at the occurrence of ischemic event . CONCLUSION The severity of stroke was not related to the whole quality of anticoagulation or to INR at the event BACKGROUND RE-LY ( R and omized Evaluation of Long-term Anticoagulation Therapy ) is an international multicenter study ( 18,113 patients from 967 centers in 44 countries ) that demonstrated the ability of dabigatran to reduce the occurrence of both stroke and hemorrhage in patients who had atrial fibrillation ( AF ) with high risks of stroke compared with patients who received warfarin . From Japan , 326 patients were r and omized in RE-LY . METHODS AND RESULTS RE-LY was design ed to compare 2 fixed doses ( 110 mg or 150 mg , twice daily ) of dabigatran , each administered in a blinded manner , with open-label use of warfarin . There were no major differences in patient demographic information among the overall study population and Japanese patients . However , in Japanese patients , the proportion of prior stroke was higher but prior myocardial infa rct ion was lower than in the overall . The yearly rate for the primary endpoints ( stroke and systemic embolism ) was 1.38 , 0.67 and 2.65%/year for 110 mg and 150 mg dabigatran twice daily and warfarin , respectively . These results were similar to the overall results ( 1.54 , 1.11 and 1.71%/year for each group , respectively ) . For any bleeding , the relative risk of dabigatran at 110 mg and 150 mg twice daily over warfarin was 0.79 and 1.06 , respectively , which was similar to the findings overall ( dabigatran 110 mg twice daily : 0.78 ; 150 mg twice daily : 0.91 ) . CONCLUSIONS In RE-LY , the efficacy and safety profiles of dabigatran for Japanese AF patients at high risk of stroke were essentially the same as for the study population overall PURPOSE The purpose of this study was to evaluate whether low molecular weight heparin ( LMWH ) could be equal or more effective than conventional oral anticoagulants ( OAs ) in the long-term treatment of deep venous thrombosis ( DVT ) . METHODS One hundred fifty-eight patients with symptomatic DVT of the lower limbs confirmed by means of duplex ultrasound scan were r and omized to receive 3 to 6 months ' treatment with nadroparine calcium or acenocoumarol . Quantitative and qualitative duplex scan scoring systems were used to study the evolution of thrombosis in both groups at 1 , 3 , 6 , and 12 months . RESULTS During the 12-month surveillance period , two ( 2.5 % ) of the 81 patients who received LMWH and seven ( 9 % ) of the 77 patients who received OAs had recurrence of venous thrombosis ( not significant ) . In the LMWH group no cases of major bleeding were found , and four cases ( 5.2 % ) occurred in the OA group ( not significant ) . The mortality rate was nine ( 11.1 % ) in the LMWH group and 7.8 % in the OA group ( not significant ) . The quantitative mean duplex scan score decreased in both groups during the follow-up and had statistical significance after long-term LMWH treatment on iliofemoral DVT ( 1 , 3 , 6 , and 12 months ) , femoropopliteal DVT ( 1 - 3 months ) , and infrapopliteal DVT ( first month ) . Duplex scan evaluation showed that the rate of venous recanalization significantly increased in the common femoral vein at 6 and at 12 months and during each point of follow-up in the superficial and popliteal veins in the LMWH group . Reflux was significantly less frequent in communicating veins after LMWH treatment ( 17.9 % vs 32.2 % in the OA group ) . The reflux rates in the superficial ( 22.4 % in the LMWH group , 30.6 % in OA group ) and deep ( 13.4 % vs 17.7 % ) venous system showed no significant differences between groups . CONCLUSIONS The unmonitored subcutaneous administration of nadroparine in fixed daily doses was more effective than oral acenocoumarol with laboratory control adjustment in achieving recanalization of leg thrombi . With nadroparine , there was less late valvular communicating vein insufficiency , and it was at least as efficacious and safe as oral anticoagulants after long-term administration . These results suggest that LMWHs may therefore represent a real therapeutic advance in the long-term management of DVT OBJECTIVES We sought to compare the tolerability and safety of three fixed doses of ximelagatran versus warfarin in patients with nonvalvular atrial fibrillation ( NVAF ) . BACKGROUND Anticoagulants such as warfarin lower the risk of stroke in patients with NVAF . Ximelagatran is a novel , oral direct thrombin inhibitor with predictable pharmacokinetics and no known food or pharmacokinetic drug interactions . METHODS This was a 12-week , r and omized , parallel-group , dose-guiding study of NVAF patients with at least one additional risk factor for stroke . The primary end point was the number of thromboembolic events and bleedings . Three groups received ximelagatran ( n = 187 ) at 20 , 40 , or 60 mg twice daily , given in a double-blind fashion , without routine coagulation monitoring . In a fourth group , warfarin ( n = 67 ) was managed and monitored according to normal routines , aim ing for an International Normalized Ratio of 2.0 to 3.0 . RESULTS A total of 254 patients received study drug . One ischemic stroke ( nonfatal ) and one transient ischemic attack ( TIA ) occurred in the ximelagatran group . Two TIAs occurred in the warfarin group . No major bleeds were observed in the ximelagatran group . One major bleed occurred in a warfarin-treated patient . The number of minor and multiple minor bleeds was low , but there was a slight increase by ximelagatran dose . The 60-mg dose result ed in the same number of bleeding events as that with warfarin . S-alanine aminotransferase was increased in eight patients ( 4.3 % ) taking ximelagatran , but normalized with continuous treatment or cessation of the drug . CONCLUSIONS Fixed oral doses of ximelagatran up to 60 mg twice daily were well tolerated , without the need for dose adjustment or coagulation monitoring BACKGROUND Warfarin sodium reduces stroke risk in patients with atrial fibrillation , but international normalized ratio ( INR ) monitoring is required . Target INRs are frequently not achieved , and the risk of death , bleeding , myocardial infa rct ion ( MI ) , and stroke or systemic embolism event ( SEE ) may be related to INR control . METHODS We analyzed the relationship between INR control and the rates of death , bleeding , MI , and stroke or SEE among 3587 patients with atrial fibrillation r and omized to receive warfarin treatment in the SPORTIF ( Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation ) III and V trials . The mean+/-SD follow-up was 16.6 + /- 6.3 months . Patients were divided into 3 equal groups ( those with good control [ > 75 % ] , those with moderate control [ 60%-75 % ] , or those with poor control [ < 60 % ] ) according to the percentage time with an INR of 2.0 to 3.0 . Outcomes were compared according to INR control . The main outcome measures were death , bleeding , MI , and stroke or SEE . RESULTS The poor control group had higher rates of annual mortality ( 4.20 % ) and major bleeding ( 3.85 % ) compared with the moderate control group ( 1.84 % and 1.96 % , respectively ) and the good control group ( 1.69 % and 1.58 % , respectively ) ( P<.01 for all ) . Compared with the good control group , the poor control group had higher rates of MI ( 1.38 % vs 0.62 % , P = .04 ) and of stroke or SEE ( 2.10 % vs 1.07 % , P = .02 ) . CONCLUSIONS In patients with atrial fibrillation taking warfarin , the risks of death , MI , major bleeding , and stroke or SEE are related to INR control . Good INR control is important to improve patient outcomes OBJECTIVES The aim of the present study was to evaluate whether elevated D-dimer levels can predict subsequent thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy . BACKGROUND Atrial fibrillation is associated with hemostatic abnormalities even during oral anticoagulant therapy . D-dimer levels reflect a pro-thrombogenic state and thus might serve as a marker of thromboembolic and cardiovascular events . METHODS This was a single-center , prospect i ve , observational study . Patients with atrial fibrillation ( 269 patients , age 74 + /- 9 years , 160 paroxysmal atrial fibrillation ) treated with warfarin ( target prothrombin time-international normalized ratio : 1.5 to 3.0 ) were included . D-dimer levels were measured to assess the relationship of this parameter with subsequent thromboembolic and cardiovascular events . End points were thromboembolic events and combined cardiovascular events ( thromboembolic events , cerebral hemorrhage , myocardial infa rct ion , cardiovascular death ) . RESULTS D-dimer levels were elevated ( > or = 0.5 microg/ml ) in 63 ( 23 % ) patients . During an average follow-up period of 756 + /- 221 days , 10 ( 1.8%/year ) thromboembolic events ( 8 ischemic strokes , 1 transient ischemic attack , and 1 peripheral embolism ) and 27 ( 4.8%/year ) combined cardiovascular events ( 10 thromboembolisms , 9 deaths from heart failure , 3 sudden deaths , 2 myocardial infa rct ions , and 3 cerebral hemorrhages ) occurred . Patients with elevated D-dimer levels experienced higher thromboembolic and combined cardiovascular events . Cox proportional hazard model revealed that elevated D-dimer levels were associated with both thromboembolic ( p < 0.01 , hazard ratio : 15.8 ; 95 % confidence interval : 3.33 to 75.5 ) and combined cardiovascular ( p < 0.01 , hazard ratio : 7.64 ; 95 % confidence interval : 3.42 to 17.1 ) events . CONCLUSIONS D-dimer might be a useful marker of both thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy Due to heightened risk for thromboembolic complications , nonvalvular atrial fibrillation ( NVAF ) presents an absolute indication for long-term oral anticoagulation therapy . This was an observational , analytical , r and omised , one-year clinical study , conducted in the Blood Transfusion Institute Sarajevo , Bosnia & Herzegovina . The aim of this study was to present the oral anticoagulation treatment in terms of International normalised ratio ( INR ) monitoring and warfarin/acenocoumarol dose titration in 117 patients with NVAF . INR values , the doses of warfarin and acenocoumarol , as well as the tendency and adequacy of their changes were monitored . Percentages of the therapeutic INR values were 51,77 % and 53,62 % , subtherapeutic 42,84 % and 35,86 % , and supratherapeutic 5,39 % and 10,53 % for the warfarin and acenocoumarol treatment , respectively . The average total weekly doses ( TWD ) which most frequently achieved the therapeutic INR values were 27,89+/-12,34 mg and 20,44+/-9,94 mg , for warfarin and acenocoumarol , respectively . The dose changes with the INR values 1,7 or lower/3,3 or higher were omitted in 13,46 % and 15,63 % , and with the INR values 1,8 - 3,2 were noted in 8,62 % and 13,48 % of all the check-up visits in the warfarin and acenocoumarol group , respectively . The annual dose changes were noted in 24,65 % and 31,41 % , and the daily dose changes in 74,43 % and 73,36 % of all the check-up visits of warfarin and acenocoumarol group , respectively . We can conclude that the management of the oral anticoagulation treatment in our country is in accordance with the relevant recommendations , but with the present tendency toward underdosing and unnecessary frequent dose changing BACKGROUND Anticoagulation control quality affects the incidence of thromboembolic events in atrial fibrillation ( AF ) patients . However , the effects of anticoagulation control quality on the prothrombotic state of AF patients are unclear . METHODS AND RESULTS Ninety-five AF patients who had been treated with warfarin were prospect ively followed-up for 449 ± 92 days . We analyzed whether time in the therapeutic range ( TTR ) of the international normalized ratio ( INR ) of prothrombin time , percentage of INR values in the range ( % INR ) , and coefficient of variation of INR values ( CV-INR ) were related to D-dimer levels . The mean values of TTR , % INR , and CV-INR were 62 % , 59 % , and 0.19 , respectively , and their median values were 67 % , 63 % , and 0.19 , respectively . TTR was significantly correlated with % INR ( R(2 ) = 0.917 , P<0.01 ) , but not with CV-INR ( R(2 ) = 0.050 , P = 0.26 ) . The mean and median D-dimer levels were 0.79 and 0.60 µg/ml , respectively . Low TTR , low % INR , and high CV-INR were found to contribute to high D-dimer levels ( P = 0.02 , 0.03 , and 0.02 , respectively ) . CONCLUSIONS In AF patients treated with warfarin , not only the duration outside the target INR range , but also the fluctuation in INR level may influence the prothrombotic state BACKGROUND Guidelines recommend warfarin as the st and ard of care for patients with atrial fibrillation ( AF ) at moderate or high risk for stroke . This phase II study assessed the effects of 2 doses of the factor Xa inhibitor apixaban vs. warfarin in Japanese patients with non-valvular AF . The composite primary endpoint was major and clinical ly relevant non-major ( CRNM ) bleeding . METHODS AND RESULTS Two hundred and twenty-two patients with AF and 1 or more additional risk factors for stroke were r and omized ( 1:1:1 ) to double-blind apixaban 2.5 or 5 mg b.i.d . or open-label warfarin ( target international normalized ratio 2.0 - 3.0 ; 2.0 - 2.6 if age ≥ 70 years ) for 12 weeks . The primary endpoint occurred in 1 patient ( 1.4 % ) in each apixaban group and 4 ( 5.3 % ) warfarin patients . There were no strokes , systemic emboli , myocardial infa rct ions , or deaths in either apixaban group . The warfarin group had 2 ischemic strokes and 1 subarachnoid hemorrhage , but there were no deaths . Major and CRNM bleeds each occurred with higher frequency in the warfarin group vs. either apixaban group . Most adverse events were mild or moderate . No patients had hepatic aminotransferase elevations greater than 3 times the upper limit of normal . CONCLUSIONS In Japanese patients with AF , apixaban 2.5 and 5 mg b.i.d . were well tolerated over 12 weeks . A global phase III trial , which includes Japanese patients , is ongoing ( Clinical Trials.gov Identifier NCT00787150 ) BACKGROUND In patients with venous thromboembolism ( VTE ) , identifying clinical risk factors for recurrence during the initial 3 months of anticoagulant therapy and knowledge of the time course of recurrence may help clinicians decide about the frequency of clinical surveillance and the appropriateness of outpatient treatment . METHODS Analysis of a r and omized controlled trial data base involving 1021 patients with VTE ( 750 with deep vein thrombosis [ DVT ] and 271 with pulmonary embolism [ PE ] ) who were followed up for 3 months after the start of anticoagulant therapy . All patients received initial treatment with unfractionated heparin or a low-molecular-weight heparin ( reviparin ) and a coumarin derivative starting the first or second day of treatment , with a target international normalized ratio of 2.0 to 3.0 . RESULTS Four independent clinical risk factors for recurrent VTE were identified : ( 1 ) cancer ( odds ratio [ OR ] , 2.72 ; 95 % confidence interval [ CI ] , 1 . 39 - 5.32 ) , ( 2 ) chronic cardiovascular disease ( OR , 2.27 ; 95 % CI , 1 . 08 - 4.97 ) , ( 3 ) chronic respiratory disease ( OR , 1.91 ; 95 % CI , 0.85 - 4 . 26 ) , and ( 4 ) other clinical ly significant medical disease ( OR , 1.79 ; 95 % CI , 1.00 - 3.21 ) . Older age was associated with a decreased risk for recurrent VTE ( OR , 0.76 ; 95 % CI , 0.64 - 0.92 ) . Previous VTE , sex , and idiopathic VTE were not risk factors for recurrence . In patients with DVT or PE , there was no significant difference in the rates of recurrent nonfatal VTE ( 4.8 % vs 4.1 % ; P = .62 ) , major bleeding ( 2.9 % vs 2.2 % ; P = .53 ) , and non-VTE death ( 6.4 % vs 7.8 % ; P = .45 ) , but recurrent fatal PE was more frequent in patients with PE than DVT ( 2 . 2 % vs 0 % ; P<.01 ) . There was a clustering of recurrent VTE episodes during the initial 2 to 3 weeks after the start of treatment . CONCLUSIONS During the initial 3 months of anticoagulant therapy , recurrent VTE is more likely to occur in patients with cancer , chronic cardiovascular disease , chronic respiratory disease , or other clinical ly significant medical disease . Patients with PE are as likely to develop recurrent VTE as those with DVT ; however , recurrence is more likely to be fatal in patients who initially present with PE . Arch Intern Med . 2000;160:3431 - 3436 BACKGROUND Edoxaban is a once-daily ( QD ) oral , direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation ( NVAF ) . The aim of this study was to evaluate the safety of edoxaban in Japanese patients with NVAF . METHODS AND RESULTS A total of 536 NVAF patients ( CHADS2 ≥1 ) were r and omized to receive double-blinded edoxaban 30 , 45 , or 60 mg QD or open-label warfarin ( international normalized ratio [ INR ] 2.0 - 3.0 for age < 70 years ; 1.6 - 2.6 for age ≥70 years ) for 12 weeks . The primary endpoint was the incidence of all bleeding events ( major , clinical ly relevant non-major , and minor bleeds ) . Patients underwent CT and /or MRI to assess asymptomatic intracranial hemorrhage ( ICH ) . Secondary endpoints included thromboembolic events and pharmacodynamic indices . The mean incidence of all bleeding events for edoxaban 30 , 45 , and 60 mg , and warfarin was 18.5 % , 22.4 % , 27.7 % , and 20.0 % , respectively . There were no statistically significant differences among the edoxaban groups and no significant differences from the warfarin group . There were no asymptomatic ICH events in any group . One episode of cerebral infa rct ion was observed in the edoxaban 45-mg group . Subgroup analysis suggested low body weight ( ≤60 kg ) was associated with higher bleeding risk . CONCLUSIONS Edoxaban 30 , 45 , and 60 mg QD in patients with NVAF was associated with a numerical increase in all bleeding across the dose range , but this was not statistically significant , nor was any dose compared with warfarin CONTEXT In patients with nonvalvular atrial fibrillation , warfarin prevents ischemic stroke , but dose adjustment , coagulation monitoring , and bleeding limit its use . OBJECTIVE To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , multicenter trial ( 2000 - 2001 ) conducted at 409 North American sites , involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors . INTERVENTIONS Adjusted-dose warfarin ( aim ing for an international normalized ratio [ INR ] 2.0 to 3.0 ) or fixed-dose oral ximelagatran , 36 mg twice daily . MAIN OUTCOME MEASURES The primary end point was all strokes ( ischemic or hemorrhagic ) and systemic embolic events . The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0 % per year according to the intention-to-treat model . RESULTS During 6405 patient-years ( mean 20 months ) of follow-up , 88 patients experienced primary events . The mean ( SD ) INR with warfarin ( 2.4 [ 0.8 ] ) was within target during 68 % of the treatment period . The primary event rate with ximelagatran was 1.6 % per year and with warfarin was 1.2 % per year ( absolute difference , 0.45 % per year ; 95 % confidence interval , -0.13 % to 1.03 % per year ; P<.001 for the predefined noninferiority hypothesis ) . When all-cause mortality was included in addition to stroke and systemic embolic events , the rate difference was 0.10 % per year ( 95 % confidence interval , -0.97 % to 1.2 % per year ; P = .86 ) . There was no difference between treatment groups in rates of major bleeding , but total bleeding ( major and minor ) was lower with ximelagatran ( 37 % vs 47 % per year ; 95 % confidence interval for the difference , -14 % to -6.0 % per year ; P<.001 ) . Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0 % of patients treated with ximelagatran , usually within 6 months and typically declined whether or not treatment continued ; however , one case of documented fatal liver disease and one other suggestive case occurred . CONCLUSIONS The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy , but the potential for hepatotoxicity requires further investigation BACKGROUND AND AIM Several factors are associated with an increased risk of recurrent venous thromboembolism ( VTE ) . The aim of the study was to investigate whether the quality of oral anticoagulation therapy ( OAT ) is a long-term risk factor for recurrence of VTE after OAT interruption . METHODS AND RESULTS A total of 297 patients ( 170 males ) with a recent acute unprovoked VTE episode were prospect ively monitored during OAT in our anticoagulation clinic and followed up for 21 months after OAT interruption . Recurrent events were recorded in 42 subjects for 493 years of follow-up [ 14.1 % of patients ; 8.5 % patient-years ( pt-y ) ] after OAT withdrawal . The rate of recurrence was not correlated to OAT duration . Subjects experiencing recurrence after OAT interruption had spent significantly more time at markedly subtherapeutic international normalized ratio ( INR ) levels ( < 1.5 ) and less time within the therapeutic range ( 2.0 - 3.0 INR ) during OAT . Relative risk ( RR ) of recurrence was significantly higher [ 2.77 ( 95 % confidence interval ( CI ) 1.49 - 5.18 ; P = 0.001 ) and 2.70 ( 95 % CI 1.39 - 5.25 ; P = 0.003 ) at univariate and multivariate analysis , respectively ] in those who spent more time ( upper quintile ) at INR values < 1.5 , being especially evident in the first 90 days of OAT . RR was significantly higher at univariate [ 2.05 ( 95 % CI 1.07 - 3.96 ; P = 0.031 ) ] but not at multivariate [ 1.98 ( 95 % CI 0.98 - 4.0 ; P = 0.056 ) ] analysis when the entire OAT period was considered . Subjects in the upper quintile of time spent at INR values < 1.5 had significantly higher D-dimer values when OAT was stopped and after 3 months . CONCLUSIONS The amount of time that subjects with an acute unprovoked VTE event spend at near-normal INR values ( < 1.5 ) during the first 3 months of treatment is associated with higher D-dimer values measured during OAT and after its interruption and is a significant risk factor for late VTE recurrence BACKGROUND One of the causes of unstable anticoagulant control in patients using vitamin K antagonists is a fluctuating intake of vitamin K. Research suggests that patients with a low dietary intake of vitamin K have a less stable anticoagulant control than patients with a higher intake . OBJECTIVES To study whether supplementation with a low daily dose of vitamin K improves anticoagulant control . METHODS We performed a double-blind , r and omized , placebo-controlled trial . 200 patients of the Leiden anticoagulation clinic , who used the vitamin K antagonist phenprocoumon , were r and omized to receive either adjusted-dose phenprocoumon and 100 mug vitamin K once daily or adjusted-dose phenprocoumon and a placebo . Treatment duration was 24 weeks . The primary outcome was the percentage of time the International Normalized Ratio was within the therapeutic range . RESULTS The time in the therapeutic range was 85.5 % in the placebo group and 89.5 % in the vitamin K group ( adjusted difference 3.6 % ; 95 % CI -0.8 % to 8.0 % ) . The time below the therapeutic range was 3.1 % in the placebo group and 2.1 % in the vitamin K group ( adjusted difference -0.7 % ; 95 % CI -2.5 % to 1.1 % ) and the time above the therapeutic range was 11.4 % in the placebo group and 8.5 % in the vitamin K group ( adjusted difference -2.9 % ; 95 % CI -6.9 % to 1.1 % ) . The relative risk ( RR ) of a maximal stability in the vitamin K group compared to the placebo group was 1.8 ( 95 % , CI 1.1 - 2.7 ) . CONCLUSION Supplementation of vitamin K antagonists with 100 mug vitamin K improves stability of anticoagulant therapy . Because the risk of side effects is inversely related to anticoagulant stability , such an improvement is likely to reduce the number of bleeding and thrombotic events The efficacy of adjusted-dose oral anticoagulant treatment ( OAT ) in the prevention of stroke in atrial fibrillation ( AF ) is well documented . Available data show that AF patients are widely heterogeneous in terms of ischaemic stroke risk . The role of female gender as a predictor of stroke risk is inconsistent , in particular it is unclear if warfarin treatment is able to prevent stroke equally in both sexes . We performed a prospect i ve study on 780 AF patients on OAT , followed by an Anticoagulation Clinic , to evaluate if female gender is a risk factor for stroke among patients on OAT and if the quality of anticoagulation is different between genders . No difference was found in relation to the quality of anticoagulation between genders ( p=0.5 ) . During follow-up 33 patients had major bleedings ( rate 1.37 x 100 pt/yrs ) but no difference was found between genders in bleeding risk . Forty patients had ischaemic events [ rate 1.66 x 100 pt/yrs ; males rate 1.2 x 100 pt/yrs ; females rate 2.43 x 100 pt/yrs ; p=0.042 ; relative risk ( RR ) of females vs. males 2.0 ( 95 % confidence interval [ CI ] 1.3 - 3.1 ) ; p= 0.004 ] . The higher rate of ischaemic events in females with respect to males was confirmed at Cox regression analysis after correction for age ( p=0.009 ) . In addition , strokes occurring in females were more disabling , and RR for severe and fatal stroke , defined according to Modified Rankin scale , of females vs. males was 3.1 ( 95 % CI 1.3 - 6.5 ; p=0.001 ) . In conclusion , our data show a higher risk of stroke in anticoagulated AF females with respect to males , despite a similar quality of anticoagulation Oral anticoagulant therapy has been shown to be effective for several indications . The optimal intensity of anticoagulation for each indication , however , is largely unknown . To determine this optimal intensity , r and omised clinical trials are conducted in which two target levels of anticoagulation are compared . This approach is inefficient , since the choice of the target levels will be arbitrary . Moreover , the achieved intensity is not taken into account . We propose a method to determine the optimal achieved intensity of anticoagulation . This method can be applied within a clinical trial as an " efficacy- analysis " , but also on data gathered in day-to-day patient care . In this method , INR-specific incidence rates of events , either thromboembolic or hemorrhagic , are calculated . The numerator of the incidence rate is based on data on the INR at the time of the event . The denominator consists of the person-time at each INR value , summed over all patients , and is calculated from all INR measurements of all patients during the follow-up interval . This INR-specific person-time is calculated with the assumption of a linear increase or decrease between two consecutive INR determinations . Since the incidence rates may be substratified on covariates , efficient assessment of the effects of other factors ( e.g. age , sex , comedication ) by multivariate regression analysis becomes possible . This method allows the determination of the optimal pharmacological effects of anticoagulation , which can form a rational starting point for choosing the target levels in subsequent clinical trials Oral anticoagulants ( OA ) are the drug of choice for stroke prevention in patients with non-rheumatic atrial fibrillation ( NRAF ) . This clear benefit/risk ratio comes from several r and omized clinical trials ( RCT ) in which highly selected patients were strictly monitored . The aim of this study was to ascertain whether the safety of OA was also obtained outside the setting of clinical trials in consecutive patients starting treatment and routinely followed at Italian anticoagulation clinics . A total of 433 patients with NRAF were enrolled in the ISCOAT study and followed up for a mean of 1.4 years . Two patients ( 0.3 % per year ) suffered from a complete non-fatal ischemic stroke , 8 patients ( 1.3 % per year ) died of thrombosis-related vascular death , and 11 patients ( 11 events , 1.8 % per year ) suffered from major bleedings ( 2 fatal ) . Major bleeding occurred more frequently in patients > 75 years of age ( 6 events , 5.1 % per year ) than in younger patients ( 5 events , 1.0 % per year ) . The cumulative incidence of major bleeding in patients over 75 years of age ( 10.8 % ; 95 % CI , 1.8 - 19.8 ) was significantly higher than in younger patients ( 2.8 % ; 95 % CI , 0.3 - 5.3 , p = 0.006 ) . Major primary bleeding unrelated to organic lesions ( 7 patients , 1 male and 6 females ) occurred in 5 elderly patients ( > 75 years old ) with a cumulative incidence ( 9.6 % ; 95 % CI 0.8 - 18.4 ) significantly higher than in younger patients ( 1.2 % ; 95 % CI , 0 - 3.0 , p = 0.0003 ) . Univariate analysis revealed a higher frequency of major primary bleeding in females , in diabetic patients and in in those who had suffered a previous thromboembolic event . Multivariate analysis revealed that only age grater than 75 years was independently related to major primary bleedings ( RR 6.6 ; 95 % CI 1.2 - 37 , p = 0.032 ) . Minor bleedings ( n = 27 ) were not more frequent in elderly patients ( 6 % vs 4 % per year , p = ns ) . Patients were kept at optimal intensity of treatment for 63 % of the time . These data confirm the efficacy of OA but identify elderly patients as a high risk group of major bleeding Background / Aims : Low rates and poor quality of oral anticoagulation ( OAC ) have been reported in patients with atrial fibrillation ( AF ) . We therefore sought to investigate the prescription patterns at discharge , adherence and quality of OAC in cerebrovascular disease patients with AF . Methods : Consecutive ischemic stroke ( IS ) and transient ischemic attack ( TIA ) patients were prospect ively documented in 11 German stroke centers . A central telephone follow-up after 1–2 years assessed the current antithrombotic medication and results of coagulation checks . Results : Of 1,463 surviving patients with AF , 30.5 % were discharged on OAC and 13.9 % on high-dose heparin . Of 329 AF patients discharged on OAC and with consent for follow-up , 88.7 % of surviving patients were still on OAC at the follow-up . Of these , 52.7 % reported coagulation values out of the therapeutic range during the preceding 3 months . A recurrent IS was seen in 9 patients ( 2.1%/year ) and an intracranial hemorrhage in 2 . Conclusion : We found an important underuse of OAC following TIA or IS mainly in older patients and with greater stroke-related disability . Although the reported coagulation checks showed an only moderate rate within therapeutic ranges , safety and efficacy of OAC in this cohort seem comparable to previous r and omized and observational trials in AF patients AIMS In atrial fibrillation ( AF ) patients , age > or=75 years is one of the major risk factors for stroke . However , it is not clear if an upper limit for the indication to OAT exists . METHODS AND RESULTS For this reason , we performed a prospect i ve study on 290 AF patients on OAT aged > or=75 years ( median age 82 years , total follow-up period 814 pt/years ) followed by our Anticoagulation Clinic . Seventeen major bleeding events were recorded ( rate 2.1 x 100 pt/years ) , 11 of which cerebral ( 1.35 x 100 pt/years ) . The occurrence of major bleedings was associated with history of previous TIA or stroke [ OR 3.4 ( 1.1 - 12.5 ) , p=0.01 ] and with diabetes [ OR 4.4 ( 1.3 - 14.7 ) p=0.01 ] . We found a trend to a progressive increase in the rate of bleeding risk with the increase of the CHADS2 score : patients with score 4 - 6 showed a rate of 3.4 x 100 pt/years with respect to 1.5 x 100 pt/years of patients with lower score . Number Needed to Harm ( NNH ) was calculated in relation to different classes of age ( 75 - 89 , 80 - 84 , > or=85 years ) and to CHADS2 score . For patients in CHADS2 score 1 - 3 NNH remained stable across the different age classes . Instead for patients in CHADS2 score 4 - 6 , NNH varied among the 3 groups of ages , reaching a value of 10 in patients > or=85 years . CONCLUSION Our data suggest that : 1 ) in AF patients older than 75 years with CHADS2 score 1 - 3 the risk of bleeding is low , 2 ) in AF patients > 85 years with CHADS2 4 - 6 the risk of bleeding is high so that the use of OAT should be highly individualised BACKGROUND Anticoagulants are more effective than antiplatelet agents at reducing stroke risk in patients with atrial fibrillation , but whether this benefit outweighs the increased risk of bleeding in elderly patients is unknown . We assessed whether warfarin reduced risk of major stroke , arterial embolism , or other intracranial haemorrhage compared with aspirin in elderly patients . METHODS 973 patients aged 75 years or over ( mean age 81.5 years , SD 4.2 ) with atrial fibrillation were recruited from primary care and r and omly assigned to warfarin ( target international normalised ratio 2 - 3 ) or aspirin ( 75 mg per day ) . Follow-up was for a mean of 2.7 years ( SD 1.2 ) . The primary endpoint was fatal or disabling stroke ( ischaemic or haemorrhagic ) , intracranial haemorrhage , or clinical ly significant arterial embolism . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N89345269 . FINDINGS There were 24 primary events ( 21 strokes , two other intracranial haemorrhages , and one systemic embolus ) in people assigned to warfarin and 48 primary events ( 44 strokes , one other intracranial haemorrhage , and three systemic emboli ) in people assigned to aspirin ( yearly risk 1.8%vs 3.8 % , relative risk 0.48 , 95 % CI 0.28 - 0.80 , p=0.003 ; absolute yearly risk reduction 2 % , 95 % CI 0.7 - 3.2 ) . Yearly risk of extracranial haemorrhage was 1.4 % ( warfarin ) versus 1.6 % ( aspirin ) ( relative risk 0.87 , 0.43 - 1.73 ; absolute risk reduction 0.2 % , -0.7 to 1.2 ) . INTERPRETATION These data support the use of anticoagulation therapy for people aged over 75 who have atrial fibrillation , unless there are contraindications or the patient decides that the benefits are not worth the inconvenience R and omized trials have indicated that well-managed anticoagulation with warfarin could prevent more than half of the strokes related to atrial fibrillation . However , many patients with atrial fibrillation who are eligible for this therapy either do not receive it or are not maintained within an optimal prothrombin time-international normalized ratio ( INR ) range . We sought to determine whether an anticoagulation service within a managed care organization would be a feasible alternative for providing anticoagulation care . We performed a multi-site r and omized trial in six large managed care organizations in the United States . Subjects were aged 65 years or older and had nonvalvular atrial fibrillation . At each site , physician practice s were divided into two geographically defined practice clusters ; each site was r and omly assigned to have one intervention and one control cluster . The intervention cluster received an anticoagulation service that satisfied specifications for high- quality anticoagulation care and was coordinated through the managed care organization . Control clusters continued with their usual provider-based care . We measured the proportion of time that warfarin-treated patients in each of the clusters ( intervention and control ) were in the target range for the INR at baseline , and again during a follow-up period . Five of the six selected sites succeeded at developing an anticoagulation service . Patients in the intervention and control clusters had similar demographic characteristics , contraindications to warfarin , and risk factors for stroke . Among patients ( n = 144 in the intervention clusters ; n = 118 in the control clusters ) for whom data were available during the baseline and follow-up periods , the changes in percentages of time in the target range were similar for those in the intervention clusters ( baseline : 47.7 % ; follow-up : 55.6 % ) and in the control clusters ( baseline : 49.1 % ; follow-up : 52.3 % ; intervention effect : 5 % ; 95 % confidence interval : -5 % to 14 % ; P = 0.32 ) . Although it was feasible in a managed care organization to implement anticoagulation services that were tailored to local circumstances , provision of this service did not improve anticoagulation care compared with usual care . The effect of the anticoagulation service was limited by the utilization of the service , the degree to which the referring physician supports strict adherence to recommended target ranges for the INR , and the ability of the anticoagulation service to identify and to respond to out-of-range values promptly Der Großteil der Patienten mit Vorhofflimmern ist durch ein thromboembolisches Ereignis gefährdet . Die Komplikationsrate kann durch eine effiziente Antikoagulation um zwei Drittel reduziert werden . Ob die Qualität der Therapieüberwachung durch das Selbstmanagement bei Patienten mit Vorhofflimmern ( SMAAF-Studie ) i m Vergleich zur herkömmlichen bei Hausarzt betreuten Patienten verbessert werden kann , war Gegenst and dieser prospektiven Multicenter- Studie . Bei Eignung zum Selbstmanagement sollten 2 000 Patienten in die beiden Studienarme r and omisiert werden . I m Untersuchungszeitraum von 12/99 bis 07/01 gaben lediglich 202 Patienten ( 64,3±9,2 Jahre , 69,3 % Männer ) ihr Einverständnis . Bei vorzeitigem Studienabbruch aufgrund zu niedriger Patientenzahl beschränkt sich der Gruppenvergleich auf die Auswertung gemessener INR-Werte mittels zweiseitigem t-Test . Von den 202 eingeschlossenen Patienten wurden 101 der Selbstmanagement-Gruppe ( 64,6±9,6 Jahre , 71,4 % Männer ) und 101 ( 64,1±8,9 Jahre , 61,4 % Männer , n.s . ) der Hausarztgruppe zugeordnet . Die Gesamtzahl der INR-Messungen betrug 2 865 , wobei 2 072 auf Patienten i m Selbstmanagement und 793 auf die Hausarztgruppe entfielen . Die Werte lagen bei Patienten i m Selbstmanagement mit 67,8 % i m Vergleich zur Hausarztgruppe mit 58,5 % signifikant häufiger ( p=0,0061 ) i m Zielbereich . Bezüglich der Verweildauer i m therapeutischen Bereich best and zwar ein Trend zugunsten der Selbstmanagement-Gruppe , jedoch kein signifikanter Unterschied ( 178,8±126 Tage vs. 155,9±118,4 Tage ) . In der Selbstmanagement- Gruppe traten zwei schwere Blutungen , in der Hausarztgruppe ein thromboembolisches Ereignis auf . Die Therapieüberwachung der oralen Antikoagulation durch das INR-Selbstmanagement ist bei Patienten mit Vorhofflimmern der Betreuung durch den Hausarzt nicht unterlegen . Most patients with atrial fibrillation are at risk of suffering thromboembolic events . This risk can be reduced by twothirds by efficient anticoagulation . This prospect i ve multi-center trial investigated whether the quality of treatment can be improved by self-management in patients with atrial fibrillations ( SMAAF Study ) compared to conventional patient management by the family doctor . Two thous and patients suitable for self-manage- ment were to be r and omized into the two arms of the study . In the period of investigation from December 1999 to July 2001 , only 202 patients ( 64.3±9.2 years , 69.3 % men ) consented to participate . The study was discontinued prematurely since the number of patients was too low . As a consequence , the group comparison is confined to the evaluation of the INR values measured using the two-tailed t test . Of the 202 patients included , 101 were assigned to the self-management group ( 64.6±9.6 years , 71.4 % men ) and 101 ( 64.1±8.9 years , 61.4 % men , n.s . ) were assigned to the group managed by the family doctor . The total number of INR measurements was 2 865 . This comprised 2 072 measurements in patients under self-management and 793 in the family doctor group . The values were within the target range significantly more frequently ( p=0.0061 ) in patients under self-management ( 67.8 % ) as compared to the family doctor group ( 58.5 % ) . There was a trend with regard to the time within target range , but the difference was not significant ( 178.8±126 days as compared to 155.9±118.4 days ) . In the self-management group , there were two severe hemorrhages , and there was one thromboembolic event in the family doctor group . Management of oral anticoagulation by INR self-management in patients with atrial fibrillation is not inferior to conventional care BACKGROUND Atrial fibrillation is a common problem in older people . The evidence base for the safety of warfarin and aspirin in atrial fibrillation is largely derived from selective research studies and secondary care . Further assessment of the safety of warfarin in older people with atrial fibrillation in routine primary care is needed . AIM To measure the complication rates and adequacy of warfarin control in a cohort of patients with atrial fibrillation managed in primary care and compare them with published data from controlled trials and community patients with atrial fibrillation not receiving warfarin . DESIGN OF STUDY Retrospective review of regional cohort . SETTING Twenty-seven general practice s in southwest Scotl and . METHOD Case note review of 601 patients previously identified as having atrial fibrillation by GPs . RESULTS The average age of our cohort was 77 years at recruitment . Two hundred and sixty-four ( 44 % ) patients died within 5 years of follow up . Three hundred and nine of the 601 ( 51 % ) patients with atrial fibrillation took warfarin at some stage during this study . INR ( international normalised ratio ) was maintained between 2 and 3 for 68 % of the time . Bleeding risk was higher in patients taking warfarin than in those on aspirin or no antithrombotic therapy ( warfarin 9.0 % per year versus aspirin 4.7 % per year versus no therapy 4.6 % per year ) . The annual risk of any bleeding complication on warfarin ( 9 % ) was similar to that recorded in r and omised trials ( 9.2 % ) whereas the annual risk of severe bleeding was approximately double ( 2.6 versus 1.3 % ) . CONCLUSION Adequacy of anticoagulant control was broadly comparable to that reported in clinical trials , whereas the risk of severe bleeding was higher , possibly reflecting the older age and the comorbidities of our unselected cohort BACKGROUND Oral anticoagulation therapy ( OAT ) , which aims to prevent thromboembolism in patients with atrial fibrillation ( AF ) , is underused in subjects who are over the age of 80 yr because of the associated bleeding risk . The aim of this study was to evaluate the efficacy and safety of OAT with low ( 2.0 ) vs. st and ard ( 2.5 ) PT/international normalised ratio ( INR ) targets in patients over the age of 80 . MATERIAL S AND METHODS Of 233 patients aged 80 yr or older with AF on OAT , 58 had unstable PT/INR values and achieved reduced targets . These patients were enrolled as a group ( A ) in a case-control study and were treated with a low ( 2.0 ) PT/INR target . They were compared with a second group ( B ) of 58 additional patients who were matched for age and CHADS scores and treated with a st and ard ( 2.5 ) PT/INR target . Group A OAT parameters were also compared before and after the PT/INR reduction . The time in the therapeutic range ( TTR% ) , PT/INR values > 5 , haemorrhages and strokes were prospect ively evaluated in the two groups after 2 yr of follow-up . RESULTS Of the 116 enrolled patients , 55 group A and 57 group B patients were evaluated . The TTR was 72.59 % in group A and 64.43 % in group B ( P < 0.01 ) . The percent of PT/INR values > 5 was 0.68 % for group A and 1.42 % for group B ( P < 0.05 ) . Haemorrhages and thromboses occurred only in group B patients . The before and after analysis in group A showed that a low INR target produced an increase in the TTR ( 53.05 % vs. 72.59 % ; P < 0.0001 ) and a reduction in the PT/INR values > 5 ( 1.72 % vs. 0.68 % ; P < 0.001 ) . CONCLUSIONS A low PT/INR target seems effective and safe in Italian patients with AF over the age of 80 . Further trials are needed to confirm the hypothesis generated by this study BACKGROUND The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor , such as recent surgery , than after an episode associated with a permanent , or no , risk factor . Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor . METHODS In this double-blind study , patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were r and omly assigned to continue warfarin or to placebo for an additional 2 months . Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up . RESULTS Of 84 patients assigned to placebo , five ( 6.0 % ) had recurrent venous thromboembolism , compared with three of 81 ( 3.7 % ) assigned to warfarin , result ing in an absolute risk difference of 2.3%[95 % confidence interval ( CI ) - 5.2 , 10.0 ] . The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8 % per patient-year in those who received warfarin for 1 month and 3.2 % per patient-year in those who received warfarin for 3 months ( rate difference of 3.6 % per patient-year ; 95 % CI - 3.8 , 11.0 ) . There were no major bleeds in either group . CONCLUSION Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinical ly important decrease in bleeding CONTEXT Warfarin has been shown to be highly efficacious for preventing thromboembolism in atrial fibrillation in r and omized trials , but its effectiveness and safety in clinical practice is less clear . OBJECTIVE To evaluate the effect of warfarin on risk of thromboembolism , hemorrhage , and death in atrial fibrillation within a usual care setting . DESIGN Cohort study assembled between July 1 , 1996 , and December 31 , 1997 , and followed up through August 31 , 1999 . SETTING Large integrated health care system in Northern California . PATIENTS Of 13,559 adults with nonvalvular atrial fibrillation , 11,526 were studied , 43 % of whom were women , mean age 71 years , with no known contraindications to anticoagulation at baseline . MAIN OUTCOMES Ischemic stroke , peripheral embolism , hemorrhage , and death according to warfarin use and comorbidity status , as determined by automated data bases , review of medical records , and state mortality files . RESULTS Among 11,526 patients , 397 incident thromboembolic events ( 372 ischemic strokes , 25 peripheral embolism ) occurred during 25,341 person-years of follow-up , and warfarin therapy was associated with a 51 % ( 95 % confidence interval [ CI ] , 39%-60 % ) lower risk of thromboembolism compared with no warfarin therapy ( either no antithrombotic therapy or aspirin ) after adjusting for potential confounders and likelihood of receiving warfarin . Warfarin was effective in reducing thromboembolic risk in the presence or absence of risk factors for stroke . A nested case-control analysis estimated a 64 % reduction in odds of thromboembolism with warfarin compared with no antithrombotic therapy . Warfarin was also associated with a reduced risk of all-cause mortality ( adjusted hazard ratio , 0.69 ; 95 % CI , 0.61 - 0.77 ) . Intracranial hemorrhage was uncommon , but the rate was moderately higher among those taking vs those not taking warfarin ( 0.46 vs 0.23 per 100 person-years , respectively ; P = .003 , adjusted hazard ratio , 1.97 ; 95 % CI , 1.24 - 3.13 ) . However , warfarin therapy was not associated with an increased adjusted risk of nonintracranial major hemorrhage . The effects of warfarin were similar when patients with contraindications at baseline were analyzed separately or combined with those without contraindications ( total cohort of 13,559 ) . CONCLUSIONS Warfarin is very effective for preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small . Results of r and omized trials of anticoagulation translate well into clinical care for patients with atrial fibrillation OBJECTIVE The goal of this study was to investigate the complications and control of warfarin treatment in patients with nonvalvular atrial fibrillation ( NVAF ) newly referred to an outpatient anticoagulation clinic . METHODS This study included new patients with NVAF who were referred to an anticoagulation clinic for warfarin therapy over a recruitment period of 21 months . To reflect real-world clinical practice , patient selection for anticoagulation and patient management were left to the referring physicians , who were blinded to their patients ' participation in the study . Patients were interviewed in person at the first clinic visit and then by telephone every 4 to 6 weeks . They were question ed about any bleeding or thromboembolic events . RESULTS A total of 402 patients were included ( 100 % of all new referrals over 21 months ) . The mean ( SD ) age was 72.3 ( 10.3 ) years , and 224 ( 56 % ) patients were men . The mean ( SD ) international normalized ratio ( INR ) was 2.4 ( 0.31 ) . Patients were followed up for a mean ( SD ) of 19 ( 8.1 ) months ( range , 1.0 - 31.0 months ) . They spent a mean ( SD ) 66 % ( 18.3 ) of time in the target range of INR ( ie , 2.0 - 3.0 ) . Annual event rates were 1.7 % ( 95 % CI , 0.4%-3.0 % ) for major bleeding , 16.6 % ( 95 % CI , 13.0%-20.2 % ) for minor bleeding , 1.2 % ( 95 % CI , 0.1%-2.3 % ) for ischemic stroke , and 0.3 % ( 95 % CI , 0.2%-0.8 % ) for transient ischemic attacks . There were no cases of hemorrhagic stroke or fatal bleeding . Variability of INR and number of medications were identified as risk factors for bleeding ( P = 0.03 and P = 0.001 , respectively ) . There was no significant association between age and bleeding . CONCLUSIONS Based on this analysis , the risks of long-term oral anticoagulation therapy in an outpatient anticoagulation clinic appear to reflect the results of clinical trials . Rates of ischemic stroke , major bleeding , and anticoagulation control were comparable . There was no age-related risk of complications BACKGROUND There are two approaches to the treatment of atrial fibrillation : one is cardioversion and treatment with antiarrhythmic drugs to maintain sinus rhythm , and the other is the use of rate-controlling drugs , allowing atrial fibrillation to persist . In both approaches , the use of anticoagulant drugs is recommended . METHODS We conducted a r and omized , multicenter comparison of these two treatment strategies in patients with atrial fibrillation and a high risk of stroke or death . The primary end point was overall mortality . RESULTS A total of 4060 patients ( mean [ + /-SD ] age , 69.7+/-9.0 years ) were enrolled in the study ; 70.8 percent had a history of hypertension , and 38.2 percent had coronary artery disease . Of the 3311 patients with echocardiograms , the left atrium was enlarged in 64.7 percent and left ventricular function was depressed in 26.0 percent . There were 356 deaths among the patients assigned to rhythm-control therapy and 310 deaths among those assigned to rate-control therapy ( mortality at five years , 23.8 percent and 21.3 percent , respectively ; hazard ratio , 1.15 [ 95 percent confidence interval , 0.99 to 1.34 ] ; P=0.08 ) . More patients in the rhythm-control group than in the rate-control group were hospitalized , and there were more adverse drug effects in the rhythm-control group as well . In both groups , the majority of strokes occurred after warfarin had been stopped or when the international normalized ratio was subtherapeutic . CONCLUSIONS Management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy , and there are potential advantages , such as a lower risk of adverse drug effects , with the rate-control strategy . Anticoagulation should be continued in this group of high-risk patients BACKGROUND Vitamin K antagonists for secondary prevention in patients with deep vein thrombosis ( DVT ) require monitoring and dose adjustments . The synthetic factor Xa inhibitor , SanOrg34006 , has predictable pharmacokinetics and may be administered once weekly without dose adjustments . METHODS After 5 - 7 days of enoxaparin treatment , patients with proximal DVT were r and omized to receive 2.5 , 5.0 , 7.5 or 10 mg of SanOrg34006 subcutaneously once weekly or warfarin ( INR , 2.0 - 3.0 ) for 12 weeks . The primary efficacy outcome was the composite of change in thrombotic burden , as assessed by ultrasonography and perfusion lung scanning at baseline and week 12 + /- 1 , and clinical thromboembolic events . This outcome was classified as normalization , no relevant change , or deterioration . Other outcomes were major and other clinical ly relevant bleeding . RESULTS A total of 659 patients were r and omized and treated . In 614 ( 93 % ) patients the primary efficacy outcome was evaluable . The rates of normalization and deterioration were similar in all SanOrg34006 groups ( P = 0.4 ) and did not differ from the warfarin group . There was a clear dose-response for major bleeding among patients treated with SanOrg34006 ( P = 0.003 ) . Patients receiving 2.5 mg SanOrg34006 had less bleeding than did warfarin recipients ( P = 0.03 ) . CONCLUSIONS SanOrg34006 dosed at 2.5 mg appears as effective as higher dosages and warfarin for secondary prevention in DVT and was not associated with major bleeding . Therefore , 2.5 mg of SanOrg34006 administered subcutaneously once weekly might be a suitable alternative to dose-adjusted oral vitamin K antagonist An Anticoagulation Clinic Service ( ACS ) has been proposed as one strategy for improving warfarin treatment for patients with atrial fibrillation . In the Managing Anticoagulation Services Trial ( MAST ) , ACSs meeting specifications for high quality care were established in six managed care organizations ( MCOs ) which had the patients and re sources to support this initiative . The trial followed 1165 patients age > or=65 years who had atrial fibrillation as the primary reason for anticoagulation and were enrolled in a participating MCO . The 593 patients in the intervention group saw physicians in a practice cluster which had r and omly been assigned to have access to an ACS . These physicians used the ACS on average for about 48 % of eligible patients . The 572 patients in the control group received care from physicians in a practice cluster which could not refer patients to the ACS established for the trial but was otherwise unrestricted . The two clusters were compared on the proportion of time warfarin-treated patients were in the target range ( 2 - 3 ) prothrombin time-international normalized ratio ( INR ) during a 9-month baseline and a 9-month follow-up period . Among patients ( n = 264 ) for whom data were available for both periods , the changes in percentages of time in the target range were similar in the intervention cluster ( baseline : 47.7 % ; follow-up 55.6 % ) and in the control cluster ( baseline : 49.1 % ; follow-up : 52.3 % ; intervention effect : 5 % ; 95 % confidence interval : -5 % to 14 % ; P = 0.32 ) . In both practice clusters , patients had subtherapeutic INR values ( 1.5 to 1.99 ) about one fourth of the time . Providing an ACS in a managed care setting did not appear to improve anticoagulation care over the usual care provided at the sites in this trial but could be a reasonable consideration in a practice setting where time in target range is less than 50 % . A higher rate of utilization and a more aggressive stance toward subtherapeutic INR values could potentially enhance the effectiveness of an ACS OBJECTIVE The present study was design ed to evaluate the long-term efficacy and safety of once-daily enoxaparin plus warfarin for the outpatient ambulatory treatment of lower-limb deep venous thrombosis ( DVT ) . METHODS A total of 246 patients , comprising 128 men ( mean age , 54.28±16.48 years ) and 118 women ( mean age , 50.11±16.47 years ) with symptomatic lower extremity DVT , were included in this open-label , single-arm , multicenter , phase IV clinical trial conducted at 14 centers in Turkey . All patients were administered subcutaneous enoxaparin ( 1.5 mg/kg , once-daily ) until international normalized ratio ( INR ) levels reached to 2 to 3 , followed by oral warfarin ( 5 mg/d ) for at least 3 months and elastic compression stockings ( 30 - 40 mm Hg ) . Clinical signs ( leg circumference ) , symptoms ( edema , pain , tenderness ) , recanalization rates upon duplex ultrasound examination , laboratory findings ( D-dimer and INR levels ) , and postthrombotic syndrome status with CEAP classification were the efficacy parameters evaluated every 3 months during 18 months of follow-up . Safety end points included minor and major bleeding as well as serious adverse events . RESULTS Ambulatory treatment with enoxaparin plus warfarin significantly reduced physical symptoms , including tenderness , edema , pain ( P<.001 ) , and the circumference of the affected leg ( P<.001 ) . The leg circumference difference in almost all patients was < 1.5 cm at the end of 18 months ( P<.001 ) . Recanalization rates for occluded iliofemoral vein were 76.1 % at 3 months and 86.5 % at 18 months ( P<.001 ) . An early and significant decrease obtained in D-dimer levels on day 10 continued to decline significantly until month 6 and remained unchanged afterwards ( P<.001 ) . Of four patients diagnosed with major bleeding during oral anticoagulant use , three recovered with conservative treatment ( reduction in hemoglobin levels in 2 developed at visit 2 [ day 10 ] and intracranial bleeding in 1 developed at visit 3 [ day 30 ] ) , and one patient required a hysterectomy after menorrhagia developed at visit 7 ( month 18 ) . Two of the 65 ( 9.9 % ) adverse events documented were serious adverse events , but none of the serious adverse events leading to death were related to the study medications . CONCLUSION Ambulatory treatment with enoxaparin plus warfarin seems to be effective in symptomatic healing and in clinical improvement by reducing thrombus formation and organization at all levels of lower extremity venous system with DVT , without a significant major bleeding risk . Therefore , the results of our conventional conservative treatment are in line with 1A level evidence reported in the recent American College of Chest Physicians guideline The objective of the present study was to evaluate the efficacy , safety and healthcare re source utilization of long-term treatment with tinzaparin in symptomatic patients with acute pulmonary embolism as compared to st and ard therapy . In this open-label trial , 102 patients with objective ly confirmed pulmonary embolism were r and omized to receive , after initial treatment with tinzaparin , either tinzaparin ( 175 IU/kg/day ) or international normalized ratio-adjusted acenocoumarol for 6 months . Clinical endpoints were assessed during the 6 months of treatment . A pharmacoeconomic analysis was carried out to evaluate the cost of the long-term treatment with tinzaparin in comparison with the st and ard one . In an intention-to-treat analysis , one of 52 patients developed recurrent venous thromboembolism in the tinzaparin group compared with none of the 50 patients in the acenocoumarol group . One patient in each group had a major haemorrhagic complication . Six patients in the acenocoumarol group had minor bleeding compared with none in the tinzaparin group ( P = 0.027 ) . Median hospital length of stay was shorter in the tinzaparin group compared to the acenocoumarol group ( 7 versus 9 days ; P = 0.014 ) . When all the direct and indirect cost components were combined for the entire population , we found a slight , nonstatistically significant ( mean difference & U20AC;345 ; 95 % CI 1382–2071 ; P = 0.69 ) reduction in total cost with tinzaparin . Symptomatic acute pulmonary embolism treatment with full therapeutic doses of tinzaparin for 6 months is a feasible alternative to conventional treatment with vitamin K antagonists AIMS In anticoagulation treatment with warfarin , the risk of thrombo-embolic events must be weighed against the risk of bleeding . Time in therapeutic range ( TTR ) is an important tool to assess the quality of anticoagulation treatment , and has been shown to correlate with less bleeding and thrombo-embolic complications . AuriculA , the Swedish national quality registry for atrial fibrillation and anticoagulation , is used for follow-up and dosage control of warfarin . This is the first report of TTR in AuriculA and , in a subgroup of two centres , bleeding and thrombo-embolic complications during 2008 . METHODS AND RESULTS Prothrombin complex ( International normalized ratio ) values from 18 391 patients in 67 different centres were analysed . The mean ( SD ) age was 70 ( 12 ) years . The main indications for warfarin treatment were : atrial fibrillation ( 64 % ) , venous thromboembolism ( 19 % ) , and heart valve dysfunction ( 13 % ) . Time in therapeutic range for all patients was 76.2 % . The mean weekly dose of warfarin decreased with age and TTR increased with age . In 4273 patients from two centres in AuriculA , the frequency of major bleedings and venous/arterial thrombo-embolism were 2.6 and 1.7 % and for atrial fibrillation , 2.6 and 1.4 % , per treatment year , respectively . A correlation between age and the risk of major bleeding ( P < 0.001 ) , but not thrombo-embolic complications ( P= 0.147 ) , was seen . CONCLUSION Compared with prospect i ve r and omized trials of warfarin treatment , TTR in the AuriculA population was higher . Complications were low , probably due to the organization of anticoagulation treatment in Sweden . Use of the AuriculA dosing programme could have contributed to the results by keeping dosing regimens consistent over all centres This is the first evaluation of dabigatran , an oral direct thrombin inhibitor , in patients with atrial fibrillation ( AF ) . Patients ( n = 502 ) were r and omized to receive blinded doses of 50- , 150- , or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks . Dabigatran plasma concentrations , activated partial thromboplastin time , D-dimer , urinary 11-dehydrothromboxane B(2 ) ( DTB2 ) , and liver function were measured at baseline and at 1 , 2 , 4 , 8 , and 12 weeks . Clinical end points were assessed according to the treatment received at the time of the event . Overall , 92 % of patients completed the study . Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin ( 4 of 64 ) , and the incidence was significant versus 300-mg dabigatran alone ( 0 of 105 , p < 0.02 ) . Total bleeding events were more frequent in the 300-mg ( 39 of 169 , 23 % ) and 150-mg ( 30 of 169 , 18 % ) dabigatran groups compared with the 50-mg groups ( 7 of 107 , 7 % ; p = 0.0002 and p = 0.01 , respectively ) . Thromboembolic events were limited to the 50-mg dabigatran dose groups ( 2 of 107 , 2 % ) . The mean trough d-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin ( international normalized ratio of 2 to 3 ) . Aminotransferase levels > 3 times the upper limit of normal were observed in 0.9 % of the dabigatran recipients and in none of the warfarin recipients . Two dabigatran recipients had aminotransferase levels > 5 times the upper limit of normal as a result of gallstones , which resolved . Trough activated partial thromboplastin time values were 1.2 , 1.5 , and 1.8 times the baseline level for the 50- , 150- , and 300-mg dabigatran groups , respectively . DTB2 concentrations after 12 weeks of 50- , 150- , and 300-mg dabigatran treatment were increased by 31 % , 17 % , and 23 % , respectively , versus baseline ( p = 0.02 , p = 0.03 , and p = 0.0004 ) . In conclusion , major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups . The 2 highest doses of dabigatran suppress D-dimer concentrations . Serious liver toxicity was not seen . The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution The optimal long-term treatment of acute venous thromboembolism ( VTE ) in patients with malignancy remains undefined . In particular , based on current evidence , it is uncertain whether secondary prophylaxis using st and ard intensity oral anticoagulant therapy is associated with higher risks of bleeding and recurrent thrombosis in patients with cancer than in those without cancer . This study compared the outcome of anticoagulation courses in 95 patients with malignancy with those of 733 patients without malignancy . All patients were participants in a large , nation-wide population study and were prospect ively followed from the initiation of their oral anticoagulant therapy . Based on 744 patient-years of treatment and follow-up , the rates of major ( 5.4 % vs 0.9 % ) , minor ( 16.2 % vs 3.6 % ) and total ( 21.6 % vs 4.5 % ) bleeding were statistically significantly higher in cancer patients compared with patients without cancer . Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy ( 4.2 % vs. 0.7 % ; p < 0.01 ; RR 6.2 ( 95 % CI 1.95 - 19.4 ) . There was a trend towards a higher rate of thrombotic complications in cancer patients ( 6.8 % vs. 2.5 % ; p = 0.058 ; RR 2.5 [ CI 0.96 - 6.5 ] ) but this did not achieve statistical significance . In the group of patients with cancer , the bleeding rate was high across the different INR categories and was independent of the temporally associated International Normalized Ratio ( INR ) . In contrast , the bleeding rate was increased only with INR values greater than 4.5 in the group of patients without cancer . The rate of thrombotic events was significantly higher in both cohorts when the INR was less than 2.0 . In conclusion , patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy . Safer and more effective anticoagulant therapy is needed for this challenging group of patients BACKGROUND Rivaroxaban , an oral factor Xa inhibitor , may provide a simple , fixed-dose regimen for treating acute deep-vein thrombosis ( DVT ) and for continued treatment , without the need for laboratory monitoring . METHODS We conducted an open-label , r and omized , event-driven , noninferiority study that compared oral rivaroxaban alone ( 15 mg twice daily for 3 weeks , followed by 20 mg once daily ) with subcutaneous enoxaparin followed by a vitamin K antagonist ( either warfarin or acenocoumarol ) for 3 , 6 , or 12 months in patients with acute , symptomatic DVT . In parallel , we carried out a double-blind , r and omized , event-driven superiority study that compared rivaroxaban alone ( 20 mg once daily ) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism . The primary efficacy outcome for both studies was recurrent venous thromboembolism . The principal safety outcome was major bleeding or clinical ly relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study . RESULTS The study of rivaroxaban for acute DVT included 3449 patients : 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist . Rivaroxaban had noninferior efficacy with respect to the primary outcome ( 36 events [ 2.1 % ] , vs. 51 events with enoxaparin-vitamin K antagonist [ 3.0 % ] ; hazard ratio , 0.68 ; 95 % confidence interval [ CI ] , 0.44 to 1.04 ; P<0.001 ) . The principal safety outcome occurred in 8.1 % of the patients in each group . In the continued-treatment study , which included 602 patients in the rivaroxaban group and 594 in the placebo group , rivaroxaban had superior efficacy ( 8 events [ 1.3 % ] , vs. 42 with placebo [ 7.1 % ] ; hazard ratio , 0.18 ; 95 % CI , 0.09 to 0.39 ; P<0.001 ) . Four patients in the rivaroxaban group had nonfatal major bleeding ( 0.7 % ) , versus none in the placebo group ( P=0.11 ) . CONCLUSIONS Rivaroxaban offers a simple , single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation . ( Funded by Bayer Schering Pharma and Ortho-McNeil ; Clinical Trials.gov numbers , NCT00440193 and NCT00439725 . ) BACKGROUND Warfarin prevents ischaemic stroke in patients with non-valvular atrial fibrillation , but dose adjustment , coagulation monitoring , and bleeding risk limit its use . The oral direct thrombin inhibitor ximelagatran represents a potential alternative . We aim ed to establish whether ximelagatran is non-inferior to warfarin , within a margin of 2 % per year , for prevention of stroke and systemic embolism . METHODS We r and omised 3410 patients with atrial fibrillation and one or more stroke risk factors to open-label warfarin ( adjusted-dose , international normalised ratio [ INR ] 2.0 - 3.0 ) or ximelagatran ( fixed-dose , 36 mg twice daily ) ; patients were recruited from 259 hospitals , doctor 's offices , or health-care clinics . Primary analysis was based on masked event assessment and was by intention to treat . Primary endpoint was stroke or systemic embolism . FINDINGS During 4941 patient-years of exposure ( mean 17.4 months , SD 4.1 ) , 96 patients had primary events ( 56 in the warfarin group vs 40 in the ximelagatran group ) . The primary event rate by intention to treat was 2.3 % per year with warfarin and 1.6 % per year with ximelagatran ( absolute risk reduction 0.7 % [ 95 % CI -0.1 to 1.4 ] , p=0.10 ; relative risk reduction 29 % [ 95 % CI -6.5 to 52 ] ) . Rates of disabling or fatal stroke , mortality , and major bleeding were similar between groups , but combined minor and major haemorrhages were lower with ximelagatran than with warfarin ( 29.8 % vs 25.8 % per year ; relative risk reduction 14 % [ 4 to 22 ] ; p=0.007 ) . Raised serum alanine aminotransferase was more common with ximelagatran . INTERPRETATION In high-risk patients with atrial fibrillation , fixed-dose oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolism BACKGROUND Whether the oral factor Xa inhibitor edoxaban can be an alternative to warfarin in patients with venous thromboembolism is unclear . METHODS In a r and omized , double-blind , noninferiority study , we r and omly assigned patients with acute venous thromboembolism , who had initially received heparin , to receive edoxaban at a dose of 60 mg once daily , or 30 mg once daily ( e.g. , in the case of patients with creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg ) , or to receive warfarin . Patients received the study drug for 3 to 12 months . The primary efficacy outcome was recurrent symptomatic venous thromboembolism . The principal safety outcome was major or clinical ly relevant nonmajor bleeding . RESULTS A total of 4921 patients presented with deep-vein thrombosis , and 3319 with a pulmonary embolism . Among patients receiving warfarin , the time in the therapeutic range was 63.5 % . Edoxaban was noninferior to warfarin with respect to the primary efficacy outcome , which occurred in 130 patients in the edoxaban group ( 3.2 % ) and 146 patients in the warfarin group ( 3.5 % ) ( hazard ratio , 0.89 ; 95 % confidence interval [ CI ] , 0.70 to 1.13 ; P<0.001 for noninferiority ) . The safety outcome occurred in 349 patients ( 8.5 % ) in the edoxaban group and 423 patients ( 10.3 % ) in the warfarin group ( hazard ratio , 0.81 ; 95 % CI , 0.71 to 0.94 ; P=0.004 for superiority ) . The rates of other adverse events were similar in the two groups . A total of 938 patients with pulmonary embolism had right ventricular dysfunction , as assessed by measurement of N-terminal pro-brain natriuretic peptide levels ; the rate of recurrent venous thromboembolism in this subgroup was 3.3 % in the edoxaban group and 6.2 % in the warfarin group ( hazard ratio , 0.52 ; 95 % CI , 0.28 to 0.98 ) . CONCLUSIONS Edoxaban administered once daily after initial treatment with heparin was noninferior to high- quality st and ard therapy and caused significantly less bleeding in a broad spectrum of patients with venous thromboembolism , including those with severe pulmonary embolism . ( Funded by Daiichi-Sankyo ; Hokusai-VTE Clinical Trials.gov number , NCT00986154 . ) OBJECTIVES We sought to evaluate the rate of bleeding in relation to age ( < 80 and > or = 80 years ) , the quality of anticoagulation ( expressed as time spent in international normalized ratio therapeutic range ) , and factors associated with bleeding events . BACKGROUND Stroke prevention in patients with atrial fibrillation ( AF ) is an increasingly crucial public health target , particularly in patients ages > or = 80 years . METHODS We conducted a prospect i ve observational study on 783 patients with AF on oral anticoagulant treatment ( OAT ) . RESULTS Patients spent a median 14 % , 71 % , and 15 % of time below , within , and above the intended therapeutic range , respectively . No difference in OAT quality was found between patients age < 80 and > or = 80 years . During follow-up , 94 patients experienced bleeding complications ( rate 3.7 x 100 patient/years ) , 37 major ( rate 1.4 x 100 patient/years ) , and 57 minor ( rate 2.2 x 100 patient/years ) . Different rates of major hemorrhage were observed between patients age < 80 and > or = 80 years ( 0.9 vs. 1.9 x 100 patient/years ; p = 0.004 ) . Bleeding risk also was greater in patients with a history of previous cerebral ischemic event ( odds ratio [ OR ] : 2.5 ; 95 % confidence interval : 1.3 to 4.8 ; p = 0.007 ) . A Cox regression analysis confirmed age > or = 80 years associated with bleeding risk ( OR : 2.0 ) . CONCLUSIONS These results indicate that the rate of major bleeding complications may be kept acceptably low also in very elderly AF patients on OAT , provided a careful management of anticoagulation is obtained BACKGROUND Treatment of pulmonary embolism with low-molecular-weight heparin and vitamin K antagonists , such as warfarin , is not ideal . We aim ed to assess non-inferiority of idrabiotaparinux , a reversible longlasting indirect inhibitor of activated factor X , to warfarin in patients with acute symptomatic pulmonary embolism . METHODS In our r and omised , double-blind , double-dummy , non-inferiority trial , we enrolled adults with objective ly documented acute symptomatic pulmonary embolism attending 291 centres in 37 countries . We excluded patients who were pregnant , had active bleeding , kidney failure , or malignant hypertension , or were at high risk of death , bleeding , or adverse reactions to study drugs . We r and omly allocated patients to receive 5 - 10 days ' enoxaparin 1·0 mg/kg twice daily followed by subcutaneous idrabiotaparinux ( starting dose 3·0 mg ) or adjusted-dose warfarin ( target international normalised ratio 2·0 - 3·0 ) ; regimens lasted 3 months or 6 months dependent on clinical presentation . Block r and omisation was done with a central interactive computerised system , stratified by study centre and intended treatment duration . The primary efficacy outcome was recurrent venous thromboembolism at 99 days after r and omisation . We estimated the odds ratio and 95 % CI with a Mantel-Haenzsel χ(2 ) analysis ( non-inferiority margin 2·0 ) in the intention-to-treat population . The main safety outcome was clinical ly relevant bleeding ( major or non-major ) in all patients at day 99 . This study is registered with Clinical Trials.gov , number NCT00345618 . FINDINGS Between Aug 1 , 2006 , and Jan 31 , 2010 , we enrolled 3202 patients aged 18 - 96 years . 34 ( 2 % ) of 1599 patients r and omly allocated to receive enoxaparin-idrabiotaparinux and 43 ( 3 % ) of 1603 patients r and omly allocated to receive enoxaparin-warfarin had recurrent venous thromboembolism ( odds ratio 0·79 , 95 % CI 0·50 - 1·25 ; p(non-inferiority)=0·0001 ) . 72 ( 5 % ) of 1599 patients in the enoxaparin-idrabiotaparinux group and 106 ( 7 % ) of 1603 patients in the enoxaparin-warfarin group had clinical ly relevant bleeding ( 0·67 , 0·49 - 0·91 ; p(superiority)=0·0098 ) . We noted similar differences in outcomes in those patients treated to 6 months . INTERPRETATION Idrabiotaparinux could provide an attractive alternative to warfarin for the long-term treatment of pulmonary embolism , and seems to be associated with reduced bleeding . FUNDING Sanofi-Aventis ( Paris , France ) We performed a r and omized dose-ranging study , double-blind for rivaroxaban doses and open-label for the comparator ( low-molecular-weight heparin followed by vitamin K antagonists ) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombosis . A total of 543 patients with acute deep-venous thrombosis received rivaroxaban 20 , 30 , or 40 mg once daily or comparator . Treatment lasted for 84 days . The primary efficacy outcome was the 3-month incidence of the composite of symptomatic venous thromboembolic complications and asymptomatic deterioration in thrombotic burden as assessed by comparison of ultrasound and perfusion lung scanning at day 84 with baseline . The main safety outcome was the composite of major bleeding and clinical ly relevant nonmajor bleeding . A total of 449 ( 83 % ) of the 543 patients could be included in the per- protocol population . The primary efficacy outcome occurred in 6.1 % , 5.4 % , and 6.6 % of the rivaroxaban 20- , 30- , and 40-mg treatment groups , respectively , and in 9.9 % of those receiving st and ard therapy . The main safety outcome occurred in 5.9 % , 6.0 % , and 2.2 % of the rivaroxaban 20- , 30- , and 40-mg treatment groups , respectively , and in 8.8 % of those receiving st and ard therapy . These results with simple fixed-dose oral regimens justify phase 3 evaluations ( www . Clinical Trials.gov no . NCT00395772 )

Our data suggests a genetic contribution to some types of haemorrhagic stroke , with no overall responsible single gene but rather supporting a polygenic aetiology . Importantly , for several alleles previously found to be associated with protection from ischaemic stroke , there was a trend towards an increased risk of haemorrhagic stroke

BACKGROUND The genetic basis of haemorrhagic stroke has proved difficult to unravel , partly hampered by the small numbers of subjects in any single study . A meta- analysis of all c and i date gene association studies of haemorrhagic stroke ( including ruptured subarachnoid haemorrhage and amyloid angiopathy-related haemorrhage ) was performed , allowing more reliable estimates of risk .

BACKGROUND AND PURPOSE Factor V Leiden and a prothrombin gene variant , G20210A , are mutations associated with a thrombotic risk . The aim of our study was to assess whether these mutations increase the risk of stroke in women under 45 years of age . METHODS We conducted a case-control study in western Washington state . Case patients were women aged 18 to 44 years with a first stroke ( n = 106 ) . Control subjects were women without stroke recruited from the same region by use of r and om-digit telephone dialing ( n = 391 ) . All were interviewed and provided blood specimens , which were genotyped for these mutations . RESULTS Factor V Leiden was found in 0.9 % of case patients , a single patient with a subarachnoid hemorrhage , and in 4.1 % of control subjects . The odds ratio ( OR ) for any stroke was 0.2 ( 95 % confidence interval [ CI ] , 0.03 to 1.7 ) . The prothrombin variant was found in 1.9 % of case patients , 1 with a venous stroke and 1 with an ischemic stroke , and in 1.6 % of control subjects . The OR for any stroke was 1.48 ( 95 % CI , 0.14 to 9.17 ) . ORs for stroke types were also not statistically significant . CONCLUSIONS In this study , neither factor V Leiden nor the prothrombin variant ( G20210A ) was an important risk factor for stroke in young women . In this setting , screening for these mutations can not be recommended . Unanswered by this study is whether screening would be useful in select patients , such as those with a strong family history of thrombophilia or those with venous strokes Background —The outcome of cardiac surgery is influenced by several factors , but the impact of specific genetic variants has not been systematic ally explored . Because blood conservation is a pressing issue in cardiac surgery , we tested the hypothesis that factor V Leiden ( FVL ) , a common coagulation factor polymorphism , may protect against blood loss and transfusion in patients undergoing cardiac surgery . Methods and Results —We enrolled 517 patients undergoing cardiac surgery , including 26 heterozygous FVL carriers , and evaluated the impact of FVL on chest tube output and transfusion by using univariate and multivariate techniques . For patients with FVL , blood loss at 6 ( 238±131 mL ) and 24 hours ( 522±302 mL ) was significantly lower than that for noncarriers ( 358±259 mL and 730±452 mL;P < 0.001 and P = 0.001 , respectively ) . In a multivariate regression analysis , controlling for ethnicity and factors known to affect blood loss , FVL was a significant independent contributor at both time points . Using a similar regression approach , FVL did not have a significant effect on the number of units transfused . However , logistic regression of the risk of receiving any transfusion during hospitalization demonstrated a significant independent protective effect of FVL on overall transfusion risk . Conclusions —FVL represents a common genetic trait that may protect against blood loss and transfusion in this population . This study demonstrates that genetic variability can affect the outcome of cardiac surgery Background and Purpose — Conflicting reports in the literature exist with regard to the association of apolipoprotein E ( apo E ) alleles and lobar intracerebral hemorrhage ( ICH ) . We genotyped 12 single-nucleotide polymorphisms in the 5′ upstream regulatory , exonic , and intronic regions of the apo E gene and performed genotype and haplotype association analyses . Methods — We prospect ively enrolled subjects with hemorrhagic stroke and matched them with 2 controls based on age , race , and sex . Each case was review ed by a physician to determine case status and location of the ICH . Multivariate logistic-regression modeling with backward elimination was used to determine significant risk factors for lobar ICH . Associations at the genotype and haplotype levels and linkage disequilibrium were conducted according to st and ard statistical methods . Results — Between May 1997 and December 2002 , 315 cases of ICH were recruited , of whom 107 were lobar ICH cases matched to 205 controls . No association was found for apo E2 , E3 , or E4 with nonlobar ICH . Independent , significant risk factors for lobar ICH included apo E4 , untreated hypertension , anticoagulant use , a first-degree relative with ICH , and ≤high school education ( compared with > high school education ) . Treated hypercholesterolemia compared with “ no history of hypercholesterolemia ” was associated with a decreased risk of lobar ICH . Haplotype association analysis demonstrated a significant association of the apo E gene with lobar ICH among whites ( P<0.0001 ) and blacks ( P=0.0024 ) . Conclusions — Apo E4 is independently associated with lobar ICH but not nonlobar ICH . Haplotypes of the apo E gene are associated with lobar ICH . Untreated hypertension is a risk factor for lobar ICH Intracerebral hemorrhage ( ICH ) is a common and serious type of stroke . Recent studies have shown that inherited factors that affect the devlopment of the vessel wall can increase the risk of ICH . We studied endoglin as a c and i date gene in patients with sporadic ICH , since mutations in this gene can cause telangiectasia formation . One hundred three patients with sporadic ICH and 202 controls were studied . The polymerase chain reaction and single‐str and conformational polymorphism analysis were used to screen for mutations in exon 7 of the endoglin gene . No coding mutations in exon 7 were identified in the ICH patients or controls . A 6‐base intronic insertion was found 26 bases beyond the 3′ end of exon 7 . The homozygous form of the insertion was present in 9 of 103 ( 8.7 % ) ICH patients compared with 4 of 202 ( 2.0 % ) controls , p = 0.012 ( odds ratio 4.8 [ 95 % confidence interval , 1.28 , 21.60 ] ) . Analysis of the endoglin transcript around the insertion did not reveal any changes in the RNA sequence . There were no obvious clinical features that distinguished the ICH patients with the homozygous insertion from the other patients . The pathophysiologic mechanism underlying this association remains to be determined The homozygous deletion allele of the angiotensin converting enzyme gene ( ACE/DD ) , homozygous threonine allele of the angiotensinogen gene ( AGN/TT ) , and the epsilon4 allele of the apolipoprotein E gene ( apoE/epsilon4 ) are reported to be associated with ischemic heart disease . Cerebrovascular disease ( CVD ) is another atherosclerotic disease ; and the effects of these polymorphisms on CVD have been confusing . In this study , we investigated whether ACE/DD , AGN/TT , and apoE/epsilon4 genotypes are associated with CVD and whether genetic risk is enhanced by the effect of one upon another . We ascertained these genotypes in patients with cerebral infa rct ion ( n = 55 ) and cerebral hemorrhage ( n = 38 ) , diagnosed by brain computed tomography . Control subjects for the infa rct ion group and the hemorrhage group were r and omly selected from 583 subjects matched for age , gender , and history of hypertension with patients . Frequency of ACE/DD genotype was higher in the patients with infa rct ion than in the controls ( chi2 = 6.1 , P < .05 ) . The AGN/TT genotype was not associated with either infa rct ion or hemorrhage , but it increased the relative risk for cerebral infa rct ion in the subjects with ACE/DD genotype ( chi2 = 8.0 , P < .01 , odds ratio ; 11.7 , 95 % confidence intervals : 1.4 to 96.0 ) . There was no significant association between apoE/epsilon4 and CVD . These results suggest that ACE/DD predicts cerebral infa rct ion , but not cerebral hemorrhage , and that AGN/TT enhances the risk for cerebral infa rct ion associated with ACE/DD To determine the prevalence of the factor V Leiden gene mutation in relation to the phenotypes of cerebral infa rct ion and cerebral hemorrhage , we studied 386 r and omly selected cases of acute stroke and 247 control subjects . Factor V genotype was determined by amplification of a 267-bp sequence of exon/intron 10 of the factor V gene . Levels of prothrombin fragment F(1 + 2 ) , a marker of thrombin generation , were determined in both acute and convalescent stroke and related to factor V genotype . Prothrombin fragment F(1 + 2 ) was assessed by using an enzyme-linked immunosorbent assay . Sixteen stroke cases ( 4.1 % ) were identified as having the mutation compared with 14 ( 5.6 % ) control subjects . Prothrombin fragment F(1 + 2 ) levels were estimated in 191 cases and found to be elevated both acutely and after 3 months , but they were not related to factor V genotype . Prothrombin fragment F(1 + 2 ) is elevated in acute stroke and requires further evaluation in relation to cerebrovascular disease . These results suggest that the factor V Leiden gene mutation is not a risk factor for arterial thrombosis causing stroke Abstract The ɛ4 allele of apolipoprotein E ( apoE ) is found more commonly among patients with Alzheimer ’s disease ( AD ) than in the normal population . ApoE is associated with brain amyloid , a component of cerebral amyloid angiopathy ( CAA ) , which is both a pathological feature of AD and a frequent cause of lobar intracerebral hemorrhage ( ICH ) . We hypothesized that the frequency of ɛ4 allele is higher in patients with CAA-related ICH than in hypertensive ICH and in the normal population . To test this hypothesis we compared the frequency of apoE alleles in four population s : 24 patients with lobar ICH , 24 matched patients with hypertensive ICH , 24 matched normal controls , and 173 population controls . Although there was a tendency to a higher frequency of apoE ɛ4 in lobar ICH patients , we found no significant differences in the frequency of this allele between the four studied population s. In addition we did not confirm the finding of some authors of a higher frequency of apoE ɛ2 in patients with lobar ICH than in the normal population . Previous studies on the subject are discussed . The relationship between apoE polymorphism and lobar CAA-related ICH remains to be clearly defined OBJECT The identification of polymorphisms associated with an increase in the risk of developing disease is integral to the development of genetic biomarkers to identify individuals at risk . Based on reports indicating a role for angiotensin-converting enzyme ( ACE ) in the pathogenesis of intracranial aneurysms ( IAs ) as well as hypertension , an independent risk factor for IAs , the authors investigated the association between an insertion/deletion ( I/D ) polymorphism in the ACE gene and IAs in a Caucasian population in the US . METHODS The patient population consisted of 162 r and omly selected Caucasian patients who underwent surgical repair of an IA at Memorial-Hermann Hospital ( Houston , TX ) and had no family history of the disease . The ACE I/D polymorphism was typed using polymerase chain reaction amplification of genomic DNA , and allele and genotype frequencies were compared between the patients with IAs and 143 healthy Caucasian volunteers ( control group ) by performing logistic regression and chi-square tests . The ACE I/D allele frequencies did not differ significantly between the patient and control population s. There were similar allele and genotype frequencies in male and female study participants in both patient and control population s. The authors found no evidence of an association between the allelic or genotypic distribution of the ACE I/D polymorphism and aneurysmal subarachnoid hemorrhage or unruptured IAs . CONCLUSIONS Contrary to findings in two European Caucasian population s ( one British and one Polish ) , this polymorphism did not contribute to the risk of developing IAs in a Caucasian population in the US Networks of investigators have begun sharing best practice s , tools and methods for analysis of associations between genetic variation and common diseases . A Network of Investigator Networks has been set up to drive the process , sponsored by the Human Genome Epidemiology Network . A workshop is planned to develop consensus guidelines for reporting results of genetic association studies . Published literature data bases will be integrated , and unpublished data , including ' negative ' studies , will be captured by online journals and through investigator networks . Systematic review s will be exp and ed to include more meta-analyses of individual-level data and prospect i ve meta-analyses . Field synopses will offer regularly up date d overviews The exact role of the fibrinolytic system in the pathogenesis of stroke remains to be established . Elevated circulating levels of plasminogen activator inhibitor-1 , the principle inactivator of the fibrinolytic system , have been related to the development of myocardial infa rct ion . There is evidence that a polymorphism in the promoter region of the PAI-1 gene is associated with circulating PAI-1 levels . We studied a common single nucleotide insertion/deletion ( 4G/5 G ) polymorphism by PCR in 558 patients with stroke , the pathological type of which was established by cranial computed tomography , and in 172 controls . 4G/5 G genotype and PAI-1 activity were investigated in relation to 1 ) stroke type and 2 ) mortality occurring within four weeks , three months and six months of the stroke . No difference in genotype frequency was observed when all cases of stroke were compared with controls nor between the clinical ly determined subtypes of cerebral infa rct ion . PAI-1 activity was significantly higher in patients with stroke ( n = 245 ) both at presentation ( 11.6 U/ml ) and after three months ( 11.8 U/ml ) , in paired sample s , than in control subjects ( 8.8 U/ml , p < 0.0001 ) . Thirty-seven ( 6.2 % ) , 86 ( 14.5 % ) and 122 ( 20.5 % ) patients had died within one , three and six months of admission , respectively . PAI-1 activity was independently associated with all-cause mortality at one and three months after stroke ( p = 0.02 and p = 0.03 respectively ) , but not after six months . In this population the 4G/5 G promoter polymorphism is not associated with an increased risk of stroke . PAI-1 levels were elevated at the time of acute stroke which persisted after three months . PAI-1 level but not genotype was associated with early mortality following stroke Aggregation of subarachnoid haemorrhage has been described in numerous families,1 but whether relativxes of patients are at increased risk is unknown . If they are , they might benefit from screening for unruptured intracranial aneurysms since the outcome of subarachnoid haemorrhage is poor and asymptomatic aneurysms can now be repaired with low morbidity and mortality . We therefore studied the cumulative incidence of subarachnoid haemorrhage among first and second degree relatives of patients with recent haemorrhage . We prospect ively collected a series of 163 patients with subarachnoid haemorrhage verified by computed tomography from the University Hospitals of Rotterdam , Utrecht , and Amsterdam , and for every patient we constructed a pedigree including all first and second degree relatives . All these relatives were interviewed by telephone in a st and ardised manner ; they were asked about episodes of subarachnoid haemorrhage , sudden severe headache , stroke , and sudden death . For deceased relatives a next of kin was interviewed about the cause of Background and Purpose There have been relatively few community-based studies of long-term prognosis after acute stroke . This study aim ed to provide precise estimates of the absolute and relative risks of dying in an unselected cohort of patients with a first-ever stroke . Methods Six hundred seventy-five patients were registered by a community-based stroke register ( the Oxfordshire Community Stroke Project ) and prospect ively followed up for up to 6.5 years . Their relative risk of death was calculated using age- and sex-specific mortality rates for Oxfordshire . Results During the first 30 days , 129 ( 19 % ) patients died . Patients who survived at least 30 days after a first-ever stroke thereafter had an average annual risk of death of 9.1 % , 2.3 -fold the risk in people from the general population . Although the absolute ( about 15 % ) and relative ( about threefold ) risks of death were highest in these 30-day survivors over the first year after the stroke , they were at increased risk of dying over the next few years ( range of relative risk for individual years , 1.1 - 2.9 ) . Predictably , older patients had a worse absolute survival but , relative to the general population , stroke also increased the relative risk of dying in younger patients . During the first 30 days stroke accounts for most deaths ; after this time nonstroke cardiovascular disease becomes increasingly important and is the most common cause of death after the first year . Conclusions These data highlight the importance of long-term secondary prevention of vascular events in stroke patients , targeted as much at the cardiovascular as at the cerebrovascular circulation OBJECT It is becoming apparent that the presence of certain genetic variations ( polymorphisms ) may increase the individual 's susceptibility to cardiovascular diseases , even in the absence of a family history . We hypothesized that brain aneurysms more prone to rupture may be identified on the basis of an individual 's genotype for endothelial nitric oxide synthase ( eNOS ) , a critical vasomodulatory protein found to be increasingly relevant to the pathobiology of aneurysms . METHODS Patients ' clinical data were recorded prospect ively . Genomic DNA was isolated from blood sample s obtained from individuals presenting consecutively to the Mayo Clinic with ruptured ( 58 patients ) or unruptured ( 49 patients ) intracranial saccular aneurysms . Using polymerase chain reaction and gene microarray technology , the following eNOS genetic polymorphisms were studied : intron-4 27-base pair variable number of t and em repeats ( 27 VNTR ) ; promoter single nucleotide polymorphism ( T-786C SNP ) ; and exon-7 SNP ( G894 T SNP ) . Both groups of patients had similar demographic and clinical characteristics . For all three polymorphisms , variant alleles ( p < or = 0.003 ) and their corresponding genotypes ( p < or = 0.006 ) were found two to four times more frequently in patients with ruptured aneurysms than in patients with unruptured aneurysms . Strikingly , the odds ratio for presenting with a ruptured brain aneurysm among individuals demonstrating the copresence of all three variant alleles was 11.4 ( 95 % confidence interval 1.7 - 75.9 , p = 0.004 ) . CONCLUSIONS The authors have uniquely identified a set of t and em eNOS gene variations whose presence can be used to identify patients with aneurysms likely to rupture . We believe that if this finding is reproducible in a large multicenter study , in addition to known anatomical factors a rapid and cost-effective screening tool will become available to clinicians as a genetic aid to predict the risks of rupture in patients presenting with unruptured intracranial aneurysms Few studies have assessed the frequency of familial clustering in intracerebral hemorrhage ( ICH ) . Of 144 patients with ICH prospect ively assessed , 14 ( 9.8 % ) had a positive family history of ICH ( FH+ ) . Four pedigrees had more than two affected family members . Comparisons between FH+ and FH– prob and s demonstrated no significant differences in race , age , sex , ICH type or location . An underlying genetic etiology may account for familial clustering in some ICH patients

Conclusions : Dipeptidyl peptidase-4 inhibitors in patients with chronic kidney disease caused a modest reduction in hemoglobin A1c versus placebo , but not when compared with sulfonylureas or albiglutide , or when used in patients on dialysis . Additional active-comparator studies are needed to further eluci date the role of dipeptidyl peptidase-4 inhibitors in patients with chronic kidney disease stages 3–5 or on dialysis

Objective : This up date d meta- analysis determines the effect of dipeptidyl peptidase-4 inhibitors on glycemic and tolerability outcomes in patients with type 2 diabetes mellitus and chronic kidney disease with glomerular filtration rate of ⩽60 mL/min or on dialysis .

Abstract Introduction The aim of the present study was to determine the effect of sitagliptin on microalbuminuria in patients with type 2 diabetes mellitus . Material s and Methods A total of 85 patients with type 2 diabetes mellitus ( age > 20 years , < 80 years , hemoglobin A1c [ HbA1c ] < 8.4 % ) were r and omized to patients taking sitagliptin 50 mg or other oral glucose‐lowering agents . The following parameters were evaluated at 0 , 3 and 6 months after the treatment : bodyweight , blood pressure , HbA1c , fasting plasma glucose , fasting plasma insulin , low‐density lipoprotein cholesterol , high‐density lipoprotein cholesterol , triglycerides , estimated glomerular filtration rate and urinary albumin excretion . The primary outcome was changes in urinary albumin excretion at 6 months . Results Significant and comparable falls in HbA1c and fasting plasma glucose were found in both groups . However , sitagliptin significantly reduced urinary albumin excretion within 6 months , especially in patients with high urinary albumin at baseline . A total of 27 patients with normoalbuminuria showed a reduction in urinary albumin excretion , suggesting that sitagliptin prevents the development of albuminuria . A total of 15 patients with albuminuria showed a reduction in urinary albumin excretion , suggesting the beneficial effect of sitagliptin in the early stage of diabetic nephropathy . There was a significant correlation between improvement of proteinuria and that of diastolic blood pressure . Conclusions The results suggested that sitagliptin improved albuminuria , in addition to improving glucose . The mechanism of the reduction of albuminuria by sitagliptin could be a direct effect , as well as an increase in active glucagon‐like peptide‐1 , independently affecting blood pressure , bodyweight and glucose metabolism . This trial was registered with the University Hospital Medical Information Network ( UMIN no. # 000010871 ) AIM To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug ( OAD ) . METHODS This multicentre , r and omized , parallel group , phase III study compared linagliptin treatment ( 5 mg once daily , n = 336 ) with placebo ( n = 167 ) for 24 weeks in type 2 diabetes patients . Before r and omization , patients pretreated with one OAD underwent a washout period of 6 weeks , which included a placebo run-in period during the last 2 weeks . Patients previously untreated with an OAD underwent a 2-week placebo run-in period . The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment . RESULTS Linagliptin treatment result ed in a placebo-corrected change in HbA1c from baseline of -0.69 % ( p < 0.0001 ) at 24 weeks . In patients with baseline HbA1c ≥ 9.0 % , the adjusted reduction in HbA1c was 1.01 % ( p < 0.0001 ) . Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5 % at 24 weeks than those in the placebo arm ( 47.1 and 19.0 % , respectively ; odds ratio , OR = 4.2 , p < 0.0001 ) . Fasting plasma glucose improved by -1.3 mmol/l ( p < 0.0001 ) with linagliptin vs. placebo , and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postpr and ial glucose of -3.2 mmol/l ( p < 0.0001 ) . Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio ( p = 0.025 ) , Homeostasis Model Assessment -%B ( p = 0.049 ) and disposition index ( p = 0.0005 ) . There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention . Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin . CONCLUSIONS Monotherapy with linagliptin produced a significant , clinical ly meaningful and sustained improvement in glycaemic control , accompanied by enhanced parameters of β-cell function . The safety profile of linagliptin was comparable with that of placebo BACKGROUND The cardiovascular safety and efficacy of many current antihyperglycemic agents , including saxagliptin , a dipeptidyl peptidase 4 ( DPP-4 ) inhibitor , are unclear . METHODS We r and omly assigned 16,492 patients with type 2 diabetes who had a history of , or were at risk for , cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years . Physicians were permitted to adjust other medications , including antihyperglycemic agents . The primary end point was a composite of cardiovascular death , myocardial infa rct ion , or ischemic stroke . RESULTS A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group ( 7.3 % and 7.2 % , respectively , according to 2-year Kaplan-Meier estimates ; hazard ratio with saxagliptin , 1.00 ; 95 % confidence interval [ CI ] , 0.89 to 1.12 ; P=0.99 for superiority ; P<0.001 for noninferiority ) ; the results were similar in the " on-treatment " analysis ( hazard ratio , 1.03 ; 95 % CI , 0.91 to 1.17 ) . The major secondary end point of a composite of cardiovascular death , myocardial infa rct ion , stroke , hospitalization for unstable angina , coronary revascularization , or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group ( 12.8 % and 12.4 % , respectively , according to 2-year Kaplan-Meier estimates ; hazard ratio , 1.02 ; 95 % CI , 0.94 to 1.11 ; P=0.66 ) . More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure ( 3.5 % vs. 2.8 % ; hazard ratio , 1.27 ; 95 % CI , 1.07 to 1.51 ; P=0.007 ) . Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups ( acute pancreatitis , 0.3 % in the saxagliptin group and 0.2 % in the placebo group ; chronic pancreatitis , < 0.1 % and 0.1 % in the two groups , respectively ) . CONCLUSIONS DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events , though the rate of hospitalization for heart failure was increased . Although saxagliptin improves glycemic control , other approaches are necessary to reduce cardiovascular risk in patients with diabetes . ( Funded by AstraZeneca and Bristol-Myers Squibb ; SAVOR-TIMI 53 Clinical Trials.gov number , NCT01107886 . ) Results of the main Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial indicate that intensive glucose lowering increases cardiovascular and all-cause mortality . As the contribution of mild-to-moderate chronic kidney disease ( CKD ) to these risks is not known , we assessed the impact on cardiovascular outcomes in this population . Renal function data were available on 10,136 patients of the original ACCORD cohort . Of those , 6,506 were free of CKD at baseline and 3,636 met the criteria for CKD . Participants were r and omly assigned to a treatment strategy of either intensive or st and ard glycemic goal . The primary outcome , all-cause and cardiovascular mortality , and prespecified secondary outcomes were evaluated . Risk for the primary outcome was 87 % higher in patients with than in those without CKD ( hazard ratio of 1.866 ; 95 % CI : 1.651 - 2.110 ) . All prespecified secondary outcomes were 1.5 to 3 times more frequent in patients with than in those without CKD . In patients with CKD , compared with st and ard therapy , intensive glucose lowering was significantly associated with both 31 % higher all-cause mortality ( 1.306 : 1.065 - 1.600 ) and 41 % higher cardiovascular mortality ( 1.412 : 1.052 - 1.892 ) . No significant effects were found in patients without CKD . Thus , in high-risk patients with type II diabetes , mild and moderate CKD is associated with increased cardiovascular risk . Intensive glycemic control significantly increases the risk of cardiovascular and all-cause mortality in this population OBJECTIVE To evaluate the efficacy and long-term safety of linagliptin added to basal insulins in type 2 diabetes inadequately controlled on basal insulin with or without oral agents . RESEARCH DESIGN AND METHODS A total of 1,261 patients ( HbA1c ≥7.0 % [ 53 mmol/mol ] to ≤10.0 % [ 86 mmol/mol ] ) on basal insulin alone or combined with metformin and /or pioglitazone were r and omized ( 1:1 ) to double-blind treatment with linagliptin 5 mg once daily or placebo for ≥52 weeks . The basal insulin dose was kept unchanged for 24 weeks but could thereafter be titrated according to fasting plasma glucose levels at the investigators ’ discretion . The primary end point was the mean change in HbA1c from baseline to week 24 . The safety analysis incorporated data up to a maximum of 110 weeks . RESULTS At week 24 , HbA1c changed from a baseline of 8.3 % ( 67 mmol/mol ) by −0.6 % ( −6.6 mmol/mol ) and by 0.1 % ( 1.1 mmol/mol ) with linagliptin and placebo , respectively ( treatment difference −0.65 % [ 95 % CI −0.74 to −0.55 ] [ −7.1 mmol/mol ] ; P < 0.0001 ) . Despite the option to uptitrate basal insulin , it was adjusted only slightly upward ( week 52 , linagliptin 2.6 IU/day , placebo 4.2 IU/day ; P < 0.003 ) , result ing in no further HbA1c improvements . Frequencies of hypoglycemia ( week 24 , linagliptin 22.0 % , placebo 23.2 % ; treatment end , linagliptin 31.4 % , placebo 32.9 % ) and adverse events ( linagliptin 78.4 % , placebo 81.4 % ) were similar between groups . Mean body weight remained unchanged ( week 52 , linagliptin −0.30 kg , placebo −0.04 kg ) . CONCLUSIONS Linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight OBJECTIVE To compare the efficacy and safety of weekly albiglutide with daily sitagliptin , daily glimepiride , and placebo . Research Design And Methods Patients with type 2 diabetes receiving metformin were r and omized to albiglutide ( 30 mg ) , sitagliptin ( 100 mg ) , glimepiride ( 2 mg ) , or placebo . Blinded dose titration for albiglutide ( to 50 mg ) and glimepiride ( to 4 mg ) was based on predefined hyperglycemia criteria . The primary end point was change in HbA1c from baseline at week 104 . Secondary end points included fasting plasma glucose ( FPG ) , weight , and time to hyperglycemic rescue . RESULTS Baseline characteristics were similar among the albiglutide ( n = 302 ) , glimepiride ( n = 307 ) , sitagliptin ( n = 302 ) , and placebo ( n = 101 ) groups . Baseline HbA1c was 8.1 % ( 65.0 mmol/mol ) ; mean age was 54.5 years . The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg , respectively . At week 104 , albiglutide significantly reduced HbA1c compared with placebo ( −0.9 % [ −9.8 mmol/mol ] ; P < 0.0001 ) , sitagliptin ( −0.4 % [ −4.4 mmol/mol ] ; P = 0.0001 ) , and glimepiride ( −0.3 % [ −3.3 mmol/mol ] ; P = 0.0033 ) . Outcomes for FPG and HbA1c were similar . Weight change from baseline for each were as follows : albiglutide −1.21 kg ( 95 % CI −1.68 to −0.74 ) , placebo −1.00 kg ( 95 % CI −1.81 to −0.20 ) , sitagliptin −0.86 kg ( 95 % CI −1.32 to −0.39 ) , glimepiride 1.17 kg ( 95 % CI 0.70–1.63 ) . The difference between albiglutide and glimepiride was statistically significant ( P < 0.0001 ) . Hyperglycemic rescue rate at week 104 was 25.8 % for albiglutide compared with 59.2 % ( P < 0.0001 ) , 36.4 % ( P = 0.0118 ) , and 32.7 % ( P = 0.1504 ) for placebo , sitagliptin , and glimepiride , respectively . Rates of serious adverse events in the albiglutide group were similar to comparison groups . Diarrhea ( albiglutide 12.9 % , other groups 8.6–10.9 % ) and nausea ( albiglutide 10.3 % , other groups 6.2–10.9 % ) were generally the most frequently reported gastrointestinal events . CONCLUSIONS Added to metformin , albiglutide was well tolerated ; produced superior reductions in HbA1c and FPG at week 104 compared with placebo , sitagliptin , and glimepiride ; and result ed in weight loss compared with glimepiride AIM To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus ( T2DM ) and renal impairment . METHODS In this multicentre , r and omized , parallel-group , double-blind , placebo-controlled study , patients with glycated haemoglobin ( HbA1c ) 7 - 11 % and creatinine clearance < 50 ml/min were stratified by baseline renal impairment ( moderate , severe or end-stage on haemodialysis ) , and r and omized ( 1 : 1 ) to saxagliptin 2.5 mg once daily or placebo for 12 weeks . Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study . The absolute change in HbA1c from baseline to week 12 ( primary efficacy end-point ) was analysed using an analysis of covariance model with last observation carried forward methodology . RESULTS A total of 170 patients were r and omized and treated . The adjusted mean decrease from baseline to week 12 in HbA1c was statistically significantly greater in the saxagliptin group than in the placebo group ; the difference between treatments was -0.42 % ( 95 % confidence interval : -0.71 to -0.12 % , p = 0.007 ) . Adjusted mean HbA1c decreases from baseline to week 12 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate ( -0.64 vs. -0.05 % ) and severe ( -0.95 vs. -0.50 % ) renal impairment . HbA1c reductions were similar between saxagliptin and placebo in the subgroup with end-stage renal disease on haemodialysis ( -0.84 vs. -0.87 % ) . Saxagliptin was generally well tolerated ; incidences of adverse events and hypoglycaemic events were similar to placebo . CONCLUSIONS Saxagliptin 2.5 mg once daily is a well-tolerated treatment option for patients with inadequately controlled T2DM and renal impairment BACKGROUND Treatment with oral antihyperglycemic agents has not been well characterized in patients with type 2 diabetes and end-stage renal disease ( ESRD ) . The efficacy and safety of sitagliptin and glipizide monotherapy in patients with type 2 diabetes and ESRD on dialysis therapy were assessed in this study . STUDY DESIGN 54-week , r and omized , double-blind , parallel-arm study . SETTING & PARTICIPANTS From 31 clinical sites in 12 countries , 129 patients 30 years or older with type 2 diabetes and ESRD who were on dialysis therapy and had a hemoglobin A1c ( HbA1c ) level of 7%-9 % were r and omly assigned 1:1 to treatment . INTERVENTION Monotherapy with sitagliptin , 25 mg daily or glipizide ( initiated with 2.5 mg daily and titrated up to a potential maximum dose of 10 mg twice daily or down to avoid hypoglycemia ) . OUTCOMES Primary end points were 54-week change in HbA1c level from baseline and tolerability with sitagliptin . A secondary end point was the comparison of sitagliptin versus glipizide on the incidence of symptomatic hypoglycemia . RESULTS Of 129 patients r and omly assigned , 64 were in the sitagliptin group ( mean baseline age , 61 years ; HbA1c , 7.9 % ) and 65 were in the glipizide group ( mean baseline age , 59 years ; HbA1c , 7.8 % ) . After 54 weeks , the least squares mean change from baseline in HbA1c level was -0.72 % ( 95 % CI , -0.95 % to -0.48 % ) with sitagliptin and -0.87 % ( 95 % CI , -1.11 % to -0.63 % ) with glipizide , for a difference of 0.15 % ( 95 % CI , -0.18 % to 0.49 % ) . The incidences of symptomatic hypoglycemia and severe hypoglycemia were 6.3 % versus 10.8 % ( between-group difference , -4.8 % [ 95 % CI , -15.7 % to 5.6 % ] ) and 0 % versus 7.7 % ( between-group difference , -7.8 % [ 95 % CI , -17.1 % to -1.9 % ] ) in the sitagliptin and glipizide groups , respectively . Higher incidences ( ie , 95 % CI around between-treatment difference excluded 0 ) of cellulitis and headache were found with sitagliptin compared to glipizide ( 6.3 % vs 0 % , respectively , for both ) . LIMITATIONS Small sample size limits between-group comparisons . CONCLUSIONS Treatment with sitagliptin or glipizide monotherapy was effective and well tolerated over 54 weeks in patients with type 2 diabetes and ESRD who were receiving dialysis OBJECTIVE Pre clinical data suggest that linagliptin , a dipeptidyl peptidase-4 inhibitor , may lower urinary albumin excretion . The ability of linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system ( RAAS ) inhibition in humans was analyzed by pooling data from four similarly design ed , 24-week , r and omized , double-blind , placebo-controlled , phase III trials . RESEARCH DESIGN AND METHODS A pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria ( defined as a urinary albumin-to-creatinine ratio [ UACR ] of 30−3,000 mg/g creatinine ) while receiving stable doses of RAAS inhibitors . Participants were r and omized to either linagliptin 5 mg/day ( n = 162 ) or placebo ( n= 55 ) . The primary end point was the percentage change in geometric mean UACR from baseline to week 24 . RESULTS UACR at week 24 was reduced by 32 % ( 95 % CI −42 to −21 ; P < 0.05 ) with linagliptin compared with 6 % ( 95 % CI −27 to + 23 ) with placebo , with a between-group difference of 28 % ( 95 % CI −47 to −2 ; P = 0.0357 ) . The between-group difference in the change in HbA1c from baseline to week 24 was −0.61 % ( −6.7 mmol/mol ) in favor of linagliptin ( 95 % CI −0.88 to −0.34 % [ −9.6 to −3.7 mmol/mol ] ; P < 0.0001 ) . The albuminuria-lowering effect of linagliptin , however , was not influenced by race or HbA1c and systolic blood pressure ( SBP ) values at baseline or after treatment . CONCLUSIONS Linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction . This observation was independent of changes in glucose level or SBP . Further research to prospect ively investigate the renal effects of linagliptin is underway OBJECTIVE To evaluate weekly subcutaneous albiglutide versus daily sitagliptin in renally impaired patients with type 2 diabetes and inadequately controlled glycemia on a regimen of diet and exercise and /or oral antihyperglycemic medications . RESEARCH DESIGN AND METHODS In this phase III , r and omized , double-blind , multicenter , 52-week study , the primary study end point was HbA1c change from baseline at week 26 in patients with renal impairment , as assessed with estimated glomerular filtration rate and categorized as mild , moderate , or severe ( ≥60 to ≤89 , ≥30 to ≤59 , and ≥15 to ≤29 mL/min/1.73 m2 , respectively ) . Secondary end points included fasting plasma glucose ( FPG ) , weight , achievement of treatment targets , hyperglycemic rescue , and safety . RESULTS Baseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years , BMI of 30.4 kg/m2 , HbA1c of 8.2 % ( 66 mmol/mol ) , and diabetes disease duration of 11.2 years . HbA1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin ( −0.83 % vs. −0.52 % , P = 0.0003 ) . Decreases in HbA1c , FPG , and weight were seen through week 52 . Time to hyperglycemic rescue through week 52 was significantly longer for albiglutide than sitagliptin ( P = 0.0017 ) . Results of safety assessment s were similar between groups , and most adverse events ( AEs ) were mild or moderate . The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as follows : overall , 31.7 % , 25.2 % ; diarrhea , 10.0 % , 6.5 % ; nausea , 4.8 % , 3.3 % ; and vomiting , 1.6 % , 1.2 % , respectively . CONCLUSIONS Once-weekly albiglutide therapy in renally impaired patients with type 2 diabetes provided statistically superior glycemic improvement with almost similar tolerability compared with daily sitagliptin therapy OBJECTIVE Patients with type 2 diabetes mellitus ( T2DM ) and chronic kidney disease have an increased risk of micro- and macrovascular disease , but limited options for antihyperglycemic therapy . We compared the efficacy and safety of sitagliptin with glipizide in patients with T2DM and moderate-to-severe chronic renal insufficiency and inadequate glycemic control . RESEARCH DESIGN AND METHODS Patients ( n = 426 ) were r and omized 1:1 to sitagliptin ( 50 mg every day [ q.d . ] for moderate renal insufficiency and 25 mg q.d . for severe renal insufficiency ) or glipizide ( 2.5 mg q.d . , adjusted based on glycemic control to a 10-mg twice a day maximum dose ) . R and omization was stratified by : 1 ) renal status ( moderate or severe renal insufficiency ) ; 2 ) history of cardiovascular disease ; and 3 ) history of heart failure . RESULTS At week 54 , treatment with sitagliptin was noninferior to treatment with glipizide in A1C change from baseline ( −0.8 vs. −0.6 % ; between-group difference −0.11 % ; 95 % CI −0.29 to 0.06 ) because the upper bound of the 95 % CI was less than the prespecified noninferiority margin of 0.4 % . There was a lower incidence of symptomatic hypoglycemia adverse events ( AEs ) with sitagliptin versus glipizide ( 6.2 and 17.0 % , respectively ; P = 0.001 ) and a decrease in body weight with sitagliptin ( −0.6 kg ) versus an increase ( 1.2 kg ) with glipizide ( difference , −1.8 kg ; P < 0.001 ) . The incidence of gastrointestinal AEs was low with both treatments . CONCLUSIONS In patients with T2DM and chronic renal insufficiency , sitagliptin and glipizide provided similar A1C-lowering efficacy . Sitagliptin was generally well-tolerated , with a lower risk of hypoglycemia and weight loss versus weight gain , relative to glipizide OBJECTIVE To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [ creatinine clearance ( CrCl ) > or = 30 to < 50 ml/min ] or severe renal insufficiency [ CrCl < 30 ml/min including patients with end-stage renal disease ( ESRD ) on dialysis ] . The efficacy of sitagliptin in this patient population was also assessed . METHODS In a 54-week , r and omized , double-blind , parallel-group study , patients with baseline glycosylated haemoglobin A(1c ) ( HbA(1c ) ) values of 6.5 - 10 % were allocated ( 2:1 ) to sitagliptin ( for 54 weeks ) or the sequence of placebo ( for 12 weeks ) followed by active treatment with glipizide ( for 42 weeks ) . To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily , patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily . Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day . RESULTS Patients ( N = 91 ) with a mean baseline HbA(1c ) value of 7.7 % ( range : 6.2 - 10.3 % ) were r and omized to sitagliptin ( n = 65 ) or placebo ( n = 26 ) . After 12 weeks , the mean change [ 95 % confidence interval ( CI ) ] from baseline in HbA(1c ) was -0.6 % ( -0.8 , -0.4 ) in the sitagliptin group compared with -0.2 % ( -0.4 , 0.1 ) in the placebo group [ between-group difference ( 95 % CI ) = -0.4 % ( -0.7 , -0.1 ) ] . At 54 weeks , patients continuously treated with sitagliptin had a mean change ( 95 % CI ) from baseline in HbA(1c ) of -0.7 % ( -0.9 , -0.4 ) . The overall incidence of adverse experiences was generally similar between groups . Between-group differences in incidences of specific clinical adverse experiences were generally small ; however , the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group ( 4.6 % ) compared with the placebo/glipizide group ( 23.1 % ) . Consistent with the high mortality risk in this patient population , there were six deaths during this 54-week study [ 5 of 65 patients ( 7.7 % ) in the sitagliptin group and 1 of 26 patients ( 3.8 % ) in the placebo/glipizide group ] ; no death was considered by the investigator to be drug related . The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups . CONCLUSIONS In this study , sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency , including patients with ESRD on dialysis BACKGROUND A substantial proportion of patients with type 2 diabetes are elderly ( ≥65 years ) but this group has been largely excluded from clinical studies of glucose-lowering drugs . We aim ed to assess the effectiveness of linagliptin , a dipeptidyl peptidase-4 inhibitor , in elderly patients with type 2 diabetes . METHODS In this r and omised , double-blind , parallel-group , multinational phase 3 study , patients aged 70 years or older with type 2 diabetes , glycated haemoglobin A1c ( HbA1c ) of 7·0 % or more , receiving metformin , sulfonylureas , or basal insulin , or combinations of these drugs , were r and omised ( by computer-generated r and omisation sequence , concealed with a voice-response system , stratified by HbA1c level [ < 8·5 % vs ≥8·5 % ] and insulin use [ yes vs no ] , block size four ) in a 2:1 ratio to once-daily oral treatment with linagliptin 5 mg or matching placebo for 24 weeks . Investigators and participants were masked to assignment throughout the study . The primary endpoint was change in HbA1c from baseline to week 24 . This trial is registered with Clinical Trials.gov , number NCT01084005 . FINDINGS 241 community-living out patients were r and omised ( 162 linagliptin , 79 placebo ) . Mean age was 74·9 years ( SD 4·3 ) . Mean HbA1c was 7·8 % ( SD 0·8 ) . At week 24 , placebo-adjusted mean change in HbA1c with linagliptin was -0·64 % ( 95 % CI -0·81 to -0·48 , p<0·0001 ) . Overall safety and tolerability were much the same between the linagliptin and placebo groups ; 75·9 % of patients in both groups had an adverse event ( linagliptin n=123 , placebo n=60 ) . No deaths occurred . Serious adverse events occurred in 8·6 % ( 14 ) of patients in the linagliptin group and 6·3 % ( five ) patients in the placebo group ; none were deemed related to study drug . Hypoglycaemia was the most common adverse event in both groups , but did not differ between groups ( 24·1 % [ 39 ] in the linagliptin group , 16·5 % [ 13 ] in the placebo group ; odds ratio 1·58 , 95 % CI 0·78 - 3·78 , p=0·2083 ) . INTERPRETATION In elderly patients with type 2 diabetes linagliptin was efficacious in lowering glucose with a safety profile similar to placebo . These findings could inform treatment decisions for achieving individualised glycaemic goals with minimal risk in this important population of patients . FUNDING Boehringer Ingelheim Background Few data exist as to whether dipeptidyl peptidase (DPP)-4 inhibitors affect cardio-renal interaction , which is a strong independent prognostic factor for cardiovascular disease ( CVD ) , in diabetic patients . We evaluated the effects of a DPP-4 inhibitor on atherogenic low-density lipoprotein ( LDL ) heterogeneity and albuminuria in diabetics as an indicator of the severity of diabetic nephropathy . Methods Type 2 diabetes patients ( n = 47 ) inadequately controlled with diabetes therapy were treated with vildagliptin 50 mg bid for 8 weeks . LDL heterogeneity was evaluated on the basis of the patients ’ small dense ( sd ) LDL levels and sd-LDL proportion ( sd-LDL/LDL cholesterol [ LDL-C ] ) . The level of albuminuria was evaluated on the basis of the urinary albumin-to-creatinine ratio ( UACR ) . Results After 8 weeks of treatment , there was no significant change in serum LDL-C level , but the serum sd-LDL level had decreased significantly by 8.8 % , and the UACR had also decreased significantly by 44.6 % . Triglyceride (TG)-metabolism-related markers ( TG , remnant-like particle cholesterol , apolipoprotein [ apo ] B , apoC-2 , and apoC-3 ) had decreased significantly . The Δ ( absolute change from baseline ) sd-LDL values correlated positively with ΔTG-metabolism-related markers , but not with the Δ hemoglobin ( Hb ) A1c or Δ fasting blood sugar ( ΔFBS ) . Furthermore , multivariate regression analysis revealed that Δsd-LDL proportion , but not ΔHbA1c or ΔFBS , was an independent predictor of ΔUACR ( β = 0.292 , p = 0.0016 ) . Conclusions Although this was a single-arm study , treatment of type 2 diabetes with vildagliptin might prevent the progression of CVD complicating diabetes by improving LDL heterogeneity , and it might improve renal function by decreasing albuminuria . A r and omized controlled trial is warranted OBJECTIVE Therapeutic options are limited for diabetes patients with renal disease . This report presents 52-week results from a study assessing the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus ( T2DM ) and renal impairment . DESIGN Double-blind study in patients stratified by baseline renal impairment ( moderate , severe or end-stage renal disease [ ESRD ] on haemodialysis ) r and omised to saxagliptin 2.5 mg once daily or placebo added to other antidiabetic drugs in use at baseline , including insulin . PATIENTS A total of 170 adults with glycated haemoglobin ( HbA(1c ) ) 7 - 11 % and creatinine clearance < 50 ml/min or ESRD were r and omised and treated . MEASUREMENTS Absolute changes in HbA(1c ) and fasting plasma glucose ( FPG ) from baseline to week 52 were evaluated using analysis of covariance ( ANCOVA ) with last observation carried forward . Repeated- measures analyses were also performed . RESULTS Adjusted mean decrease in HbA(1c ) was greater with saxagliptin than placebo ( difference , -0.73 % , p < 0.001 [ ANCOVA ] ) . Reductions in adjusted mean HbA(1c ) were numerically greater with saxagliptin than placebo in patients with renal impairment rated as moderate ( -0.94 % vs. 0.19 % respectively ) or severe ( -0.81 % vs. -0.49 % ) , but similar to placebo for those with ESRD ( -1.13 % vs. -0.99 % ) . Reductions in adjusted mean FPG were numerically greater with saxagliptin in patients with moderate or severe renal impairment . Saxagliptin was generally well tolerated ; similar proportions of patients in the saxagliptin and placebo groups reported hypoglycaemic events ( 28 % and 29 % respectively ) . CONCLUSIONS Saxagliptin 2.5 mg once daily offers sustained efficacy and good tolerability for patients with T2DM and renal impairment AIMS To examine the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [ HbA(1c ) 53 - 86 mmol/mol ( 7.0 - 10.0 % ) ] by metformin and sulphonylurea combination treatment . METHODS A multi-centre , 24-week , r and omized , double-blind , parallel-group study in 1058 patients comparing linagliptin ( 5 mg once daily ) and placebo when added to metformin plus sulphonylurea . The primary endpoint was the change in HbA(1c ) after 24 weeks . RESULTS At week 24 , the linagliptin placebo-corrected HbA(1c ) adjusted mean change from baseline was -7 mmol/mol ( -0.62 % ) [ 95 % CI -8 to -6 mmol/mol ( -0.73 to -0.50 % ) ; P < 0.0001 ] . More participants with baseline HbA(1c ) ≥ 53 mmol/mol ( ≥ 7.0 % ) achieved an HbA(1c ) < 53 mmol/mol ( < 7.0 % ) with linagliptin compared with placebo ( 29.2 % vs. 8.1 % , P < 0.0001 ) . Fasting plasma glucose was reduced with linagliptin relative to placebo ( -0.7 mmol/l , 95 % CI -1.0 to -0.4 ; P<0.0001 ) . Improvements in homeostasis model assessment of β-cell function were seen with linagliptin ( P<0.001 ) . The proportion of patients who reported a severe adverse event was low in both groups ( linagliptin 2.4 % ; placebo 1.5 % ) . Symptomatic hypoglycaemia occurred in 16.7 and 10.3 % of the linagliptin and placebo groups , respectively . Hypoglycaemia was generally mild or moderate ; severe hypoglycaemia was reported in 2.7 and 4.8 % of the participants experiencing hypoglycaemic episodes in the linagliptin and placebo groups , respectively . No significant weight changes were noted . CONCLUSIONS In patients with Type 2 diabetes , adding linagliptin to metformin given in combination with a sulphonylurea significantly improved glycaemic control and this was well tolerated . Linagliptin could provide a valuable treatment option for individuals with inadequate glycaemic control despite ongoing combination therapy with metformin and a sulphonylurea BACKGROUND The EXAMINE trial showed non-inferiority of the DPP-4 inhibitor alogliptin to placebo on major adverse cardiac event ( MACE ) rates in patients with type 2 diabetes and recent acute coronary syndromes . Concerns about excessive rates of in-hospital heart failure in another DPP-4 inhibitor trial have been reported . We therefore assessed hospital admission for heart failure in the EXAMINE trial . METHODS Patients with type 2 diabetes and an acute coronary syndrome event in the previous 15 - 90 days were r and omly assigned alogliptin or placebo plus st and ard treatment for diabetes and cardiovascular disease prevention . The prespecified exploratory extended MACE endpoint was all-cause mortality , non-fatal myocardial infa rct ion , non-fatal stroke , urgent revascularisation due to unstable angina , and hospital admission for heart failure . The post-hoc analyses were of cardiovascular death and hospital admission for heart failure , assessed by history of heart failure and brain natriuretic peptide ( BNP ) concentration at baseline . We also assessed changes in N-terminal pro-BNP ( NT-pro-BNP ) from baseline to 6 months . This study is registered with Clinical Trials.gov , number NCT00968708 . FINDINGS 5380 patients were assigned to alogliptin ( n=2701 ) or placebo ( n=2679 ) and followed up for a median of 533 days ( IQR 280 - 751 ) . The exploratory extended MACE endpoint was seen in 433 ( 16·0 % ) patients assigned to alogliptin and in 441 ( 16·5 % ) assigned to placebo ( hazard ratio [ HR ] 0·98 , 95 % CI 0·86 - 1·12 ) . Hospital admission for heart failure was the first event in 85 ( 3·1 % ) patients taking alogliptin compared with 79 ( 2·9 % ) taking placebo ( HR 1·07 , 95 % CI 0·79 - 1·46 ) . Alogliptin had no effect on composite events of cardiovascular death and hospital admission for heart failure in the post hoc analysis ( HR 1·00 , 95 % CI 0·82 - 1·21 ) and results did not differ by baseline BNP concentration . NT-pro-BNP concentrations decreased significantly and similarly in the two groups . INTERPRETATION In patients with type 2 diabetes and recent acute coronary syndromes , alogliptin did not increase the risk of heart failure outcomes . FUNDING Takeda Development Center Americas Abstract Aims /hypothesisThere are limited data comparing dipeptidyl peptidase-4 ( DPP-4 ) inhibitors directly . We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment ( RI ) . Methods This study was a parallel-arm , r and omised , multicentre , double-blind , 24 week study conducted in 87 centres across Brazil and the USA . Patients with type 2 diabetes , either drug naive or treated with any glucose-lowering agents , who had inadequate glycaemic control ( HbA1c 6.5–10.0 % [ 48–86 mmol/mol ] ) and an estimated GFR < 30 ml min−1 [ 1.73 m]−2 were r and omised ( via interactive voice response technology ) to vildagliptin 50 mg once daily or sitagliptin 25 mg once daily . These doses are recommended in this patient population and considered maximally effective . Participants , investigators and the sponsor were blinded to group assignment . Efficacy endpoints included change in HbA1c and fasting plasma glucose ( FPG ) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events . Results In total , 148 patients were r and omised , 83 to vildagliptin and 65 to sitagliptin . All patients were analysed . After 24 weeks , the adjusted mean change in HbA1c was −0.54 % ( 5.9 mmol/mol ) from a baseline of 7.52 % ( 59 mmol/mol ) with vildagliptin and −0.56 % ( 6.1 mmol/mol ) from a baseline of 7.80 % ( 62 mmol/mol ) with sitagliptin ( p = 0.874 ) . FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin ( p = 0.185 ) . Both treatments were well tolerated with overall similar safety profiles . Conclusions /interpretationAt their recommended doses for severe RI , vildagliptin ( 50 mg once daily ) compared with sitagliptin ( 25 mg once daily ) demonstrated similar efficacy and both drugs were well tolerated . This study provides further support for the use of DPP-4 inhibitors in patients with severe RI . Trial registration : Clinical Trials.gov NCT00616811 ( completed ) Funding : This study was planned and conducted by The potent and selective dipeptidyl peptidase-4 inhibitor vildagliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose . We conducted a prospect i ve , open-label , parallel group , controlled study of 51 patients with type 2 diabetic patients undergoing hemodialysis ( HD ) during the 24-week study period . Patients were assigned to two groups : the vildagliptin group ( n = 30 ) and the control group ( n = 21 ) . Vildagliptin was administered at 50 mg/day for the first 8 weeks . Then doses were titrated by dose-doubling to a maximum of 100 mg/day if hemoglobin A1c ( HbA1c ) or glycated albumin ( GA ) target levels had not been reached . No vildagliptin was administered to the controls . The average final dose of vildagliptin was 80 ± 5 mg daily . After 24 weeks , vildagliptin had decreased average HbA1c levels from 6.7 % baseline to 6.1 % , average GA levels from 24.5 % baseline to 20.5 % and average postpr and ial plasma glucose levels from 186 mg/dL baseline to 140 mg/dL ( all p < 0.0001 ) . In the control group , we observed no such changes . Vildagliptin efficacy did not differ according to age or body mass index , but the GA reduction was significantly greater in the anti-diabetic agents-naïve group . Furthermore , in patients with higher baseline GA levels , a higher vildagliptin dosage was required to produce a noticeable effect . No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient . Vildagliptin was effective as a treatment for diabetic patients undergoing HD Dipeptidyl peptidase-4 ( DPP-4 ) inhibitor is a new class of anti-diabetic drug which exerts its glucose-lowering action by suppressing the degradation of a gut incretin hormone glucagon-like peptide-1 ( GLP-1 ) . To eluci date whether treatment with stronger DPP-4 inhibitor on top of angiotensin II type 1 receptor blocker ( ARB ) provides greater renal protective effects , we performed a crossover study with two DPP-4 inhibitors , sitagliptin and alogliptin , in twelve type 2 diabetic patients with incipient nephropathy taking ARBs . This study consisted of three treatment periods : sitagliptin 50 mg/day for 4 weeks ( first period ) , alogliptin 25 mg/day for 4 weeks ( second period ) , and sitagliptin 50 mg/day for 4 weeks ( third period ) . Significant changes in body mass index , blood pressure , serum lipids , serum creatinine , estimated glomerular filtration rate , and HbA1c were not observed among the three treatment periods . Reduced urinary levels of albumin and an oxidative stress marker 8-hydroxy-2'-deoxyguanosine ( 8-OHdG ) , increased urinary cAMP levels , and elevated plasma levels of stromal cell-derived factor-1α ( SDF-1α ) which is a physiological substrate of DPP-4 were observed after the switch from sitagliptin to a stronger DPP-4 inhibitor alogliptin . Given a large body of evidence indicating anti-oxidative action of cAMP and up-regulation of cellular cAMP production by SDF-1α , the present results suggest that more powerful DPP-4 inhibition on top of angiotensin II type 1 receptor blockade would offer additional protection against early-stage diabetic nephropathy beyond that attributed to glycemic control , via reduction of renal oxidative stress by SDF-1α-cAMP pathway activation AIM To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase-4 ( DPP-4 ) inhibitor linagliptin administered as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control . METHODS This 24-week , r and omized , placebo-controlled , double-blind , parallel-group study was carried out in 82 centres in 10 countries . Patients with HbA1c levels of 7.0 - 10.0 % on metformin and a maximum of one additional antidiabetes medication , which was discontinued at screening , continued on metformin ≥1500 mg/day for 6 weeks , including a placebo run-in period of 2 weeks , before being r and omized to linagliptin 5 mg once daily ( n = 524 ) or placebo ( n = 177 ) add-on . The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment , evaluated with an analysis of covariance ( ANCOVA ) . RESULTS Mean baseline HbA1c and fasting plasma glucose ( FPG ) were 8.1 % and 9.4 mmol/l , respectively . Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c ( -0.49 vs. 0.15 % ) , FPG ( -0.59 vs. 0.58 mmol/l ) and 2hPPG ( -2.7 vs. 1.0 mmol/l ) ; all p < 0.0001 . Hypoglycaemia was rare , occurring in three patients ( 0.6 % ) treated with linagliptin and five patients ( 2.8 % ) in the placebo group . Body weight did not change significantly from baseline in both groups ( -0.5 kg placebo , -0.4 kg linagliptin ) . CONCLUSIONS The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin result ed in a significant and clinical ly meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia AIM Assess long-term safety and efficacy of the dipeptidlyl peptidase-4 ( DPP-4 ) inhibitor vildagliptin in 369 patients with type 2 diabetes mellitus ( T2DM ) and moderate or severe renal impairment ( RI ) . METHODS Double-blind , r and omized , parallel-group , 52-week clinical trial comparing safety and efficacy of vildagliptin ( 50 mg qd , n = 216 ) and placebo ( n = 153 ) added to ongoing stable antihyperglycaemic treatment , in patients with T2DM and moderate or severe ( glomerular filtration rate [ GFR ] ≥ 30 to < 50 ml/min/1.73 m(2 ) and < 30 ml/min/1.73 m(2 ) ) RI . RESULTS The study population comprised 122 and 89 patients with moderate RI and 94 and 64 patients with severe RI r and omized to vildagliptin and placebo , respectively , with the majority of patients receiving background insulin therapy ( 72 % and 82 % for moderate and severe RI , respectively ) . After 1 year , the between-treatment difference in adjusted mean change in A1C was -0.4 ± 0.2 % ( p = 0.005 ) in moderate RI ( baseline = 7.8 % ) and -0.7 ± 0.2 % ( p < 0.0001 ) in severe RI ( baseline = 7.6 % ) . In patients with moderate RI , similar proportions of patients experienced any adverse event ( AE ) ( 84 vs. 85 % ) , any serious adverse event ( SAE ) ( 21 vs. 19 % ) , any AE leading to discontinuation ( 5 % vs. 6 % ) and death ( 1 % vs. 0 % ) with vildagliptin and placebo , respectively . This was also true for patients with severe RI : AEs ( 85 % vs. 88 % ) , SAEs ( 25 % vs. 25 % ) , AEs leading to discontinuation ( 10 % vs. 6 % ) and death ( 3 % vs. 2 % ) . CONCLUSIONS In patients with T2DM and moderate or severe RI , vildagliptin added to ongoing antidiabetic therapy had a safety profile similar to placebo during 1-year observation . Furthermore , relative to placebo , a clinical ly significant decrease in A1C was maintained throughout 1-year treatment with vildagliptin Glucose-lowering treatment options for type 2 diabetes mellitus patients with chronic kidney disease are limited . We evaluated the potential for linagliptin in combination with insulin in type 2 diabetes mellitus patients with mild-to-severe renal impairment . Data for participants in two phase 3 trials with linagliptin who were receiving insulin were analysed separately ( n = 811 ) . Placebo-adjusted mean HbA1c changes from baseline were −0.59 % ( mild renal impairment ) and −0.69 % ( moderate renal impairment ) after 24 weeks and −0.43 % ( severe renal impairment ) after 12 weeks . Drug-related adverse events with linagliptin were similar to placebo ( mild renal impairment : 19.9 % vs 26.5 % ; moderate renal impairment : 22.0 % vs 25.0 % ; severe renal impairment : 46.3 % vs 43.6 % , respectively ) . Frequencies of hypoglycaemia in patients with mild , moderate and severe renal impairment were 34.9 % , 35.6 % and 66.7 % with linagliptin and 37.5 % , 39.7 % and 49.1 % with placebo , respectively . Episodes of severe hypoglycaemia were low ( ⩽5.6 % ) . Adding linagliptin to insulin in type 2 diabetes mellitus patients with chronic kidney disease improved glucose control and was well tolerated BACKGROUND Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin , a dipeptidyl peptidase 4 inhibitor , to usual care in patients with type 2 diabetes and cardiovascular disease . METHODS In this r and omized , double-blind study , we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy . Open-label use of antihyperglycemic therapy was encouraged as required , aim ed at reaching individually appropriate glycemic targets in all patients . To determine whether sitagliptin was noninferior to placebo , we used a relative risk of 1.3 as the marginal upper boundary . The primary cardiovascular outcome was a composite of cardiovascular death , nonfatal myocardial infa rct ion , nonfatal stroke , or hospitalization for unstable angina . RESULTS During a median follow-up of 3.0 years , there was a small difference in glycated hemoglobin levels ( least-squares mean difference for sitagliptin vs. placebo , -0.29 percentage points ; 95 % confidence interval [ CI ] , -0.32 to -0.27 ) . Overall , the primary outcome occurred in 839 patients in the sitagliptin group ( 11.4 % ; 4.06 per 100 person-years ) and 851 patients in the placebo group ( 11.6 % ; 4.17 per 100 person-years ) . Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome ( hazard ratio , 0.98 ; 95 % CI , 0.88 to 1.09 ; P<0.001 ) . Rates of hospitalization for heart failure did not differ between the two groups ( hazard ratio , 1.00 ; 95 % CI , 0.83 to 1.20 ; P=0.98 ) . There were no significant between-group differences in rates of acute pancreatitis ( P=0.07 ) or pancreatic cancer ( P=0.32 ) . CONCLUSIONS Among patients with type 2 diabetes and established cardiovascular disease , adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events , hospitalization for heart failure , or other adverse events . ( Funded by Merck Sharp & Dohme ; TECOS Clinical Trials.gov number , NCT00790205 . ) BACKGROUND To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes , regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies . We assessed cardiovascular outcomes with alogliptin , a new inhibitor of dipeptidyl peptidase 4 ( DPP-4 ) , as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome . METHODS We r and omly assigned patients with type 2 diabetes and either an acute myocardial infa rct ion or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy . The study design was a double-blind , noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . RESULTS A total of 5380 patients underwent r and omization and were followed for up to 40 months ( median , 18 months ) . A primary end-point event occurred in 305 patients assigned to alogliptin ( 11.3 % ) and in 316 patients assigned to placebo ( 11.8 % ) ( hazard ratio , 0.96 ; upper boundary of the one-sided repeated confidence interval , 1.16 ; P<0.001 for noninferiority ) . Glycated hemoglobin levels were significantly lower with alogliptin than with placebo ( mean difference , -0.36 percentage points ; P<0.001 ) . Incidences of hypoglycemia , cancer , pancreatitis , and initiation of dialysis were similar with alogliptin and placebo . CONCLUSIONS Among patients with type 2 diabetes who had had a recent acute coronary syndrome , the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo . ( Funded by Takeda Development Center Americas ; EXAMINE Clinical Trials.gov number , NCT00968708 . ) AIM Assess safety/tolerability and efficacy of the DPP-4 inhibitor vildagliptin in 515 patients with type 2 diabetes mellitus ( T2DM ) and moderate or severe renal impairment ( RI ) . METHODS Double-blind , r and omized , parallel-group , placebo-controlled , 24-week clinical trial assessing safety and efficacy of vildagliptin ( 50 mg qd ) added to current antidiabetic therapy , in patients with T2DM and moderate or severe RI ( GFR ≥ 30 to < 50 or < 30 ml/min/1.73 m(2 ) ) . RESULTS The study population comprised of 165 and 129 patients with moderate RI and 124 and 97 patients with severe RI r and omized to vildagliptin and placebo , respectively , with most patients receiving background insulin therapy ( 68 and 81 % for moderate and severe RI , respectively ) . After 24 weeks , the between-treatment difference in the adjusted mean change in A1C was -0.5 ± 0.1 % ( p < 0.0001 ) in moderate RI ( baseline A1C = 7.9 % ) and -0.6 ± 0.1 % ( p < 0.0001 ) in severe RI ( baseline A1C = 7.7 % ) . In patients with moderate RI , similar proportions of those receiving vildagliptin or placebo experienced any AE ( 68 vs. 73 % ) , any SAE ( 9 vs. 9 % ) , any AE leading to discontinuation ( 3 vs. 5 % ) or death ( 1 vs. 1 % ) . This was also true for patients with severe RI : AEs ( 73 vs. 74 % ) , SAEs ( 19 vs. 21 % ) , AEs leading to discontinuation ( 9 vs. 6 % ) and death ( 2 vs. 4 % ) . CONCLUSIONS In this 24-week study of 515 patients with T2DM and moderate or severe RI , vildagliptin added to ongoing antidiabetic therapy had a safety profile similar to placebo . Further , relative to placebo , vildagliptin elicited a statistically and clinical ly significant decrease in A1C in patients with moderate or severe RI

Based on pooled data from r and omized trials published from 1995 to 2016 , the anticipated survival benefit from surgical treatment result ing from earlier detection of metastases has not been achieved

BACKGROUND After potentially curative resection of primary colorectal cancer , patients may be monitored by measurement of carcinoembryonic antigen and /or CT to detect asymptomatic metastatic disease earlier .

Background The possible benefit for patients from follow‐up examinations after curative surgery for colorectal cancer is unproven . The purpose of this study was to determine whether survival is improved by frequent follow‐up examinations Objective To assess whether colon cancer follow-up can be organised by general practitioners ( GPs ) without a decline in the patient 's quality of life ( QoL ) and increase in cost or time to cancer diagnoses , compared to hospital follow-up . Design R and omised controlled trial . Setting Northern Norway Health Authority Trust , 4 trusts , 11 hospitals and 88 local communities . Participants Patients surgically treated for colon cancer , hospital surgeons and community GPs . Intervention 24-month follow-up according to national guidelines at the community GP office . To ensure a high follow-up guideline adherence , a decision support tool for patients and GPs were used . Main outcome measures Primary outcomes were QoL , measured by the global health scales of the European Organisation for Research and Treatment of Cancer QoL Question naire ( EORTC QLQ C-30 ) and EuroQol-5D ( EQ-5D ) . Secondary outcomes were cost-effectiveness and time to cancer diagnoses . Results 110 patients were r and omised to intervention ( n=55 ) or control ( n=55 ) , and followed by 78 GPs ( 942 follow-up months ) and 70 surgeons ( 942 follow-up months ) , respectively . Compared to baseline , there was a significant improvement in postoperative QoL ( p=0.003 ) , but no differences between groups were revealed ( mean difference at 1 , 3 , 6 , 9 , 12 , 15 , 18 , 21 and 24-month follow-up appointments ) : Global Health ; Δ−2.23 , p=0.20 ; EQ-5D index ; Δ−0.10 , p=0.48 , EQ-5D VAS ; Δ−1.1 , p=0.44 . There were no differences in time to recurrent cancer diagnosis ( GP 35 days vs surgeon 45 days , p=0.46 ) ; 14 recurrences were detected ( GP 6 vs surgeon 8) and 7 metastases surgeries performed ( GP 3 vs surgeon 4 ) . The follow-up programme initiated 1186 healthcare contacts ( GP 678 vs surgeon 508 ) , 1105 diagnostic tests ( GP 592 vs surgeon 513 ) and 778 hospital travels ( GP 250 vs surgeon 528 ) . GP organised follow-up was associated with societal cost savings ( £ 8233 vs £ 9889 , p<0.001 ) . Conclusions GP-organised follow-up was associated with no decline in QoL , no increase in time to recurrent cancer diagnosis and cost savings . Trial registration Clinical Trials.gov identifier NCT00572143 BACKGROUND Although colonoscopy plays an important role in postoperative surveillance of patients with colorectal cancer , the optimum protocol for colonoscopic surveillance has not been established . OBJECTIVE Our purpose was to compare the efficacy of 2 different colonoscopic surveillance strategies in terms of both survival and recurrence resectability . DESIGN Prospect i ve , r and omized , controlled trial . SETTING A teaching hospital in Sun Yat-sen University . PATIENTS Three hundred twenty-six consecutive patients undergoing radical surgery for colorectal cancer . INTERVENTION In the intensive colonoscopic surveillance group ( ICS group , n = 165 ) , colonoscopy was performed at 3-month intervals for 1 year , at 6-month intervals for the next 2 years , and once a year thereafter . In the routine colonoscopic surveillance group ( RCS group , n = 161 ) , colonoscopy was performed at 6 months , 30 months , and 60 months postoperatively . MAIN OUTCOME MEASUREMENTS AND RESULTS The 5-year survival rate was 77 % in the ICS group and 73 % in the RCS group ( P > .05 ) . Postoperative colorectal cancer was detected in 13 patients ( 8.1 % ) in the ICS group and in 18 patients ( 11.4 % ) in the RCS group . In the ICS group , there were more asymptomatic postoperative colorectal cancers ( P = .04 ) , more patients had reoperation with curative intent ( P = .048 ) , and the probability of survival after postoperative colorectal cancer was higher ( P = .03 ) . LIMITATION Lack of detailed characterization of metachronous colorectal adenomas in these patients . CONCLUSIONS Although the patients in the ICS group had more curative operations for postoperative colorectal cancer and survived significantly longer , ICS itself did not improve overall survival OBJECTIVE To determine whether an intensified follow-up of patients with colorectal cancer can lead to improved reresectability and a better long-term survival . DESIGN A prospect i ve r and omized trial of 106 patients . SETTING Oulu University Hospital , a referral center in northern Finl and . PATIENTS A total of 106 consecutive patients who underwent radical resection for colorectal cancer , 54 of whom were r and omized into a conventional follow-up group and 52 into an intensified follow-up group . MAIN OUTCOME MEASURES After a 5-year follow-up , the time of detection of recurrence , the recurrence rates , the first method showing recurrence , the mode of recurrence , reresectability , and survival were compared between the groups . RESULTS The recurrences were identified earlier in the intensified follow-up group than in the conventional follow-up group ( mean + /- SD , 10 + /- 5 months vs 15 + /- 10 months ) . The overall recurrence rate was 41 % , with 39 % in the conventional group and 42 % in the intensified group . Carcinoembryonic antigen determination was the most common method showing recurrence in both groups . Endoscopy and ultrasound were beneficial in the intensified follow-up group , but computed tomography failed to improve the diagnostics . The mode of recurrence did not differ between the groups . Radical resections were performed on 19 % ( 8/43 ) of the patients , 14 % ( 3/21 ) in the conventional group and 22 % ( 5/22 ) in the intensified group . The cumulative 5-year survival was 54 % in the conventional group and 59 % in the intensified group . CONCLUSION Earlier detection of recurrent colorectal cancer by intensified follow-up does not lead to either significantly increased reresectability or improved 5-year survival Introduction The COLOFOL trial , a prospect i ve r and omized multicenter trial comparing two follow-up regimes after curative surgical treatment for colorectal cancer , focuses on detection of asymptomatic recurrences . This paper aims to describe the design and recruitment procedure in the COLOFOL trial , comparing demographic characteristics between r and omized patients and eligible patients not included in the study . Material s and methods COLOFOL was design ed as a pragmatic trial with wide inclusion criteria and few exclusion criteria , in order to obtain a sample reflecting the general patient population . To be eligible , patients had to be 75 years or younger and curatively resected for stage II or III colorectal cancer . Exclusion criteria were hereditary colorectal cancer , no signed consent , other malignancy , and life expectancy less than 2 years due to concomitant disease . In four of the 24 participating centers , we scrutinized hospital inpatient data to identify all colorectal cancer patients who underwent surgery , in order to ascertain all eligible patients who were not included in the study and to compare them with enrolled patients . Results Of a total of 4,445 eligible patients , 2,509 patients were r and omized ( 56.4 % inclusion rate ) . A total of 1,221 eligible patients were identified in the scrutinized hospitals , of which 684 ( 56 % ) were r and omized . No difference in age or sex distribution was observed between r and omized and nonr and omized eligible patients . However , a difference was noted in tumor location and stage distribution , with 5.6 % more patients in the r and omized group having colon cancer and 6.7 % more patients having stage II disease . Conclusion Patients in the two study arms were not only demographically similar , but also similar to nonincluded eligible patients , apart from stage and localization . The analyses will be stratified by these variables . Taken together , we conclude that our trial results will be robust and possible to extrapolate to the target population IMPORTANCE Intensive follow-up after surgery for colorectal cancer is common practice but is based on limited evidence . OBJECTIVE To assess the effect of scheduled blood measurement of carcinoembryonic antigen ( CEA ) and computed tomography ( CT ) as follow-up to detect recurrent colorectal cancer treatable with curative intent . DESIGN , SETTING , AND PARTICIPANTS R and omized clinical trial in 39 National Health Service hospitals in the United Kingdom ; 1202 eligible participants were recruited between January 2003 and August 2009 who had undergone curative surgery for primary colorectal cancer , including adjuvant treatment if indicated , with no evidence of residual disease on investigation . INTERVENTIONS Participants were r and omly assigned to 1 of 4 groups : CEA only ( n = 300 ) , CT only ( n = 299 ) , CEA+CT ( n = 302 ) , or minimum follow-up ( n = 301 ) . Blood CEA was measured every 3 months for 2 years , then every 6 months for 3 years ; CT scans of the chest , abdomen , and pelvis were performed every 6 months for 2 years , then annually for 3 years ; and the minimum follow-up group received follow-up if symptoms occurred . MAIN OUTCOMES AND MEASURES The primary outcome was surgical treatment of recurrence with curative intent ; secondary outcomes were mortality ( total and colorectal cancer ) , time to detection of recurrence , and survival after treatment of recurrence with curative intent . RESULTS After a mean 4.4 ( SD , 0.8 ) years of observation , cancer recurrence was detected in 199 participants ( 16.6 % ; 95 % CI , 14.5%-18.7 % ) overall ; 71 of 1202 participants ( 5.9 % ; 95 % CI , 4.6%-7.2 % ) were treated for recurrence with curative intent , with little difference according to Dukes staging ( stage A , 5.1 % [ 13/254 ] ; stage B , 6.1 % [ 34/553 ] ; stage C , 6.2 % [ 22/354 ] ) . Surgical treatment of recurrence with curative intent was 2.3 % ( 7/301 ) in the minimum follow-up group , 6.7 % ( 20/300 ) in the CEA group , 8 % ( 24/299 ) in the CT group , and 6.6 % ( 20/302 ) in the CEA+CT group . Compared with minimum follow-up , the absolute difference in the percentage of patients treated with curative intent in the CEA group was 4.4 % ( 95 % CI , 1.0%-7.9 % ; adjusted odds ratio [ OR ] , 3.00 ; 95 % CI , 1.23 - 7.33 ) , in the CT group was 5.7 % ( 95 % CI , 2.2%-9.5 % ; adjusted OR , 3.63 ; 95 % CI , 1.51 - 8.69 ) , and in the CEA+CT group was 4.3 % ( 95 % CI , 1.0%-7.9 % ; adjusted OR , 3.10 ; 95 % CI , 1.10 - 8.71 ) . The number of deaths was not significantly different in the combined intensive monitoring groups ( CEA , CT , and CEA+CT ; 18.2 % [ 164/901 ] ) vs the minimum follow-up group ( 15.9 % [ 48/301 ] ; difference , 2.3 % ; 95 % CI , -2.6 % to 7.1 % ) . CONCLUSIONS AND RELEVANCE Among patients who had undergone curative surgery for primary colorectal cancer , intensive imaging or CEA screening each provided an increased rate of surgical treatment of recurrence with curative intent compared with minimal follow-up ; there was no advantage in combining CEA and CT . If there is a survival advantage to any strategy , it is likely to be small . TRIAL REGISTRATION is rct n.org Identifier : 41458548 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 PURPOSE Although systematic postoperative surveillance of patients with colorectal cancer has been demonstrated to improve survival , it remains unknown whether a more intensive strategy provides any significant advantage . This prospect i ve , multicenter , r and omized , controlled trial was aim ed at comparing the efficacy of two different surveillance strategies in terms of both survival and recurrence resectability . PATIENTS AND METHODS Patients with stage II or III colorectal cancer were allocated r and omly to either a simple surveillance strategy including clinical evaluation and serum carcinoembryonic antigen monitoring , or an intensive strategy in which abdominal computed tomography or ultrasonography , chest radiograph , and colonoscopy were added . RESULTS A total of 259 patients were included : 132 were observed according to the simple strategy and 127 were observed according to the intensive strategy . Both groups were similar with respect to baseline characteristics and rate and type of tumor recurrence . After a median follow-up of 48 months , there was no difference in the probability of overall survival in the whole series ( hazard ratio [ HR ] = 0.87 ; 95 % CI , 0.49 to 1.54 ; P = .62 ) . However , the intensive strategy was associated with higher overall survival in patients with stage II tumors ( HR = 0.34 ; 95 % CI , 0.12 to 0.98 ; P = .045 ) and in those with rectal lesions ( HR = 0.09 ; 95 % CI , 0.01 to 0.81 ; P = .03 ) , mainly due to higher rate of resectability for recurrent tumors . Colonoscopy was responsible for the detection of the highest proportion ( 44 % ) of resectable tumor recurrence in the intensive arm . CONCLUSION A more intensive surveillance strategy improves the prognosis of patients with stage II colorectal cancer or those with rectal tumors . Inclusion of regular performance of colonoscopy seems justified up to the fifth year of follow-up , at least Background All patients who undergo surgery for colon cancer are followed up according to the guidelines of the Norwegian Gastrointestinal Cancer Group ( NGICG ) . These guidelines state that the aims of follow-up after surgery are to perform quality assessment , provide support and improve survival . In Norway , most of these patients are followed up in a hospital setting . We describe a multi-centre r and omized controlled trial to test whether these patients can be followed up by their general practitioner ( GP ) without altering quality of life , cost effectiveness and /or the incidence of serious clinical events . Methods and Design Patients undergoing surgery for colon cancer with histological grade Dukes 's Stage A , B or C and below 75 years of age are eligible for inclusion . They will be r and omized after surgery to follow-up at the surgical outpatient clinic ( control group ) or follow-up by the district GP ( intervention group ) . Both study arms comply with the national NGICG guidelines . The primary endpoints will be quality of life ( QoL ) ( measured by the EORTC QLQ C-30 and the EQ-5D instruments ) , serious clinical events ( SCEs ) , and costs . The follow-up period will be two years after surgery , and quality of life will be measured every three months . SCEs and costs will be estimated prospect ively . The sample size was 170 patients . Discussion There is an ongoing debate on the best method of follow-up for patients with CRC . Due to a wide range of follow-up programmes and paucity of r and omized trials , it is impossible to draw conclusions about the best combination and frequency of clinic ( or family practice ) visits , blood tests , endoscopic procedures and radiological examinations that maximize the clinical outcome , quality of life and costs . Most studies on follow-up of CRC patients have been performed in a hospital outpatient setting . We hypothesize that postoperative follow-up of colon cancer patients ( according to national guidelines ) by GPs will not have any impact on patients ' quality of life . Furthermore , we hypothesize that there will be no increase in SCEs and that the incremental cost-effectiveness ratio will improve . Trial registration This trial has been registered at Clinical Trials.gov . The trial registration number is : This trial examined the optimal setting for follow-up of patients after treatment for colon cancer by either general practitioners or surgeons . In all , 203 consenting patients who had undergone potentially curative treatment for colon cancer were r and omised to follow-up by general practitioners or surgeons . Follow-up guidance recommended three monthly clinical review and annual faecal occult blood tests ( FOBT ) and were identical in both study arms . Primary outcome measures ( measured at baseline , 12 and 24 months were ( 1 ) quality of life , SF-12 ; physical and mental component scores , ( 2 ) anxiety and depression : Hospital Anxiety and Depression Scale and ( 3 ) patient satisfaction : Patient Visit-Specific Question naire . Secondary outcomes ( at 24 months ) were : investigations , number and timing of recurrences and deaths . In all , 170 patients were available for follow-up at 12 months and 157 at 24 months . At 12 and 24 months there were no differences in scores for quality of life ( physical component score , P=0.88 at 12 months ; P=0.28 at 24 months : mental component score , P=0.51 , P=0.47 ; adjusted ) , anxiety ( P=0.72 ; P=0.11 ) depression ( P=0.28 ; P=0.80 ) or patient satisfaction ( P=0.06 , 24 months ) . General practitioners ordered more FOBTs than surgeons ( rate ratio 2.4 , 95 % CI 1.4–4.4 ) , whereas more colonoscopies ( rate ratio 0.7 , 95 % CI 0.5–1.0 ) , and ultrasounds ( rate ratio 0.5 , 95 % CI 0.3–1.0 ) were undertaken in the surgeon-led group . Results suggest similar recurrence , time to detection and death rates in each group . Colon cancer patients with follow-up led by surgeons or general practitioners experience similar outcomes , although patterns of investigation vary Objective In patients who have undergone a potentially curative resection of colorectal cancer , does a ‘ second-look ’ operation to resect recurrence , prompted by monthly monitoring of carcinoembryonic antigen , confer a survival benefit ? Design A r and omised controlled trial recruiting patients from 1982 to 1993 was recovered under the Restoring Invisible and Ab and oned Trials ( RIAT ) initiative . Setting 58 hospitals in the UK . Participants From 1982 to 1993 , 1447 patients were enrolled . Of these 216 met the criteria for carcinoembryonic antigen ( CEA ) elevation and were r and omised to ‘ Aggressive ’ or ‘ Conventional ’ arms . Interventions ‘ Second-look ’ surgery with intention to remove any recurrence discovered . Primary outcome measure Survival . Results By February 1993 , 91/108 patients had died in the ‘ Aggressive arm ’ and 88/108 in the ‘ Conventional ’ arm ( relative risk=1.16 , 95 % CI 0.87 to 1.37 ) . By 2011 a further 25 r and omised patients had died . Kaplan-Meier analysis showed no difference in long-term survival . Conclusions The trial was closed in 1993 following a recommendation from the Data Monitoring Committee that it was highly unlikely that any survival advantage would be demonstrated for CEA prompted second-look surgery . This conclusion was confirmed by repeat analysis of survival times after 20 years . Trial registration number IS RCT N76694943 AIMS This paper aims to evaluate the diagnostic efficacy and costs of follow-up tailored according to risk of recurrence compared with minimal surveillance . METHODS A total of 358 patients treated by surgery alone for colorectal cancer were prospect ively divided into two groups of 200 and 158 patients considered at high and low risk of recurrence respectively , according to prognostic factors . They were further r and omized into two subgroups : group 1 , 192 patients undergoing risk-adapted follow-up , intensive and low-intensity ; group 2 , 145 patients undergoing minimal surveillance . Twenty-one cases dropped out . Median follow-up was 61.5 months and 42 months for cases at high risk ( intensive follow-up ) and at low risk ( low-intensity follow-up ) respectively . RESULTS At the end of the study , 52.6 % of patients undergoing risk-adapted follow-up and 57.2 % undergoing minimal follow-up had developed recurrence . In patients at high risk , a significant difference in the incidence of curative re-operations was observed between the subgroups undergoing risk-adapted follow-up and subgroups undergoing minimal surveillance ( P<0.05 ) . The actuarial 5 year survival of patients at high and at low risk of recurrence undergoing risk-adapted follow-up is significantly better than that of cases undergoing minimal follow-up . The economic costs for 34 patients in the intensive follow-up group and for the 57 patients in the low-intensity follow-up group who were free from disease after primary surgery was very similar . CONCLUSIONS Risk-adapted follow-up has significantly improved the targeting of curative re-operations and overall survival of patients independently of risk of recurrence and has allowed a reduction in the costs of following up of disease-free patients Abstract . In a prospect i ve r and omised study , 597 patients subjected to curative surgery for colorectal cancer were allocated to either a group with frequent follow-up or a control group with follow-up every 5 years . The pattern of recurrence is review ed . An equal number of recurrences was detected in the two groups , but the recurrence was diagnosed 9 months earlier in patients followed frequently , and the diagnostic characteristics of various tests dependent upon how often they were used . It is unlikely that frequent follow-up after curative surgery for colorectal cancer has a large positive influence upon survival , but a small benefit from an intensive follow-up program can not be ruled out . The present results indicate that clinical examination , digital rectal examination , proctoscopy , colonoscopy and chest x-ray should be included in such a programme , whereas others ( blood haemoglobin , faecal occult blood test , double contrast braium enema , serum alanine aminotransferase , and serum bilirubin ) should be avoided , having a low sensitivity for detecting recurrent colorectal cancer . Résumé . Cinq-cent-soixante-dix-sept patients ayant subi un traitement chirurgical curatif d'un cancer colo-rectal ont été inclus dans une étude prospect i ve r and omisée et ont été soumis soit à un follow-up fréquent soit à un contrôle tous les 5 ans . Les modalités de récidive sont analysés . Un nombre égal de patients ont développé des récidives dans les 2 groupes et la récidive est diagnostiquée 9 mois plus tôt dans le groupe ayant subi un follow-up à intervalles rapprochés ; les caractéristiques diagnostiques des différents tests utilisés dépendent de la fréquence de leur usage . Il est improbable qu'un follow-up à intervalles rapprochés et après chirurgie curative d'un cancer colo-rectal ait une influence très positive sur la survie des opérés mais un petit nombre de patients pourraient bénéficier d'un programme de follow-up intensif . Les résultats présents indiquent que l'examen clinique , le toucher rectal , la proctoscopie , la colonoscopie et la radio du thorax devraient être inclus dans un tel programme alors que d'autres investigations ( l'hémoglobine sanguine , la recherche de sang fécal occulte , un lavement barytéà double contraste , le dosage sérique de l'alanine aminotransférase et de la bilirubine sérique ) pourraient être évités car ces examens ne montrent qu'une faible sensitivité dans la délection des récidives de cancers colo-rectaux BACKGROUND & AIMS Guidelines on the type and frequency of follow-up of patients after curative surgery for colorectal cancer are unclear . The aim of this study was to determine the survival benefit of a planned follow-up program . METHODS Three hundred twenty-five patients who underwent curative resection of colorectal cancer were prospect ively r and omized to either intensive or st and ard follow-up . After stratification according to Dukes ' stage and site in the colon or rectum , patients were r and omized to intensive follow-up of yearly colonoscopy , computerized tomography ( CT ) of the liver , and chest radiography and clinical review and simple screening vs. structured clinical review and simple screening tests only . RESULTS On completion of 5-year follow-up , there was no significant difference in survival between the two groups . Yearly colonoscopy failed to detect any asymptomatic local recurrences . Only one asymptomatic curable metachronous colon tumor was detected . Liver CT result ed in earlier detection of hepatic metastases but did not increase the number of curative hepatectomies . Only 1 patient had an asymptomatic CT-detected liver metastasis , and another had an asymptomatic chest radiography-detected lung metastasis . Both had curative resections . CONCLUSIONS Yearly colonoscopy , liver CT , and chest radiography will not improve survival from colorectal cancer when added to symptom and simple screening review PURPOSE : This study investigated the value of intense follow-up compared with no follow-up after curative surgery of cancer in the colon or rectum . METHODS : One hundred seven patients were r and omized to no follow-up ( control group ; n=54 ) or intense follow-up ( follow-up group ; n=53 ) after surgery and early postoperative colonoscopy . Patients in the follow-up group were followed at frequent intervals with clinical examination , rigid proctosigmoidoscopy , colonoscopy , computed tomography of the pelvis ( in patients operated with abdominoperineal resection ) , pulmonary x-ray , liver function tests , and determinations of carcinoembryonic antigen and fecal hemoglobin . Follow-up ranged from 5.5 to 8.8 years after primary surgery . RESULTS : Tumor recurred in 18 patients ( 33 percent ) in the control group and in 17 patients ( 32 percent ) in the follow-up group . Reresection with curative intent was performed in three patients in the control group and in five patients ( four of whom were asymptomatic ) in the follow-up group . In the follow-up group two asymptomatic patients with elevated carcinoembryonic antigen levels were disease-free three and five and one-half years after reresection and were the only patients apparently cured by reresection . No patient underwent surgery for metastatic disease in the liver or lungs . Symptomatic metachronous carcinoma was detected in one patient ( control group ) after three years . Five-year survival rate was 67 percent in the control group and 75 percent in the follow-up group ( P > 0.05 ) ; the corresponding cancer-specific survival rates were 71 percent and 78 percent , respectively . CONCLUSION : Intense follow-up after resection of colorectal cancer did not prolong survival in this study PURPOSE Surgery remains the primary treatment of colorectal cancer . Data are lacking to delineate the optimal surveillance strategy following resection . A large-scale multi-center European study is underway to address this issue ( Gruppo Italiano di Lavoro per la Diagnosi Anticipata-GILDA ) . METHODS Following primary surgery with curative intent , stratification , and r and omization at GILDA headquarters , colon cancer patients are then assigned to a more intensive or less intensive surveillance regimen . Rectal cancer patients undergoing curative resection are similarly r and omized , with their follow-up regimens placing more emphasis on detection of local recurrence . Target recruitment for the study will be 1500 patients to achieve a statistical power of 80 % ( assuming an alpha of 0.05 and a hazard-rate reduction of > 24 % ) . RESULTS Since the trial opened in 1998 , 985 patients have been r and omized from 41 centers as of February 2004 . There were 496 patients r and omized to the less intensive regimens , and 489 r and omized to the more intensive regimens . The mean duration of follow-up is 14 months . 75 relapses ( 15 % ) and 32 deaths ( 7 % ) had been observed in the two more intensive follow-up arms , while 64 relapses ( 13 % ) and 24 deaths ( 5 % ) had been observed in the two less intensive arms as of February 2004 . CONCLUSIONS This trial should provide the first evidence based on an adequately powered r and omized trial to determine the optimal follow-up strategy for colorectal cancer patients . This trial is open to US centers , and recruitment continues Objective To analyse the ongoing process of recruiting patients into a multicenter r and omized trial on follow‐up after curative surgery for colorectal cancer . The trial is registered in Clinical Trials Registration BACKGROUND Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries . About 75 % of cases are first diagnosed when the disease is classified as localized or regional , undergo potentially curative treatment and enter a post-treatment surveillance program . Although such programs drain significant re sources from health systems , empirical evidence of their efficacy is scanty . PATIENTS AND METHODS Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment ( surgery and adjuvant radiochemotherapy , if indicated ) were eligible for the trial and r and omized to two different surveillance programs . These programs differed greatly in the frequency of diagnostic imaging . They had similar schedules of physical examinations and carcinoembryonic antigen ( CEA ) assessment s. Patients received baseline and yearly health-related quality -of-life ( HR-QoL ) question naires . Primary outcomes were overall survival ( OS ) and QoL. RESULTS From 1998 to 2006 , 1228 assessable patients were r and omized , 933 with colon cancer and 295 with rectal cancer . More than 90 % of patients had the expected number of diagnostic procedures . Median follow-up duration was 62 months [ interquartile range ( IQR ) 51 - 86 ] in the minimal surveillance group and 62 months ( IQR 50 - 85 ) in the intensive group . At primary analysis , 250 patients had recurred and 218 had died . Intensive surveillance anticipated recurrence , as shown by a significant difference in mean disease-free survival of 5.9 months . Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences . HR-QoL of life scores did not differ between regimens . CONCLUSION Our findings support the conclusions of other r and omized clinical trials , which show that early diagnosis of cancer recurrence is not associated with OS benefit . CLINICAL TRIALSGOV NCT02409472 One-hundred and six consecutive patients were included in a prospect i ve study of intensive monitoring after radical resection for colorectal cancer , 54 being r and omized into a conventional follow-up group ( Group I ) and 52 into an intensified follow-up group ( Group II ) . After a median follow-up of 2 years the overall rate of detection recurrence in Group I was 24 % ( 13/54 ) and in Group II 25 % ( 13/52 ) . The recurrence rates among those followed up for at least 2 years were 36 % ( 10/28 ) and 30 % ( 9/30 ) , respectively . Of the recurrences in Group I , one was local , five regional and six distant , and the corresponding figures in Group II were three , four and five . One radical extirpation of a local perineal recurrence has been performed in Group I , whereas two intestinal reresections for local anastomotic recurrences and two hepatic resections for solitary hepatic metastases have been performed in Group II . Mortality to date is 13 % ( 7/54 ) in Group I and 8 % ( 4/52 ) in Group II . Two adenomatous polyps have been removed from the colon in Group I during endoscopic surveillance and seven in Group II . These preliminary results encourage us to continue the trial up to 5 years after primary surgery PURPOSE : This prospect i ve , r and omized , single-center study was design ed to evaluate the influence of follow-up on detection and resectability of local recurrences and on survival after radical surgery for colorectal cancer . METHODS : Between 1987 and 1990 , 207 consecutive patients who underwent curative resections for primary untreated large-bowel carcinoma were r and omly assigned to a conventional follow-up group ( Group A ; n=103 ) and to an intense follow-up group ( Group B ; n=104 ) . All the patients were followed up prospect ively , and the outcome was known for all of them at five years . Patients in Group A were seen at six-month intervals for one year , and once a year thereafter . Patients in Group B were checked every three months during the first two years , at six-month intervals for the next three years , and once a year thereafter . RESULTS : Of the 103 patients in Group A , local recurrence was detected in 20 ; 9 ( 13 percent ) of these patients had colon cancer , and 11 ( 29 percent ) had rectal cancer . Of the 104 patients in Group B , local recurrence was detected in 26 ; 12 ( 16 percent ) of these patients had colon cancer , and 14 ( 45 percent ) had rectal cancer . Twelve cases ( 60 percent ) of local recurrence in Group A and 24 cases ( 92 percent ) in Group B were detected at scheduled visits ( P<0.05 ) . Local recurrences were detected earlier in patients of Group B ( 10.3±2.7vs . 20.2±6.1 months;P<0.0003 ) . Curative re-resection was possible in 2 patients ( 10 percent ) in Group A , 1 with colon cancer and 1 with rectal cancer , and in 17 patients ( 65 percent ) in Group B , 6 with colon cancer and 11 with rectal cancer ( P<0.01 ) . Of the Group B patients who had curative re-resections of local recurrence , 8 ( 47 percent ) were disease-free and long-term survivors as of the last follow-up , and 2 ( 11.7 percent ) were alive , but with a new recurrence . The 2 patients in Group A who had curative re-resections died as a result of cancer . The five-year survival rate in Group A was 58.3 percent and in Group B was 73.1 percent . The difference is statistically significant ( P < 0.02 ) . CONCLUSIONS : Our data support use of an intense follow-up plan after primary resection of large-bowel cancer , at least in patients with rectal cancer AIM The value of frequent Carcino-Embryonic Antigen ( CEA ) measurements and CEA-triggered imaging for detecting recurrent disease in colorectal cancer ( CRC ) patients was investigated in search for an evidence -based follow-up protocol . METHODS This is a r and omized-controlled multicenter prospect i ve study using a stepped-wedge cluster design . From October 2010 to October 2012 , surgically treated non-metastasized CRC patients in follow-up were followed in eleven hospitals . Clusters of hospitals sequentially changed their usual follow-up care into an intensified follow-up schedule consisting of CEA measurements every two months , with imaging in case of two CEA rises . The primary outcome measures were the proportion of recurrences that could be treated with curative intent , recurrences with definitive curative treatment outcome , and the time to detection of recurrent disease . RESULTS 3223 patients were included ; 243 recurrences were detected ( 7.5 % ) . A higher proportion of recurrences was detected in the intervention protocol compared to the control protocol ( OR = 1.80 ; 95%-CI : 1.33 - 2.50 ; p = 0.0004 ) . The proportion of recurrences that could be treated with curative intent was higher in the intervention protocol ( OR = 2.84 ; 95%-CI : 1.38 - 5.86 ; p = 0.0048 ) and the proportion of recurrences with definitive curative treatment outcome was also higher ( OR = 3.12 , 95%-CI : 1.25 - 6.02 , p-value : 0.0145 ) . The time to detection of recurrent disease was significantly shorter in the intensified follow-up protocol ( HR = 1.45 ; 95%-CI : 1.08 - 1.95 ; p = 0.013 ) . CONCLUSION The CEAwatch protocol detects recurrent disease after colorectal cancer earlier , in a phase that a significantly higher proportion of recurrences can be treated with curative intent

BACKGROUND Cognitive-behavioural therapy (CBT)-based guided self-help ( GSH ) has been suggested to be an effective intervention for mild to moderate anxiety and depression , yet the evidence seems inconclusive , with some studies reporting that GSH is effective and others finding that GSH is ineffective . Meta- analysis indicated the effectiveness of GSH at post-treatment , although GSH was found to have limited effectiveness at follow-up or among more clinical ly representative sample s. Studies that reported greater effectiveness of GSH tended to be of lower method ological quality and generally involved participants who were self-selected rather than recruited through clinical referrals . Further rigorous evidence based on clinical population s that examines longer-term outcomes is required before CBT-based GSH interventions can be deemed effective for adults accessing primary care services for treatment of anxiety and depression

GSH differs in important respects from other levels of self-help , yet the literature regarding exclusively guided self-help interventions for anxiety and depression has not been review ed systematic ally .

BACKGROUND Effective internet-based programs for depression usually incorporate a component that provides telephone or email contact . Open access websites , without such contact , show high rates of attrition and poorer outcomes . The present study was design ed as an exploratory investigation of the parameters that influence the effectiveness and retention of users on open access websites . We investigated whether brief cognitive behaviour therapy ( CBT ) was as effective as an extended version , whether add-on components of behaviour therapy or stress management contributed to positive outcomes , and whether longer programs were associated with greater attrition . METHOD An online r and omized controlled trial ( RCT ) was conducted between 13 January 2005 and 26 May 2005 ( 19 weeks ) . A total of 2794 registrants ( 1846 women and 948 men ; median age category 35 - 44 years ) with elevated scores on the Goldberg Depression Scale of 5.96 ( S.D.=2.09 ) elected online to be r and omized to one of six versions of a CBT website . The versions were compiled consisting of various components of brief CBT , extended CBT , behaviour strategies , stress management and problem solving . RESULTS A total of 20.4 % of participants completed the assigned intervention . The interaction of measurement occasion and treatment version was significant [ F(13,131)=2.20 , p=0.01 ] . A single module of brief introductory CBT was not effective in reducing depression symptoms . However , extended CBT with or without the addition of behaviour strategies result ed in the reduction of depression . CONCLUSIONS Brief CBT-based interventions are not as effective as extended interventions . However , longer programs are associated with higher rates of dropout Current approaches to the treatment of panic disorder ( PD ) include a treatment package consisting of relaxation training ( RT ) , cognitive therapy ( CT ) , and exposure-based components . In an examination of the separate effects of RT and CT without formally taught exposure of any form , 64 PD patients were assigned r and omly to one of these treatment protocol s or to a minimal-contact control ( MCC ) condition . Both RT and CT were superior to the MCC condition on a variety of measures pertaining to panic , global psychological functioning , agoraphobic fear , and other associated fears . A significantly greater percentage of patients were classified as treatment responders ( based on a composite index ) after CT ( 82 % ) and RT ( 68 % ) , compared with the control group ( 36 % ) . On measures of agoraphobic fear , CT patients fared slightly better than RT patients . Some support was demonstrated for specific cognitive changes after CT , although treatment specificity was not strongly supported overall . These results are discussed in light of current theories of PD and the presumed importance of exposure in its treatment Mild depressive syndromes are highly prevalent among primary -care patients . Evidence -based treatment recommendations need to be derived directly from this diagnostically heterogeneous group . The primary aim was to assess the efficacy of sertraline and cognitive-behavioural group therapy for treatment of depressed primary -care patients , the secondary aim was to evaluate if receiving treatment according to free choice is associated with a better outcome than r and omization to a particular treatment . We conducted a r and omized , placebo-controlled , single-centre , 10-wk trial with five arms : sertraline ( flexible dosages up to 200 mg/d ) ( n = 83 ) ; placebo ( n = 83 ) ; manual-guided cognitive-behavioural group therapy ( one individual session and nine group sessions per 90 min ) ( n = 61 ) ; guided self-help group ( control condition , n = 59 ) ; and treatment with sertraline or cognitive-behavioural group therapy according to patients ' choice ( n = 82 ) . From 1099 consecutively screened adult patients , 368 formed the intent-to-treat population with milder forms of depression . Primary outcome was a global efficacy measure combining z-converted Hamilton Depression Rating Scale and clinician-rated Inventory for Depressive Symptomatology scores . Sertraline was superior to placebo ( p = 0.03 ) . Outcome for guided self-help groups was worse compared to cognitive-behavioural group therapy ( p = 0.002 ) and compared to all other treatment arms including pill placebo ( secondary analyses ) . Outcome in the patients ' choice arm was similar to that in the sertraline and cognitive-behavioural group therapy . Overall , sertraline is efficacious in primary -care patients with milder forms of depression . The superiority of cognitive-behavioural group therapy over guided self-help groups might partly be explained by ' nocebo ' effects of the latter BACKGROUND Although effective therapies for social phobia exist , many individuals refrain from seeking treatment owing to the embarrassment associated with help-seeking . Internet-based cognitive-behavioural self-help can be an alternative , but adherence is a problem . AIMS To evaluate a 9-week programme of internet-based therapy design ed to increase treatment adherence by the addition of short weekly telephone calls , nine in all , with a total duration of 95 min . METHOD In a r and omised controlled trial the effects of internet-based cognitive-behavioural therapy in the treatment group ( n=29 ) were compared with a waiting-list control group ( n=28 ) . RESULTS Compared with the control group the treated participants experienced greater reductions on measures of general and social anxiety , avoidance and depression . Adherence to treatment was high , with 93 % finishing the complete treatment package . One year later all improvements were maintained . CONCLUSIONS This study provides evidence to support the use of internet-based treatment supplemented by short , weekly telephone calls 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 Background Guided self-help programs for depression ( with associated therapist contact ) have been successfully delivered over the Internet . However , previous trials of pure self-help Internet programs for depression ( without therapist contact ) , including an earlier trial conducted by us , have failed to yield positive results . We hypothesized that methods to increase participant usage of the intervention , such as postcard or telephone reminders , might result in significant effects on depression . Objectives This paper presents a second r and omized trial of a pure self-help Internet site , ODIN ( Overcoming Depression on the InterNet ) , for adults with self-reported depression . We hypothesized that frequently reminded participants receiving the Internet program would report greater reduction in depression symptoms and greater improvements in mental and physical health functioning than a comparison group with usual treatment and no access to ODIN . Methods This was a three-arm r and omized control trial with a usual treatment control group and two ODIN intervention groups receiving reminders through postcards or brief telephone calls . The setting was a nonprofit health maintenance organization ( HMO ) . We mailed recruitment brochures by US post to two groups : adults ( n = 6030 ) who received depression medication or psychotherapy in the previous 30 days , and an age- and gender-matched group of adults ( n = 6021 ) who did not receive such services . At enrollment and at 5- , 10- and 16-weeks follow-up , participants were reminded by email ( and telephone , if nonresponsive ) to complete online versions of the Center for Epidemiological Studies Depression Scale ( CES-D ) and the Short Form 12 ( SF-12 ) . We also recorded participant HMO health care services utilization in the 12 months following study enrollment . Results Out of a recruitment pool of 12051 approached subjects , 255 persons accessed the Internet enrollment site , completed the online consent form , and were r and omized to one of the three groups : ( 1 ) treatment as usual control group without access to the ODIN website ( n = 100 ) , ( 2 ) ODIN program group with postcard reminders ( n = 75 ) , and ( 3 ) ODIN program group with telephone reminders ( n = 80 ) . Across all groups , follow-up completion rates were 64 % ( n = 164 ) at 5 weeks , 68 % ( n = 173 ) at 10 weeks , and 66 % ( n = 169 ) at 16 weeks . In an intention-to-treat analysis , intervention participants reported greater reductions in depression compared to the control group ( P = .03 ; effect size = 0.277 st and ard deviation units ) . A more pronounced effect was detected among participants who were more severely depressed at baseline ( P = .02 ; effect size = 0.537 st and ard deviation units ) . By the end of the study , 20 % more intervention participants moved from the disordered to normal range on the CES-D. We found no difference between the two intervention groups with different reminders in outcomes measures or in frequency of log-ons . We also found no significant intervention effects on the SF-12 or health care services . Conclusions In contrast to our earlier trial , in which participants were not reminded to use ODIN , in this trial we found a positive effect of the ODIN intervention compared to the control group . Future studies should address limitations of this trial , including relatively low enrollment and follow-up completion rates , and a restricted number of outcome measures . However , the low incremental costs of delivering this Internet program makes it feasible to offer this type of program to large population s with widespread Internet access 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 Research suggests that depressive disorders exist on a continuum , with subthreshold symptoms causing considerable population burden and increasing individual risk of developing major depressive disorder . An alternative strategy to professional treatment of subthreshold depression is population promotion of effective self-help interventions that can be easily applied by an individual without professional guidance . The evidence for self-help interventions for depressive symptoms is review ed in the present work , with the aim of identifying promising interventions that could inform future health promotion campaigns or stimulate further research . Methods A literature search for r and omised controlled trials investigating self-help interventions for depressive disorders or depressive symptoms was performed using PubMed , PsycINFO and the Cochrane Data base of Systematic Review s. Reference lists and citations of included studies were also checked . Studies were grouped into those involving participants with depressive disorders or a high level of depressive symptoms , or non- clinical ly depressed participants not selected for depression . A number of exclusion criteria were applied , including trials with small sample sizes and where the intervention was adjunctive to antidepressants or psychotherapy . Results The majority of interventions search ed had no relevant evidence to review . Of the 38 interventions review ed , the ones with the best evidence of efficacy in depressive disorders were S-adenosylmethionine , St John 's wort , bibliotherapy , computerised interventions , distraction , relaxation training , exercise , pleasant activities , sleep deprivation , and light therapy . A number of other interventions showed promise but had received less research attention . Research in non- clinical sample s indicated immediate beneficial effects on depressed mood for distraction , exercise , humour , music , negative air ionisation , and singing ; while potential for helpful longer-term effects was found for autogenic training , light therapy , omega 3 fatty acids , pets , and prayer . Many of the trials were poor quality and may not generalise to self-help without professional guidance . Conclusion A number of self-help interventions have promising evidence for reducing subthreshold depressive symptoms . Other forms of evidence such as expert consensus may be more appropriate for interventions that are not feasible to evaluate in r and omised controlled trials . There needs to be evaluation of whether promotion to the public of effective self-help strategies for subthreshold depressive symptoms could delay or prevent onset of depressive illness , reduce functional impairment , and prevent progression to other undesirable outcomes such as harmful use of substances 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 BACKGROUND Preliminary results have demonstrated the clinical efficacy of computerised cognitive-behavioural therapy ( CBT ) in the treatment of anxiety and depression in primary care . AIMS To determine , in an exp and ed sample , the dependence of the efficacy of this therapy upon clinical and demographic variables . METHOD A sample of 274 patients with anxiety and /or depression were r and omly allocated to receive , with or without medication , computerised CBT or treatment as usual , with follow-up assessment at 6 months . RESULTS The computerised therapy improved depression , negative attributional style , work and social adjustment , without interaction with drug treatment , duration of preexisting illness or severity of existing illness . For anxiety and positive attributional style , treatment interacted with severity such that computerised therapy did better than usual treatment for more disturbed patients . Computerised therapy also led to greater satisfaction with treatment . CONCLUSIONS Computer-delivered CBT is a widely applicable treatment for anxiety and /or depression in general practice BACKGROUND The dem and for time-consuming psychotherapy of phobia/panic exceeds the supply of trained therapists . Delegating routine therapy aspects to a computer might ease this problem . METHOD Ninety-three out- patients with phobia or panic disorder were r and omized in a 2 : 2 : 1 ratio to have self-exposure therapy guided either mainly by a st and -alone computer system ( FearFighter ) or entirely face-to-face by a clinician , or to have mainly computer-guided self-relaxation as a placebo . Both computer groups ( FearFighter and relaxation ) had brief back-up advice from a clinician . Primary outcome measures were self- and blind-assessor ratings of Main Problem and Goals , and Global Phobia . RESULTS Drop-outs occurred significantly more often in the two self-exposure groups ( 43 % if mainly computer-guided , 24 % if entirely clinician-guided ) than with self-relaxation ( 6 % ) ; the difference between the two self-exposure groups was not significant . Even with all drop-outs included , the mainly computer-guided exposure group and the relaxation group had 73 % less clinician time per patient than did the entirely clinician-guided exposure group . The two self-exposure groups had comparable improvement and satisfaction at post-treatment and at 1-month follow-up , while relaxation was ineffective . Mean improvement on the primary outcome measures ( self- and assessor-rated ) was 46 % computer , 49 % clinician , 9 % relaxation at post-treatment ( week 10 ) and 58 % computer , 53 % clinician and -4 % relaxation at 1-month follow-up ( week 14 ) . Mean effect sizes on the primary outcome measures were 2.9 computer , 3.5 clinician and 0.5 relaxation at post-treatment ; and 3.7 computer , 3.5 clinician and 0.5 relaxation at 1-month follow-up . The assessor did not rate patients at follow-up . CONCLUSIONS Despite its ( non-significantly ) higher dropout rate , self-exposure therapy for panic/ phobia cut clinician time per patient by 73 % without losing efficacy when guided mainly by a computer rather than entirely by a clinician . The finding needs confirmation at a follow-up that is longer and includes a blind assessor . Self-relaxation had the highest rate of completers but was ineffective Background Mood and anxiety disorders are highly prevalent and have a large impact on the lives of the affected individuals . Therefore , optimal treatment of these disorders is highly important . In this study we will examine the effectiveness of a stepped care program for primary care patients with mood and anxiety disorders . A stepped care program is characterized by different treatment steps that are arranged in order of increasing intensity . Methods This study is a r and omised controlled trial with two conditions : stepped care and care as usual , whereby the latter forms the control group . The stepped care program consists of four evidence based interventions : ( 1 ) Watchful waiting , ( 2 ) Guided self-help , ( 3 ) Problem Solving Treatment and ( 4 ) Medication and /or specialized mental health care . The study population consists of primary care attendees aged 18–65 years . Screeners are sent to all patients of the participating general practitioners . Individuals with a Diagnostic and Statistical Manual of mental disorders ( DSM ) diagnosis of major depression , dysthymia , panic disorder ( with or without agoraphobia ) , generalized anxiety disorder , or social phobia are included as well as individuals with minor depression and anxiety disorders . Primary focus is the reduction of depressive and anxiety symptoms . Both conditions are monitored at 8 , 16 and 24 weeks . Discussion This study evaluates the effectiveness of a stepped care program for patients with depressive and anxiety disorder . If effective , a stepped care program can form a worthwhile alternative for care as usual . Strengths and limitations of this study are discussed . Trial Registration Current Controlled Trails : IS RCT N17831610 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 Background Current guidelines for the management of depression suggest the use of guided self-help for patients with mild to moderate disorders . However , there is little consensus concerning the optimal form and delivery of this intervention . To develop acceptable and effective interventions , a phased process has been proposed , using a modelling phase to examine and develop an intervention prior to preliminary testing in an exploratory trial . This paper ( a ) describes the modelling phase used to develop a guided self-help intervention for depression in primary care and ( b ) reports data from an exploratory r and omised trial of the intervention . Methods A guided self-help intervention was developed following a modelling phase which involved a systematic review , meta synthesis and a consensus process . The intervention was then tested in an exploratory r and omised controlled trial by examining ( a ) fidelity using analysis of taped guided self-help sessions ( b ) acceptability to patients and professionals through qualitative interviews ( c ) effectiveness through estimation of the intervention effect size . Results Fifty eight patients were recruited to the exploratory trial . Seven professionals and nine patients were interviewed , and 22 tapes of sessions analysed for fidelity . Generally , fidelity to the intervention protocol was high , and the professionals delivered the majority of the specific components ( with the exception of the use of feedback ) . Acceptability to both professionals and patients was also high . The effect size of the intervention on outcomes was small , and in line with previous analyses showing the modest effect of guided self-help in primary care . However , the sample size was small and confidence intervals around the effectiveness estimate were wide . Conclusion The general principles of the modelling phase adopted in this study are design ed to draw on a range of evidence , potentially providing an intervention that is evidence -based , patient-centred and acceptable to professionals . However , the pilot outcome data did not suggest that the intervention developed was particularly effective . The advantages and disadvantages of the general methods used in the modelling phase are discussed , and possible reasons for the failure to demonstrate a larger effect in this particular case are outlined BACKGROUND Common mental health problems account for up to 40 % of all general practitioner ( GP ) consultations . Patients have limited access to evidence -based psychological therapies . Cognitive behavioural therapy self-help strategies offer one potential solution . AIM To determine differences in clinical outcome , patient satisfaction and costs , between a cognitive behavioural-based self-help package facilitated by practice nurses compared to ordinary care by GPs for mild to moderate anxiety and depression . DESIGN OF STUDY R and omised controlled trial . SETTING Seventeen primary healthcare teams . METHOD Patients presenting to their GP with mild to moderate anxiety and /or depression were recruited to the study and r and omised to receive either a self-help intervention facilitated by practice nurses or ordinary care . The self-help intervention consisted of up to three appointments : two 1 week apart and a third 3 months later . There were no restrictions on ordinary care . RESULTS Intention-to-treat analysis showed that patients treated with practice nurse-supported cognitive behavioural therapy self-help attained similar clinical outcomes for similar costs and were more satisfied than patients treated by GPs with ordinary care . On-treatment analysis showed patients receiving the facilitated cognitive behavioural therapy self-help were more likely to be below clinical threshold at 1 month compared to the ordinary care group ( odds ratio [ OR ] = 3.65 , 95 % confidence interval [ CI ] = 1.87 to 4.37 ) . This difference was less well marked at 3 months ( OR = 1.36 , 95 % CI = 0.52 to 3.56 ) . CONCLUSION Facilitated cognitive behavioural self-help may provide a short-term cost-effective clinical benefit for patients with mild to moderate anxiety and depression . This has the potential to help primary care provide a choice of effective psychological as well as pharmacological treatments for mental health problems BACKGROUND Cognitive Behaviour Therapy self-help has been recommended in the NICE guidelines for the treatment of anxiety and depression . However , little is known about who benefits from self-help and the potential drawbacks and problems of using this approach . AIMS To address the current gap in knowledge , we contacted accredited BABCP practitioners to examine practitioner use and attitudes to self-help , current trends of use , and to identify possible problems with this therapy . METHOD A 50 % r and om sample of all accredited BABCP practitioners was approached , and the overall response rate for the survey was 57.6 % . RESULTS Self-help material s were seen positively by therapists and were used by 99.6 % , mainly as an adjunct to individual therapy . Only 38.2 % had been trained in the use of self-help , with those trained being more likely to recommend self-help . Higher levels of patient motivation , credibility , likely adherence , self-efficacy and a lower degree of hopelessness were the five factors identified by more than 70 % of respondents as predicting successful patient outcome with self-help . Non-compliance and a lack of detection of a worsening of the patient 's clinical state due to reduced therapist contact were viewed as being the most important problems with self-help by more than 70 % of respondents . CONCLUSIONS Preferable patient characteristics for self-help have been identified , as have potential problems and adverse consequences 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 The present study investigated the effectiveness of bibliotherapy and minimal therapist-contact interventions in the treatment of panic attacks . Individuals were r and omly assigned to one of three conditions : ( 1 ) bibliotherapy alone ( BT ) ; ( 2 ) bibliotherapy plus phone contact ( BT+PC ) ; or ( 3 ) phone contact alone ( PC ) . Assessment ( pre- and post-treatment ) and treatment ( 8 weeks in duration ) were conducted via mail and phone . Individuals receiving BT and BT+PC exhibited significant reductions from pre- to post-treatment on panic cognitions and fear of having a panic attack . Individuals receiving BT+PC exhibited significant reductions from pre- to post-treatment on panic symptoms and avoidance . In addition , individuals in the BT and BT+PC groups were more likely to exhibit clinical ly significant improvement on most dependent measures relative to PC alone . On some measures , individuals in the BT+PC group did clinical ly better than individuals in the BT group . Results of the present study also suggest that diagnosis may play some role in outcome OBJECTIVE This study evaluated a 10-week Internet-based bibliotherapy self-help program with short weekly telephone calls for people suffering from panic disorder with or without agoraphobia . METHOD After the authors confirmed the diagnosis by administering the Structured Clinical Interview for DSM-IV by telephone , 60 participants were r and omly assigned to either a wait-listed control group or a multimodal treatment package based on cognitive behavior therapy plus minimal therapist contact via e-mail . A 10-minute telephone call was made each week to support each participant . Total mean time spent on each participant during the 10 weeks was 3.9 hours . The participants were required to send in homework assignments before receiving the next treatment module . RESULTS Analyses were conducted on an intention-to-treat basis , which included all r and omly assigned participants . From pretreatment to posttreatment , all treated participants improved significantly on all measured dimensions ( bodily interpretations , maladaptive cognitions , avoidance , general anxiety and depression levels , and quality of life ) . Treatment gains on self-report measures were maintained at the 9-month follow-up . A blind telephone interview after the end of treatment revealed that 77 % of the treated patients no longer fulfilled the criteria for panic disorder , whereas all of the wait-listed subjects still suffered from it . CONCLUSIONS This study provides evidence to support the use of treatment distributed via the Internet with the addition of short weekly telephone calls to treat panic disorder . Replication should be made to compare self-help and telephone treatment based on cognitive behavior methods with nonspecific interventions 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 This study compared the relative short- and longer-term efficacy of therapist-guided and unguided use of a cognitive behavioral self-help manual for binge eating [ Fairburn , C. G. ( 1995 ) . Overcome binge eating . New York : The Guilford Press . ] Forty women ( 82.5 % with binge eating disorder ) were r and omized to one of the two treatment levels . Results indicate that both conditions represent viable means of treating binge eating . Overall , patients improved their eating behavior , eliminated any inappropriate compensatory behaviors , reduced their shape concern , weight concern , and other symptoms of eating-related psychopathology , and improved their general psychological functioning . The guided self-help condition was notably superior in reducing the occurrence of binge eating and its associated symptomatology , as well as lowering interpersonal sensitivity . A high degree of general psychopathology was a negative prognostic indicator . The implication s for a stepped-care approach to treating binge eating are discussed Due to treatment accessibility and cost issues , interest in self-help programs ( e.g. , bibliotherapy , telehealth ) for common psychological disorders is growing . Research supporting the efficacy of such a program for social anxiety , however , is limited . The present study examined the efficacy of an 8-week self-directed cognitive behavioral treatment with minimal therapist involvement for social phobia based on a widely available self-help book . Twenty-one adults with social phobia initially received either treatment ( i.e. assigned readings in the workbook with limited therapist contact ) or were wait-listed . Wait-listed patients eventually received the same self-directed treatment . Results revealed that the self-help/minimal therapist contact treatment was superior to wait-list on most outcome measures . Across the entire sample , reductions in social anxiety , global severity , general anxiety , and depression were observed at posttest and 3-month follow-up . These findings provide preliminary support for using this self-help workbook for individuals with mild to moderate social anxiety in conjunction with infrequent therapist visits to reinforce the treatment principles . Study limitations and future directions are discussed 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 Behavioural methods of treating anxiety have been shown to be highly effective but are not widely available in general practice where most people suffering from anxiety are treated . This study reports a development in service delivery which is simple , inexpensive and does not make great time dem and s on general practitioners or require them to extend their training and expertise . The study shows that for patients suffering from panic disorder or generalized anxiety disorder the use of an anxiety management booklet in addition to their usual treatment from their general practitioner produces clinical ly and statistically significant improvements . Of particular importance is the speed of response to the booklet . Within the first two weeks those patients who received the booklet were significantly less anxious than the controls . The booklet was acceptable to patients and recommendations are made about how to incorporate it into clinical practice The effectiveness of minimal-contact cognitive bibliotherapy was examined with a group of 80 depressed adults who were recruited from the community . Minimal-contact cognitive bibliotherapy was found to be superior to a waiting-list control group . The results were both statistically and clinical ly significant , and the treatment group maintained their levels of improvement at 3-month follow-up . The results also indicated significant decreases in dysfunctional attitudes and automatic negative thoughts after treatment . It appeared that the treatment also served a psychoeducational function . The interventive and preventive implication s of these results are discussed 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 BACKGROUND Anxiety disorders are prevalent in primary care . Psychological treatment is effective but time-consuming , and there are waiting lists for secondary care . Interest has therefore grown in developing guidelines for treatment that would be feasible in primary care . AIM To compare the effectiveness and feasibility of guided self-help , the Anxiety Disorder Guidelines of the Netherl and s College of General Practitioners and cognitive behavioural therapy ( CBT ) . DESIGN OF STUDY R and omised controlled study lasting 12 weeks with follow-up at 3 and 9 months for primary care patients with panic disorder and /or generalised anxiety disorder . SETTING The first two forms of treatment were carried out by 46 GPs who were r and omly assigned to one or the other form . CBT was carried out by cognitive behaviour therapists in a psychiatric outpatient clinic . METHOD Participants ( n = 154 ) were r and omly assigned to one of the three forms of treatment . The main outcome measure used was the state subscale of the Spielberger Anxiety Inventory . RESULTS All three forms of treatment gave significant improvement between pre-test and post-test , and this improvement remained stable between post-test and the follow-ups . The results obtained with the three treatment forms did not differ significantly over time . The feasibility of the Anxiety Disorder Guidelines was low compared with that of guided self-help . CONCLUSION Our results indicate that primary care patients with prevalent anxiety disorders for whom the GP does not find referral necessary can be adequately treated by the GP . Psychiatric outpatient clinic referral does not give superior results . Guided self-help is easier for the GP to carry out than a less highly-structured treatment like that laid down in the Anxiety Disorder Guidelines Current traditional methods of mental healthcare service delivery , based on ' specialists ' providing ' outpatient appointments ' for formal therapy , are often inappropriate for the needs of patients in primary care . The estimated numbers of adults with mental health problems are immense , and it is this , combined with Department of Health initiatives aim ed at improving choice and access , which make it essential that new ways of delivering services are explored . This trial examines the use of an assisted self-help treatment package for mild to moderate stress/anxiety [ Assisted Bibliotherapy ( AB ) ] with an adult clinical population referred by their general practitioner . Assisted Bibliotherapy is a brief intervention ( 8 weeks ) , with limited therapist contact ( 20-min sessions ) . Non-parametric statistical testing of scores from the Zung Anxiety Scale and the Clinical Outcomes in Routine Evaluation ( CORE ) question naire indicated positive results . There was significant improvement at post-treatment , which was maintained at 3 month follow-up . The results from this trial and a previous trial of AB by Kupshik & Fisher in 1999 , indicate that it is an effective treatment which could be used as part of a stepped care approach to managing and treating stress/anxiety in primary care 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 BACKGROUND Non-professional treatment programmes are presumed to relieve the extensive need for care of anxiety and depression disorders . This study investigates the effectiveness of cognitive self- therapy ( CST ) in the treatment of depression or generalized anxiety disorder . METHOD Patients ( n=151 ) were r and omized to receive CST or treatment as usual ( TAU ) in a trial lasting for 18 months , measuring symptoms ( SCL-90 ; main outcome ) , social functions , quality of life and utilization of care . RESULTS Patients in both conditions improved significantly , but no difference was found between the conditions . Reduction of symptoms , improvement of social functions and medical utilization were maintained at the end of the 18 months . Medical care utilization ( therapist contact and hospitalization ) was lower for CST than for TAU . No suicides occurred . CONCLUSIONS Cognitive self-therapy is likely to decrease the need for care of chronic depression and anxiety disorders , but it has not been proven to be more effective than treatment as usual BACKGROUND There are significant barriers to accessing effective psychological therapy in primary care result ing from a lack of suitably trained therapists to meet current dem and . More efficient service delivery using minimal interventions ( such as bibliotherapy ) provided by paraprofessional therapists may be one method of overcoming these problems , and is the subject of attention in the UK and elsewhere . A r and omized trial was conducted to test the clinical effectiveness of this model . Assistant psychologists delivered a guided self-help intervention to patients with anxiety and depression who were currently waiting for psychological therapy . METHOD A total of 114 patients were r and omized either to guided self-help or a waiting-list control group . All patients were followed up 3 months later , prior to starting conventional psychological therapy . Measures included self-reported adherence to the intervention , anxiety and depressive symptoms , social functioning and patient satisfaction . RESULTS Adherence to the guided self-help intervention was acceptable and patients reported satisfaction with the intervention . However , there were no statistically significant differences between groups in anxiety and depression symptoms at 3 months . CONCLUSIONS The results demonstrate that this model of guided self-help did not provide additional benefit to patients on a waiting list for psychological therapy . The results are considered in the context of possible internal and external validity threats , and compared with previous trials of minimal interventions . The implication s of the results for the design of future minimal interventions are considered BACKGROUND The purpose of the study was to examine whether the addition of a brief individual self-help package to st and ard primary -care treatment of depression with antidepressants is associated with any additional improvements in clinical outcome . METHOD Individuals with major depressive disorder who were prescribed an antidepressant were recruited through their general practitioner ( GP ) and allocated r and omly to st and ard treatment alone or st and ard treatment plus self-help . Assessment s of symptoms , social adjustment , global functioning , satisfaction with treatment and knowledge about the management of the disorder were completed at three time points over 26 weeks . RESULTS One hundred and twelve individuals agreed to participate and 96 met criteria for inclusion in the r and omized controlled trial . Subjects in both treatment conditions improved substantially over the study period ; the mean Beck Depression Inventory ( BDI ) score fell from 27.3 to 13.9 in the intention-to-treat analysis . There were no between group differences in outcome on any of the primary outcome measures , nor did these approach even marginal significance . Patients and GPs were highly satisfied with the self-help programme , and the intervention as compared to the control group reported significantly greater improvements in knowledge about depression and satisfaction with information received about depression . CONCLUSIONS An individualized self-help package improved perceived knowledge about depression but did not have identifiable effects on outcome when offered to patients treated in primary care . The study was sufficiently well powered to detect relatively small effects Abstract Objectives To compare the effectiveness of cognitive behaviour therapy delivered by telephone with the same therapy given face to face in the treatment of obsessive compulsive disorder . Design R and omised controlled non-inferiority trial . Setting Two psychology outpatient departments in the United Kingdom . Participants 72 patients with obsessive compulsive disorder . Intervention 10 weekly sessions of exposure therapy and response prevention delivered by telephone or face to face . Main outcome measures Yale Brown obsessive compulsive disorder scale , Beck depression inventory , and client satisfaction question naire . Results Difference in the Yale Brown obsessive compulsive disorder checklist score between the two treatments at six months was −0.55 ( 95 % confidence interval −4.26 to 3.15 ) . Patient satisfaction was high for both forms of treatment . Conclusion The clinical outcome of cognitive behaviour therapy delivered by telephone was equivalent to treatment delivered face to face and similar levels of satisfaction were reported . Trial registration Current Controlled Trials IS RCT N500103984 [ controlled-trials.com ] 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

There are no high quality data on the efficacy of dietary intervention for the prevention of type 2 diabetes . More well- design ed , long-term studies , providing well-reported , high- quality data are required before proper conclusions can be made into the best dietary advice for the prevention of diabetes mellitus in adults

BACKGROUND Prevention of type 2 diabetes in adults is a far better option than treatment , to alleviate pressure on health care providers and re sources . However , there is no current review of the evidence regarding the efficacy of a diet-only intervention for prevention . OBJECTIVES To assess the effects of type and frequency of dietary advice for the prevention of type 2 diabetes mellitus .

D iabetes is one of the most costly and burdensome chronic diseases of our time and is a condition that is increasing in epidemic proportions in the U.S. and throughout the world ( 1 ) . The complications result ing from the disease are a significant cause of morbidity and mortality and are associated with the damage or failure of various organs such as the eyes , kidneys , and nerves . Individuals with type 2 diabetes are also at a significantly higher risk for coronary heart disease , peripheral vascular disease , and stroke , and they have a greater likelihood of having hypertension , dyslipidemia , and obesity ( 2–6 ) . There is also growing evidence that at glucose levels above normal but below the diabetes threshold diagnostic now referred to as pre-diabetes , there is a substantially increased risk of cardiovascular disease ( CVD ) and death ( 5,7–10 ) . In these individuals , CVD risk factors are also more prevalent ( 5–7,9,11–14 ) , which further increases the risk but is not sufficient to totally explain it . In contrast to the clear benefit of glucose lowering to prevent or retard the progression of microvascular complications associated with diabetes ( 15– 18,21 ) , it is less clear whether the high rate of CVD in people with impaired glucose homeostasis , i.e. , those with impaired fasting glucose ( IFG ) , impaired glucose tolerance ( IGT ) , or diabetes , is caused by elevated blood glucose levels or will respond to treatments that lower blood glucose . Epidemiological studies have shown a clear relationship ( 19,20 ) , whereas intervention trials in people with diabetes suggest , but have not demonstrated , a clear benefit of glycemic control ( 15,16,21,22 ) . Additionally , there are no studies that have investigated a benefit of glucose lowering on macrovascular disease in subjects with only pre-diabetes ( IFG or IGT ) but not diabetes . Although the treatment of diabetes has become increasingly sophisticated , with over a dozen pharmacological agents available to lower blood glucose , a multitude of ancillary supplies and equipment available , and a clear recognition by health care professionals and patients that diabetes is a serious disease , the normalization of blood glucose for any appreciable period of time is seldom achieved ( 23 ) . In addition , in well-controlled socalled “ intensively ” treated patients , serious complications still occur ( 15–18,21 ) , and the economic and personal burden of diabetes remains . Furthermore , microvascular disease is already present in many individuals with undiagnosed or newly diagnosed type 2 diabetes ( 11,24– 28 ) . Given these facts , it is not surprising that studies have been initiated in the last decade to determine the feasibility and benefit of various strategies to prevent or delay the onset of type 2 diabetes . Two early reports ( 29,30 ) suggested that changes in lifestyle can prevent diabetes , but weaknesses in study design limited their general relevance . Recently , however , four well- design ed r and omized controlled trials have been reported ( 31–35 ) . In the Finnish study ( 31 ) , 522 middleaged ( mean age 55 years ) obese ( mean BMI 31 kg/m ) subjects with IGT were r and omized to receive either brief diet and exercise counseling ( control group ) or intensive individualized instruction on weight reduction , food intake , and guidance on increasing physical activity ( intervention group ) . After an average follow-up of 3.2 years , there was a 58 % relative reduction in the incidence of diabetes in the intervention group compared with the control subjects . A strong correlation was also seen between the ability to stop the progression to diabetes and the degree to which subjects were able to achieve one or more of the following : lose weight ( goal of 5.0 % weight reduction ) , reduce fat intake ( goal of 30 % of calories ) , reduce saturated fat intake ( goal of 10 % of calories ) , increase fiber intake ( goal of 15 g/1,000 kcal ) , and exercise ( goal of 150 min/week ) . No untoward effects of the lifestyle interventions were observed . In the Diabetes Prevention Program ( DPP ) ( 32–34 ) , the 3,234 enrolled subjects were slightly younger ( mean age 51 years ) and more obese ( mean BMI 34 kg/m ) but had nearly identical glucose intolerance compared with subjects in the Finnish study . About 45 % of the participants were from minority groups ( e.g , AfricanAmerican , Hispanic ) , and 20 % were 60 years of age . Subjects were r and omized to one of three intervention groups , which included the intensive nutrition and exercise counseling ( “ lifestyle ” ) group or either of two masked medication treatment groups : the biguanide metformin group or the placebo group . The latter interventions were combined with st and ard diet and exercise recommendations . After an average follow-up of 2.8 years ( range 1.8–4.6 years ) , a 58 % relative reduction in the progression to diabetes was observed in the lifestyle group ( absolute incidence 4.8 % ) , and a 31 % relative reduction in the progression of diabetes was observed in the metformin group ( absolute incidence 7.8 % ) compared with control subjects ( absolute incidence 11.0 % ) . ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● BACKGROUND Polyunsaturated fatty acids ( PUFAs ) and monounsaturated fatty acids ( MUFAs ) have been shown to positively affect blood lipids ; however , their comparative effects on insulin sensitivity are unclear . OBJECTIVE Our objective was to investigate whether chronic intake of MUFAs or PUFAs improves insulin sensitivity in people with type 2 diabetes via stimulation of the endogenous gut hormone glucagon-like peptide 1 [ 7 - 36 ] amide ( GLP-1 ) . DESIGN Nine overweight people with type 2 diabetes received isoenergetic high-MUFA ( 20.3 + /- 3.5 % of total energy ) or high-PUFA ( 13.4 + /- 1 . 3 % ) diets for 24 d in a r and omized , double-blind crossover design . RESULTS Weight and glycemic control remained stable throughout the study . Despite a significant change in the plasma triacylglycerol linoleic-oleic acid ratio ( L : O ) with both diets ( MUFA : from 0.46 + /- 0.03 to 0.29 + /- 0.02 , P : < 0.005 ; PUFA : from 0.36 + /- 0.04 to 0.56 + /- 0.05 , P : < 0.05 ) and the phospholipid L : O ( 1.7 + /- 0.1 to 2.0 + /- 0.3 ; P : = 0.04 ) during consumption of the PUFA diet , this change was not associated with a change in insulin sensitivity , measured by the short-insulin-tolerance test . There was a significant reduction in the ratio of total to HDL cholesterol during consumption of the PUFA diet ( 5.2 + /- 0.4 compared with 4.7 + /- 0.3 ; P : = 0.005 ) but no change with the MUFA diet . There was no change in the fasting or postpr and ial incremental area under the curve in response to an identical st and ard test meal for glucose , insulin , triacylglycerol , nonesterified fatty acids , or GLP-1 . CONCLUSIONS Over the 3-wk intervention period , diet-induced change in the triacylglycerol or phospholipid L : O was not associated with either increased stimulation of GLP-1 or a change in insulin sensitivity in people with type 2 diabetes Aims /hypothesis . The aim of the Diabetes Prevention Study is to assess the efficacy of an intensive diet-exercise programme in preventing or delaying Type II ( non-insulin-dependent ) diabetes mellitus in subjects with impaired glucose tolerance , to evaluate the effects of the intervention programme on cardiovascular risk factors and to assess the determinants for the progression to diabetes in persons with impaired glucose tolerance . Methods . A total of 523 overweight subjects with impaired glucose tolerance ascertained by two oral glucose tolerance tests were r and omised to either a control or intervention group . The control subjects received general information at the start of the trial about the lifestyle changes necessary to prevent diabetes and about annual follow-up visits . The intervention subjects had seven sessions with a nutritionist during the first year and a visit every 3 months thereafter aim ed at reducing weight , the intake of saturated fat and increasing the intake of dietary fibre . Intervention subjects were also guided individually to increase their physical activity . Results . During the first year , weight loss in the first 212 study subjects was 4.7 ± 5.5 vs 0.9 ± 4.1 kg in the intervention and control group , respectively ( p < 0.001 ) . The plasma glucose concentrations ( fasting : 5.9 ± 0.7 vs 6.4 ± 0.8 mmol/l , p < 0.001 ; and 2-h 7.8 ± 1.8 vs 8.5 ± 2.3 mmol/l , p < 0.05 ) were significantly lower in the intervention group after the first year of intervention . Favourable changes were also found in blood pressure , serum lipids and anthropometric indices in the intervention group . Conclusion /interpretation . The interim results show the efficacy and feasibility of the lifestyle intervention programme . [ Diabetologia ( 1999 ) 42 : 793–801 Context Weight loss and exercise decrease the development of diabetes in people with impaired glucose tolerance , but the effectiveness of these interventions in people with normal glucose tolerance is unknown . Contribution Using data from a large r and omized , controlled trial of cardiovascular disease prevention in men , the investigators show that participants with normal glucose tolerance at baseline developed diabetes at similar rates whether they received the diet and exercise intervention or usual care . However , the intervention was associated with lower risk of diabetes among nonsmokers . Implication s While diet and exercise may reduce the development of diabetes in nonsmokers with normal glucose metabolism at baseline , this benefit was not apparent among smokers . The Editors Epidemiologic studies have identified several potentially modifiable risk factors for type 2 diabetes mellitus , including obesity , a diet in which a high proportion of calories comes from fat , and low levels of physical activity ( 1 - 7 ) . Authorities have advocated that trials should test promising hypotheses about the primary prevention of type 2 diabetes ( 1 ) . R and omized intervention studies have demonstrated that , among those who already have impaired glucose tolerance , interventions that promote weight loss and increased exercise can reduce the risk for incident diabetes ( 8 - 10 ) . However , interventions should occur before at-risk individuals develop impaired glucose tolerance . A 2-year r and omized trial of diet , exercise , or both in individuals with a parental history of diabetes showed a statistically imprecise lower risk for developing diabetes in the intervention group ( 11 ) . To test such a hypothesis in groups who do not necessarily have a parental history of diabetes would be expensive . Strategies proposed for the primary prevention of type 2 diabetes include weight reduction , reduced dietary fat intake , and increased exercise ( 2 , 4 , 7 ) . These interventions are similar to those developed for preventing coronary heart disease ; therefore , examination of type 2 diabetes incidence rates in coronary heart disease prevention trials can provide preliminary evidence on the potential of such interventions to reduce type 2 diabetes risk . The Multiple Risk Factor Intervention Trial ( MRFIT ) enrolled 12866 middle-aged men at high risk for coronary heart disease and delivered either special intervention or usual care over 6 to 7 years . The research ers obtained fasting glucose values yearly , and participants self-reported their use of insulin or oral hypoglycemic agents . The glucose values and reports of diabetes medication use enable estimation of diabetes incidence during the trial . Previous reports from MRFIT have described risk factors for the development of diabetes in the usual care group ( 12 ) and the risk for death associated with incident diabetes in the combined special intervention and usual care groups ( 13 ) . In this paper , we compare the incidence of diabetes in the intervention and control groups of the MRFIT , report on an unexpected subgroup finding related to baseline cigarette smoking status , and explore reasons for the different results among smokers and nonsmokers . Methods Procedures Detailed descriptions of the MRFIT have been published ( 14 - 17 ) . Briefly , between 1973 and 1976 , the MRFIT investigators screened 361662 men for eligibility at 22 U.S. clinical centers . Of this group , 12866 men age 35 to 57 years were r and omly assigned : 6428 men to the special intervention group and 6438 men to the usual care group . Screening occurred at 3 visits . At the first screening visit , investigators assessed the risk for coronary heart disease by using measurements of serum cholesterol level , diastolic blood pressure , and self-reported cigarette smoking ( 14 ) . Men who were in the upper 15 % ( changed to 10 % after one third of the screening was completed ) of risk were invited to attend a second screening visit . Because of the eligibility criteria used in the MRFIT , the usual relationships among these risk factors were modified . For example , nonsmokers had to have higher blood pressure and lipid levels on average than smokers to be eligible for the trial . At the second screening visit , a blood sample was taken after an overnight fast . A central laboratory at the Institute of Medical Sciences in San Francisco , California , analyzed the blood sample s by using a protocol previously described ( 18 ) and measured serum glucose in the fasting sample and in a sample taken 1 hour after a 75-g oral glucose load . The MRFIT also measured height and weight ( after the patient had disrobed ) . Individuals with body weight 150 % or more of desirable weight were excluded from the trial ( defined as 0.9 of the average for men of the same height in the 19601962 National Health Examination Survey [ 19 ] ) . We used body mass index ( BMI ) as the measure of relative weight in our report . Men without evidence of cardiovascular or other life-threatening diseases were invited to attend a third screening visit . At this visit , eligible men who consented to the trial were r and omly assigned . All participants had annual examinations for at least 6 years . A fasting blood sample was taken at each annual examination , from which serum glucose concentration and plasma lipid levels were measured . In addition , at the sixth annual visit , a blood sample taken 1 hour after a 75-g oral glucose load was obtained . At each annual examination , participants were asked whether a physician had told them that they had diabetes at any time in the previous 12 months . Each participant was also asked whether he was using insulin or oral hypoglycemic agents . In the MRFIT , 24-hour dietary recalls were obtained at baseline and during follow-up ( 20 , 21 ) . We cited data from baseline and year 6 in our report . Intervention Details of the intervention program of the MRFIT have been reported ( 16 , 22 ) . Briefly , the special intervention group received nutritional counseling that was aim ed at reducing saturated fat and dietary cholesterol consumption and increasing polyunsaturated fat intake . Smokers participated in a behavioral intervention program aim ed at cessation . In men at or more than 115 % of desirable weight , reductions in caloric intake and increases in moderate physical activity were recommended . Elevated blood pressure was treated pharmacologically according to a stepped-care protocol that started with 50 mg of chlorthalidone or hydrochlorothiazide if weight reduction and moderate salt restriction did not achieve the desired blood pressure goals . Definition of Diabetes The definition of incident diabetes followed the American Diabetes Association ( ADA ) guidelines ( 23 ) . With this definition , a participant was considered to have developed diabetes if at any annual visit the fasting glucose level was 7 mmol/L or greater ( 126 mg/dL ) or the participant reported taking insulin or oral hypoglycemic agents . Use of a single fasting glucose determination to design ate diabetic participants is consistent with the ADA criteria for epidemiologic studies . Exclusions The MRFIT attempted at baseline to exclude men with identified diabetes from the trial . The trial excluded individuals who were using hypoglycemic drugs , as well as those who were not being treated but who exhibited clinical symptoms of hyperglycemia ( 15 ) . Despite these exclusion criteria , the trial included 42 men who reported ( without confirmation ) taking insulin , 414 men with a baseline fasting glucose level of 7 mmol/L or greater ( 126 mg/dL ) , and 52 men with a glucose level of 16.65 mmol/L or greater ( 300 mg/dL ) 1 hour after a 75-g oral glucose load . We excluded these 508 men and an additional 531 men ( 291 in the usual care group and 240 in the special intervention group ) with fewer than 2 fasting glucose values throughout the trial from our analyses , leaving 11827 men ( 5893 in the usual care group and 5934 in the special intervention group ) who , by our criteria , were at risk for developing diabetes over the next 6 years ( Figure ) . Figure . Description of study exclusions . Statistical Analysis We used time-to-event methods appropriate for interval-censored data to compare incidence of diabetes in the special intervention and usual care groups ( 24 ) . We estimated the cumulative percentage of patients developing diabetes , assuming that participants at risk who did not attend an annual visit did not meet our criteria for diabetes . We used proportional hazards regression models to study the influence of baseline predictors on hazard ratio estimates and to investigate treatment by subgroup interactions . We also used these models to study the influence of risk factor changes on the incidence of diabetes and on special interventionusual care hazard ratios . We checked the proportional hazards assumption by including a covariate corresponding to the interaction of failure time and special intervention or usual care . In these models , we up date d risk factor levels ( for example , BMI , use of antihypertensive drugs , and smoking status ) annually and considered them to be time-dependent covariates . With this approach , we considered the latest values of risk factors ( those immediately preceding diabetes ) and baseline levels as predictors . We also used longitudinal regression models for binary data ( 25 ) . With these models , participants could be classified as diabetic on several annual visits or at 1 annual visit and not the next . We used analysis of variance with covariates corresponding to baseline level of the factor being considered to compare risk factor levels at 6 years for special intervention and usual care men , both overall and according to baseline cigarette smoking status . With these models , we also investigated the interaction between treatment and smoking status . Both time-to-event analyses and analyses of variance are stratified by clinical center . We performed all analyses by using SAS , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) . Role of the Funding OBJECTIVE To describe the 1 ) lifestyle intervention used in the Finnish Diabetes Prevention Study , 2 ) short- and long-term changes in diet and exercise behavior , and 3 ) effect of the intervention on glucose and lipid metabolism . RESEARCH DESIGN AND METHODS There were 522 middle-aged , overweight subjects with impaired glucose tolerance who were r and omized to either a usual care control group or an intensive lifestyle intervention group . The control group received general dietary and exercise advice at baseline and had an annual physician 's examination . The subjects in the intervention group received additional individualized dietary counseling from a nutritionist . They were also offered circuit-type resistance training sessions and advised to increase overall physical activity . The intervention was the most intensive during the first year , followed by a maintenance period . The intervention goals were to reduce body weight , reduce dietary and saturated fat , and increase physical activity and dietary fiber . RESULTS The intervention group showed significantly greater improvement in each intervention goal . After 1 and 3 years , weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 and 0.9 kg in the control group , respectively . Measures of glycemia and lipemia improved more in the intervention group . CONCLUSIONS The intensive lifestyle intervention produced long-term beneficial changes in diet , physical activity , and clinical and biochemical parameters and reduced diabetes risk . This type of intervention is a feasible option to prevent type 2 diabetes and should be implemented in the primary health care system Clinical trials have demonstrated that lifestyle changes can prevent type 2 diabetes , but the importance of leisure-time physical activity ( LTPA ) is still unclear . We carried out post hoc analyses on the role of LTPA in preventing type 2 diabetes in 487 men and women with impaired glucose tolerance who had completed 12-month LTPA question naires . The subjects were participants in the Finnish Diabetes Prevention Study , a r and omized controlled trial of lifestyle changes including diet , weight loss , and LTPA . There were 107 new cases of diabetes during the 4.1-year follow-up period . Individuals who increased moderate-to-vigorous LTPA or strenuous , structured LTPA the most were 63 - 65 % less likely to develop diabetes . Adjustment for changes in diet and body weight during the study attenuated the association somewhat ( upper versus lower third : moderate-to-vigorous LTPA , relative risk 0.51 , 95 % CI 0.26 - 0.97 ; strenuous , structured LTPA , 0.63 , 0.35 - 1.13 ) . Low-intensity and lifestyle LTPA and walking also conferred benefits , consistent with the finding that the change in total LTPA ( upper versus lower third : 0.34 , 0.19 - 0.62 ) was the most strongly associated with incident diabetes . Thus increasing physical activity may substantially reduce the incidence of type 2 diabetes in high-risk individuals OBJECTIVE To determine whether reducing dietary fat would reduce body weight and improve long-term glycemia in people with glucose intolerance . RESEARCH DESIGN AND METHODS A 5-year Follow-up of a 1-year r and omized controlled trial of a reduced-fat ad libitum diet versus a usual diet . Participants with glucose intolerance ( 2-h blood glucose 7.0 - 11.0 mmol/l ) were recruited from a Workforce Diabetes Survey . The group that was r and omized to a reduced-fat diet participated in monthly small-group education sessions on reduced-fat eating for 1 year . Body weight and glucose tolerance were measured in 136 participants at baseline 6 months , and 1 year ( end of intervention ) , with follow-up at 2 years ( n = l04 ) , 3 years ( n = 99 ) , and 5 years ( n = 103 ) . RESULTS Compared with the control group , weight decreased in the reduced-fat-diet group ( P < 0.0001 ) ; the greatest difference was noted at 1 year ( -3.3 kg ) , diminished at subsequent follow-up ( -3.2 kg at 2 years and -1.6 kg at 3 years ) , and was no longer present by 5 years ( 1.1 kg ) . Glucose tolerance also improved in patients on the reduced-fat diet ; a lower proportion had type 2 diabetes or impaired glucose tolerance at 1 year ( 47 vs. 67 % , P < 0.05 ) , but in subsequent years , there were no differences between groups . However , the more compliant 50 % of the intervention group maintained lower fasting and 2-h glucose at 5 years ( P = 0.041 and P = 0.026 respectively ) compared with control subjects . CONCLUSIONS The natural history for people at high risk of developing type 2 diabetes is weight gain and deterioration in glucose tolerance . This process may be ameliorated through adherence to a reduced fat BACKGROUND Type 2 diabetes mellitus is increasingly common , primarily because of increases in the prevalence of a sedentary lifestyle and obesity . Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known . METHODS We r and omly assigned 522 middle-aged , overweight subjects ( 172 men and 350 women ; mean age , 55 years ; mean body-mass index [ weight in kilograms divided by the square of the height in meters ] , 31 ) with impaired glucose tolerance to either the intervention group or the control group . Each subject in the intervention group received individualized counseling aim ed at reducing weight , total intake of fat , and intake of saturated fat and increasing intake of fiber and physical activity . An oral glucose-tolerance test was performed annually ; the diagnosis of diabetes was confirmed by a second test . The mean duration of follow-up was 3.2 years . RESULTS The mean ( + /-SD ) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group ; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group ( P<0.001 for both comparisons between the groups ) . The cumulative incidence of diabetes after four years was 11 percent ( 95 percent confidence interval , 6 to 15 percent ) in the intervention group and 23 percent ( 95 percent confidence interval , 17 to 29 percent ) in the control group . During the trial , the risk of diabetes was reduced by 58 percent ( P<0.001 ) in the intervention group . The reduction in the incidence of diabetes was directly associated with changes in lifestyle . CONCLUSIONS Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects OBJECTIVE To assess the effects of lifestyle intervention on cardiovascular risk factors in general and especially on fibrinolysis . DESIGN R and omized clinical study . SUBJECTS A total of 186 subjects with impaired glucose tolerance and obesity . INTERVENTIONS The intervention programme included a low-fat , high-fibre diet and regular physical exercise . Half of the participants ( n = 93 ) took part in a one-month learning and training session using different behavioural modification techniques and conducted in a full-board wellness centre ( intense intervention group ) . The other half ( n = 93 ) was r and omized a one-hour counselling session with a specially trained nurse ( usual care group ) . Follow-up was carried out after 12 months . MAIN OUTCOME MEASURES Body weight , oxygen consumption , plasminogen activator inhibitor type 1 ( PAI-1 ) activity , tissue plasminogen activator ( tPA ) antigen , fibrinogen and fasting plasma insulin measured at the start of the programme and at follow-up after 1 year . RESULTS The intense intervention group had a mean weight decline by 1 year of 5.4 kg compared to 0.5 kg in the usual care group . Oxygen consumption in the intense group increased 10 % vs. a 1 % decline in the usual care group . In the intense group , PAI-1 activity decreased 31 % ( -10.1 U mL(-1 ) ) , which was significantly more than in the usual care group ( 12 % ; -3.0 U mL(-1 ) ) . The corresponding reductions in tPA antigen were 14 % ( -1.65 microg L(-1 ) ) and 6 % ( -0.69 microg L(-1 ) ) . CONCLUSIONS The present r and omized study shows that an intense lifestyle programme has sustained beneficial effects on fibrinolysis OBJECTIVE To determine whether diet and endurance exercise improved adiposity-related measurements in Japanese Americans with impaired glucose tolerance ( IGT ) . RESEARCH DESIGN AND METHODS This study compared the effects of an American Heart Association ( AHA ) step 2 diet ( < 30 % of total calories as fat , < 7 % saturated fat , 55 % carbohydrate , and < 200 mg cholesterol daily ) plus endurance exercise for 1 h three times a week ( treatment group ) with an AHA step 1 diet ( 30 % of total calories as fat , 10 % saturated fat , 50 % carbohydrate , and < 300 mg cholesterol ) plus stretching exercise three times a week ( control group ) on BMI , body composition ( % fat ) , and body fat distribution at 6 and 24 months of follow-up in 64 Japanese American men and women with IGT , 58 of whom completed the study . RESULTS At 6 months , the treatment group showed significantly greater reduction in percent , body fat ( -1.4 + /- 0.4 vs. -0.3 + /- 0.3 % ) ; BMI ( -1.1 + /- 0.2 vs. -0.4 + /- 0.1 kg/m(2 ) ) ; subcutaneous fat by computed tomography at the abdomen ( -29.3 + /- 4.2 vs. -5.7 + /- 5.9 cm(2 ) ) , thigh ( -13.2 + /- 3.6 vs. -3.6 + /- 3.0 cm(2 ) ) , and thorax ( -19.6 + /- 3.6 vs. -8.9 + /- 2.6 cm(2 ) ) ; and skinfold thickness at the bicep ( -2.0 + /- 0.6 vs. 1.1 + /- 0.6 mm ) and tricep ( -3.7 + /- 0.8 vs. -0.9 + /- 0.6 mm ) , which continued despite moving to home-based exercise for the last 18 months . CONCLUSIONS Diet and endurance exercise improved BMI , body composition , and body fat distribution and , thus , may delay or prevent type 2 diabetes in Japanese Americans with IGT OBJECTIVE Individuals with impaired glucose tolerance ( IGT ) have a high risk of developing NIDDM . The purpose of this study was to determine whether diet and exercise interventions in those with IGT may delay the development of NIDDM , i.e. , reduce the incidence of NIDDM , and thereby reduce the overall incidence of diabetic complications , such as cardiovascular , renal , and retinal disease , and the excess mortality attributable to these complications . RESEARCH DESIGN AND METHODS In 1986 , 110,660 men and women from 33 health care clinics in the city of Da Qing , China , were screened for IGT and NIDDM . Of these individuals , 577 were classified ( using World Health Organization criteria ) as having IGT . Subjects were r and omized by clinic into a clinical trial , either to a control group or to one of three active treatment groups : diet only , exercise only , or diet plus exercise . Follow-up evaluation examinations were conducted at 2-year intervals over a 6-year period to identify subjects who developed NIDDM . Cox 's proportional hazard analysis was used to determine if the incidence of NIDDM varied by treatment assignment . RESULTS The cumulative incidence of diabetes at 6 years was 67.7 % ( 95 % CI , 59.8–75.2 ) in the control group compared with 43.8 % ( 95 % CI , 35.5–52.3 ) in the diet group , 41.1 % ( 95 % CI , 33.4–49.4 ) in the exercise group , and 46.0 % ( 95 % CI , 37.3–54.7 ) in the diet-plus-exercise group ( P < 0.05 ) . When analyzed by clinic , each of the active intervention groups differed significantly from the control clinics ( P < 0.05 ) . The relative decrease in rate of development of diabetes in the active treatment groups was similar when subjects were stratified as lean or overweight ( BMI < or ≥ 25 kg/m2 ) . In a proportional hazards analysis adjusted for differences in baseline BMI and fasting glucose , the diet , exercise , and diet-plus-exercise interventions were associated with 31 % ( P < 0.03 ) , 46 % ( P < 0.0005 ) , and 42 % ( P < 0.005 ) reductions in risk of developing diabetes , respectively . CONCLUSIONS Diet and /or exercise interventions led to a significant decrease in the incidence of diabetes over a 6-year period among those with IGT Self-referred subjects ( N = 227 ) thought to be at risk of developing non-insulin-dependent diabetes mellitus ( NIDDM ) and with fasting plasma glucose ( FPG ) in the range of 5.5 to 7.7 mmol . L-1 on two consecutive tests 2 weeks apart were r and omized to reinforced or basic healthy-living advice . They were simultaneously allocated either to a sulfonylurea group or a control group in a two-by-two factorial design . A total of 201 subjects in three English and two French centers completed 1 year 's follow-up study . Reinforced advice recommending dietary modification and increased exercise was given every 3 months , and basic advice was given once at the initial visit . Glycemia was monitored by FPG , dietary compliance by body weight and food diaries , and fitness compliance by bicycle ergometer assessment and exercise diaries . Both reinforced and basic advice groups had a significant mean reduction in body weight ( 1.5 kg ) at 3 months , although the weight subsequently returned to baseline . After 1 year , subjects allocated to reinforced advice versus basic advice ( 1 ) reported a lower fat intake ( 34.1 % v 35.8 % , P = .04 ) with no difference in lipid profiles , ( 2 ) had improved fitness as shown by increased calculated maximal oxygen uptake ( [ Vo2max ] 2.39 v 2.18 L.min-1 , P = .007 ) with no change in insulin sensitivity , ( 3 ) showed no change in FPG , glucose tolerance , or hemoglobin A1c ( HbA1c ) , and ( 4 ) showed a greater tendency to withdraw from the study ( 16 % v 7 % , P = .03 ) . In conclusion , reinforced healthy-living advice given to self-referred subjects with increased FPG did not encourage sufficiently pronounced life-style changes for significantly greater effects on body weight and glycemia in a 1-year study than basic healthy-living advice BACKGROUND Type 2 diabetes affects approximately 8 percent of adults in the United States . Some risk factors -- elevated plasma glucose concentrations in the fasting state and after an oral glucose load , overweight , and a sedentary lifestyle -- are potentially reversible . We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes . METHODS We r and omly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo , metformin ( 850 mg twice daily ) , or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week . The mean age of the participants was 51 years , and the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 34.0 ; 68 percent were women , and 45 percent were members of minority groups . RESULTS The average follow-up was 2.8 years . The incidence of diabetes was 11.0 , 7.8 , and 4.8 cases per 100 person-years in the placebo , metformin , and lifestyle groups , respectively . The lifestyle intervention reduced the incidence by 58 percent ( 95 percent confidence interval , 48 to 66 percent ) and metformin by 31 percent ( 95 percent confidence interval , 17 to 43 percent ) , as compared with placebo ; the lifestyle intervention was significantly more effective than metformin . To prevent one case of diabetes during a period of three years , 6.9 persons would have to participate in the lifestyle-intervention program , and 13.9 would have to receive metformin . CONCLUSIONS Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk . The lifestyle intervention was more effective than metformin OBJECTIVE To compare and assess the single and joint effect of diet and exercise intervention for 1 year on insulin resistance and the development leading toward the insulin resistance syndrome . RESEARCH DESIGN AND METHODS An unmasked , r and omized 2 × 2 factorial intervention trial was applied with a duration of 1 year for each participant . The trial comprised 219 men and women with diastolic blood pressure of 86–99 mmHg , HDL cholesterol < 1.20 mmol/l , triglycerides > 1.4 mmol/l , total cholesterol of 5.20–7.74 mmol/l , and BMI > 24 kg/m2 . Participants were r and omly allocated to diet group ( n = 35 ) , diet and exercise group ( n = 67 ) , exercise group ( n = 54 ) , and control group ( n = 43 ) . The diet included increased intake of fish and reduced total fat intake . The exercise program entailed supervised endurance exercise three times a week . Baseline cross-sectional changes and 1-year changes in insulin resistance , fasting serum levels of insulin , C-peptide , proinsulin , glucose , and lipids as well as weight , mean blood pressure , and plasminogen activator inhibitor 1 ( PAI-1 ) values were recorded . RESULTS The cross-sectional results at baseline showed significant correlations between the calculated insulin resistance and BMI ( r = 0.54 ) and correlations between the mean blood pressure ( mBP ) ( r = 0.26 ) and PAI-1 ( r = 0.40 ) . The 1-year diet intervention gave a significant decrease in the calculated insulin resistance from 4.6 to 4.2 and a positive correlation between the changes in insulin resistance and changes in BMI ( r = 0.40 ) . The diet and exercise intervention also led to significantly decreased insulin resistance ( from 5.0 to 4.0 ) . The exercise intervention did not significantly change insulin resistance . CONCLUSIONS The cross-sectional and 1-year intervention results supported each other and underscored the important connection between increased BMI and the development leading toward the insulin resistance syndrome Even in individuals who are unwilling to make prudent changes in their diets and sedentary habits , the administration of certain nutrients and /or drugs may help to prevent or postpone the onset of type 2 diabetes . The evident ability of fiber-rich cereal products to decrease diabetes risk , as documented in prospect i ve epidemiological studies , may be mediated primarily by the superior magnesium content of such foods . High-magnesium diets have preventive ( though not curative ) activity in certain rodent models of diabetes ; conversely , magnesium depletion provokes insulin resistance . Epidemiology also strongly suggests that regular moderate alcohol consumption has a major favorable impact on diabetes risk , particularly in women ; this may reflect a direct insulin-sensitizing effect on muscle and , in women , a reduced risk for obesity . Chromium picolinate can also aid muscle insulin sensitivity , and initial reports suggest that it is an effective therapy for type 2 diabetes . High-dose biotin has shown therapeutic activity in diabetic rats and in limited clinical experience ; increased expression of glucokinase in hepatocytes may mediate this benefit . Other nutrients that might prove to aid diabetic glycemic control , and thus have potential for prevention , include coenzyme Q and conjugated linoleic acids ( CLA ) . Since the nutrients cited here - including ethanol in moderation - appear to be quite safe and ( with the exception of CLA ) quite affordable , supplementation with these nutrients may prove to be a practical strategy for diabetes prevention . Drugs such as metformin and troglitazone , which are expensive and require regular physician monitoring to avoid potentially dangerous side-effects , would appear to be less practical options from cost-effectiveness , convenience and safety st and points , given the fact that the population at-risk for diabetes is huge The purpose of this study was to investigate the effect of 1-year diet intervention , exercise intervention and both combined on blood pressure ( BP ) in normotensives and mild hypertensives . Two hundred and nineteen sedentary middle aged men and women with slightly deranged coronary heart disease ( CHD ) risk factors were r and omised to a control , a diet , an exercise and a diet + exercise group . Based on baseline diastolic BP , participants were divided into tertiles , giving baseline average BP of 141.4/96.7 in tertile 1 , 130.7/87.6 in tertile 2 and 121.9/79.0 in tertile 3 . The 1-year net-difference in BP between the intervention groups and the control group decreased across the tertiles ; in tertile 1 being -11.2/-6.7 ( p < 0.05 ) , -11.3/-6.7 ( p < 0.05 for systolic BP only ) and -7.0/-5.1 ( NS ) in the combined , diet and exercise group respectively . Triglycerides , HDL cholesterol , and insulin variables were significantly and favourably changed , the changes being most marked in the combined group . The results show that diet and diet + exercise are about equally effective in reducing BP , and the effects may be dependent on the baseline level . Within the upper tertile of baseline BP , the decline in BP in the combined intervention and the diet group are almost comparable to those obtained with drug treatment . In addition , other important CHD risk factors were all changed in a beneficial direction

This review found no conclusive evidence that metformin treatment before or during ART cycles improved live birth rates in women with PCOS . However , the use of this insulin-sensitising agent increased clinical pregnancy rates and decreased the risk of OHSS

BACKGROUND The use of insulin-sensitising agents , such as metformin , in women with polycystic ovary syndrome ( PCOS ) who are undergoing ovulation induction or in vitro fertilisation ( IVF ) cycles has been widely studied . Metformin reduces hyperinsulinaemia and suppresses the excessive ovarian production of and rogens . As a consequence , it is suggested that metformin could improve assisted reproductive techniques ( ART ) outcomes , such as ovarian hyperstimulation syndrome ( OHSS ) , pregnancy and live birth rates . OBJECTIVES To determine the effectiveness and safety of metformin as a co-treatment during IVF or intracytoplasmic sperm injection ( ICSI ) in achieving pregnancy or live birth in women with PCOS .

BACKGROUND To study the effect of metformin before and during assisted reproductive technology ( ART ) on the clinical pregnancy rate ( CPR ) in non-obese women with polycystic ovary syndrome ( PCOS ) . METHODS A multi-centre , prospect i ve , r and omized , double-blind study was conducted in eight IVF clinics in four Nordic countries . We enrolled 150 PCOS women with a body mass index < 28 kg/m(2 ) , and treated them with 2000 mg/day metformin or identical placebo tablets for ≥ 12 weeks prior to and during long protocol IVF or ICSI and until the day of pregnancy testing . The primary outcome measure was CPR . Secondary outcome measures included spontaneous pregnancy rates during the pretreatment period , and the live birth rate ( LBR ) . RESULTS Among IVF treated women ( n = 112 ) , biochemical pregnancy rates were identical in both groups ( 42.9 % ) , and there were no significant differences in the metformin versus the placebo group in CPR [ 39.3 versus 30.4 % ; 95 % confidence interval ( CI ) : -8.6 to 26.5 ] . The LBR was 37.5 versus 28.6 % ( 95 % CI : -8.4 to 26.3 ) . However , prior to IVF there were 15 ( 20.3 % ) spontaneous pregnancies in the metformin group and eight ( 10.7 % ) in the placebo group ( 95 % CI : -1.9 to 21.1 ; P = 0.1047 ) . According to intention to treat analyses ( n = 149 ) ; significantly higher overall CPR were observed in the metformin versus placebo group ( 50.0 versus 33.3 % ; 95 % CI : -1.1 to 32.3 ; P = 0.0391 ) . LBR was also significantly higher with use of metformin versus placebo ( 48.6 versus 32.0 ; 95 % CI : 1.1 to 32.2 ; P = 0.0383 ) . No major unexpected safety issues or multiple births were reported . More gastrointestinal side effects occurred in the metformin group ( 41 versus 12 % ; 95 % CI : 0.15 to 0.42 ; P < 0.001 ) . CONCLUSIONS Metformin treatment for 12 weeks before and during IVF or ICSI in non-obese women with PCOS significantly increases pregnancy and LBRs compared with placebo . However , there was no effect on the outcome of ART per se . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00159575 Estimates of the prevalence of the polycystic ovary syndrome ( PCOS ) in the general population have ranged from 2 - 20 % . The vast majority of these reports have studied White population s in Europe , used limited definitions of the disorder , and /or used bias population s , such as those seeking medical care . To estimate the prevalence of this disorder in the United States and address these limitations , we prospect ively determined the prevalence of PCOS in a reproductive-aged population of 369 consecutive women ( 174 White and 195 Black ; aged 18 - 45 yr ) , examined at the time of their preemployment physical . Body measures were obtained , and body hair was quantified by a modified Ferriman-Gallwey ( F-G ) method . All exams were initially performed by 2 trained nurses , and any subject with an F-G score above 3 was reexamined by a physician , the same for all patients . Of the 369 women , 277 ( 75.1 % ) also agreed to complete a question naire and have additional blood drawn . Subjects were studied regardless of current estrogen/progestin hormonal use ( 28.5 % ) . PCOS was defined as 1 ) oligoovulation , 2 ) clinical hyper and rogenism ( i.e. hirsutism ) and /or hyper and rogenemia , and 3 ) exclusion of other related disorders , such as hyperprolactinemia , thyroid abnormalities , and non-classic adrenal hyperplasia . Hirsutism was defined by a F-G score of 6 or more , and hyper and rogenemia was defined as a total or free testosterone , and rostenedione , and /or dehydroepi and rosterone sulfate level above the 95th percentile of control values [ i.e. all eumenorrheic women in the study , who had no hirsutism ( F-G < or = 5 ) or acne and were receiving no hormonal therapy ; n = 98 ] . Considering all 369 women studied , White and Black women had similar mean ages ( 29.4 + /- 7.1 and 31.1 + /- 7.8 yr , respectively ) , although White women had a lesser body mass than Black women ( 24.9 + /- 6.1 vs. 29.2 + /- 8.1 kg/m2 , respectively ; P < 0.001 ) . Of these 7.6 % , 4.6 % , and 1.9 % demonstrated a F-G score of 6 or more , 8 or 10 , respectively , and there was no significant racial difference , with hirsutism prevalences of 8.0 % , 2.8 % , and 1.6 % in Whites , and 7.1 % , 6.1 % , and 2.1 % in Blacks , respectively . Of the 277 women consenting to a history and hormonal evaluation , 4.0 % had PCOS as defined , 4.7 % ( 6 of 129 ) of Whites and 3.4 % ( 5 of 148 ) of Blacks . In conclusion , in our consecutive population of unselected women the prevalence of hirsutism varied from 2 - 8 % depending on the chosen cut-off F-G score , with no significant difference between White and Black women . Using an F-G score of 6 or more as indicative of hirsutism , 3.4 % of Blacks and 4.7 % of Whites had PCOS as defined . These data suggest that PCOS may be one of most common reproductive endocrinological disorders of women Gonadotrophin treatment in clomiphene citrate resistant polycystic ovarian syndrome ( PCOS ) patients , using either low-dose step-up or low-dose step-down protocol s , is highly effective to achieve singleton live births . Concomitant use of gonadotrophin releasing hormone analogues ( GnRHa ) , which will block the endogenous feedback for monofollicular development during the low-dose step-up protocol , should not be employed . It is more difficult to induce ovulation in patients with more ' severe ' PCOS , characterized by obesity and insulin resistance . There is need for optimization of starting doses for both the low-dose step-up and step-down protocol s. Such optimization will prevent hyperstimulation due to a starting dose far above the FSH threshold , as well as minimize the time-consuming low-dose increments by starting with a higher dose in women with augmented FSH threshold . External validation of reported models for prediction of FSH response is warranted for tailoring and optimizing treatment for everyday clinical practice . Although preliminary , the partial cessation of follicular development , along with regression leading to atresia , lends support to the LH ceiling theory , emphasizing the delicate balance and need for both FSH and LH in normal follicular development . Future well- design ed r and omized controlled trials will reveal whether IVF with or without in-vitro maturation of the oocytes will improve safety and efficacy compared with classical ovulation induction strategies OBJECTIVE To evaluate the effects of metformin on the ovarian response to gonadotropins given for in vitro fertilization ( IVF ) programs in patients with polycystic ovary syndrome ( PCOS ) and reduced ovarian reserve . DESIGN Prospect i ve , parallel , r and omized , double-blind , placebo-controlled clinical trial . SETTING Academic departments of obstetrics and gynecology , and a private IVF center . PATIENT(S ) Primary infertile patients with PCOS older than 35 years and /or with a basal follicle-stimulating hormone ( FSH ) level higher than 10 IU/L who were scheduled for IVF cycles . INTERVENTION(S ) Gonadotropin-releasing hormone agonist flare-up protocol and high starting doses of recombinant FSH plus metformin or placebo tablets . MAIN OUTCOME MEASURE(S ) Primary end point : cancellation rate for low ovarian response . Secondary end-points : other clinical , biochemical , and reproductive data . RESULT ( S ) Enrollment was stopped after 88 participants had been r and omized and analyzed due to an unacceptable increased risk of poor ovarian response in the metformin arm . Statistically significant differences between the metformin and placebo groups were observed in the dose of gonadotropins used , peak estradiol levels , and the number of dominant follicles , retrieved oocytes , and metaphase II oocytes . CONCLUSION ( S ) In patients with PCOS and reduced ovarian reserve , metformin worsened the response to gonadotropins , and its administration should be stopped before the start of controlled ovarian hyperstimulation for IVF programs . CLINICAL TRIALS IDENTIFICATION NUMBER : NCT01208740 BACKGROUND Our aim was to investigate the effect of pre-treatment with metformin in women with polycystic ovary syndrome ( PCOS ) scheduled for IVF stimulation . METHODS Seventy-three oligo/amenorrhoeic women with polycystic ovaries and at least one of the following criteria : hyper and rogenaemia , elevated LH/FSH ratio , hyperinsulinism , decreased SHBG levels or hirsutism , were studied . Normal weight and overweight patients were r and omized separately in a prospect i ve , r and omized , double blind study . All patients were treated for at least 16 weeks with metformin ( 1000 mg bid ) or placebo ending on the day of HCG injection . RESULTS No differences were found in the primary end-points : duration of FSH stimulation 14.4 ( 13.1 - 15.7 ) versus 14.2 ( 12.6 - 15.7 ) days or estradiol on the day of HCG injection 6.8 ( 5.3 - 8.2 ) versus 7.6 ( 5.6 - 9.6 ) nmol/l in the metformin and placebo groups , respectively . The secondary end-points number of oocytes , fertilization rates , embryo quality , pregnancy rates and clinical pregnancy rates were equal . However , in the normal weight subgroup ( BMI < 28 kg/m(2 ) , n = 27 ) , pregnancy rates following IVF were 0.71 ( 0.63 - 0.79 ) versus 0.23 ( 0.15 - 0.31 ) in the metformin and placebo groups , respectively ( P = 0.04 ) . Overall clinical pregnancy rates were equal : 0.51 ( 0.34 - 0.68 ) versus 0.44 ( 0.27 - 0.62 ) in the metformin and placebo groups , respectively . However , in the normal weight subgroup , clinical pregnancy rates were 0.67 ( 0.43 - 0.91 ) and 0.33 ( 0.06 - 0.60 ) , respectively ( P = 0.06 ) . CONCLUSIONS Pre-treatment with metformin prior to conventional IVF/ICSI in women with PCOS does not improve stimulation or clinical outcome . However , among normal weight PCOS women , pre-treatment with metformin tends to improve pregnancy rates . Further studies in subgroups of PCOS women are required BACKGROUND Metformin appears to improve reproductive function in some women with polycystic ovary syndrome ( PCOS ) . We wished to explore the effect of metformin in women with PCOS undergoing IVF . METHODS A r and omized , placebo-controlled , double-blind study was carried out between 2001 and 2004 . Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were r and omized to receive metformin ( MET ) , 850 mg , or placebo ( PLA ) tablets twice daily from the start of the down-regulation process until the day of oocyte collection . The primary outcome was to be an improvement in the overall fertilization rate . RESULTS One-hundred and one IVF/ICSI cycles were r and omized to receive metformin ( 52 ) or to receive placebo ( 49 ) . There was no difference in the total dose of rFSH required per cycle ( median dose : MET = 1200 U , PLA = 1300 U ; P = 0.937 ) . The median number of oocytes retrieved per cycle ( MET = 17.2 , PLA = 16.2 ; P = 0.459 ) and the overall fertilization rates ( MET = 52.9 % , PLA = 54.9 % ; P = 0.641 ) did not differ . However , both the clinical pregnancy rates beyond 12 weeks gestation per cycle ( MET = 38.5 % , PLA = 16.3 % ; P = 0.023 ) and per embryo transfer ( MET = 44.4 % , PLA = 19.1 % ; P = 0.022 ) were significantly higher in those treated with metformin . Furthermore , a significant decrease in the incidence of severe ovarian hyperstimulation syndrome ( OHSS ) was observed ( MET = 3.8 % , PLA = 20.4 % ; P = 0.023 ) , and this was still significant after adjustment for BMI , total rFSH dose and age ( OR = 0.15 ; 95 % CI : 0.03 , 0.76 ; P = 0.022 ) . CONCLUSION Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS OBJECTIVE To evaluate the effect of metformin therapy on hyper and rogenism , insulin resistance , cervical scores , ovulation , and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled study . SETTING Infertility clinic of a tertiary referral center . PATIENT(S ) Fifty-six women with clomiphene citrate-resistant PCOS . INTERVENTION(S ) Two cycles of oral metformin therapy ( 850 mg , twice daily ) in group I and placebo therapy ( twice daily ) in group II . Clomiphene citrate ( 100 mg/day ) on cycle days 3 - 7 of the second cycle in both groups . MAIN OUTCOME MEASURE(S ) Insulin , T , DHEAS , FSH , LH , body mass index ( BMI ) , waist-to-hip ratio , endometrial thickness , cervical score , ovulation , and pregnancy rates in clomiphene-induced cycles after metformin therapy . RESULT ( S ) Metformin therapy result ed in a significant decrease in total T , LH level , LH/FSH ratio , insulin resistance , and mean BMI . No difference in waist-to-hip ratio , DHEAS level , and fasting insulin level was observed . Clomiphene citrate induction result ed in higher ovulation rates and thicker endometrium in the metformin group than in the placebo group . There was higher cumulative pregnancy rate in the metformin group ; however , there was no significant difference in the pregnancy rate between the two groups . CONCLUSION ( S ) Metformin therapy not only decreases hyper and rogenism and insulin resistance but also improves ovulation rates , cervical scores , and pregnancy rates in clomiphene citrate-resistant women with PCOS Summary This study was conducted to determine the efficacy of metformin vs placebo in women with polycystic ovary syndrome ( PCOS ) undergoing IVF treatment . A total of 66 CC-resistant patients were studied prospect ively . The women were r and omly assigned to receive 850 mg of metformin ( n = 34 ) or placebo ( n = 32 ) twice daily that started 1 month before commencing the IVF treatment and continued to the day of the pregnancy test . Compared with the metformin-treated group , women who received a placebo had a significant increase in terms of days of stimulation with HMG , number of HMG ampoules , number of follicles > 14 mm , number of oocytes retrieved , number of mature eggs , fertilisation rate and oestradiol level on the day of hCG administration . Similarly , women in the placebo group showed a significant increase in poor quality embryos , cancellation rate and the rate of ovarian hyperstimulation syndrome , as compared with the metformin-treated group . On the other h and , women who received metformin showed a significantly higher number of good quality embryos and implantation rate when compared with the placebo controls . Despite the transfer of a similar number of embryos , an insignificant increased in the pregnancy rate along with significant reduction in the abortion rate was observed in the metformin-treated group as compared with the placebo controls . No fetal abnormalities were encountered in the babies born in the metformin-treated group . It is concluded that metformin affects positively the quality of both oocytes and embryos without a significant increase in the pregnancy rate . It decreases significantly the rates of abortion and ovarian hyperstimulation syndrome This study was design ed to determine if metformin therapy improves ovarian stimulation and IVF outcomes in coasted patients with clomiphene-resistant polycystic ovarian syndrome ( PCOS ) . A retrospective data analysis was performed on women with clomiphene citrate-resistant PCOS treated with or without metformin , who underwent 72 cycles of IVF-embryo transfer with intracytoplasmic sperm injection ( ICSI ) . In 59 cycles , patients were coasted to allow oestradiol concentrations to drop before human chorionic gonadotrophin administration . In patients undergoing coasting , the outcome of IVF with ICSI was compared in those who were treated and untreated . In patients treated with metformin , follicular fluid concentrations of testosterone and insulin were significantly lower ( 60.5 + /- 5 versus 79.1 + /- 6 ng/dl ; P < 0.05 and 18 + /- 2.5 versus 22 + /- 2.4 micro IU/ml ; P < 0.05 respectively ) , and the mean number of oocytes retrieved ( 22.3 + /- 2.4 versus 19.7 + /- 1.6 ) did not differ . The metformin-treated group showed an increase in the mean number of mature oocytes , oocytes fertilized and cleaving embryos ( 4-cell or greater by 72 h ) . However , in the group of patients undergoing coasting , maximum oestradiol concentrations and number of days of coasting were all lower in the metformin-treated group with increased clinical pregnancy rates ( 71 versus 30 % , P < 0.05 ) . Therefore , metformin use appears beneficial in improving IVF outcomes in clomiphene citrate-resistant PCOS patients Metformin effectively restores insulin sensitivity in insulin-resistant women with polycystic ovary syndrome ( PCOS ) . We examined whether metformin , given prior to and during ovarian stimulation for in vitro fertilization ( IVF ) , altered follicle stimulating hormone ( FSH ) requirement and increased the number of collected oocytes in these women . Seventeen insulin-resistant women with PCOS were recruited to our IVF unit to receive two consecutive cycles of ovarian stimulation with or without metformin co-treatment , the order of treatments being r and omized using a table of r and om numbers . Metformin treatment ( 1500 mg/day ) started 3 weeks before downregulation with buserelin acetate and was continued throughout ovarian stimulation with human recombinant FSH . Nine women completed both cycles , the results of eight women being excluded because of pregnancy after the first cycle ( n = 4 ) or because the protocol of the study was not followed ( n = 4 ) . Mean total FSH dose was 2301 IU ( range 1500 - 6563 IU ) in metformin cycles and 2174 IU ( range 1200 - 3900 IU ) in parallel control cycles , while the mean number of collected oocytes was 8.6 ( range 2 - 28 ) and 4.6 ( range 1 - 16 ) , respectively . Bayesian analysis showed probabilities of 0.05 that metformin reduces FSH requirement by at least 10 % , and of 0.61 that at least 10 % more oocytes are collected after metformin co-treatment . Co-administration of metformin is therefore likely to increase the number of oocytes collected after ovarian stimulation in insulin-resistant women with PCOS but is unlikely to reduce the requirement for FSH OBJECTIVE Low- grade chronic inflammation , evaluated by serum C-reactive protein ( CRP ) levels , has been connected with the polycystic ovary syndrome ( PCOS ) . Effects of metformin on CRP before and during IVF treatment in women with PCOS are unknown . DESIGN A prospect i ve double-blind placebo-controlled study . SETTING Single-center IVF clinic . PATIENT(S ) Sixty-three PCOS women . INTERVENTION(S ) Treatment with 2000 mg/day metformin or identical placebo tablets for at least 14 weeks before and then during IVF treatment , ending on the day of hCG injection . MAIN OUTCOME MEASURE(S ) The CRP levels at five time points ending on the day of ovum collection . RESULT ( S ) At inclusion of infertile untreated PCOS women , body mass index associated with CRP in multivariable regression analysis ( r = 0.18 ) . And rogen levels did not associate with CRP levels . Metformin did not influence CRP levels during pretreatment or IVF cycle . After hCG injection , CRP increased in both the metformin and the placebo groups with no significant difference between the groups . CONCLUSION ( S ) In infertile PCOS women , CRP levels are unaffected by metformin treatment . The CRP level increases during IVF treatment , and this increase is unaffected by concomitant metformin . We observed an association between CRP levels and body mass index OBJECTIVE Aim of our study was to analyze the influence of insulin receptor sensitization on the course of controlled ovarian stimulation in the program of assisted reproduction and to identify the availability of ovarian response improvement due to the reduced production of intraovarian and rogens . Further we tried to identify the preventive influence of metformin on development of ovarian hyperstimulation syndrome . DESIGN Prospect i ve r and omized controlled study of 172 patients involved in the assisted reproduction program from May 2000 to December 2001 . SETTING Centre of Assisted Reproduction , Department of Gynecology and Obstetrics , Medical Faculty , Masaryk University and University Hospital , Brno . MATERIAL AND METHODS Patients undergoing the ovarian stimulation with increased risk of development of ovarian hyperstimulation syndrome due to the polycystic ovarian syndrome were included in the study and r and omized to two groups . ( 1 ) Women in the first group used the insulin receptor sensitizing drug metformin together with gonadotropins , and ( 2 ) women in the second group underwent the classic stimulation protocol alone . The control group ( 3 ) consisted of patients with intact ovarian function and different infertility factor . Complex hormonal status was assessed before the treatment initiation and the level of and rogens in the follicular fluid was investigated in all patients . RESULTS Metformin during gonadotropin stimulation has significantly reduced the risk of ovarian hyperstimulation syndrome in women with PCOS . Significantly lower intraovarian and rogen levels were documented in comparison to women without metformin and also when compared to patients with intact ovarian function . Metformin had also significantly reduced estradiol blood levels at the day of hCG application without significant influence on the number of obtained oocytes . CONCLUSIONS The risk of ovarian hyperstimulation syndrome development was significantly decreased in patients with PCOS in consequence to insulin receptors sensitization Abstract Objective . To examine the effect of metformin therapy on ovarian response in clomiphene-resistant PCOS patients . Design . R and omized prospect i ve study . Setting . Zeynep Kamil Hospital IVF Center . Patients . Thirty-two female PCOS patients with clomiphene citrate resistance . Interventions . Test group A received 2 × 850 mg/day metformin therapy for 8 weeks , followed by gonadotropin induction . Only gonadotropin induction was applied to Control group B.Main outcome measures . Total gonadotropin dosage , duration of gonadotropin therapy , estradiol level on HCG-day , number of follicles with ≥16 mm diameter , number of cases with hyperstimulation development , number of cancelled cycles , endometrial thickness on HCG-day , pregnancy outcome , multiple pregnancy rate . Results . The total gonadotropin doses given to metformin- study group was significantly lower than the control group . In addition , duration of therapy , HCG level , plasma estradiol level on HCG-day in the study group was significantly lower than in the control group . Conclusions . Metformin therapy has led to a higher pregnancy outcome , as well as to a decrease in hyperstimulation risk , cycle cancellations , and multiple pregnancy rates with a lower gonadotropin dosage One hundred and two women with insulin-resistant polycystic ovary syndrome were r and omized to treatment with a vitamin B preparation , metformin , or both , in conjunction with st and ard infertility treatment . Plasma homocysteine levels were significantly reduced by both B vitamins and metformin , but to a greater degree by B vitamins , and higher pregnancy rates were associated with vitamin B treatment OBJECTIVE To test whether metformin administration reduces the incidence of ovarian hyperstimulation syndrome ( OHSS ) in infertile high-risk patients with polycystic ovary syndrome ( PCOS ) who have been treated with gonadotropins for IVF . DESIGN Parallel , r and omized , double-blind , placebo-controlled clinical trial . SETTING Academic departments , general hospital , and IVF centers . PATIENT(S ) One hundred twenty patients with PCOS at high risk for OHSS . INTERVENTION(S ) Gonadotropins ovarian stimulation for IVF and metformin ( 500 mg three times daily ) or placebo tablets ( three times daily ) . MAIN OUTCOME MEASURE(S ) The primary end point of the current clinical trial was the rate of OHSS . Anthropometric and reproductive data were evaluated . RESULT ( S ) The total OHSS and cancellation rates were significantly reduced in patients treated with metformin . The relative risk for OHSS was of 0.28 ( 95 % confidence interval , 0.11 - 0.67 ) . With metformin the stimulation length and the total amount of gonadotropins used were significantly increased , whereas the peak E(2 ) levels were significantly reduced . CONCLUSION ( S ) In patients with PCOS who are at high risk for OHSS and who have been stimulated with gonadotropins for IVF cycles , metformin reduces the risk of OHSS by modulating the ovarian response to the stimulation . REGISTRATION ID NUMBER FROM CLINICAL TRIALS.GOV : NCT01233206

It is uncertain whether the strategies tested improved the implementation of policies , practice s or programmes that promote child healthy eating , physical activity and /or obesity prevention . No intervention improved the implementation of all policies and practice s targeted by the implementation strategies relative to a comparison group . Current research provides weak and inconsistent evidence of the effectiveness of such strategies in improving the implementation of policies and practice s , childcare service staff knowledge or attitudes , or child diet , physical activity or weight status .

BACKGROUND Despite the existence of effective interventions and best- practice guideline recommendations for childcare services to implement policies , practice s and programmes to promote child healthy eating , physical activity and prevent unhealthy weight gain , many services fail to do so . OBJECTIVES The primary aim of the review was to examine the effectiveness of strategies aim ed at improving the implementation of policies , practice s or programmes by childcare services that promote child healthy eating , physical activity and /or obesity prevention . The secondary aims of the review were to:1 . describe the impact of such strategies on childcare service staff knowledge , skills or attitudes;2 . describe the cost or cost-effectiveness of such strategies;3 . describe any adverse effects of such strategies on childcare services , service staff or children;4 . examine the effect of such strategies on child diet , physical activity or weight status .

INTRODUCTION This study evaluated whether intervening with child care providers would increase physical activity ( PA ) and reduce adiposity in preschoolers . METHODS This was a two-arm , parallel group , cluster RCT whereby six child care centers were r and omly assigned in equal numbers to intervention ( n=40 children ) or control ( n=43 children ) . Participants were aged 3 - 5 years and attended licensed child care centers . Child care providers received two 3-hour train-the-trainer workshops and a training manual at program initiation aim ed at increasing structured and unstructured PA through active play . Control child care centers implemented their st and ard curriculum . PA and sedentary behavior were measured by accelerometry , and body composition was measured using bioelectrical impedance at baseline and 6 months . Data were collected in 2011 - 2012 and analyzed in April 2015 . RESULTS Linear mixed-effects modeling showed that at 6 months , children in the intervention group demonstrated greater increases in minutes per preschool day spent in overall PA ( 22.5 minutes , 95 % CI=8.9 , 36.1 , p=0.002 ) , and light-intensity PA ( 16.1 minutes , 95 % CI=5.2 , 26.7 , p=0.004 ) , but changes between groups in moderate to vigorous PA did not differ . The intervention group showed greater reductions in body fat percentage ( -1.9 % , 95 % CI=-3.5 , -0.3 , p=0.023 ) and fat mass ( -0.3 kg , 95 % CI=-0.7 , -0.1 , p=0.018 ) , but groups did not differ on fat-free mass , BMI , or z- BMI . CONCLUSIONS Provider-led intervention in child care centers increased preschoolers ' PA and reduced adiposity , therefore may represent a viable approach to promoting PA and related health benefits in preschool-aged children . TRIAL REGISTRATION This study is registered at www . clinical trials.gov NCT02293278 BACKGROUND Sugar-sweetened beverages and maternal weight are strong drivers of child obesity , but few studies have targeted these risk factors as an obesity prevention strategy in children . OBJECTIVE The objective of this study was to test the efficacy of a smartphone-delivered intervention to reduce parent-provided sugar-sweetened beverage and juice ( SSB/juice ) consumption among children ages 3 - 5 and maternal weight . METHODS Mothers with overweight or obesity , who had a child ages 3 - 5 that consumed at least 12 fl . oz./day of SSB/juice ( N = 51 dyads ) were r and omized to the Smart Moms group that received one group session , lessons on a mobile website , and text messages , or to a waitlist control group . Mothers self-monitored their children 's beverages in addition to their own beverages , high-calorie foods , and weight . Assessment s at baseline , 3 , and 6 months included dietary recalls to measure SSB/juice intake and objective ly measured maternal weight . RESULTS Using linear mixed models controlling for baseline values , child age and race , there was a greater reduction in child SSB/juice in Smart Moms compared with control at 6 months ( -9.7 oz./day vs. 1.7 oz./day , p < .01 ) . Mothers in Smart Moms lost 2.4 kg at 6 months compared with a 0.9-kg gain in the control group ( p < .01 ) . CONCLUSIONS An intervention delivered using mHealth technologies can target mothers to change child dietary behaviours and improve maternal weight , which suggests a novel approach to family-based obesity prevention Background The primary aim of this study was to evaluate the effectiveness of an intervention to increase the implementation of healthy eating and physical activity policies and practice s by centre-based childcare services . The study also sought to determine if the intervention was effective in improving child dietary intake and increasing child physical activity levels while attending childcare . Methods A parallel group , r and omised controlled trial was conducted in a sample of 128 childcare services . Intervention strategies included provision of implementation support staff , securing executive support , staff training , consensus processes , academic detailing visits , tools and re sources , performance monitoring and feedback and a communications strategy . The primary outcome of the trial was the proportion of services implementing all seven healthy eating and physical activity policies and practice s targeted by the intervention . Outcome data were collected via telephone surveys with nominated supervisors and room leaders at baseline and immediately post-intervention . Secondary trial outcomes included the differences between groups in the number of serves consumed by children for each food group within the Australian Guide to Healthy Eating and in the proportion of children engaged in sedentary , walking or very active physical activity assessed via observation in a r and om sub sample of 36 services at follow-up . Results There was no significant difference between groups for the primary trial outcome ( p = 0.44 ) . Relative to the control group , a significantly larger proportion of intervention group services reported having a written nutrition and physical activity policy ( p = 0.05 ) and providing adult-guided activities to develop fundamental movement skills ( p = 0.01 ) . There were no significant differences between groups at follow-up on measures of child dietary intake or physical activity . Conclusions The findings of the trial were equivocal . While there was no significant difference between groups for the primary trial outcome , the intervention did significantly increase the proportion of intervention group services implementing two of the seven healthy eating and physical activity policies and practice s. High levels of implementation of a number of policies and practice s at baseline , significant obesity prevention activity in the study region and higher than previously reported intra-class correlation of child behaviours may , in part , explain the trial findings .Trial registration Australian Clinical Trials Registry ( reference ACTRN12612000927820 ) BACKGROUND The prevalence of obesity in the United States is a significant public health problem . Many obesity-related risk factors are more prevalent in minority population s. Given the recalcitrant nature of weight loss interventions for adults , prevention of overweight and obesity has become a high priority . The present study reports baseline data from an obesity prevention intervention developed for minority preschool children . METHODS Hip-Hop to Health Jr. is a 5-year r and omized controlled intervention that targets 3- to 5-year-old minority children enrolled in 24 Head Start programs . Our primary aim is to test the effect of the intervention on change in body mass index . Data were collected on sociodemographic , anthropometric , behavioral , and cognitive variables for the children and parents at baseline . RESULTS Participants included 416 black children , 337 black parents , 362 Latino children , and 309 Latino parents . Using body mass index for age and sex > or = the 95th percentile as the definition of overweight , 15 % of the black children and 28 % of the Latino children were overweight . More than 75 % of the parents were either overweight or obese . DISCUSSION The development of interventions to effectively prevent or control obesity early in life is crucial . These data highlight the escalating problem of weight control in minority population Background Little is known about preschool-aged children ’s levels of physical activity ( PA ) over the course of the day . Using time-stamped data , we describe the levels and patterns of PA in a population -based sample of four-year-old British children . Methods Within the Southampton Women ’s Survey the PA levels of 593 4-year-old children ( 51 % female ) were measured using ( Actiheart ) accelerometry for up to 7 days . Three outcome measures : minutes spent sedentary ( < 20 cpm ) ; in light ( LPA : ≥20 – 399 cpm ) and in moderate-to-vigorous activity ( MVPA : ≥400 cpm ) were derived . Average daily activity levels were calculated and then segmented across the day ( morning , afternoon and evening ) . MVPA was log-transformed . Two-level r and om intercept models were used to analyse associations between activity level and temporal and demographic factors . Results Children were active for 67 % ( mean 568.5 SD 79.5 minutes ) of their daily registered time on average , with 88 % of active time spent in LPA . All children met current UK guidelines of 180 minutes of daily activity . There were no differences in children ’s average daily levels of sedentary activity and LPA by temporal and demographic factors : differences did emerge when activity was segmented across the day . Sex differences were largest in the morning , with girls being more sedentary , spending fewer minutes in LPA and 18 % less time in MVPA than boys . Children were more sedentary and less active ( LPA and MVPA ) in the morning if they attended childcare full-time compared to part-time , and on weekend mornings compared to weekdays . The reverse was true for weekend afternoons and evenings . Children with more educated mothers were less active in the evenings . Children were less sedentary and did more MVPA on summer evenings compared to winter evenings . Conclusions Preschool-aged children meet current physical activity guidelines , but with the majority of their active time spent in LPA , investigation of the importance of activity intensity in younger children is needed . Activity levels over the day differed by demographic and temporal factors , highlighting the need to consider temporality in future interventions . Increasing girls ’ morning activity and providing opportunities for daytime activity in winter months may be worthwhile Background There is considerable scope to improve the delivery of practice s that increase the physical activity of children in centre based childcare services . Few studies have reported the effectiveness of interventions to address this , particularly at a population level . The primary aim of this study was to describe the impact of an intervention to increase the adoption of multiple policies and practice s to promote physical activity in centre based childcare services . Methods A quasi experimental study was conducted in centre based childcare services ( n = 228 ) in New South Wales ( NSW ) , Australia and involved a three month intervention to increase the adoption of eight practice s within childcare services that have been suggested to promote child physical activity . Intervention strategies to support the adoption of practice s included staff training , re sources , incentives , follow-up support and performance monitoring and feedback . R and omly selected childcare services in the remainder of NSW acted as a comparison group ( n = 164 ) and did not receive the intervention but may have been exposed to a concurrent NSW government healthy eating and physical activity initiative . Self reported information on physical activity policies , fundamental movement skills sessions , structured physical activity opportunities , staff involvement in active play and provision of verbal prompts to encourage physical activity , small screen recreation opportunities , sedentary time , and staff trained in physical activity were collected by telephone survey with childcare service managers at baseline and 18 months later . Results Compared with the comparison area , the study found significantly greater increases in the prevalence of intervention services with a written physical activity policy , with policy referring to placing limits on small screen recreation , and with staff trained in physical activity . In addition , non-significant trends towards a greater increase in the proportion of intervention services conducting daily fundamental movement skill sessions , and such services having a physical activity policy supporting physical activity training for staff were also evident . Conclusion The intervention was effective in improving a number of centre based childcare service policies and practice s associated with promoting child physical activity . Adoption of a broader range of practice s may require more intensive and prolonged intervention support OBJECTIVE Determine whether Color Me Healthy ( CMH ) , an interactive nutrition and physical activity program for preschool children , increases fruit and vegetable consumption . DESIGN Intervention study . Data were collected at baseline , 1 week post-intervention , and 3 months post-intervention . SETTING Child care centers . PARTICIPANTS Preschool children ( n = 263 ) in 17 child care centers . INTERVENTION Child care centers were r and omly assigned to 1 of 2 conditions ; children ( n = 165 ) in 10 centers received the CMH curriculum , and children ( n = 98 ) in 7 centers acted as comparisons and did not receive the curriculum . MAIN OUTCOME MEASURES Process and outcome evaluation . Consumption of fruit and vegetable snacks . ANALYSIS Data were analyzed using repeated- measures analysis of variance and hierarchical linear modeling . RESULTS Children who received CMH significantly increased their consumption of fruit snacks by approximately 20.8 % and vegetable snacks by approximately 33.1 % between baseline assessment and the assessment conducted 3 months after the completion of the CMH program . Hierarchical linear modeling determined that group assignment ( ie , CMH or control ) was the only significant predictor of fruit and vegetable consumption . CONCLUSIONS AND IMPLICATION S Findings suggest that CMH may be used in child care setting s for developing healthful eating habits BACKGROUND The Child Health Initiative for Lifelong Eating and Exercise is a multicomponent obesity-prevention intervention , which was evaluated among Head Start ( HS ) centers in American Indian and predominantly Hispanic communities in rural New Mexico . This study examines the intervention 's foodservice outcomes : fruits , vegetables , whole grains , discretionary fats , added sugars , and fat from milk served in meals and snacks . METHODS Sixteen HS centers were r and omized to intervention/comparison groups , following stratification by ethnicity and preintervention median body mass index of enrolled children . The foodservice component included quarterly trainings for foodservice staff about food purchasing and preparation . Foods served were evaluated before and after the 2-year intervention , in the fall 2008 and spring 2010 . RESULTS The intervention significantly decreased fat provided through milk and had no significant effect on fruit , vegetables and whole-grain servings , discretionary fats , and added sugar served in HS meals and snacks . When effect modification by site ethnicity was examined , the effect on fat provided through milk was only found in American Indian sites . CONCLUSIONS Foodservice interventions can reduce the amount of fat provided through milk served in HS . More research is needed regarding the implementation of foodservice interventions to improve the composition of foods served in early education setting Background To address the public health crisis of overweight and obese preschool-age children , the Nutrition And Physical Activity Self Assessment for Child Care ( NAP SACC ) intervention was delivered by nurse child care health consultants with the objective of improving child care provider and parent nutrition and physical activity knowledge , center-level nutrition and physical activity policies and practice s , and children ’s body mass index ( BMI ) . Methods A seven-month r and omized control trial was conducted in 17 licensed child care centers serving predominantly low income families in California , Connecticut , and North Carolina , including 137 child care providers and 552 families with racially and ethnically diverse children three to five years old . The NAP SACC intervention included educational workshops for child care providers and parents on nutrition and physical activity and consultation visits provided by trained nurse child care health consultants . Demographic characteristics and pre - and post-workshop knowledge surveys were completed by providers and parents . Blinded research assistants review ed each center ’s written health and safety policies , observed nutrition and physical activity practice s , and measured r and omly selected children ’s nutritional intake , physical activity , and height and weight pre- and post-intervention . Results Hierarchical linear models and multiple regression models assessed individual- and center-level changes in knowledge , policies , practice s and age- and sex-specific st and ardized body mass index ( z BMI ) , controlling for state , parent education , and poverty level . Results showed significant increases in providers ’ and parents ’ knowledge of nutrition and physical activity , center-level improvements in policies , and child-level changes in children ’s z BMI based on 209 children in the intervention and control centers at both pre- and post-intervention time points . Conclusions The NAP SACC intervention , as delivered by trained child health professionals such as child care health consultants , increases provider knowledge , improves center policies , and lowers BMI for children in child care centers . More health professionals specifically trained in a nutrition and physical activity intervention in child care are needed to help reverse the obesity epidemic . Trial registration National Clinical Trials Number Background Young children are prone to low levels of physical activity in childcare . Research ers have identified that preschoolers tend to be more active outdoors than indoors , with higher activity levels occurring during the first 10 minutes of outdoor playtime . Additionally , interventions incorporating either staff training or the inclusion of play equipment have been effective at increasing children ’s activity in this setting . As such , the overarching objective of the Supporting Physical Activity in the Childcare Environment ( SPACE ) intervention is to improve the physical activity levels of preschoolers during childcare hours , utilizing a combination of the above components . The purpose of this manuscript is to provide a detailed account of the protocol , innovative methods , and evaluation plans used in the implementation of the SPACE study ; in an effort to support the development of further research in this field . Methods / Design The SPACE study , a cluster r and omized controlled trial , involves 22 childcare centres r and omly allocated to either the experimental ( n = 11 ) or the control ( n = 11 ) group . Childcare centres receiving the intervention will adopt an 8-week physical activity intervention with the following components : 1 . shorter , more frequent bouts of outdoor playtime ( 4 × 30 min periods rather than 2 × 60 min periods ) ; 2 . new portable play equipment ( e.g. , obstacle course , balls ) ; and , 3 . staff training ( 1 × 4 hr workshop ) . Actical accelerometers will be used to assess total physical activity with measurements taken at baseline ( i.e. , week 0 ) , immediately post-intervention ( i.e. , week 8) , and at 6- and 12-month follow-up . As secondary objectives , we aim to evaluate the effectiveness of the intervention on preschoolers ’ : a ) sedentary time ; b ) st and ardized body mass index scores ( percentiles ) ; c ) health-related quality of life ; and childcare providers ’ physical activity-related knowledge and self-efficacy to implement physical activity . Discussion The SPACE study aims to increase the low levels of physical activity observed within childcare centres . The findings of this work may be useful to policy makers and childcare providers to consider modifications to the current childcare curriculum and associated outdoor play time . Trial registration IS RCT N70604107 ( October 8 , 2014 Background As part of childhood obesity prevention initiatives , Early Care and Education ( ECE ) programs are being asked to implement evidence -based strategies that promote healthier eating and physical activity habits in children . Translation of evidence -based interventions into real world ECE setting s often encounter barriers , including time constraints , lack of easy-to-use tools , and inflexible intervention content . This study describes translation of an evidence -based program ( NAPSACC ) into an online format ( Go NAPSACC ) and a r and omized pilot study evaluating its impact on centers ’ nutrition environments . Methods Go NAPSACC retained core elements and implementation strategies from the original program , but translated tools into an online , self-directed format using extensive input from the ECE community . For the pilot , local technical assistance ( TA ) agencies facilitated recruitment of 33 centers , which were r and omized to immediate ( intervention , n = 18 ) or delayed ( control , n = 15 ) access groups . Center directors were oriented on Go NAPSACC tools by their local TA providers ( after being trained by research ers ) , after which they implemented Go NAPSACC independently with minimal TA support . The Environment and Policy Assessment and Observation instrument ( self-report ) , collected prior to and following the 4-month intervention period , was used to assess impact on centers ’ nutrition environments . Process data were also collected from a sample of directors and all TA providers to evaluate program usability and implementation . Results Demographic characteristics of intervention and control centers were similar . Two centers did not complete follow-up measures , leaving 17 intervention and 14 control centers in the analytic sample . Between baseline and follow-up , intervention centers improved overall nutrition scores ( Cohen ’s d effect size = 0.73 , p = 0.15 ) , as well as scores for foods ( effect size = 0.74 , p = 0.16 ) , beverages ( effect size = 0.54 , p = 0.06 ) , and menus ( effect size = 0.73 , p = 0.08 ) , but changes were not statistically significant . Conclusions Core elements of NAPSACC were effectively translated into online tools and successfully implemented by center directors . Results suggest that the online program may have retained its ability to drive change in centers ’ nutrition environments using a streamlined , self-directed , and flexible implementation approach . Results need to be confirmed in a larger more definitive trial . Trial registration NCT02889198 ( retrospectively registered ) OBJECTIVE The aim of the present study was to evaluate the effects of a 1-year family-based healthy lifestyle intervention implemented through day-care centres on toddlers ' BMI Z-scores and reported activity- and dietary-related behaviours . DESIGN Pilot cluster-r and omized controlled trial . SETTING Seventy child-care centres in three different intervention communities and three paired-matched control communities in Fl and ers , Belgium . SUBJECTS A sample of 203 Belgian toddlers aged 9 - 24 months was included in the study . Objective ly assessed weight and height were used to calculate BMI Z-scores . A parental-report question naire was used to assess children 's lifestyle behaviours . RESULTS Positive intervention effects were found on BMI Z-score . No intervention effects were found for activity- and dietary-related behaviours targeted by the intervention . In both intervention and control groups , daily consumption of water , soft drinks , sweets and savoury snacks increased while daily consumption of fruit and vegetables decreased over 1 year . Daily physical activity remained stable but screen-time behaviour increased in both groups over time . CONCLUSIONS The study showed that a family-based healthy lifestyle intervention implemented through day-care centres can lead to healthier weight outcomes in toddlers . In both groups , an unhealthier lifestyle pattern was observed over 1 year which underlines the importance of the early childhood period as the focus of future behavioural interventions Background Systematic review s of the effects of healthcare interventions frequently include non-r and omized studies . These are subject to confounding and a range of other biases that are seldom considered in detail when synthesizing and interpreting the results . Our aims were to assess the reliability and usability of a new Cochrane risk of bias ( RoB ) tool for non-r and omized studies of interventions and to determine whether restricting analysis to studies with low or moderate RoB made a material difference to the results of the review s. Methods and Findings We selected two systematic review s of population -based , controlled non-r and omized studies of the relationship between the use of thiazolidinediones ( TZDs ) and cyclooxygenase-2 ( COX-2 ) inhibitors and major cardiovascular events . Two epidemiologists applied the Cochrane RoB tool and made assessment s across the seven specified domains of bias for each of 37 component studies . Inter-rater agreement was measured using the weighted Kappa statistic . We grouped studies according to overall RoB and performed statistical pooling for ( a ) all studies and ( b ) only studies with low or moderate RoB. Kappa scores across the seven bias domains ranged from 0.50 to 1.0 . In the COX-2 inhibitor review , two studies had low overall RoB , 14 had moderate RoB , and five had serious RoB. In the TZD review , six studies had low RoB , four had moderate RoB , four had serious RoB , and two had critical RoB. The pooled odds ratios for myocardial infa rct ion , heart failure , and death for rosiglitazone versus pioglitazone remained significantly elevated when analyses were confined to studies with low or moderate RoB. However , the estimate for myocardial infa rct ion declined from 1.14 ( 95 % CI 1.07–1.24 ) to 1.06 ( 95 % CI 0.99–1.13 ) when analysis was confined to studies with low RoB. Estimates of pooled relative risks of cardiovascular events with COX-2 inhibitors compared with no nonsteroidal anti-inflammatory drug changed little when analyses were confined to studies with low or moderate RoB. The exception was a rise in the relative risk associated with ibuprofen from 1.07 ( 95 % CI 0.97–1.18 ) to 1.14 ( 95 % CI 1.03–1.26 ) . The main limitation of our study was testing the instrument on a narrow range of pharmacoepidemiological studies ; we can not assume our findings extend to a broader range of interventions and setting s. Conclusions The Cochrane RoB tool highlighted a wide range of risks of bias in studies included in two widely cited review s and had the potential to change the conclusions of the review s. Systematic review s that incorporate non-r and omized studies of medical interventions should include a detailed assessment of RoB for each included study Exercise has been found to be effective for prevention of weight gain and maintenance of a stable weight in adults . The objective of this study was to evaluate the effect of a school-based aerobic exercise program on the obesity indexes of preschool children . Subjects were 292 second-year elementary school pupils from 2 kindergartens in Hat Yai municipality , Songkhla province , southern Thail and . A specially design ed exercise program , including a 15-min walk before beginning the morning class and a 20-min aerobic dance session after the afternoon nap , 3 times a week , was conducted for 29.6 wk . Weight , height , and triceps skinfold thickness were measured 4 times . At the end of the study , the prevalence of obesity , using 95th percentile National Center for Health Statistics triceps-skinfold-thickness cutoffs , of both the exercise and control groups decreased . That of the exercise group decreased from 12.2 % at baseline to 8.8 % ( Wilcoxon signed-rank test , P = 0.058 ) , whereas that of the control group decreased from 11.7 % to 9.7 % ( Wilcoxon signed-rank test , P = 0.179 ) . A sex difference in the response of body mass index ( BMI ) to exercise was observed . Girls in the exercise group had a lower likelihood of having an increasing BMI slope than the control girls did ( odds ratio : 0.32 ; 95 % CI : 0.18 , 0.56 ) . In conclusion , our study suggests that a 29.6-wk school-based exercise program can prevent BMI gain in girls and may induce a remission of obesity in preschool-age children Background North Carolina Nutrition and Physical Activity Self- Assessment for Child Care ( NAP SACC ) re sources improve child body mass index ( BMI ) when the re sources are introduced by nurses to child care providers , and offered with workshops and incentives . In San Francisco , public health and child care agencies partnered to adapt NAP SACC re sources into an annual “ Healthy Apple ” quality improvement program ( HAP ) . Methods This cluster r and omized controlled trial pilot-tested integration of the HAP with bi-annual public health screenings by nurses . All child care centers that participated in Child Care Health Program ( CCHP ) screenings in San Francisco in 2011–2012 were offered routine services plus HAP in 2012–2013 ( CCHP + HAP , n = 19 ) or routine services with delayed HAP in 2014–2015 ( CCHP + HAP Delayed , n = 24 ) . Intention-to-treat analyses ( robust SE or mixed models ) used 4 years of screening data from 12 to 17 CCHP + HAP and 17 to 20 CCHP + HAP Delayed centers , regarding 791 to 945 children ages 2 to 5y , annually . Year-specific , child level models tested if children in CCHP + HAP centers had greater relative odds of exposure to 3 index best practice s and smaller Autumn-to-Spring changes in BMI percentile and z-score than children in CCHP + HAP Delayed centers , controlling for age , sex , and Autumn status . Multi-year , child care center level models tested if HAP support modified year-to-year changes ( 2013–2014 and 2014–2015 vs 2011–2012 ) in child care center annual mean Autumn-to-Spring BMI changes . Results In 2011–2012 , the CCHP + HAP and CCHP + HAP Delayed centers had similar index practice s ( < 15 % of children were exposed to a physical activity curriculum , staff joining in active play , and drinking water pitchers ) and annual BMI changes . In 2013–2014 : 60 % of children in CCHP + HAP centers were exposed to the 3 index practice s vs 19 % in CCHP + HAP Delayed centers ; Mean ( SE ) child BMI percentile ( −2.6 ( 0.9 ) , p = 0.003 ) and z-score ( −0.08 ( 0.03 ) , p = 0.007 ) decreased more in CCHP + HAP vs CCHP + HAP Delayed centers . In 2014–2015 , after all centers were offered HAP , the index practice s and BMI changes were improved for all centers vs 2011–2012 . Conclusions Integration of the HAP with existing public health nursing services was associated with significantly more children exposed to best practice s and improvement in child BMI change . The results warrant continued integration of HAP into local public health infrastructure . Trial registration IS RCT N18857356 ( 24/04/2015 ) Retrospectively registered Purpose . To test whether implementing a staff wellness program affects the nutrition and physical activity environment at child care centers . Design . Quasi-experimental controlled trial . Setting . Child care centers in low income neighborhoods in California . Subjects . Eighty-two staff members at 13 centers completed the study . Intervention . Intervention and control groups received training and education about nutrition and physical activity . The intervention group also participated in a worksite wellness program . Measures . Staff members ' personal health habits , self-efficacy in working with families on nutrition and physical activity , and changes in children 's food and physical activity environments were assessed . Analysis . Statistical software was used to analyze change scores for pre-post measures and to test differences for end point — only measures . Results . Although significant differences in staff members ' personal health behaviors were not observed , staff from intervention sites exhibited more positive changes in their comfort level in talking to parents about nutrition and physical activity . Intervention sites reported providing more fresh fruits ( p = .004 ) and vegetables ( p = .03 ) to children as part of regular meals and snacks and serving more fresh fruits ( p = .05 ) at children 's celebrations . Control sites reported greater increases in sweetened foods ( p = .02 ) and sweetened beverages ( p = .05 ) at children 's celebrations . Conclusion . The wellness intervention shows promise in improving the children 's food environment in a child care setting BACKGROUND Poor adaptive learning behaviors ( ie , distractibility , inattention , and disruption ) are associated with behavior problems and underachievement in school , as well as indicating potential attention-deficit hyperactivity disorder . Strategies are needed to limit these behaviors . Physical activity ( PA ) has been suggested to improve behavior in school-aged children , but little is known about this relationship in preschoolers . This study examined the effects of a PA intervention on classroom behaviors in preschool-aged children . METHODS Eight preschool classrooms ( n = 71 children ; age = 3.8 ± 0.7 y ) with children from low socioeconomic environments were r and omized to a locomotor-based PA ( LB-PA ) or unstructured free playtime ( UF-PA ) group . Both interventions were implemented by classroom teachers and delivered for 30 minutes per day , 5 days per week for 6 months . Classroom behavior was measured in both groups at 3 time points , whereas PA was assessed at 2 time points over a 6-month period and analyzed with hierarchical linear modeling . RESULTS Linear growth models showed significant decreases in hyperactivity ( LB-PA : -2.58 points , P = .001 ; UF-PA : 2.33 points , P = .03 ) , aggression ( LB-PA : -2.87 points , P = .01 ; UF-PA : 0.97 points , P = .38 ) and inattention ( LB-PA : 1.59 points , P < .001 ; UF-PA : 3.91 points , P < .001 ) . CONCLUSIONS This research provides promising evidence for the efficacy of LB-PA as a strategy to improve classroom behavior in preschoolers OBJECTIVE We examined the outcomes of the Child Health Initiative for Lifelong Eating and Exercise ( CHILE ) study , a group r and omized controlled trial to design , implement , and test the efficacy of a trans-community intervention to prevent obesity in children enrolled in Head Start centers in rural American Indian and Hispanic communities in New Mexico . METHODS CHILE was a 5-year evidence -based intervention that used a socioecological approach to improving dietary intake and increasing physical activity of 1898 children . The intervention included a classroom curriculum , teacher and food service training , family engagement , grocery store participation , and healthcare provider support . Height and weight measurements were obtained four times ( fall of 2008 , spring and fall of 2009 , and spring of 2010 ) , and body mass index ( BMI ) z-scores in the intervention and comparison groups were compared . RESULTS At baseline , demographic characteristics in the comparison and intervention groups were similar , and 33 % of all the children assessed were obese or overweight . At the end of the intervention , there was no significant difference between the two groups in BMI z-scores . CONCLUSIONS Obesity prevention research among Hispanic and AI preschool children in rural communities is challenging and complex . Although the CHILE intervention was implemented successfully , changes in overweight and obesity may take longer than 2years to achieve This study examined the effectiveness of an active play intervention on fundamental movement skills of 3- to 5-year-old children from deprived communities . In a cluster r and omized controlled trial design , six preschools received a re source pack and a 6-week local authority program involving staff training with help implementing 60-minute weekly sessions and postprogram support . Six comparison preschools received a re source pack only . Twelve skills were assessed at baseline , postintervention , and at a 6-month follow-up using the Children ’s Activity and Movement in Preschool Study Motor Skills Protocol . One hundred and sixty-two children ( Mean age = 4.64 ± 0.58 years ; 53.1 % boys ) were included in the final analyses . There were no significant differences between groups for total fundamental movement skill , object-control skill or locomotor skill scores , indicating a need for program modification to facilitate greater skill improvements Objective To investigate the effect of a preschool physical activity intervention program delivered in licensed childcare setting s , with or without a parent‐facilitated home component , on children 's daily physical activity , sedentary time , and body composition . Study design For this cluster r and omized controlled trial , 18 childcare centers were r and omly allocated in equal numbers to the typical curriculum comparison group , childcare intervention alone ( CC ) , or childcare intervention with parental involvement . Accelerometers were used to asses physical activity and sedentary time , and body composition was measured by bioelectrical impedance . Results Linear mixed model regression analyses showed no differences between the CC , the childcare intervention with parental involvement , and the comparison groups in changes from baseline to 6 months in total physical activity ( P for time × group interaction = .665 ) or moderate‐to‐vigorous physical activity ( P for time × group interaction = .164 ) when adjusted for baseline physical activity levels . Furthermore , no group differences were found for changes in light physical activity , sedentary time , or anthropometric variables . Conclusions An affordable and easily scalable preschool intervention program delivered in licensed childcare setting s , with or without the addition of a parent‐driven home physical activity promotion , seems to have no significant effect on physical activity , sedentary time , or body composition . Trial registration IS RCT N : IS RCT N94022291 Purpose . Examine the effectiveness of the “ Eat Healthy , Stay Active ! ” pilot program , a multisite , 6-month educational intervention to promote healthy nutrition and physical activity among Head Start staff , parents , and children . Design . Comparison of within-group preintervention and postintervention knowledge and behavior , along with anthropomorphic measurements . Setting . The study was conducted in a convenience sample of six large Head Start agencies in five states . Subjects . Participants included 496 staff , 438 parents , and 112 preschool children . Intervention . The 6-month intervention consisted of core trainings and reinforcing activities for staff and parents that aligned with children 's curricula . Measures . Pre-post question naires and anthropometric measurements examined changes in body mass index ( BMI ) , knowledge , and behaviors related to nutrition and physical activity . Analysis . Paired t-tests to compare preintervention and postintervention weights and BMI ; multiple regression analyses to examine associations between weight changes and other covariates , including knowledge and behavior changes , controlling for sociodemographic variables . Results . Each group of participants demonstrated significant reductions in BMI ( mean = 30.1 to 29.2 ; p < .001 in adults and 17.0 to 16.6 ; p < 0.001 in children ) and in the proportion of obese children ( 30 % to 21 % ; p < .001 ) and adults ( 45 % to 40 % ; p < .001 ) . Child weight changes correlated with parent weight changes . Conclusion . This intervention showed promising initial results , with potential effectiveness as an intervention to promote healthier behaviors among adults and children in Head Start setting Background Childhood obesity and physical inactivity are increasing dramatically worldwide . Children of low socioeconomic status and /or children of migrant background are especially at risk . In general , the overall effectiveness of school-based programs on health-related outcomes has been disappointing . A special gap exists for younger children and in high risk groups . Methods / Design This paper describes the rationale , design , curriculum , and evaluation of a multicenter preschool r and omized intervention study conducted in areas with a high migrant population in two out of 26 Swiss cantons . Twenty preschool classes in the German ( canton St. Gallen ) and another 20 in the French ( canton Vaud ) part of Switzerl and were separately selected and r and omized to an intervention and a control arm by the use of opaque envelopes . The multidisciplinary lifestyle intervention aim ed to increase physical activity and sleep duration , to reinforce healthy nutrition and eating behaviour , and to reduce media use . According to the ecological model , it included children , their parents and the teachers . The regular teachers performed the majority of the intervention and were supported by a local health promoter . The intervention included physical activity lessons , adaptation of the built infrastructure ; promotion of regional extracurricular physical activity ; playful lessons about nutrition , media use and sleep , funny homework cards and information material s for teachers and parents . It lasted one school year . Baseline and post-intervention evaluations were performed in both arms . Primary outcome measures included BMI and aerobic fitness ( 20 m shuttle run test ) . Secondary outcomes included total ( skinfolds , bioelectrical impedance ) and central ( waist circumference ) body fat , motor abilities ( obstacle course , static and dynamic balance ) , physical activity and sleep duration ( accelerometry and question naires ) , nutritional behaviour and food intake , media use , quality of life and signs of hyperactivity ( question naires ) , attention and spatial working memory ability ( two vali date d tests ) . Research ers were blinded to group allocation . Discussion The purpose of this paper is to outline the design of a school-based multicenter cluster r and omized , controlled trial aim ing to reduce body mass index and to increase aerobic fitness in preschool children in culturally different parts of Switzerl and with a high migrant population .Trial Registration Trial Registration : clinical trials.gov Introduction Childhood overweight and obesity tracks into adulthood , increasing the risk of developing future chronic disease . Implementing initiatives promoting healthy eating and physical activity in childcare setting s has been identified as a priority to prevent excessive child weight gain . Despite this , few trials have been conducted to assess the effectiveness of interventions to support population -wide implementation of such initiatives . The aim of this study is to assess the effectiveness of a multicomponent intervention in increasing the implementation of healthy eating and physical activity policies and practice s by centre-based childcare services . Methods and analysis The study will employ a parallel group r and omised controlled trial design . A sample of 128 childcare services in the Hunter region of New South Wales , Australia , will be recruited to participate in the trial . 64 services will be r and omly allocated to a 12-month implementation intervention . The remaining 64 services will be allocated to a usual care control group . The intervention will consist of a number of strategies to facilitate childcare service implementation of healthy eating and physical activity policies and practice s. Intervention strategies will include implementation support staff , securing executive support , consensus processes , staff training , academic detailing visits , performance monitoring and feedback , tools and re sources , and a communications strategy . The primary outcome of the trial will be the prevalence of services implementing all healthy eating and physical activity policies and practice s targeted by the intervention . To assess the effectiveness of the intervention , telephone surveys with nominated supervisors and room leaders of childcare services will be conducted at baseline and immediately postintervention . Ethics and dissemination The study was approved by the Hunter New Engl and Human Research Ethics Committee and the University of Newcastle Human Research Ethics Committee . Study findings will be disseminated widely through peer- review ed publications and conference presentations . Trial registration number Australian Clinical Trials Registry ACTRN12612000927820 Background Early childhood services have been identified as a key setting for promoting healthy eating and physical activity as a means of preventing overweight and obesity . However , there is limited evidence on effective nutrition and physical activity programs in this setting . The purpose of this study was to evaluate Munch and Move , a low-intensity , state-wide , professional development program design ed to support early childhood professionals to promote healthy eating and physical activity among children in their care . Methods The evaluation involved 15 intervention and 14 control preschools ( n = 430 ; mean age 4.4 years ) in Sydney , New South Wales , Australia and was based on a r and omised-control design with pre and post evaluation of children 's lunchbox contents , fundamental movement skills ( FMS ) , preschool policies and practice s and staff attitudes , knowledge and confidence related to physical activity , healthy eating and recreational screen time . Results At follow up , FMS scores for locomotor , object control and total FMS score significantly improved by 3.4 , 2.1 and 5.5 points more ( respectively ) in the intervention group compared with the control group ( P < 0.001 ) and the number of FMS sessions per week increased by 1.5 ( P = 0.05 ) . The lunchbox audit showed that children in the intervention group significantly reduced sweetened drinks by 0.13 serves ( i.e. , 46 ml ) ( P = 0.05 ) . Conclusion The findings suggest that a low intensity preschool healthy weight intervention program can improve certain weight related behaviours . The findings also suggest that change to food policies are difficult to initiate mid-year and potentially a longer implementation period may be required to determine the efficacy of food policies to influence the contents of preschoolers lunchboxes This study investigated the food offered to children under 5 years of age in UK day care , the influence of the childcare providers on a child 's diet and their attitudes towards this role . A postal survey of a r and omised quota sample of childcare providers enquired after the range of food on offer and explored attitudes towards the role of food in health and the role of promoting health . Themes emerging from these data were explored by in-depth interviews with a sample of 18 childcare providers and 7 Local Authority Early Years Service staff . We received 194 ( 56 % ) responses to 345 copies of the question naire . Half ( 46 % ) of nurseries and 23 % of childminders provided a fruit or vegetable with the main meal 5 days a week . Only 14 % of nurseries and 21 % of childminders provided a dairy food ( i.e. calcium-rich ) at the main meal every day . Almost all the childcare providers saw themselves as responsible for promoting healthy diet , but it was rare for them to have had any formal training in nutrition , while current dietary guidance was perceived as too vague to be useful . The study also highlighted tensions on the issue of food provision between those delivering childcare and parents ; further research should explore the parents ' perspectives . Nursery staff and childminders should have access to carefully design ed advice on nutritionally appropriate food and drink services for under-fives Being active offers many physical and emotional benefits contributing to a higher health-related quality of life ( HRQoL ) ; however , this relationship remains unexplored among preschoolers ( aged 2.5 - 5 years ) . This study examined the impact of the Supporting Physical Activity in the Childcare Environment ( SPACE ) , which was an intervention implemented using a cluster r and omized controlled trial on preschoolers ' HRQoL. Childcare centres were r and omly allocated to the experimental ( n = 11 ) or control ( n = 11 ) conditions , and preschoolers ' HRQoL was measured using the parent-report Pediatric Quality of Life Inventory 4.0 ( 3 subscales : physical , psychosocial , and total HRQoL ) at baseline , post-intervention ( i.e. , week 8) , and 6- and 12-month follow-up . A linear mixed-effects model was used to determine if preschoolers in the experimental condition displayed an increased HRQoL post-intervention and at follow-up compared with preschoolers in the control condition . Preschoolers ( n = 234 ) with HRQoL data at baseline and one additional time-point were retained for analyses . Body mass index was not found to impact significantly on the intervention , and no statistically significant interaction effects were found for any of the 3 HRQoL variables . In conclusion , the SPACE intervention had no impact on preschoolers ' HRQoL. Given the scarcity of research in this population , additional exploration is necessary to better underst and the potential impact of physical activity participation on preschoolers ' ABSTRACT This study targeted to examine the effect of the ToyBox-intervention , a kindergarten-based , family-involved intervention , aim ing to improve preschooler ’s energy-related behaviours ( e.g. , physical activity ) on motor performance ability . Physical activity sessions , classroom activities , environmental changes and tools for parents were the components of the 1-year intervention . The intervention and control were cluster-r and omised , and children ’s anthropometry and two motor test items ( jumping from side to side , JSS and st and ing long jump , SLJ ) were assessed . A total of 1293 ( 4.6 ± 0.69 years ; 52 % boys ) from 45 kindergartens in Germany were included ( intervention , n = 863 ; control , n = 430 ) . The effect was assessed using generalised estimating equation . The intervention group showed a better improvement in JSS ( Estimate 2.19 jumps , P = 0.01 ) and tended to improve better in SLJ ( Estimate 2.73 cm , P = 0.08 ) . The intervention was more effective in boys with respect to SLJ ( P of interaction effect = 0.01 ) . Children aged < 4.5 years did not show a significant benefit while older children improved ( JSS , Estimate 3.38 jumps , P = 0.004 ; SLJ , Estimate 4.18 cm , P = 0.04 ) . Children with low socio-economic status improved in JSS ( Estimate 5.98 jumps , P = 0.0001 ) . The ToyBox-intervention offers an effective strategy to improve specific components of motor performance ability in early childhood . Future programmes should consider additional strategies specifically targeting girls and younger aged children . Abbreviations : BMI : body mass index ; SES : socio-economic status ; JSS : jumping from side to side ; SLJ : st and ing long jump ; SD : st and ard deviation ; GEE : generalised estimating Introduction The implementation of dietary guidelines in childcare setting s is recommended to improve child public health nutrition . However , foods provided in childcare services are not consistent with guidelines . The primary aim of the trial is to assess the effectiveness of a web-based menu planning intervention in increasing the mean number of food groups on childcare service menus that comply with dietary guidelines regarding food provision to children in care . Methods and analysis A parallel group r and omised controlled trial will be undertaken with 54 childcare services that provide food to children within New South Wales , Australia . Services will be r and omised to a 12-month intervention or usual care . The experimental group will receive access to a web-based menu planning and decision support tool and online re sources . To support uptake of the web program , services will be provided with training and follow-up support . The primary outcome will be the number of food groups , out of 6 ( vegetables , fruit , breads and cereals , meat , dairy and ‘ discretionary ’ ) , on the menu that meet dietary guidelines ( Caring for Children ) across a 1-week menu at 12-month follow-up , assessed via menu review by dietitians or nutritionists blinded to group allocation . A nested evaluation of child dietary intake in care and child body mass index will be undertaken in up to 35 r and omly selected childcare services and up to 420 children aged approximately 3–6 years . Ethics and dissemination Ethical approval has been provided by Hunter New Engl and and University of Newcastle Human Research Ethics Committees . This research will provide high- quality evidence regarding the impact of a web-based menu planning intervention in facilitating the translation of dietary guidelines into childcare services . Trial findings will be disseminated widely through national and international peer- review ed publications and conference presentations . Trial registration Prospect ively registered with Australian New Zeal and Clinical Trial Registry ( ANZCTR ) ACTRN12616000974404 Background Within the ToyBox- study , a kindergarten-based , family-involved intervention was developed to prevent overweight and obesity in European preschoolers , targeting four key behaviours related to early childhood obesity , including water consumption . The present study aim ed to examine the effect of the ToyBox-intervention ( cluster r and omized controlled trial ) on water intake and beverage consumption in European preschoolers and to investigate if the intervention effects differed by implementation score of kindergartens and parents/caregivers . Method A sample of 4964 preschoolers ( 4.7±0.4 years ; 51.5 % boys ) from six European countries ( Belgium , Bulgaria , Germany , Greece , Pol and , Spain ) was included in the data analyses . A st and ardized protocol was used and parents/caregivers filled in socio-demographic data and a food-frequency question naire . To assess intervention effects , multilevel repeated measures analyses were conducted for the total sample and for the six country-specific sample s. Based on the process evaluation question naire of teachers and parents/caregivers , an implementation score was constructed . To assess differences in water intake and beverage consumption by implementation score in the total sample , multilevel repeated measures analyses were performed . Results Limited intervention effects on water intake from beverages and overall beverage consumption were found . However , important results were found on prepacked fruit juice consumption , with a larger decrease in the intervention group compared to the control group . However , also a decline in plain milk consumption was found . Implementation scores were rather low in both kindergartens and parents/caregivers . Nevertheless , more favorable effects on beverage choices were found in preschoolers whose parents/caregivers and kindergarten teachers had higher implementation scores compared to those with lower implementation scores . Conclusion The ToyBox-intervention can provide the basis for the development of more tailor-made interventions . However , new strategies to improve implementation of interventions should be created Background The preschool years are a critical window for obesity prevention efforts ; representing a time when children establish healthy eating habits and physical activity patterns . Underst and ing the context in which these behaviors develop is critical to formulating a model to address childhood obesity . The Colorado LEAP Study , an intervention study design ed to prevent early childhood obesity , utilizes a social ecological approach to explore individual , family and environmental factors and their relationship to child weight status over a 3 year timeframe . Methods The study is located in 5 rural Colorado preschool centers and elementary schools ( 2 treatment and 3 control ) . Treatment sites receive The Food Friends ® nutrition ( 12 weeks ) and physical activity ( 18 weeks ) interventions during preschool . Observational measures assess 3 layers of the social ecological model including individual , family and organizational inputs . Children ’s food preferences , food intake , gross motor skills , physical activity ( pedometers/accelerometers ) , cognitive , physical and social self-competence and height/weight are collected . Parents provide information on feeding and activity practice s , child ’s diet , oral sensory characteristics , food neophobia , home food and activity environment , height/weight and physical activity ( pedometers ) . School personnel complete a school environment and policy assessment . Measurements are conducted with 3 cohorts at 4 time points – baseline , post-intervention , 1- and 2-year follow-up . Discussion The design of this study allows for longitudinal exploration of relationships among eating habits , physical activity patterns , and weight status within and across spheres of the social ecological model . These methods advance traditional study design s by allowing not only for interaction among spheres but predictively across time . Further , the recruitment strategy includes both boys and girls from ethnic minority population s in rural areas and will provide insights into obesity prevention effects on these at risk population s . Trial registration Clinical Trials.gov : NCT01937481 BACKGROUND Formation of diet and physical activity habits begins during early childhood . However , many preschool-aged children in the United States do not achieve recommendations for a nutritious diet or active lifestyle . Two important spheres of influence , home and child care , could ensure that children receive consistent health messages . Innovative approaches that engage both parents and child care providers in a substantial way are needed . Social marketing , a promising approach for health promotion targeting children , uses principles that recognize the need to engage multiple stakeholders and to emphasize benefits and overcome barriers associated with behavior change . Yet , application of social marketing principles in interventions for preschool-age children is limited . METHODS Healthy Me , Healthy We ( HMHW ) is 2-arm , cluster r and omized controlled trial to evaluate the effect of a 8-month social marketing campaign on the diet and physical activity behaviors of preschool children ( 3 - 4years old ) , their parents , and child care providers . The campaign is delivered by the child care center and includes br and ed classroom and at-home activities and material s. Primary outcomes are children 's diet quality ( assessed with Healthy Eating Index scores ) and minutes of non-sedentary activity ( measured via accelerometers ) . Secondary outcomes assess children 's body mass index , nutrition and physical activity practice s at the child care center and at home , and health behaviors of child care providers and parents . CONCLUSION HMHW is an innovative approach to promoting healthy eating and physical activity in preschool children . The campaign targets children during a key developmental period and leverages a partnership between providers and parents to affect behavior change Background Obesity is the most common chronic pediatric disease in westernized , especially low socioeconomic societies . We previously demonstrated the beneficial effects of a r and omized prospect i ve school-based health education program for low socioeconomic status Arab-Israeli kindergarten children . Methods To examine whether the effects of our program on nutrition and physical activity knowledge and preferences , anthropometric measures , and fitness persisted one year after the end of intervention . We were able to perform the one year follow-up in 203 kindergarten children ( 59 % of our 342 original cohort ; 85 control , 118 intervention ) . Results At one year following the intervention BMI and BMI percentiles approached baseline level in both the intervention ( 16.4±0.2 kg/m2 and 61.5±2.4 % , respectively ) and control group participants ( 16.5±0.2 kg/m2 and 58.5±3.3 % , respectively ) . Yet , a year after the end of the intervention , the decrease in BMI % ile from baseline was significantly greater in the intervention group ( -7.8±1.5 vs. -1.9±1.9 , p<0.012 ) . Nutritional and physical activity knowledge and preferences , and physical fitness remained significantly elevated in the intervention compared to the control group participants . Conclusions The beneficial effects of a kindergarten dietary-physical activity intervention applied by the kindergarten teachers , on nutrition and physical activity knowledge and preferences , fitness , and BMI percentile were evident one year after the end of intervention . This promising program may play a role in health promotion , prevention and treatment of childhood obesity Background Today ’s children are more overweight than previous generations and physical inactivity is a contributing factor . Modelling and promoting positive behaviour in the early years is imperative for the development of lifelong health habits . The social and physical environments where children spend their time have a powerful influence on behaviour . Since the majority of preschool children spend time in care outside of the home , this provides an ideal setting to examine the ability of an intervention to enhance movement skills and modify physical activity behaviour . This study aims to evaluate the efficacy of the Activity Begins in Childhood ( ABC ) intervention delivered in licensed daycare setting s alone or in combination with a parent-driven home physical activity-promotion component to increase preschoolers ’ overall physical activity levels and , specifically , the time spent in moderate to vigorous physical activity . Methods / design This study is a single site , three-arm , cluster-r and omized controlled trial design with a daycare centre as the unit of measurement ( clusters ) . All daycare centres in the National Capital region that serve children between the ages of 3 and 5 , expressing an interest in receiving the ABC intervention will be invited to participate . Those who agree will be r and omly assigned to one of three groups : i ) ABC program delivered at a daycare centre only , ii ) ABC program delivered at daycare with a home/parental education component , or iii ) regular daycare curriculum . This study will recruit 18 daycare centres , 6 in each of the three groups . The intervention will last approximately 6 months , with baseline assessment prior to ABC implementation and follow-up assessment s at 3 and 6 months . Discussion Physical activity is an acknowledged component of a healthy lifestyle and childhood experiences as it has an important impact on lifelong behaviour and health . Opportunities for physical activity and motor development in early childhood may , over the lifespan , influence the maintenance of a healthy body weight and reduce cardiovascular disease risk . If successful , the ABC program may be implemented in daycare centres as an effective way of increasing healthy activity behaviours of preschoolers . Trial registration Current Controlled Trials : IS RCT N94022291 . Registered in December 2012 , first cluster r and omized in April 2013 Objective To measure whether the benefits of a single education and self management structured programme for people with newly diagnosed type 2 diabetes mellitus are sustained at three years . Design Three year follow-up of a multicentre cluster r and omised controlled trial in primary care , with r and omisation at practice level . Setting 207 general practice s in 13 primary care sites in the United Kingdom . Participants 731 of the 824 participants included in the original trial were eligible for follow-up . Biomedical data were collected on 604 ( 82.6 % ) and question naire data on 513 ( 70.1 % ) participants . Intervention A structured group education programme for six hours delivered in the community by two trained healthcare professional educators compared with usual care . Main outcome measures The primary outcome was glycated haemoglobin ( HbA1c ) levels . The secondary outcomes were blood pressure , weight , blood lipid levels , smoking status , physical activity , quality of life , beliefs about illness , depression , emotional impact of diabetes , and drug use at three years . Results HbA1c levels at three years had decreased in both groups . After adjusting for baseline and cluster the difference was not significant ( difference −0.02 , 95 % confidence interval −0.22 to 0.17 ) . The groups did not differ for the other biomedical and lifestyle outcomes and drug use . The significant benefits in the intervention group across four out of five health beliefs seen at 12 months were sustained at three years ( P<0.01 ) . Depression scores and quality of life did not differ at three years . Conclusion A single programme for people with newly diagnosed type 2 diabetes mellitus showed no difference in biomedical or lifestyle outcomes at three years although there were sustained improvements in some illness beliefs . Trial registration Current Controlled Trials IS RCT N17844016 BACKGROUND More than half of 3- to 6-year-old children attend child-care centers . Dietary intakes of children attending child-care centers tend to fall short of Dietary Reference Intakes ( DRIs ) . OBJECTIVE Our aim was to examine macro-/micronutrient content of child-care center menus , compare menus to one third of DRIs , and determine menu differences by population density . METHODS A stratified , r and om , geographically proportionate sample of Oklahoma child-care centers was obtained . Child-care centers providing all-day care for 2- to 5-year-old children were contacted to complete a telephone question naire and asked to send in that month 's menus for the 3- to 4-year-old children . Overall means and st and ard deviations of the nutrient content of 5 days of lunch menus were calculated . Comparisons were made to both the 1- to 3-year-old and 4- to 8-year-old DRIs . One- sample t tests compared mean nutrient content of lunches to one third of the DRIs for the overall sample and urban/rural classification . Independent t tests compared nutrient content of urban and rural lunches . PARTICIPANTS / SETTING One hundred sixty-seven child-care centers were contacted ; 83 completed the study ( 50 % response ) . RESULTS Menus provided statistically significantly insufficient carbohydrate , dietary fiber , iron , vitamin D , and vitamin E. Calcium was higher than the 1- to 3-year-old DRI , but lower than the 4- to 8-year-old DRI . Folate was higher than the 1- to 3-year-old DRI , but not different from the 4- to 8-year-old DRI . Sodium was higher than the DRI for both age groups . Thirty-four child-care centers ( 41 % ) were classified as urban and 49 ( 59 % ) as rural . Urban menus provided less than the 4- to 8-year-old DRI for folate , but rural child-care center menus did not . CONCLUSIONS Oklahoma child-care center menus appear to provide adequate protein , magnesium , zinc , vitamin A , and vitamin C , but may be deficient in key nutrients required for good health and proper development in preschool-aged children . These issues can be addressed by including food and nutrition practitioners in the process to ensure child-care center menus are a useful re source and nutritionally appropriate for preschool children BACKGROUND School programs can be effective in modifying knowledge , attitudes , and habits relevant to long-term risk of chronic diseases associated with sedentary lifestyles . As part of a long-term research strategy , we conducted an educational intervention in preschool facilities to assess changes in preschoolers ' knowledge , attitudes , and habits toward healthy eating and living an active lifestyle . METHODS Using a cluster design , we r and omly assigned 14 preschool facilities in Bogotá , Colombia to a 5-month educational and playful intervention ( 7 preschool facilities ) or to usual curriculum ( 7 preschool facilities ) . A total of 1216 children aged 3 - 5 years , 928 parents , and 120 teachers participated . A structured survey was used at baseline , at the end of the study , and 12 months later to evaluate changes in knowledge , attitudes , and habits . RESULTS Children in the intervention group showed a 10.9 % increase in weighted score , compared with 5.3 % in controls . The absolute adjusted difference was 3.90 units ( 95 % confidence interval [ CI ] , 1.64 - 6.16 ; P < .001 ) . Among parents , the equivalent statistics were 8.9 % and 3.1 % , respectively ( absolute difference 4.08 units ; 95 % CI , 2.03 to 6.12 ; P < .001 ) , and among teachers , 9.4 % and 2.5 % , respectively ( absolute difference 5.36 units ; 95 % CI , -0.29 - 11.01 ; P = .06 ) . In the intervened cohort 1 year after the intervention , children still showed a significant increase in weighted score ( absolute difference of 6.38 units ; P < .001 ) . CONCLUSIONS A preschool-based intervention aim ed at improving knowledge , attitudes , and habits related to healthy diet and active lifestyle is feasible , efficacious , and sustainable in very young children Background This paper details the research protocol for a study funded by the Australian Research Council . An integrated approach towards helping young children respond to the significant pressures of ‘ 360 degree marketing ’ on their food choices , levels of active play , and sustainability consciousness via the early childhood curriculum is lacking . The overall goal of this study is to evaluate the efficacy of curriculum interventions that educators design when using a pedagogical communication strategy on children ’s knowledge about healthy eating , active play and the sustainability consequences of their toy food and toy selection s. Methods / Design This cluster-r and omised trial will be conducted with 300 , 4 to 5 year-old children attending pre-school . Early childhood educators will develop a curriculum intervention using a pedagogical communication strategy that integrates content knowledge about healthy eating , active play and sustainability consciousness and deliver this to their pre-school class . Children will be interviewed about their knowledge of healthy eating , active play and the sustainability consequences of their food and toy selection s. Parents will complete an Eating and Physical Activity Question naire rating their children ’s food preferences , digital media viewing and physical activity habits . All measures will be administered at baseline , the end of the intervention and 6 months post intervention . Informed consent will be obtained from all parents and the pre-school classes will be allocated r and omly to the intervention or wait-list control group . Discussion This study is the first to utilise an integrated pedagogical communication strategy developed specifically for early childhood educators focusing on children ’s healthy eating , active play , and sustainability consciousness . The significance of the early childhood period , for young children ’s learning about healthy eating , active play and sustainability , is now un question ed . The specific teaching and learning practice s used by early childhood educators , as part of the intervention program , will incorporate a sociocultural perspective on learning ; this perspective emphasises building on the play interests of children , that are experienced within the family and home context , as a basis for curriculum provision . Trial Registration Australian New Zeal and Clinical Trials Registry ACTRN12614000363684 : Date registered : Background Childcare services represent a key setting to implement nutritional interventions to support the development of healthy eating behaviours in young children . Childcare-specific nutritional guidelines outlining recommendations for provision of food in care have been developed . Despite this , research suggests that few childcare services currently implement these guidelines . This study aim ed to examine the impact of providing printed educational material s on childcare service cooks ’ intentions to use nutritional guidelines and provide fruit and vegetables on their menu . Findings A r and omised controlled trial was conducted with 77 childcare services ( 38 control and 39 intervention ) . Intervention service cooks were mailed a two-page educational material together with a menu planning checklist . Intervention development and evaluation was guided by the theory of planned behaviour . Outcome data assessing intentions to use nutritional guidelines and serves of fruit and vegetables provided on menus ( primary outcomes ) as well as secondary outcomes ( attitudes , behavioural regulation and social norms ) were collected via a telephone interview with cooks . Relative to the comparison group , cooks in the intervention arm had significantly higher intentions to use the guidelines ( p value 0.0005 ) , accompanied by significant changes in perceived behavioural control ( p value 0.0008 ) and attitudes ( p value 0.0071 ) . No significant difference in serves of fruit ( p value 0.7278 ) and vegetables ( p value 0.0573 ) was observed . Conclusions The use of educational material s can improve childcare service cooks ’ intentions to use nutritional guidelines ; however , as a st and alone strategy , it may not improve provision of food on menus Background Obstructive sleep apnea ( OSA ) and hypertension are well-known cardiovascular risk factors . Their control could reduce the burden of heart disease across population s. Several drugs are used to control hypertension , but the only consistently effective treatment of OSA is continuous positive airway pressure . The identification of a drug capable of improving OSA and hypertension simultaneously would provide a novel approach in the treatment of both diseases . Methods / Design This is a r and omized double-blind clinical trial , comparing the use of chlorthalidone with amiloride versus amlodipine as a first drug option in patients older than 40 years of age with stage I hypertension ( 140 to 159/90 to 99 mmHg ) and moderate OSA ( 15 to 30 apneas/hour of sleep ) . The primary outcomes are the variation of the number of apneas per hour and blood pressure measured by ambulatory blood pressure monitoring . The secondary outcomes are adverse events , somnolence scale ( Epworth ) , ventilatory parameters and C reactive protein levels . The follow-up will last 8 weeks . There will be 29 participants per group . The project has been approved by the ethics committee of our institution . Discussion The role of fluid retention in OSA has been known for several decades . The use of diuretics are well established in treating hypertension but have never been appropriately tested for sleep apnea . As well as testing the efficacy of these drugs , this study will help to underst and the mechanisms that link hypertension and sleep apnea and their treatment . Trial registration Clinical Trials.gov : The aim of this study was to describe the research output and citation rates ( academic impact ) of public health dissemination and implementation research according to research design and study type . A cross sectional bibliographic study was undertaken in 2013 . All original data -based studies and review articles focusing on dissemination and implementation research that had been published in 10 r and omly selected public health journals in 2008 were audited . The electronic data base ‘ Scopus ’ was used to calculate 5-year citation rates for all included publications . Of the 1648 publications examined , 216 were original data -based research or literature review s focusing on dissemination and implementation research . Of these 72 % were classified as descriptive/epidemiological , 26 % were intervention and just 1.9 % were measurement research . Cross-sectional studies were the most common study design ( 47 % ) . Review s , r and omized trials , non-r and omized trials and decision/cost-effectiveness studies each represented between 6 and 10 % of all output . Systematic review s , r and omized controlled trials and cohort studies were the most frequently cited study design s. The study suggests that publications that had the greatest academic impact ( highest citation rates ) made up only a small proportion of overall public health dissemination and implementation research output OBJECTIVE To determine the impact of an implementation intervention design ed to introduce policies and practice s supportive of healthy eating in centre-based child-care services . Intervention strategies included staff training , re sources , incentives , follow-up support , and performance monitoring and feedback . DESIGN A quasi-experimental design was used to assess change over 20 months in healthy eating policy and practice in intervention and comparison child-care services . SETTING The Hunter New Engl and ( HNE ) region of New South Wales ( NSW ) , Australia . SUBJECTS All centre-based child-care services ( n 287 ) in the intervention region ( HNE ) were invited and 240 ( 91 % response rate ) participated . Two hundred and ninety-six services in the rest of NSW were r and omly selected as a comparison region and 191 participated ( 76 % response rate ) . A sub- analysis was conducted on those services that provided children food ( n 196 at baseline and n 190 at follow-up ) . Ninety-six provided menus for analysis at baseline ( HNE , n 36 ; NSW , n 50 ) and 102 provided menus at follow-up ( HNE , n 50 ; NSW , n 52 ) . RESULTS Services in the intervention region were significantly more likely to provide only plain milk and water for children ( P = 0.018 ) and to engage parents in nutrition policy or programmes ( P = 0.002 ) . They were also more likely ( P = 0.056 ) to have nutrition policy on home packed food . In addition , menus of services that provided lunch were significantly more likely to comply with healthy eating guidelines for sweetened drinks ( P < 0.001 ) , fruit ( P < 0.001 ) and vegetables ( P = 0.01 ) . CONCLUSIONS An implementation intervention was able to modify policy and practice in a large number of child-care services so that they were more supportive of healthy eating Inactivity and an unhealthy diet amongst others have led to an increased prevalence of overweight and obesity even in young children . Since most health behaviours develop during childhood health promotion has to start early . The setting kindergarten has been shown as ideal for such interventions . “ Join the Healthy Boat ” is a kindergarten-based health promotion programme with a cluster-r and omised study focussing on increased physical activity , reduced screen media use , and sugar-sweetened beverages , as well as a higher fruit and vegetable intake . Intervention and material s were developed using Bartholomew 's Intervention Mapping approach considering B and ura 's social-cognitive theory and Bronfenbrenner 's ecological framework for human development . The programme is distributed using a train-the-trainer approach and currently implemented in 618 kindergartens . The effectiveness of this one-year intervention with an intervention and a control group will be examined in 62 kindergartens using st and ardised protocol s , material s , and tools for outcome and process evaluation . A sample of 1021 children and their parents provided consent and participated in the intervention . Results of this study are awaited to give a better underst and ing of health behaviours in early childhood and to identify strategies for effective health promotion . The current paper describes development and design of the intervention and its implementation and planned evaluation . Trial Registration . The study is registered at the German Clinical Trials Register ( DRKS ) , Freiburg University , Germany , ID : DRKS00010089 OBJECTIVE To evaluate the impact on nutrition- and health-related practice of two methods of delivery of a nutrition and health intervention in Irish full-day-care pre-schools : training of pre-school managers only or training of managers and their staff . DESIGN A simple r and omised study with pre-schools divided into two training groups : ' manager trained ' and ' manager and staff trained ' . Direct observational data --food and fluid provision , physical activity , outdoor time , staff practice s and availability of nutrition and health re sources --were recorded during one full day spent in each pre-school both pre- and post-intervention , using a specifically developed and vali date d Pre-school Health Promotion Activity Scored Evaluation Form . Post-intervention , self- assessment data were also collected using the same evaluation tool . SETTING Pre-schools , Midl and s of Irel and . SUBJECTS A convenience sample of forty-two pre-schools registered with the Irish Health Service Executive . RESULTS From pre- to post-intervention , significant improvement ( P < 0.05 ) in nutrition- and health-related practice was observed within both intervention delivery groups in all areas evaluated : environment , food service , meals and snacks . No additional effect attributable to staff training was observed . Scores assigned by direct independent observation were lower than pre-school self- assessment scores . CONCLUSIONS The implementation of a training intervention in pre-schools significantly improved practice with no significant benefit of additional staff training . Direct independent observation is required to quantify practice accurately Background Inadequate fruit and vegetable consumption in childhood increases the risk of developing chronic disease . Despite this , a substantial proportion of children in developed nations , including Australia , do not consume sufficient quantities of fruits and vegetables . Parents are influential in the development of dietary habits of young children but often lack the necessary knowledge and skills to promote healthy eating in their children . The aim of this study is to assess the efficacy of a telephone-based intervention for parents to increase the fruit and vegetable consumption of their 3- to 5-year-old children . Methods / Design The study , conducted in the Hunter region of New South Wales , Australia , employs a cluster r and omised controlled trial design . Two hundred parents from 15 r and omly selected preschools will be r and omised to receive the intervention , which consists of print re sources and four weekly 30-minute telephone support calls delivered by trained telephone interviewers . The calls will assist parents to increase the availability and accessibility of fruit and vegetables in the home , create supportive family eating routines and role-model fruit and vegetable consumption . A further two hundred parents will be r and omly allocated to the control group and will receive printed nutrition information only . The primary outcome of the trial will be the change in the child 's consumption of fruit and vegetables as measured by the fruit and vegetable subscale of the Children 's Dietary Question naire . Pre-intervention and post-intervention parent surveys will be administered over the telephone . Baseline surveys will occur one to two weeks prior to intervention delivery , with follow-up data collection calls occurring two , six , 12 and 18 months following baseline data collection . Discussion If effective , this telephone-based intervention may represent a promising public health strategy to increase fruit and vegetable consumption in childhood and reduce the risk of subsequent chronic disease . Trial registration Australian Clinical Trials Registry Background Around a fifth of children starting school in Engl and are now overweight/obese . There is a paucity of interventions with the aim of obesity prevention in preschool-age children in the UK . Previous research has demonstrated some positive results in changing specific health behaviours , however , positive trends in overall obesity rates are lacking . Preschool setting s may provide valuable opportunities to access children and their families not only for promoting healthy lifestyles , but also to develop and evaluate behaviour-change interventions . Methods This paper presents a cluster r and omised feasibility study of a theory based behaviour-change preschool practitioner-led intervention tested in four preschool centres in the North East of Engl and . The primary outcome measures were to test the acceptability and feasibility of the data collection measures and intervention . Secondary measures were collected and reported for extra information . At baseline and post intervention , children ’s anthropometric , dietary and physical activity measures as well as family ‘ active ’ time data were collected . The preschool practitioner-led intervention included family intervention tasks such as ‘ family goal - setting activities ’ and ‘ cooking challenges ’ . Preschool activities included increasing physical activity and providing activities with the potential to change behaviour with increased knowledge of and acceptance of healthy eating . The process evaluation was an on-going monthly process and was collected in multiple forms such as question naires , photographs and verbal feedback . Results ‘ Gatekeeper ’ permission and lower-hierarchal adherence were initially a problem for recruitment and methods acceptance . However , at intervention end the preschool teachers and parents stated they found most intervention methods and activities acceptable , and some positive changes in family health behaviours were reported . However , the preschool centres appeared to have difficulties with enforcing everyday school healthy eating policies . Conclusions The findings from the current study may have implication s for nursery practitioners , nursery setting s , Local Educational Authorities and policy makers , and contributes to the body of literature . However , further work with preschool practitioners is required to determine how personal attitudes and school policy application can be supported to implement successfully such an intervention . Trial registration IS RCT N12345678 ( 16/02/17 ) retrospectively registered Background There is concern about the lack of diversity in children ’s diets , particularly low intakes of fruit and vegetables and high intakes of unhealthy processed food . This may be a factor in the rising prevalence of obesity . A reason for the lack of diversity in children ’s diets may be food neophobia . This study aim ed to promote a healthy and varied diet among toddlers in kindergarten . The primary objectives were to reduce food neophobia in toddlers , and promote healthy feeding practice s among kindergarten staff and parents . Secondary objectives were to increase food variety in toddlers ’ diets and reduce future overweight and obesity in these children . Methods This is an ongoing , cluster r and omized trial . The intervention finished in 2014 , but follow-up data collection is not yet complete . Eighteen r and omly selected kindergartens located in two counties in Norway with enrolled children born in 2012 participated in the intervention . The kindergartens were matched into pairs based on background information , and r and omly assigned to the intervention or control groups . A 9-week multi-component intervention was implemented , with four main elements : 1 ) kindergarten staff implemented a pedagogical tool ( Sapere method ) in daily sessions to promote willingness to try new food ; 2 ) kindergarten staff prepared and served the toddlers a cooked lunch from a menu corresponding to the pedagogical sessions ; 3 ) kindergarten staff were encouraged to follow 10 meal principles on modeling , responsive feeding , repeated exposure , and enjoyable meals ; and 4 ) parents were encouraged to read information and apply relevant feeding practice s at home . The control group continued their usual practice s. Preference taste tests were conducted to evaluate behavioral food neophobia , and children ’s height and weight were measured . Parents and staff completed question naires before and after the intervention . Data have not yet been analyzed . Discussion This study provides new knowledge about whether or not a Sapere-sensory education and healthy meal intervention targeting children , kindergarten staff , and parents will : reduce levels of food neophobia in toddlers ; improve parental and kindergarten feeding practice s ; improve children ’s dietary variety ; and reduce childhood overweight and obesity . Trial registration IS RCT N74823448 DOI 10.1186/IS RCT The aim of the Bright Start study was to develop and test the effectiveness of a school environment intervention , supplemented with family involvement , to reduce excessive weight gain by increasing physical activity and healthy eating practice s among kindergarten and first grade American Indian children . Bright Start was a group-r and omized , school-based trial involving 454 children attending 14 schools on the Pine Ridge Reservation in South Dakota . Children were followed from the beginning of their kindergarten year through the end of first grade . Main outcome variables were mean BMI , mean percent body fat , and prevalence of overweight/obese children . The goals of the intervention were to : increase physical activity at school to at least 60 min/day ; modify school meals and snacks ; and involve families in making behavioral and environmental changes at home . At baseline , 32 % of boys and 25 % of girls were overweight/obese . While the intervention was not associated with statistically significant change in mean levels of BMI , BMI -Z , skinfolds or percentage body fat , the intervention was associated with a statistically significant net decrease of 10 % in the prevalence of overweight . Intervention children experienced a 13.4 % incidence of overweight , while the control children experienced a corresponding incidence of 24.8 % ; a difference of −11.4 % ( p=0.033 ) . The intervention significantly reduced parent reported mean child intakes of sugar-sweetened beverages , whole milk and chocolate milk . Changes in duration of school physical activity were not significant . Because obesity is the most daunting health challenge facing American Indian children today , more intervention research is needed to identify effective approaches Background Young children are not participating in recommended levels of physical activity and exhibit high levels of sedentary behaviour . Childcare services provide access to large numbers of young children for prolonged periods , yet there is limited experimental evidence regarding the effectiveness of physical activity interventions implemented in this setting . The aim of this study is to assess the effectiveness and acceptability of a multi-component physical activity intervention , delivered by childcare service staff , in increasing the physical activity levels of children attending long day care services . Methods / Design The study will employ a cluster r and omised controlled trial design . Three hundred children aged between 3 - 5 years from twenty r and omly selected long day care services in the Hunter Region of New South Wales , Australia will be invited to participate in the trial . Ten of the 20 long day care services will be r and omly allocated to deliver the intervention with the remaining ten services allocated to a wait list control group . The physical activity intervention will consist of a number of strategies including : delivering structured fundamental movement skill activities , increasing physical activity opportunities , increasing staff role modelling , providing children with a physical activity promoting indoor and outdoor environment and limiting children 's small screen recreation and sedentary behaviours . Intervention effectiveness will be measured via child physical activity levels during attendance at long day care . The study also seeks to determine the acceptability and extent of implementation of the intervention by services and their staff participating in the study . Discussion The trial will address current gaps in the research evidence base and contribute to the design and delivery of future interventions promoting physical activity for young children in long day care setting s . Trial registration Australian New Zeal and Clinical Trials Registry Background Although surveillance data are limited in the US Affiliated Pacific , Alaska , and Hawaii , existing data suggest that the prevalence of childhood obesity is similar to or in excess of other minority groups in the contiguous US . Strategies for addressing the childhood obesity epidemic in the region support the use of community-based , environmentally targeted interventions . The Children ’s Healthy Living Program is a partnership formed across institutions in the US Affiliated Pacific , Alaska , and Hawaii to design a community r and omized environmental intervention trial and a prevalence survey to address childhood obesity in the region through affecting the food and physical activity environment . Methods / Design The Children ’s Healthy Living Program community r and omized trial is an environmental intervention trial in four matched-pair communities in American Samoa , the Commonwealth of the Northern Mariana Isl and s , Guam , and Hawaii and two matched-pair communities in Alaska . A cross-sectional sample of children ( goal n = 180 ) in each of the intervention trial communities is being assessed for outcomes at baseline and at 24 months ( 18 months post-intervention ) . In addition to the collection of the participant-based measures of anthropometry , diet , physical activity , sleep and acanthosis nigricans , community assessment s are also being conducted in intervention trial communities . The Freely Associated States of Micronesia ( Federated States of Micronesia , and Republics of Marshall Isl and s and Palau ) is only conducting elements of the Children ’s Healthy Living Program sampling framework and similar measurements to provide prevalence data . In addition , anthropometry information will be collected for two additional communities in each of the 5 intervention jurisdictions to be included in the prevalence survey . The effectiveness of the environmental intervention trial is being assessed based on the RE- AIM ( reach , effectiveness , adoption , implementation , maintenance ) framework . Discussion The Children ’s Healthy Living Program environmental trial is design ed to focus on capacity building and to maximize the likelihood of sustainable impact on childhood obesity-related behaviors and outcomes . The multiple measures at the individual , community , and environment levels are design ed to maximize the likelihood of detecting change . This approach enhances the likelihood for identifying and promoting the best methods to promote health and well-being of the children in the underserved US Affiliated Pacific Region . Trial registration NIH clinical trial # Background Medically treated injuries have been shown to increase with increasing body mass index ( BMI ) . Information is lacking on the frequency and type of injuries and illnesses among overweight and obese adults who engage in regular physical activities as part of weight loss or weight gain prevention programs . Methods Sedentary adults with BMI s between 25 and 40 kg/m2 ( n = 397 ) enrolled in one of two r and omized clinical trials that emphasized exercise as part of a weight loss or weight gain prevention program . Interventions differed by duration of the exercise goal ( 150 , 200 , or 300 minutes/week or control group ) . Walking was prescribed as the primary mode of exercise . At six month intervals , participants were asked , " During the past six months , did you have any injury or illness that affected your ability to exercise ? " Longitudinal models were used to assess the effects of exercise and BMI on the pattern of injuries/illnesses attributed to exercise over time ; censored linear regression was used to identify predictors of time to first injury/illness attributed to exercise . Results During the 18-month study , 46 % reported at least one injury/illness , and 32 % reported at least one injury that was attributed to exercise . Lower-body musculoskeletal injuries ( 21 % ) were the most commonly reported injury followed by cold/flu/respiratory infections ( 18 % ) and back pain/injury ( 10 % ) . Knee injuries comprised one-third of the lower-body musculoskeletal injuries . Only 7 % of the injuries were attributed to exercise alone , and 59 % of the injuries did not involve exercise . BMI ( p ≤ 0.01 ) but not exercise ( p ≥ 0.41 ) was significantly associated with time to first injury and injuries over time . Participants with higher BMI s were injured earlier or had increased odds of injury over time than participants with lower BMI s. Due to the linear dose-response relationship between BMI and injury/illness , any weight loss and reduction in BMI was associated with a decrease risk of injury/illness and delay in time to injury/illness . Conclusions Overweight and obese adults who were prescribed exercise as part of weight loss or weight gain prevention intervention were not at increased risk of injury compared to overweight adults r and omized not to participate in prescribed exercise . Since onset of injury/illness and pattern of injuries over time in overweight and obese individuals were attributed to BMI , weight reduction may be an avenue to reduce the risk of injury/illness in sedentary and previously sedentary overweight and obese adults . Trial Registration Clinical trials.gov NCT00177502 and Background The prevalence of obesity increased while certain measures of physical fitness deteriorated in preschool children in China over the past decade . This study tested the effectiveness of a multifaceted intervention that integrated childcare center , families , and community to promote healthy growth and physical fitness in preschool Chinese children . Methods This 12-month study was conducted using a quasi-experimental pretest/posttest design with comparison group . The participants were 357 children ( mean age = 4.5 year ) enrolled in three grade levels in two childcare centers in Beijing , China . The intervention included : 1 ) childcare center intervention ( physical activity policy changes , teacher training , physical education curriculum and food services training ) , 2 ) family intervention ( parent education , internet website for support , and family events ) , and 3 ) community intervention ( playground renovation and community health promotion events ) . The study outcome measures included body composition ( percent body fat , fat mass , and muscle mass ) , Body Mass Index ( BMI ) and BMI z-score and physical fitness scores in 20-meter agility run ( 20M-AR ) , broad jump for distance ( BJ ) , timed 10-jumps , tennis ball throwing ( TBT ) , sit and reach ( SR ) , balance beam walk ( BBW ) , 20-meter crawl ( 20M-C ) ) , 30-meter sprint ( 30M-S ) ) from a norm referenced test . Measures of process evaluation included monitoring of children ’s physical activity ( activity time and intensity ) and food preparation records , and fidelity of intervention protocol implementation . Results Children in the intervention center significantly lowered their body fat percent ( −1.2 % , p < 0.0001 ) , fat mass ( −0.55 kg , p < 0.0001 ) , and body weight ( 0.36 kg , p < 0.02 ) and increased muscle mass ( 0.48 kg , p < 0.0001 ) , compared to children in the control center . They also improved all measures of physical fitness except timed 10-jumps ( 20M-AR : −0.74 seconds , p < 0.0001 ; BJ : 8.09 cm , p < 0.0001 ; TBT : 0.52 meters , p < 0.006 ; SR : 0.88 cm , p < 0.03 ; BBW : −2.02 seconds , p < 0.0001 ; 30M-S : −0.45 seconds , p < 0.02 ; 20M-C : −3.36 seconds , p < 0.0001 ) . Process evaluation data showed that the intervention protocol was implemented with high fidelity . Conclusions The study demonstrated that a policy-driven multi-faceted intervention can improve preschool children ’s body composition and physical fitness . Program efficacy should be tested in a r and omized trial . Trial registration ChiCTR-ONRC-14004143 The preschool years offer an opportunity to interrupt the trajectory toward obesity in black children . The Hip-Hop to Health Jr. Obesity Prevention Effectiveness Trial was a group-r and omized controlled trial assessing the feasibility and effectiveness of a teacher-delivered weight control intervention for black preschool children . The 618 participating children were enrolled in 18 schools administered by the Chicago Public Schools . Children enrolled in the nine schools r and omized to the intervention group received a 14-week weight control intervention delivered by their classroom teachers . Children in the nine control schools received a general health intervention . Height and weight , physical activity , screen time , and diet data were collected at baseline and postintervention . At postintervention , children in the intervention schools engaged in more moderate-to-vigorous physical activity ( MVPA ) than children in the control schools ( difference between adjusted group means = 7.46 min/day , P = 0.02 ) . Also , children in the intervention group had less total screen time ( -27.8 min/day , P = 0.05 ) . There were no significant differences in BMI , BMI Z score , or dietary intake . It is feasible to adapt an obesity prevention program to be taught by classroom teachers . The intervention showed positive influences on physical activity and screen time , but not on diet . Measuring diet and physical activity in preschool children remains a challenge , and interventions delivered by classroom teachers require both intensive initial training and ongoing individualized supervision OBJECTIVE To determine the feasibility , acceptability , and reported impact of a nutrition and physical activity environmental intervention in child care . DESIGN Self- assessment instrument completed pre- and post-intervention by r and omly assigned intervention and comparison child care centers . SETTING Child care centers in 8 counties across North Carolina . PARTICIPANTS A convenience sample of 19 child care centers ( 15 intervention and 4 comparison ) . INTERVENTION Intervention centers completed the self- assessment instrument at baseline and then selected 3 environmental improvements to make over the 6-month intervention period with assistance from a trained NAP SACC Consultant . MAIN OUTCOME MEASURE Changes in pre- and post-intervention self-assesment of the nutrition and physical activity child care environment with additional process measures to evaluate project implementation , feasibility and acceptability . ANALYSIS Comparison of pre- and post-test scores for the intervention group using a Wilcoxon signed-rank test and descriptions of environmental changes . RESULTS Intervention centers rated themselves higher at follow-up than at baseline , and relative to comparison centers , reported a variety of environmental nutrition and physical activity improvements confirmed by research staff . CONCLUSIONS AND IMPLICATION S The NAP SACC pilot intervention shows promise as an approach to promote healthy weight environments in preschool setting s. Additional evaluation of the project is needed using a greater number of centers and a more objective outcome measure Objectives Child care centers have recently become targets for overweight prevention efforts directed at young children . Child Care Health Consultants ( CCHCs ) , who provide consultation to these centers , receive little training on the basic nutrition and physical activity principles important for the promotion of child healthy weight . Traditional approaches , such as in-person training , are limited in their ability to disseminate health information to a geographically diverse population of health professionals . The purpose of this study was to determine if web-based training is as effective as in-person training . Methods A r and omized controlled trial was conducted between August 2005 and June 2006 with 50 CCHCs . Web-based and in-person trained CCHCs were compared to each other and to controls . The main outcome of this study was performance on a test of nutrition knowledge related to childhood overweight measured by a 28-item multiple choice test administered pre- and post-training . Results Results from the ANCOVA model suggest that web trained CCHCs performed similarly to in-person trained CCHCs on the knowledge test ( P < .0001 ) . Additionally , both training groups improved significantly compared to controls ( P < .0001 for each group ) . Conclusions This study found no significant differences in post-training knowledge between in-person and web trained Child Care Health Consultants . Scores on the post-training knowledge test were within 0.5 points for the in-person and web trained groups . These results demonstrate that web-based instruction is as effective as in-person training on improving basic nutrition and physical activity knowledge for promoting healthy weight in preschool children OBJECTIVE To examine protocol fidelity among teachers involved in a six-month cluster-r and omized physical activity ( PA ) intervention . METHODS In 2011 , preschools in Springfield , MA were r and omized to short bouts of structured PA ( SBS-PA , n=5 ) or unstructured playtime ( UPA , n=5 ) . SBS-PA provided structured PA in the classroom during the first 10 min of gross-motor playtime followed by 20 min of unstructured playtime . UPA consisted of 30 min of unstructured playtime . All teachers ( SBS-PA and UPA ) received a written study protocol and 1.5h of training . SBS-PA also received videos to use to lead structured PA and 1.5 additional hours of training . Study fidelity and process evaluation were assessed twice weekly via semi-structured question naire . RESULTS Only 56.6 % of SBS-PA and 75.2 % of UPA free playtimes lasted for 30 min ; 86.3 % of SBS-PA teachers implemented structured PA during the first 10 min of gross-motor playtime but only 67.2 % delivered the intervention as instructed . Only 68.5 % of SBS-PA teachers implemented the 20-minute unstructured playtime . SBS-PA teachers reported that time limitations was a major barrier in implementing the design ed intervention . Pre-post changes in PA did not differ between groups . CONCLUSION Limited fidelity to intervention protocol likely impacted study findings . Future studies should focus on strategies to improve adherence among intervention leaders Background While farmers ’ markets are a potential strategy to increase access to fruits and vegetables in rural areas , more information is needed regarding use of farmers ’ markets among rural residents . Thus , this study ’s purpose was to examine ( 1 ) socio-demographic characteristics of participants ; ( 2 ) barriers and facilitators to farmers ’ market shopping in southern rural communities ; and ( 3 ) associations between farmers ’ market use with fruit and vegetable consumption and body mass index ( BMI ) . Methods Cross-sectional surveys were conducted with a purposive sample of farmers ’ market customers and a representative sample of primary household food shoppers in eastern North Carolina ( NC ) and the Appalachian region of Kentucky ( KY ) . Customers were interviewed using an intercept survey instrument at farmers ’ markets . Representative sample s of primary food shoppers were identified via r and om digit dial ( RDD ) cellular phone and l and line methods in counties that had at least one farmers ’ market . All question naires assessed socio-demographic characteristics , food shopping patterns , barriers to and facilitators of farmers ’ market shopping , fruit and vegetable consumption and self-reported height and weight . The main outcome measures were fruit and vegetable consumption and BMI . Descriptive statistics were used to examine socio-demographic characteristics , food shopping patterns , and barriers and facilitators to farmers ’ market shopping . Linear regression analyses were used to examine associations between farmers ’ market use with fruit and vegetable consumption and BMI , controlling for age , race , education , and gender . Results Among farmers ’ market customers , 44 % and 55 % ( NC and KY customers , respectively ) reported shopping at a farmers ’ market at least weekly , compared to 16 % and 18 % of NC and KY RDD respondents . Frequently reported barriers to farmers ’ market shopping were market days and hours , “ only come when I need something ” , extreme weather , and market location . Among the KY farmers ’ market customers and NC and KY RDD respondents , fruit and vegetable consumption was positively associated with use of farmers ’ markets . There were no associations between use of farmers ’ markets and BMI . Conclusions Fruit and vegetable consumption was associated with farmers ’ market shopping . Thus , farmers ’ markets may be a viable method to increase population -level produce consumption Healthy Children , Strong Families ( HCSF ) is a 2-year , community-driven , family-based r and omized controlled trial of a healthy lifestyles intervention conducted in partnership with four Wisconsin American Indian tribes . HCSF is composed of 1 year of targeted home visits to deliver nutritional and physical activity curricula . During Year 1 , trained community mentors work with 2–5-year-old American Indian children and their primary caregivers to promote goal -based behavior change . During Year 2 , intervention families receive monthly newsletters and attend monthly group meetings to participate in activities design ed to reinforce and sustain changes made in Year 1 . Control families receive only curricula material s during Year 1 and monthly newsletters during Year 2 . Each of the two arms of the study comprises 60 families . Primary outcomes are decreased child body mass index ( BMI ) z-score and decreased primary caregiver BMI . Secondary outcomes include : increased fruit/vegetable consumption , decreased TV viewing , increased physical activity , decreased soda/sweetened drink consumption , improved primary caregiver biochemical indices , and increased primary caregiver self-efficacy to adopt healthy behaviors . Using community-based participatory research and our history of university – tribal partnerships , the community and academic research ers jointly design ed this r and omized trial . This article describes the study design and data collection strategies , including outcome measures , with emphasis on the communities ’ input in all aspects of the research Background : Be Active Eat Well ( BAEW ) was a multifaceted community capacity-building program promoting healthy eating and physical activity for children ( aged 4–12 years ) in the Australian town of Colac . Objective : To evaluate the effects of BAEW on reducing children 's unhealthy weight gain . Methods : BAEW had a quasi-experimental , longitudinal design with anthropometric and demographic data collected on Colac children in four preschools and six primary schools at baseline ( 2003 , n=1001 , response rate : 58 % ) and follow-up ( 2006 , n=839 , follow-up rate : 84 % ) . The comparison sample was a stratified r and om selection of preschools ( n=4 ) and primary schools ( n=12 ) from the rest of the Barwon South Western region of Victoria , with baseline assessment in 2003–2004 ( n=1183 , response rate : 44 % ) and follow-up in 2006 ( n=979 , follow-up rate : 83 % ) . Results : Colac children had significantly lower increases in body weight ( mean : −0.92 kg , 95 % CI : −1.74 to −0.11 ) , waist ( −3.14 cm , −5.07 to −1.22 ) , waist/height ( −0.02 , −0.03 to −0.004 ) , and body mass index z-score ( −0.11 , −0.21 to −0.01 ) than comparison children , adjusted for baseline variable , age , height , gender , duration between measurements and clustering by school . In Colac , the anthropometric changes were not related to four indicators of socioeconomic status ( SES ) , whereas in the comparison group 19/20 such analyses showed significantly greater gains in anthropometry in children from lower SES families . Changes in underweight and attempted weight loss were no different between the groups . Conclusions : Building community capacity to promote healthy eating and physical activity appears to be a safe and effective way to reduce unhealthy weight gain in children without increasing health inequalities OBJECTIVE To evaluate acceptance of soy-enhanced compared with traditional menus by preschool children . Soy-enhanced foods were substituted on a traditional cycle menu , and the amount eaten , energy , and nutrient values for traditional and soy-enhanced lunches were compared . DESIGN A traditional three-week cycle menu , using the Child and Adult Care Food Program ( CACFP ) meal pattern guidelines , was used to develop a comparable soy-enhanced menu . Traditional and soy-enhanced lunches were r and omly assigned to respective days . Foods were portioned onto individual plates using st and ardized measuring utensils . Individual plate waste techniques were used to collect food waste . Subjects/ setting Participants were preschool children , three to six years of age and of white and Hispanic origin , attending a part-day Head Start program . Statistical analyses performed Analysis of covariance was used to adjust lunch and food intakes for differences in average amounts of foods served . The Nutrient Data System was used to calculate energy and nutrient content of lunches . Analysis of variance was used to calculate differences in amounts eaten , energy values , and nutrient values of traditional and soy-enhanced lunches and foods . Data analyses were performed with the Statistical Analysis Software ( version 8.0 , 1999 , SAS Institute , Cary , NC ) . RESULTS Soy-enhanced foods were successfully substituted for 23 traditional foods included in the cycle menus . Soy-enhanced foods tended to be higher in energy , protein , and iron . Traditional lunches tended to be higher in fat , saturated fat , and vitamin A. Consumption was significantly less for energy , protein , fiber , and iron from foods eaten from traditional compared with soy-enhanced lunch menus . Applications/ conclusions Acceptance of soy-enhanced lunches was shown because there were no significant differences in the average amount eaten ( grams per meal ) between traditional and soy-enhanced lunches . Preschool programs can substitute soy-enhanced for traditional foods , which will add variety to the diet without sacrificing taste , energy , or nutrient value . The fat and energy content of the lunches was higher than recommended , and soy-enhanced foods were not always lower in fat . There is a need for the food industry and foodservice personnel to address the energy and fat content of all foods served in lunches to preschool children because a few extra calories added to the daily intakes can contribute to weight gain Purpose : To explore whether the physical activity ( PA ) component of the Coordinated Approach to Child Health Early Childhood ( CATCH EC ) program helps increasing preschoolers ’ PA during active times at preschool . Design : Nonr and omized controlled experimental study . Setting : Head Start centers in Houston , Texas , 2009 to 2010 school year . Participants : A total of 439 preschoolers aged 3 to 5 years ( 3 intervention centers , n = 220 ; 3 comparison centers , n = 219 ) . Intervention : The CATCH EC preschool-based teacher-led nutrition and PA program . Measures : Preschoolers ’ PA was measured at baseline and postintervention using the System for Observing Fitness Instruction Time – Preschool version , a direct observation method measuring PA at the classroom level . Parent surveys provided demographic data . Analysis : Pre-to-post changes in preschoolers ’ PA were examined using the Mann-Whitney U test . Results : Results show a significant decrease in the percentage time preschoolers spent in level 2 PA ( low activity ) at intervention ( P = .005 ) and comparison ( P = .041 ) centers . Indoor vigorous activity increased significantly on an average by + 6.04 % pre-to-post intervention among preschoolers in the intervention group ( P = .049 ) ; no significant change was found in the comparison group . Conclusion : The CATCH EC favorably increased indoor vigorous PA level among low-income children attending Head Start BACKGROUND Previous studies on physical activity interventions in preschools have reported limited effectiveness . Participatory community-based approaches hold promise for increasing intervention effectiveness and involving parents as key stakeholders in a sustainable way . PURPOSE To assess whether a participatory parent-focused approach using parents as agents of behavioral change enhances the efficacy of a preschool physical activity ( PA ) intervention . DESIGN Two-armed , cluster- RCT with preschool as unit of r and omization and children as unit of analysis . SETTING / PARTICIPANTS 39 South German preschools applying for an existing state-sponsored PA program with 826 children ( 52 % boys , aged 5.0±0.2 years ) , with 441 allocated to the intervention arm . INTERVENTION Control preschools received a state-sponsored program consisting of twice-weekly gym classes over 6 months . In intervention preschools , this program was augmented by motivating parents to develop and implement their own project ideas for promoting children 's PA . MAIN OUTCOME MEASURES Primary outcomes included mean accelerometry counts and time spent in moderate- to vigorous-intensity PA or sedentary behavior . Secondary outcomes were BMI , percentage body fat , quality of life , sleep quality , and general health . Outcomes were measured at baseline and at 6 and 12 months in both study arms ( time period : 2008 - 2010 ) . Using an intention-to-treat- analysis , linear multilevel regression models assessed change over time and across study arms , adjusted for age , gender , season , and preschool location . Analysis was conducted in 2011 . RESULTS In 15 intervention preschools , parents implemented 25 PA projects . Compared with controls , intervention arm children were 11 minutes less sedentary per day ( 95 % CI=5.39 , 17.01 , p=0.014 ) ; had significantly more mean accelerometry counts ( 1.4 counts/15 seconds [ 95 % CI=0.22 , 2.54 ] , p=0.019 ) ; and showed benefits in perceived general health and quality of life . All other outcomes showed no difference between study arms . CONCLUSIONS A participatory preschool intervention focusing on parents as agents of behavioral change may be able to promote PA and reduce sedentary behavior in preschoolers . These benefits may go beyond the effects of existing nonparticipatory interventions . TRIAL REGISTRATION This study is registered at clinical trials.gov NCT00987532 BACKGROUND AND OBJECTIVES : Lower concentrations of oxygen ( O2 ) ( ≤30 % ) are recommended for preterm resuscitation to avoid oxidative injury and cerebral ischemia . Effects on long-term outcomes are uncertain . We aim ed to determine the effects of using room air ( RA ) or 100 % O2 on the combined risk of death and disability at 2 years in infants < 32 weeks ’ gestation . METHODS : A r and omized , unmasked study design ed to determine major disability and death at 2 years in infants < 32 weeks ’ gestation after delivery room resuscitation was initiated with either RA or 100 % O2 and which were adjusted to target pulse oximetry of 65 % to 95 % at 5 minutes and 85 % to 95 % until NICU admission . RESULTS : Of 6291 eligible patients , 292 were recruited and 287 ( mean gestation : 28.9 weeks ) were included in the analysis ( RA : n = 144 ; 100 % O2 : n = 143 ) . Recruitment ceased in June 2014 , per the recommendations of the Data and Safety Monitoring Committee owing to loss of equipoise for the use of 100 % O2 . In non-prespecified analyses , infants < 28 weeks who received RA resuscitation had higher hospital mortality ( RA : 10 of 46 [ 22 % ] ; than those given 100 % O2 : 3 of 54 [ 6 % ] ; risk ratio : 3.9 [ 95 % confidence interval : 1.1–13.4 ] ; P = .01 ) . Respiratory failure was the most common cause of death ( n = 13 ) . CONCLUSIONS : Using RA to initiate resuscitation was associated with an increased risk of death in infants < 28 weeks ’ gestation . This study was not a prespecified analysis , and it was underpowered to address this post hoc hypothesis reliably . Additional data are needed BACKGROUND This study evaluated the effect of a " move and learn " curriculum on physical activity ( PA ) in 3- to 5-year-olds attending a half-day preschool program . METHODS Classrooms were r and omized to receive an 8-week move and learn program or complete their usual curriculum . In intervention classes , opportunities for PA were integrated into all aspects of the preschool curriculum , including math , science , language arts , and nutrition education . Changes in PA were measured objective ly using accelerometry and direct observation . RESULTS At the completion of the 8-week intervention , children completing the move and learn curriculum exhibited significantly higher levels of classroom moderate-to-vigorous physical activity ( MVPA ) than children completing their usual curriculum . Significant differences were also noted for classroom VPA over the final 2 weeks . CONCLUSION The results suggest that integrating movement experiences into an existing early childhood curriculum is feasible and a potentially effective strategy for promoting PA in preschool children A preschool-based intervention to improve children ’s self-regulation improves self-regulation but has no effect on child BMI or obesity-related behaviors . OBJECTIVES : To determine the effect of an intervention to improve emotional and behavioral self-regulation in combination with an obesity-prevention program on the prevalence of obesity and obesity-related behaviors in preschoolers . METHODS : This was a cluster-r and omized intervention trial in Head Start ( HS ) classrooms conducted in each of 4 academic years from 2011 to 2015 . Participants ( 697 children ; 49 % boys ; mean age : 4.1 ± 0.5 years ; 48 % white , 30 % African American , 12 % Hispanic ) were r and omly assigned by classroom to 1 of 3 intervention arms : ( 1 ) HS + Preschool Obesity Prevention Series ( POPS ) + Incredible Years Series ( IYS ) ( HS enhanced by the POPS [ program targeting evidence -based obesity-prevention behaviors ] and the IYS [ program to improve children ’s self-regulation ] ) , ( 2 ) HS+POPS , or ( 3 ) HS . Primary outcomes were changes in prevalence of obesity , overweight/obesity , BMI z score , and teacher-reported child emotional and behavioral self-regulation ; secondary outcomes were dietary intake , outdoor play , screen time , and parent nutrition knowledge and nutrition self-efficacy . RESULTS : HS+POPS+IYS improved teacher-reported self-regulation compared with HS+POPS ( P < .001 ) and HS ( P < .001 ) , but there was no effect on the prevalence of obesity ( 16.4 % preintervention to 14.3 % postintervention in HS+POPS+IYS versus 17.3 % to 14.4 % in HS+POPS [ P = .54 ] versus 12.2 % to 13.0 % in HS [ P = .33 ] ) . There was no effect of HS+POPS compared with HS alone ( P = .16 ) . There was no effect on other outcomes except for sugar-sweetened beverage intake ( HS+POPS+IYS result ed in a greater decline than HS ; P = .005 ) . CONCLUSIONS : An intervention for parents and children to improve HS preschoolers ’ emotional and behavioral self-regulation in combination with an obesity-prevention curriculum did not reduce obesity prevalence or most obesity-related behaviors OBJECTIVE Overweight ( OW ) and low fit children represent cardiovascular high-risk groups . A multidimensional school-based lifestyle intervention performed in 652 preschoolers reduced skinfold thickness and waist circumference , and improved fitness , but did not affect BMI . The objective of this study is to examine whether the intervention was equally effective in OW ( ≥90th national percentile ) and /or low fit ( lowest sex- and age-adjusted quartile of aerobic fitness ) children compared to their normal weight and normal fit counterparts . DESIGN AND METHODS Cluster r and omized controlled single blinded trial , conducted in 2008/09 in 40 r and omly selected preschool classes in Switzerl and . The intervention included a playful physical activity program and lessons on nutrition , media use and sleeps . Primary outcomes were BMI and aerobic fitness ; secondary outcomes included sum of four skinfolds , waist circumference and motor agility . Modification of intervention effects by BMI -group and fitness-group was tested by interaction terms . RESULTS Compared to their counterparts , OW children ( n = 130 ) had more beneficial effects on waist circumference ( p for interaction = 0.001 ) and low fit children ( n = 154 ) more beneficial effects on all adiposity outcomes ( p for interaction ≤0.03 ) . The intervention effects on both fitness outcomes were not modified by BMI - or fitness-group ( all p for interaction ≥0.2 ) . Average intervention effect sizes for BMI were -0.12 , -0.05 , -0.26 and -0.02 kg/m(2 ) and for aerobic fitness were 0.40 , 0.30 , 0.12 and 0.36 stages for OW , normal weight , low fit and normal fit children , respectively . CONCLUSIONS This multidimensional intervention was equally and for some adiposity measures even more effective in high-risk preschoolers and represents a promising option for these children OBJECTIVE Hip-Hop to Health Jr. was a diet/physical activity intervention design ed to reduce gains in BMI ( kilograms per meter squared ) in preschool minority children . RESEARCH METHODS AND PROCEDURES Twelve predominantly Latino Head Start centers participated in a group-r and omized trial conducted between Fall 2001 and Winter 2003 . Six centers were r and omized to a culturally proficient 14-week ( three times weekly ) diet/physical activity intervention . Parents participated by completing weekly homework assignments . The children in the other six centers received a general health intervention that did not address either diet or physical activity . The primary outcome was change in BMI , and secondary outcomes were changes in dietary intake and physical activity . Measures were collected at baseline , post-intervention , and at Years 1 and 2 follow-up . RESULTS There were no significant differences between intervention and control schools in either primary or secondary outcomes at post-intervention , Year 1 , or Year 2 follow-ups . DISCUSSION When Hip-Hop to Health Jr. was conducted in predominantly black Head Start centers , it was effective in reducing subsequent increases in BMI in preschool children . In contrast , when the program was conducted in Latino centers , it was not effective . Although the intervention did not prevent excessive weight gain in Latino children , it was very well received . Future interventions with this population may require further cultural tailoring and a more robust parent intervention Background Physical activity levels among preschoolers in childcare are low and sedentary time high . The Supporting Physical Activity in the Childcare Environment ( SPACE ) intervention had three components : 1 . portable play equipment ; 2 . staff training ; and , 3 . modified outdoor playtime ( i.e. , shorter , more frequent periods ) . This study aim ed to examine the effectiveness of the SPACE intervention on preschoolers ’ physical activity levels and sedentary time during childcare hours ( compared to st and ard care ) . Methods Via a single-blind cluster r and omized controlled trial , 338 preschoolers ( 39.86 ± 7.33 months ; 52 % boys ) from 22 centre-based childcare facilities ( 11 experimental , 11 control ) were enrolled . Preschoolers wore an Actical ™ accelerometer for 5 days during childcare hours at baseline , post-intervention , and 6- and 12-month follow-up , and were included in the analyses if they had a minimum of two valid days ( 5 h each day ) at baseline and one additional time point . Intervention effectiveness was tested using a linear mixed effects model for each of the four outcome variables ( i.e. , sedentary time , light physical activity [ LPA ] , moderate-to-vigorous physical activity [ MVPA ] , and total physical activity [ TPA ] ) . Fixed effects were further evaluated with t-tests , for which degrees of freedom were estimated using a Satterthwaite approximation . Results One hundred and ninety-five preschoolers were retained for analyses . The intervention did not significantly impact LPA . MVPA was significantly greater among children in the experimental group when comparing post-intervention to pre-intervention , t(318 ) = 3.50 , p = .0005 , but no intervention effects were evident at 6- or 12-month follow-up . TPA was significantly greater for children in the intervention group at post-intervention when compared to pre-intervention , t(321 ) = 2.70 , p = .007 , with no intervention effects evident at later time periods . Finally , sedentary time was significantly lower among preschoolers in the experimental group when comparing post-intervention to pre-intervention , t(322 ) = 2.63 , p = .009 , with no significant effects at follow-up . Conclusions The SPACE intervention was effective at increasing MVPA and TPA among preschoolers , while simultaneously decreasing sedentary time . The ability of the SPACE intervention to target higher intensity activity is promising , as MVPA levels have been documented to be low in centre-based childcare . The changes in physical activity were not sustained long term ( 6- or 12-month follow-up).Trial registration IS RCT N70604107 ( October 8 , 2014 ) Abstract Good nutrition in the early years of life is vitally important for a child 's development , growth and health . Children 's diets in the United Kingdom are known to be poor , particularly among socially disadvantaged groups , and there is a need for timely and appropriate interventions that support parents to improve the diets of young children . The Medical Research Council has highlighted the importance of conducting developmental and exploratory research prior to undertaking full‐scale trials to evaluate complex interventions , but have provided very limited detailed guidance on the conduct of these initial phases of research . This paper describes the initial developmental stage and the conduct of an exploratory r and omised controlled trial undertaken to determine the feasibility and acceptability of a family‐centred early years ' nutrition intervention . Choosing Healthy Eating when Really Young ( CHERRY ) is a programme for families with children aged 18 months to 5 years , delivered in children 's centres in one urban ( Islington ) and one rural ( Cornwall ) location in the United Kingdom . In the development stage , a mixed‐ methods approach was used to investigate the nature of the problem and options for support . A detailed review of the evidence informed the theoretical basis of the study and the creation of a logic model . In the feasibility and pilot testing stage of the exploratory trial , 16 children 's centres , with a sample of 394 families were recruited onto the study . We hope that the methodology , which we present in this paper , will inform and assist other research ers in conducting community‐based , exploratory nutrition research in early years setting BACKGROUND With evidence of increased levels of obesity in younger children , the child-care setting is an important intervention target . Few environmental interventions exist , and none target both diet and physical activity . The Nutrition and Physical Activity Self- Assessment for Child Care ( NAP SACC ) intervention was developed to fill this research and practice gap . DESIGN R and omized controlled . SETTING / PARTICIPANTS Health professionals ( child-care health consultants ) serving child-care centers in North Carolina were recruited ( n=30 ) , r and omly assigned into intervention or delayed-intervention control groups , and trained to implement the NAP SACC program . Up to three child-care centers were recruited ( n=84 ) from each consultant 's existing caseload . INTERVENTION Implemented in 2005 , the NAP SACC intervention includes an environmental self- assessment , selection of areas for change , continuing education workshops , targeted technical assistance , and re-evaluation . Implementation occurred over a 6-month period . MAIN OUTCOME MEASURES An observational instrument , Environment and Policy Assessment and Observation ( EPAO ) , provided objective evidence of intervention impact and was completed by trained research staff blinded to study assignment . Data were collected in 2005 and 2006 . Statistical analyses were conducted in 2006 . RESULTS Intention-to-treat analysis results were nonsignificant . Exploratory analyses using only centers that completed most of the NAP SACC program suggest an intervention effect . CONCLUSIONS Factors in the intervention design , the fidelity of implementation , the selection of outcome measure , or a combination of these may have contributed to the lack of intervention effect observed . Because of this study 's use of existing public health infrastructure and its potential for implementation , future studies should address strategies for improving effectiveness OBJECTIVE To evaluate the impact of a Special Supplemental Nutrition Program for Women , Infants , and Children (WIC)-based intervention on the food and beverage intake , physical activity , and television watching of children ages 1 - 5 . DESIGN Longitudinal surveys of intervention and control participants at baseline , 6 months , and 12 months . RESULTS Analysis of variance tests showed that the intervention had a small but significant impact on TV watching and fruit intake . The intervention was most protective for children younger than 2 years of age . CONCLUSIONS AND IMPLICATION S Although the impact of the intervention was relatively small and limited to the youngest children served by WIC , findings suggest that the WIC setting is appropriate for improving healthful behaviors that are linked to reducing the rates of early childhood overweight OBJECTIVE To assess the effectiveness of an intervention programme to improve kindergarten children 's eating and leisure habits in Israel . DESIGN A cluster-r and omised controlled trial . SETTING Six full-day kindergartens in Israel were r and omly divided into three groups . Group A received the full intervention programme , which included lessons on good eating habits and daily physical exercise . Group B received a partial intervention of lessons only . Group C , the reference group , did not receive any intervention . SUBJECTS Children aged 4 - 6 years ( n 204 ) were recruited for the study . METHODS Objective data for weight and height were collected to calculate BMI Z-scores . Activity , sedentary time , sleeping hours and daily energy intake were assessed via a parental question naire . Nutritional knowledge was assessed by a single dietitian using a question naire addressed to the children . Assessment s were done at baseline and at the end of the intervention . RESULTS After adjustment for baseline levels we observed a significant reduction in daily energy intake for the full intervention group A ( P = 0.03 ) . A positive intervention effect was demonstrated on nutritional knowledge in the partial intervention group B ( P = 0.03 ) , although no significant change was demonstrated for BMI Z-score . CONCLUSIONS The study supports the incorporation of education on healthy lifestyle habits and physical activity into the curricula of kindergartens BACKGROUND The aim of the study was to objective ly determine whether the Nutrition and Physical Activity Self- Assessment for Child Care ( NAP SACC ) program improved physical activity levels during the school day . METHODS The study compared the physical activity levels of subjects from 26 daycare centers , r and omized into treatment ( N=13 ) and control ( N=13 ) groups . The subjects were 3 to 5 year olds ( N=209 , 104 males and 105 females ; age [years]=3.85±0.8 [ mean±st and ard deviation ] ) , and accelerometry was used to determine the subjects ' physical activity levels . Accelerometers were attached to each subject for 2 days before and immediately after a 6-month intervention . Height , mass , and waist were also measured . RESULTS Regression analyses indicated that the treatment group demonstrated significant increases in moderate and vigorous physical activity , as compared to the control group ( F(1 , 207)=6.3 , p<0.05 , Cohen 's d=0.30 ; F(1 , 207)=4.7 , p<0.05 , Cohen 's d=0.25 , respectively ) . The treatment group also showed significant increases in total physical activity ( F(1 , 218)=12.4 ; p<0.05 ) from pre- to post-test with significant increases in moderate and vigorous intensity physical activity ( F(1 , 218)=18.6 , p<0.05 ; F(1 , 218)=23.3 , p<0.05 , respectively ) . Regression analyses revealed significant increases in height for both groups from pre- to post-tests , but no differences were noted between groups . CONCLUSIONS Implementation of the NAP SACC program in treatment daycare facilities result ed in significant increases in objective ly measured physical activity levels , compared to the control group , demonstrating physical activity improvement in the treatment daycare centers Project Energize is a through-school nutrition and activity programme that is being evaluated in a 2-year , cluster-r and omised , longitudinal study . The present paper describes the background of the programme and study , the programme development and delivery , the study methodology including r and omisation , measurement and analysis tools and techniques , and the mix of the study population . The programme is being delivered to sixty-two primary schools with sixty-two control schools , each limb containing about 11,000 students . The children in the evaluation cohort are 5 or 10 years old at enrolment ; the r and omisation protocol has achieved post-consent enrolment of 3,000 evaluation participants , who are comparable by age , sex and school decile . End-point measures include body composition and associated physical characteristics , fitness , home and school environment and practice INTRODUCTION A majority of preschool-aged children spend a significant portion of every weekday in a preschool or child care setting , where they typically participate in limited physical activity . This study determined if an ecologic physical activity intervention in preschools increases children 's moderate- to vigorous-intensity physical activity ( MVPA ) . DESIGN RCT , with preschool as the unit of r and omization and analysis . Child physical activity was measured by accelerometry . Mixed model analysis of covariance with preschool as a r and om variable was used to test the effects of the intervention on physical activity in the total group and in sex-specific subgroups . Data were collected in 2008 - 2010 and analyzed in 2012 - 2014 . SETTING / PARTICIPANTS Children in 4-year-olds ' classrooms in 16 preschools , pair matched and assigned to intervention or control groups . INTERVENTION The intervention focused on increasing children 's physical activity by changing instructional practice s. Research ers trained preschool teachers to engage children in physical activity during ( 1 ) structured , teacher-led physical activity opportunities in the classroom ; ( 2 ) structured and unstructured physical activity opportunities at recess ; and ( 3 ) physical activity integrated into pre-academic lessons . Research staff encouraged teachers to adapt the intervention to their classrooms . MAIN OUTCOME MEASURES Minutes/hour of MVPA during the preschool day . RESULTS In an analytic sample of 379 children ( 188 intervention , 191 control ) , those in the intervention schools engaged in significantly more MVPA than children in control schools ( 7.4 and 6.6 minutes/hour , respectively ) . This difference remained significant after adjusting for parent education and length of the school day ( half versus full day ) . In the sex-specific analyses , the difference was significant for girls ( 6.8 vs 6.1 minutes/hour of MVPA , respectively ) but not for boys ( 7.9 vs 7.2 minutes/hour , respectively ) . CONCLUSIONS A flexible ecologic physical activity intervention that trains teachers to provide children with opportunities to be active throughout the school day increased MVPA in preschool children The aim of this short report was to describe the output and citation rates of public health . Data -based publications and literature review s from the year 2008 , and their 5-year citation rates were extracted from 10 r and omly selected public health journals . In total , 86.2 % of publications were descriptive/epidemiological studies , 56.8 % used cross-sectional ( 56.8 % ) design s and 77.8 % were classified as research translation stage 2 . Review s and publications describing r and omized controlled trials were the most highly cited , but were infrequently published . Strategies to address the discordance between public health research output and research citation may improve the impact of public health research OBJECTIVE . We design ed and tested a novel health promotion program for elementary schools that was based on peer teaching from older to younger schoolchildren ( “ Healthy Buddies ” ) . SUBJECTS AND METHODS . This prospect i ve pilot study compared the effect of our program ( 2–3 hours/week , 21 weeks ) in 2 Canadian elementary schools ( intervention : n = 232 children , the whole school implementing the program ; control : n = 151 ) . Older students ( 4th through 7th grade ) were given direct instruction from 1 intervention teacher and were paired with younger students ( kindergarten through 3rd grade ) for the whole school year . Students in 4th through 7th grade then acted as teachers for their younger “ buddies . ” All lessons included 3 components of healthy living : nutrition , physical activity , and healthy body image . The students first learned how to be positive buddies and learned the 3 components of a healthy life . Thereafter , they learned how to overcome challenges to living a healthy life . Outcome measures ( intervention and control schools at the beginning and end of the school year ) included vali date d question naires that assessed healthy-living knowledge , behavior and attitude , a 9-minute fitness run , self-competence , body satisfaction , disordered eating symptoms , and anthropometry ( BMI , blood pressure , and heart rate ) . RESULTS . Compared with control students , both older and younger intervention students showed an increase in healthy-living knowledge , behavior , and attitude scores and a smaller increase in systolic blood pressure . BMI and weight increased less in the intervention students in 4th through 7th grade and height more in the intervention students in kindergarten through 3rd grade . CONCLUSIONS . Our student-led curriculum improved knowledge not only in older schoolchildren but also in their younger buddies . It also decreased weight velocity in the older students . Student-led teaching may be an efficient , easy-to-implement way of promoting a healthy lifestyle from kindergarten to 7th grade BACKGROUND Healthy Start is a 3-year demonstration and education research project design ed to evaluate the effectiveness of a multidimensional cardiovascular ( CV ) risk reduction intervention in preschool centers over a 3-year period of time . METHODS Two primary interventions are employed . The first is the preschool food service intervention program design ed to reduce the total fat in preschool meals and snacks to less than 30 % of calories and reduce the saturated fat to less than 10 % of calories . The second major intervention is a comprehensive preschool health education curriculum , focused heavily on nutrition . RESULTS Effectiveness of the intervention will be determined through evaluation of changes in dietary intake of preschool children at school meals and snacks , especially with respect to intake of total and saturated fat . Evaluation of the education component will include assessment of program implementation by teachers , assessment of changes in nutrition knowledge by preschool children , and assessment of changes in home meals that children consume ( total and saturated fat content ) . Blood cholesterol will be evaluated semiannually to evaluate changes that may be due to modification of dietary intake . Growth and body fatness will also be assessed . CONCLUSIONS While substantial efforts have targeted CV risk reduction and health education for elementary school children , similar efforts aim ed at preschool children have been lacking . The rationale for beginning CV risk reduction programs for preschool children is based upon the premise that risk factors for heart disease are prevalent by 3 years of age and tend to track over time , most commonly hypercholesterolemia and obesity , both related to nutrition . Since the behavioral antecedents for nutritional risk factors begin to be established very early in life , it is important to develop and evaluate new educational initiatives such as Healthy Start , aim ed at the primary prevention of cardiovascular risk factors in preschool children . The purpose of this publication is to describe the rationale and methods for the Healthy Start project Abstract Background : Obesity is the most common chronic pediatric disease in westernized societies , with minorities and children from low socioeconomic status being mostly affected . Arab-Israelis are the largest minority population in Israel . Objective : The aim of this study is to examine the prevalence of obesity and to prospect ively study the effects of a health promotion , school-based intervention on nutrition and physical activity knowledge and preferences , anthropometric measures , and fitness in Arab-Israeli kindergarten children . Participants : One hundred fifty-four children completed a school year with combined dietary-behavioral-physical activity intervention and were compared with 188 controls ( age 4.2–6.5 years ) . Results : The prevalence of overweight and obesity among Arab-Israeli kindergarten children was 28.9 % . Compared with control , the intervention led to a significantly greater ( control vs. intervention , respectively , p<0.05 ) increase in nutrition knowledge ( 51.2±1.5%–48.9±1.6 % vs. 48.9±1.6%–85.9±1.4 % ) and preferences ( 47.4±1.5%–47.7±1.6 % vs. 45.2±1.8%–87.1±1.4 % ) , increase in physical activity knowledge ( 47.2±1.3%–47.0±1.7 % vs. 49.2±1.7%–90.8±1.3 % ) and preferences ( 52.3±1.3%–54.2±1.8 % vs. 56.2±1.4%–92.8±1.0 % ) , and improvement in fitness ( –10.2±1.6 vs. 11.6±1.4 shuttle run laps ) . The intervention was associated with favorable changes in height gain ( 5.0±0.1 vs. 6.2±0.1 cm ) , body mass index ( BMI –0.41±0.06 vs. –0.71±0.06 kg/m2 ) and BMI percentile ( –10.0±1.3 % vs. –16.2±1.2 % ) in the control and intervention groups , respectively . Conclusions : A kindergarten dietary-physical activity intervention applied by the kindergarten teachers led to a decrease in BMI , BMI percentile , improved nutrition and physical activity knowledge and preferences , and improved fitness . Such programs may play important role in health promotion , prevention , and treatment of childhood obesity in minority communities from early age Background Promotion of healthy eating and physical activity in early childhood is recommended as a global chronic disease prevention strategy . Centre-based childcare services represent a promising setting to provide children with opportunities to improve healthy eating and physical activity . Evidence to inform implementation of childcare obesity prevention guidelines into routine practice in childcare , however , is lacking . This study aims to assess the effectiveness of an intervention , delivered to childcare staff , aim ing to increasing service implementation of healthy eating and physical activity-promoting policies and practice s. Methods and analysis A pragmatic parallel group r and omised controlled trial will be undertaken with 165 childcare services in the Hunter New Engl and region of New South Wales , Australia . Services will be r and omised to receive either a 10-month evidence -based performance review intervention with other re sources to support practice change , or to a waitlist control group . The primary trial outcome is the proportion of services implementing all of the following recommended healthy eating and physical activity promoting practice s : written nutrition , physical activity and small screen recreation policies ; providing information to families regarding healthy eating ( including breastfeeding ) , physical activity and small screen time ; providing twice weekly healthy eating learning experiences to children ; providing water and only plain milk to children ; providing fundamental movement skills activities for children every day ; and limiting and using electronic screen time more for educational purpose s and learning experiences . Effectiveness will be assessed using a telephone interview of practice implementation with childcare staff at baseline and 12 months following baseline . Ethics and dissemination The study was approved by the Hunter New Engl and Human Research Ethics Committee and the University of Newcastle Human Research Ethics Committee . Study findings will be disseminated widely through peer- review ed publications and conference presentations . Trial registration number Australian New Zeal and Clinical Trials Registry ACTRN12614000972628 Purpose : To assess the impact of an early childhood obesity prevention intervention “ Healthy Caregivers – Healthy Children ” ( HC2 ) on dietary patterns and body mass index percentile ( P BMI ) over 2 school years . Design : R and omized controlled trial . Setting : Childcare centers . Participants : Low-income families . Intervention : Intervention centers ( N = 12 ) received HC2 which consisted of ( 1 ) menu modifications , ( 2 ) a healthy eating and physical activity curriculum for children , and ( 3 ) a parent curriculum for healthy meal preparation , reinforced through a role-modeling curriculum . Control centers ( N = 16 ) received an injury prevention/safety intervention . Measures : Child P BMI and parent report of child ’s consumption of fruits/vegetables and unhealthy food . Analysis : Confirmatory factor analysis verified the psychometric properties of factor scores for children ’s consumption of fruits/vegetables and unhealthy food . Growth curve analysis assessed the impact of HC2 on change in consumption of fruits/vegetables and unhealthy food and P BMI over 2 school years . Results : Children in the intervention group ( n = 754 ) had a negative slope ( β = −1.95 , st and ard error [ SE ] = 0.97 , P = .04 ) , indicating less increase in P BMI versus control children ( n = 457 ) . Stratified analyses showed that obese children in the intervention arm had a significantly higher increase in fruit/vegetable consumption versus control group obese children ( β = 0.24 , SE = 0.08 , P = .003 ) . Conclusion : The HC2 intervention result ed in the maintenance of healthy P BMI over 2 preschool years among low-income multiethnic children . These findings support efforts to implement healthy weight programs in the childcare setting INTRODUCTION Child care health consultants ( CCHCs ) are health professionals who provide consultation and referral services to child care programs . The use of CCHCs has been recommended as an important component of high- quality child care . The purpose of this study was to examine the potential association between the use of paid CCHCs and child care center director reports of ( a ) center maintenance of health records and emergency procedures and ( b ) center facilitation of health screenings and assessment s. METHOD A national , r and omized telephone survey of directors of 1822 licensed child care center directors was conducted . RESULTS With a response rate of 93 % , most directors ( 72.7 % ) reported that they did not employ a CCHC . However , directors employing CCHCs were more likely to report provision of health-promoting screenings and assessment s for children in their center . This pattern held true for both Head Start and non-Head Start centers . DISCUSSION This study suggests that CCHCs can serve as health promotion advocates in early care and education setting s , helping centers establish appropriate policies and arranging for health assessment s and screenings for children OBJECTIVES To assess the impact of a culturally proficient dietary/physical activity intervention on changes in body mass index ( BMI ) ( kg/m 2 ) . STUDY DESIGN R and omized controlled trial ( Hip-Hop to Health Jr. ) conducted between September 1999 and June 2002 in 12 Head Start preschool programs in Chicago , Illinois . RESULTS Intervention children had significantly smaller increases in BMI compared with control children at 1-year follow-up , 0.06 vs 0.59 kg/m 2 ; difference -0.53 kg/m 2 ( 95 % CI -0.91 to -0.14 ) , P = .01 ; and at 2-year follow-up , 0.54 vs 1.08 kg/m 2 ; difference -0.54 kg/m 2 ( 95 % CI -0.98 to -0.10 ) , P = .02 , with adjustment for baseline age and BMI . The only significant difference between intervention and control children in food intake/physical activity was the Year 1 difference in percent of calories from saturated fat , 11.6 % vs 12.8 % ( P = .002 ) . CONCLUSIONS Hip-Hop to Health Jr. was effective in reducing subsequent increases in BMI in preschool children . This represents a promising approach to prevention of overweight among minority children in the preschool years Obesity in Chilean children has increased markedly over the past decades . School-based obesity prevention interventions have been launched by the Ministry of Health and academic groups to tackle this condition . We summarize the main characteristics of the interventions that we have conducted and reflect on the lessons learned . Since 2002 , we conducted 1 pilot study , a 2-y controlled intervention including 6- to 12-y-old children ( Casablanca ) , another pilot study , and a 2-y controlled intervention including teachers and their 4- to 9-y-old students ( Macul ) . Both interventions consisted of training teachers to deliver contents on healthy eating , increasing physical education classes , and , additionally in Macul , teachers participated in a wellness program . BMI Z-score and obesity prevalence were compared among children in intervention and control schools by year and among students of intervention and control teachers . In the Casablanca study , the impact was greatest on the younger children during the first school year when the study received the full funding that was required . In Macul , although intervention teachers exhibited improvements in anthropometry and blood measures , the impact on the children was not related to their results . The main lessons learned from these experiences are r and om allocation of schools , although method ologically desirable , is not always possible ; participation of parents is very limited ; obesity is not recognized as a problem ; and increasing physical activity and implementing training programs for teachers is difficult due to an inflexible curriculum and lack of teachers ' time . Unless these barriers are overcome , obesity prevention programs will not produce positive and lasting outcomes Objective : We evaluated the effects of a preschool nutrition education and food service intervention “ Healthy Start , ” on two-to-five-year-old children in nine Head Start Centers in upstate NY . The primary objective was to reduce the saturated fat ( sat-fat ) content of preschool meals to < 10 % daily energy ( E ) and to reduce consumption of sat-fat by preschoolers to < 10 % E. Methods : Six centers were assigned to the food service intervention and three to control condition . Food service intervention included training workshops for cooks and monthly site visits to review progress towards goals . Child dietary intake at preschool was assessed by direct observation and plate waste measurement . Dietary intake at home was assessed by parental food record and telephone interviews . Dietary data were collected each Fall/Spring over two years , including five days of menus and recipes from each center . Dietary data were analyzed with the Minnesota NDS software . Results : Consumption of saturated fat from school meals decreased significantly from 11.0%E to 10.4%E after one year of intervention and to 8.0%E after the second year , compared with an increase of 10.2 % to 13.0 % to 11.4%E , respectively , for control schools ( p < 0.001 ) . Total caloric intake was adequately maintained for both groups . Analysis of preschool menus and recipes over the two-year period of intervention showed a significant decrease in sat-fat content in intervention preschools ( from 12.5 at baseline to 8.0%E compared with a change of 12.1%E to > 11.6%E in control preschools ( p < 0.001 ) ) . Total fat content of menus also decreased significantly in intervention schools ( 31.0 % to > 25.0%E ) compared with controls ( 29.9 % to > 28.4%E ) . Conclusions : The Healthy Start food service intervention was effective in reducing the fat and saturated fat content of preschool meals and reducing children ’s consumption of saturated fat at preschool without compromising energy intake or intake of essential nutrients . These goals are consistent with current U.S. Dietary Guidelines for children older than two years of age Currently , fewer than 15 % of children between the ages of 4 - 8 years consume the recommended levels of fruit and vegetables . In order to address this serious public health issue , a variety of nutrition programs have been implemented across the United States which have varied in their success . The present research analyzed the effectiveness of providing fruit and vegetable exposure as part of a school nutrition program . Kindergarten students at two schools ( N=59 ) were exposed to interactive activities about healthy eating and physical activity . In addition , those at one school ( n=29 ) were exposed to a variety of fruits and vegetables as part of this program . Assessment of children 's ability to identify and their willingness to try fruit and vegetables before and after the program indicated that while all children were better able to identify a range of fruit , only those who received exposure to healthful foods were more willing to try fruit after the program . There were no changes in their identification or willingness to eat vegetables . These results suggest that schools should provide exposure to a variety of healthy foods as part of their nutrition programs . Such programs should focus specifically on exposing children to vegetables because increasing children 's willingness to try foods that are typically considered unpalatable may be especially challenging OBJECTIVES Educator-led programs for physical activity and motor skill development show potential but few have been implemented and evaluated using a r and omized controlled design . Furthermore , few educator-led programs have evaluated both gross motor skills and physical activity . Therefore , the aim of this study was to evaluate a gross motor skill and physical activity program for preschool children which was facilitated solely by childcare educators . DESIGN A six-month 2-arm r and omized controlled trial was implemented between April and September 2012 in four early childhood centers in Tasmania , Australia . METHODS Educators participated in ongoing professional development sessions and children participated in structured physical activity lessons and unstructured physical activity sessions . RESULTS In total , 150 children were recruited from four centers which were r and omized to intervention or wait-list control group . Six early childhood educators from the intervention centers were trained to deliver the intervention . Gross motor skills were assessed using the Test of Gross Motor Development ( 2nd edition ) and physical activity was measured objective ly using GT3X+ Actigraph accelerometers . No statistically significant differences were identified . However , small to medium effect sizes , in favor of the intervention group , were evident for four of the five gross motor skills and the total gross motor skill score and small to medium effect sizes were reported for all physical activity outcomes . CONCLUSIONS This study highlights the potential of educator-led physical activity interventions and supports the need for further translational trials within the early childhood sector UNLABELLED BACKGROUND ; The increasing prevalence of overweight among children in the United States presents a national health priority . Higher rates of overweight/obesity among minority women place their children at increased risk . Although increased rates of overweight are observed in 4- to 5-year-old children , they are not observed in 2- to 3-year-old children . Therefore , early prevention efforts incorporating families are critical . METHODS The primary aim of Hip-Hop to Health Jr. is to alter the trajectory toward overweight/obesity among preschool African-American and Latino children . This 5-year r and omized intervention is conducted in 24 Head Start programs , where each site is r and omized to either a 14-week dietary/physical activity intervention or a general health intervention . RESULTS This paper presents the rationale and design of the study . Efficacy of the intervention will be determined by weight change for the children and parent/caretaker . Secondary measures include reductions in dietary fat and increases in fiber , fruit/vegetable intake , and physical activity . Baseline data will be presented in future papers . CONCLUSIONS The problem of overweight/obesity is epidemic in the United States . Behaviors related to diet and physical activity are established early in life and modeled by family members . Early intervention efforts addressing the child and family are needed to prevent obesity later in life . This paper describes a comprehensive , family-oriented obesity prevention program for minority preschool children Low-income youth are at increased risk for excess weight gain . Although evidence -based prevention programs exist , successful adaptation to provide wide dissemination presents a challenge . Hip-Hop to Health ( HH ) is a school-based obesity prevention intervention that targets primarily preschool children of low-income families . In a large r and omized controlled trial , HH was found to be efficacious for prevention of excessive weight gain . The Exp and ed Food and Nutrition Education Program ( EFNEP ) and the Supplemental Nutrition Assistance Program-Education ( SNAP-Ed ) are USDA-funded nutrition education programs offered to low-income families , and may provide an ideal platform for the wide dissemination of evidence -based obesity prevention programs . A research - practice partnership was established in order to conduct formative research to guide the adaptation and implementation of HH through EFNEP and SNAP-Ed . We present the design and method of a comparative effectiveness trial that will determine the efficacy of HH when delivered by peer educators through these programs compared to the st and ard EFNEP and SNAP-Ed nutrition education ( NE ) curriculum . Results from this trial will inform larger scale dissemination . The dissemination of HH through government programs has the potential to increase the reach of efficacious obesity prevention programs that target low-income children and families OBJECTIVE Despite the high prevalence of obesity among preschool-aged children , most states lack childcare center ( CCC ) nutrition and physical activity policies . The Healthy Caregivers , Healthy Children ( HC ) Phase 2 project is examining the relationship between the CCC nutrition and physical activity environment and child dietary intake/physical activity patterns and body mass index ( BMI ) . PARTICIPANTS A total of 24 " Quality Counts " ( Miami Dade County , Florida 's Quality Rating Improvement System [ QRIS ) ] ) CCCs serving low re source families with ≥50 2-to-5year olds attending have been r and omized to either intervention ( n=12 ) or control ( n=12 ) . INTERVENTION The HC2 intervention arm CCCs receive implementation of a daily curricula for ( 1 ) teachers/parents ; ( 2 ) children ; ( 3 ) snack , beverage , physical activity , and screen time policies ; and ( 4 ) technical assistance with menu modifications . Control arm schools receive an attention control safety curriculum . HC2 is delivered once a month in year 1 , quarterly in year 2 and will be disseminated throughout the Quality Counts network in year 3 . MAIN OUTCOME MEASURES Primary outcome measures include the Environment and Policy Assessment and Observation tool ( EPAO ) , st and ardized dietary intake and physical activity patterns surveys , and child BMI . The ' Reach , Effectiveness , Adoption , Implementation , and Maintenance ( RE- AIM ) ' framework will guide the interpretation of outcome measures . CONCLUSIONS CCCs are in need of evidence -based st and ardized nutrition and physical activity policies . The intersection of RE- AIM and early childhood obesity prevention in the childcare setting could generate robust and new information to the field about potential barriers , facilitators , adoption , and sustainability in this setting Objective : Given the increasing prevalence of pediatric obesity , we evaluated two kindergarten-based strategies for reducing overweight in preschool children in the Haute-Garonne Department in France . Methods : Kindergartens ( n=79 ) were r and omly assigned to one of the two strategies and followed for 2 years . In the first group ( Epidémiologie et prévention de l’obésité infantile , EPIPOI-1 ) , parents and teachers received basic information on overweight and health , and children underwent screening to identify those with overweight ( body mass index ( BMI ) ⩾90th percentile ) or at risk for overweight ( BMI between 75 and 90th percentile ) , who were then followed up by their physicians . EPIPOI-2 children , in addition , received kindergarten-based education to promote healthy practice s related to nutrition , physical activity and sedentary behaviors . Data on control children from non-intervention kindergartens ( n=40 ) were retrieved from medical records at the Division of School Health . Results : At baseline , groups differed significantly on age and school area ( underprivileged/ not ) . Owing to a significant interaction between school area and group , analyses were stratified by school area . At baseline , groups did not differ on overweight prevalence and BMI z-scores for any school area . After intervention , prevalence of overweight , BMI z-score and change in BMI z-score were significantly lower in intervention groups compared with controls in underprivileged areas . Using multilevel analysis adjusted for potential confounders , a significant effect on overweight prevalence at the end of the study was noted for EPIPOI-1 in underprivileged areas only ( odds ratio and 95 % confidence interval : 0.18 ( 0.07–0.51 ) . In non-underprivileged areas , the gain in BMI z-score was lower in EPIPOI-2 group compared with control and EPIPOI-1 . Conclusion : Our results suggest that simple measures involving increasing awareness on overweight and health , and periodic monitoring of weight and height with follow-up care when indicated , could be useful to reduce overweight in young children from underprivileged areas . A reinforced strategy with an education component , in addition , may be indicated in children in non-underprivileged areas Objective : To assess the effectiveness of a child care center-based parent and teacher healthy lifestyle role-modeling program on child nutrition and physical activity outcomes . Methods : Child care centers ( N = 28 ) serving low-income families were r and omized to intervention or control arms . Intervention centers ( N = 12 ) implemented ( 1 ) menu modifications , ( 2 ) a child 's healthy lifestyle curriculum , and ( 3 ) an adult ( teacher- and parent-focused ) healthy lifestyle role-modeling curriculum . Control centers ( N = 16 ) received an attention control safety curriculum . Nutrition and physical activity data were collected at the beginning ( T1 ) and at the end ( T2 ) of the school year . Exploratory factor analysis identified positive and negative nutrition and physical activity practice s by children , parents , and teachers . Results : Intervention parents ' baseline ( & bgr ; = .52 , p < .0001 ) and school year consumption ( & bgr ; = .47 , p < .0001 ) of fruits/vegetables significantly increased their children 's consumption of fruits/vegetables from T1 to T2 . Intervention parents significantly influenced a decrease in children 's junk food consumption ( & bgr ; = −.04 , p < .05 ) , whereas control parents significantly influenced an increase in their children 's junk food consumption ( & bgr ; = .60 , p < .001 ) from T1 to T2 . Control children showed a significant increase in junk food consumption ( & bgr ; = .11 , p = .01 ) and sedentary behavior ( & bgr ; = .09 , p < .005 ) from T1 to T2 . Teachers did not significantly influence preschool-age children 's nutrition or physical activity patterns from T1 to T2 . Conclusions : Parent nutrition and physical activity patterns significantly influence their preschool-age children 's consumption of fruits/vegetables , junk food , and level of sedentary behavior . Future obesity prevention intervention efforts targeting this age group should include parents as healthy lifestyle role models for their children Using baseline data from a r and omized experiment , this article extends and tests in the context of health , the feasibility of a recently proposed reduced form approach to ex ante evaluations of social programs with an application to a conditional cash transfer program in Nicaragua . It uses a behavioural model to estimate the impact on preventive care utilization outcomes for children younger than 3 years . It vali date s the model with the results of the experiment and then simulates two alternate policy scenarios . The model performs well in predicting the health related outcomes and shows different results for the two sets of policy scenarios . In addition , simulations are also carried out for the school component of the cash transfer program OBJECTIVE To quantify the Head Start ( HS ) teacher mediating and moderating influence on the effect of a wellness policy intervention . DESIGN Intervention trial within a larger r and omized community trial . SETTING HS preschools in Hawaii . PARTICIPANTS Twenty-three HS classrooms located within 2 previously r and omized communities . INTERVENTION Seven-month multi-component intervention with policy changes to food served and service style , initiatives for employee wellness , classroom activities for preschoolers promoting physical activity ( PA ) and healthy eating , and training and technical assistance . MAIN OUTCOME MEASURES The Environment and Policy Assessment and Observation ( EPAO ) classroom scores and teacher question naires assessing on knowledge , beliefs , priorities , and misconceptions around child nutrition and changes in personal health behaviors and status were the main outcome measures . ANALYSIS Paired t tests and linear regression analysis tested the intervention effects on the classroom and mediating and moderating effects of the teacher variables on the classroom environment . RESULTS General linear model test showed greater intervention effect on the EPAO score where teachers reported higher than average improvements in their own health status and behaviors ( estimate [ SE ] = -2.47 ( 0.78 ) , P < .05 ) . CONCLUSIONS AND IMPLICATION S Strategies to improve teacher health status and behaviors included in a multi-component policy intervention aim ed at child obesity prevention may produce a greater effect on classroom environments We have demonstrated the feasibility of implementing a multifaceted , culturally appropriate preschool-based obesity intervention program in Guangzhou , China . BACKGROUND AND OBJECTIVES : Interventions to prevent childhood obesity targeting school age children have mostly reported limited effectiveness , suggesting such prevention programs may need to start at an earlier age , but evidence has been scarce . We reported a pilot study aim ing to demonstrate the feasibility of a multifaceted intervention for preschool children and to provide a preliminary assessment of the effectiveness . METHODS : This nonr and omized controlled trial recruited children aged 3 to 6 years from 6 kindergartens in Guangzhou , China . Based on the preference of the School and Parents Committees , 4 kindergartens ( 648 children ) received a 3-component intervention ( training of kindergarten staff , initiating healthy curriculum for children , and close collaboration between families and kindergartens ) over 12 months , while the other 2 kindergartens ( 336 children ) , serving as controls , received routine health care provision . Outcome measures were the changes in BMI z score between baseline and the end of 12 months , and the prevalence of postintervention children who were overweight or obese . RESULTS : By 12 months , children within the intervention group had a smaller BMI z score increase ( 0.24 ) compared to the control ( 0.41 ) , with a difference of –0.31 ( 95 % CI –0.47 to –0.15 ) . The prevalence of overweight or obesity was also lower among the intervention group at the end of the study ( OR : 0.43 , 95 % CI 0.19 to 0.96 ) , adjusted for baseline status . CONCLUSIONS : Our results indicated a multicomponent health behavior intervention might be effective in reducing the prevalence of obesity , but the longer term effects will need confirmation from r and omized controlled trials

Conclusion Published feasibility studies for SW-CRTs are scarce and those that are being reported do not investigate issues specific to the complexities of the trial design .

Background Stepped-wedge cluster r and omised trials ( SW-CRTs ) are a pragmatic trial design , providing an unprecedented opportunity to increase the robustness of evidence underpinning implementation and quality improvement interventions . Given the complexity of the SW-CRT , the likelihood of trials not delivering on their objectives will be mitigated if a feasibility study precedes the definitive trial . It is not currently known if feasibility studies are being conducted for SW-CRTs nor what the objectives of these studies are .

Pilot studies for phase III trials - which are comparative r and omized trials design ed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas . Also commonly know as " feasibility " or " vanguard " studies , they are design ed to assess the safety of treatment or interventions ; to assess recruitment potential ; to assess the feasibility of international collaboration or coordination for multicentre trials ; to increase clinical experience with the study medication or intervention for the phase III trials . They are the best way to assess feasibility of a large , expensive full-scale study , and in fact are an almost essential pre-requisite . Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies . The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including : 1 ) the general reasons for conducting a pilot study ; 2 ) the relationships between pilot studies , proof-of-concept studies , and adaptive design s ; 3 ) the challenges of and misconceptions about pilot studies ; 4 ) the criteria for evaluating the success of a pilot study ; 5 ) frequently asked questions about pilot studies ; 7 ) some ethical aspects related to pilot studies ; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format Background Falls among hospitalised patients impose a considerable burden on health systems globally and prevention is a priority . Some patient-level interventions have been effective in reducing falls , but others have not . An alternative and promising approach to reducing inpatient falls is through the modification of the hospital physical environment and the night lighting of hospital wards is a leading c and i date for investigation . In this pilot trial , we will determine the feasibility of conducting a main trial to evaluate the effects of modified night lighting on inpatient ward level fall rates . We will test also the feasibility of collecting novel forms of patient level data through a concurrent observational sub- study . Methods / design A stepped wedge , cluster r and omised controlled trial will be conducted in six inpatient wards over 14 months in a metropolitan teaching hospital in Brisbane ( Australia ) . The intervention will consist of supplementary night lighting installed across all patient rooms within study wards . The planned placement of luminaires , configurations and spectral characteristics are based on prior published research and pre-trial testing and modification . We will collect data on rates of falls on study wards ( falls per 1000 patient days ) , the proportion of patients who fall once or more , and average length of stay . We will recruit two patients per ward per month to a concurrent observational sub- study aim ed at underst and ing potential impacts on a range of patient sleep and mobility behaviour . The effect on the environment will be monitored with sensors to detect variation in light levels and night-time room activity . We will also collect data on possible patient-level confounders including demographics , pre-admission sleep quality , reported vision , hearing impairment and functional status . Discussion This pragmatic pilot trial will assess the feasibility of conducting a main trial to investigate the effects of modified night lighting on inpatient fall rates using several new methods previously untested in the context of environmental modifications and patient safety . Pilot data collected through both parts of the trial will be utilised to inform sample size calculations , trial design and final data collection methods for a subsequent main trial . Trial registration Australian New Zeal and Clinical Trials Register ( ANZCTR ) : ACTRN12614000615684 ( cluster RCT ) and ACTRN12614000616673 ( observational sub- study ) . Date Registered : 10 June 2014 ( both studies ) . Protocol version : 1.2 ( Date d : 01 June 2014)Anticipated completion : September 2015Role of Trial Sponsor : The named sponsor for this investigator-initiated trial was the Director of the Royal Brisbane and Women ’s Hospital ( RBWH ) Safety and Quality Unit ( Therese Lee , Phone : + 61 7 3646 8111 ) . The principal investigators , SC and MA , are employed by the RBWH Safety and Quality Unit . The trial sponsor has no involvement in any aspects of study design , conduct or decision to su bmi t the report for publication . AM and MD are employed by other departments in the same organisation BACKGROUND A crucial part in the development of any intervention is the preliminary work carried out prior to a large-scale definitive trial . However , the definitions of these terms are not clear cut and many authors redefine them . Because of this , the terms feasibility and pilot are often misused . AIM To provide an introduction to the topic area of pilot and feasibility trials and draw together the work of others in the area on defining what is a pilot or feasibility study . METHODS This study used a review of definitions and advice from the published literature and from funders ' websites . Examples are used to show evidence of good practice and poor practice . RESULTS We found that research ers use different terms to describe the various stages of the research process . Some define the terms feasibility and pilot as being different whereas others argue that these terms are synonymous . All reflective papers agree that feasibility/pilot studies should not test treatment comparisons nor estimate feasible effect sizes . However , this is not universally observed in practice . SUMMARY We believe that the term ' feasibility ' should be used as an overarching term for preliminary studies and the term ' pilot ' refers to a specific type of study which resembles the intended trial in aspects such as , having a control group and r and omisation . However , studies labelled ' pilot ' should have different aims and objectives to main trials and also should include an intention for future work . Research ers should not use the title ' pilot ' for a trial which evaluates a treatment effect OBJECTIVES To determine the advantages and disadvantages of a stepped wedge design for a specific clinical application . STUDY DESIGN AND SETTING The clinical application was a pragmatic cluster r and omized surgical trial intending to find an increased percentage of curable recurrences in patients in follow-up after colorectal cancer . Advantages and disadvantages of the stepped wedge design were evaluated , and for this application , new advantages and disadvantages were presented . RESULTS A main advantage of the stepped wedge design was that the intervention rolls out to all participants , motivating patients and doctors , and a large number of patients who were included in this study . The stepped wedge design increased the complexity of the data analysis , and there were concerns regarding the informed consent procedure . The repeated measurements may bring burden to patients in terms of quality of life , satisfaction , and costs . CONCLUSION The stepped wedge design is a strong alternative for pragmatic cluster r and omized trials . The known advantages hold , whereas most of the disadvantages were not applicable to this application . The main advantage was that we were able to include a large number of patients . Main disadvantages were that the informed consent procedure can be problematic and that the analysis of the data can be complex Background A pragmatic , stepped wedge trial design can be an appealing design to evaluate complex interventions in real-life setting s. However , there are certain pitfalls that need to be considered . This paper reports on the experiences and lessons learned from the conduct of a cluster r and omized , stepped wedge trial evaluating the effect of the Hospital Elder Life Program ( HELP ) in a Dutch hospital setting to prevent older patients from developing delirium . Methods We evaluated our trial which was conducted in eight departments in two hospitals in hospitalized patients aged 70 years or older who were at risk for delirium by reflecting on the assumptions that we had and on what we intended to accomplish when we started , as compared to what we actually realized in the different phases of our study . Lessons learned on the design , the timeline , the enrollment of eligible patients and the use of routinely collected data are provided accompanied by recommendations to address challenges . Results The start of the trial was delayed which caused subsequent time schedule problems . The requirement for individual informed consent for a quality improvement project made the inclusion more prone to selection bias . Most units experienced major difficulties in including patients , leading to excluding two of the eight units from participation . This result ed in failing to include a similar number of patients in the control condition versus the intervention condition . Data on outcomes routinely collected in the electronic patient records were not accessible during the study , and appeared to be often missing during analyses . Conclusions The stepped wedge , cluster r and omized trial poses specific risks in the design and execution of research in real-life setting s of which research ers should be aware to prevent negative consequences impacting the validity of their results . Valid conclusions on the effectiveness of the HELP in the Dutch hospital setting are hampered by the limited quantity and quality of routine clinical data in our pragmatic trial . Executing a stepped wedge design in a daily practice setting using routinely collected data requires specific attention to ethical review , flexibility , a spacious time schedule , the availability of substantial capacity in the research team and early checks on the data availability and quality .Trial registration Netherl and s Trial Register , identifier : NTR3842 . Registered on 24 January 2013 Research ers should consider five questions before starting a stepped wedge trial . Why are you planning one ? Research ers sometimes think that stepped wedge trials are useful when there is little doubt about the benefit of the intervention being tested . However , if the primary reason for an intervention is to measure its effect , without equipoise there is no ethical justification for delaying implementation in some clusters . By contrast , if you are undertaking pragmatic research , where the primary reason for rolling out the intervention is for it to exert its benefits , and if phased implementation is inevitable , a stepped wedge trial is a valid option and provides better evidence than most non-r and omized evaluations . What design will you use ? Two common stepped wedge design s are based on the recruitment of a closed or open cohort . In both , individuals may experience both control and intervention conditions and you should be concerned about carry-over effects . In a third , continuous-recruitment , short-exposure design , individuals are recruited as they become eligible and experience either control or intervention condition , but not both . How will you conduct the primary analysis ? In stepped wedge trials , control of confounding factors through secular variation is essential . ‘ Vertical ’ approaches preserve r and omization and compare outcomes between r and omized groups within periods . ‘ Horizontal ’ approaches compare outcomes before and after crossover to the intervention condition . Most analysis models used in practice combine both types of comparison . The appropriate analytic strategy should be considered on a case-by-case basis . How large will your trial be ? St and ard sample size calculations for cluster r and omized trials do not accommo date the specific features of stepped wedge trials . Methods exist for many stepped wedge design s , but simulation-based calculations provide the greatest flexibility . In some scenarios , such as when the intracluster correlation coefficient is moderate or high , or the cluster size is large , a stepped wedge trial may require fewer clusters than a parallel cluster trial . How will you report your trial ? Stepped wedge trials are currently challenging to report using CONSORT principles . Research ers should consider how to demonstrate balance achieved by r and omization and how to describe trends for outcomes in both intervention and control clusters Background : Shared decision making is important to ensure that patients receive therapies aligned with their goals and values . Based upon a detailed needs assessment with diverse stakeholders , pamphlet and video decision aids for destination therapy left ventricular assist devices ( DT LVAD ) were developed to help patients and their caregivers think through , forecast , and deliberate their options . These decision aids are the foundation of the Multicenter Trial of a Shared Decision Support Intervention for Patients and their Caregivers Offered Destination Therapy for End-Stage Heart Failure ( DECIDE-LVAD ) study , a multicenter , r and omized trial aim ed at underst and ing the effectiveness and implementation of a shared decision support intervention for patients considering DT LVAD . Methods / Design : A stepped-wedge r and omized controlled trial was design ed , guided by the RE- AIM framework and modeled after an effectiveness-implementation hybrid type II design . Six DT LVAD programs from across the United States will participate . Primary outcomes include knowledge and values-treatment concordance . Patients with advanced heart failure who are being considered for DT LVAD and their caregivers are eligible with a target enrollment of 168 dyads . From August 2014 to January 2015 , an acceptability and feasibility pilot study was performed , which clarified opportunities and challenges around decision support for DT LVAD and result ed in significant modifications to the DECIDE-LVAD study . Discussion : Study findings will provide a foundation for implementing decision support interventions , including decision aids , with patients who have chronic progressive illness facing end-of-life decisions involving invasive , preference-sensitive therapy options We describe a framework for defining pilot and feasibility studies focusing on studies conducted in preparation for a r and omised controlled trial . To develop the framework , we undertook a Delphi survey ; ran an open meeting at a trial methodology conference ; conducted a review of definitions outside the health research context ; consulted experts at an international consensus meeting ; and review ed 27 empirical pilot or feasibility studies . We initially adopted mutually exclusive definitions of pilot and feasibility studies . However , some Delphi survey respondents and the majority of open meeting attendees disagreed with the idea of mutually exclusive definitions . Their viewpoint was supported by definitions outside the health research context , the use of the terms ‘ pilot ’ and ‘ feasibility ’ in the literature , and participants at the international consensus meeting . In our framework , pilot studies are a subset of feasibility studies , rather than the two being mutually exclusive . A feasibility study asks whether something can be done , should we proceed with it , and if so , how . A pilot study asks the same questions but also has a specific design feature : in a pilot study a future study , or part of a future study , is conducted on a smaller scale . We suggest that to facilitate their identification , these studies should be clearly identified using the terms ‘ feasibility ’ or ‘ pilot ’ as appropriate . This should include feasibility studies that are largely qualitative ; we found these difficult to identify in electronic search es because research ers rarely used the term ‘ feasibility ’ in the title or abstract of such studies . Investigators should also report appropriate objectives and methods related to feasibility ; and give clear confirmation that their study is in preparation for a future r and omised controlled trial design ed to assess the effect of an intervention The Consoli date d St and ards of Reporting Trials ( CONSORT ) statement is a guideline design ed to improve the transparency and quality of the reporting of r and omised controlled trials ( RCTs ) . In this article we present an extension to that statement for r and omised pilot and feasibility trials conducted in advance of a future definitive RCT . The checklist applies to any r and omised study in which a future definitive RCT , or part of it , is conducted on a smaller scale , regardless of its design ( eg , cluster , factorial , crossover ) or the terms used by authors to describe the study ( eg , pilot , feasibility , trial , study ) . The extension does not directly apply to internal pilot studies built into the design of a main trial , non-r and omised pilot and feasibility studies , or phase II studies , but these studies all have some similarities to r and omised pilot and feasibility studies and so many of the principles might also apply . The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in their reporting and conduct . We followed recommended good practice to develop the extension , including carrying out a Delphi survey , holding a consensus meeting and research team meetings , and piloting the checklist . The aims and objectives of pilot and feasibility r and omised studies differ from those of other r and omised trials . Consequently , although much of the information to be reported in these trials is similar to those in r and omised controlled trials ( RCTs ) assessing effectiveness and efficacy , there are some key differences in the type of information and in the appropriate interpretation of st and ard CONSORT reporting items . We have retained some of the original CONSORT statement items , but most have been adapted , some removed , and new items added . The new items cover how participants were identified and consent obtained ; if applicable , the prespecified criteria used to judge whether or how to proceed with a future definitive RCT ; if relevant , other important unintended consequences ; implication s for progression from pilot to future definitive RCT , including any proposed amendments ; and ethical approval or approval by a research review committee confirmed with a reference number . This article includes the 26 item checklist , a separate checklist for the abstract , a template for a CONSORT flowchart for these studies , and an explanation of the changes made and supporting examples . We believe that routine use of this proposed extension to the CONSORT statement will result in improvements in the reporting of pilot trials . Editor ’s note : In order to encourage its wide dissemination this article is freely accessible on the BMJ and Pilot and Feasibility Studies journal websites Conditional cash transfer ( CCT ) and cognitive-behavioral treatments are evidence -based approaches to reduce stimulant use and sexual risk taking . We describe the adaptation and implementation of sequential behavioral interventions for Cambodian female entertainment and sex workers ( FESW ) who use amphetamine-type stimulants ( ATS ) : ( 1 ) a 12-week CCT intervention ; and ( 2 ) a 4-week cognitive-behavioral aftercare ( AC ) group . An ongoing cluster r and omized stepped wedge trial in 10 Cambodian provinces is enrolling FESW with confirmed recent ATS use to examine the effectiveness of CCT + AC . In the first six provinces , 138 of the 183 eligible FESW ( 75 % ) enrolled in CCT and completed a median of 25 ( interquartile range 9–32 ) of the 36 urine screening visits . Of the 84 participants who were eligible for AC , 79 completed at least one session ( 94 % ) and 57 completed three or more sessions ( 68 % ) . Culturally tailored behavioral interventions to reduce ATS use and optimize HIV prevention are feasible in re source -limited setting The Consoli date d St and ards of Reporting Trials ( CONSORT ) statement is a guideline design ed to improve the transparency and quality of the reporting of r and omised controlled trials ( RCTs ) . In this article we present an extension to that statement for r and omised pilot and feasibility trials conducted in advance of a future definitive RCT . The checklist applies to any r and omised study in which a future definitive RCT , or part of it , is conducted on a smaller scale , regardless of its design ( eg , cluster , factorial , crossover ) or the terms used by authors to describe the study ( eg , pilot , feasibility , trial , study ) . The extension does not directly apply to internal pilot studies built into the design of a main trial , non-r and omised pilot and feasibility studies , or phase II studies , but these studies all have some similarities to r and omised pilot and feasibility studies and so many of the principles might also apply . The development of the extension was motivated by the growing number of studies described as feasibility or pilot studies and by research that has identified weaknesses in their reporting and conduct . We followed recommended good practice to develop the extension , including carrying out a Delphi survey , holding a consensus meeting and research team meetings , and piloting the checklist . The aims and objectives of pilot and feasibility r and omised studies differ from those of other r and omised trials . Consequently , although much of the information to be reported in these trials is similar to those in r and omised controlled trials ( RCTs ) assessing effectiveness and efficacy , there are some key differences in the type of information and in the appropriate interpretation of st and ard CONSORT reporting items . We have retained some of the original CONSORT statement items , but most have been adapted , some removed , and new items added . The new items cover how participants were identified and consent obtained ; if applicable , the prespecified criteria used to judge whether or how to proceed with a future definitive RCT ; if relevant , other important unintended consequences ; implication s for progression from pilot to future definitive RCT , including any proposed amendments ; and ethical approval or approval by a research review committee confirmed with a reference number . This article includes the 26 item checklist , a separate checklist for the abstract , a template for a CONSORT flowchart for these studies , and an explanation of the changes made and supporting examples . We believe that routine use of this proposed extension to the CONSORT statement will result in improvements in the reporting of pilot trials . Editor ’s note : In order to encourage its wide dissemination this article is freely accessible on the BMJ and Pilot and Feasibility Studies journal websites Pilot studies play an important role in health research , but they can be misused , mistreated and misrepresented . In this paper we focus on pilot studies that are used specifically to plan a r and omized controlled trial ( RCT ) . Citing examples from the literature , we provide a method ological framework in which to work , and discuss reasons why a pilot study might be undertaken . A well-conducted pilot study , giving a clear list of aims and objectives within a formal framework will encourage method ological rigour , ensure that the work is scientifically valid and publishable , and will lead to higher quality RCTs . It will also safeguard against pilot studies being conducted simply because of small numbers of available patients BACKGROUND Few prospect i ve studies have evaluated theory-driven approaches to the implementation of evidence -based opioid treatment . This study compared the effectiveness of an implementation model ( Science to Service Laboratory ; SSL ) to training as usual ( TAU ) in promoting the adoption of contingency management across a multisite opioid addiction treatment program . We also examined whether the SSL affected putative mediators of contingency management adoption ( perceived innovation characteristics and organizational readiness to change ) . METHODS Sixty treatment providers ( 39 SSL , 21 TAU ) from 15 geographically diverse satellite clinics ( 7 SSL , 8 TAU ) participated in the 12-month study . Both conditions received didactic contingency management training and those in the predetermined experimental region received 9 months of SSL-enhanced training . Contingency management adoption was monitored biweekly , whereas putative mediators were measured at baseline , 3 months , and 12 months . RESULTS Relative to providers in the TAU region , treatment providers in the SSL region had comparable likelihood of contingency management adoption in the first 20 weeks of the study , and then significantly higher likelihood of adoption ( odds ratios = 2.4 - 13.5 ) for the remainder of the study . SSL providers also reported higher levels of one perceived innovation characteristic ( Observability ) and one aspect of organizational readiness to change ( Adequacy of Training Re sources ) , although there was no evidence that the SSL affected these putative mediators over time . CONCLUSIONS Results of this study indicate that a fully powered r and omized trial of the SSL is warranted . Considerations for a future evaluation are discussed Rationale Stroke-associated pneumonia , a leading cause of hospital-acquired infection after stroke , affects a fifth of stroke survivors annually . Associated with increased risk of death and poorer rehabilitation outcomes , research suggests a possible relationship between stroke-associated pneumonia and patients ' oral health . Aim The aim of this study is to evaluate the feasibility of a r and omized controlled trial of the clinical and cost effectiveness of enhanced oral healthcare vs. usual oral healthcare for people in stroke care setting s. Design Our pilot , multicentered , pragmatic , stepped wedge , cluster r and omized controlled trial oral healthcare [ Stroke Oral healthCare pLan Evaluation ( SOCLE II ) ] will compare enhanced oral healthcare intervention and usual oral healthcare . Over 13 months , across 4 wards , we seek to recruit 400 patients ( estimating an average of 23 beds per site and a 50 % recruitment rate ) and 60 nursing staff ( estimating an average of 20 members of staff per site and a 75 % recruitment rate ) . Initially , control data ( usual oral healthcare ) will be collected from all sites . In a r and omized , stepped manner , wards will convert to deliver the enhanced oral healthcare intervention . Study outcome ( s ) Outcomes will be captured across dimensions of care ( as recommended for evaluations of complex interventions ) at baseline and weekly thereafter . Primary outcomes are pneumonia ( patients ) , knowledge and attitudes ( staff ) , and specialist dental referrals ( service ) . Secondary outcomes include oral health quality of life , plaque , antibiotics , length of stay , death ( patients ) , use of oral healthcare equipment and products , completed assessment s , and documented oral healthcare plans ( staff ) . Discussion As one of the first stepped wedge , cluster r and omized , controlled trials in stroke care mapping of the complex intervention , our choice of primary and secondary outcomes and choice of trial design are described The Gambia Hepatitis Intervention Study is a large-scale vaccination project in The Gambia , initiated in July 1986 , in which the introduction of national hepatitis B ( HBV ) vaccination of young infants progressively over a 4-year period is proposed . During this time it is anticipated that about 600,000 infants will receive a course of HBV vaccine and a similar number will not receive the vaccine . All children in the study will receive the normal childhood vaccinations . Identification data for each child will be collected and stored with information on their vaccination records . A national surveillance system will be set up to detect new cases of hepatocellular cancer and other chronic liver diseases over a period of 30 to 40 years . An attempt will be made to trace each case , of relevant age , to determine if they are included in the HBV vaccination study . In this way , the efficacy of HBV vaccine in the prevention of HCC and chronic liver diseases will be evaluated . Details of the study design are discussed Robust evidence of the effectiveness of interventions relating to policy , practice , and organisation of healthcare often comes from well conducted cluster r and omised trials . Such trials are , however , prone to recruitment bias depending on whether participants are recruited before the r and omisation of clusters and whether the recruiter is blinded to the allocation status . In most cases , participants and trial staff can not be blinded to the intervention , which might lead to performance and detection bias . Unfortunately , cluster trial reports often do not provide a clear description of the timing of trial processes and blinding , and these aspects are not covered by current reporting tools . This article proposes a graphical tool depicting the time sequence of steps and blinding status in cluster r and omised trials . The tool might be helpful at both the protocol and the report writing stages to clarify the process and to help identify potential bias in cluster r and omised trials